Whole-Genome and Segmental Homozygosity Confirm Errors in Meiosis as Etiology of Struma Ovarii.

Strumae ovarii are neoplasms composed of normal-appearing thyroid tissue that occur within the ovary and rarely spread to extraovarian sites. A unique case of struma ovarii with widespread dissemination detected 48 years after removal of a pelvic dermoid provided the opportunity to reexamine the molecular nature of this form of neoplasm. One tumor, from the heart, consisting of benign thyroid tissue was found to have whole-genome homozygosity. Another tumor from the right mandible composed of malignant-appearing thyroid tissue showed whole-genome homozygosity and a deletion of 7p, presumably the second hit that transformed it into a cancerous tumor. Specimens from 2 other cases of extraovarian struma confined to the abdomen and 8 of 9 cases of intraovarian struma showed genome-wide segmental homozygosity. These findings confirm errors in meiosis as the origin of struma ovarii. The histological and molecular findings further demonstrate that even when outside the ovary, strumae ovarii can behave nonaggressively until they receive a second hit, thereafter behaving like cancer.

Classic and "Dissecting" Gonadoblastoma in a Phenotypic Girl With a 46, XX Peripheral Karyotype and No Evidence of a Disorder of Sex Development.

Herein, we report a case of a 9-yr-old girl who had a 46, XX peripheral karyotype and apparent developmentally normal ovaries. She presented with abdominal pain and a right adnexal mass. No clinical or pathologic evidence of gonadal dysgenesis or undifferentiated gonadal tissue was detected. She underwent right salpingo-oophorectomy with rupture of the tumor at the time of operation due to recent adnexal torsion. The original pathologic diagnosis was gonadoblastoma and mixed germ cell tumor. Most significantly in our study, we identified a rare and novel pathway for the development of malignant mixed germ cell tumor from gonadoblastoma in the absence of identifiable dysgerminoma. The histologically identifiable steps of progression in our case were as follows: (1) residual islands of classic gonadoblastoma, (2) overgrowth by "dissecting" gonadoblastoma composed of transformed germ cells with clear cytoplasm and sex cord elements surrounded by a basement membrane, (3) stromal infiltration by dedifferentiated germ cells with loss of basement membrane, (4) formation of malignant mixed germ cell tumor. The dedifferentiated areas were composed of anaplastic germ cells with amphophilic cytoplasm that gradually replaced the sex cord elements by clonal expansion. Both the original transformed and the anaplastic germ cell components strongly expressed OCT4. We believe that the mixed germ cell tumor arose from the dedifferentiated germ cell component through neoplastic progression. This premise suggests that the germ cell component of "dissecting" gonadoblastoma rarely undergoes anaplastic change in the absence of transition to germinoma and can be the direct precursor of mixed germ cell tumor.

Classical gonadoblastoma: its relationship to the 'dissecting' variant and undifferentiated gonadal tissue.

Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development. Approximately 40% of such neoplasms are bilateral. Almost all gonadoblastomas occur in patients who have a Y chromosome or part thereof; testis-specific protein Y-encoded 1 (TSPY1) is the putative gene. If a gonad in a patient who has a disorder of sex development contains germ cells with delayed maturation, and also harbours the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements and hyaline basement membrane material surrounded by a variably cellular gonadal stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a non-invasive neoplasm that is the precursor of germinoma and, indirectly, other more aggressive germ cell neoplasms. Undifferentiated gonadal tissue is the precursor of classical gonadoblastoma and contains germ cells with delayed maturation that express octamer-binding transcription factor 4 (OCT4); however, other germ cells show normal maturation and express TSPY1. If all germ cells in a patient with undifferentiated gonadal tissue involute, the result is a secondary streak. Undifferentiated gonadal tissue is a non-neoplastic condition that should be distinguished clearly from 'dissecting gonadoblastoma', a neoplasm derived from classical gonadoblastoma that is the precursor of some germinomas. 'Dissecting gonadoblastoma' is a variant of classical gonadoblastoma that has unusual growth patterns and contains both sex cord and germ cell elements. Clonal expansion of germ cells is a characteristic of the late stage of 'dissecting gonadoblastoma'.

