This chapter should be cited as follows:
Lin LH, Oliva E, Glob Libr Women's Med
ISSN: 1756-2228; DOI 10.3843/GLOWM.421993

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 13

Gynecological cancer

Volume Editors: Professor Hextan Ngan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong
Professor Karen Chan, Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong

Chapter

Pathology of Ovarian, Fallopian Tube and Primary Peritoneal Cancers

First published: May 2026

AUTHOR(S)

Lawrence Hsu Lin, MD, PhD

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Esther Oliva, MD

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

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INTRODUCTION

This chapter is intended to provide an overview of the salient pathology of malignant neoplasms arising primarily in the ovary, although some also can be seen in the Fallopian tube and peritoneum, focusing on recent advances and select relevant topics for gynecologists, oncologic gynecologic surgeons and medical oncologists. Ovarian pathology represents one of the most challenging areas in gynecologic pathology due to the wide range of primary tumors arising in this organ and the relatively frequent involvement of metastatic disease, which can mimic a primary neoplasm.

The main histologic subtypes of primary ovarian, tubal and peritoneal malignancies are summarized in Table 1. In this chapter, the following categories of tumors will be discussed: epithelial, sex-cord stromal, germ cell, mesenchymal and mixed epithelial-mesenchymal neoplasms, as well as metastatic/secondary involvement by extraovarian neoplasms. Staging of ovarian, Fallopian tube and peritoneal cancer according to the International Federation of Gynecology and Obstetrics (FIGO) is summarized in Table 2.¹ Several distinctive neoplasms, either benign, borderline or malignant, may have an association with tumor predisposition genetic syndromes, outlined in Table 3.

Classification of main primary ovarian, tubal and peritoneal cancers based on WHO Classification of Female Genital Tumor (2020).²

Epithelial	High-grade serous carcinoma Low-grade serous carcinoma Endometrioid carcinoma Clear cell carcinoma Mucinous carcinoma Dedifferentiated/undifferentiated carcinoma Mesonephric-like carcinoma Malignant Brenner tumor Neuroendocrine carcinoma Mixed carcinoma Carcinosarcoma
Sex cord stromal	Granulosa cell tumor, adult and juvenile types Sertoli-Leydig cell tumor Sertoli cell tumor Gynandroblastoma Sex cord tumor with annular tubules Steroid cell tumor, not otherwise specified and Leydig cell tumor
Germ cell	Dysgerminoma Yolk sac tumor Immature teratoma Non-gestational choriocarcinoma Embryonal carcinoma Mixed germ cell tumor Somatic-type malignancies arising in teratoma
Mesenchymal and mixed epithelial-mesenchymal	Endometrioid stromal sarcoma Leiomyosarcoma Adenosarcoma Extra-gastrointestinal stromal tumor Solitary fibrous tumor Desmoplastic small round cell tumor
Others	Small cell carcinoma of ovary, hypercalcemic-type STK11 adnexal tumor Mesothelioma Hematologic malignancies

FIGO stage for primary ovarian, tubal and peritoneal cancers.

I	Tumor confined to ovaries or Fallopian tube(s)
	IA	Tumor limited to one ovary (capsule intact) or Fallopian tube; no tumor on ovarian or Fallopian tube surface; no malignant cells in ascites or peritoneal washings
	IB	Tumor limited to both ovaries (capsules intact) or Fallopian tubes; no tumor on ovarian or Fallopian tube surface; no malignant cells in the ascites or peritoneal washings
	IC	Tumor limited to one or both ovaries or Fallopian tubes, with any of the following:
		IC1	Surgical spill
		IC2	Capsule ruptured before surgery or tumor on ovarian or Fallopian tube surface
		IC3	Malignant cells in the ascites or peritoneal washings
II	Tumor involves one or both ovaries or Fallopian tubes with pelvic extension (below pelvic brim) or peritoneal cancer
	IIA	Extension and/or implants on uterus and/or Fallopian tubes and/or ovaries
	IIB	Extension to other pelvic intraperitoneal tissues
III	Tumor involves one or both ovaries or Fallopian tubes, or peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes
	IIIA1	Positive retroperitoneal lymph nodes only (cytologically or histologically proven)
		IIIA1(i)	Metastasis up to 10 mm in greatest dimension
		IIIA1(ii)	Metastasis more than 10 mm in greatest dimension
	IIIA2	Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes
	IIIB	Macroscopic peritoneal metastases beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes
	IIIC	Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ)
IV	Distant metastasis excluding peritoneal metastases
	IVA	Pleural effusion with positive cytology
	IVB	Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity)

Tumor predisposition genetic syndromes and associated ovarian, tubal or peritoneal neoplasms.

