Teratoma

A teratoma is a tumor made up of several different types of tissue, such as hair, muscle, teeth, or bone. Teratomata typically form in the tailbone (where it is known as a sacrococcygeal teratoma), ovary, or testicle.

Quotes

 * The identical clinical characteristics of the SC teratomas and EEPs imply that the SC EEPs may be monophasic teratomas as their ovarian counterparts are named. Coccyx excision is an important part of the surgical treatment of these tumors, with an apparent decrease in the recurrence rate.
 * Aktuğ T, Hakgüder G, Sarioğlu S, Akgür FM, Olguner M, Pabuçcuoğlu U (March 2000). "Sacrococcygeal extraspinal ependymomas: the role of coccygectomy". Journal of Pediatric Surgery. 35 (3): 515–518.


 * Fetus in fetu is a rare disorder. Its embryopathogensis and differentiation from teratoma has not been well established. It is a parasitic twin of a diamniotic monozygotic twin.
 * Arlikar JD, Mane SB, Dhende NP, Sanghavi Y, Valand AG, Butale PR (March 2009). "Fetus in fetu: two case reports and review of literature". Pediatric Surgery International. 25 (3): 289–292.


 * Although fetus in fetu is rare condition, correct diagnosis using imaging can be made before surgery. Complete excision is curative.
 * Arlikar JD, Mane SB, Dhende NP, Sanghavi Y, Valand AG, Butale PR (March 2009). "Fetus in fetu: two case reports and review of literature". Pediatric Surgery International. 25 (3): 289–292.


 * We conclude that SCT, although histologically benign, has an alarming potential to recur either as a benign or malignant tumor during the first 2 years of life. Close follow-up for at least 3 years (frequent examination, serum alpha-fetoprotein, and diagnostic imaging) is recommended for all patients who had undergone excision of SCT in the newborn period.
 * Bilik R, Shandling B, Pope M, Thorner P, Weitzman S, Ein SH (September 1993). "Malignant benign neonatal sacrococcygeal teratoma". Journal of Pediatric Surgery. 28 (9): 1158–1160.


 * The designation of a teratoma with malignant transformation (TMT) refers to the occurrence of somatic non-germ cell malignancies within a teratoma. While TMT is a rare but well recognised phenomenon in adult germ cell tumors (GCT), data on TMT in pediatric GCTs are lacking.
 * Biskup W, Calaminus G, Schneider DT, Leuschner I, Göbel U (2006). "Teratoma with malignant transformation: experiences of the cooperative GPOH protocols MAKEI 83/86/89/96". Klinische Padiatrie. 218 (6): 303–308.


 * Malignant transformation of pure teratomas constitutes a very rare entity in children and adolescents that is most commonly observed in postpubertal girls with ovarian teratoma. Compared to adult patients, similar malignant entities can be observed in association with teratoma. However, in our series, no sarcoma was diagnosed. In localised tumors, complete resection appears to be adequate, whereas chemotherapy should be considered in patients with R1- or R2-resection. Cisplatinum-based chemotherapy was effective as two of four relapsed patients survived tumor free. However, the ideal regimen has not yet been established and the known sensitivity of the histologic components to cytostatic drugs has to be considered in the choice of treatment. Further molecular biologic studies are necessary to understand the origin of these tumors.
 * Biskup W, Calaminus G, Schneider DT, Leuschner I, Göbel U (2006). "Teratoma with malignant transformation: experiences of the cooperative GPOH protocols MAKEI 83/86/89/96". Klinische Padiatrie. 218 (6): 303–308.


 * Teratomas are tumors that contain well- or incompletely differentiated elements of endoderm, mesoderm, and ectoderm. Well-differentiated tumors are labeled mature teratomas whereas those that are incompletley differentiated are called immature teratomas. Mature teratomas may include elements of mature bone, cartilage, teeth, hair, and squamous epithelium, a fact that most likely explains the name teratoma, which roughly means “monster tumor” in Greek. In adults, both mature and immature testicular teratomas have the potential to metastize, and the distinction carries no clear prognostic significance. Teratomas are generally associated with normal serum tumor markers, but they may cause mildly elevated serum AFP levels.
 * Chang AE, Ganz PA, Hayes DF, Kinsella T, Pass HI, Schiller JH, Stone RM, Strecher V (2007). “Oncology: An Evidence-Based Approach”. Springer Science & Business Media. p. 848.


 * Mature teratoma is the most common germ cell tumor of the ovary. The tumor is essentially a benign neoplasm and surgical resection of the tumor is the treatment of choice. Recurrence with colorectal involvement after surgical removal of the primary lesion is exceedingly rare and has not been reported in Korea. We present a 43-year-old patient with a rectal mass who had already undergone left oophorectomy due to mature cystic teratoma and right oophorectomy due to hemorrhagic corpus luteum. The rectal mass was composed of a mature teratoma tissue. We postulate that leakage of the tumor elements from the cyst wall led to peritoneal tumor implantation and invasion to the rectal wall.
 * Choi KW, Jeon WJ, Chae HB, Park SM, Youn SJ, Shin HM, et al. (September 2003). "A recurred case of a mature ovarian teratoma presenting as a rectal mass", The Korean Journal of Gastroenterology = Taehan Sohwagi Hakhoe Chi (in Korean). 42 (3): 242.


 * Teratoma is the most common germ cell tumour in childhood; mature (MT) and immature teratomas (IT) are benign tumours, but if they recur, they can be in some cases malignant.
 * Lo Curto M, D'Angelo P, Cecchetto G, Klersy C, Dall'Igna P, Federico A, et al. (April 2007). "Mature and immature teratomas: results of the first paediatric Italian study". Pediatric Surgery International. 23 (4): 315–322.


 * Our data showed that incomplete resection and female gender are important risk factors for relapse or death, more so than IT histology. The number of patients treated with CT is not sufficient to evaluate the efficacy of CT in avoiding malignant relapse.
 * Lo Curto M, D'Angelo P, Cecchetto G, Klersy C, Dall'Igna P, Federico A, et al. (April 2007). "Mature and immature teratomas: results of the first paediatric Italian study". Pediatric Surgery International. 23 (4): 315–322.


 * In both adult women and children the potential for malignant recurrence from ovarian immature teratoma has prompted the standard use of chemotherapy after complete resection of the primary tumor. The efficacy of postoperative chemotherapy in children and adolescents with ovarian immature teratoma, however, has not been established.
 * Cushing B, Giller R, Ablin A, Cohen L, Cullen J, Hawkins E, et al. (August 1999). "Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the pediatric oncology group and the children's cancer group". American Journal of Obstetrics and Gynecology. 181 (2): 353–358.


 * The results of this study suggest that surgery alone is curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum alpha-fetoprotein or microscopic foci of yolk sac tumor are present. This experience strongly supports avoiding the long-term effects of chemotherapy in most children with ovarian immature teratoma by reserving postoperative therapy for cases with relapse.
 * Cushing B, Giller R, Ablin A, Cohen L, Cullen J, Hawkins E, et al. (August 1999). "Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: a report of the pediatric oncology group and the children's cancer group". American Journal of Obstetrics and Gynecology. 181 (2): 353–358.


 * Prepubertal mature teratomas have a benign clinical course, which contrasts with the clinical behavior of teratomas in adults, which have the propensity of metastisize. This benign behavior has led to the consideration of testicular-sparing procedures rather than radical orchiectomy.
 * McDougal WS, Wein AJ, Kavoussi LR, Partin AW, Peters CA, Ramchandani P (2011). “Campbell-Walsh Urology”(10th ed.). Elsevier Health Sciences. p. 663.


 * 19. Teratomas are classifiedas mature, immature, and malignant. 20. Mature teratomas have a benign course in childhood and are successfully treated with radical orchiectomy alone. This is not true in the adult. 21. Immature teratomas generally behave in a benign fashion in childhood nless they have foci of yolk sac tumor. If the latter is the case, they should be treated as one would treat a yolk sac tumor.
 * McDougal WS, Wein AJ, Kavoussi LR, Partin AW, Peters CA, Ramchandani P (2011). “Campbell-Walsh Urology”(10th ed.). Elsevier Health Sciences. p. 663.


 * Teratomas are the most common ovarian germ cell tumors and can be either benign (mature) or malignant (immature). Mature cystic teratomas are benign tumors commonly referred to as “dermoids” and account for about 25% of ovarian neoplasms. They are most common during reproductive life and are often incidental findings. Although 20% of dermoids are bilateral, it is not recommended to bivalve the ovary in search of a dermoid that is not seen on preoperative ultrasound. Mature cystic teratomas are derived from at least two the three germ layers: ectoderm, endoderm, and mesoderm. Most frequently, their cyst walls contain skin and sebaceous glands and hair follicles and thus contain greasy, yellow sebaceous material and hair. Less commonly, these tumors include cartilage, bone, thyroid tissue, or other structures. “struma ovarii” is a particular type of mature teratoma comprised of more than 80% thyroid tissue and can be associated with hyperthyroidism. Immature teratomas are rare, making up only 4% of ovarian teratomas. Unlike the pattern seen in most ovarian tumors, immature teratomas are more frequent at a younger age, and most present before age 18. Histologically, immature teratomas are composed of partially differentiated structures that resemble fetal or embryonal cell types. Neural elements, cartilage, and epithelial tissues are common. Immature teratomas are often solid; most are unilateral, in contrast to mature cystic teratomas. Treatment for immature teratomas consists of surgical resection of the affected ovary and postoperative chemotherapy. In younger patients, an attempt is made to preserve fertility by conserving the uterus and unaffected ovary. The 5-year survival rate is between 60% and 90%l, depending on the grade and stage of the tumor.
 * Falcone T, Hurd WW (2007). “Clinical Reproductive Medicine and Surgery”. Elsevier Health Sciences. Ch. 50, p. 749


 * A unique management concern regarding benign cystic teratomas is that untreated intraperitoneal spill of their sebaceous contents can result in chemical peritonitis. Clinically, patients present with postoperative fever and illness, and can develop peritoneal granulomas, adhesions, and even a perihepatic mass. The risk of chemical peritonitis has to implications for the laparoscopic surgeon. First, if a cyst punctured during laparoscopy is found to contain sebaceous material, a cystectomy or oophorectomy should immediately be performed. Leaving behind a leaking teratoma can lead to serious consequences. Second, when a dermoid cyst is removed laparoscopically, cyst rupture (reported to occurring approximately half the cases) must be approximately treated with copious irrigation (i.e., 2 to 5L) until no oily material can be seen floating on the fluid surface. Subsequent peritonitis has not been reported using this approach after spillage from a mature cystic teratoma.
 * Falcone T, Hurd WW (2007). “Clinical Reproductive Medicine and Surgery”. Elsevier Health Sciences. Ch. 50, p. 749


 * The biologic behaviour of teratomas depends on various interdependent clinical and epidemiologic variables such as the age at diagnosis, sex, tumor site, histology which all correlate to different cytogenetic and molecular biologic aberrations. Thus, testicular teratomas of infancy are generally benign. Accordingly, prepubertal teratomas show no cytogenetic or molecular genetic aberrations. In contrast, postpubertal testicular teratomas can present as clinically malignant tumors and may show complex cytogenetic aberrations such as the isochromosome 12p, which is pathognomonic of malignant germ cell tumors. Notably, teratomas of both age groups show an at least partial erasure of the genomic imprinting, correlating with their origin from primordial germ cells. The Kiel Pediatric Tumor Registry includes 541 teratoma specimens, and among these, the most frequent tumor sites (in descending order) are: the sacrococcygeal region (33.8 %), the ovaries (31.2 %) and the testes (10.5 %). Rare localizations include the mediastinum, the retroperitoneum, the head and neck region as well as the central nervous system. The WHO classification of germ cell tumors distinguishes mature and immature teratomas as well as teratomas with malignant transformation. In immature teratomas, primitive neuroectodermal structures predominate. According to the grading system (Gonzalez-Crussi, 1982), mature teratomas (G0) are more frequent (54.5 %) than immature teratomas (G1-G3, 45.5 %). Only 7.8 % of all teratomas show the highest grade of immaturity (G3). The frequency of additional microscopic foci of malignant yolk sac tumor correlates with the grade of immaturity. In sacrococcygeal teratomas, the yolk sac tumor microfoci may give rise to a malignant relapse after incomplete resection. The rare teratomas with malignant transformation contain components with "conventional" somatic type malignancy such as leukaemia, carcinoma or sarcoma. Here, molecular genetic analysis has demonstrated the origin of the somatic malignancy from a malignant transformation within the germ cell tumor with retention of the cytogenetic changes characteristic of malignant germ cell tumors.
 * Harms D, Zahn S, Göbel U, Schneider DT (2006). "Pathology and molecular biology of teratomas in childhood and adolescence". Klinische Padiatrie. 218 (6): 296–302.


 * Teratoma arises from cells with total potential, and elements of ectoderm, mesoderm and endoderm may be seen. One is normally predominating and is the source of the malignant change. A number contain chorionic tissue and plasma and urine levels of HCG may help to establish the diagnosis. These can also be useful in following progress after treatment. Treatment is surgery plus radiotherapy.
 * Hart I, Newton RW (2012). “Endocrinology”. Springer Science & Business Media. p. 157.


 * Review of the slides from five of the original tumors identified microscopic foci of YST in four. Conclusions: Detection of such foci in neonatal tumors is important because serum alpha-fetoprotein concentrations may not be helpful since they may normally be high in the newborn period due to fetal production.
 * Hawkins E, Issacs H, Cushing B, Rogers P (November 1993). "Occult malignancy in neonatal sacrococcygeal teratomas. A report from a Combined Pediatric Oncology Group and Children's Cancer Group study". The American Journal of Pediatric Hematology/Oncology. 15 (4): 406–409.


 * In the early sixties researchers isolated a single cell type from a teratocarcinoma, a tumour derived from a germ cell. These embryonal carcinoma cells are the stem cells of teratocarcinomas which can be considered the malignant counterparts of embryonic stem cells that originate from the inner cell mass of a blastocyst stage embryo. The embryonal carcinoma cells replicate and grow in cell culture conditions.
 * Carla A Herberts; Marcel SG Kwa; Harm PH Hermsen (2011). "Risk factors in the development of stem cell therapy". Journal of Translational Medicine. 9 (29): 29. pp.1-2


 * In 1981, embryonic stem cells (ES cells) were first derived from mouse embryos. Evans and Kaufman revealed a new technique for culturing the mouse embryonic stem cells from embryos in the uterus to increase cell numbers, allowing for the derivation of ES cells from these embryos. Martin showed that embryos could be cultured in vitro and that ES cells could be derived from these embryos. In 1998, Thomson et al developed a technique to isolate and grow human embryonic stem cells in cell culture. Embryonal stem cells (ESC) are pluripotent cells that have the ability to differentiate into derivatives of all three germ layers (endoderm, mesoderm, and ectoderm). The most common assay for demonstrating pluripotency is teratoma formation.
 * Carla A Herberts; Marcel SG Kwa; Harm PH Hermsen (2011). "Risk factors in the development of stem cell therapy". Journal of Translational Medicine. 9 (29): 29. p.2


 * The local environment in which the stem cell resides may influence its tumourigenic potential. Removal of the cells from the context of a developing embryo and enforcing in vitro culture has been proposed as the cause for the increased tumourigenic potential of ESC when compared to the originator cells (the inner mass of early blastocysts). The site of human ESC administration in SCID mice is an important factor determining the rate of teratoma formation.
 * Carla A Herberts; Marcel SG Kwa; Harm PH Hermsen (2011). "Risk factors in the development of stem cell therapy". Journal of Translational Medicine. 9 (29): 29. p.5


 * Viral integration and the use of oncogenes is not the only risk factor that may lead to tumour formation following the generation of iPSCs. iPSC induction is also associated with profound and progressive changes in the epigenetic state of the chromatin. Epigenetic changes have been suggested to change the tumourigenic potential of cells, e.g. by changing in the expression of oncogenes or tumour suppressor genes. However there is currently not enough data for evaluating the possible contribution of epigenetic changes to the risk of tumour formation. Also reactivation of other (host) reprogramming factors may cause tumour formation. Furthermore it has been suggested that sustained expression of the reprogramming transgenes might suppress differentiation of iPSCs which may result in an increased tendency to teratoma formation when these cells are transplanted into patients.
 * Carla A Herberts; Marcel SG Kwa; Harm PH Hermsen (2011). "Risk factors in the development of stem cell therapy". Journal of Translational Medicine. 9 (29): 29. p.7


 * Fetus-in-fetu is an unusual condition in which a vertebrate fetus is enclosed within the abdomen of another fetus. These occurrences are usually benign. This report describes an instance of malignant recurrence after resection of a fetus-in-fetu.
 * Hopkins KL, Dickson PK, Ball TI, Ricketts RR, O'Shea PA, Abramowsky CR (October 1997). "Fetus-in-fetu with malignant recurrence". Journal of Pediatric Surgery. 32 (10): 1476–1479.


 * Fetus in fetu (FIF) is a very rare condition, with a reported incidence of one in 500,000 live births. It most likely represents a monozygotic diamniotic twin that implants itself and grows within the body of its normal karyotypically identical sibling, which typically manifests as a fetiform abdominal mass in a newborn or infant. The mass is located in the retroperitoneum in most cases, including our example, and is commonly surrounded by encapsulated fluid. However, FIF has been reported to occur in other locations, such as within the cranium, the scrotum, and the oral cavity. Usually only one fetus is present but very rarely multiple fetuses may also be present.
 * Kajbafzadeh AM, Baharnoori M (October 2006). "Fetus in fetu". The Canadian Journal of Urology. 13 (5): 3277–3278.


 * To the best of our knowledge, the case presented in this report is only the second case of a cardiac development in a teratoma in the literature. In the light of data obtained about this case and related literature, we consider that fetus-in-fetu and teratoma may not be irrelevant entities, and that they possibly have the same developmental malformation. We also suggest that such an intermediate case is a combination of fetus-in-fetu and teratoma.
 * Kazez A, Ozercan IH, Erol FS, Faik Ozveren M, Parmaksiz E (August 2002). "Sacrococcygeal heart: a very rare differentiation in teratoma". European Journal of Pediatric Surgery. 12 (4): 278–280.


 * Controversy about the derivation and use of hESCs led investigators to seek less ethically fraught but maximally useful types of stem cells. The history of iPSCs is one of seeking efficient ways to induce pluripotency that minimize the risk of teratoma development.
 * King, Nancy; Perrin, Jacob (July 7, 2014). "Ethical issues in stem cell research and therapy". Stem Cell Research & Therapy. 5 (4): 85.


 * A teratocarcinoma is a bizarre neoplasm composed of foci of undifferentiated malignant cells interspersed with a chaotic array of somatic tissues; these somatic tissues, representing each of the three embryonic germinal layers, are found in various stages of differentiation. In some of the earlier descriptions of teratocarcinomas their obvious neoplastic characteristics were overlooked, and the tumors were interpreted as maldeveloped parasitic twins. Present evidence, however, supports the theory that the somatic tissues of teratocarcinomas arise by morphogenesis from undifferentiated malignant stem cells. This theory was first proposed by Askanazy (1) in 1907 as the result of detailed histologie studies on benign cystic ovarian teratomas. He concluded that the well differ entiated somatic tissues of the teratoma developed by embryonic differentiation from either a single multipotential type of cell or from a group of cells composed of representatives of each of the embryonic germinal layers.
 * Kleinsmith LJ, Pierce GB Jr (1964). "Multipotentiality of Single Embryoncal Carcinoma Cells". Cancer Res. 24: 1544–51.


 * The Latin word homunculus literally means a structure resembling a miniature human body to designate a human being not produced by pregnancy and this definition is used in morphologic entities. This tumor should be distinguished from the more highly developed fetus-in-fetu, a malformed parasitic monozygotic twin that is found inside the body of the living child or adult. We report a case of a mature cystic teratoma containing a fetus-like structure (homunculus).
 * Lee YH, Kim SG, Choi SH, Kim IS, Kim SH (December 2003). "Ovarian mature cystic teratoma containing homunculus: a case report", Journal of Korean Medical Science. 18 (6): 905–907.


 * Mature cystic teratomas, commonly called dermoid cysts, are the most common benign germ cell tumors of the ovary, and are encountered predominantly in women in their second and third decades of life. Histologically, they display a varying admixture of elements of one or more of the three cell lines: ectodermal, endodermal, and mesodermal tissue derivatives. Despite the benign nature of these neoplasms, considerable interests have been paid on them because of the unusual histogenesis caused by the totipotency of these tumors that may give rise to any body structures or tissues and even the structure similar to a fetus. Among the previously reported mature cystic teratomas or dermoid cysts of the ovary, only 24 cases of teratoma containing homunculus have been reported (1-6). In many cases, the caudal region of the homunculus, including the lower extremities, is typically more developed than the cephalic portion and some cases (5, 6) of prominent cephalic region had been reported as in our case. Despite a number of conflicting theories (7-10) to explain the histiogenesis of teratomas, the most probable ones are misplaced blastomere and parthenogenetic development of a germ cell. Whatever the reason for the development of teratomas may be, these tumors seemingly arise from the totipotential embryonic cells broken away from the normal developmental pathway to form the various fetal tissues.
 * Lee YH, Kim SG, Choi SH, Kim IS, Kim SH (December 2003). "Ovarian mature cystic teratoma containing homunculus: a case report", Journal of Korean Medical Science. 18 (6): 905–907.


 * With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. Conclusion: Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.
 * Marina NM, Cushing B, Giller R, Cohen L, Lauer SJ, Ablin A, et al. (July 1999). "Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study". Journal of Clinical Oncology. 17 (7): 2137–2143.


 * A mixed tumour has intermixed varying histological components derived from a common stem cell. In the case of mixed germ cell tumours, virtually any combination of cell types can occur among embryonal carcinomas, dysgerminomas, teratomas and yolk sac tumours (endometrial sinus tumours). The imaging findings of mixed germ cell tumours are variable and reflect the diversity of this group of tumours. When a predominantly solid and heterogenous ovarian tumour contains fatty areas or calcifications suggestive of a mature cystic teratoma or when a mature cystic teratoma contains an enhancing solid portion, a mixed germ cell tumour diagnosis should be considered. Elevated serum a-fetoprotein *yolk sac tumour) and human chorionic gonadotropin (dyserminome) levels and younger age can help in the diagnosis of mixed germ cell tumours.
 * Millet I, Perrochia H, Pages-Bouic E, Curros-Doyon F, Rathat G, Taourel P (2014). "CT and MR of Benign Ovarian Germ Cell Tumours". In Saba L, Acharya UR, Guerriero S, Suri JS (eds.). Ovarian Neoplasm Imaging. Springer Science & Business Media. pp.164-165.


 * Growing teratoma syndrome (GTS) is a rare finding, defined as an enlarging mature teratoma that arises during or following chemotherapy for a malignant germ cell tumour, especially an immature teratoma. These tumours can undergo tissue maturation and take on an appearance more typical of mature cystic teratomas, a phenomenon also known as retroconversion. Selective elimination of malignant cells by chemotherapeutic agents or differentiation of malignant cells into mature teratoma components of malignant cells into mature teratoma components following exposure to chemotherapeutic agents may be the two possible mechanisms responsible for GTS development. As a result, this is often misinterpreted as a chemoresistant tumour or recurrence. These retroconverted masses can remain stable for a long period of time. By definition, GTS must exhibit normalisation of previously elevated tumour markers (alpha-fetoprotein [AFP] or beta human chorionic gonadotropin [HCG]), tumour enlargement or the presence of a new tumour mass and only mature teratoma elements in the pathological examination. The radiologic features include increased mass density with well-circumscribed margins, onset of internal calcification with fatty areas and cystic changes.
 * Millet I, Perrochia H, Pages-Bouic E, Curros-Doyon F, Rathat G, Taourel P (2014). "CT and MR of Benign Ovarian Germ Cell Tumours". In Saba L, Acharya UR, Guerriero S, Suri JS (eds.). Ovarian Neoplasm Imaging. Springer Science & Business Media. p.165.


 * MCT complications include torsion (16%), malignant degeneration (2%), rupture (1-2%) and infection (1%).
 * Millet I, Perrochia H, Pages-Bouic E, Curros-Doyon F, Rathat G, Taourel P (2014). "CT and MR of Benign Ovarian Germ Cell Tumours". In Saba L, Acharya UR, Guerriero S, Suri JS (eds.). Ovarian Neoplasm Imaging. Springer Science & Business Media. p.165.


 * Torsion is the most common complication associated with mature cystic teratomas. The torsion rate was reported at 3.2-16. From another standpoint, about 30% of ovarian torsions ae due to mature cystic teratomas which, along with serious cystadenomas, represent the most common cause of ovarian torsion. The classical clinical presentation includes sharp, localised right or left lower abdominal pain, tenderness, peritoneal findings and a pelvic mass. Gastrointestinal complaints with nausea and vomiting are encountered in approximately two-thirds of patients, whereas fever is an argument in favour of necrosis complicating ovary torsion.
 * Millet I, Perrochia H, Pages-Bouic E, Curros-Doyon F, Rathat G, Taourel P (2014). "CT and MR of Benign Ovarian Germ Cell Tumours". In Saba L, Acharya UR, Guerriero S, Suri JS (eds.). Ovarian Neoplasm Imaging. Springer Science & Business Media. pp. 165-166.


 * A hunter tracking down a mountain lion has stumbled upon a biological mystery. Fish and Game officials say a male mountain lion involved in an attack on a dog near Preston, Idaho, was killed last week near the Utah border. What the hunter discovered after examining the corpse can only be described as bizarre, even monstrous. A photo released Thursday by Idaho Fish and Game shows the big cat had another set of fully-formed teeth and whiskers growing out of the top of its head. Wildlife officials say they have never seen a deformity like that – but have offered up several theories. They say it’s possible the teeth could be the remnants of a conjoined twin that died in the womb and was absorbed into the other fetus. They then grew on their own. Another explanation is a so-called “teratoma” tumor. This type of abnormality, whose Greek name translates to “monster tumor,” can grow teeth and hair. In humans, it can grow fingers and toes.
 * Artemis Moshtaghian (January 11, 2016). "Deformed Mountain Lion a mystery". CNN.


 * Malignant cervical teratoma (MCT) usually appears in newborns as an enlarging mass of the neck that causes respiratory distress, requiring prompt airway control.
 * Muscatello L, Giudice M, Feltri M (November 2005). [[https://pubmed.ncbi.nlm.nih.gov/15895292/ "Malignant cervical teratoma: report of a case in a newborn". European Archives of Oto-Rhino-Laryngology. 262 (11): 899–904.


 * The child has been free from disease and healthy for 7 years since the last surgery. The preoperative diagnosis of MCT is difficult because of its rarity and non-specific clinical findings. Surgical excision is required for an adequate cure and airway repair; a long-term follow-up is mandatory to promptly treat any recurrence.
 * Muscatello L, Giudice M, Feltri M (November 2005). [[https://pubmed.ncbi.nlm.nih.gov/15895292/ "Malignant cervical teratoma: report of a case in a newborn". European Archives of Oto-Rhino-Laryngology. 262 (11): 899–904.


 * Controversy about the derivation and use of hESCs led investigators to seek less ethically fraught but maximally useful types of stem cells. The history of iPSCs is one of seeking efficient ways to induce pluripotency that minimize the risk of teratoma development.
 * Nancy MP King & Jacob Perrin; “Ethical issues in stem cell research and therapy”, Stem Cell Research & Therapy, Volume 5, Article number: 85 (Published: 07 July 2014)


 * A type of germ cell tumor that may contain several different types of tissue, such as hair, muscle, and bone. Teratomas may be mature or immature, based on how normal the cells look under a microscope. Sometimes teratomas are a mix of mature and immature cells. Teratomas usually occur in the ovaries in women, the testicles in men, and the tailbone in children. They may also occur in the central nervous system (brain and spinal cord), chest, or abdomen. Teratomas may be benign (not cancer) or malignant (cancer).
 * "NCI Dictionary of Cancer Terms". National Cancer Institute. (2011-02-02).


 * A type of germ cell tumor that is usually made up of several different types of tissue, such as hair, muscle, and bone. Mature teratomas have cells that look almost like normal cells under a microscope. Some mature teratomas make enzymes or hormones that may cause signs and symptoms of disease. They are benign (not cancer) but may come back after being removed by surgery. Mature teratomas usually occur in the sacrum or tailbone in newborns or in the testicles or ovaries at the start of puberty. They are often called dermoid cysts.
 * "Mature teratoma". National Cancer Institute. (2011-02-02).


 * Testing whether the human embryonic stem cells are pluripotent by 1) allowing the cells to differentiate spontaneously in cell culture; 2) manipulating the cells so they will differentiate to form cells characteristic of the three germ layers; or 3) injecting the cells into a mouse with a suppressed immune system to test for the formation of a benign tumor called a teratoma. Since the mouse’s immune system is suppressed, the injected human stem cells are not rejected by the mouse immune system and scientists can observe growth and differentiation of the human stem cells. Teratomas typically contain a mixture of many differentiated or partly differentiated cell types—an indication that the embryonic stem cells are capable of differentiating into multiple cell types.
 * Institutes of Health, "NIH Stem Cell Basics. What are embryonic stem cells?".


