This tumor (SCCH) is the most common undifferentiated ovarian carcinoma in women <40 years of age. The age range has been 7 months to 44 years, with a peak from 18–30 (mean, 24) years of age; only rare patients are in the first or fifth decades.

Rare SCCHs are familial and possibly heritable; it has occurred in three sisters, a mother and daughter, and two first cousins. The familial tumors are more often bilateral than sporadic cases, <1% of which are bilateral. One woman had the Li–Fraumeni syndrome and a liposarcoma of the cervix ( ).

About 60% of patients with a known serum calcium level have had hypercalcemia, SCCHs being the ovarian tumor most often associated with hypercalcemia, accounting for about 60% of such cases. The serum calcium can be used to monitor the disease and response to therapy.

The symptoms are usually related to a rapidly growing adnexal mass. Occasionally, symptoms related to the hypercalcemia, such as constipation, may be present. About two-thirds of tumors are stage II or higher.

The histogenesis is unknown. Some have suggested that these tumors may be of germ cell origin or a variant of rhabdoid tumor. However, we are not convinced and feel it is still best considered unclassified at this time.

SCCHs are usually large (mean diameter, 15 cm), predominantly solid, cream-colored masses. Rupture is present in at least 20% of cases, and necrosis, hemorrhage, and cystic degeneration are common; rare tumors are predominantly cystic.

Microscopic examination usually reveals a predominantly sheet-like arrangement of small, closely packed cells randomly interrupted by nests, cords, trabeculae, and individually disposed cells.

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  Variably sized follicles that are empty or contain eosinophilic or much less often basophilic fluid are found in 80% of tumors, but often only focally.

  
  
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  The typical small round tumor cells are rather monomorphic and usually have scanty cytoplasm, small hyperchromatic nuclei, and single small nucleoli; mitotic figures are frequent.

  
  
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  Occasionally minor foci of spindle cells or clear cells may be seen.

Large neoplastic cells with moderate to abundant amounts of eosinophilic cytoplasm are present in 50% of SCCHs. They usually represent a minor component but rarely are predominant or even the exclusive component (‘large cell variant’).

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  The eosinophilic cytoplasm may be dense and globular imparting a rhabdoid appearance.

  
  
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  The large cells typically have a large, pale, vesicular nucleus and a more prominent nucleolus than in the small cells. The nucleus is often eccentric when the cytoplasm is dense and globular.

Minor, usually inconspicuous, foci of mucinous epithelium occur in 10% of tumors as glands or cysts lined by benign to atypical mucinous epithelium; even signet-ring cells may be present. Merging of mucinous cells and typical small cells may be seen.

There is usually an inconspicuous nonspecific fibrous stroma, but it is occasionally prominent (usually only focally) and may be edematous, myxoid (particularly in areas with large cells), or, rarely, hyalinized.

Vascular invasion at the periphery of the tumors is common.

SMARCA4.

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  SCCHs exhibit inactivation of the SMARCA4 gene resulting in immunohistochemical loss of SMARCA4 (BRG1), a sensitive marker for SCCHs ( , , , , ). Additionally, and found that concomitant loss of SMARCA2 and SMARCA4 is specific for SCCH.

  
  
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  It should be noted that SMARCA4 ( BRG1 ) loss has been described in a range of other tumors, including but not limited to non-small cell lung carcinoma, thoracic sarcoma, and undifferentiated endometrial carcinoma.

  
  
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  Witkowski et al. found that 43% of patients with SCCH carried a germline SMARCA4 mutation (including all patients <15 years of age) and carriers presented at a younger age than noncarriers.

  
  
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  found mutations in the SMARCA4 gene in two SCCHs with foci of immature teratoma suggesting to them that SCCHs are embryonal tumors possibly related to malignant rhabdoid tumor. However, as noted above, the burden of clinical and pathologic evidence in our opinion does not support this histogenesis.

Immunohistochemistry is generally most useful for ruling out other tumors in the differential diagnosis, but several markers can express positivity to variable degrees. Diffuse nuclear WT1 (N-terminal) staining and variable EMA positivity is common, and only rare tumors in the differential diagnosis are positive for both. Other makers that can be expressed include cytokeratins (AE1/3, CAM5.2, CK7), calretinin, CD10, p53 (but without p53 mutations), and SALL4; less common markers include Ber-EP4, vimentin, NSE, CD56, synaptophysin, and chromogranin A.

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  Some SCCHs immunoreact for parathyroid-related polypeptide (and rarely parathormone), findings that do not always correlate with serum calcium levels.