Syndrome	Associated neoplasms
Hereditary breast and ovarian cancer syndrome	High-grade serous carcinoma of ovary, Fallopian tube and peritoneum, serous tubal intraepithelial carcinoma (STIC)
Lynch syndrome	Endometrioid, clear cell, dedifferentiated and undifferentiated carcinoma
Peutz–Jeghers syndrome	Sex cord tumor with annular tubules (SCTAT), STK11 adnexal tumor, Sertoli cell tumor, gastric-type mucinous ovarian tumors, gastric-type synchronous multifocal lesions
DICER1 syndrome	Sertoli-Leydig cell tumor, DICER1-related sarcoma/neoplasms
Ollier disease and Maffucci syndrome	Juvenile granulosa cell tumor
Rhabdoid tumor predisposition syndrome type 2	Small cell carcinoma of the ovary, hypercalcemic type
Familial adenomatous polyposis	Microcystic stromal tumor
Nevoid basal cell carcinoma syndrome (Gorlin syndrome)	Fibroma (bilateral, multinodular and extensively calcified)
von Hippel–Lindau syndrome	Clear cell papillary cystadenoma of broad ligament and steroid cell tumor
Tuberous sclerosis complex	Perivascular epithelioid cell tumor (PEComa), PEComatosis, lymphangioleiomyomatosis (LAM)
BAP1 tumor predisposition syndrome	Mesothelioma

EPITHELIAL MALIGNANCIES (CARCINOMAS)

Carcinomas are the most common ovarian malignancies with the most frequent histologic subtype being high-grade serous carcinoma, followed by endometrioid carcinoma, clear cell carcinoma, low-grade serous carcinoma and mucinous carcinoma in order of frequency.³

High-grade serous carcinoma

High-grade serous carcinoma is typically a very aggressive carcinoma, characterized by TP53 mutations and high-level copy-number alterations.⁴ Histologically, it is characterized by variably admixed slit-like, papillary, glandular, cribriform and/or solid patterns associated with cellular pseudo-stratification, high-grade nuclear atypia including significant pleomorphism, and brisk mitotic activity (>12 mitoses/10 high-power fields) (Figure 1A,B). Most of them exhibit mutant-type p53 expression (overexpression, null or cytoplasmic patterns)⁵ and are WT-1 and estrogen receptor positive on immunohistochemistry.⁶

High-grade serous carcinoma. (A) Papillary architecture and cell stratification. (B) Slit-like spaces and marked cytologic atypia. (C,D) Transitional-like morphology in a solid, pseudoendometrioid and transitional (SET) pattern. (E) Serous tubal intraepithelial carcinoma.

High-grade serous carcinoma is the main gynecologic manifestation of the hereditary breast and ovarian cancer syndrome, most often associated with germline mutations in BRCA1/2 and less frequently RAD51C, RAD51D and BRIP1.⁷ An unusual morphologic appearance of this tumor has been described as solid, pseudo-endometrioid and transitional-like (SET) pattern (Figure 1C,D), associated with homologous recombination deficiency (HRD) due to somatic or germline alterations,⁸^,⁹ which predicts sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors.

Although the ovary was originally thought to be the primary origin of high-grade serous carcinoma, it is known now that most arise from serous tubal intraepithelial carcinoma (STIC), its precursor lesion typically present at the fimbriated end of the Fallopian tube.¹⁰^,¹¹ A small percentage arise in the ovary and peritoneum without obvious precursor lesion or tubal involvement¹² (Figure 1E). Thus, the Fallopian tubes of patients with high-grade serous carcinoma are examined microscopically following the SEE-FIM (sectioning and extensively examining the fimbriated end) protocol to detect the precursor lesion.¹³

Advanced-stage high-grade serous carcinomas are typically treated with neoadjuvant chemotherapy and it is the role of the pathologist to assess the chemotherapy effect by assigning a chemotherapy response score (CRS) based on the amount of residual tumor involving the omentum (Table 4)¹⁴ as this site is thought to represent the most chemoresistant location of tumor involvement.

Chemotherapy response score (CRS).

CRS 1	No or minimal tumor response
CRS 2	Appreciable tumor response amidst viable tumor, both readily identifiable and tumor regularly distributed
CRS 3	Complete or near-complete response with no residual tumor OR minimal irregularly scattered tumor foci seen as individual cells, cell groups or nodules up to 2 mm in maximum size

Folate receptor alpha (FRα) immunohistochemistry has emerged as a companion predictive biomarker test to assess eligibility for the antibody–drug conjugate mirvetuximab soravtansine, with moderate to strong positivity in >75% of viable tumor cells considered a positive score,¹⁵ although this threshold remains under debate.