Evidence of a dual histogenetic pathway of sacrococcygeal teratomas.

AIMS: Sacrococcygeal teratomas are rare tumours that occur most frequently in neonates, although adult cases also occur. The molecular pathogenesis of these tumours and their long-term prognosis is uncertain. We investigated the i(12p) status of a large number of primary sacrococcygeal teratomas in both children and adults, including cases with malignant germ cell tumour elements. METHODS AND RESULTS: Fifty-four sacrococcygeal teratoma specimens from 52 patients were identified, and available follow-up information was obtained. Fluorescence in-situ hybridization analysis was performed to identify isochromosome 12p [i(12p)] abnormalities on paraffin blocks of the tumours. Among the 48 paediatric patients, there were 44 teratomas and four tumours with combined teratoma and yolk sac tumour (one of whom also had primitive neuroectodermal tumour). The teratomas included 37 mature teratomas and 11 immature teratomas (four grade 1, two grade 2, and five grade 3). The 44 teratomas lacking a yolk sac tumour component were all negative for i(12p). The four tumours with a yolk sac tumour component were all positive for i(12p). The four adult cases all lacked non-teratomatous germ cell tumour components, immature elements, and i(12p). Follow-up information was available for 32 patients. Two patients with teratoma had recurrence, but were alive with no evidence of disease after long-term follow-up. One patient with combined teratoma and yolk sac tumour had recurrence 7 months after resection. The other patients were alive with no evidence of disease at last follow-up. CONCLUSIONS: Our data suggest that paediatric sacrococcygeal teratomas should be considered as two distinct groups with divergent histogenetic pathways. The prognosis of these tumours is excellent, despite rare recurrence.

Loss of SMARCA4 (BRG1) protein expression as determined by immunohistochemistry in small-cell carcinoma of the ovary, hypercalcaemic type distinguishes these tumours from their mimics.

AIMS: Molecular investigation of small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) has revealed that it is a monogenetic tumour characterized by alteration of SMARCA4 (BRG1), encoding a member of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodelling complex. A large majority of cases show loss of expression of the corresponding SMARCA4/BRG1 protein. Furthermore, three cases of SCCOHT with retained SMARCA4 protein expression showed loss of SMARCB1/INI1 expression. The aim of this study was to assess the sensitivity and specificity of loss of SMARCA4 expression as a diagnostic test for SCCOHT. METHODS AND RESULTS: We performed SMARCA4 and SMARCB1 staining in 245 tumours, many of which were potentially in the differential diagnosis of SCCOHT. We also stained 56 cases of SCCOHT for SMARCA4 and 37 of these for SMARCB1. Fifty-four of the SCCOHT cases showed complete absence of SMARCA4 expression. The two cases with retained expression showed molecular alteration of SMARCA4. Of the 217 other neoplasms with interpretable staining, all retained SMARCA4 expression. Although the majority showed diffuse, strong nuclear expression, a heterogeneous, typically weak staining pattern was present in 13% of cases. All 37 cases of SCCOHT tested and all other neoplasms, apart from three malignant rhabdoid tumours, showed retained nuclear SMARCB1 expression. Loss of SMARCA4 expression had a sensitivity of 96.55% and specificity of 100%. CONCLUSIONS: Loss of SMARCA4 expression is sensitive and specific for SCCOHT. Although some mimics show heterogeneous expression, there is retention of nuclear staining in at least a part of the tumour; therefore, only complete loss of staining should be regarded as being supportive of SCCOHT.

Cervical Carcinomas With Neuroendocrine Differentiation: A Report of 28 Cases With Immunohistochemical Analysis and Molecular Genetic Evidence of Common Clonal Origin With Coexisting Squamous and Adenocarcinomas.