 * Adipose-Muse cells distinguish themselves as both easily obtainable and versatile in their capacity for differentiation, while low telomerase activity and lack of teratoma formation make these cells a practical cell source for potential stem cell therapies.
 * Ogura, Fumitaka; Wakao, Shohei; Kuroda, Yasumasa; Tsuchiyama, Kenichiro; Bagheri, Mozhdeh; Heneidi, Saleh; Chazenbalk, Gregorio; Aiba, Setsuya; Dezawa, Mari (2014). "Human Adipose Tissue Possesses a Unique Population of Pluripotent Stem Cells with Nontumorigenic and Low Telomerase Activities: Potential Implications in Regenerative Medicine". Stem Cells and Development. 23 (7): 717–28.


 * The retroperitoneal mature teratoma observed in this case showed malignant germ-cell differentiation. The above case is thought to be extremely rare, but these findings also suggest the possibility of a mature teratoma presenting as a premalignant condition. The sequence of "mature teratoma--germ-cell malignancy" is thus considered to represent a new potential pattern of early phase of carcinogenesis in teratomas.
 * Ohno Y, Kanematsu T (October 1998). "An endodermal sinus tumor arising from a mature cystic teratoma in the retroperitoneum in a child: is a mature teratoma a premalignant condition?". Human Pathology. 29 (10): 1167–1169.


 * Testicular teratomas occur in both children and adults, but their incidence and natural history are quite different. Pure teratomas are fairly common in children, comprising nearly half of all germcell tumours. They are relatively rare after puberty and comprise only 2-3% of germ cell tumours in this age group. In children, they behave as a benign tumour, whereas in adults and adolescents they are invariably malignant. Childhood testicular teratomas are uniformly benign, with no documented cases of retroperitoneal or lung metastasis in differentiated lesions. Most morbidity results from suggical or postoperative complications, such as haemorrhage or infection. The mortality is less than one per million. During and after puberty, all teratomas are regarded as malignant because even mature teratomas (composed of entirely mature histological elements) can metastasises to retroperitoneal lymph nodes or to other systems. Morbidity is associated with the growth of the tumour, which can invade or obstruct local structures and become unresectable. Malignant transformation is significantly more common in testicular teratomas than in their ovarian counterparts, and the risk of recurrence is around 20% in both mature and immature testicular teratomas. Testicular teratomas usually present as a painless scrotal mass, but sometimes present as testicular torsion. The masses are firm or hard in 83% of cases. Most are not tender and do not transilluminate. Testicular pain and scrotal swelling occasionally reported with teratomas, but these are non-specific symptoms and simply indicate torsion until proved otherwise. Hydrocoele is often associated with teratoma in childhood. On examination, the testis is diffusely enlarged, rather than nodular, although a dizcrete nodule in the upper or lower pole can sometimes be palpatated.
 * Raja SG (2007). “Access to Surgery: 500 single best answer questions in general and systematic pathology". PasTest Ltd. pp. 507-508.


 * Immature ovarian teratoma (IOT) is a rare and aggressive malignant neoplasm characterized by immature neural tissue. The cytomorphologic features have only rarely been described. We herein describe an additional case and review the literature regarding this entity. To the best of our knowledge, this is the first reported case with imprint cytology.
 * Ramalingam P, Teague D, Reid-Nicholson M (August 2008). "Imprint cytology of high-grade immature ovarian teratoma: a case report, literature review, and distinction from other ovarian small round cell tumors". ''Diagnostic Cytopathology. 36 (8): 595–599.


 * IOT has diagnostic cytologic features which show complete concordance with histology. Differential diagnoses include other small round cell neoplasms such as ovarian neuroblastoma, small cell carcinoma of hypercalcemic type, primitive neuroectodermal tumor, Wilm's tumor, desmoplastic small round cell tumor, and Non-Hodgkin lymphoma. Distinguishing IOT from these tumors can be challenging however if diligent morphologic study and/or ancillary studies are performed accurate diagnosis is possible.
 * Ramalingam P, Teague D, Reid-Nicholson M (August 2008). "Imprint cytology of high-grade immature ovarian teratoma: a case report, literature review, and distinction from other ovarian small round cell tumors". ''Diagnostic Cytopathology. 36 (8): 595–599.


 * Winegarner recounted in 1979 the use of coccygectomy to create excellent and wide-open access for drainage of extensive pelvic abscesses that occurred because of high velocity missile wounds. In the pediatric surgery literature there are multiple reports of coccygectomy improving teratoma and ependymoma recurrence rates after tumor resection. This is thought to be secondary to the presence of embryonic rests at the coccyx and the subsequent removal with coccyx excision.
 * Lindsey Ross, E.D. Adams, A. Parrish, J. Zhai, M. Chithriki, D. Magner, P.J. Johnson; “Coccygectomy a novel and definitive approach to surgical treatment of a tailgut cyst”, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 2021.


 * Preterm infants and newborns with sacrococcygeal teratomas are at high risk for prenatal and perinatal complications. The prognosis depends on size and histology of the tumor, degree of prematurity, associated malformations, route of delivery, and prompt and complete surgical removal. Virtually any tissue can be present in a sacrococcygeal teratoma, but to date, ocular lens has been documented only as lentinoids (lens-like cells), whereas flow-cytometric data have been variably interpreted. We describe a case of a sacrococcygeal teratoma in an infant of 29 weeks gestational age that is remarkable for the weight (4500 g), the presence of a completely formed eye, and intratumoral DNA ploidy heterogeneity.
 * Sergi C, Ehemann V, Beedgen B, Linderkamp O, Otto HF (1999). "Huge fetal sacrococcygeal teratoma with a completely formed eye and intratumoral DNA ploidy heterogeneity". Pediatric and Developmental Pathology. 2 (1): 50–57.


 * This case represents an example of infra-tentorial CNS tissue that was well-differentiated and organized to an exceptionally high degree in an ovarian mature teratoma. Various degenerative changes have been documented in CNS tissue in ovarian teratomas, but the dendritic abnormalities of Purkinje cells seen in the present case are novel findings.
 * Shintaku M, Sakuma T, Ohbayashi C, Maruo M (April 2017). [https://onlinelibrary.wiley.com/doi/epdf/10.1111/neup.12360 "Well-formed cerebellum and brainstem-like structures in a mature ovarian teratoma: Neuropathological observations". Neuropathology. 37 (2): 122–128.


 * At an early stage during differentiation, mESCs become dependent on extrinsic factors and lose their tumorigenic capacity (Chambers and Smith, 2004; Blum and Benvinisty, 2008), implying some link between tumorigenicity and mitogen-independent proliferation in pluripotent cells (see Ying et al., 2008). The tumorigenic properties of pluripotent cells can be rationalized by the activity of several genes, which in other contexts are involved in tumor progression. The proto-oncogene c-myc for example, plays key roles in pluripotent cell establishment and maintenance (Cartwright et al., 2005). Moreover, an ESC-specific form of Ras (ERas) that drives PI3K is required for robust teratoma formation in transplantation assays and contributes to the rapid cell division of mESCs (Takahashi et al., 2003).
 * Singh, Amar M.; Dalton, Stephen (2009-08-07). “The cell cycle and Myc intersect with mechanisms that regulate pluripotency and reprogramming". Cell Stem Cell. 5 (2): p.144.


 * Gastric teratomas are very rare and usually benign. Only a few cases of gastric teratomas with malignant components have been reported. This report describes recurrence of a yolk sac tumor following resection of a neonatal immature gastric teratoma. Gastric teratoma recurring as a malignant lesion has not been previously reported. Recurrence of immature gastric teratomas should be considered, and a periodic follow-up check with alpha-fetoprotein level should be mandatory.
 * Ukiyama E, Endo M, Yoshida F, Tezuka T, Kudo K, Sato S, et al. (July 2005). "Recurrent yolk sac tumor following resection of a neonatal immature gastric teratoma". Pediatric Surgery International. 21 (7): 585–588.


 * The recurrence of intracranial mature teratomas as germ cell tumors of different histological types is rarely reported. The authors describe the first case of the malignant transformation of an intracranial mature teratoma into a yolk sac tumor in a 16-year-old boy who presented with a 1-month history of anorexia and somnolence.
 * Utsuki S, Oka H, Sagiuchi T, Shimizu S, Suzuki S, Fujii K (June 2007). "Malignant transformation of intracranial mature teratoma to yolk sac tumor after late relapse. Case report". Journal of Neurosurgery. 106 (6): 1067–1069.


 * Muse cells transplanted into immunodeficient mouse testes did not form teratomas for up to 6 mo, but transplantation of Muse-iPS cells resulted in teratoma formation within 12 wk, indicating that nontumorigenic Muse cells acquired tumorigenic proliferation activity after iPS cell induction.
 * Wakao, S.; Kitada, M.; Kuroda, Y.; Shigemoto, T.; Matsuse, D.; Akashi, H.; Tanimura, Y.; Tsuchiyama, K.; Kikuchi, T.; Goda, M.; Nakahata, T.; Fujiyoshi, Y.; Dezawa, M. (2011). "Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts". Proceedings of the National Academy of Sciences. 108 (24): 9879


 * Both ES and induced pluripotent stem (iPS) cells show germ line transmission and/or teratoma formation in addition to their ability to generate trilineage cells and self-renew. Epiblast stem cells (EpiSCs), another plutipotent stem cell type, however, do not form teratomas under certain circumstances, nor do they generally participate in germ line transmission. Thus, plutpotent stem cells do not always meet the strict requirements of teratoma formation or germ line transmission, and the self-renewal abilities and differentiation into trilineage cells are more essential and common requirements for plutpotent stem cells. These two properties are sufficiently comprehensive to represent their high differentiation ability beneficial for regenerative medicine, rather than setting limits in pluripotency by including germ line transmission and/or teratoma formation abilities.
 * Shohei Wakao, Yoshiro Kushida, Mari Dezawa; "Muse Cells Endogenous Reparative Plutipotent Stemcells”, (November 27, 2018), ed. Mari Dezawa, Chapter 2 Basic Characteristics of Muse Cells, p.16

"Squamous cell carcinoma arising in a mature cystic teratoma of the ovary in young patient with elevated carbohydrate antigen 19-9" (2008)
Arioz DT, Tokyol C, Sahin FK, Koker G, Yilmaz S, Yilmazer M, Ozalp S (2008). "Squamous cell carcinoma arising in a mature cystic teratoma of the ovary in young patient with elevated carbohydrate antigen 19-9". European Journal of Gynaecological Oncology. 29 (3): 282–284.
 * Squamous cell carcinoma is the most common type of malignant transformation in mature cystic teratomas. It mainly effects postmenopausal women but is rarely seen in young patients.
 * p.282


 * Squamous cell carcinomas originating from dermoid cysts are rare tumors especially seen in elderly patients with high levels of tumor markers (like CEA, SCCA). Every case may not have the same characteristics and management should be individualized.
 * p.282


 * Mature cystic teratomas, also known as dermoid cysts, are the most common ovarian tumors in women during reproductive years. Rarely does this type of tumor show malignant transformation (approximately 2% of cases). Any component may become malignant and squamous cell carcinoma is the most frequent type (80% of cases) of malignant transformation in dermoid cysts. Most of the patients are postmenopausal women and the mean age ranges from 51 to 55 years (minimum 21 and maximum 87 years old). Carbohydrate antigen 19-9 (CA19-9) tumor marker is a high-molecular-weight glycoprotein, frequently elevated in gastrointestinal adenocarcinomas. CA19-9 levels may also increase in dermoid cysts and in malignant transformation of dermoid cysts.
 * p.282


 * Malignant transformations are extremely rare complications of mature cystic teratomas. Squamous cell carcinoma accounts for 80% of malignant transformations in dermoid cysts. Although germ cell tumors are seen in younger age groups this type of tumor is especially observed in older age. Older age seems to be related with malignant transformation. Squamous cell carcinoma secondary to a dermoid cyst has very seldomly been seen in younger patients (10% in younger than 35 years). Preoperative diagnosis of squamous cell carcinoma arising from a dermoid cyst is very difficult as it does not have specific symptoms. Only intraoperative diagnosis is possible for such cases. Researchers have worked on various tumor markers and clinical parameters.
 * p.283


 * In the literature, squamous cell carcinomas arising in a mature cystic teratoma are seen mainly in postmenopausal ages and generally together with tumor markers like CEA and SCCA.
 * p.283

"Malignant transformation of a well-organized sacrococcygeal fetiform teratoma in a newborn male" (May 2007)
Chen YH, Chang CH, Chen KC, Diau GY, Loh IW, Chu CC (May 2007). "Malignant transformation of a well-organized sacrococcygeal fetiform teratoma in a newborn male". Journal of the Formosan Medical Association Taiwan Yi Zhi. 106 (5): 400–402.
 * A sacrococcygeal teratoma is the most common germ cell tumor occurring in childhood. Fetiform teratoma (FT) is a rare variant of a teratoma and has yet to be clearly defined. A FT is a teratoma that has the appearance of a fetus and presents as a grossly developed mass of internal organs, has a similar appearance to the exterior of a fetus, or resembles a part of a fetus without an axial skeleton. This is the first case of a FT reported in a male and also the first case of a FT with a benign histopathologic appearance which later transformed into a malignancy.
 * p.400


 * FT is a very rare condition, and between 1983 and 2005, only 10 cases have been reported in the literature. The pathogenesis of FT is still unclear; therefore, there are several similar nomenclatures which are used for the tumor. It is believed that a FT is a rare variant of a well-formed teratoma, or a malformed parasitic monozygotic twin enclosed in the body of its partner as a tumor mass. There exists controversy whether a teratoma with systemic organized structures should be termed a “well-differentiated teratoma” or “FT”. The term well-differentiated teratoma often refers to the histopathologic grade; however, FT suggests that a teratoma appears grossly to be a fetus. The case reported herein is the only reported case of a FT that had a complete gastrointestinal tract, including salivary glands, an esophagus, a stomach, a small intestine, and a colon. Interestingly, this case is also the first case in which a FT has been reported to occur in a male.
 * p.401


 * It is important to differentiate FT from FIF. The former may be malignant, while the latter is generally considered to be benign. The main difference between a FT and a FIF is that a FIF has a separate spinal column with symmetrically developed organs. Although it is difficult to make the proper diagnosis preoperatively, proceeding with a complete resection of the mass is appropriate. Even following total resection of the FT as determined by visual inspection, one should consider that an incomplete resection with residual tumor could occur, most often, due to rupture of the cystic part of the FT during the procedure with concomitant tumor seeding.
 * pp.401-402


 * To our knowledge, teratomas have shown the capacity for malignant change, including FT. Surprisingly, there have been no such previous case reports. Therefore, we are reporting the first case of a well-developed FT which became malignant. The AFP level served as a good biomarker for the FT, even considering the wider reference ranges which exist in the infant period. Determining a preoperative AFP level is necessary to establish a baseline for the disease. Since FT has the potential for malignant recurrence after complete resection, regular follow-up should be instituted.
 * p.402

"Fetus-in-fetu in the pelvis: report of a case and literature review" (November 2005)
Chua JH, Chui CH, Sai Prasad TR, Jabcobsen AS, Meenakshi A, Hwang WS (November 2005). "Fetus-in-fetu in the pelvis: report of a case and literature review", Annals of the Academy of Medicine, Singapore. 34 (10): 646-649.
 * It remains controversial whether fetus-in-fetu is a distinct entity or represents a highly organised teratoma. Du Plessis et al reported an interesting patient with both a well-formed fetus-in-fetu and a malignant teratoma, stating that was “a potential triplet situation gone awry, resulting in the host, his parasitic twin and a teratoma arising from a third embryo which may have escaped the influence of a primary organizer”. Previous investigators have hypothesized that fetus-in-fetu results from a modified process of twinning, and have traced a progression from normal twins to conjoined symmetrial twins, though parasitic fetuses and fetal inclusion, and finally to teratoma.
 * p.648


 * Willis believes that teratomas originate from the early separation of a focus of multi-potential tissue in the growing embryo that develops ina chaotic way in the host organism. According to Willis, the presence of an axial skeleton distinguishes a teratoma from fetus-in-fetu. The presence of a separate spina column indicates that the fetus has passed through a primary stage of gastrulation, involving formation of neural tube, metamerisation, and symmetrical development around this axis. However, not all the reported cases of fetus-infetu have an identifiable spine. Metamerisation is believed to have nevertheless occurred in the presence of well-differentiated limbs with hands, phalanges, and nails. The presence of nervous tissue plexuses in the digestive tube, and melanocytes in the skin also implied the existence of notochord during development. Dederici et al and Eng et al proposed that in the presnece of structures with an advanced grade of fetal organisation such as eyes, parts of the central nervous system, wel-developed limb-like processes, skin and colon, the diagnosis of fetus-in fetu can be applied, even in the absence of a real axial structure. Willis' theory has been supported by genetic, cytogenetic, and serologic assessments. Studies on blood group systems and chromosome cultures from the host and fetus showed no difference between the two. When intra-abdominal gonads were found, these corresponded histologically to the sex of the bearer. These studies virtually excluded dizygosity or aneuploidy, and indicated that the fetus-in-ftu was derived from the same zygote tissue as its host. Our baby and his included fetus shared the same 46XY karyotype, thereby supporting Willis' theory. Early incorporation of the parasitic twin into the abdomen of the host would explain the ultrasonographic finding of a singleton fetus at 20 weeks of gestation.
 * p.648


 * Although there was little evidence of organogenesis in our included fetus, mature somatic tissues from ectodermal (neuro-epithelium, ganglia), endodermal (colon) and mesodermal (bone and cartilage) origins were present. These, together with the presence of a complete vertebral column with appropriate arrangement of the limbs around it, distinguish our fetus from a teratoma.
 * p.649.

"Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis" (January 2011)
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (January 2011). [nihms316554.pdf "Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis"]. The Lancet. Neurology. 10 (1): 63–74.
 * In 2005, a syndrome of memory deficits, psychiatric symptoms, decreased consciousness, and hypoventilation was reported in four young women with ovarian teratomas. Specific autoantibodies to the N-methyl D-aspartate receptor (NMDAR) were soon detected in these and eight other patients with similar neurological symptoms, seven of whom also had ovarian teratomas. During the following 3 years we identified 419 other patients with this syndrome, many of them children and young adults with or without an associated tumour.
 * pp.1-2


 * About 80% of patients with anti-NMDAR encephalitis are women. The detection of an underlying tumour is dependent of age, sex, and ethnic background. Figure 2 shows the distribution of 400 patients grouped by age and the presence or absence of a tumour. When compared with a previous series, these data show that, with increased awareness of this disorder, the disease is being more frequently recognised in younger teenagers and children. Analysis of these 400 patients confirms that the younger the patient, the less likely that a tumour will be detected, and that in female patients older than 18 years, the frequency of an underlying teratoma is much the same as we initially reported (webappendix p 1). Black women are more likely to have an underlying ovarian teratoma than are patients of other ethnic groups (webappendix p 2) Only 5% of male patients older than 18 years had an underlying tumour. Detection of tumours other than teratoma is not very common—eg, of 400 patients studied, only 7 (2%) had a tumour other than an ovarian teratoma (webappendix p 1). One patient with neuroblastoma and another with Hodgkin’s lymphoma have been reported. The ovarian teratomas of 25 patients showed expression of NMDAR in all cases. The expression of NR1 by other tumours has been examined in only one patient with breast cancer and proved positive (unpublished). Whether tumours other than teratomas are true associations or unrelated coincident disorders is unknown.
 * pp.4-5


 * About 75% of patients with NMDAR antibodies recover or have mild sequelae; all other patients remain severely disabled or die. Management of anti-NMDAR encephalitis should initially focus on immunotherapy and the detection and removal of a teratoma.
 * p.5

"Diagnosis and characterization of fetal sacrococcygeal teratoma with prenatal MRI" (October 2006)
Danzer E, Hubbard AM, Hedrick HL, Johnson MP, Wilson RD, Howell LJ, et al. (October 2006). "Diagnosis and characterization of fetal sacrococcygeal teratoma with prenatal MRI". AJR. American Journal of Roentgenology. 187 (4): W350–W356.
 * OBJECTIVE. The purpose of this study was to determine whether prenatal MRI provides additional information about fetal sacrococcygeal teratoma compared with prenatal sonography.
 * p.w350


 * Our results show that ultrafast fetal MRI is a useful adjunct to the prenatal evaluation of fetal sacrococcygeal teratoma. Compared with sonography, MRI more accurately characterized the intrapelvic and abdominal extent of the tumors and provided more information on compression of adjacent organs. The additional anatomic resolution provided by MRI resulted in more accurate prenatal counseling and improved preoperative planning for surgical resection.
 * p.w350


 * Although rare, sacrococcygeal teratoma is the most common tumor of the fetus and the neonate, with a reported incidence of one in 35,000 to 40,000 live births. It has been defined as either a neoplasm composed of tissues from all three germ layers or a neoplasm formed from multiple tissues foreign to the part and lacking organ specificity. These tumors arise from totipotent somatic cells that originate from the primitive knot (Hensen's node) or caudal cell mass and escape normal inductive influences. The natural history of prenatally diagnosed sacrococcygeal teratoma differs from postnatally diagnosed sacrococcygeal teratoma. Malignant degeneration, the primary cause of death in postnatal sacrococcygeal teratoma, is rare in utero. The high mortality rate of fetal sacrococcygeal teratoma is attributed to tumor mass and associated dystocia, preterm labor caused by secondary polyhydramnios, and development of hydrops and placentomegaly (secondary to high-output cardiac failure associated with arteriovenous shunting). Prenatal assessment of the fetus is critical for counseling the parents and planning surgical options. Also, with the development of in utero treatment for sacrococcygeal teratoma, it is important to select appropriate candidates for fetal surgery. Because of acoustic shadowing by the fetal pelvic bones, sonography cannot always define the most cephalad extent of sacrococcygeal teratoma. Prenatal MRI for evaluating uterine and fetal anatomy has improved with the development of ultrafast MRI techniques. Fetal MRI has been successfully performed with echo-planar and RARE imaging. MRI offers superior anatomic resolution, regardless of fetal orientation, and it provides an image display that is more intuitively comprehensible to the patient and to many consulting physicians. Despite the increasing use of prenatal MRI, to our knowledge only a few small case series have been published comparing the advantages and disadvantages of prenatal sonography and MRI of sacrococcygeal teratoma. This study compared the diagnostic utility of prenatal MRI and transabdominal sonography for evaluation of sacrococcygeal teratoma to determine whether MRI could provide additional valuable clinical information.
 * pp.w350-351


 * Ultrafast MRI using sequences that acquire an image in less than 0.4 seconds allows fetal imaging without the necessity for fetal sedation or paralysis. To date, several small case series have sown that prenatal MRI is useful in the assessment of sacrococcygeal teratoma. However, the question remains whether MRI is equivalent, superior, or complementary to sonography for prenatal assessment of sacrococcygeal teratoma. To be generally accepted, a newly applied diagnostic device must fulfill a number of requirements. First, it must be safe and not expose the patient to unnecessary risks. Second, it must be able to diagnose the underlying problem. Third, it should provide additional useful information that is not provided by a currently established method. Finally, in the current fiscal environment, the new diagnostic procedure should be cost effective. Our results suggest that MRI fulfills these criteria for diagnostic evaluation of fetal sacrococcygeal teratoma.  Multiple experimental and clinical studies support the safety of MRI for fetal imaging. Although the potential exists for teratogenic effect, we limit MRI to fetuses at more than 18 weeks’ gestation and have seen no ill effects attributable to MRI. Our results clearly show that MRI is superior to sonography in assessing the intrapelvic and intraspinal extent of tumor and in discerning the presence and physiologic effects of compression of pelvic organs by the tumor. These advantages allow more accurate prognostic counseling for patients presenting with sacrococcygeal teratoma and improve pre and perinatal management by providing accurate data for decisions regarding fetal surgery, tumor decompression, and timing of delivery.
 * p.w354


 * Optimal management of fetal sacrococcygeal teratoma requires accurate imaging of the precise intrapelvic and intraabdominal extent of tumor, the content of the tumor, and the physiologic effects of tumor compression on the pelvic organs or bone structure. MRI proved superior to sonography in all of these requirements. Our results show that sonography does not always precisely assess the intrapelvic extension of the tumor. The advantage of MRI is primarily related to the absence of acoustic shadowing by the fetal pelvic bones that interferes with sonography visualization.
 * p.w354


 * MRI also enhanced the assessment of the content of sacrococcygeal teratoma. Fetal sacrococcygeal teratoma may be cystic, solid, or mixed in sonographic appearance and may contain characteristic echogenic patterns secondary to areas of tumor necrosis, cystic degeneration, internal hemorrhage, and calcification. The prognosis of prenatally detected sacrococcygeal teratoma seems to be related not only to the size of the mass but also to its content. Fetuses with predominantly solid and highly vascularized masses have a poorer prognosis than fetuses with tumors that are mainly cystic and avascular in appearance. The solid, vascularized masses require closer surveillance for the evolution of high-output physiology. Sonography seems to be sufficient for evaluating mainly cystic and extrapelvic sacral masses; however, when the tumor appears to be echogenic, it is more difficult for sonography to characterize the sacrococcygeal teratoma content.
 * p.w354-w355


 * Tumor involvement or compression of adjacent organs is an important contributor to the morbidity of sacrococcygeal teratoma, and accurate prenatal assessment is important for the timing of intervention and comprehensive prenatal counseling. Urologic complications are the most common cause of morbidity from sacrococcygeal teratoma, occurring in at least 41% of our patients. Tumor compression of the bladder outlet caused urinary retention followed by secondary renal deterioration, oligohydramnios, and pulmonary hypoplasia in one fetus. Other published series have described severe urologic problems with prenatally detected sacrococcygeal teratoma.  The highest incidence of urologic complications in our series (67%) was seen in patients with type III tumors.  Furthermore, damage to the innervation of the lower urinary tract in sacrococcygeal teratoma may be caused by compression or infiltration of sacral nerves by the tumor; intraspinal extension of the tumor; or trauma to the pelvic, splanchnic, or hypogastric nerves during tumor resection.
 * p.w355


 * Surgeons at our institution found that MRimages helped them mentally visualize the content and extent of the sacrococcygeal teratoma before delivery. In most cases, neonatal surgery is required soon after cesarean delivery, and the anatomic details of tumor extent and involvement of adjacent structures may affect the surgical approach.
 * p.w355


 * Our results show that ultra fast fetal MRI is a powerful addition to the prenatal evaluation of  fetuses   with   sacrococcygeal teratoma. Based on our experience using prenatal MRI for evaluation of fetal sacrococcygeal teratoma, we recommend that all fetuses with appearance of sacrococcygeal teratoma on sonography undergo MRI evaluation to assess exact tumor size, content, and intraabdominal extent to optimize  pre-,  peri-,  and  postnatal management.
 * p.w355

“Antenatal Consults: A Guide for Neonatologists and Paediatricians – E-Book.” (2012)
Davies M, Inglis G, Jardine L, Koorts P (2012). [https://books.google.com/books?id=soTU42jrIkUC&pg=PA298#v=onepage&q&f=false “Antenatal Consults: A Guide for Neonatologists and Paediatricians – E-Book.” Elsevier Health Sciences. Chapter 55 Teratomas-Sacococcygeal and Neck, p. 298.
 * The word teratoma is derived from the Greek for monster, and it was first used by Virchow in 1869 for a sacroccygeal mass. A teratoma is a tumour composed of multiple tissues foreign to the site of origin; classically described as having all three embryonic layers (endoderm, mesoderm and ectoderm). Recent definitions recognise monodermic teratomas. Tumours generally occur in the midline, with 35-60% being sacroccygeal teratomas. About 8% of all teratomas are cervical.
 * p.298


 * There are three theories on how teratomas develop: 1. Derivation from toripotent primordial germ cells-Originating from endometral cells of the yolk sac near the allantosis, these cells migrate to the gonadal ridges during weeks 4 and 5 of gestation. Cells that don't reach their target may give rise to midline teratomas anywhere from the brain to the coccygeal area. 2. Originating from remnants in Hensen's node of the primitive streak-In weeks 3 caudal midline cells in Hensen's node give rise to all three germ layers of the embryo. The primitive streak shortens and disappears by the end of week 3. Persistence would explain the commonest site of a teratoma being sacrococcygeal. 3. Incomplete twinning.
 * p.298


 * Teratomas are the most common neoplasm in newborn infants. The incidence is 1 in 35,000-40,000 live births. There is a 4:1 female to male ratio.
 * p.298


