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Final diagnosis:
Central-type Primitive neuroectodermal tumor (cPNET)
Central-type primitive neuroectodermal tumors (cPNET) are aggressive malignant neoplasms whose constituent cells resemble those of a primordial neural etiology [2-5]. They have high propensity to metastasize and can occur as primary lesions in some body sites, including the organs of the female genital tract. [3, 4, 6] Within the uterus and ovary, they may be seen in either pure form or in association with other neoplasms, such as carcinosarcoma in the uterus or teratomas in the ovary. In fact, within the ovary, cPNETs are generally considered to be monophasic teratomas composed entirely of neuroectodermal cells. [4, 7-9]
PNETs can be subdivided into two main categories, central type (cPNET) and Ewing’s/peripheral type (pPNET). This subclassification is based upon apparent embryologic differences wherein the central type tumors are of a CNS linked lineage and the peripheral type tumors are of a peripheral lineage [4, 10]. PNETs of the ovary predominately fall into the central subtype, although peripheral PNETs can also be seen. [4, 5, 7, 11] Distinguishing these two subcategories can be challenging due to the overlapping morphologic features and immunohistochemical profile. [4, 5] Histologically, both subtypes are composed of small blue cells, with a high nuclear to cytoplasmic ratio, pleomorphic hyperchromatic nuclei, and variable mitoses and apoptosis. The central subtype will frequently show mixed morphologies, with components resembling other CNS neoplasms of a more differentiated lineage [9].
Immunohistochemically, both subtypes will show positivity for markers of neuronal differentiation, such as neuron specific enolase (NSE), synaptophysin, chromogranin, and glial fibrillary acidic protein (GFAP). Peripheral PNET is associated with the t(11;22)(q24;q12) chromosomal translocation, resulting in the EWSR1-FLI1 fusion, a feature not seen in the central subtype [12, 13]. This results in an over expression of MIC2 (CD99), which can be visualized via immunohistochemistry. Therefore, the peripheral subtype would show diffuse positivity for CD99 (membranous staining) and the central subtype would be negative [2, 6, 12].
The differential diagnosis of PNETs in the ovary is wide and might include immature teratoma, undifferentiated carcinoma, high grade endometrioid adenocarcinoma and small round blue cell tumors of the ovary, such as neuroendocrine carcinoma, juvenile granulosa cell tumor, intra-abdominal desmoplastic small round cell tumor and lymphoma, amongst others.[1]
Immature teratomas will show a spectrum of neuroepithelial differentiation and also an admixture of endodermal, mesodermal, and ectodermal tissue. Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) will display various architectural patterns with at least focal follicle-like formation and mucinous epithelium. Ovarian small cell carcinoma of pulmonary type (OSCCPT) is comprised of solid, sheets or nest of small to medium-sized cells with scant cytoplasm, nuclear molding and hyperchromatic nuclei with salt and pepper chromatin pattern. High grade endometrioid adenocarcinomas can show focal glandular formation with extensive keratin expression when compared to PNET. Undifferentiated carcinomas (UC) are commonly composed of sheets of dyscohesive monotonous cells with areas of necrosis. Although UC can show positivity for neuroendocrine markers, it should be focal (<10% of tumor) [15] compared with PNTEs. Juvenile granulosa cell tumor is commonly comprised of eosinophilic polygonal cells arranged in solid and conspicuous follicle-like spaces with basophilic secretions. Intraabdominal desmoplastic stromal tumor would show nests of small round cells with scant cytoplasm in a background of desmoplastic stroma. Lymphoma would typically include a component of small, normal appearing lymphocytes admixed with larger more atypical cells. Table 1 shows helpful immunohistochemical stains for the differential diagnoses workup.
Unfortunately, due to the rarity of these neoplasms, good prognostic and therapeutic information is limited. The paucity of meaningful data is further reduced when the scope is restricted to include only central type PNETs of the ovary. Like most malignancies, the clinical stage and presence of distant metastases are the most significant prognostic factors. Overall, primary PNET of the ovary is considered to be a germ cell tumor and is generally treated accordingly. Chemotherapeutic regimens generally include cisplatin, doxorubicin, ifosfamide, vincristine, cyclophosphamide, dactinomycin, and VP-16 but the optimal therapeutic regimen is controversial. [14]
References:
1. McCluggage, W.G., Ovarian neoplasms composed of small round cells: a review. Adv Anat Pathol, 2004. 11(6): p. 288-96.
2. Rosai, J. and L. Ackerman, Rosai and Ackerman's surgical pathology (11th ed.). 2018, Philaelphia, PA: Elsevier.
3. Mills, S., et al., Sternberg's diagnostic surgical pathology (6th ed.). 2015, Philadelphia, PA: Wolters Kluwer.
4. WHO Classification of Tumors of Female Reproductive Organs ed. R. Kurman, et al. 2016, Geneva, Switzerland: WHO Press.
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10. Chao, X., Y. Bi, and L. Li, Ovarian primary primitive neuroectodermal tumor: a review of cases at PUMCH and in the published literature. Orphanet J Rare Dis, 2019. 14(1): p. 147.
11. Li, Y.P., et al., Primary Ewing Family of Tumor Arising in the Ovary: A Case Report. Int J Gynecol Pathol, 2019. 38(5): p. 470-473.
12. Ambros, I.M., et al., MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer, 1991. 67(7): p. 1886-93.
13. Kovar, H., et al., Overexpression of the pseudoautosomal gene MIC2 in Ewing's sarcoma and peripheral primitive neuroectodermal tumor. Oncogene, 1990. 5(7): p. 1067-70.
14. Xiao, C., et al., Clinical analysis of primary primitive neuroectodermal tumors in the female genital tract. Int J Gynecol Cancer, 2014. 24(3): p. 404-9.
15. Altrabulsi B, Malpica A, Deavers MT, Bodurka DC, Broaddus R, Silva EG. Undifferentiated carcinoma of the endometrium. Am J Surg Pathol. 2005 Oct;29(10):1316-21. doi: 10.1097/01.pas.0000171003.72352.9a. PMID: 16160474.