Low-grade serous carcinoma

Low-grade serous carcinoma has a morphologic, immunohistochemical and molecular profile as well as clinical behavior that significantly differ from those of high-grade serous carcinoma. These tumors display a variety of patterns, including small nests, glands, papillae and inverted macropapillae often free floating in spaces associated with low-grade nuclear atypia (<3x variation in size) and low mitotic activity (<12 mitoses/10 high-power fields) (Figure 2A,B). A background of serous borderline tumor may be seen in association with a low-grade serous carcinoma. Serous borderline tumors with micropapillary or cribriforming architecture (Figure 2C,D) are more frequently associated with or at increased risk of progressing to low-grade serous carcinoma.¹⁶^,¹⁷ The most common molecular alterations involve the RAS and RAF pathway (KRAS, NRAS and BRAF) with wild-type p53 expression (heterogeneous expression) and positivity for estrogen receptor and WT-1.⁶ Low-grade serous carcinoma is characterized by a relatively indolent behavior when compared to high-grade serous carcinoma.¹⁸^,¹⁹^,²⁰ Rarely, low-grade serous carcinoma may show high-grade transformation,²¹ which behaves more aggressively and has been shown to acquire additional molecular alterations such as TP53.²¹

Low-grade serous carcinoma. (A) Free floating small nests/papillae and micropapillae. (B) Inverted macropapillae. (C) Micropapillary (resembling a medusa head) and (D) cribriforming architecture in a borderline component.

Endometrioid carcinoma

Endometrioid carcinoma is often seen in association with endometriosis (endometriotic cyst) or adenofibroma and shows the same morphologic characteristics as those of its endometrial counterpart with relatively well-formed glands often back-to-back or cribriforming (Figure 3A) that may coexist with papillary and solid architectural patterns. As in the endometrium, these tumors are graded depending on the percentage of solid component (Grade 1, <5%; Grade 2, 5–50%; Grade 3, >50%) and nuclear atypia (Grade 1 and 2 carcinomas with high-grade nuclear atypia are upgraded by one grade). Presence of squamous and mucinous differentiation (Figure 3A,B) are confirmatory features of an endometrioid carcinoma. However, endometrioid carcinoma in the ovary can show a wide morphologic spectrum with variants that may closely mimic other ovarian tumors, including sex-cord like morphology with cords, trabeculae or small tubules (mimicking granulosa cell tumor, Sertoli cell tumor or Sertoli-Leydig cell tumor) (Figure 3C),²² spindled cells (mimicking carcinosarcoma) (Figure 3D),²³ corded and hyalinized (CHEC) (mimicking carcinosarcoma) (Figure 3E),²⁴ with extensive secretory change (mimicking clear cell carcinoma) and pilomatrixoma-like (mimicking squamous cell carcinoma) (Figure 3F).²⁵^,²⁶ Nuclear beta-catenin positivity by immunohistochemistry and mutations in CTNNB1 are characteristic of sex cord-like, spindled, corded and hyalinized, and pilomatrixoma-like variants,²⁵^,²⁷^,²⁸ which often lack PAX8 expression (a commonly used Müllerian marker). Seromucinous carcinomas are currently considered a variant of endometrioid carcinoma with prominent mucinous differentiation due to their significant histologic and molecular overlap.²⁹

Endometrioid carcinoma. (A) Squamous differentiation. (B) Mucinous differentiation. (C) Sex cord-like morphology. (D) Spindled transitioning to glands with low-grade cytologic features. (E) Corded and hyalinized (CHEC). (F) Pilomatrix-like with basaloid appearance and ghost cells.

Ovarian endometrioid carcinoma can co-occur with an endometrial endometrioid carcinoma and, based on pathologic criteria, are classified as low-risk (synchronous or independent primaries) or high-risk (advanced stage metastatic tumor). This distinction is important since low-grade, low-stage, synchronous primaries have indolent behavior³⁰^,³¹ while metastatic tumors are more aggressive and require adjuvant therapy.³² The finding of distinct histology in both tumors, presence of precursor lesion (atypical hyperplasia/endometrial intraepithelial neoplasia in the endometrium and endometriosis or adenofibroma in the ovary), absence or only early myometrial invasion, absence of lymphovascular invasion, unilateral ovarian involvement with no surface involvement and absence of other sites of metastasis support independent primaries.³² Despite the favorable outcome of tumors classified as independent by pathologic criteria, targeted next-generation sequencing has demonstrated that the vast majority of co-occurring ovarian and endometrial endometrioid carcinomas are clonally related, likely explained by migration of abnormal endometrial tissue to the ovary.³³^,³⁴ Rare examples of clonally independent tumors have been reported in the setting of cancer predisposition syndromes (Lynch syndrome and constitutional mismatch repair-deficiency syndrome).³⁵ The most common molecular alterations in endometrioid carcinoma involve PTEN, PIK3CA, ARID1A, CTNNB1 and KRAS genes.³⁶ High-grade endometrioid carcinomas may show aberrant p53 expression with associated TP53 mutations. Approximately 7–14% of endometrioid carcinomas exhibit mismatch repair protein deficiency³⁷^,³⁸ and can be associated with Lynch syndrome.