Cervical neuroendocrine carcinomas are rare, aggressive tumors and their immunohistochemical features and clonal relationship to coexisting tumors are incompletely described. Twenty-eight cases were identified (17 small cell, 9 large cell, and 2 mixed), 10 of which had an invasive squamous or adenocarcinoma component. Staining for synaptophysin, chromogranin A, TTF1, c-kit, CD44, and p16 was performed. Analyses for loss of heterozygosity (LOH) at 5 polymorphic microsatellite markers (D3S1300, D9S171, D11S914, D13S319, and TP53) and X-chromosome inactivation were performed. Of 17 cases with available blocks, 13 (76%) were synaptophysin+, 8 (47%) were chromogranin A+, 8 (47%) were TTF1+, 7 (41%) were c-kit+, and 6 (35%) were CD44+. Strong patchy or strong diffuse p16 staining was seen in all cases. LOH and X-chromosome inactivation analysis were performed for 17 cases, 8 of which had a coexisting squamous or adenocarcinoma component. Five of the 8 (63%) cases with 2 components showed allelic loss in both components. All 5 of these cases demonstrated identical LOH between the neuroendocrine and squamous or adenocarcinoma components. Nonrandom X-chromosome inactivation was seen in the neuroendocrine and other components in 4 of the 8 cases. In all 4 cases the pattern of inactivation was identical between the 2 components. Cervical neuroendocrine carcinomas have features similar to other extrapulmonary neuroendocrine carcinomas, including expression of TTF1, c-kit, and CD44. Consistent staining for p16 is also seen. Concordant genetic alterations support common clonal origin for neuroendocrine carcinomas with a coexisting squamous or adenocarcinoma component.

Expression of Transcription Factors and Nuclear Receptors in Mixed Germ Cell-Sex Cord Stromal Tumor and Related Tumors of the Gonads.

In this study, we compare the expression of OCT4, SALL4, and TSPYL1 in mixed germ cell-sex cord stromal tumor (MGC-SCST) of either gonad to that of normal adult testis, classic and spermatocytic seminoma, intratubular germ cell neoplasia, unclassified, gonadoblastoma, and dysgerminoma to determine the entity or entities that most closely resemble MGC-SCST by immunohistochemistry of germ cells. The most useful transcription factor was OCT4. In addition, to its already described value in distinguishing germinoma and embryonal carcinoma from yolk sac tumor and in differentiating classic from spermatocytic seminoma, we found that OCT4 is useful in confirming or ruling out potential malignancy in MGC-SCST of either gonad. Expression of OCT4 in most ovarian MGC-SCSTs resembles that of dysgerminoma, whereas most testicular examples resemble that of spermatocytic seminoma and normal adult testis. Thus, most MGC-SCSTs of the ovary are potentially malignant, and corresponding tumors of the testis are mostly benign; however, exceptions likely can be detected by the use of OCT4, potentially leading to more appropriate clinical management in some cases. SALL4 is an underutilized transcription factor that is useful in distinguishing testicular MGC-SCST from sex cord stromal tumor, unclassified in those neoplasms where the germ cells are sparse or unevenly distributed. Compared with other transcription factors studied, TSPY and its congener TSPYL1 have little value in the assessment of germ cell tumors because of their relatively wide range of expression in normal adult testis and in germ cell tumors.

Perspectives on signet ring stromal cell tumor and related signet ring cell lesions of the gonads.

In this article, we discuss advances in our knowledge of the pathology of signet ring stromal cell tumor and related signet ring cell lesions of the ovary and a single case of signet ring stromal cell tumor of the testis. We divide ovarian signet ring cell lesions into 3 categories that reflect differences in their pathogenesis and histologic appearance. With 1 exception, all authentic cases of signet ring stromal cell tumor have been unilateral. Cases of ovarian signet ring stromal cell tumor from the literature can arise in 2 ways. The majority of cases arise multifocally from fibroma, whereas the remainder likely arise directly from the ovarian stroma. In difficult cases, immunocytochemistry provides improved diagnostic accuracy in distinguishing signet ring stromal cell tumor and its mimics from Krukenberg tumor. The most useful antibodies in this regard are epithelial membrane antigen and vimentin.

On the pathogenesis of sclerosing stromal tumor of the ovary: a neoplasm in transition.