 * Teratomas are usually isolated lesions. They may form part of the Currarino triad (anorectal malformation, sacral anomaly, presacral mass). Other anomalies reported are: urogenital (hypospadias, vesicoureteral reflux, vaginal or uterine duplications); congenital dislocation of the hip; central nervous system lesions (anencephaly, trigonocephaly, Dandy-Walker malformations, spina bigida, myelomeningocoele); Klinefelter syndrome (strongly associated with mediastinal teratoma); and rare associations with trisomies 13 and 21, anterior diaphragmatic hernia, congenital heart defects, Beckwith-Wiedemann syndrome, pterygium, cleft lip and palate, Proteous syndorme, Schinzel-Giedion syndrome. Other anomalies relate to the physical effects of the tumour itself, such as pulmonary hypoplasia (cervical tumour) and urinary obstruction *sacrococcygeal teratomas).
 * p.299


 * In recent series, overall survival of those with antenatally diagnosed sacrococcygeal teratomas approaches 80%, and of liveborn infants it approaches 95%. Vascular steal and increased metabolic demand from the (highly vascular) tumour can lead to high output cardiac failure. This can lead to polyhydramnios, cardiomegaly, fetal hydrops and intrauterine death. Mortality approaches 100% if these complications arise prior to 37 weeks gestation. Mirror syndrome (maternal pre-eclampsia associated with fetal and placental hydrops) has been described in mothers of fetuses with sacrococcgygeal teratomas. There is a 10% risk of malignancy at birth. The Kasaback-Merritt phenomenon (consumptive coagulopathy and thrombocytopaenia) may ensue, due to highly flow through tumour vessels. This in turn may lead to haemorrhage to and from the tumour.
 * p.299

"Defining the Teratoma as a Model for Multi-lineage Human Development" (2020-11-25)
McDonald, Daniella; Wu, Yan; Dailamy, Amir; Tat, Justin; Parekh, Udit; Zhao, Dongxin; Hu, Michael; Tipps, Ann; Zhang, Kun; Mali, Prashant (2020-11-25). [ncbi.nlm.nih.gov/pmc/articles/PMC7704916/pdf/nihms-1637949.pdf "Defining the Teratoma as a Model for Multi-lineage Human Development"]. Cell. 183 (5): 1402–1419.e18.
 * We propose that the teratoma, a recognized standard for validating pluripotency in stem cells, could be a promising platform for studying human developmental processes. Performing single cell RNA-seq of 179,632 cells across 23 teratomas from 4 cell lines, we found teratomas reproducibly contain approximately 20 cell types across all 3 germ layers, the inter-teratoma cell type heterogeneity was comparable to organoid systems, and that the teratoma gut and brain cell types correspond well to similar fetal cell types. Cellular barcoding confirmed that injected stem cells robustly engraft and contribute to all lineages. Using pooled CRISPR-Cas9 knockout screens, we showed that teratomas can simultaneously assay the effects of genetic perturbations across all germ layers. Additionally, we demonstrated teratomas can be molecularly sculpted via miRNAregulated suicide gene expression to enrich for specific tissues. Taken together, the teratoma is a promising platform for modeling multi-lineage development, pan-tissue functional genetic screening, and tissue engineering
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 * The teratoma is characterized as a model for multi-lineage human development with cell types represented across all 3 germ layers; is utilized to enable assaying of the effects of genetic perturbations simultaneously across multiple cell types; and a molecular sculpting strategy is presented to enrich for specific tissues.
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 * The teratoma is characterized as a model for multi-lineage human development with cell types represented across all 3 germ layers; is utilized to enable assaying of the effects of genetic perturbations simultaneously across multiple cell types; and a molecular sculpting strategy is presented to enrich for specific tissues. Richard et al., 2000; Hodge et al., 2019) While there have been studies on human embryonic development (Miller et al., 2014; Zhu et al., 2018), such studies are limited by a scarcity of relevant biological material and key ethical constraints. There has thus been a push to establish models specific to human development.
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 * We propose here the use of teratomas as a model for studying human development (Lensch et al., 2007). The teratoma displays multi-lineage differentiation to all germ layers, has vascularized 3D structure, bears regions of complex tissue-like organization, and is relatively straightforward to implement. Early teratoma research revealed that teratomas derive from pluripotent germ cells which resemble embryonic cells (Stevens, 1962, 1967; THURLBECK, WLLIAM M., 1973; Stevens and Pierce., 1975). PSC-derived teratomas are generated by directly injecting PSCs into immunodeficient mice, where the cells will attach and differentiate in a semi-random fashion into all three germ layers (Willis, 1934, 1935; THURLBECK, WLLIAM M., 1973; Bocker, 2002). In this regard, teratoma formation is the gold standard to validate pluripotency and developmental potential of hPSC lines (Smith, Luong and Stein, 2009; Avior, Biancotti and Benvenisty, 2015). There has also been some progress in utilizing the inherent differentiation potential of teratomas to derive highly sought-after cell types. For instance, teratomas were recently utilized to derive skeletal myogenic progenitors by injecting PSCs into the tibialis anterior muscle of mice to enrich for muscle cell types in the teratomas that formed in those muscles (Chan et al., 2018). Additionally, some groups have successfully enriched for hematopoietic stem cells (HSCs) from teratomas utilizing strategies such as human umbilical vein endothelial cell (HUVEC) pooling (Suzuki et al., 2013; Tsukada et al., 2017; Philipp et al., 2018; Amabile et al., 2019). However, the semi-random nature of teratoma development has previously made characterization of teratomas difficult, as the different lineages can often be found in close spatial proximity.
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 * We further validated the cell type annotations by correlating the expression of each teratoma cell type with the expression of cell types from the Mouse Organogenesis Cell Atlas (Cao et al., 2019), demonstrating that each teratoma cell type generally correlates with at least one fetal mouse cell type (Figure S1D). While most of the teratoma cell types correlate to the expected mouse cell type, there are some discrepancies that may be due to differences in developmental stage, mouse/human specific expression, as well as the fact that a broad correlation analysis may not be able to distinguish closely related cell types (Figure S1D). For example, Hematopoietic Stem Cells (HSCs) from the teratoma correlate with fetal mouse endothelial cells, reflecting the endothelial origin of HSCs (Zovein et al., 2008). The MSC/Fib subtypes, as well as Pericytes, all broadly correlate to the same block of mesenchymal fetal mouse cell types which reflects their similar developmental origins (Cathery et al., 2018). Retinal Pigment Epithelia are a type of Ependymal Cell, and thus correlate accordingly (Wolburg et al., 2009). Melanoblasts and Retinal Neurons are also both derived from the neural crest and may share some marker genes such as MITF, although they are not as closely related as the other cell type correlations discussed previously (Goding, 2000; Mort et al., 2015). And finally, Kidney Progenitors do not correlate well with any fetal mouse cell type, although there were no Kidney cell types in the fetal mouse data at the level of annotation we used (Figure S1D). Overall, we used canonical marker genes and mouse cell atlases to generate a preliminary annotation of the cell types found in the teratoma scRNA-seq datasets.
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 * Assessing heterogeneity between teratomas (especially between teratomas generated from different stem cell lines) is critical for assessing the reproducibility and utility of this model. Towards this, we generated additional teratomas (per Figure 1A) with H9 ESCs, HUES62 ESCs, and PGP1 iPSCs, and assessed the cell type composition of the teratomas (Figure 2A, Table S1B). We ran 10X sequencing on each teratoma, integrated the expression profiles, classified cell types using the H1 teratomas as reference, and visualized the cell types with aUMAP scatterplot (Figure 2B) while also showing the relative contribution of each cell line teratoma to the UMAP embedding (Figure S2A). We also assessed the distribution of cell types represented in each individual H1 teratoma alongside the H9, HUES62, and PGP1 teratomas (Figure 2C, Figure S2B). We then compared the germ layer representation between all teratomas using zebrafish and Mouse Organogenesis Cell Atlas single-cell datasets for reference (Wagner et al., 2018; Pijuan-Sala et al., 2019) (Figure 2D). Teratomas are comprised mostly of mesoderm and neuroectoderm, with less endoderm (Figure 2D). The mesoderm is primarily from MSC/Fibroblasts in H1 teratomas, while teratomas from different cell lines show more variability in terms of the MSC/Fibroblast fraction (Figure 2D, Figure S1B). The relatively low fraction of endoderm in both the teratomas as well as the zebrafish and mouse embryo models indicate that endoderm is prevalent during development (Figure 2D). Qualitatively, while there is variability in cell type representation among the different teratomas, every teratoma contains most of the major cell types (Figure 2C). By computing the scaled mutual information between cell type assignments and teratoma assignments, we can compute a quantitative metric of this heterogeneity across teratomas (Figure 2E) (Kim et al., 2016). We find that the cell type heterogeneity across the H1 teratomas is similar to that of patterned brain organoids (Velasco et al., 2019), while the teratomas generated from different cell lines have a much higher level of heterogeneity (Figure 2E). Interestingly, line-specific kinetics were present in regard to teratoma growth with PGP1 teratomas growing the fastest and HUES62 the slowest (Figure S2C). Some of this accelerated growth may be due to chromosomal abnormalities as karyotyping has shown the PGP1 line has material translocated to 7q34 (BRAF) (Figure S2D).
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 * Results showed that across the three teratomas, over 25% of cells engraft, out of a total of 10 million injected cells, which suggests that no major bottlenecking occurs during teratoma formation (Figure S2F). This is especially important in the context of using teratomas in high-throughput genetic screens, as one must ensure that there are enough cells contributing to the final tumor so that none of the elements of the genetic screen are lost.
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 * We found that retinal epithelium is an outlier with both a high teratoma bias, and a high barcode bias (Figure 2H). Myofibroblast cells also have a relatively high barcode and teratoma bias score while Early Neurons, Radial Glia, Mid/Hindgut have high teratoma bias score (Figure 2H). Both the barcode bias and teratoma bias scores are scaled by the number of cells in each cell type (Methods). Taken together, we found teratomas to generally contain the same major cell types at 10 weeks of growth: a large fraction of MSC/Fibroblast and neuronal cell types, and a small fraction of endoderm. RPE shows both a high degree of variability across teratomas and a high level of lineage priming. Notably, the level of heterogeneity between teratomas generated from H1 stem cells is comparable to that observed in organoids (de Souza, 2017; Quadrato et al., 2017; Velasco et al., 2019), but there is a much higher level of heterogeneity among teratomas derived from different PSC lines. This reflects known epigenetic variability across those lines (Ortmann and Vallier, 2017). Taken together, we found teratomas to generally contain the same major cell types at 10 weeks of growth: a large fraction of MSC/Fibroblast and neuronal cell types, and a small fraction of endoderm. RPE shows both a high degree of variability across teratomas and a high level of lineage priming. Notably, the level of heterogeneity between teratomas generated from H1 stem cells is comparable to that observed in organoids (de Souza, 2017; Quadrato et al., 2017; Velasco et al., 2019), but there is a much higher level of heterogeneity among teratomas derived from different PSC lines. This reflects known epigenetic variability across those lines (Ortmann and Vallier, 2017).
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 * We next assessed the transcriptional similarity of the teratoma cell types to human fetal cell types, using published single-cell RNA-seq datasets from the human neuroectoderm and gut, to determine their utility as a tool for modeling human development. We looked at which human embryonic stage the 10-week teratoma cell types most resemble, projected the teratoma data onto the fetal data to assess global transcriptional similarity, and compared the expression of key cell type marker genes (Figure 3A) Due to the semi-random nature of teratoma differentiation, it is possible that different cell types will resemble different stages of embryonic development.
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 * W To further assess the similarity of the teratoma neuro-ectoderm cell types to the fetal prefrontal cortex cell types, we defined a panel of neuronal cell type marker genes: DCX, NEUROD1, HES5, SOX2, HMGB2, VIM, DLX1 and then correlated the expression of these marker genes between the teratoma cells and fetal brain cells for every matched cell type (Figure 3A, Figure 3E). We found a fairly high correlation overall, with R = 0.82 for Radial Glia, R = 0.93 for Cycling Progenitors, R = 0.84 for Interneurons, and R = 0.77 for Early Neurons (Figure 3E). We also looked at the cell type proportions in the fetal prefrontal cortex versus the teratoma, showing that the teratoma has far more progenitor cells such as Radial Glia, and fewer early neurons with no detectable mature neurons (Figure 3F). We also ran a differential expression as well as a geneset enrichment analysis between the matched teratoma and fetal prefrontal cortex cell types to assess the differences between the teratoma and fetal cells (Figure S3A, S3B). All four cell types showed similar top differentially expressed genes as well as genesets, suggesting that the main differences between the teratoma and fetal cells are global and not cell type specific (Figure S3A, 3B). The teratoma cells have a higher expression of genes related to organ morphogenesis while the fetal cells express genes related to methylation, suggesting the teratoma cells may not have the same epigenetic signatures as fetal cells (Figure S3A, S3B).
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 * Overall, we were able to show that the teratoma neuro-ectoderm and gut cell types are transcriptionally similar to their fetal counterparts, while also identifying the developmental stage of the teratoma cells. We validated the presence of six cell types (2 per germ layer) using RNAScope ISH and histology, which also showed that these cell types contain some degree of spatial organization (Figure 3G, Figure S3I, Table 1). Thus, we were able to further validate the teratoma neuro-ectoderm and gut cell types by mapping them onto reference fetal human scRNA-seq datasets and probing the spatial expression of canonical marker genes DCX, HES5, and CDX2 (Table 1, Table S3C). We also probed the spatial expression of FOXJ1, TNNT2, and THY1, adding more evidence to the Ciliated Epithelium, Cardiac Muscle, and MSC/Fibroblast cell type annotations (Table 1, Table S3C).
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 * To establish the utility of the teratoma system as a model for human development, we next performed a single-cell genetic knockout screen using CRISPR-Cas9. To identify key developmental genes to include in our screen, we compiled a list of 24 major organ/lineage specification genes that are embryonic lethal upon knockout in mice (Table S4A). Studying the effects of these genes using cell lines or organoid models would typically require different experiments and different models for each cell lineage, as even a single gene can have functions across cell types, and even different germ layers. With the teratoma model, we can screen the effects of these genetic perturbations in all major cell lineages and germ layers in the same experiment.
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 * While we were able to demonstrate the teratoma’s unique ability to assess the multi-lineage function of embryonic lethal genes, we also wanted to see if the teratoma could model human neural disorders.
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 * Since the teratoma is vascularized and has the potential to yield mature tissue, we sought to sculpt the teratoma towards specific lineages, which could allow for focused developmental modeling and tissue engineering. We used endogenously expressed micro RNAs (miRNAs) (Ambros, 2004; Bartel, Lee and Feinbaum, 2004; Bartel, 2018), which are often unique to specific cell types, lineages, or disease states (Lu et al., 2005; Shivdasani, 2006). Specifically, we appended tissue specific miRNA target sequences to the 5’ and 3’ UTR of a GFP fluorescent suicide gene (HSV-tk-GFP), thereby suppressing its expression in a miRNA specific lineage of interest (Figure 4E, Table S5G) (Miki et al., 2015; Nissim et al., 2017; Hirosawa et al., 2017). This design ensures that cell types that do not express the miRNA are killed by the suicide gene in the presence of gancliclovir (GCV), thus selecting for our desired lineage (Figure 4F).
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 * In summary, we developed a miRNA circuit that enables us to engineer the teratoma towards a desired lineage. We demonstrated this circuit in vitro using miR-126 (endothelial lineage) and miR-21 (cancer), and in vivo using miR-124 (neuro-ectoderm lineage). Our in vivo results showed that administering GCV through multiple sites resulted in improved neuroectoderm enrichment. Our miRNA circuit can be extended to any cell-type specific miRNA, and could have applications in studying developmental biology and human disease, as well as in tissue engineering.
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 * The teratoma has the potential to be a fully vascularized, multi-lineage model for human development. Its major advantages are that it can grow to a large size due to its vascularization, and it can produce a wide array of relatively mature cell types from all major developmental lineages. Additionally, as we demonstrated with our CRISPR-Cas9 knockout screens, the teratoma’s ability to generate cells from all lineages enables a comprehensive assessment of the effect of genetic perturbations on human development within a single integrated experiment. Furthermore, we show the teratoma can be engineered using miRNA circuits to grow/enrich specific tissues of interest in vivo. Future studies with this model could explore increasing tissue maturity with extended growth/larger animal hosts. Benchmarking with human patient-derived teratomas would also be valuable, especially as many of these often can become quite mature. Another critical future study is assessing the impact of different dissociation methods on teratoma cell type proportion. The ability to achieve greater cell numbers with the most current single cell RNA sequencing protocols, such as SPLiT-seq (Rosenberg et al., 2018) and sci-RNA-seq (Cao et al., 2017), will be vital for identifying additional cell types. A time series analysis of teratomas at multiple stages of maturity could help uncover developmental pathways that the cell types follow. Additionally, pooling different cell types together with PSCs prior to injection may help aid in cellular enrichment/maturity in the teratoma (i.e. HUVECs to enrich for HSC populations) (Philipp et al., 2018) or enriching for desired cell types based on injection site (Chan et al., 2018). Growing patient-specific teratomas could benefit disease research through isogenic iPSC lines aiding in understanding the disease state in various tissues that otherwise may be inaccessible with current technologies. Finally, further optimization is necessary on the miRNA molecular sculpting technology, specifically generating stable miRNA cell lines by insertion in loci such as AAVS1, and optimizing the timing, dosing, and route for GCV administration. Taken together, we believe the teratoma is a promising platform for modeling multi-lineage human development, pan-tissue functional genetic screening, and cellular engineering.
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 * Every model system has its intrinsic strengths and weaknesses, and below we discuss some of the limitations of the teratoma system and also considerations towards improving it for enabling basic science and engineering studies. One issue with the teratoma system (and organoids) is the intrinsic degree of heterogeneity (de Souza, 2017; Quadrato et al., 2017; Capowski et al., 2019; Phipson et al., 2019). In this regard, we found the use of internal controls when conducting perturbation experiments was important. For example, in our CRISPR-Cas9 screen, each teratoma contained both gene targeting guides and non-targeting controls, enabling us to compare cell type proportion shifts within each teratoma without having to worry about heterogeneity between teratomas. While the teratoma has regions of organization and maturity, these may develop in an asynchronous manner. This lack of synchronization may prove to be a barrier in accessing certain mature cell types that need a highly ordered cellular context to develop. Also, since the teratoma contains cell types from all lineages, finding a single dissociation protocol that captures as many cell types as possible is a challenge. The choice of dissociation method can drastically change the cell types profiled in single cell RNA-seq, and it is likely that the set of cell types we see in our data is biased by our dissociation protocol (Denisenko et al., 2019). It may be the case that no single dissociation method can capture all cell types, and it will be necessary to design specific dissociation protocols to capture specific tissues
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 * Safety switches based on suicide genes will also be critical for eliminating potential residual undifferentiated cells, and mouse cells within the teratoma, to mitigate impact on safety and utility in tissue engineering applications.
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"Ovarian Goiter as a Rare Cause of Hyperthyroidism" (2016)
Frysak Z, Schovanek J, Halenka M, Metelkova I, Duskova M, Karasek D (2016). "Ovarian Goiter as a Rare Cause of Hyperthyroidism". Acta Endocrinologica. 12 (3): 335–338.
 * Ovarian goiter also named as struma ovarii has been rarely presented as a clinical curiosity. By definition struma ovarii is a mature teratoma composed either exclusively or predominantly of thyroid tissue, mostly diagnosed between the ages 40 and 60 years. The common clinical features are pelvic pain, palpable abdominal tumor mass, and ascites. Clinical and biochemical features of hyperthyroidism are uncommon (<10%), however, thyreoglobulin (TGB) can be elevated. For a well-educated clinician aware of this diagnosis, ultrasonography and radionuclide imaging represent a method of choice to confirm this diagnosis.
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 * Ovarian teratomas can be comprised of a single cell type, so called monophasic, represented usually by struma ovarii or less frequently carcinoid tumors. Nomenclature can be confusing, but approximately 20 % of any ovarian teratomas contain thyroid tissue; <5% of teratomas are struma ovarii, by definition the thyroid tissue represents half or more of the tumor, histopathologically composed of normal thyroid-type tissue with follicles filled by colloid resembling eutopic thyroid tissue. This tissue rarely produces sufficient amounts of thyroid hormones to cause clinical signs of hyperthyroidism. Similarly to the thyroid gland the ectopic thyroid tissue may function autonomously. Malignant struma ovarii represents 0.01 % of all ovarian tumors and 5-10% of all struma ovarii (mostly papillocarcinomas) with prevalent good prognosis. In general, it is the most common sporadic histopathological finding revealed by the resection of the tumor masses during adnexectomy.
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 * We find important to point out the difficulties in diagnosing the ovarian goiter, since the time to confirm the diagnosis, ranged from 6 months to 26 years, 7.75 years on average.
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"Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups" (March 2000)
Göbel U, Schneider DT, Calaminus G, Haas RJ, Schmidt P, Harms D (March 2000). "Germ-cell tumors in childhood and adolescence. GPOH MAKEI and the MAHO study groups". Annals of Oncology. 11 (3): 263–271.
 * In mature and immature teratoma the treatment is surgical. The risk of recurrence can be estimated from the parameters primary site (with the coccygeal tumors being most at risk), histological grade of immaturity and completeness of the primary resection including the adjacent organ of origin (coccyx, ovary, testis etc.). In case of a microscopically complete tumor resection there is no role for adjuvant chemo- or radiotherapy irrespective of the histological grade of immaturity. Malignant germ-cell tumors (GCT) account for 2.9% of all malignant tumors of children younger than 15 years of age. More than half of the tumors occur at extragonadal sites such as the ovaries (26%), the coccygeal region (24%), the testes (18%) and the brain (18%) represent then primary sites. In patients with extensive tumor growth, metastatic disease or secreting intracranial tumors a delayed tumor resection after preoperative chemotherapy is preferable. In these patients malignant non-seminomatous GCT may be diagnosed clinically due to the increased serum or cerebrospinal fluid levels of the tumor markers AFT and/or [J-HCG. Current risk adapted treatment protocols containing cisplatinum allow long-term remissions in about 80% including patients with bulky or metastatic tumors. In the cisplatinum era the prognostic factors like histology, primary site of the tumor and initial tumor stage have partly lost their former impressive significance in infants and children. On the other hand the completeness of the primary tumor resection according to oncological standards has been established as the most powerful prognostic parameter superior to tumor marker levels or primary site of the tumor.
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 * Malignant germ-cell tumors are rare tumors contributing 2.9% to the central Tumor Registry of the German Society for Pediatric Oncology and Hematology. In Germany the incidence of malignant GCT is 0.6/ 100,000 children, varying significantly according to sex and age. Teratoma contribute additional 50% so that from these data the overall incidence of GCT can be estimated as 0.9/100,000. In neonates mature and immature teratoma predominate (girls: 0.9/100,000, boys: 2.6/100,000). In the first years of life the overall incidence of GCT decreases (< 0.1/100,000 for both sexes at five years of age). Simultaneously, among toddlers the relative proportion of malignant entities, especially yolk sac tumors (YST) increases. The incidence of gonadal tumors, mainly seminomas and dysgerminomas, increases with the onset of puberty. In young men GCT represent the most common malignant tumor entity (yearly incidence: 7-8/100,000). In general, girls have a higher overall incidence of GCT, but boys are more at risk of malignant GCT. GCT are characterized by a high heterogeneity of their histological differentiation, but they show a similar histological pattern independent of their primary site or sex. They are classified according to the WHO-classification of testicular and ovarian tumors, respectively. The histological evaluation of GCT is difficult because of the heterogeneous appearance of the tumors and because of conflicting terminology. Therefore, the initial diagnostic work-up should include the evaluation by an experienced pediatric pathologist and according to the guidelines of the German GCT protocols a central reference histology is mandatory in order to achieve a standardized and reliable histopathological diagnosis and grading. According to the holistic concept of Teilum GCT arise from totipotent primordial germ cells which are capable of embryonic and extraembryonic differentiation. Yolk sac tumors (YST) and choriocarcinoma (CHC) follow an extraembryonic differentiation pattern and are characterized by a significant secretion of al-fetoprotein (AFP) or human choriogonadotropin (HCG or (3-HCG), respectively. Embryonal carcinoma (EC) represent tumors of immature totipotent cells. Teratoma display an embryonal differentiation mimicking organ structures of all germ layers. In teratoma the histological grade of immaturity is defined by the extent of immature (predominantly neuroepithelial) elements. Finally, the germinomatous tumors [synonyms: seminoma (testis), dysgerminoma (ovary), germinoma (brain)] may be interpreted as tumors displaying morphological features of undifferentiated germ epithelium. Interestingly, in contrast to testicular GCT of adult patients pediatric GCT do not develop from intratubular in situ carcinoma. The histological subentities show a highly heterogeneous biology and clinical course. In most patients the response to the different therapeutic modalities can be predicted from the histological appearance and the tumor marker profile (Table 1). Twenty-five percent of all pediatric GCT present as tumors with more than one histological type. In this situation therapy and prognosis depend on the tumor entity with the highest malignancy.
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 * Pediatric GCT show a pattern of cytogenetic aberrations which is different from their adult counterparts. More than 80% of adult malignant GCT display a distinct and specific chromosomal aberration, the isochromosome 12p. The remaining isochromosome 12p-negative tumors frequently show an amplification of 12p (homogeneously staining regions or tandem repeats). These aberrations have been observed in both, testicular and ovarian tumors, and in extragonadal mediastinal GCT.
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 * In children younger than 15 years the most common primary sites are the ovary (26%), the coccyx (24%), the testis (18%) and the brain (18%). In infancy coccygeal tumors are by far most prevalent. Other extragonadal sites are the mediastinum (4%), the retroperitoneum (4%) and the vagina (2%). The relative incidence of GCT with regard to the histological subentities and the primary site shows a characteristic age-dependent pattern. Teratomas of the coccyx are most commonly found in neonates, while ovarian teratomas occur between the 6th and the 14th year of age. Coccygeal tumors in children older than four years usually present as malignant YST, and half of the patients with relapsing teratoma present with a malignant histology, most common YST. Among the ovarian tumors, dysgerminoma are most prevalent during puberty, whereas the other malignant entities develop at all ages. Germinomatous tumors can also appear at extragonadal sites like the brain (approx. 50% of all intracranial GCT) or mediastinum but they have not been observed yet at the coccyx.
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 * Malignant GCT are characterized by their infiltrative growth pattern and by lymphogenous and hematogenous spread. The testicular GCT spread into the retroperitoneal lymph nodes, while spread into inguinal lymph nodes occurs in stage pT4 tumors, only. In ovarian GCT lymphogenous spread can be observed in the lymph nodes at the renal hilus. In intraabdominal and intracranial GCT dissemination can occur via ascites or cerebrospinal fluid, respectively. The most common sites of distant metastases are the lungs and the liver. In a recent evaluation of 95 patients with sacrococcygeal YST registered in the German cooperative protocols 15% of the patients had lymph node metastases while 35% suffered from distant metastases at diagnosis. Compared to adults brain metastases of extracranial GCT are extremely rare. Relapses most commonly present as local recurrence at the primary site of the tumor.
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 * In most patients the diagnosis can be established with regard to the clinical picture, the typical localization, tumor imaging and the measurement of the tumor markers. In neonates and young infants the physiologically elevated AFP-levels have to be considered. In children older than two years an elevation of the AFP levels of more than 100 ug/1 is highly indicative for a malignant GCT with a component of YST. Nevertheless, an acute liver disease with an elevation of the AFP-levels due to hepatocellular regeneration, AFP secreting liver tumors like hepatoblastoma and hepatocellular carcinoma and some rare tumors (e.g., pancreaticoblastoma), rare cases of hereditary persistence of AFP or hereditary diseases associated with elevated AFP-levels (e.g., hereditary tyrosinemia, ataxia teleangiectatica) should be excluded. In some teratoma with a higher degree of immaturity elevation of the AFP can be observed and correlates with the histological detection of small foci of YST. Nevertheless, in case of a complete tumor resection microfoci of YST would not urge to change the therapeutic strategy.
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 * Treatment of pediatric GCT is based on a multimodal strategy that includes surgery, chemo- and radiotherapy. Depending on their distinct biology the histological subentities differ significantly in their response to chemo and radiotherapy. Germinomatous tumors are highly sensitive to both radio- and chemotherapy. On the other hand, the therapeutic impact of radiotherapy has not yet been clearly defined in non-germinomatous malignant GCT. Treatment data show that EC, CHC and YST show a restricted sensitivity only to high doses (>50 Gy) of irradiation. Compared to their malignant counterparts, in immature teratoma the therapeutic role of chemo- or radiotherapy still has to be determined. Therefore, in these tumors the complete surgery represents the mainstay of treatment.
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 * Historical reports of the 1980s discussed treatment regimen including vincristine, adriamycin, actinomycin D and cyclophosphamide combined with irradiation. Radiotherapy was administered simultaneously to chemotherapy up to a dose of 30 Gy. The entire chemotherapy was continued for 18-20 months. Thirty percent of the patients survived. Ten percent died of toxicity complication. Ablin et al. reported about 93 children with extracranial malignant germ-cell tumors treated between 1978-1984. Patients received a combination of vinblastine, bleomycin, cisplatinum, cyclophosphamide, actinomycin D and doxorubicin. The observed toxicity aside hematological effects was mainly cardiac due to doxorubicin and pulmonary as induced by bleomycin, but no toxic death was recorded. The achieved event-free survival rates were around 50%.
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 * Data of the UKCCSG study on malignant germ-cell tumors registered between 1979 and 1987 described the results of several chemo-regimen: Low-dose VAC treatment was seen to be ineffective (EFS 8%). The combination platinum, vinblastine and bleomycin (days 2, 9, 16) caused unacceptable pulmonary toxicity due to bleomycin whereas the combination of bleomycin (day 1 only), etoposide and cisplatinum showed superior results with no proven pulmonary complication (EFS 84%). Good results were also obtained with high-dose VAC with or without doxorubicin resulting in an EFS of 87% Cisplatinum has been demonstrated as the most effective single chemotherapeutic agent in both childhood and adult GCT From the 1980s etoposide has been introduced as the first drug active in cisplatinum resistant GCT. Recently, there have been attempts to replace cisplatinum by carboplatinum in order to reduce the cumulative nephro- and ototoxicity (e.g. JEB, Table 2). Some studies have shown the superior efficacy of carboplatinum regimen compared to nonplatinum regimen previously applied in children. On the other hand, an analysis of prognostic factors in non-seminomatous GCT revealed that even in localized tumors an intensive cisplatinum-based chemotherapy resulted in higher survival rates than carboplatinum therapy. In summary, the regimens PEI, BEP, PVB, CarboPEI and JEB (Table 2) have a synergistic cytotoxic activity and can be regarded as standard regimens that are applied in currently open pediatric GCT protocols. Encouraged by the results of previous studies, attempts have been made to reduce the cumulative chemotherapy doses by introducing shorter but more intensive regimen.
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 * In general different strategies have been applied in pediatric GCT protocols. Some have stratified chemotherapy according to the response to treatment (e.g., one standard chemotherapy regimen to a total of two cycles after complete remission). In other protocols therapy is stratified according to initial diagnostic parameters, and only in case of insufficient response to treatment therapy is further intensified.
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 * In intracranial germinoma, which account for 50% of all intracranial GCT and do not secret significant amounts of (3-HCG, a histological verification of the tumor is mandatory. According to the current SIOPCNS-GCT 96 protocol patients can be treated either with craniospinal irradiation with 24 Gy and a tumor boost of 16 Gy or with a multimodal treatment including two cycles of chemotherapy (CarboPEI, Table 2) followed by a focal irradiation (40 Gy). As GCT may arise in neighborhood to sensitive structures like the chiasma opticum, it is recommended to consult a reference radiotherapist for detailed recommendation on optimal treatment techniques. It has been demonstrated that a five-year event-free survival of 91% and five-year overall survival of 94% can be achieved by radiotherapy only. With the combined chemo- and radiotherapy approach a three-year relapse-free survival of 96% and an overall three-year survival of 98% has recently been reported, but it has to be considered that in this study two of the four observed relapses occurred after the evaluated three-year observation period. The secreting intracranial GCT (YST, CHC, EC) show an inferior prognosis compared to germinoma. In these patients four cycles of cisplatinum based chemotherapy (PEI, Table 2) are applied, followed by a delayed tumor resection and radiotherapy. The radiotherapy is stratified according to the initial staging. Non-metastatic tumors receive focal irradiation (54 Gy), whereas patients with intracranial or spinal metastases or tumor cells in the CSF receive a craniospinal irradiation (30 Gy plus 24 Gy tumor boost). The summary of several cooperative protocols and the preliminary data of the SIOP-CNS-GCT 96 protocol suggest that a long term remission can be obtained in about two thirds of patients.
 * p.267