  
  
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  found that ~80% of SCCH tumor samples immunohistochemically express histone methyltransferase EZH2 suggesting that pharmacologic inhibition of EZH2 may be useful in treating these tumors.

Ultrastructural findings have included epithelial features (cell junctions and partial investment by basal lamina), abundant dilated RER, and microfilaments, the last forming paranuclear whorls in the large eosinophilic tumor cells.

Flow cytometry on paraffin-embedded material has shown that the tumor cells are diploid.

Granulosa cell tumor (GCTs), adult (AGCT) or juvenile type (JGCT).

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  The cells in AGCTs have a more regular arrangement and pale grooved nuclei and lack the highly malignant nuclear features and high mitotic rate of SCCHs, even allowing for the occasional AGCT with brisk mitotic activity. Paradoxically, bizarre nuclei are more common in AGCTs.

  
  
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  JGCTs also usually have a more orderly architecture and cells with uniformly eosinophilic, pale, or clear cytoplasm, this finding being only focal in SCCHs. JGCTs often have a theca cell component. Large pleomorphic to bizarre nuclei are more common in JGCTs than SCCHs.

  
  
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  AGCTs and JGCTs are typically positive for inhibin and FOXL2. Calretinin is not helpful, being positive in both SCCHS and GCTs.

Malignant lymphoma. The common epithelial growth patterns (including follicle-like structures) in SCCHs and the differing cytologic features of the two tumors aid, with immunohistochemical and ultrastructural findings helpful if necessary.

SCC of pulmonary type, primary ( Chapter 14 ) or metastatic ( Chapter 18 ) and dysgerminoma ( Chapter 15 ).

Other small cell malignant tumors ( Appendix 15 ), such as primitive neuroectodermal tumors, primary or metastatic malignant melanoma, metastatic alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor ( Chapter 20 ). A variety of distinctive pathologic features evident on routinely stained slides generally facilitate these differential diagnoses. The clinical background and immunohistochemical features will also be helpful in some cases.

Undifferentiated carcinoma, not otherwise specified (vs large cell variant of SCCH). The diagnosis of large cell variant of SCCH should be considered in a young patient with an undifferentiated ovarian carcinoma, with a diligent search for typical SCCH.

Poorly differentiated oxyphilic carcinomas (e.g. squamous cell carcinoma arising in dermoids and anaplastic carcinomas arising in mucinous cystic tumors) and potentially others ( Appendix 14 ). Thorough sampling is crucial to uncover inclusionary or exclusionary findings; immunostains may also be helpful.

Foci of nonspecific carcinoma with small tumor cells in surface epithelial carcinomas; such tumors may focally have bizarre tumor giant cells (not a feature of SCCH) and other exclusionary features on thorough sampling

The differential diagnosis with other tumors is greatly facilitated by immunohistochemical loss of SMARCA4 , a sensitive and specific marker of SCCH.

SCCH are highly aggressive, at least half having extraovarian disease at laparotomy. Spread is mostly within the pelvis and abdomen, but may be hematogenous.

Only a third of patients with FIGO stage IA disease (see Table 13.4 for staging) have disease-free follow-up periods and almost all patients with higher-stage tumors die of disease, usually within 2 years.

Rare patients with high-stage tumors have survived over 4 years after intensive chemotherapy, radiation therapy, or both. More recently, Witkowski et al. found that autologous stem cell rescue achieved 5 year survivals of 71% for stages II–IV compared to 25% for patients receiving conventional chemotherapy.

Recently, reported responses to anti-PD1 immunotherapy in four patients diagnosed with SCCH. PD-L1 expression and T-cell infiltration were detected in 10 of 11 tumors. Given the low mutational burden of this tumor, these findings were unexpected. They suggested that PD-L1 may act as a pathway of adaptive immune resistance.

In addition to stage I disease, potentially favorable prognostic features include age >30 years, a normal preoperative calcium level, a tumor size <10 cm, an absence of large cells, treatment by bilateral oophorectomy, and postoperative multiagent chemotherapy and radiotherapy.

These tumors are thought to be of wolffian origin because they most often arise in the broad ligament where wolffian remnants are common. The ovarian tumors have the same histologic features as those in the broad ligament ( Chapter 11 ).

The ovarian tumors typically occur in adults, and are associated with the usual symptoms of an ovarian tumor. Almost all are stage I.

The tumors are almost invariably unilateral, encapsulated, average 12 cm in diameter, and are solid or solid and cystic. The solid tissue is often lobulated and gray–white to tan or yellow, and rubbery to firm.