Sclerosing stromal tumor (SST) is a distinctive benign ovarian stromal neoplasm first reported in 1973. Although its initial description supports its characterization as an ovarian stromal tumor, its exact pathogenesis remains uncertain. It is usually hormonally inactive, but occasional tumors are estrogenic or androgenic, and virilization can occur during pregnancy. We report 11 cases of SST, 6 of which were associated with another type or other types of ovarian stromal tumor. In 4 of these, a transition from thecoma of either typical or luteinized type to SST was observed. Our index case was that of a 16-yr-old girl who had a typical thecoma that underwent involutional changes in an extensive subserosal portion of the tumor with conversion to SST. In our series, 3 cases of SST underwent transformation to ovarian myxoma, one of which also contained a component of thecoma. The active SST components stained for inhibin, steroidogenic factor 1, and α-smooth muscle actin, but were negative or occasionally weakly positive for desmin.

Involuting luteinized thecoma of the ovary.

Spontaneous tumor involution in ovarian stromal tumors is a poorly understood phenomenon. In this report, we describe a rare case of luteinized thecoma that showed extensive involutional changes, such that cellular elements diagnostic of luteinized thecoma were sparse. The convoluted contour of the tumor resembled that observed in a corpus albicans; however, the neoplasm was considerably larger, and the contents of the nodule differed from that of a corpus albicans. The diagnosis of luteinized thecoma was established by the identification of residual aggregates of neoplastic theca cells and a nodule of lutein cells that were positive for inhibin and steroidogenic factor-1. Features of involution within the tumor included a few theca and lutein cells with pyknotic nuclei and abundant cytoplasmic lipid, occasional large adipocytes among the lutein cells, extensive hyalinization, dystrophic calcification, a myxohyaline nodule, and adipose metaplasia. It is likely that some of the aforementioned changes are the result of accompanying ischemia. Cleaved caspase-3 staining patterns were negative within residual lutein and theca cells; thus, we were unable to establish the occurrence of apoptotic bodies.

The pathogenesis of ovarian myxoma: a neoplasm sometimes arising from other ovarian stromal tumors.

Ovarian myxoma is a rare distinctive benign ovarian stromal neoplasm that occurs predominantly in young women and is hormonally inactive. Although typically classified as an ovarian stromal tumor, its exact pathogenesis remains uncertain. We report 4 cases of ovarian myxoma, 3 of which were associated with another type or other types of ovarian stromal tumor and 1 occurred as a pure myxoma. In 2 cases, the myxoma arose from a sclerosing stromal tumor, and the third, most likely arose from a luteinized theca cell tumor (LTCT). Myxoid transformation of the connective tissue of the parent neoplasm appears to be a precursor of ovarian myxoma in some instances. We believe that the occurrence of trisomy 12 or other genetic abnormalities may play a role in this transformation. Whether or not associated with another type of ovarian stromal tumor, ovarian myxoma can be suspected macroscopically by its cystic gelatinous appearance and sharp circumscription. The most important differential diagnosis is a low-grade sarcoma with myxomatous features. We believe that myxomas arising from different anatomic sites likely are genetically, histologically, and biologically distinct. For purposes of classification, they should be considered as separate tumor types.

Ovarian yolk sac tumors in older women arising from epithelial ovarian tumors or with no detectable epithelial component.

Yolk sac tumor (YST) occurs rarely in older women, either in association with a variety of ovarian epithelial tumors or, considerably less often, without an identifiable epithelial precursor. The patients often have elevated serum levels of α-fetoprotein that roughly correlate with the amount of the YST component. In postmenopausal women with an ovarian mass and elevated serum levels of α-fetoprotein, a tumor of this type should be suspected. Endometrioid carcinoma is the most common putative precursor, and the tumor is often associated with an endometriotic cyst; however, malignant Müllerian mixed tumor and mucinous neoplasms have also been reported as precursors. We report 4 cases of YST in postmenopausal women. Of the 3 cases with an identified epithelial component, 1 was serous carcinoma, another was clear cell adenocarcinoma, and the third was an admixture of endometrioid and clear cell adenocarcinoma arising from an endometriotic cyst. Although a precursor epithelial ovarian neoplasm, typically a malignancy (somatic carcinoma), is usually identified, no precursor neoplasm was observed in 1 of our cases and in 5 cases from the literature. We believe that YSTs in older women, whether or not an epithelial component is detected histologically, constitute a single entity that is distinct from YSTs in younger patients and should be treated aggressively. Neoplasms with a YST component in older women are less responsive to the chemotherapy currently used for ovarian germ cell tumors; therefore, adjuvant therapy should include platinum-based chemotherapy designed to treat both epithelial ovarian cancer and germ cell tumors. Of the 24 reported cases, including our own, 17 died of neoplasms within 25 months and another was living with disease at 2 months. However, 2 more recent patients treated aggressively with platinum-based chemotherapy designed to treat both epithelial and germ cell tumor components with stage 1 disease are living and have been disease free >1 year after operation.