 * Both gonadal and extragonadal GCT are treated according to a similar therapeutic concept: only in small, non-metastatic tumors in which the radiographic examinations shows no evidence of invasive growth beyond the organ of origin a primary resection is indicated. In patients with bulky, invasive or metastatic tumors a preoperative chemotherapy followed by a delayed tumor resection is preferred to avoid the risk of incomplete resection. A decline of the tumor markers according to their serum half-life indicates for a favorable response to chemotherapy. Tumor resection is considered complete, if it is performed as en bloc resection of the tumor including the adjacent organ of origin. On microscopy the resection margins must be free of tumor cells. In testicular tumors a high inguinal orchidectomy is mandatory. Ovarian tumors must be resected including the ovary and the Fallopian tube. In coccygeal tumors the complete en toto resection including the whole coccyx is essential. A recently published review summarizes the standard surgical procedures in gonadal and extragonadal pediatric GCT in detail. In patients with tumor residues after an initial tumor resection a second-look surgery is essential to achieve a secondary complete resection. In general, there is no role for debulking surgery in pediatric GCT. Usually, surgery of metastases is not indicated unless they show an insufficient response to chemotherapy.
 * p.267


 * Teratoma represent a distinct histological entity that shows a significant diversity of the clinical course in dependence of the histological grade of immaturity. Mature teratoma are considered as benign tumors, whereas immature teratoma may show clinical features of malignancy. The surgical treatment should follow the same principles as outlined above for the malignant GCT. The risk of recurrence can be estimated from the parameters primary site of the tumor, histological grade of immaturity and completeness of the tumor resection. Nevertheless, the role of adjuvant chemotherapy has not yet been established, but recent reports have shown that chemotherapy is not indicated after complete tumor resection, even if there were small foci of malignant YST.
 * p.268


 * A complete clinical remission is defined as normalization of the tumor-markers within the age-related normal range and the absence of suspective residual structures, even in patients with normalized tumor markers, as these structures may represent remaining mature teratoma. If any of these criteria is not fulfilled, a diagnostic reevaluation and - if necessary - change or intensification of treatment is highly indicated. Most relapses occur within the first two years after diagnosis, although in some patients late recurrences up to five years after diagnosis of an intracranial germinoma or sacrococcygeal teratoma have been observed. Therefore, the initial follow-up examinations after completion of chemotherapy must be performed in short intervals, including frequent (i.e., weekly) controls of the tumor markers AFP and (3-HCG. In watch-and-wait patients the decline of the AFP values must be evaluated with regard to its serum half-life of approximately six to seven days. Especially in infants younger than two years in whom the interpretation of AFP may be difficult due to the physiologically elevated serum levels it has been proven helpful to compare the AFP decline with the graph given in Figure 1. A slower decline or a secondary rise of the AFP levels strongly indicate for an incomplete tumor resection or a recurrence of YST. In addition, the follow-up examinations must include repeated imaging of the primary site of tumor. In case of residual structures after chemotherapy a resection of these residues is indicated, since mature teratoma may have remained which bears the risk of a later tumor progression. Positron emission tomography examinations have not been proven useful in this situation, as these cannot distinguish between mature teratoma and residual necrosis or scars.
 * p.268


 * In intracranial tumors repeated endocrinological examinations at diagnosis and during follow-up are mandatory, since especially tumors of the suprasellar region can be associated with endocrinological symptoms like diabetes insipidus or panhypopituiarism. In children treated with cisplatinum-containing polychemotherapy (esp. plus ifosfamide) the renal function has to be monitored carefully for tubular nephropathy. In children a prolonged phosphaturia can lead to renal rachitism with consecutive growth retardation, while adolescents are at risk of renal osteomalacia. These long-term sequelae can be avoided by supplementation of phosphate and vitamin D. Further attention should be drawn to the risk of therapy-related secondary leukemia that depends on treatment intensity and modality. In the German series the cumulative risk at 10 years follow-up was 1.0% for patients that received chemotherapy only and 4.2% for patients that were treated with both radio and chemotherapy (Kaplan-Meier estimates).
 * p.268


 * In conclusion, we prefer cisplatinum containing regimen in patients with relapsed tumors, if the organ toxicities related to the previous treatment allow further cisplatinum therapy. On the other hand patients suffering from severe cisplatinum-related toxicity may be treated with a combination of carboplatinum and highdose etoposide (at 400-600 mg/m2 on three days). In our experience high-dose chemotherapy with stem-cell support, as it has been applied in adult patients, has resulted in long-term remissions only in those patients in whom a clinical complete remission could be achieved prior to high-dose chemotherapy. Therefore, we regard high dose chemotherapy as indicated for consolidation treatment, only.
 * p.268


 * In our experience more than 90% of relapses occur at the primary site of the tumor. For example in the above mentioned series of 95 sacrococcygeal YST only one patient had a distant recurrence, whereas nine patients had a local and four patients a combined local and distant relapse. Therefore, relapse chemotherapy must be accompanied by an intensive local therapy, preferably complete resection of the recurrent tumor after tumor-reduction by preoperative chemotherapy. We could demonstrate that patients with local recurrences and poor response to conventional chemotherapy may profit from locoregional hyperthermia combined with platinum-based chemotherapy. This approach significantly enhanced local tumor control. To our knowledge, newly developed drugs like paclitaxel or gemcitabine which have been recently applied in phase I and II studies in relapsed adult GCT have not yet been studied in children with relapsing or refractory GCT. In conclusion, as the insufficient local tumor control at the primary site of tumor represents the main problem in most patients, further significant advances in relapsing GCT may probably be based on a further improvement of local therapy.
 * pp.268-269


 * In the pre-cisplatinum era the prognosis was determined by the parameters histology, primary site and tumor stage. The malignant non-germinomatous intracranial GCT showed the most unfavorable prognosis with an EFS of 5% followed by the malignant sacrococcygeal GCT (5%-10%, own experience in non-protocol patients retrospectively reported during the MAKEI 83 period). The introduction of cisplatinum to GCT treatment led to a significant improvement of the prognosis with now more than 80% of all patients being cured.
 * p.269


 * It has to be considered that a further differentiation between each site and histological subentity is mandatory, as a specific histology may bear a different prognosis dependent of the site. For example the non-germinomatous intracranial GCT remain to be high at risk, although by current protocols long-term remissions can be achieved in approx. Two-third of all patients, depending on the intensity (i.e., cumulative cisplatinum dose) of chemotherapy. On the other hand intracranial germinoma have an excellent prognosis with an EFS of approximately 95%. Among the extracranial tumors the testicular GCT have the most favorable prognosis (EFS 97%) even despite malignant (e.g., YST) histology and irrespective of the initial tumor stage.
 * p.269


 * In conclusion, in the cisplatinum era the previous prognostic parameters like histology, primary site and tumor stage have partly lost their former impressive prognostic relevance, while the completeness of the tumor resection seems to establish as a new, highly relevant prognostic factor. In advanced and infiltrating tumors the rate of complete resections can be significantly increased by a preoperative chemotherapy. Moreover, preoperative chemotherapy helps to avoid extended surgery with the risk of severe mutilation. Therefore, this strategy appears to be most appropriate in advanced and infiltrating tumors.
 * p.269


 * Central documentation and evaluation of children with GCT has allowed to introduce risk adapted therapy protocols stratified according to a standardized diagnostic work-up including tumor markers, tumor stage and histology. As the complete tumor resection has been established as a valuable prognostic parameter, site specific surgical standards must be defined. Furthermore, it has to be determined in how far biological parameters (e.g., specific genetic aberrations) may help to further define distinct risk groups.
 * pp.269-270

“Extragonadal Teratomas. Atlas of Tumor Pathology, Second Series, Fascicle 18” (1982)
Gonzalez-Crussi F (1982) [https://link.springer.com/chapter/10.1007/0-387-21581-6_2 “Extragonadal Teratomas. Atlas of Tumor Pathology, Second Series, Fascicle 18”]. Armed Forces Institute of Pathology, Washington D.C.
 * Germ cell tumors are a varied group of benign and malignant neoplasms derived from primordial germ cells (Figure 2.1). They occur in several different sites, both gonadal and extragonadal, the latter in midline locations such as the sacrococcygeal, retroperitoneal, mediastinal, cervical, and pineal regions. Most germ cell tumors of the fetus and infant are histologically benign and are diagnosed as either mature or immature teratomas (Table 2.1). Yolk sac tumor (endodermal sinus tumor) occurs alone or in association with infant teratomas. Yolk sac tumors of the sacrococcygeal area and testis are far more prevalent than those arising from the cervix or vagina. Neither germinoma nor choriocarcinoma has been described in association with infant teratomas. Primary or metastatic choriocarcinoma may present in the newborn or infant with widespread metastases, elevated chorionic gonadotropin levels, and severe bleeding tendencies (Table 2.1). The classification of germ cell tumors by The World Health Organization (WHO) is the foundation for most contemporary classifications (Table 2.2). According to this classification, germ cell neoplasms are divided into seven histological types: dysgerminoma (or seminoma), yolk sac tumor, embryonal carcinoma, polyembryoma, choriocarcinoma, teratoma, and mixed germ cell tumors. Sometimes the allinclusive term “germinoma” is applied to seminoma, dysgerminoma, and pineal germinoma, since all three are similar in microscopic appearance. Gonadoblastoma, a neoplasm typically found in dysgenetic gonads, is listed as a separate category of ovarian tumors, although germ cells are present in addition to Sertoli cells.
 * p.5


 * Teratoma is defined as a true tumor composed of multiple tissues foreign to, and capable of growth in excess of, those characteristic of the part from which it is derived. However it is sometimes difficult to make a distinction between teratomas and structures that result from abortive attempts at twinning. An even progression can be traced from normal twins to conjoined twins, parasitic twins, and fetus-in-fetu. Careful studies reveal a break in the progression from an oriented, longitudinal, partially symmetrical structure of a twin to the jumbled, disordered, irregular growth of a teratoma in which one, two, or three tissues predominate. Despite the apparent progression from twins to fetus-in-fetu to teratomas, some investigators deny a relationship. The distinction is based primarily on the fact that teratomas are capable of independent growth, whereas structures included under malformations are limited in their potentiality for growth to a rate similar to the part of the body they resemble. Teratomas are observed in several locations at birth, but the most common sites are the sacrococcygeal area and neck (Figures 2.2–2.4). Other locations are the brain, pineal gland, retroperitoneum, anterior mediastinum, stomach, heart and pleura, pharynx, base of the skull, upper jaw, gonads, pelvis, liver, and subcutaneous tissue (Figures 2.5–2.11). The types of tissues found in fetal and infant teratomas are practically the same regardless of the site of origin.
 * p.5


 * Teratoma Mass at site of origin (e.g., sacrococcygeal, Tissues derived from all three germ layers cervical areas) Immature teratoma: immature neuroglial and neuroepithelial tissues Fetus-in-fetu Fetiform mass found most often in Mature tissues and vertebral axis present retroperitoneal area Yolk sac tumor Gonadal or sacrococcygeal mass; associated Six histological patterns; reticular and papillary most common with sacrococcgeal or other teratomas ones in infants; perivascular Schiller-Duval bodies; PAS hyaline droplets; FP cytoplasms Embryonal carcinoma Mass alone or associated with a teratoma Embryonal epithelial cells with large vesicular nuclei and big nucleoli; solid, papillary, and glandular patterns; tumor cells for placental alkaline phosphatase and cytokeratin; FP; syncytiotrophoblastic hCG giant cells Polyembryoma Gonadal or sacrococcgeal mass; found in Tiny embryoid bodies with two vesicles resembling amniotic combination with yolk sac tumor and yolk sac cavities separated by a two- to three-cell-layer embryonic disk; FP and hCG Choriocarcinoma Abdominal mass, widespread metastases Soft, hemorrhagic, necrotic mass; cytotrophoblasts and giant on imaging studies; severe bleeding syncytiotrophoblasts with cells intermediate between the two; tendencies; increased serum and urinary hCG,b cytokeratin, and placental lactogen hCG Gonadoblastoma Gonadal dysgenesis, 46,XY or 45,X0/46,XY Malformed gonad(s) (e.g., streak ovary, with small, tan karyotype calcified nodules; large germ cells encircled by smaller, round, darkly staining Sertoli cells forming microfollicles with hyaline bodies and foci of calcification.
 * p.6

"Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection" (September 2010)
Gutierrez-Aranda I, Ramos-Mejia V, Bueno C, Munoz-Lopez M, Real PJ, Mácia A, et al. (September 2010)."Human induced pluripotent stem cells develop teratoma more efficiently and faster than human embryonic stem cells regardless the site of injection". Stem Cells. 28 (9): 1568–1570.
 * Human embryonic stem cell (hESC) and reprogrammed/induced pluripotent stem cell (iPSC) research is becoming the flavor of the month for downstream applications such as drug screening, disease modeling, and future regenerative medicine and cell therapies. Pluripotency (the ability to give rise to any cell type of the three germ layers: mesoderm, ectoderm, and endoderm) is the defining feature of hESCs and iPSCs. In vivo teratoma formation in immune-compromised mice is the ‘‘gold-standard’’ assay to define bona fide pluripotent stem cells capable of generating tumoral disorganized structures containing tissues representing the three germ layers. Despite the importance of teratoma assay as an extended screen for the pluripotency of hESCs and iPSCs and as in vivo assay to explore molecular and cellular mechanisms underlying the biology of human teratomas and their transition to teratocarcinomas, there are no standard procedures for performing this assay. Different studies on hESCs have correlated the site of implantation with the efficiency of teratoma formation and histology tissue composition. However, limited data are available regarding the teratoma development latency. More importantly, no study so far has compared side-by-side the efficiency, latency, and histological tumor composition of hESCs- and iPSCs-derived teratomas. In addition, a new generation of immunodeficient mice has been developed: the NOD/SCID IL2Rc / mouse. This strain carries a IL2Rc-chain deficiency that blocks signaling through multiple cytokine receptors leading to many innate immune defects. The non obese diabetic/severe combined immune-deficient (NOD/SCID) IL2Rc / strain facilitates engraftment and tumor formation and does not develop thymic lymphoma, ensuring a longer lifespan of inoculated mice.
 * p.1568


 * In hESCs, the rate of teratoma formation was 81% subcutaneously versus 94% intratesticularly (n ¼ 30 mice; Fig. 1B). However, the intratesticular injection, despite showing higher efficiency of teratoma formation, displayed a slightly longer latency (66 vs. 59 days; p-value > 0.05). There were no site-specific differences in the teratoma composition at the histological level (Fig. 1C). Interestingly, when iPSCs were transplanted the rate of teratoma formation was 100% (n ¼ 16 mice), regardless the type of injection. More importantly, iPSCs seem more aggressive in vivo as the latency was shortened 52% (from 59 days to 31 days) upon subcutaneous injection and 26% (from 66 days to 49 days) upon intratesticular injection. As with hESCs, no differences in teratoma composition were observed either.
 * p.1568


 * To the best of our knowledge, this is the first study comparing side-by-side the efficiency, latency, and teratoma composition between hESCs and iPSCs. We found clear differences in the efficiency and latency but not in the teratoma histological composition. Further experiments are still demanded to gain insights into the higher aggressiveness in vivo of iPSCs as compared with hESCs. Ploidy, analyzed by conventional G-banding karyotype, could not explained these differences because all but two pluripotent stem cell lines were euploid: the aneuploid lines were one hESC (AND1) and one iPSC (iAND4). It is worth emphasizing, however, that karyotype analysis is not a high-resolution technique detecting fine genomic aberrations, with a euploid karyotype not being therefore indicative of an overall cellular genomic stability. Whether or not specific tiny genomic insults (detectable by high-resolution methods such as comparative genomic hybridazation (CGH)-arrays and single-nucleotide polymorphism analysis) or epigenetic differences may explain the higher aggressiveness in vivo of iPSCs still needs to be elucidated. We envision that these data may be useful not only for stem cells scientists addressing pluripotency issues and studying mechanisms underlying specific germ-layer/tissue differentiation but also for cancer researchers developing in vivo models for germ cell tumors.
 * pp.1568-1569

=== "Multiregion exome sequencing of ovarian immature teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components" (June 2020) === Heskett MB, Sanborn JZ, Boniface C, Goode B, Chapman J, Garg K, et al. (June 2020). "Multiregion exome sequencing of ovarian immature teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components". Modern Pathology. 33 (6): 1193–1206.
 * Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multi-region whole exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from 10 females with ovarian immature teratomas, with bilateral tumors present in 5 cases and peritoneal dissemination in 7 cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the 4 analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from nondisjunction errors during meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian immature teratomas from germ cells.
 * pp.1-2


 * Germ cell tumors (GCTs) are a diverse group of neoplasms that display remarkable heterogeneity in their anatomical site, histopathology, prognosis, and molecular characteristics. GCTs can occur in the ovaries, testes, and extragonadal sites, with the most common extragonadal locations being the anterior mediastinum, retroperitoneum, and intracranially in the pineal region. GCTs are classified by the World Health Organization into seven histological subtypes: mature teratoma, immature teratoma, seminoma/ dysgerminoma/germinoma (depending on site of origin in the testis, ovary, or extragonadal), yolk sac tumor, embryonal carcinoma, choriocarcinoma, and mixed germ cell tumor. GCTs are the most common non-epithelial tumors of the ovary, but only account for approximately 3% of all ovarian cancers. Greater than 90% of ovarian GCTs are composed entirely of mature teratoma (commonly termed “dermoid cyst”), which is the only benign subtype of ovarian GCT. Among the malignant subtypes, dysgerminoma is the most common and immature teratoma is the second most common. Ovarian teratomas contain tissue elements from at least 2 of the 3 germ cell layers and frequently display a disorganized mixture of mature tissues including skin and hair (ectoderm), neural tissue (ectoderm), fat (mesoderm), muscle (mesoderm), cartilage (mesoderm), bone (mesoderm), respiratory epithelium (endoderm), and gastrointestinal epithelium (endoderm). Teratomas can occur in the mature form, composed exclusively of mature tissues, or the immature form, which contains variable amounts of immature elements (usually primitive neuroectodermal tissue consisting of primitive neural tubules) in a background of mature teratoma. Not infrequently, malignant GCTs of the ovary contain a mixture of different histologic subtypes (e.g. both dysgerminoma and yolk sac tumor), for which the designation mixed germ cell tumor is used, often with the approximate fraction of each histologic subtype specified by the diagnostic pathologist. Extensive tissue sampling and microscopic review of ovarian GCTs are required to appropriately evaluate for the presence of admixed malignant subtypes, which is critical for appropriately guiding prognosis and patient management.
 * p.2


 * The majority of malignant ovarian GCTs (57%) are confined to the ovary at time of diagnosis (stage I) which confers a 99% 5-year survival. Even when distant metastases are present at time of diagnosis (stage IV), 5-year survival of ovarian GCT is relatively high at 69%. This long-term survival in females even with disseminated or metastatic ovarian GCTs reflects the sensitivity of these tumors to the standard cytotoxic chemotherapy regimen of bleomycin, etoposide, and cisplatin. Somatic mutation and DNA copy number analysis of testicular GCTs has now been performed by The Cancer Genome Atlas Research Network and several other groups. These analyses have revealed a very low mutation rate (approximately 0.3 somatic mutations per Mb) and only three genes harboring recurrent somatic mutations at significant frequency (KIT, KRAS, and NRAS), in which mutations are exclusively present in seminomas but not non-seminomatous GCTs. Copy number analysis has revealed that testicular GCTs are often hyperdiploid, with the majority (>80%) harboring isochromosome 12p or polysomy 12p that is present in both seminomas and non-seminomatous GCTs.
 * pp.2-3


 * Beyond dysgerminomas, few studies have performed genome-level analysis of ovarian GCTs, and the genetic basis of ovarian teratomas (both mature and immature forms) remains unknown. Polysomy 12 and KIT mutations have been found in ovarian mixed germ cell tumors containing a dysgerminoma component, but have not been identified in pure teratomas. Early studies of ovarian mature teratomas reported that tumor karyotypes were nearly always normal (i.e. 46,XX), but chromosomal zygosity markers were often homozygous in the tumor. This loss of heterozygosity may be explained by the hypothesis that teratomas and other germ cell tumors arise from primordial germ cells due to one of five different plausible meiotic abnormalities, each producing distinct chromosomal patterns of homozygosity. Parthenogenesis (from the Greek parthenos: ‘virgin’, and genesis: ‘creation’) is used to describe the development of germ cell tumors from unfertilized germ cells via these different mechanisms of origin, which potentially include nondisjunction errors during meiosis I, nondisjunction errors during meiosis II, whole genome duplication of a mature ovum, and fusion of two ova. However, no studies to date have used genome-level sequencing analysis to identify the specific parthenogenetic mechanism giving rise to individual ovarian GCTs.
 * p.3


 * Our analyses define ovarian immature teratoma as a genetically distinct entity amongst the broad spectrum of human cancer types studied to date, which is characterized by a 2N near-diploid genome, paucity of somatic mutations, and extensive allelic imbalances. Our results further shed light on the parthenogenetic origin of ovarian teratomas and reveal that diverse meiotic errors are likely to drive development of this germ cell tumor.
 * p.3


 * Identical patterns of genomic loss of heterozygosity among mature, immature, and disseminated components in an ovarian teratoma confirm a single clonal origin We next compared the regions of the genome affected by copy-neutral loss of heterozygosity among the different tumor regions sequenced for each individual patient. In the 5 females with unilateral ovarian disease (patients c, d, e, i, and k), we observed the identical pattern of allelic imbalance across the genome in each of the different tumor components, including immature teratoma, mature teratoma with different histologic patterns of differentiation, and disseminated teratomatous elements in the peritoneum. These results confirm a single clonal origin for all teratomatous components, both in the primary ovarian tumor and disseminated in the peritoneum, for women with unilateral ovarian immature teratomas.
 * pp.7-8


 * Bilateral ovarian teratomas originate independently Four patients in this cohort (b, g, h, and j) had bilateral ovarian teratomas that were both independently sequenced and analyzed for patterns of copy-neutral loss of heterozygosity across the genome. We found that tumors from the left and right ovaries had different patterns of allelic imbalance across the genome in each of the different tumor components studied, providing evidence that bilateral ovarian teratomas originate independently. Furthermore, all of the peritoneal disseminated components harbored a pattern of allelic imbalance that was identical to one of the two ovarian tumors, enabling deduction of the specific ovarian tumor from which the disseminated disease was clonally related.
 * p.8


 * Patterns of genomic loss of heterozygosity in ovarian immature teratomas can be used to deduce meiotic error mechanism of origin Five distinct parthenogenetic mechanisms of origin have been proposed to describe the development of germ cell tumors from unfertilized germ cells, which include nondisjunction errors during meiosis I, nondisjunction errors during meiosis II, whole genome duplication of a mature ovum, and fusion of two ova. Distinct chromosomal zygosity patterns are predicted to result from each of these different mechanisms, which are illustrated in Figure 4. We used the chromosomal zygosity patterns from the whole exome sequencing data to deduce the meiotic mechanism of origin for the 15 distinct tumor clones identified in the 10 female patients. Five of the tumor clones were deduced to result from nondisjunction errors during meiosis I, 6 from nondisjunction errors during meiosis II, 3 from whole genome duplication of a mature ovum, and 1 from fusion of two ova (Table 2). These findings indicate that meiotic abnormalities at multiple stages during germ cell development can contribute to the development of ovarian teratomas.
 * p.8


 * We present the first multi-region exome sequencing analysis of ovarian immature teratomas including mature, immature, and disseminated components. We report a strikingly low abundance of somatic mutations and infrequent copy number aberrations, without pathogenic mutations identified in any well-described oncogenes or tumor suppressor genes, as well as an absence of any novel genes harboring recurrent mutations across the cohort. We generated high-resolution zygosity maps of ovarian teratomas that deepen understanding of the parthenogenetic mechanisms of origin of ovarian teratomas from primordial germ cells originally proposed nearly 50 years ago. Ovarian teratoma is genetically unique among all human tumor types studied to date given its extremely low mutation rate and extensive genomic loss of heterozygosity. Our findings suggest that meiotic nondisjunction events producing a 2N near-diploid genome with extensive allelic imbalances are responsible for the development of ovarian immature teratomas. Analysis of the multi-region exome sequencing data was used to study the clonal relationship of immature and mature teratoma elements, as well as admixed foci of yolk sac tumor, and also disseminated teratoma in the peritoneum. We find that all these different tumor components are indistinguishable based on chromosomal copy number alterations and loss of heterozygosity patterns, indicating a shared clonal origin. This finding suggests that epigenetic differences are likely responsible for the striking variation in differentiation patterns in teratomas, and also for the development of immature elements in ovarian teratomas. Ovarian immature teratomas may therefore be one of the only human tumor types where epigenetic dysregulation occurring in the absence of additional somatic alterations is responsible for the transformation from a benign to malignant neoplasm.
 * pp.8-9


 * Two theories currently exist to explain the origin of gliomatosis peritonei arising in the setting of gonadal teratomas: the first being that it is derived from peritoneal dissemination of teratoma with differentiation into mature glial cells, and the other being spontaneous metaplasia of peritoneal stem cells to glial tissue. A prior study of five samples had concluded that gliomatosis peritonei was genetically unrelated to the primary ovarian teratoma based on zygosity analysis of a small number of microsatellite markers. However, our study based on genotyping data from thousands of informative polymorphic loci unequivocally demonstrated that gliomatosis peritonei was clonally related to the ovarian primary immature teratoma in all cases in this cohort, thereby supporting the first theory of origin.
 * p.9