Clear cell carcinoma

Clear cell carcinoma is characterized by tubulocystic, papillary and solid architectural patterns often associated with hyalinized stroma (Figure 4). The tumor cells can exhibit clear or eosinophilic cytoplasm and typically display uniform nuclear atypia with hobnailing and minimal pseudo-stratification in contrast to high-grade serous carcinoma.³⁹ They usually lack estrogen and progesterone receptor expression and are positive for Napsin-A, AMACR and HNF1-beta.³⁹^,⁴⁰ p53 immunostain shows mutant-type pattern in 5–24% of clear cell carcinomas.³⁹^,⁴¹^,⁴² The classic grading systems do not reliably predict prognosis in these tumors⁴³ and they are considered by definition high-grade. Stage is the most important predictor of outcome, with patients with early-stage tumors showing good outcomes, while advanced disease is associated with unfavorable prognosis and poor response to adjuvant treatment.⁴⁴^,⁴⁵^,⁴⁶ Clear cell carcinoma harbors frequent molecular alterations in ARID1A and PIK3CA genes.⁴⁷^,⁴⁸ It is important to note that clear cell carcinoma may be associated with paraneoplastic manifestations including thromboembolic events,⁴⁹ hypercalcemia,⁵⁰ and rare presentations such as cerebellar degeneration⁵¹ and bilateral diffuse uveal melanocytic proliferation.⁵²

Clear cell carcinoma. (A) Large polypoid mass arising within an endometriotic cyst. (B) Tubulocystic pattern in an adenofibromatous background. (C) Papillary architecture with hyalinization and hobnailing cells with clear to eosinophilic cytoplasm.

As noted in endometrioid carcinoma, clear cell carcinoma often arises from endometriosis and can be associated with Lynch syndrome.⁵³ These two tumor types can co-occur and represent the most common type of mixed ovarian carcinoma.⁵⁴^,⁵⁵ Both can be categorized into four prognostically relevant molecular groups according to The Cancer Genome Atlas (TCGA) endometrial cancer classification and PROMISE algorithm: POLE-ultramutated, mismatch repair-deficient (MMRd)/microsatellite instability-high (MSI-H), no specific molecular profile (NSMP)/copy number low, and p53-abnormal/copy-number high.³⁶^,⁴⁸^,⁵⁶ POLE-mutant tumors are associated with favorable outcomes, p53-abnormal carcinomas have the worst outcomes, and MMRd and NSMP have an intermediate prognosis.⁴¹^,⁵⁷^,⁵⁸

Undifferentiated carcinoma

Undifferentiated carcinoma is a highly aggressive tumor that lacks morphologic and robust immunohistochemical evidence of epithelial lineage and is characterized by diffuse growth of non-cohesive cells that may show focal rhabdoid morphology. When an undifferentiated carcinoma is associated with an identifiable carcinoma, typically low-grade endometrioid (other subtypes can also be seen), it is referred to as 'dedifferentiated carcinoma'⁵⁹^,⁶⁰ (Figure 5). Undifferentiated and dedifferentiated carcinoma often lack expression of Müllerian and common epithelial markers but can be focally and weakly positive for claudin4, EMA and cytokeratin18. They frequently show abnormal expression of SWI/SNF (SWItch/Sucrose Non-Fermentable) complex components (ARID1A/B, SMARCA2/BRM, SMARCA4/BRG and SMARCB1/INI1) (82%), mismatch repair protein deficiency (26%), and mutant-type p53 pattern (10%).⁵⁹^,⁶⁰^,⁶¹ It is important to be aware that these tumors may not be detected in the primary setting (due to sampling issues) and be present only as metastatic disease, which can make the diagnosis extremely challenging as numerous undifferentiated neoplasms are in the differential diagnosis, including sarcomas and melanoma, among others.

Dedifferentiated carcinoma. (A) Undifferentiated component (lower right) juxtaposed to well-differentiated endometrioid carcinoma (upper left; arrows). (B) Well-formed glands in differentiated component. (C) Undifferentiated component displays sheets of non-cohesive cells with brisk mitotic activity.

Mucinous carcinoma

Mucinous tumors can be diagnostically challenging due to their marked intratumoral heterogeneity, underscoring the importance of comprehensive sampling guided by careful gross examination and clinical findings. The differential diagnosis of an ovarian mucinous neoplasm includes primary mucinous carcinoma arising in mucinous borderline tumor, primary mucinous carcinoma arising in a teratoma, endometrioid carcinoma with extensive mucinous differentiation (seromucinous carcinoma), metastatic/secondary involvement by mucinous tumor and rarely Sertoli-Leydig cell tumor with prominent heterologous mucinous component.⁶²