Mixed germ cell-sex cord stromal tumour of the testis and ovary: comparison and contrast.

Mixed germ cell-sex cord stromal tumours (MGC-SCSTs) of the testis and ovary differ significantly in their histological appearance, clinical behaviour, and molecular genetics. Until recently, the germ cells of testicular MGC-SCST were considered to be invariably histologically bland, whereas those from neoplasms that arise in the ovary have histological features characteristic of premalignancy. However, a recent histological and molecular genetic study demonstrated histological abnormalities and multiple chromosomal losses and gains in a small subset of testicular cases, thus providing the first evidence that testicular MGC-SCSTs can exceptionally show histological and molecular abnormalities. All cases of testicular MGC-SCST reported to date have been clinically benign, whereas ovarian examples are sometimes the precursor of a malignant germ cell neoplasm that can be clinically aggressive. Both genetic and epigenetic influences likely account for dissimilarities in these uncommon gonadal neoplasms.

Gonadoblastoma: origin and outcome.

Classical gonadoblastoma occurs almost entirely in the dysgenetic gonads of an individual who has a disorder of sex development; however, a small number of cases arise in individuals with a normal peripheral karyotype and no evidence of a disorder of sex development. Those gonadoblastomas that occur in an individual who has a Y chromosome or part thereof express testis specific protein Y-encoded 1 (TSPY1). If a gonad in those individuals contains germ cells with delayed maturation and also harbors the TSPY1 gene, the cells can undergo transformation to classical gonadoblastoma. The latter consists of rounded islands composed of germ cells, sex cord elements, and hyaline basement membrane material surrounded by a variably cellular stroma that sometimes contains steroid cells. Classical gonadoblastoma can be interpreted as a noninvasive or an in situ neoplasm that is the precursor of germinoma in some individuals and, indirectly, of other more aggressive germ cell neoplasms. The "dissecting" variant is derived from classical gonadoblastoma and is characterized by unusual growth patterns. Undifferentiated gonadal tissue is the precursor of gonadoblastoma; however, if all germ cells in an individual with undifferentiated gonadal tissue involute, the result is a secondary streak gonad. Undifferentiated gonadal tissue is a non-neoplastic condition resembling a streak gonad but additionally contains germ cells with delayed maturation that express octamer-binding transcription factor 4; however, other germ cells, show normal maturation and express TSPY1.

Gonadoblastoma versus ovarian mixed germ cell-sex cord stromal tumor in women or girls with no evidence of a disorder of sex development: A problem in differential diagnosis.

Gonadoblastoma occurring in a normal girl or woman has been confused with ovarian mixed germ cell-sex cord stromal tumor (MGC-SCST) due to a lack of knowledge that the former occurs occasionally in a normal woman or girl. In this article, we develop histological criteria that facilitate the distinction of gonadoblastoma in an individual with a normal karyotype and no evidence of a disorder of sex development from ovarian MGC-SCST. We reviewed the histological findings of gonadoblastoma occurring in normal individuals and compared them to cases of ovarian MGC-SCST in our files. The histological findings of gonadoblastoma differ substantially from those of ovarian MGC-SCST. Importantly, gonadoblastoma contains two types of transformed germ cells, some histologically benign and others premalignant, whereas MGC-SCST contains only a single type, typically premalignant in the ovary and benign in the testis. Furthermore, degenerative changes of hyalinization and calcification are common in gonadoblastoma, whereas they are extremely rare in MGC-SCST. Although the great majority of cases of gonadoblastoma occur in an individual with a disorder of sex development and an abnormal karyotype, a substantial number arise in a normal woman or girl with no evidence of a disorder of sex development. In the latter circumstance, it is important to distinguish gonadoblastoma from ovarian MGC-SCST. It is very likely that those gonadoblastomas arising in a normal individual develop through a different molecular pathway than the ones that occur in the dysgenetic gonads of an individual with a disorder of sex development.