 * We found that tumors from the left and right ovaries had different patterns of loss of heterozygosity across the genome in each of the different tumor components that were sequenced, providing evidence that bilateral ovarian teratomas originate independently. Additionally, all of the disseminated components in the peritoneum harbored a pattern of allelic imbalance that was identical to one of the two ovarian tumors, enabling assignment of origin to the specific ovarian primary tumor. Why a significant proportion of women with ovarian teratomas also develop genetically independent teratomas in the contralateral ovary (either synchronously or metachronously) remains undefined. Analysis of the constitutional DNA sequence data from the 10 patients in our cohort, 5 of whom had bilateral ovarian teratomas, did not identify pathogenic variants in the germline known to be associated with increased cancer risk. However, the possibility of an unidentified germline risk allele(s) responsible for teratoma development remains a possibility. Given the extensive loss of heterozygosity across the genomes of ovarian teratomas, pinpointing any single responsible gene amongst the numerous common regions of allelic imbalance is a significant obstacle.
 * pp.9-10


 * In summary, our multi-region whole exome sequencing analysis of ovarian immature teratomas has revealed that multiple different meiotic errors can give rise to these genetically distinct tumors that are characterized by extensive allelic imbalances and a paucity of somatic mutations and copy number alterations.
 * p.10

“The 5-minute Obstetrics and Gynecology Consult” (2008)
Hillard PJ, Hillard PA (2008). “The 5-minute Obstetrics and Gynecology Consult”. “Ovarian Tumors, Germ Cell”, Vernon T. Cannon, Jean A. Hurteau; Lippincott Williams & Wilkins. p. 140.
 * Basics *Description Malignant germ-cell tumors are derived from the primordial germ cells of the ovary: - <5-7% of ovarian cancers - Mainly occur in young women and adolescent girls - The most common germ-cell tumor is the benign mature cystic teratoma (“dermoid” tumor)
 * Age-Related Factors Median age 16-20 with a range of 6-46 years
 * Staging *FIGO (International Federation of Gynecology and Obstetrics) staging used for malignant ovarian germ-cell tumors. *Stage 1: Tumor limited to the ovary: -IA: Tumor limited to 1 ovary, no ascites, intact capsule -IB: Tumor limited to both ovaries, no ascites, intact capsule -IC Tumor either stage IA or IB, but with ascites preset containing malignant cells or with ovarian capsule involvement or rupture or with positive peritoneal washings Stage II: Tumor involving 1 or both ovaries with extension to the pelvis: IIA: Extension to the uterus or tubes IIB: Involvement of both ovaries with extension to other pelvis tissues. IIC: Tumor either stage IIA or IIB, but with ascites present containing malignant cells or with ovarian capsule involvement or rupture or with positive peritoneal washings *Stage III: Tumor involving 1 or both ovaries with tumor implants outside the pelvis or with positive retroperitoneal or inguinal nodes. Superficial liver metastases qualify as stage III: -IIIA:Tumor limited to the pelvis with negative nodes but with microscopic seeding of the abdominal peritoneal surface IIIB: Negative nodes, tumor implants in the abdominal cavity <= 2cm IIIC: Positive nodes or tumor implants in the abdominal cavity > 2cm *Stage IV: Distant metastases present
 * p.140


 * Epidemiology Germ-cell tumors account for up to 60% of ovarian tumors occuring <20 years of age. 1/3 of these are malignant.
 * p.140


 * Pregnancy Considerations *Account for 25% of all malignant tumors in pregnnact: Stage IA, dysgerminomas can be removed and the pregnancy continued. *In patients with advanced dysgerminomas, continuation of the pregnancy depends on gestational age. *Chemotherapy can be used to treat dysgerminomas in the 2nd and 3rd trimesters.
 * p.140


 * Risk factors Young female
 * p.140


 * Genetics Karyotopic abnormalities are common, and an association between dysgerminoma and dysgenic gonads is well recognized.
 * p.140


 * Pathophysiology WHO classification of ovarian germ-cell tumors. *Dysgerminoma: - Variant: With dyncytiotrophoblast cells *Yolk sac tumor (endodermal sinus tumor): -Variant: Polyvesicular viteline tumor: Hepatopoid Glandular: Variant, endometroid *Embryonal carcinoma *Polyembryoma *Choriocarcinoma *Teratomas: Immature Mature: Solid Cystic (dermoid cyst) with and without secondary tumor formation Fetiform (homonculous) - Monodermal and highly specialized: Struma ovarii: With or without thyroid tumor Carcinoid (insular, trabecular) Strumal carcinoid Mucinous carcinoid Neuroectodermal tumors Sebaceous tumors Others *Mixed (specify types)
 * p.140


 * Dermoid Cyst (Mature Cystic Teratomas) Occur bilaterally in 12% of cases * Most contain sebaceous material and hair but can contain elements of all 3 germ-cell layers (endoderm, mesoderm, and ectoderm). *In older patients (>40) malignant transformation of dermoids should be ruled out. Squamous carcinoma is found in 1% of dermoid cysts.
 * p.140


 * Dysgerminoma *Comprise ~ 50% of ovarian germ-cell tumors *Bilateral in 10% of cases Dysgerminomas may be present in 10% of normal-appear in contralateral ovaries. *Predilection for lymphatic spread Elevated serum LDH 5% contain multinucleated syncyiotrophoblastic giant cells that can produce hCG. C-kit expression may be targeted for treatment with inhibitors of c-kit, such a Gleevec.
 * p.140


 * Yolk-Sac Tumors (Endodermal Sinus Tumors) *Bilateral in <5% of cases Account for ~25% of ovarian germ-cell tumors *More friable on examination than dysgerminomas *Distinct reticular pattern with Schiller-Duval bodies on microscopic examination *Commonly contains periodic acid-Schiff (PAS)-positive hyaline bodies Cells stain positive for AFP and secrete AFP in serum.
 * p.140


 * Immature Teratomas *~20% of ovarian germ-cell tumors *Bilateral in <5% of cases but contralateral ovary may contain a dermoid cyst in 10% of cases *Contains all 3 primordial germ cell layers. *Graded from 1-3 based on content of primitive neuroectodermal tissue *May be associated with mature glial peritoneal implants (gliomatosis peritonei) *May experience growing teratoma syndrome during chemotherapy due to glial implants
 * p.140


 * Embryonal Carcinomas and Choriocarcinomas *May produce hCG May have irregular uterine bleeding
 * p.140


 * Associated Conditions *Hyperthyroidism *Carcinoid syndrome *Ovarian torsion *Isosexual precovity related to hCG production *Primary amenorrhea, virilization, developmental abnormalities of the genitalia +- pelvic mass
 * p.140


 * Diagnosis Signs and symptoms History *Menstrual history *Symptoms of pelvic mass
 * p.140


 * Review of Systems Abdominal pain/acute abdomen usually caused by: -Rupture -Hemorrhage -Torsion * Abdominal distention *Fever *Vaginal bleeding *Symptoms of hyperthyoidism (Struma ovarii) * Symptoms of carcinoid syndrome
 * p.140


 * Physical exam *Abdominal/Pelvis mass *Acute abdomen *Isosexual precovity due to hCG secretion * Primary amenorrhea, virilization, developmental abnormalities of the genitalia +- pelvic mass
 * p.140

"Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine" (2009)
Knoepfler, Paul S. (2009). "Deconstructing Stem Cell Tumorigenicity: A Roadmap to Safe Regenerative Medicine". Stem Cells. 27 (5): 1050–6.
 * Many of the earliest stem cell studies were conducted on cells isolated from tumors rather than from embryos. Of particular interest was research on embryonic carcinoma cells (EC), a type of stem cell derived from teratocarcinoma. The EC research laid the foundation for the later discovery of and subsequent work on embryonic stem cells (ESC). Both ESC isolated from the mouse (mESC) and then later from humans (hESC) shared not only pluripotency with their EC cousins, but also robust tumorigenicity as each readily form teratoma. Surprisingly, decades after the discovery of mESC, the question of what drives ESC to form tumors remains largely an open one. This gap in the field is particularly serious as stem cell tumorigenicity represents the key obstacle to the safe use of stem cell-based regenerative medicine therapies. Although some adult stem cell therapies appear to be safe, they have only a very narrow range of uses in human disease. Our understanding of the tumorigenicity of human induced pluripotent stem cells (IPSC), perhaps the most promising modality for future patient-specific regenerative medicine therapies, is rudimentary. However, IPSC are predicted to possess tumorigenic potential equal to or greater than that of ESC. Here, the links between pluripotency and tumorigenicity are explored. New methods for more accurately testing the tumorigenic potential of IPSC and of other stem cells applicable to regenerative medicine are proposed. Finally, the most promising emerging approaches for overcoming the challenges of stem cell tumorigenicity are highlighted.
 * p.1050


 * The link between stem and tumor cells in science is a very old one. The earliest research on highly pluripotent stem cells was conducted not on normal stem cells, but instead on embryonic carcinoma cells (EC) derived from teratocarcinoma. EC had unusual stem-like properties that attracted a great deal of attention at the time, including a surprising degree of plasticity. Teratocarcinoma and its benign cousin teratoma are the best examples of tumors with substantial populations of pluripotent stem cells as well as differentiated tissues. It may not be widely appreciated that when embryonic stem cells (ESC) were first isolated from the mouse by two independent groups more than a decade after the discovery of EC, the existing knowledge base and reagents related to EC played pivotal roles. In fact, in one case ESC were established and cultured in EC conditioned media. It was also noted that ESC expressed the same markers as EC. Thus, EC were the touchstone to which ESC were initially compared and the fact that ESC shared so many properties with established EC lines was argued as validation that ESC were pluripotent stem cells. ESC and EC could be differentiated into a myriad of cell types and formed teratoma with many diverse tissues, suggesting the exciting conclusion that both these cell types had robust pluripotency. However, these studies also raised an important, still largely unanswered question. Why would ESC, supposedly normal counterparts to EC, also have the ability to cause tumors? The simplest but most troublesome answer is that ESC and EC are in fact, as was originally assumed, quite similar types of cells. Removing the inner cell mass (ICM) from the context of the early embryo and enforcing the culture of ICM cells in vitro produces a new cell type that does not normally exist in nature, that is, ESC. Although ESC mirror many of the normal, desired properties of the ICM cells such as near totipotency, they are not simply an in vitro manifestation of ICM cells but also almost certainly contain distinct properties, some of a more tumorigenic nature. The fact that the ESC field began with and in some ways depended on the much earlier discovery of EC highlights the intimate link between stem and tumor cells as well as between pluripotency and tumorigenicity. The shift to a potentially more tumorigenic state as ICM cells transition to ESC in vitro may be driven by the method of creating ESC via selecting for those unique ICM cells that can be forced to grow in vitro. This selective process is predicted to go hand-in-hand with epigenetic changes that enable such growth. Thus, driving ICM cells to become ESC may be at the same time creating a cell type that is inescapably also pushed toward a tumorigenic phenotype. Just how different ESC are from ICM cells remains an intriguing question. It is important to note that even transplants of whole early embryos can drive teratoma formation as well so some of the forces driving teratoma formation are intrinsic to ICM cells and not because of their in vitro growth to produce ESC.
 * pp.1050-1051


 * It is remarkable that, to date, one of the most common assays for demonstrating and studying the pluripotency of stem cells, including induced pluripotent stem cells (IPSC), is the teratoma assay. Often this is referred to as a pluripotency assay, but of course it is also a tumor assay. The fact that a key assay of stemness is also a tumor assay further illustrates the strong link between stem and tumor cells, a reality too rarely discussed in the field when interpreting results from teratoma assays. Even ignoring for the moment the ability of ESC and IPSC to produce malignant tumors in some cases, the production of benign teratoma as a side effect in humans given a hypothetical regenerative medicine therapy in the future, would be unacceptable. Such tumors could be numerous and would prove highly destructive to surrounding normal or regenerating tissue. Thus, a key concept is that stem cells, even those with potent self-renewal and pluripotency, will almost certainly never be directly used in regenerative medicine if they cannot be proven to lack the ability to cause teratoma in mice.
 * p.1051


 * Part of the challenge of resolving issues related to stem cell safety is that only few in vivo studies have been reported, particularly on human cells such as human ESC (hESC). Some studies with introduction of hESC into animal models have given apparently encouraging results. An example of such a study was one where rats were given a hESC transplant. They not only showed improvement of their Parkinson’s disease symptoms, but at least for the 3 months of the study also did not develop detectable teratoma. On the other hand, another study using an animal model system and stem cell transplant failed because of teratoma formation. In all such studies, particularly with a negative result where no teratoma were detected, it is unclear whether the apparent lack of tumorigenesis is related to the inherent properties of the transplanted stem cells or rather reflects the level of immunosuppression in the animal model being used (i.e., a false negative). Lack of teratoma in animal models with stem cell transplants may most often be reflective of a failure of engraftment due to immune cells in the host killing the stem cells. Fortunately, new, improved humanized mouse model systems are continually being developed that may be more useful for assessing the tumorigenicity of stem cells. Teratoma is not the only concern as hESC can also form malignant tumors. A recent study found robust malignant tumor-inducing capacity of hESC including H1 and HSF-6. IPSC can also form both teratoma as well as malignant tumors such as neuroblastoma and follicular carcinoma. Thus, the potential risk to human patients from both teratoma and malignant tumors is quite real, yet remains difficult to estimate as no human trials of hESC or IPSC have been conducted at this time.
 * pp.1051-1052


 * If one accepts the model that making a cell more stem-like predisposes that cell to cause a tumor, then IPSC are predicted to be inherently more tumorigenic than their nonstem cells of origin such as fibroblasts. However, even beyond this kind of modeling there are compelling reasons for worrying about IPSC tumorigenicity based on actual published data. Of greatest concern is that nearly all IPSC described in published works have been demonstrated to cause teratoma, proving pluripotency but also tumorigenicity, and that mice genetically derived to contain some tissues from IPSC have a malignant tumor incidence of 20%. Genetic changes intrinsic to the IPSC generation process may pose risk of enhancing tumorigenesis through both the introduced genes themselves and in theory via the potential changes at specific integration sites. The IPSC field is evolving rapidly and moving away from methods of induction that rely on genetic changes. This approach is in its early days with some very promising initial results, but predictions are that such a move generally should reduce tumorigenicity and improve safety. However, important questions remain. Will it ever be possible to make IPSC with absolutely no genetic changes? Can IPSC ever totally escape from dependence (whether via genetic or nongenetic approaches) on Myc, KLF4, and other possible oncogenes? Although it may appear that the IPSC field has already answered this affirmatively for Myc in that IPSC can be generated without added Myc, the omission of Myc reduces the efficiency of IPSC generation and yet these IPSC can still produce tumors in the form of teratoma. These studies also do not address the role of endogenous Myc. In IPSC generated without genetic addition of Myc, the cells of origin may well be characterized by unusually high levels of endogenous Myc proteins required for the reprogramming and could make the cells prone to tumorigenesis.
 * p.1052


 * Researchers appear to be disinclined to put human IPSC into mouse embryos, perhaps due to the ban on putting hESC into a mouse embryo and taking it beyond day 8 of growth. Thus, other than their robust teratoma inducing abilities, the reality is that the stem cell field knows almost nothing about the tumorigenicity of mouse IPSC and essentially nothing about that of human IPSC in a context relevant to regenerative medicine.
 * pp.1052-1053


 * The notion that a wide variety of tumors beyond those such as teratocarcinoma and teratoma may contain stem cells is gaining widespread acceptance. These tumor or cancer stem cells, also termed tumor-initiating cells, seem to share many traits with normal stem cells, but are predicted to have at least partially impaired pluripotency. In that sense, tumor stem cells may be akin to racecars with accelerators (indefinite self-renewal potential) but bad brakes (differentiation potential/pluripotency).
 * pp.1053-1054


 * [A] study of use of hESC for Parkinsonian rats found that differentiation of the cells prior to transplant lowered the incidence of teratoma. However, high levels of natural killer (NK) cells in many rat and mouse animal models appear to kill most or all injected stem cells, questioning the validity of such safety studies when results are negative. Further complicating the story is the observation that ESC are in fact more susceptible to killing by NK cells than are differentiated ESC due to differences in cell surface proteins.
 * p.1054


 * In theory, the simplest approach to regenerative medicine and the one expected to lead to robust regenerative tissue growth would seem to be to use stem cells themselves, but ones that had been treated in such a way that they were no longer tumorigenic. Of course, at this time no such methodology exists and the notion of using stem cells directly for transplants would appear to be strongly out of favor with regulators due to the robust ability of hESC to form teratoma.
 * p.1055

"What is a teratoma? Research & treatment" (2021-01-14)
Knoepfler P (2021-01-14). "What is a teratoma? Research & treatment". The Niche.
 * Not all tumors are created equal and some like teratomas are particularly unusual.
 * Teratomas are germ cell tumors. What this means is that the cells that gave rise to the tumor in the first place were a powerful stem cell called a “germ cell”.  Normally, germ cells make reproductive cells including sperm and eggs. You could think of them as reproductive stem cells. However, sometimes things can go wrong with germ cells such that they don’t do their normal job or end up in the wrong place or both. Note that teratoma is one of those funny words that can be plural even without adding an “S” at the end so if you wanted to write about 2 such tumors, you could write either “two teratoma” or “two teratomas.” There are also different types of these tumors including cystic teratoma in which there are fluid filled sacs inside.
 * During the development of teratoma tumors it is thought that germ cells acquire mutations or other changes. As a result, instead of making sperm or eggs, the altered germ cells randomly produce a variety of tissues. Sometimes teratoma tumors have a whole array of mature tissue types in them. For instance, when a surgeon or researcher cuts into a teratoma, they may find glands, eye tissue, bone, cartilage and more. A different teratoma from another patient may contain a distinct mix of tissues like digestive glands, skin, sweat glands, and hair. This means that every teratoma is going to be very different and the more precise answer to the question ‘what is a teratoma?’ will depend on the patient and the nature of each tumor. These different mixtures of tissues and cell types found inside teratomas reflect the power of germ cells to make any cell in the body, which is called pluripotency. Note that totipotent stem cells are slightly different in that they can make any cell in the body plus umbilical cord and placenta too.
 * Because teratoma are germ cell tumors, they often arise in the locations where you’d find normal germ cells: the testes and ovaries. More rarely they can occur elsewhere in the body and it’s thought that these teratoma occur in part because of germ cells being in the wrong place, perhaps due to a glitch much earlier during embryonic development.
 * Tumors and cancers often have names ending in “oma”. This suffix oma means tumor or cancer. The “terat” part of the teratoma name comes from the Greek word “teras” meaning monster. So “teratoma” literally means “monster tumor.” It is thought that the name was given because, frankly, teratoma look so disturbing and weird when cut open give the array of tissue types in them, sometimes including teeth.
 * Teratomas are the subject of many research studies trying to get at a better understanding of why these tumors arise exactly and to define treatments (more below). Importantly, teratoma are also produced in laboratory stem cell research in rodents. True pluripotent stem cells like IPS cells and hESCs have the power to develop teratoma when implanted subcutaneously in rodents. Hence we have a “teratoma assay” to measure pluripotency. Research on teratoma production by stem cells provides insights into the properties of the stem cells and also into how teratoma form. In my own lab we have produced teratoma for such studies and you can see examples of stained sections of these teratoma above. While freshly isolated and sliced teratoma look kind of monstrous, when you stain sections they can look quite beautiful as exemplified in the 2 images I’ve included in this post.
 * Fortunately, the vast majority of teratoma are benign tumors. What this means is that unlike aggressive cancers, teratoma often do not invade surrounding tissues and are less likely to cause death in patients. Teratoma tend to grow as a self-contained roughly spherical or ovoid mass. As a result, teratoma surgery is almost always successful in removing the entire tumor. Surgery is the main form of treatment for benign teratoma. In less common cases, teratoma-like tumors (sometimes in such cases called teratocarcinoma instead) are or become full-blown cancers, which are much more dangerous. In such cases, the tumor is usually removed as much as possible surgically, followed in some cases by chemotherapy or radiation. To my knowledge, there is no established way to prevent teratomas.
 * Because differentiated human pluripotent stem cells are being developed as the basis for numerous regenerative medicine therapies, there is concern that residual undifferentiated stem cells could lead to teratoma formation in injected patients, and researchers are working to develop methods to address this concern.

"Inhibition of pluripotent stem cell-derived teratoma formation by small molecules" (August 2013)
Lee MO, Moon SH, Jeong HC, Yi JY, Lee TH, Shim SH, et al. (August 2013). "Inhibition of pluripotent stem cell-derived teratoma formation by small molecules". Proceedings of the National Academy of Sciences of the United States of America. 110 (35): E3281–E3290.
 * The future of safe cell-based therapy rests on overcoming teratoma/ tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro- and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC- or hiPSC-derived cells. Taken together, these results provide the “proof of concept” that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.
 * p.3281


 * [T]here are major technical and scientific obstacles remaining to be overcome before hPSCbased cell therapy becomes a realistic therapeutic modality. Most of all, it is of utmost importance to avoid possible teratoma/ tumor formation that can arise from any remaining undifferentiated pluripotent stem cells present in the differentiated cell mixture. Indeed, a systematic transplantation study demonstrated that the teratoma-forming propensity of various mouse iPSC-derived neurospheres correlated with the persistence of residual undifferentiated cells. Because hESCs and hiPSCs also exhibit marked variations in differentiation efficiencies (and remaining undifferentiated cells), it is critical to remove all residual hiPSCs with teratoma potential before their clinical application. Despite numerous attempts at blocking teratoma formation, including introduction of suicide genes or selecting the desired cell type, immunodepletion, or introducing cytotoxic antibody, a clinically viable strategy to eliminate teratoma formation remains to be developed.
 * p.3281


 * We found that quercetin/YM155-induced selective cell death is sufficient to completely inhibit teratoma formation after transplantation of human pluripotent stem cell (hPSC)-derived cells. These data provide the first “proof of concept” that small molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.
 * p.3281


 * Remarkably, we found that a short exposure of a mixed population of hPSC-derived cells to inhibitors of survivin, such as quercetin (QC) or YM155, is sufficient to eliminate remaining undifferentiated hPSCs without affecting their differentiated counterparts, leading to complete inhibition of teratoma formation after transplantation. Moreover, differentiated cell types from hPSCs [i.e., dopaminergic neuronal cells and smooth-muscle cells (SMCs)] survived well and retained their function after exposure to QC or YM155. Furthermore, we found that, upon exposure to QC, p53 prominently accumulated in mitochondria, triggering the intrinsic apoptotic pathway in undifferentiated hPSCs. Our data illustrate the “proof of concept” that small-molecule targeting of hPSC-specific antiapoptotic factors is an efficient strategy to eliminate the risk of teratoma formation in pluripotent stem cell-based therapy.
 * pp.3281-3282


 * On the basis of the unique signature of pro- and antiapoptotic gene expression, we speculated that inhibiting key antiapoptotic factors would induce apoptotic cell death of residual undifferentiated hPSCs and thus prevent tumor/teratoma for mation after transplantation of hPSC-derived cells. In particular, we sought to test chemical inhibitors of Bcl10 and survivin that are relatively enriched in hESCs compared with differentiated cell types (Fig. 1). Indeed, we found that ABT737 and QC, inhibiting Bcl-2 family proteins and survivin, respectively, triggered robust apoptosis of hESCs and hiPSCs but not that of their differentiated counterparts (Fig. 2). However, because ABT737 is not Bcl10-specific and exerts modest levels of nonspecific cytotoxicity to certain differentiated cell types, we focused on the effects of the survivin inhibitor QC in this study.
 * p.3288


 * QC, a ubiquitous dietary flavonoid, is widely found in many fruits and vegetables, including apples and green tea. QC has been extensively investigated for its ability to inhibit the proliferation of various types of cancer cells and tumor growth, which is found to be related, at least in part, to its inhibition of survivin expression. Remarkably, QC triggered rapid and robust apoptosis only in hPSCs but not in their differentiated counterparts (Figs. 2–4). Furthermore, a single exposure of undifferentiated hESCs to QC completely prevented teratoma formation after in vivo transplantation, whereas differentiated cells derived from hPSCs survived and remained functionally intact (Fig. 4 and Figs. S2 and S4). In addition, QC treatment does not seem to influence differentiation of hESCs into three germ layer lineages (Fig. 4C and D and Fig. S3). Notably, a single exposure to QC followed by in vitro culture and differentiation was sufficient to completely prevent teratoma formation after transplantation of the resulting cells (Fig. 4E). In contrast, QC treatment had no effect on the survival and function of fully differentiated cells from hPSCs, such as dopamine neurons and SMCs (Figs. S2 and S4). The undifferentiated hESC-specific cell death in response to QC occurred through p53 mitochondrial accumulation, triggering mitochondrial apoptosis (Fig. 3). Interestingly, we also found that another survivin inhibitor, YM155, which shares similar molecular structure with QC, can efficiently induce apoptotic cell death of both hESCs and hiPSCs, further validating our notion that small molecules inhibiting key antiapoptotic factors (e.g., survivin) represent a viable strategy to prevent the potential risk of tumor/teratoma formation in hPSCbased cell therapy. Surprisingly, YM155 is more potent than QC (up to three orders of magnitude) and effectively induced hPSCs cell death in the nanomolar ranges (Fig. 5), although other flavonoids, such as GA (found to be effective in mouse embryonic stem cells (Fig. S1D) and KP, were not effective in hESCs, considering their close structural similarity with QC (Fig. 5A). Transplantation of YM155-treated cells resulted in complete prevention of teratoma formation (Fig. 5F). In contrast, it was noncytotoxic to differentiated cells at the concentration range tested in this study (Fig. 5D). For instance, dopamine neurons derived from hESCs exposed to YM155 for 24 h survived well and functionally intact, as examined by dopamine uptake function (Fig. S7 C and D). Taken together, we propose that small molecules such as QC and YM155 induce selective apoptosis of residual undifferentiated hPSCs via survivin inhibition and can prevent tumor/teratoma formation in hESC- or hiPSC-based cell therapy.
 * p.3288


 * In summary, we found that hPSCs have a unique and biased signature of pro- and antiapoptotic gene expression, which may be critical for their hypersensitivity to genotoxic stimuli. In particular, two antiapoptotic genes, BIRC5 and BCL10, are selectively enriched in hESCs, and their inhibition leads to selective cell death of undifferentiated hPSCs but does not affect lineagespecific differentiation or functionality of differentiated cells. Furthermore, on the basis of their specific expression in ESCs and teratomas, survivin antagonists were proposed as a strategy to avoid teratoma formation for clinical application of hESCs. Indeed, our data show that a single exposure of hESCs or hiPSCs with such inhibitors (e.g., QC and YM155) is sufficient to eliminate tumor formation. Because hPSC-derived mixed populations can be exposed in vitro to these chemicals for a short time, washed off, and can be further differentiated, the resulting cells may represent a safe transplantable cell source with no or minimal risk for tumor/teratoma formation.
 * pp.3288-3289

"Ovarian teratoma and endometritis in a mare" (November 2005)
Lefebvre R, Theoret C, Doré M, Girard C, Laverty S, Vaillancourt D (November 2005)."Ovarian teratoma and endometritis in a mare". The Canadian Veterinary Journal. 46 (11): 1029–1033.
 * Tumors, in particular those involving ovarian tissue, are uncommon in horses. The granulosa and theca cell tumor is the most commonly reported ovarian neoplasm in this species, while the teratoma is extremely rare. Teratomas are composed of totipotential germ cells that undergo somatic differentiation into 2 or more germinal cell layers and have a variety of mature tissues arranged haphazardly throughout the tumor. They arise most often within the ovary or testicle because of their germ cell origin. Whereas the granulosa theca cell tumor (GTCT) displays well-differentiated structures (endoderm, ectoderm, and mesoderm), teratomas, also called teratocarcinomas, contain less well-differentiated embryonic elements and, in addition, mature structures. The inner cell mass gives rise to early embryonic endoderm, ectoderm, and mesoderm, which usually differentiate into different tissues like adipose, osseous, dental, respiratory epithelial, neural, etc. Initially, Centre Hospitalier Universitaire Vétérianaire (CHUV) of the University of Montreal because of infertility and the presence of an anovulatory follicle, is described.
 * p.1029


 * In this category, the GTCT is the most commonly reported ovarian tumor. Granulosa and theca cells usually coexist in the same neoplasm and produce different hormones, varying the clinical characteristics of the condition. The high levels of inhibin, which inhibits release of follicule-stimulating hormone, then alter the normal ovarian cycle and provoke anestrus. Estrogens cause continuous or intermittent estrus, while androgens, such as T, will stimulate stallion-like behavior, including aggressiveness, mounting, and squealing. In more than 50% of GTCT, serum T concentrations will exceed 70 pg/mL, while stallion-like behavior is generally associated with a concentration of T greater than 100 pg/mL.
 * p.1030


 * Of the 5 cases of equine ovarian teratoma reported in the literature, 3 mares were Arabian and all were nulliparous. Catone et al described the clinicopathological features of an ovarian teratoma in an Andalusian mare. The mare described in this report was also of Arabian breed, but she had foaled prior to presentation. Because the number of cases is so small, it is difficult to draw any conclusion about breed predilection.
 * pp.1030-1031