Mucinous carcinoma is diagnosed based on the presence of expansile and/or infiltrative (destructive) growth (Figure 6A–C). Expansile pattern, by far the most common, is characterized by confluent growth of atypical mucinous glands with minimal or absent intervening stroma (Figure 6B). Infiltrative growth is defined by irregular, angulated, sometimes poorly formed glands, tumor nests or single cells within a desmoplastic stroma (Figure 6C). The pattern of invasion is a better predictor of behavior than the different grading classifications used in these tumors, with infiltrative growth being associated with worse prognosis.⁶³ A histologic pitfall of destructive invasion includes ruptured mucinous glands with mucin extravasation and associated stromal response, particularly when seen as small tumor nests; in this instance, histiocytes are often noted and the neighboring glands are not overtly malignant, which may help support the absence of an infiltrative growth⁶⁴ Rarely, ovarian mucinous neoplasms, more often borderline mucinous tumors (with or without intraepithelial carcinoma) can harbor mural nodules, which are classified as sarcoma-like, anaplastic carcinoma or sarcoma.⁶⁵^,⁶⁶ The former has no prognostic impact, but anaplastic carcinomas and sarcomas are associated with a worse prognosis when compared to usual mucinous carcinomas.⁶⁷^,⁶⁸^,⁶⁹^,⁷⁰ Mucinous carcinomas can harbor molecular alterations in CDKN2A, KRAS, TP53 and ERBB2 amplifications, in order of frequency.⁷¹ Anaplastic carcinoma may be associated with SWI/SNF alterations, especially when displaying a rhabdoid morphology, but its clinical significance is not currently clear.⁷²

Mucinous carcinoma. (A) Solid areas (white arrows) within a large multicystic mass correspond to mucinous carcinoma arising in a background of borderline tumor. (B) Expansile invasion. (C) Destructive/infiltrative invasion (arrows indicate infiltrating tumor cells). (D,E) Low-grade mucinous neoplasm arising in a teratoma resembling tumor of appendiceal origin (arrows in E indicate teratomatous elements represented by respiratory epithelium with underlying lymphoid infiltrate).

Metastatic adenocarcinomas and mucinous neoplasms secondarily involving the ovary, typically arising from the gastrointestinal tract, pancreatobiliary system or cervix, can mimic primary ovarian mucinous carcinomas and sometimes even borderline tumors.⁷³^,⁷⁴^,⁷⁵^,⁷⁶^,⁷⁷ A combination of clinicopathologic features and immunohistochemical findings can be helpful in the differential diagnosis.⁶² Large (>10–13 cm), unilateral ovarian tumors without surface involvement or lymphovascular invasion would favor a primary carcinoma.⁷⁸ On the contrary, the finding of pseudomyxoma peritonei, surface ovarian involvement, nodularity (Figure 7A), discordance between degree of architectural complexity and cytologic atypia, signet ring cells (Figure 7B,C), single infiltrating cells, and absence of background mucinous borderline or teratoma are more in keeping with metastases. However, one should be aware that many exceptions to these guidelines exist, especially when dealing with metastatic pancreatobiliary tumors that may closely mimic a primary ovarian tumor while the extraovarian tumor may be very small.⁷⁵^,⁷⁶ Molecular profiling of both ovarian and extraovarian tumor can aid in establishing their clonal relationship, particularly in challenging cases.⁷⁹

Metastatic mucinous carcinoma with signet ring cells from gastric origin (Krukenberg tumor). (A) Multinodular, solid, bilateral ovarian masses. (B) Numerous signet ring cells infiltrating fibromatous stroma. (C) Cytokeratin highlights signet ring cells.

A common origin of secondary ovarian involvement is the appendix; therefore, in the setting of a mucinous neoplasm involving the ovary that is associated with extravasated mucin on the peritoneum (pseudomyxoma peritonei), ovarian or Fallopian tube surfaces, the appendix needs to be examined intraoperatively and excised even when thought to be grossly normal. Appendiceal neoplasms involving the ovary typically show abundant extracellular dissecting mucin, hypermucinous tall cells with scalloped contours and subepithelial clefts within the ovary.⁸⁰ Mucinous neoplasms arising from a teratoma (Figure 6D,E) are indistinguishable morphologically and immunohistochemically from appendiceal mucinous neoplasms;⁸¹ thus, comprehensive sampling is recommended to reveal the teratomatous components of the tumor.

The immunohistochemical profile of primary and metastatic mucinous carcinomas shows significant overlap with variable positivity for CK7, CK20 and CDX2. PAX8 is negative in more than half of primary mucinous carcinomas.⁸² With exception of tumors arising in teratoma, SATB2 is typically negative in primary ovarian mucinous but positive in metastatic carcinomas from the lower gastrointestinal tract.⁸³ Loss of SMAD4 is frequent in pancreatic tumors and uncommon in primary ovarian mucinous carcinoma with rare exceptions.⁸⁴^,⁸⁵ Ultimately, if there is suspicion of metastasis, correlation with imaging and other pertinent tests is recommended.