The microscopic appearance is identical to that of the broad ligament tumors ( Chapter 11 ), including frequent positivity for inhibin.

Rare tumors have highly atypical features, including sarcomatous transformation. High-stage tumors have had an average of 14 mf/10 hpf.

Sex cord tumors, particularly Sertoli cell tumors ( Chapter 16 ).

Cellular fibroma. Rare wolffian tumors have a prominent growth of fusiform to spindle cells, but other distinctive patterns, such as sieve-like, will be diagnostic.

Ovarian ependymomas. Differential features include perivascular pseudorosettes and GFAP positivity.

Endometrioid adenocarcinoma ( Chapter 14 ).

Most stage I tumors have a benign course. The rare patients with high-stage tumors died of disease or were alive with disease at last follow-up.

Rete cysts and cystadenomas (cysts >1 cm in diameter) have occurred in women 23–80 (mean, 59) years of age. The cystadenomas are often large and may result in a palpable mass. Elevated testosterone levels due to adjacent hilus cell hyperplasia may cause androgenic manifestations.

Because rete cystadenomas are often misdiagnosed as serous cystadenoma, their frequency is likely much higher than suggested by the small number of reported cases.

Rete adenomas usually occur in middle-aged or elderly patients; most are incidental microscopic findings. The one well-documented rete adenocarcinoma occurred in a 52-year-old woman with ascites.

Rete cysts and rete cystadenomas are hilar but may expand into the medulla and rarely the cortex. The cystadenomas, which may reach 24 cm in diameter (mean, 8.7), are typically unilocular but may be multilocular, and usually have thin walls and a smooth lining. The one reported rete adenocarcinoma was bilateral and was grossly nonspecific.

Rete cystadenomas have walls of fibrovascular tissue and smooth muscle and little or no stroma of ovarian type, and most have an irregular lining with irregularly spaced shallow crevices.

Rete cysts and cystadenomas are lined by cuboidal, columnar, or most often flattened cells with bland nuclear features. In half the reported cases, the cyst walls contained hilus cells that were typically hyperplastic.

Rete adenomas are well-circumscribed hilar proliferations of closely packed elongated small tubules; some tubules may be dilated and contain simple papillae. The tubules and papillae are lined by a single layer of cuboidal to columnar cells resembling those of the normal rete.

The rete adenocarcinoma consisted of branching hollow or solid tubules and cysts containing papillae with fibrovascular or hyalinized cores. The tubules and papillae were lined by atypical cuboidal nonciliated cells, and focally, transitional-like cells; mitotic figures were numerous.

Rete cysts and cystadenomas are distinguished from other benign ovarian and paraovarian cysts on the basis of a combination of their hilar location (not always clearly establishable in large tumors), mural smooth muscle and/or hilus cells, their characteristic crevices, and an absence or rarity of ciliated cells.

Rete adenomas may resemble FATWOs, but unlike the latter typically have a uniform small tubular pattern.

Rare examples of rete hyperplasia ( Chapter 12 ), in contrast to adenomas, have merged almost imperceptibly with the normal rete and their margins have been poorly circumscribed.

Rete adenocarcinomas are distinguished from retiform SLCTs by their greater nuclear atypicality and an absence of other typical SLCT patterns. The retiform appearance of the tubules aids in the differential with a transitional cell carcinoma.

Fibroma (vs typical leiomyoma) and cellular fibroma (vs cellular leiomyoma). Fibromas are much more common than leiomyomas and are composed of fibroblastic cells often arranged in a storiform pattern. Immunostaining for smooth muscle markers may be helpful in difficult cases, although fibromas may stain for SMA.

Gastrointestinal stromal tumor (GIST). Rare GISTs metastasize to the ovary ( Chapter 18 ), and when low grade, can resemble a leiomyoma. An index of suspicion, especially in a patient with a history of a GIST, and immunohistochemical staining facilitate the diagnosis.

The differential diagnosis of ovarian leiomyomas with unusual features includes a wide variety of ovarian tumors.

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  A sex cord – stromal tumor may be suggested if cords of cells are present, as in some leiomyomas with hydropic change or hyalinization.

  
  
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  Epithelioid leiomyomas need to be distinguished from other ovarian tumors composed of oxyphilic or clear cells ( Appendices 14 and 6 , respectively).

  
  
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  Establishing the correct diagnosis requires an index of suspicion, and appreciation of foci of more typical smooth muscle differentiation that may be present in some tumors, and immunostaining for desmin and other markers.