 * The fact that the mare had regular estrous cycles before referral is not surprising, because a teratoma, like other nonfunctional ovarian tumors, does not produce hormones that negatively affect reproductive physiology.
 * p.1031


 * Teratomas are diagnosed incidentally during a routine examination of the reproductive system. Although normally developing follicles reach 4 to 5 cm in diameter during the breeding season, an enlarged ovary in the mare is described as having a diameter exceeding 10 to 12 cm. Ultrasonography is very useful to determine the stage of the estrous cycle, to assess the status and the number of preovulatory follicles, to characterize the developing CL, and, finally, to assist in the diagnosis of ovarian irregularities. Although the aforementioned types of ovarian tumors differ in their clinical and ultrasonographic characteristics, more than 1 type can coexist in the same animal.
 * p.1031


 * Because of the low number of cases, it is difficult to prognosticate on long-term outcome; however, taking into account the teratoma’s characteristics, fertility and survival rates should compare favorably with those following any other elective abdominal surgery. The grade II endometritis of the present mare carries a 50% to 80% expected foaling rate. The clinical interest of this case lies in the difficulty to differentiate an ovarian teratoma from other conditions affecting the ovaries and the relative infertility that could be associated with it. A complete reproductive history and a series of transrectal and ultrasonographic examinations over a certain period of time might be necessary to establish a presumptive clinical diagnosis. For final diagnosis, histopathological examination of the ovarian tissue is necessary.
 * p.1032

"First description of malignant retrobulbar and intracranial teratoma in a lesser kestrel (Falco naumanni)" (August 2008)
López RM, Múrcia DB (August 2008). "First description of malignant retrobulbar and intracranial teratoma in a lesser kestrel (Falco naumanni)". Avian Pathology. 37 (4): 413–414.
 * Teratomas are defined as germ cell origin neoplasms that can be rarely found in either humans or animals. Their most common localization is the gonads, although extragonadal localization has also been observed. In avian medicine, there is scarce literature about the occurrence of teratomas and their clinical implications, and this is mainly in wildlife birds . For this reason, we report the first description of a teratoma with both retrobulbar and intracranial locations in a 10-day-old chick of a lesser kestrel (Falco naumanni) born in captivity. The raptor was treated in a centre of wildlife rehabilitation because of the presence of left periocular swelling and exopthalmos. The bird worsened rapidly with signs of vestibular syndrome, ataxia and depression, and euthanasia was practised for humanitarian reasons. Histological examination characterized both masses as malignant teratomas based on the presence of tissues of the three germ cell layers and the presence of both anaplastic foci and immature tissues.
 * p.413


 * Teratomas are germ cell origin neoplasms that contain recognizable elements of the three germ layers (ectoderm, mesoderm and endoderm). They most commonly arise from gonadal tissue in both humans and animals, although an extragonadal localization along the body midline in the mediastinum or in the central neuraxis can also be found. Teratomas affect generally juvenile or young adult animals. In avian medicine, intracranial teratomas have been poorly described and mainly referred to chickens (Jones, 1964; Campbell, 1969) and ducks (Homer & Riggs, 1991). For retrobulbar teratomas, there is one description reported by Schelling (1994) in a Great blue heron (Ardea herodias). In this article, we report the first description of a teratoma with both retrobulbar and intracranial locations in a raptor.
 * p.413


 * Teratomas are an uncommon neoplasia that may be classified as benign (mature) or malignant (immature) depending of the degree of a malignant component or the presence of undifferentiated elements resembling those of the embryo (Schafield &  Cotran,  1999). The pathogenesis of extragonadal teratomas still remains unclear, although they probably originate from diploid pluripotent progenitor cells (Wagneret al., 1997) or from a wrong involvement and enfoldment of embryonic cells in different maturation stages during migration (Sano, 2001).  Some of those cells escape the killing immune mechanisms, producing a variety of tissues that are foreign for the part in which they grow, in some cases undergoing neoplastic transformation.
 * pp.413-414


 * Although there are some descriptions of teratomas in raptors, all of them refer to other anatomic regions different from the head.
 * p.414

"N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications" (March 2018)
Makuch M, Wilson R, Al-Diwani A, Varley J, Kienzler AK, Taylor J, et al. (March 2018). "N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications". Annals of Neurology. 83 (3): 553–561.
 * Introduction: N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown.
 * p.553


 * Interpretation: Serum NR1-IgM and NR1-IgG, alongside the consistent production of NR1-IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1-IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR-antibody encephalitis.
 * p.553


 * These experiments show that, for several years through the course of NMDAR-antibody encephalitis, NR1-specific IgM can be detected in patient sera, together with NR1- specific B cells both in the circulation and in the teratoma tissue. Furthermore, under the experimental conditions presented, the circulating B cells can produce NR1-IgG at levels proportional to serum NR1-IgG. These collective findings suggest that persistent germinal center activity may be responsible for the ongoing production of NR1- IgG and argue against a dominant contribution from LLPCs to circulating NR1-IgG. Based on these data, future immunotherapies might aim to interfere with the active germinal center responses in NMDAR-antibody encephalitis to terminate ongoing antibody production.
 * p.557


 * Third, together with ongoing NR1-IgM production, the presence of circulating B cells with the capacity to produce NR1-antibodies may suggest that lymph nodes are actively producing NR1-reactive B cells. This effect may be through antigen-dependent B cell generation or through polyclonal bystander activation of preformed memory B cells. By analogy, the ovarian teratomas express the NR1 autoantigen and neurons with abnormal morphology, which may break immune tolerance. In addition, we and others have observed intra-teratoma lymphocyte-rich structures with dense T and B cell infiltrations, and our data show that these tumor-resident B cells also have the capacity to generate NR1-specific antibodies. Therefore, the ovarian teratoma contains foci highly reminiscent of germinal center structures, and these collective observations provide a scientific basis to explain why early teratoma removal improves patient outcomes. However, NR1-specific cells may exit this putative site of immunization and seed other lymphoid organs, explaining ongoing antibody production after teratoma excision. Because both lymph nodes and teratomas contain germinal center–like structures, it is intriguing that somatic hypermutation was limited in many NR1-specific B cells isolated from CSF. Given that NR1-reactive IgM and IgA are frequently detected in many disease populations, and CD40- ligand had a limited influence on NR1-IgG production in our study, it may be that natıve autoreactive B cells with few immunoglobulin mutations are sufficient for pathogenic NR1-IgG production. Nevertheless, it should be noted that some patients had undetectable NR1-IgM levels, and teratomas are observed in the minority of patients, and hence it remains possible that germinal center reactions may not be active in all patients.
 * p.560


 * Finally, the presence of active germinal centers in the periphery, together with the higher absolute levels of NR1- IgG in serum than CSF and the disease association with ovarian teratomas, all strongly support the initial peripheral generation of NR1 antibodies. How the peripherally generated NR1-specific cells cross the blood–brain barrier and are retained to produce relative intrathecal synthesis of NR1-IgG, upon normalization for total IgG levels, is a separate question, and it may be that their activation in the periphery is sufficient to induce ligands which facilitate transmigration into the CNS. In summary, this study demonstrates: NR1-IgG and -IgM production from circulating PBMC cultures, teratoma-based germinal center–like structures which can generate NR1-IgG, and the detection of serum NR1-IgM for long durations after disease onset. Taken together, these data suggest that germinal centers have the capacity to generate NMDAR-antibodies. Therapeutic interventions in humans with NMDAR-antibody encephalitis are required to further examine this hypothesis.
 * p.560

"Malignant transformation in a mature teratoma with metastatic deposits in the omentum: a case report" (2012)
Mandal S, Badhe BA (2012). "Malignant transformation in a mature teratoma with metastatic deposits in the omentum: a case report". Case Reports in Pathology. 2012
 * Malignant transformation in a mature cystic teratoma (MCT) is extremely rare. Its incidence is 0.17–2% of all cases. MCT with deposits in the omentum is even rarer. The exact incidence is not known. The prognosis of malignant transformation of the MCT is very poor. Extensive literature search has revealed only 3 such cases.
 * p.542


 * Malignant transformation of an MCT is an uncommon complication occurring in approximately 0.17–2% of all mature cystic teratomas. Although any of the constituent tissues of teratoma has the potential to undergo malignant transformation, squamous cell carcinoma is the most commonly associated cancer. However malignant transformation with metastasis to the omentum is extremely rare. Rarely, other tumors (0.2–1.4%) can arise in an MCT like adenocarcinoma, basal cell carcinoma, adenosquamous carcinoma, thyroid carcinoma, sebaceous carcinoma, malignant melanoma, sarcoma, carcinoid tumor, and neuroectodermal tumour.
 * p.543


 * The low incidence of secondary malignant transformation of mature cystic teratoma explains why a few reports have been published. It has been thought that squamous cell carcinoma in mature cystic teratoma arises from metaplastic squamous epithelium. Furthermore, high-risk human papillomavirus infection has also been thought to be associated with ovarian squamous-cell carcinoma. Mostly mature cystic teratomas are detected 15–20 years before they undergo secondary malignant transformation. Cytogenetic abnormalities might precede histological changes, and prolonged exposure to various carcinogens in the pelvic cavity might cause the malignant changes in mature tissue. Thus, squamous-cell carcinoma in mature cystic teratoma is more common in postmenopausal patients. Pelvic ultrasonography can help in early detection of these tumours in women of childbearing age. Grossly these tumours show presence of nodular, papillary, or cauliflower-like growths protruding into the cyst cavities or nodules or plaques within the cyst walls along with areas of capsular invasion. Serum tumour markers like squamous cell carcinoma antigen, CA125, CA19-9, and CEA are useful in distinguishing mature cystic teratoma from malignant transformation. Tissue polypeptide antigen and macrophage colony stimulating factor may also help to predict malignant transformation in this tumour.
 * pp.543-544


 * Because all preoperative diagnostic procedures can sometimes be unreliable in excluding malignant disease, all mature cystic teratomas in women more than 30 years that show unusual adherence, solid or firm, friable, myxomatous, or variegated areas should arouse suspicion. Hence, surgical approach should be chosen carefully based on the results of clinical and imaging investigations as well as tumour marker profiles. Removal of the entire tumour, in accordance with oncosurgical treatment principles, is essential, following which complete cytoreduction can further improve the outcome in these patients. Alkylating drugs can be given for chemotherapy regimens, whereas, radiotherapy can lead to greater morbidity. To conclude, early detection and complete surgical resection are important for long-term survival. Adequate sampling is essential in these ovarian tumors to establish their teratomatous origin and avoid an erroneous diagnosis.
 * p.544

"Mature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience" (July 2008)
Mann JR, Gray ES, Thornton C, Raafat F, Robinson K, Collins GS, et al. (July 2008). "Mature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience". Journal of Clinical Oncology. 26 (21): 3590–3597.
 * Teratomas are derived from the three germinal layers. Tissues are differentiated in mature teratoma (MT) which generally behaves benignly after complete resection. Immature teratoma (IT) is characterized by containing immature neural tissue and greater propensity for recurrence. Sacrococcygeal teratomas occur mostly in neonates and infants, testicular ones mainly in the first 5 years of life and ovarian mostly between 5 and 15 years of age. Complete surgical resection without damaging vital structures is preferred. Recurrence may be benign (MT or IT), malignant (mostly yolk sac tumor [YST]), occasionally other malignant germ cell tumor (GCT) types, or malignant non-GCT. The place of chemotherapy is unclear, except for YST recurrence, when platinum-based chemotherapy is usually successful.
 * p.3590


 * The presence of HL correlated with higher stage and grade, raised alpha-fetoprotein (AFP) levels and higher likelihood of recurrence.
 * p.3590


 * For our study, microfoci were reported when one or more microfoci were seen, each occupying not more than two adjacent high-power fields (HPF; 40 objective). When YST foci bigger than two adjacent HPF were found, the tumor was classified as malignant teratoma.
 * p.3590


 * For YST recurrence, after investigations including biopsy, carboplatin, etoposide, and bleomycin (JEB) chemotherapy was given, as in the concurrent UKCCSG protocol for malignant GCTs, then further surgery if needed. Other recurrences were treated at the clinician’s discretion, usually surgically. In girls with ovarian tumors, the development of another teratoma in the contralateral ovary was not counted as recurrence.
 * p.3591


 * Generally testicular tumors presented before the fifth birthday, ovarian between 5 and 15 years, and sacrococcygeal tumors at birth or in infancy. Thoracic tumors occurred throughout infancy and childhood, those at other sites mainly during infancy. The high proportion of females is due to ovarian tumors and female preponderance in sacrococcygeal teratomas (male 22, female 76).
 * p.3591


 * For IT, univariate analyses showed significantly worse EFS for nongonadal tumors, higher stage, incomplete resection, and higher grade, with young age borderline. HLs were not statistically significant. The results for OS were similar except for incomplete resection and grade. Multivariate analyses for EFS showed incomplete resection and higher grade to be the most important factors. For MT and IT, young age and nongonadal site were not independent risk factors for EFS.
 * p.3594


 * Our results confirmed significantly better EFS and OS in MT than IT, the greater risk of recurrence for sacrococcygeal than ovarian or testicular tumors and that complete resection is important.
 * p.3596


 * The data confirm increased risk after tumor rupture and support removing the coccyx with sacrococcygeal tumors, to reduce risk. They also suggest that in ovarian IT GP increases risk; a larger series is needed to confirm this. None of six patients with nodal gliomatosis relapsed. Cyst fluid aspiration or spillage during surgery, which were not coded as incomplete resection, were not generally associated with relapse, as reported for spillage elsewhere. The results are consistent with reports that higher grade IT are more likely to recur than lower and that the presence of HL is associated with raised AFP2, but unlike the American experience, HLs were not predictive of relapse.
 * p.3596


 * Enucleation of benign teratomas to preserve gonadal function, not discussed in previous pediatric publications, might be considered if feasible and safe (especially in girls with bilateral ovarian tumors) as none of five boys and eight girls with MT or one girl with IT whose tumors were enucleated relapsed. While there were no relapses among five boys who had scrotal incisions, we recommend inguinal incision for every testicular lesion if the operator cannot be sure it is not malignant. All girls with ovarian tumors had laparotomy, except one who had laparoscopic enucleation of her tumor. However, while laparoscopy is useful for evaluating abdominal lesions, it may not be valuable for excising most ovarian teratomas.
 * p.3596


 * [W]e remain reluctant to use adjuvant chemotherapy after surgery. This is being studied in the German case-control trial MAKEI 200415 for high-risk sacrococcygeal teratomas, aiming to prevent YST relapse. However, we do recommend close oncological follow-up, including AFP monitoring, of all patients with sacrococcgeal teratoma to permit early diagnosis and treatment of YST recurrence (reported in some 10% of patients) and for all other patients except those with completely resected gonadal tumors and normal preoperative AFP and HCG. Our late effects data are incomplete and subject to ongoing study. While many patients are in excellent health, some have substantial morbidity, as reported from the Netherlands in 79 survivors of sacrococcygeal teratomas. In conclusion, in pure MT and IT, surgery should remain the mainstay of treatment. While for YST recurrence, JEB is highly effective, for pure MT and IT, no clear benefit from JEB chemotherapy has been demonstrated. Careful follow-up is recommended, with AFP monitoring, especially for sacrococcygeal tumors.
 * p.3596

"Sacrococcygeal Teratoma" (2007)
"Sacrococcygeal Teratoma". NORD (National Organization for Rare Disorders). (2007).
 * Sacrococcygeal teratomas are rare tumors that develop at the base of the spine by the tailbone (coccyx) known as the sacrococcygeal region. Although most of these tumors are non-cancerous (benign), they may grow quite large and once diagnosed, always require surgical removal. It is likely that all sacrococcygeal teratomas are present at birth (congenital) and most are discovered before birth by a routine prenatal ultrasound examination or an exam indicated for a uterus too large for dates. In rare cases, sacrococcygeal teratomas may be cancerous (malignant) at birth and many will become malignant if surgical resection is not performed. In extremely rare cases, sacrococcygeal tumors may be seen in adults. Most of these represent slow growing tumors that originated prenatally. In the majority of these cases, the tumor is benign, but may cause lower back pain and genitourinary and gastrointestinal symptoms. The cause of sacrococcygeal teratomas is unknown.
 * The symptoms that occur with sacrococcygeal teratomas vary widely depending upon the size and specific location of the tumor. Small tumors often do not cause any symptoms (asymptomatic) and can usually be removed surgically after birth without difficulty. However, larger sacrococcygeal tumors can cause a variety of complications before and after birth. Sacrococcygeal teratomas can grow rapidly in the fetus and require very high blood flow resulting in fetal heart failure, a condition known as hydrops. This is manifest as dilation of the heart, and the collection of fluid in tissues of the body, including the skin and body cavities such as around the lungs (pleural effusion), around the heart (pericardial effusion), and/or in the abdominal cavity (ascites). If neglected, hydrops can also be dangerous for the mother resulting in similar symptoms of swelling, hypertension, and fluid on the lungs with shortness of breath. In addition to hydrops, which can occur in approximately 15% of very large fetal sacrococcygeal teratomas, these tumors can cause polyhydramnios (too much amniotic fluid), fetal urinary obstruction (hydronephrosis), bleeding into the tumor or rupture of the tumor with bleeding into the amniotic space, or dystocia (a condition where the fetus cannot be delivered due to the size of the tumor. It is very important to have very close monitoring during pregnancy to recognize these symptoms as early as possible. In adults, sacrococcygeal teratomas may not cause symptoms (asymptomatic). In some cases, they may cause progressive lower back pain, weakness, and abnormalities due to obstruction of the genitourinary and gastrointestinal tracts. Such symptoms include constipation and increased frequency of stools or urinary tract infections. In rare cases, sacrococcygeal tumors cause partial paralysis (paresis) of the legs and tingling or numbness (paresthesia).
 * The cause of sacrococcygeal teratomas is unknown. Sacrococcygeal teratomas are germ cell tumors. Germ cells are the cells that develop into the embryo and later on become the cells that make up the reproductive system of men and women. Most germ cell tumors occur in the testes or ovaries (gonads) or the lower back. When these tumors occur outside of the gonads, they are known as extragonadal tumors. Researchers do not know how extragonadal germ cell tumors form. One theory suggests that germ cells accidentally migrate during to unusual locations early during the development of the embryo (embryogenesis). Normally, such misplaced germ cells degenerate and die, but in cases of extragonadal teratomas researchers speculate that these cells continue to undergo mitosis, the process where cells divide and multiply, eventually forming a teratoma. Sacrococcygeal teratomas are thought to arise from an area under the coccyx called “Henson’s Node”. This is an area where primitive cells persist (germ cells) that can give rise to cells of the three major tissue layers of an embryo: ectoderm, endoderm, and mesoderm. These embryonic layers eventually give rise to the various cells and structures of the body. Sacrococcygeal teratomas can contain mature tissue that looks like any tissue in the body, or immature tissue resembling embryonic tissues.
 * Sacrococcygeal teratomas occur in females more often than males by a 4:1 ratio. Malignancy is more common in males. The prevalence of these tumors is estimated to be between 1 in 30,000-70,000 live births. Sacrococcygeal teratomas are the most common solid tumor found in newborn babies (neonates). The sacrococcygeal region is the most common site for a teratoma in infants. Sacrococcygeal teratomas affecting adults is extremely rare. Adults cases often represent tumors that were present at birth (congenital), but not detected until adulthood.
 * In most cases, sacrococcygeal teratomas are diagnosed at birth when a large tumor is detected protruding from the sacral region. Many sacrococcygeal teratomas are found incidentally on routine prenatal ultrasounds or they may be detected on an ultrasound that is obtained because the uterus is too large for the stage of pregnancy due to the bulk of the tumor, or accumulation of amniotic fluid. During an ultrasound, reflected sound waves create an image of the developing fetus. Even small sacrococcygeal teratomas may be visible on an ultrasound picture. In some cases, a sample of the amniotic fluid or maternal serum may be taken and studied to determine the levels of alpha-fetoprotein (AFP). AFP is a normal fetal plasma protein that when elevated may indicate the presence of certain conditions such as a sacrococcygeal teratoma. If a sacrococcygeal teratoma is diagnosed prenatally a careful examination is usually done to rule out other anomalies. In some institutions a fetal MRI scan is also performed to better delineate the anatomy of the tumor and displaced structures. For large sacrococcygeal teratomas, very frequent ultrasounds and echocardiograms (to measure the size of the cardiac chambers and blood flows) are required to monitor for signs of evolving hydrops. During an echocardiogram, reflected sound waves are used to take pictures of the heart. It is extremely important that a medical team experienced with large fetal sacrococcygeal teratoma follows the pregnancy. All fetuses with large sacrococcygeal teratomas need delivery by a “classical” cesarean section (large incision in the uterus) to avoid tumor rupture and hemorrhage at the time of delivery. Most fetuses with large tumors are born premature and need expert perinatal care from a multidisciplinary team. In adults, a diagnosis of sacrococcygeal teratoma may be suspected during a routine pelvic or rectal examination that detects the presence of a mass or tumor. A diagnosis of sacrococcygeal teratoma may be confirmed by surgical removal and microscopic examination of affected tissue (biopsy). One procedure is known as fine needle aspiration, in which a thin, hollow needle is passed though the skin and inserted into the nodule or mass to withdraw small samples of tissue for study. In addition to an ultrasound, other specialized imaging techniques may be used to diagnose a tumor as well as evaluate the size, placement, and extension of the tumor and to serve as an aid for future surgical procedures. After birth, such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. In cases of malignant sacrococcygeal teratomas, laboratory tests and specialized imaging tests may also be conducted to determine possible infiltration of regional lymph nodes and the presence of distant metastases.
 * When an individual is diagnosed with a sacrococcygeal teratoma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. Certain of the same diagnostic tests described above may be used in staging. Sacrococcygeal teratomas are classified according to the American Academy of Pediatrics Surgical Section: Type I – the tumor is predominantly external with a very minimal internal component. Type I is rarely associated with malignancy. Type II – the tumor is predominantly external but has some internal extension into the presacral space. Type III – the tumor is visible externally, but is predominantly located in the pelvic area with some extension into the abdomen. Type IV – the tumor is not visible externally and is located in the presacral space. Type IV has the highest rate of malignancy.
 * The initial management of a fetus with a sacrococcygeal teratoma requires the coordinated efforts of a perinatal team of medical professionals such as maternal fetal medicine physicians to deliver the infant, and pediatric surgeons and neonatologists to resect the tumor and manage the medical issues of the infant who can sometimes be critically ill. All prenatally diagnosed sacrococcygeal teratomas require resection during the neonatal period and if the tumor is large, as quickly as possible to avoid rupture of the tumor. Resection always involves resection of the tumor along with the coccyx. Failure to resect the coccyx is associated with a 30% local recurrence rate of the tumor. This can usually be done from the back of the neonate but for some tumors with extensive extension into the pelvis and abdomen, an abdominal incision must also be performed. Most children that undergo early resection of sacrococcygeal teratomas ultimately do well with a very low incidence of malignant or benign tumor recurrance, and normal urogenital, bowel, and lower extremity neurologic function. These children are usually followed by the pediatric surgeon by rectal examinations and interval serum AFP levels to monitor for recurrence for 3 years before they are considered cured with no possibility of tumor recurrence. In rare instances where malignancy is diagnosed by the pathologist after resection a team of medical professionals who specialize in the diagnosis and treatment of cancer (medical oncologists) will need to be consulted. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location and corresponding complications; extent of the primary tumor (stage); whether it has spread to lymph nodes or distant sites; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient or parents, based upon the specifics of the case; a thorough discussion of the potential benefits and risks; and other appropriate factors. In rare cases, complications resulting from a sacrococcygeal teratoma may necessitate intervention before birth (prenatally). Interventions such as tapping the amniotic fluid (amniocentesis) to reduce the volume and delay the onset of preterm labor may be required. If the tumor has hemorrhaged and the fetus is anemic, a fetal blood transfusion may be helpful. Occasionally, an obstructed fetal urinary tract will need to be treated by a vesicoamniotic shunt (a catheter between the bladder and amniotic fluid) to relieve the obstruction and prevent damage to the kidneys. In rare cases when the fetus is documented to be in the early stages of hydrops, open fetal surgery may be required (surgery on the fetus in the womb) to “debulk” the tumor and reduce the demand for blood flow. After removal of the bulk of the tumor, the fetus is returned to the womb so that the hydrops can improve prior to birth. Although this has been successful about 50% of the time, it is a major undertaking and extensive consideration of the risks to the mother is appropriate. Although radio frequency ablation (a technique where a needle is inserted into the tumor and radiofrequency energy is applied to the tumor to destroy blood flow) has been reported, all survivors have had complications of damage to the genitourinary system so this approach is considered highly experimental. In adults, surgical removal of the entire tumor and the tailbone (coccyx) is the main treatment option. Removal of the coccyx lowers the chance of recurrence. For benign tumors surgical removal of the tumor is usually sufficient. However, for malignant tumors, affected individuals should receive additional treatment with chemotherapy and radiation therapy. Because malignant sacrococcygeal teratomas are extremely rare, especially in adults, no standard chemotherapeutic regimen or radiation therapy has been established.