Mesonephric-like carcinoma

Mesonephric-like carcinoma is a newly reported subtype of adenocarcinoma associated with an aggressive behavior and a tendency to metastasize to the lungs. It is characterized by a diverse array of architectural patterns (glandular, cribriforming, papillary, sieve-like, glomeruloid), ovoid, cuboidal to spindle cells with scant cytoplasm (imparting a basaloid or blue appearance on low power), nuclear grooves and nuclear clearing (papillary thyroid carcinoma-like nuclear features) (Figure 8).⁸⁶^,⁸⁷^,⁸⁸ They may be pure or associated with another Müllerian epithelial neoplasm (serous, endometrioid or mucinous). As there is significant morphologic overlap with endometrioid carcinoma, by definition, mesonephric-like carcinoma should lack squamous or mucinous differentiation and be negative or only minimally positive for estrogen and progesterone receptors. GATA3 and/or TTF1 positivity support the diagnosis. Despite their aggressive behavior, these tumors show p53 wild-type pattern.⁸⁹ KRAS mutations are the most common molecular alteration and expression of mismatch repair proteins is preserved.⁹⁰^,⁹¹

Mesonephric-like adenocarcinoma. (A) Papillary architecture and 'blue' appearance due to high nuclear-to-cytoplasmic ratio. (B) Glandular and solid patterns mimic endometrioid carcinoma. (C) Cells with ovoid nuclei and prominent clearing, reminiscent of papillary thyroid carcinoma.

Carcinosarcoma

Carcinosarcoma is an aggressive malignant neoplasm harboring both carcinomatous and sarcomatous components. Its clinical behavior and pattern of spread is more akin to carcinomas despite the presence of malignant mesenchymal elements, which are thought to represent transdifferentiation from the malignant epithelial component.⁹²^,⁹³ The latter is more often a serous carcinoma although, not infrequently, a hybrid serous-endometrioid morphology is noted. The mesenchymal component can be homologous or may have heterologous elements with chondrosarcomatous and rhabdomyoblastic differentiation commonly seen. Metastatic and recurrent disease typically present as pure carcinoma. Carcinosarcoma is typically characterized by TP53 mutations although a small subset is associated with mismatch repair protein deficiency and, rarely, TP53-wild-type tumors with mismatch repair proficiency are observed.⁹⁴^,⁹⁵^,⁹⁶

MALIGNANT SEX CORD STROMAL TUMORS

This category of neoplasms is distinctive to the gonads and can be associated with hormonal manifestations and malignant behavior. Immunohistochemistry is helpful in establishing a sex cord stromal origin of tumors as they are calretinin (less specific), inhibin, SF-1 and FOXL2 positive (except if poorly differentiated); however, it is of limited utility to differentiate among histologic subtypes within this category. The most common sex cord stromal tumor with malignant potential is granulosa cell tumor, which is classified into adult and juvenile types.

Adult granulosa cell tumor

Adult-type granulosa cell tumor is seen predominantly in adult patients with peak incidence between 50–55 years. Due to their estrogenic production, patients are at increased risk of developing endometrial hyperplasia and carcinoma. Serum inhibin may be helpful in the preoperative setting and monitoring for recurrence.⁹⁷ Adult granulosa cell tumor may be associated with hemoperitoneum⁹⁸ and grossly can be extensively hemorrhagic and necrotic, simulating a carcinoma. It can show a diverse array of histologic patterns including nested, trabecular, insular, macrofollicular or diffuse (Figure 9A,B). The tumor cells are typically ovoid with inconspicuous nucleoli, nuclear grooves (resembling coffee beans) (Figure 9C), variable mitotic activity and can form Call-Exner bodies (small, rounded spaces surrounded by palisaded tumor cells). Some have prominent fibromatous stroma (mimicking cellular fibroma) or prominent thecoma-like foci (mimicking a thecoma).⁹⁹^,¹⁰⁰ Reticulin stain showing reticulin fibers around tumor cell clusters is helpful to support a diagnosis of granulosa cell tumor in addition to mutation analysis with FOXL2 mutations, present in most of such tumors.¹⁰⁰^,¹⁰¹ Rarely, other pathogenic variants have been reported in the absence of FOXL2 mutations, including in the FGFR1 gene.¹⁰²^,¹⁰³ TERT promoter mutations have been linked to aggressive and recurrent disease,¹⁰⁴^,¹⁰⁵ which can occur many years after the initial diagnosis.¹⁰⁶ Recent studies have demonstrated the potential utility of FOXL2 and TERT promoter mutation detection via circulating tumor DNA in the primary diagnosis and monitoring of recurrence of adult granulosa cell tumors.¹⁰⁷^,¹⁰⁸ These tumors may show high-grade transformation, characterized by areas with an undifferentiated morphology associated with high-grade nuclear atypia and brisk mitotic activity juxtaposed to typical areas of adult granulosa cell tumor. High-grade transformation has been linked to the presence of TP53 mutations and aggressive clinical behavior.¹⁰⁹

(A–C) Adult granulosa cell tumors, showing trabecular/insular (A) and (B) diffuse patterns, and cells with scant cytoplasm and ovoid, grooved nuclei (C). (D–F) Juvenile granulosa cell tumors, showing nodular growth (D), irregular follicles (E) and cells with abundant pale to eosinophilic cytoplasm lacking grooves (F).