Malignant struma ovarii: an analysis of 88 cases, including 27 with extraovarian spread.

Struma ovarii that display extraovarian spread or later recurrence is exceedingly rare. Among 88 patients with "malignant" struma ovarii followed for prolonged periods, several features helped to predict the adverse clinical course. Adhesions (graded 2 to 4+), peritoneal fluid (> or =1 L) or ovarian serosal rent were worrisome features, occurring in 74% of 27 biologically malignant tumors but only 10% of 61 clinically benign tumors. The size of the strumal component rather than the overall size of the ovarian teratoma also had some predictive value. Tumors with a strumal component < or =6 cm recurred rarely (7%), whereas 33% of the consult and 88% of the literature cases > or =12 cm were clinically malignant. Except for a papillary pattern or poorly differentiated cancer, no microscopic feature reliably predicted the clinical outcome, including those typically associated with malignancy in primary thyroid tumors. Among the consult cases, 7% with histologic follicular adenomas and 29% with papillary carcinomas were clinically malignant. Unequivocal vascular invasion was rare, precluding assessment of its effect. Optically clear nuclei, when extensive, were useful to diagnose papillary carcinoma, but were present nevertheless in smaller numbers in both macrofollicular and microfollicular adenomas. Eight tumors confined initially to the ovary (stage 1) recurred. Papillary carcinomas recurred earlier (average 4 y) than follicular adenomatous neoplasms (average 11 y, range: 1-29 y). Overall, the survival rate for all patients was 89% at 10 years and 84% at 25 years, indicating the need for routine long-term follow-up.

Highly differentiated follicular carcinoma arising from struma ovarii: a report of 3 cases, a review of the literature, and a reassessment of so-called peritoneal strumosis.

Struma ovarii has elicited considerable interest because of its many unique features since Ludwig Pick first elucidated its relationship to teratoma in the early part of the 20th century. The most common thyroid-type malignancies to arise in struma ovarii are papillary and follicular carcinomas. In this article, we describe a newly recognized neoplasm originating from struma ovarii that we interpret as follicular carcinoma with a high degree of differentiation. By definition, all of these cases have an innocuous appearance resembling that of nonneoplastic thyroid tissue in both the ovary and sites of dissemination. Including our own, 14 cases in the literature spread to the peritoneum, and 4 metastasized to more distant sites. The peritoneal involvement more often was diagnosed at the same time as the ovarian struma; however, the systemic dissemination occurred subsequent to oophorectomy. Our index patient with highly differentiated follicular carcinoma (HDFCO) developed peritoneal dissemination and para-aortic lymph node metastases 26 years after excision of ovarian struma. Vascular invasion was not identified in any of the cases; however, the primary neoplasm extended to the surface of the ovary in 2 cases with peritoneal involvement. Because of its harmless histological appearance, this form of follicular carcinoma characteristically cannot be diagnosed until the neoplasm spreads beyond the ovary, thus, showing evidence of aggressive behavior. The corollary of this observation is that cases having the histological appearance of ordinary struma ovarii can rarely behave in a malignant fashion. Although cases of typical thyroid-type carcinoma with extraovarian dissemination are relatively easy to diagnose, those with an innocuous histological appearance present nosological and diagnostic difficulties. The differential diagnosis of peritoneal dissemination of struma includes HDFCO, the typical types of thyroid cancer, and so-called strumosis. We have studied the relationship of HDFCO to cases reported as peritoneal strumosis or similar terms and doubt the existence of the latter as a distinct clinicopathologic entity. The treatment of choice for patients with HDFCO is local resection of the extraovarian tumor with subsequent thyroidectomy followed by radioactive iodine ablation.