"Ovarian Germ Cell Tumors" (2014)
Noor MR, Hseon TE, Jeffrey LJ, eds. (2014). "Ovarian Germ Cell Tumors". Gynaecologic Cancer: A Handbook for Students and Practitioners. CRC Press.
 * Immature teratoma contains primitive, immature or embryonal structures, and it may also have mature tissues (Fig. 13.6). Immature teratomas are more commonly unilateral, and bilaterality is only in less than 5% of cases. Immature teratoma constitutes 20% of primitive germ cell tumour. It is predominantly solid or predominantly cystic, predominantly solid tumours are more common. Solid components may consist of the nervous system, cartilage or bone, while the cystic component is often filled with serous/mucinous/sebaceuous/hairs. Immature elements are almost always predominantly neuroectodermal (embryonal). The grading of immature teratoma is shown in Table 13.3 The grading of immature teratoma by O'Conner and Norris is based on the amount of immature neural tissue contents: (A) low-grade immature teratoma and (b) high-grade (grades 2 and 3) immature teratoma. Immature teratoma exhibits malignant behavior and grows rapidly if the tumour is of high grade and spread by peritoneal transplantation and metastasized primarily through lymphatic channels. The treatment is similar to other malignant ovarian germ cell tumours. Extraovarian implants of mature glial tissue can occur anywhere, but it does not upstage the disease.
 * p.446


 * Growing Teratoma Syndrome The growing teratoma syndrome (GTS) is a condition characterized by immature teratoma in the ovary with distance implantation/metastases of mature teratoma (benign). GTS was first described by Loghtets et al. Characerized by an enlarged neoplastic mass of non-seminomatous germ cell tumours following chemotherapy. The previously elevated tumour markers will become normal and GTS can occur in both non-seminomatous germ cell tumours of testis and ovary. The incidence of GTS in germ cell tumour of the testis is 1.9-7.6%, but it is less common in the ovary. Typically patients with GTS will initially diagnose as immature teratoma of any grade and treated with surgery followed by chemotherapy. GTS develops either during or after completion of chemotherapy. Patients with GTS present with increasing abdominal distension despite normalization of their tumour markers. Histologically, GTS is demonstrated as the presence of mature elements (mature teratoma) consisting of normal mature tissue elements such as normal skin elements, respiratory tract mucosa, mature cartilage, bone, and glial tissue. There will be no immature elements or malignant component found in any of the sections. Some gynaecologic literature described these phenomena as “chemotherapeutic retroconversion”. The underlying mechanism of GTS is not fully understood. There are three theories: (a) Chemotherapy destroys only the immature malignant cells, leaving the mature benign teratomatous elements. (b) Chemotherapy alters the cell kinetics toward transformation from a totipotent malignant germ cell toward a benign mature teratoma. (c) An inherent and spontaneous differentiation of malignant cells into benign tissues. Chemotherapy just prolongs the course of the disease (patients survive long enough) to permit “spontaneous evolution” to occur. GTS is always confused with recurrent immature teratoma. CT scans and colour Doppler may sow multiple anechoic areas, calcification and absence of neovascularization. Treatment is by surgical resection, but chemotherapy and radiotherapy are ineffective and if the GTS is left untreated, some of its elements may transform into a malignant tumour. Some medical therapies have produced a response in patient with unresectable GTS such as interferon (KTTAN: Tonkin) and bevacizumab (mego).
 * pp.447-448

“Questions in Daily Urologic Practice: Updates for Urologists and Diagnostic Pathologists” (2009)
Oyasu R, Yang XJ, Yoshida O (2009). “Questions in Daily Urologic Practice: Updates for Urologists and Diagnostic Pathologists”. Springer Science & Business Media.
 * How do germ cell tumors in infants and children differ from those in postpubertal males and females. Answer Germ cell tumors (GCTs) in the pediatric population differ significantly from adult GCTs in several respects. First, the incidence is much lower than adults. Second, GCTs occur more commonly at extragonadal sites during the first several years. Third, except for ovarian dysgerminoma, which develops in girls after age 8, teratoma and yolk sac tumor (YST) are the only GCTs in this age group. The sacroccygeal region is the most common extragoadal site, and teratoma is the most common type at this location. In the testis, YST is more common than teratoma, whereas in the ovary teratoma is more common than YST and there are twice as many mature teratomas as the immature type. YST is malignant. Teratoma is benign in children. Although the presence of immature elements per se does not affect prognosis, immature teratoma of high grade is significantly associated with foci of YST and higher stages of the disease. The overall prognosis is still excellent. Intratubular germ cell neoplasia of unclassified type, the precursor of adult GCTs, is not identified in tubules adjacent to teratoma or YST in the prepubertal testis. A difference in the genetic mechanism is suggested.
 * p.253


 * The behavior of immature teratoma of the ovary is dependent on the degree of immaturity. This commonly accepted view may not apply to the immature teratomas in the pediatric patient. A recent authentic study reports that immaturity per se does not affect prognosis, but YST which develops significantly associated with the increasing degree of immaturity of teratoma affects prognosis adversely.
 * p.253


 * Germ cell tumors (GCTs) in children (prepubertal) vastly differ from those in adults (postpubertal, to be exact). The major differences are as follows: (1) GCTs occur more commnly at extragonadal sites during the first several years; (2) teratomas and yolk sac tumors (YSTs) are the only types except for a small number of dysgerminomas in the ovary; (3) YST is malignant but teratomas of the testis and extragonadal sites, and most of the ovarian teratomas are benign, in contrast to the adult testicular teratoma, which is malignant regardless of the degree of differentiation. In a recent review, Ulbriht proposed a reasonable (albeit provocative) histogenetic classification to account for the biologic difference of GCTs in children and adults: The fundamental difference in the genetic makeup produces two types of gonadal teratomas, benign and malignant. The benign tumors are derived from “benign (nontransformed)” germ cells and include the usual mature ovarian teratoma, prepubertal testicular teratoma (extragoadal site teratomas included), and testicular dermoid/epidermoid cysts. The postpubertal testicular teratomas is malignant because it originates in a malignant ger cell locates in atrophic tubules, recognizable as intratubular germ cell neoplasia of unclassified type (IGCNU) through the intermediate forms such as embryonal carcinoma or YST. Additionally, some gonadal teratomas become malignant because of “post-teratomatous malignant transformation”; such tumor usually occurs in the ovary of a young girl and women and exhibits a spectrum of biologic behavior ranging from grade 1 to 3 depending on the amount of immature tissues. Immature teratomatous components, such as neuroectodermal tissue or blastema of Wilms tumor, may also occur in the postpubertal testicular teratoma, but they have no established clinical significance because the adult teratoma, regardless of degree of differentiation, behaves in a malignant fashion.
 * pp.253-254


 * The proposal of Ulbright seems to account for the differences in biologic behavior of tratomas by age, organ, and sex but has not addressed the genetic basis responsible for the differences. An inevitable question is what the basic genetic difference(s) between the two types of teratoma is. If the ovarian teratomas in adolescents and young women are derived from a “benign” germ cell but immature elements make the tumor more aggressive, why, then, do the immature elements in the prepubertal testicular teratoma not likewise behave aggressively? What is the genetic difference between YST and teratoma in the prepubertal age group?
 * p.254


 * Based on data reported in the world literature, the gonadal and extragonadal GCTs in prepubertal males and females can be summarized as follows. Incidence The incidence of the total GCTs at all sites in the prepubertal population is not available. The incidence of testicular GCTs in the prepubertal population is much lower than in postpubertal males (0.12/100 000 vs. 6.0/1000 000). YST is more common than teratoma, with a reported ratio of 6:1 to 3:1. However, in a British registry series, more teratomas than Sts were reported. A small number of dysgerminomas occur in the ovary.
 * p.254


 * Tumor Sites and Type Germ cell tumors occur more commonly at extragonadal sites. They are, in descending order of frequency: sacroccygeal region (42% of cases), ovary (24%), testis (9%), mediastinum (7%), central nervous system (6%), and retroperitoneum (4%). Teratoma is the most common type in the sacrococcgyeal site, and almost exclusively occurs before the age of 2 years with a fourfold predominance in girls, whereas in the testis the YST is far more common than teratoma.
 * p.254


 * Age There is a bimodal age distribution curve for teratoma in girls: one peak at under 3 years of age and a second peak after the age of 8 years. The first peak is exclusively due to sacroccygeal teratomas and the second to ovarian teratomas. Among boys during the first 2 years of life, teratoma is more common at extragonadal sites than in the testis. After that period, the incidence remains low at any sites until after puberty.
 * p.254


 * Germ Cell Tumors of the Testis Teratoma represents 14%-22% of GCTs in the testis. YST is far more common than teratoma in the testis (59%-86%).
 * p.255


 * Germ Cell Tumors of the Ovary Teratomas are more common than YSTs, and mature teratomas are twice as common as the immature type. In contrast to seminoma, which is rare to nonexistent during the prepubertal period, dysgerminoma (ovarian counterpart of seminoma) commonly accounts for about 9% of prepubertal GCTs and occurs in an older age group (median age 153 months), in contrast to that of TSTs (pure) (24 months).
 * p.255


 * Clinical Behavior of Yolk Sac Tumor The yolk sac tumor is a malignant GCT. In contrast to that in postpubertal patients, it occurs mostly in a pure form. Metastases occur less frequently (9%) than in adults (61%). In the series of 212 patients with YSTs registered in the Prepubertal Testis Tumor Registry of the American Academy of Pediatrics, Section of Urology, 33 patients (16%) presented with metastasis.
 * p.255


 * Clinical Behavior of Teratoma by Site, Sex, and Age It has been categorically accepted that childhood teratomas are benign irrespective of the sites and presence of immature elements and run a benign course provided they are excised completely. Recently, several hitherto undescribed findings were reported in a study by the Combined Pediatric Oncology Group/Children's Cancer Group. Expert review of 135 immature teratoma cases revealed that 60 cases were pure immature teratomas, and 75 were mixed teratomas and YSTs but with a major component of immature teratoma. When immature teratomas were graded by their proportion of neural and blastemal components, significant correlations were detected between stage and the presence of foci of YST (P < 0.02) and between the presence of high grade teratoma and the presence of foci of YST (P < 0.001). The grade of immature elements per se did not affect prognosis, but the presence of YT foci did. Nevertheless, the overall 2- to 6-year survival rate was excellent (96%) and was related o the presence of YST. The adverse effects of YST components on teratomas had been pointed out earlier by Harms and Janig.
 * p.255


 * Congenital Teratomas Congenital (perinatal) teratoma refers to those detected in utero and identified within 1 week of age. It is the most common perinatal tumor, comprising 37%-53% of congenital neoplasms. Congenital teratomas tend to be extragonadal, and most of them are at the sacrococcgyeal region. In a study of 22 fetal and neonatal tumors reported by Heerema-McKinney et al., the grade of teratoma (proportion of immature elements) and foci of YST did not adversely affect the outcome. Outcome was determined predominantly by whether the tumor was completely respectable.
 * p.255


 * Intratubular Germ Cell Neoplasia of Unclassified Type and Intratubular Atypical Germ Cells in Prepubertal Testes If the molecular mechanism of prepubertal GCTs is different from that for adult GCTs, IGCNU may not be found. Indeed, this is the case. IGCNU is extremely rare to nonexistent. Exceptional are cryptorchid testes, male pseudohermaphroditism, and gonadal dysgenisis, all of which are known to develop invasive GCTs in the later life. The seminiferous tubules adjacent to GCTs, in prepubertal children frequently contain a variable number of atypical germ cells that have abundant clear cytoplasm and enlarged nuclei. These cells may also be observed in the testes of normal boys. These cells are immunohistochemically negative for placental-like alkaline phosphatase (PLAP) and are not considered by most observers to represent IGCNU. Recently, atypical cells that were negative for PLAP but positive for p53 and proliferating cell nuclear antigen (PCNA) were described adjacent to a mature teratoma by Renedo and Trainer. They equated these cells with IGCNU. Another case, described by Hu et al., was a 15 month-old boy with a pure testicular YST. Located within adjacent tubules were atypical cells that were rich in gloycogen, focally positive for PLAP, and triploid in DNA content. In contrast, YST cells showed modal teraploidy. The authors concluded that these cells represented IGCNU that differed from the usual adult IGCNU in showing only minimal intratubular proliferation. The precise nature of these atypical cells and possible relation to IGNCU in adults would have become clearer if additional IGCNU markers that are not available had been used. Hawkins et al. Attempted to characterize the atypical clear cells with antibodies against PLAP and c-kit, another marker of IGCNU. In none of the 28 cases were the atupical cells found adjacent to GCTs immunoreactive to PLAP or c-kit. However, five of seven cases were positive for PCNA. Ummunoreactivity to p53 was present in the two cases examined. The authors concluded that the germ cells adjacent to infantile GCT are proliferative but not neoplastic.
 * pp.255-256


 * In summary, IGCNU as defined morphologically and immunohistochemically in adults is not identified in tubules adjacent to teratomas or YSTs in prepubertal testes. Therefore, genetic mechanisms are differentfrom those in adults. The only exceptions are in the abnormal testes associated with crupochidism, male pseudohermaphroditism, and gonadal gysgenesis. The IGCNU observed in these testes is probably the precursor of adult-type GCTs.
 * p.256


 * What is the malignant transformation (or somatic malignancy) of germ cell tumors? What is the clinical significance of this transformation? Answer Malignant transformation in adult germ cell tumors (GCTs) refers to the development of a new type of neoplasm of somatic cell differentiation. It can be found in the orchiectomy specimen as well as the post chemotherapy retroperitoneal lymph nodes because of its refractories to the cisplantin-based chemotherapy. The most frequently reported types are rhabdomyosarcoma, sarcomas not otherwise classified, primitive neuroectodermal tumor, and adenocarcoma. Their origin from GCTs is supported by demonstrating i(12p) chromosome in the tumor cells. Clinically, occurrence of malignant transformation is suspected when there is evidence of tumor progression despite improved tumor markets. Cure or longterm survival may be expected if the tumor is removed surgically. Chemotherapy optimal against the tumor of concern should be considered for patients with advanced-stage cancer.
 * p.258


 * As was discussed under Question 1, the primordial germ cell gives rise to five basic forms of GCTs in postpubertal men: (1) seminoma, which can be equated to the neoplastic counterpart of undifferentiated early-stage embryonic cells; (2)embryonal carcinoma, which is comparable to the embryo of 10 days to 2 weeks of gestation; (3) yolk sac tumor, which resembled the developing rodent endodermal sinus structure; (4) choriocarcinoma, which is a neoplastic counterpart of the extraembryonic (placental) structures; and (5) teratoma, which represents the neoplastic counterpart of the developing fetal structure and consists of cells derived from the three germ layers (endoderm, mesoderm, ectoderm). The organization in teratomas varies. When a teratoma is made up of well-differentiated cells arranged in a recognizable tissue or organ structure, it is referred to as a mature teratoma. For example, it consists of structures resembling intestinal mucosa and the underlying smooth muscle layer, cartilage, bone, glial cells, and/or skeletal muscle cells. Teratoma, immature type, on the other hand, consists of cells at an early stage of fetal development. For example, skeletal muscle may be at the stage of rhabdomyoblast and neural structure at the stage of primitive neuroepithelium. These immature cells still represent component of an immature teratoma coexist in with other immature or mature germ cell elements.
 * p.258


 * On rare occasions, some of the mature and immature teratomatous components undergo cytologically malignant alterations and exhibit expansile or infiltrative growth. When overgrowth of somatic malignant cells occurs in the background of GCT, it is referred to as a teratoma with malignant transformation or somatic malignant transformation. Unfortunately, the term “teratoma with malignant transformation” can be misleading, because it gives the impression that the underlying teratoma component is benign. Obviously this is incorrect.
 * p.258


 * Tumor's germ cell origin is supported by the almost universal coexistance of GCT elements, mainly teratoma or a yolk sac tumor. The most convincing evidence is the presesence of i(12p) in malignant transformed cells including leukemia cells. In Motzer's series, i(12p) was identified in 11 of 12 cases that included adenocarcinoma, PNET, sarcoma, and leukemia.
 * p.260


 * What is the clinical significance of somatic malignancy? Malignant transformation may be an incidental finding in the resected specimens, including the testis and retroperitoneal lymph nodes, or in the tumor mass that has remained after cisplantin-based chemotherapy. Surgical resection of the residual mass is performed in patients with nonseminornatous GCTs who have attained normal serum marker levels after cisplatin-containing chemotherapy. The presence of necrotic debris requires no further therapy. Enlargement of a tumor mass in the context of declining or normal tumor markers represents a growing teratoma or a secondary somatic malignancy. Resected surgical specimens must be evaluated microscopically for the presence of somatic malignancy.
 * p.260

“Treatment of Cancer” (2008)
Price P, Sikora K, Illidge T (2008). “Treatment of Cancer”(Fifth ed.). CRC Press.
 * Germ-cell cancers are rare malignancies of young adult life which occur in males in 97-98 per cent of cases. Histologically identical neoplasms may arise in multiple sites. Whilst the most common primary site is the testis other recognized primary sites include the retroperitoneum, mediastinum, pineal/superasellar area, the ovary and (in infants) the sacro-coggygeal region. This chapter focuses predominantly on testicular germ-cell cancers, but also includes sections on primary mediastinal and retroperitoneal disease. Over 95 per cent of patient presenting with a germ-cell tumour can expect to be cured.
 * p. 706


 * This is the most common cancer of young men aged less than 35 years of age, but still comprises of only 1 per cent of male cancers. Approximately 1:400-450 males in the UK will develop a testicular ger-cell cancer in their lifetime, comprising, in the year 2000, approximately 2000 cases (7 cases per 100,000 population per year). Germ-cell cancers of the testis are divided histiologically into testicular seminoma and teratoma; these two subtypes occur with approximately equal incidence. The median age of onset of teratoma is 25-30 years, and of seminoma approximately a decade later. Germ-cell tumours of the tetis are rare before the age of 15 and comparatively rare after the age of 60, when large-cell non-Hodgkin's lymphoma becomes the commonest type of testicular cancer. Evidence from a variety of Western nations has shown a markedly increasing incidence of both types of germ-cell cancer in the last 40-50 years, with many countries reporting a two-fold to three-fold increase in rates during this period. Simultaneously there is strong evidence to suggest that sperm counts are falling, and it seems likely that the same aeriological events underlie both abnormalities.
 * p.706


 * Germ-cell tumours of the tetis occur more commonly in white populations. The highest recorded incidence is seen in Nordic countries, in particular Denmark and Norway; however, paradoxically, the incidence in Finland is low. The main predisposing factor in the development of germ-cell cancer is tesicular maldescent. If either testis fails to descend normally, the incidence of testicular cancer rises approximately five-fold (both testes are at increased risk_, and if both are maldescended, the incidence rises ten-fold. Patient undergoing orchidectomy for a germ-cell cancer have a markedly increased risk of developing contralateral disease- estimated at 4-5 per cent – and those with a family history of testicular germ-cell cancer (particularly siblings) have an increased risk of developing a tumour themselves of approximately five-fold to ten-fold. Additional risk factors are Down's syndrome, the presence of testicular atrophy or dysgenesis, and a previous history of mumps orchitis. Other possible risk factors include higher social class, high maternal and low birth weight, and infection with human immunodeficiency virus (HIV). The incidence of testicular maldescent is rising in the UK. Whereas this abnormality is present in only 10 percent of patients presenting with testicular cancer, it is thought that common prenatal influences underlie the rising incidence of both abnormalities. Interestingly, the incidence of testicular cancer among Danish males born during the period of invasion in World War II was markedly lower, suggesting a possible nutritional influence on the mother and developing male fetus.
 * pp.706-707


 * Forty-five to 50 per cent of patients with germ-cell cancer of the testis have either pure malignant teratoma or (in approximately 15 per cent of cases) a combined malignant teratoma and seminoma. These latter cases are managed exclusively as teratoma.
 * p.713


 * Approximately 60 per cent of patients with testicular teratoma will have stage 1 disease at first presentation, i.e. normal physical examination and CT scans of chest, abdomen and pelvis; serum markers is initially elevated should fall to within the normal range. There is currently no proven role for PET scanning in these patients. Although this technique will aid early detection of metastatic disease in some cases, this is not likely to affect the already excellent outcome for these patients. Management approaches for these patients vary and may include surveillance, adjuvant chemotherapy or retroperitoneal lymph-node dissection (RPLND), although the last-mentioned approach is not used in the UK. There is no role for irradiation. Treatment is guided by the known risk factors for metastatic disease, and patients are generally divided into high-risk and low-risk groups, determined by the pathological features in the resected testis. The major factor predicting relapse is vascular (i.e. venous or lymphatic) invasion by cancer. This feature is present in approximately 25 per cent of cases and, when present, predicts a risk of subsequent relapse of approximately 50 per cent.
 * p.713


 * Following orchidectomy for stage 1 teratoma, the overall risk of relapse is 25-30 percent. Relapses usually occur within a few months and are rare beyond 18-24 months. No standard surveillance protocol has been agreed; however, most oncologists recommend tumour marker measurement (AFP and hCG) and a chest X-ray monthly for 1 year, then 2- monthly for 1 year. IN a Medical Research Council (MRC) trial (TE-08), the necessary frequency of CT scanning was evaluated, comparing a total of three whole-body scans (0, 3 and 12 months after orchidectomy) and six (0, 3, 6, 9, 12 and 12 months after orchedectomy) and six (0, 3, 6, 9, 12 and 24 months). No difference in outcome was found, and this study also confirmed the results of an earlier series suggesting that chest CT scanning post-staging could be replaced by a chest X-ray without detriment to the patient. This CT surveillance programme – initial whole-body staging CT scan followed by abdominal scanning only at 3 months and 1 year – can now be regarded as the standard approach. If patients without evidence of vascular invasion are selected for surveillance, the risk of relapse is only 15 per cent, versus 40-50 per cent for those with this feature. Follow-up, however, should be the same. The overall cure rate should approach 100 per cent, as salvage chemotherapy is highly effective (see “Treatment of metastatic teratoma' below).
 * p.713


 * Adjuvant chemotherapy has been tested in patients with stage 1 teratoma with a high risk of subsequent spread, identified by the presence of vascular invasion. Two cycles of modified bleomycin, etoposide and cisplatin (BEP, see “treatment of metastatic teratoma”) chemotherapy, given with a total dose of etoposide of 360 mg/m2 in each course (Box 30.2), have been shown to reduce the relapse rate from 40 pe cent to 1 per cent. This treatment approach has been widely adopted in the UK, but should be regarded as a matter of choice for patients, as cure rates should be exceptionally high whether or not this approach is taken. Those rara patients relapsing after adjuvant chemotherapy are reported as having a poor prognosis, but there are inadequate data in this area at present.
 * pp.713-714


 * In the USA and many European countries, RPLND remains a routine treatment approach to stage 1 teratoma. The advent of more limited and therefore nerve-sparing surgery has dramatically reduced the previously common complication of retrograde ejaculation. Approximately 70-80 per cent of cases will have negative histology (pathological stage 1_; however, despite this finding, 10 per cent of unselected patients will relapse, almost always outside the abdomen. Patients in whom nodal disease is found and completely resected (stage 1II) have been reported in early series as having a 50 per cent relapse rate if no further treatment is given. However, if patients with raised tumour markers prior to surgery (stage IM) are excluded from surgery, results can be excellent in experienced hands, with relapse rates of less than 5 per cent recorded for pathological stage 1, and 10 per cent for low-volume pathological stage II. Adjuvant chemotherapy (e.g., two cycles of BEP) is recommended if malignant nodes larger than 2 cm are found; for remaining cases, chemotherapy given at the time of relapse may well suffice, and should result in virtually universal cure.
 * p.714


 * In the USA and many European countries RPLND remains the treatment of choice for early stage II patients, although increasingly patients with elevated serum markers, vascular invasion in the primary or tumour masses greater than 3 cm in diameter are treated with primary chemotherapy. In the UK, combination chemotherapy is regarded as the treatment of choice, and patients who have residual masses at the completion of treatment have these surgically excised at that time.
 * p.714


 * Metastatic testicular teratoma is a heteogenous disease in which spread frequently occurs by lymphatic and, or vascular route. Unlike other malignancies, disease bulk may have no relevance to prognosis, as many of the more bulky metastatic masses largely comprise teratoma differentiated. In addition, these neoplasms are characterized by elevation of serum markers (AFP, hCG and LDH) – it has been known for many years that the degree of elevation of these markets relates to prognosis. A wide variety of different prognostic factor classifications were in use in the 1980s and the 1990s; these bore little relationship to each other, and it proved increasingly difficult to translate clinical trial data between groups because of their use. In 1997, this situation was finally resolved when the International Germ Cell Consensus Classification (IGCCC) – a prognostic factor-based staging system – was introduced and widely adopted. This classification resulted from worldwide collaboration. Retrospective clinical data were collected on more than 5000 patients with metastatic testicular teratoma or primary mediastinal or retroperitoneal teratoma who had been treated with cisplatin-containing chemotherapy. The median follow-up time was 5 years. Extensive data were analysed with regard to tumour markers, site of primary and sites and extent of metastatic disease. It rapidly became apparent that the main determinant of prognosis was the degree of elevation of all three tumour markers. Two additional adverse features were the presence of a mediastinal primary and spread to visceral sites (e.g., liver, bone and brain).
 * p.714


 * Metastatic testicular teratoma is a highly chemo-sensitive disease. The introduction of cisplatin, vinblastine and bleomycin (PVB) by the Indiana group in the late 1970s ranks as one of the single most important advances in oncology. Thirty years ago, 5-10 per cent of patients with metastatic teratoma were cured, whereas at present 85-90 per cent of such patients should be cured. This neoplasm is rare and its treatment complex. There is clear evidence that referral to specialist treatment centres, particularly for patients with intermediate-prognosis and poor-prognosis disease, improves survival.” Chemotherapy protocols should be strictly adhered to and surgery considered in all cases post-chemotherapy where indicated. Patients with non-threatening metastatic disease may wish to consider banking sperm prior to chemotherapy, although sperm counts frequently recover despite such treatment. The standard therapy for patients with all stages of metastatic testicular teratoma is BEP chemotherapy, which is given at 21-day intervals at a variety of doses and in a variety of schedules (see Box 30.2), including the following. Adjuvant therapy for high-risk stage 1 disease. In these cases, BEP is given for two courses with reduced-dose etoposide. Good-risk teratoma: BEP is given for three courses. Intermediate-prognosis or poor-prognosis disease: BEP is given for four courses. Impatient admission is required for BEP chemotherapy, although the possibility of delivering this treatment on an outpatient basis is being explored. The treatment can almost always be delivered at full dose, on time (every 3 weeks). Certainly full-dose therapy should be given on day 1 if the white cell count is >= 3.0 X 10(9)/L with a platlet count >= 120 X 10(9)/L. Cisplatin, given as part of BEP, is generally administered in divided dose, and is equally effective given twice daily (50 mg/m(2)) or five times per day (20mg/m(2)).” Intravenous bleomycin can be given virtually regardless of blood counts, but should be used with considerable care in older patients (> 40 years) or if the serum creatine is elevated or the creatine clearance reduced below 60mL/min (see below). There is no evidence that the use of additional growth factors (e.g. filgratism) is necessary or affect treatment results.(25)”
 * p.715


 * Cure rates for good-prognosis disease (see Box 30.3) should exceed 95 per cent in the group defined by IGCCC criteria. Commencing from early studies in which four courses of BEP were regarded as standard, a number of important studies have attempted to reduce treatment toxicity while maintaining efficacy in these patients.
 * p.715


 * In summary, these studies have shown that whereas bleomycin clearly increases myleotoxicity, and causes occasional mortality from bleoycin liung, overall failure-free survival is improved when this drug is used. One of these studies compared BEP X 3 against EP X 4. Although survival in his study was equivalent, more adverse cancer events occurred in the group of patients receiving EP, and BEP was recommended as standard therapy. It is now generally recommended that if three cycles of BEP are to be used, bleomycin should be given weekly to a total doe of 270 000 units, a cumulative dose that should rarely be complicated by bleomycin lung.
 * p.715


 * There is at present no role for carboplatin in the initial therapy of metastatic teratoma.
 * p.716


 * Three cycles of BEP chemotherapy with bleomycin given to a total dose of 270 000 units have clearly been shown to be standard therapy for these patients. In occasional patients, when there are concerns about bleomycin dose, in particular older patients, it remains reasonable to treat with four cycles of EP (which, in the author's non-evidence-based practice, is supplementated with a single dose of bleomycin 30 000 units at 3-weekly intervals). Occasional patient intolerant of intravenous infusions because of severe learning difficulties can still be created by substituting carboplatin for displatin, although it has to be accepted that cure rates will be lower.
 * p.716


 * Approximately 30 per cent of patients with teratoma fall into the intermediate-prognosis and poor-prognosis group. These patients often have rapidly progressive disease and treatment should proceed with relative urgency. Disease in the chest can be bulky and associated with intrapulmonary haemorrhade. Occasional patients have ensuing rapidly progressive dyspnoea and require urgent therapy, with careful attention to the avoidance of excess hydration. Abdominal disease can be associated with inferior vena cava obstruction (particularly with right-sides tumours) or with utetric obstruction that may require stending. Clinicians should be aware of the possibility of central nervous system (CNS) disease in these patients. Standard chemotherapy remains BEP (etoposide dose 500mg/m(2) per course) given for four courses with a total bleomycin dose (40 000 units weekly) of 360 000 units There is no evidence that filgratism or other growth factors ad to the efficacy of this regime. A number of phase II trials have explored dose escalation of displatin, increased dose intensity and addition/substitution of other drugs (particularly ifosfamide), but have failed to improve on the results achieved with BEP – whilst at the same time increasing toxicity.” A number of more intensive treatment approaches to these patients have been explored.
 * pp.716-717


 * Malignant teratoma can involve the CNS at presentation or at relapse, then either in isolation (sanctuary site relapse) or in association with progressive systemic disease. Metastases may be single or multiple. Spinalcord compression may also occur, usually secondary to contiguous spread of tumour from an adjacent vertebral body or para-aortic mass. Meningeal disease occurs but is rare. Central nervous system disease is most commonly seen in patients with a high present hCG (e.g. ?10 000 IU/L) or with multiple (>20) lung metastases, anda routine CT or MRI brain scan is indicated at initial evaluation in such cases. The management of CNS disease at presentation is controversial. It has been proposed that if a single metastasis is present and potentially resectable, and the systemic disease is clinically non-threatening, craniotomy and resecution should be considered as an initial measure. In practice, such patients are extremely rare, and for the majority BEP chemotherapy should be commenced urgently. It is usually recommended that this treatment is supplemented by whole-brain irradiation, but there is little evidence to support the use of this additional treatment. The cure rates for patients presenting with CNS disease approach 50-60 per cent. Similar results should be achieved in patients with sanctuary site relapse after chemotherapy, in which there is no systemic disease. These cases commonly occur at a single site, which ideally should be resected then irradiated. Patients with end-stage disease involving CNS and peripheral sites should usually be treated palliatively.
 * p.717


 * Patients receiving chemotherapy for metastatic teratoma should be monitored by sequential tumour marker measurements and simple radiological examinations (e.g. chest x-ray). A common phenomenon following the first chemotherapy administration is for the tumour markers to i for 7-10 days (tumour 'flare'), presumably as a result of tumour-cell necrosis. Tumour markers should then fall consistently, although, not uncommonly, marker levels do not fall at half-life rates. The tumour markers fall into the normal range in the great majority of patients. However, those patients with very high initial serum markers, particularly those with choriocarinoma and a very high hCG, commonly develop a plateau in the range of 10-50 IU/L. Whereas rising tumour markets clearly represent relapse of cancer, this is not necessarily the case with patients who have achieved a plateau. These patients can be observed- or, where necessary, operated on to rescet residual masses- after which the tumour markers fall permanently to normal in around 50 per cent of cases, often despite the absence of histological evidence of cancer in resected masses. In the remaining cases, rapid relapse generally occurs, requiring combination chemotherapy. Radiologically, tumour masses usually respond promptly to chemotherapy, although, paradocxically, those of choriocarcinoma are often slow to respond. This may be a particular problem where gross pulmonary disease is present. It is important to be aware that growth of metastatic tumour (most commonly in the abdomen) may occur whilst tumour markets are falling. This is known as the 'growing teratoma syndrome' and is commonly due to expansion of masses of differentiated teratoma (Fig. 20.7). This should not be regarded as failure of chemotherapy, and surgery is indicated. Timing this relative to chemotherapy administration must be subject to the site and extent of tumour masses, the level of tumour markets and the response of disease at other sites.
 * p.717