Juvenile granulosa cell tumor

Juvenile-type granulosa cell tumor, in contrast to the adult counterpart, is typically seen in the first three decades of life. Patients with Ollier disease and Maffucci syndrome are at increased risk of developing this type of granulosa cell tumor.¹¹⁰ It often displays a nodular or diffuse architecture with formation of variably sized follicles (Figure 9D,E). The tumor cells lack grooves and show ample, pale to eosinophilic cytoplasm and variable mitotic activity (Figure 9F). A variety of mutations have been reported in these tumors, including AKT1, GNAS, IDH1 and IDH2, while FOXL2 mutations are consistently absent.¹¹¹ The presence of anaplasia, defined as sheet-like growth, marked cytologic atypia, necrosis and brisk mitotic activity compared to background conventional morphology, has been associated with poorer prognosis, TP53 mutations and MYC amplifications/gains.¹¹²

Sertoli-Leydig cell tumor

Sertoli-Leydig cell tumor is composed of Sertoli and Leydig cells and is typically associated with androgenic manifestations, although some may present with estrogenic symptoms and, rarely, elevated alpha-fetoprotein (AFP) levels.¹¹³^,¹¹⁴ This tumor is also part of the spectrum of gynecologic tumors that can be seen in patients with DICER1 tumor predisposing syndrome, which also includes cervical embryonal rhabdomyosarcomas¹¹⁵ and emerging DICER1-altered sarcomas/neoplasms (some resembling pleuropulmonary blastoma).¹¹⁶^,¹¹⁷ Sertoli-Leydig cell tumor is classified as well-, moderately and poorly differentiated depending on the appearance of the Sertoli cell component. Well-differentiated tumors display well-formed Sertoli tubules intermixed with variably conspicuous Leydig cells and are considered clinically benign (Figure 10A). Moderately differentiated neoplasms are characterized by a vaguely nodular architecture, with nests, trabeculae and poorly formed tubules of Sertoli cells and peripheral and/or closely admixed Leydig cells (Figure 10B). The diagnosis of a poorly differentiated Sertoli-Leydig cell tumor can be very challenging, since it is composed of mitotically active spindled cells (Figure 10C), sometimes indistinguishable from a sarcoma. Sampling is crucial to identify a minor component of moderately differentiated Sertoli-Leydig cell tumor to establish this diagnosis. Moderately and poorly differentiated tumors can display heterologous elements, most commonly mucinous epithelium (which may rarely may be the most salient component), as well as skeletal muscle and fetal cartilage¹¹⁸^,¹¹⁹ and retiform morphology¹²⁰ (Figure 10D–F). It is crucial to exclude the possibility of overgrowth by embryonal rhabdomyosarcoma in moderate to poorly differentiated tumors as this indicates poorer prognosis.¹¹⁹ Moderately and poorly differentiated Sertoli-Leydig cell tumors can show malignant behavior and are typically characterized by DICER1 mutations,¹²¹^,¹²² not seen in well-differentiated tumors.¹²³

Sertoli-Leydig cell tumors. (A) Well-differentiated with Sertoli tubules and abundant Leydig cells. (B) Moderately differentiated with Sertoli cells forming trabeculae and scant Leydig cells. (C) Poorly differentiated with spindle cells mimicking a sarcoma. (D) Retiform pattern. (E) Heterologous mucinous elements. (F) Rhabdomyosarcomatous differentiation.

Gynandroblastoma

Gynandroblastoma is a neoplasm exhibiting a variable mixture of granulosa cell and Sertoli-Leydig cell components. Recent molecular data have shown that tumors with admixed juvenile granulosa and Sertoli-Leydig morphology harbor DICER1 alterations¹²⁴ and, in conjunction with the clinicopathologic characteristics, support that these neoplasms could represent Sertoli-Leydig cell tumor with follicular differentiation.¹²⁵ Tumors showing predominant adult granulosa morphology, with areas of hollow or solid tubules resembling Sertoli cell tumors, do not harbor DICER1 mutations and, in a subset, exhibit FOXL2 mutations and copy-number gains.¹⁰³