Typical thyroid-type carcinoma arising in struma ovarii: a report of 4 cases and review of the literature.

Struma ovarii has elicited considerable interest because of its many unique features since Ludwig Pick first elucidated its relationship to teratoma in the early part of the 20th century. In this article, we report 3 cases of papillary and 1 of follicular thyroid carcinoma; 2 of these cases were associated with mature cystic teratoma. Metastases occurred in 2 patients, and 1 died of neoplasm. In regard to the occurrence of thyroid-type carcinoma in struma ovarii, precise terminology should be used, and the expression malignant struma ovarii was avoided as a diagnostic term. Upon review of the literature, papillary carcinoma and follicular carcinoma are the most frequent types of malignancy to occur in ovarian struma; other forms of thyroid carcinoma occur only rarely. The diagnostic criteria for cases of papillary carcinoma are similar to those described in the cervical thyroid gland and are based primarily on nuclear and architectural features. In reference to follicular carcinoma, invasion into the surrounding ovarian tissue, vascular invasion, or metastasis is evidence of malignancy. Histological malignancy in a struma does not necessarily equate with biological malignancy, and the majority of thyroid-type carcinomas do not spread beyond the ovary. Occasionally, metastases of ovarian struma have an innocuous histological appearance, and such cases are referred to as highly differentiated follicular carcinoma of ovarian origin (HDFCO). Because its histological appearance resembles that of nonneoplastic thyroid, HDFCO characteristically cannot be diagnosed until the neoplasm spreads beyond the ovary. In this article, we apply the term typical thyroid carcinoma to those forms of thyroid malignancy arising in ovarian struma that closely resemble the types described in the cervical thyroid gland to distinguish them from HDFCO. Typical follicular carcinoma is more aggressive than the somewhat more common papillary carcinoma, and HDFCO is the least aggressive of these tumor types. Cases of thyroid-type carcinoma arising in the ovary sometimes lack evidence of preexisting struma. The more aggressive thyroid-type neoplasms can arise in thyroid tissue within a mature cystic teratoma, or they may overgrow and replace the struma. Primary thyroid-type carcinoma must be distinguished from rare instances of ovarian metastases that originate in the cervical thyroid gland and the less differentiated forms from other ovarian neoplasms such as clear cell adenocarcinoma and tumors with an oxyphilic appearance. In the differential diagnosis with other ovarian neoplasms, cases of thyroid-type carcinoma associated with strumal carcinoid should not be diagnosed as malignant strumal carcinoid because the latter diagnosis might lead to suboptimal therapy.

Protein expression of the transcription factors DMRT1, TCLF5, and OCT4 in selected germ cell neoplasms of the testis.

In the present study, we investigated protein expression of the transcription factors mammalian doublesex and mab-3 related transcription factor 1 (DMRT1), basic helix-loop-helix transcription factor-like 5 (TCLF5), and octamer-binding transcription factor 4 (OCT4) in normal human spermatogenesis, testicular mixed germ cell-sex cord stromal tumor (MGC-SCST), spermatocytic tumor, and seminoma. In normal human spermatogenesis, DMRT1 is expressed in the nuclei of spermatogonia but not in those of more mature germ cells. By way of contrast, TCLF5 is expressed in the nuclei of some clusters of primary spermatocytes that have entered meiosis 1, in secondary spermatocytes, and in round (early) spermatids in the seminiferous tubules of adults during the reproductive years. OCT4 is expressed in primordial germ cells but not in the seminiferous tubules of the normal adult testis during the reproductive years. DMRT1 is expressed in the germ cells of both testicular MGC-SCST and spermatocytic tumor, whereas TCLF5 is not expressed in either neoplasm. These low-grade neoplasms, however, differ histologically in that all the germ cell nuclei of testicular MGC-SCST resemble spermatogonia, whereas in spermatocytic tumor, the nuclei of the medium-sized and large cells resemble those of primary spermatocytes. Both neoplasms lack expression of OCT4. By way of contrast, in seminoma, a fully malignant testicular germ cell tumor, the germ cell nuclei express OCT4 but do not express either DMRT1 or TCLF5.