 * Once chemotherapy is completed, complete radiological and marker re-evaulation is indicated. Residual masses are common, particularly in patients with initially bulky disease and where elements of teratoma differentiated were present in the primary tumour (and therefore possibly in a proportion of metastates). It is not possible absolutely to predict the composition of residual masses; these may contain necrotic tissue, teratoma differentiated or cancer (although the last-mentioned is uncommon in the absence of rising tumour markers). Many masses comprise a mixture of these histological elements. Except in special circumstances (marker plateau), surgery is not recommended in this last group. In all other cases, it is recommended that all abnormal masses visualized on abdominal CT scan be excised, certainly if these are more than 1.0 cm in diameter. However, clinical sense dictates that high tumour masses at presentation that are resolving satisfactorily (e.g. 20 cm retroperitoneal mass reducing to 2 cm) may be observed for a short while to see if they regress further spontaneously. In the UKK, template RLND is used where possible, with, in addition, the removal of all visibly abnormal disease sites. When bulky disease is present this surgery can be complex, and occasionally patients will require resection of a kidney, the inferior vena cava or a length of aorta in order to achieve complete removal of tumour masses. Residual lung masses seen on chest X-ray should also be resected if this is technically feasible, and combined thorocolaparotomy is a possibility if both abdominal and lung masses require resection. When this combined approach is not reasonable, laparotomy is generally performed first, with observation of the pulmonary masses during the time of recovery. If the primary tumour is still present, orchidectomy is recommended post-chemotherapy. Careful histological evaluation of resected tissue by an experienced histopathologist is essential. Completely resected necrotic tissue or teratoma differentiated (which may appear quite dyspastic) required no further therapy (Fig. 30.8). Patients in whom cancer is resected should be considered for further chemotherapy – generally with two more courses of BEP. This is, however, an individualized patient decision.
 * pp.717-718


 * Following chemotherapy and surgery (where necessary), a baseline CT scan of all previously abnormal areas should be obtained. Further short-internal CT is not necessary if this study is normal. Patients should initially be monitored monthly with marker estimations. Chest X-rays are only worthwhile is metastatic disease s still visible in the chest after chemotherapy. Relapse from complete remission is relatively unusual (10-15 per cent of cases), occurring most commonly in patients with initial poor-prognosis disease or with residual unresectable disease in the chest or abdomen. In Southhampton, the relapse rate from complete remission is 12 per cent. Half these relapses occur within 2 years of completing chemotherapy and half later. Relapses at up to 20-25 years post-chemotherapy have been recorded, particularly in patients with initial bulky disease, unresectable masses or resected teratoma differentiated. After an initial close surveillance policy, post-chemotherapy follow-up can eb rapidly reduced to 6 monthly then yearly. Currently patients treated with chemotherapy alone who achieve complete remission should probably be followed for at least 5 years. Those in whom residual masses remain, or in whom teratoma differentiated has been resected, should be followed for life. There may be a role for follow-up CT scans in these latter patients, perhaps at 5-year intervals.
 * p.718

"Growing teratoma syndrome" (2014)
Scavuzzo A, Santana Ríos ZA, Noverón NR, Jimenez Ríos MA (2014). "Growing teratoma syndrome". Case Reports in Urology. 2014: 139425.
 * Growing teratoma syndrome (GTS) is a rare condition related to both testicular and ovarian carcinoma. The incidence of GTS after testicular NSGCT is 1.9–7.6%, while in the setting of ovarian germ cell neoplasia is unknown. It is characterized by an increase in metastatic mass caused by mature teratoma in patients with no viable germ cell tumor during or after chemotherapy. According to Logothetis criteria, the definition of GTS includes (1) normalization of serum tumor markers, alpha fetoprotein, and human chorionic gonadotropin; (2) enlarging or new masses despite appropriate chemotherapy for nonseminomatous germ cell tumors; and (3) the exclusive presence of mature teratoma in the resected specimen. Surgical treatment and prognosis are highly dependent on the timing of diagnosis.
 * p.1


 * The etiology of GTS is unknown but there are two mustquoted hypotheses: chemotherapy cures immature malignant cells but remains untreated and grows the mature benign teratomatous elements; chemotherapy alters the cell kinetics toward transformation from a totipotent malignant germ cell toward a benign mature teratoma. While the growing teratomas are considered benign, they have rapid expansion with median linear growth of 0,5– 0,7 cm/month and volume increase of 9,2–12,9 cm3 /month, though the growth patterns are variable. Their behaviour is unpredictable for aggressive local spread and potential malignant degeneration.
 * p.3


 * This syndrome has been reported in the retroperitoneum (the most common site), lung, cervical lymph nodes, mediastinum, supraclavicular lymph nodes, inguinal lymph nodes, forearm, mesentery, liver, and pineal gland. According to Andre et al., there are elements that predict the development of GST: the presence of teratoma mature in the primary NSGCT, no decrease in the size of tumor during chemotherapy; the presence of teratoma in postchemotherapy residual masses. So, close follow-up by radiological imaging, possibly after 2 cycles of chemotherapy, for early recognition of GST is necessary in patients with factors risk. Keep in mind that when surgery is delayed, prevalent complications are caused by local compression, including obstructive renal failure or bowel, duodenal, bile duct, or large vessel obstruction. Expeditious surgery is important, as with time, so it can develop unresectable disease. Surgical resection is currently the gold standard treatment for GST, since teratomas are resistant to chemotherapy and radiotherapy. Two described cases are bulky teratomas (defined as >10 cm) with high volume that represent a technical challenge for possible intraoperative complications. In a series reported the volume of the tumor is associated with increased difficulty in dissecting the tumor mass from major vascular structures; the risk of resection of vena cava and nephrectomy rate were 7,1 and 31,3%, respectively. The involvement of vascular structure or other organs is not considered as contraindication for the surgery. Still our cases suggest that it is possible to carry out the surgery procedure also in front of large tumors, taking into account the possibility of eventual resection and reconstruction of adjacent vascular structures. So we found that transverse abdominal incision is safe and an appropriate broader access rather a midline laparotomy. Aggressive surgery with resection of major abdominal vascular and visceral structure is necessary for giant tumors to obtain complete excision of retroperitoneal mass. Various series supported that surgical treatment is curative and the local recurrence is lower when the tumor is completely removed. Local recurrence may be attributable to inadequate and incomplete resection. Data reported into two large studies, by Spiess et al., the 5- year overall survival were 89-90% in patients who underwent complete resection.
 * pp.3-4


 * Patients with advanced germ cell tumors should receive coordinated care by treating urologist and oncologist to recognize promptly GST and to achieve good outcomes. Complete surgical treatment is recommended, even if it is technically challenging, to avoid mechanical complication and malignant transformations. In cases of bulky teratomas, surgery should be performed at a highly specialized center with a skilled surgeon.
 * p.4

"Teratomas in infancy and childhood. A 54-year experience at the Children's Hospital Medical Center" (September 1983)
Tapper D, Lack EE (September 1983). "Teratomas in infancy and childhood. A 54-year experience at the Children's Hospital Medical Center". Annals of Surgery. 198 (3): 398–410.
 * Immature teratomas were significantly larger than mature tumors in nearly all sites where statistical analysis was possible. The single most important factor affecting prognosis was whether the tumor could be resected successfully at initial surgery. No patient who did not undergo surgery, or in whom only partial resection was possible, survived the disease--regardless of other treatments used. Based upon the experience reported here the authors conclude: 1) complete surgical resection is the treatment of choice for all childhood teratomas; and 2) this is one of the few childhood tumors where decisions regarding adjuvant therapy must be individualized, particularly with regard to site of origin and age of the patient.
 * p.398


 * TERATOMAS are neoplasms composed of tissue elements foreign to the organ or anatomic site of origin, and in childhood these tumors are notable for their diversity in anatomic location and biologic behavior. Etymologically the word teratoma is derived from the Greek "teratos" which literally means monster. As such, this clearly denotes the disturbed or malformed growth and appearance of these tumors. The earliest record of a sacrococcygeal teratoma was inscribed on a Babylonian cuneiform tablet dated approximately 600 B.C. In the modern era, Drs. Gross and Clatworthy described forty infants and children who presented with sacrococcygeal teratoma and made important suggestions regarding appropriate treatment.' Teratomas display various degrees of differentiation, ranging from primitive somatic elements to highly organized axial and metameric structures meriting in one extreme the designation of fetus-in-fetu. They can affect individuals of all ages, but those occurring in childhood are of special interest since biologic behavior is strongly related to age at diagnosis and anatomic site of origin.
 * p.398


 * Histologically, teratomas typically contain tissue elements of tridermal lineage, i.e., ectoderm, endoderm, and mesoderm; but in recent decades, this definition has become less stringent with the acceptance of examples that are composed of only bidermal ingredients. In the classification of ovarian teratomas, there are even highly specialized variants that are considered to be monodermal, i.e., ovarian carcinoid tumors. The issue of histogenesis remains complex and unsettled, particularly for extra-ovarian tumors. Popular theories of histogenesis include origin from primordial germ cells and primitive somatic cells that have escaped influence of organizers and inducers. In recent decades, there have been a number of clinical and pathologic studies of teratomas arising in specific organs or sites such as ovary, testes, sacrococcygeal region, mediastinum, and retroperitoneum. There have been relatively few accounts of a large series detailing the cumulative experience from a single institution devoted to pediatric care. Some previous studies have included patients with frankly malignant germ cell elements (e.g., embryonal carcinoma), thereby making comparison with the results from studies with only pure teratomas difficult.
 * pp.398-399


 * The term teratoma as used herein refers to a neoplasma containing at least two germ layer derivatives typically foreign to the anatomic site of origin which, on initial resection or biopsy, contained no frankly malignant elements such as embryonal carcinoma.
 * p.399


 * Exclusive of testes, staging criteria for teratomas in other anatomic sites are not well defined and specification of extent of disease remains more or less descriptive.
 * p.399


 * Briefly, the histologic grade of the primary or metastatic tumor was based upon the degree of immaturity of the tissue elements present and the amount of primitive neuroepithelial components. By convention, mature teratomas are composed of well-differentiated tissue elements and were assigned a grade of 0. Increasing grades of immaturity from I to III were assigned when immature tissues (predominantly neuroepithelial) became progressively more prevalent in representative tissue section as outlined by Norris et al. Assignment of a meaningful and reproducible histologic grade depends to a large extent upon an adequate sampling of the resected primary tumor. Once again, it should be emphasized that tumors containing any recognizable component of embryonal carcinoma at the time of initial therapy were excluded.
 * p.399


 * The most common clinical manifestation of teratomas as a group is a mass lesion with signs or symptoms ascribable to specific location and consequent impingement upon or compression of adjacent organs or tissues (Fig. 1). The age at diagnosis and anatomic location of the tumor together establish many of the clinical and pathologic correlates and ultimately the prognosis. The clinical features of some of the more commonly occurring teratomas are considered separately.
 * p.399


 * Sacrococcygeal teratomas. These tumors accounted for 40% of all teratomas in the first two decades of life and were overwhelmingly the most common type in early childhood (Table 1). In our experience, they rank as the most common type of congenital neoplasm and typically present in the newborn era as an exophytic mass (AAP types I and II) which is usually midaxial in location (Fig. 2). Some tumors display para-axial growth away from the midline. Rare tumors of large size cause birth dystocia, and in two cases, there was evidence of high output heart failure presumably due to vascular shunting through the tumor. Changes in overlying skin such as redundancy or patchy, dark discoloration can simulate a hemangioma or lymphangioma (Fig. 3). There was a decided predilection for females in a ratio of 7:1. There were no significant differences in age or AAP type of tumor for children with mature versus immature teratomas. Immature teratomas were significantly larger than the mature ones (11.6 cm versus 7.5 cm) (Table 2).
 * pp.399, 401


 * Ovarian teratomas. The ovary is second only to the sacrococcygeal area as the most common site for the appearance of teratomas in childhood (Table 1). Ovarian teratomas (Table 3) are quite rare within the first 24 months of life and seldom appear before 6 years of age. The mean age at diagnosis was 13 years and was similar for patients with immature and mature teratomas. Patients typically presented with symptoms or signs ascribable to an intraabdominal adnexal mass, and a palpable tumor was usually apparent on physical examination. Five patients had bilateral mature tumors (7%). The immature teratomas of the ovary were significantly larger than the mature ones (17.9 cm versus 8.7 cm) (Table 3). Retroperitoneal teratomas. These tumors posed a significant problem in the differential diagnosis of an intraabdominal mass due to the young age of the patients (mean age, 5 months) and the consequent confusion with Wilms' tumor, neuroblastoma, and other intraabdominal masses (Table 4). As with teratomas in other sites, the presence of calcification or bony structures on plain radiographs was a useful diagnostic aid, but was apparent only in a minority of cases. Teratomas ofthe head and neck region (Table 5). Each of these tumors was diagnosed in the immediate newborn period and they were similar to those arising in the sacrococcygeal region. The most common site of origin was the anterior or lateral neck, followed by the face, oro- or nasopharynx, and orbit. Sex distribution was roughly equal. Clinically, some of the tumors simulated a lymphangioma or cyst hygroma, particularly those that were cervical in location. The solid, nonfluctuant nature of the tumor, coupled with the occasional calcification evident by radiography, provided valuable aid in resolving the differential diagnosis. Mediastinal teratomas. The mean age at diagnosis was 8 months and the affected children usually manifested a combination of symptoms such as dyspnea, cough, fever, or chest pain. Chest radiography demonstrated a mediastinal mass in most cases with localization in the anterior/superior mediastinum. In one patient, the tumor was located in the posterior mediastinum (case 9) (Table 6). A small but important subset of teratomas was situated within the pericardial sac near the base of the heart (cases 5 and 10) (Table 6). Both of these newborns presented with signs and symptoms mimicking congenital heart disease or idiopathic cardiomegaly. Testicular teratomas. Testicular teratomas, like the ovarian group, were present more commonly outside the newborn period (Table 7). The mean age at presentation was 31/2 years. Younger children commonly have testicular teratomas, whereas the adolescent more commonly has a germ-cell neoplasm.
 * p.401


 * Teratomas arising in other sites follow similar patterns. Those in the central nervous system, liver, abdominal wall, and soft tissue of the back frequently present as masses in the newborn period. Immature teratomas were significantly larger than the mature ones.
 * pp.401-402


 * Teratomas vary considerably in size, depending upon site of origin and whether or not histologically immature elements were predominant. The largest tumors arose in the ovaries followed by retroperitoneum, sacrococcygeal region, and mediastinum (Table 1). The tumors had a similar gross appearance, regardless of site, and were well circumscribed with no direct invasion of adjacent soft tissue or bony structures. The tumors, regardless of site, typically had a variegate gross appearance on cross section, reflecting the diversity of tissue elements present and the presence or absence of immature elements. As a general rule, immature teratomas were more solid on section than the mature ones (Fig. 4). Necrosis and/or hemorrhage were unusual macroscopic features, even in immature teratomas of high grade. When present, these features were more often seen in the larger neoplasms, arising in the ovary, retroperitoneum, or sacrococcygeal region.
 * pp.402-405


 * Two or more embryonic germ layer derivatives were apparent in each of the tumors, and all three were well represented in 90% or more of the cases (Fig. 5). The expression of tissue types and their arrangement and degree of differentiation varied from case to case and even within areas of the same tumor, depending upon extent and adequacy of sampling.
 * p.405


 * Complete surgical resection remains the prime goal in each case, but anatomic localization of tumor proved to be the most significant extenuating factor in optimal management and clinical outcome. Optimal treatment of sacrococcygeal teratomas was end block removal of the tumor along with the coccyx. Significant presacral extension (AAP types III and IV) presented some technical difficulties. While mature and immature teratomas were deemed equally resectable, children with immature tumors experienced significantly greater blood loss during surgery. The tumors that were least amenable to complete resection were those arising in the retroperitoneum and central nervous system (Tables 5 and 8). Complete removal was hampered by extensive local growth or close relation with adjacent vital structures. Intrapericardial teratomas present difficulties in management as well as diagnosis due to close relation with the great vessels at the base of the heart.
 * p.405


 * In this series, there were 21 tumor-related deaths (9%). When this mortality was analyzed according to anatomic location, children with central nervous system tumors experienced the highest fatality rate (66%), regardless of whether the tumor was histologically mature or immature. This was a reflection of technical difficulties in complete surgical resection that was possible in only two cases (Table 8). Patients with immature ovarian teratomas ranked second in terms of fatal out-come (38%) (Table 3). Another patient (case 15) underwent successful resection of an immature ovarian teratoma, but 8 years later developed endodermal sinus tumor of the contralateral ovary and died with massive intraabdominal carcinomatosis 1 year later. An additional patient (case 10) (Table 3) is currently alive with presumptive evidence of metastatic immature teratoma in the lung parenchyma. Tumor-related deaths in the other areas were as follows: retroperitoneum-27% (Table 5), mediastinum- 18% (Table 6), sacrococcygeal region- 15% (Table 2), and head and neck region 14% (Table 5).
 * pp.405-406


 * Within the last decade, adjuvant radiation and chemotherapy have been added to the treatment of many patients with immature teratomas or teratomas that could not be completely resected.
 * p.406


 * The opportunity to examine a large series of teratomas treated at a single institution over more than 5 decades has allowed us to place into perspective and comparatively analyze their clinical and pathologic features. The differential diagnosis, treatment, and prognosis for childhood teratomas is strongly influenced by anatomic location of the primary tumor and age of the patient. The clinical stage or extent of disease and histologic grade of immaturity are also significant features but assume greatest importance with immature ovarian teratomas. With regard to histologic grading, it is encumbent upon the pathologist to adequately sample the primary tumor or its metastases. In general, one histologic section for every 1 to 2 cm of tumor diameter appears adequate.
 * pp.406-407


 * The most important variable affecting long-term survival is the surgeon's ability to completely resect the tumor. Although resectability in some instances may be a reflection of size and histologic immaturity of the primary tumor, it is most often related to the strategic localization of the tumor, thus defying complete or safe removal. This is most apparent for retroperitoneal and central nervous system tumors. The overall mortality for children with mature teratomas was significantly less than for those with immature tumors. Twenty per cent of all the tumors were classified as immature. The most common teratomas in infancy are those arising in the sacrococcygeal region. Adverse prognostic factors include older age at diagnosis, a substantial presacral or endopelvic component (AAP type II-IV), and the presence of endodermal sinus tumor (yolk sac tumor, Teilum tumor). It is important to recognize these frankly malignant elements.
 * p.407


 * Each tumor had been well sampled at the time of initial surgery to exclude the presence of frankly malignant elements. However, there is some doubt, in our opinion, as to whether the original tumor had been resected in its entirety. If this is true, it suggests that histologically immature tumors may have the capacity to spawn frankly malignant elements if allowed to persist.
 * p.407


 * Sacrococcygeal tumors with any recognizable embryonal carcinoma at inception must be considered separately with regard to survival analysis. Noseworthy et al. reported that of 19 children with sacrococcygeal tumors containing embryonal carcinoma, either pure or admixed with teratomatous elements, none survived.
 * p.408


 * With regard to ovarian teratomas, the single most important prognostic factor is clinical stage. The degree of immaturity ofthe primary tumor seems to correlate with extra-ovarian spread while the histologic grade of the metastases determined the ultimate prognosis. This was amply demonstrated in a series of 58 immature ovarian teratomas reported by Norris et al. When survival was stratified according to histologic grade of the primary tumor, the following was observed: grade I-81% survival; grade II-60% survival; and grade 111-30% survival. It should be stressed that clinical staging can yield some unreliable or misleading information, particularly in a retrospective analysis. Often, there is failure to carefully inspect the peritoneum and upper abdomen for gross or microscopic disease, which can only be revealed by biopsy or omentectomy. The combination of careful staging and accurate assessment of histologic grade is most valuable in establishing a prognostic profile. Some ovarian teratomas contain frankly malignant germ cell elements such as embryonal carcinoma, and the prognosis in these cases is significantly less favorable.
 * p.408


 * Adjuvant therapy has an established role in the management of immature ovarian teratomas, particularly the use of combination chemotherapy. In this overview of childhood teratomas, immature teratomas of the ovary are the only situation where adjuvant therapy can be recommended on a routine basis. Its use for immature teratomas in other sites must be evaluated on an individual basis, particularly for those tumors in early infancy where histology is not an entirely reliable predictor of subsequent biologic behavior. The prognosis for children with retroperitoneal teratomas and teratomas in other selected sites, such as the central nervous system, depends primarily upon the adequacy of resection. With regard to retroperitoneal tumors, there is some indication in our material that advanced histologic grade correlates with larger tumor size and, hence, unresectablility. In patients with large teratomas not amenable to complete surgical resection, adjuvant radiation and/or chemotherapy might make a subsequent complete resection possible. This approach may prove beneficial in patients with retroperitoneal teratomas, a group who had one of the highest incidences of incomplete resection and very poor survival.
 * p.408


 * A recent review of immature mediastinal teratomas by Carter et al. showed a favorable prognosis for young children where tumors are characterized as space-occupying but non-aggressive neoplasms. Infants with intrapericardial tumors, mature or immature, posed different problems since they can clinically masquerade as cardiomegaly. Those correctly diagnosed often present significant technical problems due to cardiac tamponade and compression of the great vessels at the base of the heart. Since ultimate outcome seems dependent upon complete resection, it may be appropriate to aggressively try to resect these tumors. This might necessitate cardiopulmonary bypass and hypothermic arrest to completely excise the tumor.
 * p.408


 * In conclusion, it is encumbent upon the surgeon to make every effort to completely excise the teratoma. This might include cardiopulmonary bypass for large mediastinal tumors, adjunctive radiation and chemotherapy to shrink central nervous system or retroperitoneal teratomas to allow resectability, and careful staging of the peritoneal surfaces in an ovarian teratoma to rule out concommitant intraabdominal disease. Careful assessment of age and location is important in establishing a reliable prognostic profile. The pathologist assumes an important role in accurate determination of histologic grade, adequacy of resection, and the presence or absence of unfavorable histologic elements such as embryonal carcinoma. Tumors containing frankly malignant elements should be separated with regard to planning therapy and subsequent analysis of survival data. Survival of patients with immature teratomas in selected sites, (e.g., ovary) may be improved by routine adjuvant therapy. Similar teratomas in other sites must be evaluated on an individual basis, particularly in infancy. Finally, long-term follow-up is recommended for all patients, particularly those with immature teratomas.
 * p.408


 * DISCUSSION DR. JUDSON G. RANDOLPH (Washington, D.C.): I wish to corroborate the authors' conclusions in one area of this study by referring to the data accumulated several years ago in a national review of sacrococcygeal teratoma. My co-workers in this were Dr. Peter Altman, now at Columbia Presbyterian, and Dr. John Lilly, now at Colorado; and these data have the inherent strengths and weaknesses of all combined national studies; that is, large numbers, but individual variation. (Slide) This shows a comparison of types of sacrocoxxygeal teratoma, and we noticed, as would be obvious, that when there is an external position, then complete surgical excision is much more likely; and as the tumor extended into the abdomen, fewer could be excised completely, and so the survival rate was influenced. (Slide) This particular slide shows a point that I think Dr. Tapper made very well, and that is that malignant changes occur in teratoma as time runs on. In those tumors which were resected before 2 months, the survival rate was about 90%, whereas after 2 months biologic changes had occurred with respect to malignancy which made curative resection much more difficult to achieve. I think that the temporally related changes in teratoma are significant, and will influence, in spite of the best surgical effort, certain results. I have two questions for the authors. Do teratomas in different locations behave differently with respect to their propensity to mature and develop malignant potential? Second, with respect to decisions at the operating table, can we get representative biopsies from these tumors in one or two places, or can frozen sections sometimes be misleading?
 * p.409


 * DR. J. ALEX HALLER, JR. (Baltimore, Maryland): I am sure we are going to be able to get information from the published data that will be invaluable to us in the prospective evaluation of children who are being treated currently in our different children's centers. One of the things that has been of great concern to me and, I am sure, others who care for these children, particularly with the large presacral teratomas, is the return, or lack of return, of function as a result of the distortion of the rectum, urethra and vagina. (Slide) Dr. Tapper indicated that there was striking distortion in this area as a result of these very large masses of tumors. Sometimes the rectum lies almost over the sacrum; at other times, the perineum is distorted completely above the pubic symphysis. Although there is good survival, the real question in my mind has been, are we going to have incontinent children, or problems with that perineal area? I would like to ask Dr. Tapper, in his follow-up studies, has he noted a major problem with functional disturbance? We have now followed seven children into teenage with large presacral teratomas, and each of those children has had absolutely normal rectal and urinary function. There has been a delay in toilet training in several of them, simply because of the time required for the return of some of these structures to normal anatomic relationship, but all are currently continent, and I wonder if that has also been his experience. I would like to ask him one final question. Dr. Tapper implied that chemotherapy may be indicated in the treatment of the presacral teratoma on the basis of good results from similar management of ovarian teratomas. This concerns me somewhat, because, if I understand the statistics correctly, the long-term results of the surgical resection of ovarian teratomas and presacral teratomas are just about exactly the same. I am concerned that, while there may be a response in ovarian tissue, that may be specific rather than because of its being in that particular position. What evidence is there that we should begin projecting the use of potential poisons in children who have a 90% longterm survival with adequate resection initially?
 * p.409


 * DR. JAMES A. O'NEILL, JR. (Philadelphia, Pennsylvania): These are relatively rare tumors, and in most major institutions really occur only a very few times a year. This series is a classic in terms of difficulty of pathologic interpretation. For example, in a recent instance, only one of 22 slides was characteristic of malignant change; and therefore this becomes a problem. My first question relates to one of the things we have had a recent interest in. In order to differentiate those tumors which may be more mature from those which have a greater malignant potential, we have been looking at tumor markers, such as AFP, HCG, and CEA, either in serum or in tissue. From your series, Dr. Tapper, have you any additional information regarding the use of markers? I too agree with Dr. Haller's concern regarding the addition of adjuvant chemotherapy. We are dealing with very small, delicate subjects. The adjuvant chemotherapeutic approach is an exceedingly toxic one, and all of us have patients who have died primarily on the basis of application of chemotherapy in the neonatal age group. Therefore, if one is to take on a, perhaps, prophylactic approach under these circumstances without more definitive evidence of probable malignancy, what regimens would you select in terms of modifying very toxic chemotherapeutic regimens.
 * p.409

"Spectrum of ovarian tumors in a referral hospital in Nepal" (2014)
Vaidya S, Sharma P, KC S, Vaidya SA (2014). "Spectrum of ovarian tumors in a referral hospital in Nepal". Journal of Pathology of Nepal. 4 (7): 539–543.
 * Results: Of the 363 ovarian tumors, 293 (80.72%) cases were benign, 57 (15.70%) were malignant and 13 (3.58%) were borderline. Germ cell tumour was the most common class of tumour and seen in 187 (51.52%) cases, followed by surface epithelial in 158 (43.53%) cases. The age distribution of the patients ranged from 10-82 years with a median age of 33 years. Benign tumors were more common than malignant ones in all age groups. Conclusion: Most of the ovarian tumors in this study were of germ cell origin. The incidence of malignant germ cell tumors was also significantly higher than in other studies. Mature cystic teratoma was the most common benign tumour while serous carcinoma was the most common malignancy. The incidence of malignant germ cell tumors was higher compared to other studies.
 * p.539


 * In this study, 80.72% (n=292) of the ovarian tumors were benign. This is similar to data from the west and the subcontinent, including Nepal. The frequency of borderline and malignant tumors in the subcontinent was variable from 0.72 to 4.33% and 9.5 to 30.96%, respectively. In our study, mature cystic teratoma was the most common benign tumour (57%) where as serous carcinoma was the commonest malignancy (29.82%). Similar findings were reported in other studies. Germ cell tumors constitute 15-30% of all ovarian tumors. However, in one North American study, the figure was surprisingly high 58%. Similar high incidence of 51.52% was also observed in our study. About 95% of these tumors are benign (predominantly mature cystic teratomas) while the incidence of malignant ovarian germ cell tumors ranges from 1 to 6% as reported in the west and from 5 to 20% in Asia. In our study, the incidence of benign germ cell tumors was similar to the numbers reported elsewhere. However, the incidence of germ cell malignancies was much higher accounting for 31.58% of all ovarian cancers.
 * p.542


 * In agreement with other studies, most ovarian tumors were seen in the reproductive age group, between 20-40 years. Benign tumors of all were seen in all age groups. Malignant surface epithelial tumors occurred mostly after the 4th decade. Similar observations were also made in other studies. In patients under the age of 21 years, approximately 60% of the ovarian tumors are of germ cell origin, and as many as one third of germ cell tumors are malignant, accounting for two thirds of ovarian cancers in the first two decades. In our study, 68.18% of the tumors seen in this age group were of germ cell origin and 20% of these germ cell tumors were malignant.
 * p.542


 * In our study, most of the tumors were of germ cell origin. The incidence of malignant germ cell tumors was higher than in other studies. Mature cystic teratoma was the most common benign tumour while serous carcinoma was the commonest malignancy. Benign tumors were more common than malignancies in all age groups. Malignant surface epithelial tumors were mostly seen after the 4th decade while malignant germ cell tumors were observed in a younger age group.
 * p.543