Sex cord tumor with annular tubules

Sex cord tumor with annular tubules (SCTAT) is a rare distinctive neoplasm associated with Peutz–Jeghers syndrome in a subset.¹²⁶ Its histological appearance is characteristic, with sharply demarcated, round nests and tubules containing basement membrane-like material. Tumor cells are columnar, with pale cytoplasm and basally located nuclei at the periphery of the nests, whereas cells in the inner portion are polarized towards the centers of the tubules (Figure 11A–C).¹²⁶^,¹²⁷ In patients with Peutz–Jeghers syndrome, tumors are frequently bilateral, microscopic and incidental findings (Figure 11B,C) associated with benign behavior, as opposed to tumors in patients without Peutz–Jeghers syndrome, which present as a unilateral expansile mass (Figure 11A) with potential malignant behavior.¹²⁷^,¹²⁸

Sex cord tumor with annular tubules (SCTAT). (A) Tumor in a non-syndromic patient with large nests, some with secondary cystic change, forming a large unilateral mass. (B–C) Microscopic, rounded tumor nests (arrows), composed of tubules with basement-membrane-like material and antipodal distribution of nuclei, in a patient with Peutz–Jeghers syndrome.

Steroid cell tumor

Steroid cell tumor (not otherwise specified) can be associated with hormonal manifestations, most commonly androgenic,¹²⁹ and may rarely present with Cushing syndrome¹³⁰ or estrogenic symptoms.¹³¹ This tumor is characterized by nests and sheets of large polygonal cells with voluminous eosinophilic, clear to foamy cytoplasm with prominent nucleoli (Figure 12). While predicting clinical behavior of these neoplasms is challenging, several pathologic features have been associated with malignant behavior, including older age (>65 years), large tumor size (>7 cm), increased mitotic activity, necrosis, hemorrhage and marked cytologic atypia.¹²⁹^,¹³² Steroid cell tumors can harbor VHL mutations and be a manifestation of von Hippel Lindau disease.¹³³

Steroid cell tumor (not otherwise specified). Tumor cells displaying abundant clear (A) to eosinophilic (B), foamy (C) cytoplasm with delicate vasculature.

MALIGNANT GERM CELL TUMORS

Germ cell tumors typically occur in the first three decades of life and secrete different proteins, which can be detected in blood and serve as biomarkers. Immunohistochemical stains in conjunction with morphologic features are helpful in the differential diagnosis of germ cell tumors. A common and helpful feature in malignant germ cell tumors is the finding of chromosome 12 abnormalities, typically isochromosome 12p or 12p amplifications,¹³⁴^,¹³⁵^,¹³⁶ except for immature teratomas, unless when part of a mixed germ cell tumor.¹³⁷

Dysgerminoma

Dysgerminoma is the most common malignant ovarian germ cell tumor (Figure 13A). Patients typically show elevated serum lactate dehydrogenase (LDH) levels and rarely human chorionic gonadotropin (hCG) levels (in tumors with syncytiotrophoblast cells). It rarely may be associated with hypercalcemia.¹³⁸ Dysgerminoma is also the most common germ cell tumor in patients with gonadal dysgenesis and can arise in a background of gonadoblastoma (in-situ tumor).¹³⁹^,¹⁴⁰ Grossly, it is typically unilateral and has a homogeneous soft creamy cut surface. Morphologically, it is characterized by sheets and nests of monotonous polygonal cells with abundant clear or eosinophilic cytoplasm, large nuclei with one or more prominent nucleoli separated by thin fibrous septa associated with a lymphocytic infiltrate.¹⁴¹ Rarely, scattered syncytiotrophoblast cells (this finding in isolation should not prompt diagnosis of choriocarcinoma) and poorly formed small granulomas can be seen.¹⁴² Dysgerminomas are positive for SALL4, OCT3/4, CD117 and D2–40¹⁴³ and often show KIT mutations and amplifications¹⁴⁴ although other molecular alterations have also been reported. Disease free survival in patients with dysgerminoma is approximately 90% at 5 years with stage being the best predictor of outcome.¹⁴⁵^,¹⁴⁶^,¹⁴⁷

Malignant germ cell tumors. (A) Dysgerminoma: rounded to polygonal, monotonous tumor cells with clear cytoplasm, delicate fibrous septa and associated lymphocytic infiltrate. (B) Yolk sac tumor: reticular and microcystic patterns and cells with cytoplasmic clearing. (C) Immature teratoma: immature neuroepithelium (defining feature), fetal-type cartilage and squamous epithelium. (D) Embryonic-type neuroectodermal tumor/primitive neuroectodermal tumor (ENT/PNET): overgrowth of primitive, small, round blue cells. (E) Choriocarcinoma: syncytiotrophoblast (multinucleated) and mononuclear trophoblast (cytotrophoblast and intermediate trophoblast) in a biphasic arrangement. (F) Embryonal carcinoma: high-grade primitive cells with brisk mitotic activity arranged in glandular and solid architecture (almost always as part of a malignant mixed germ cell tumor).

Yolk sac tumor

Yolk sac tumor is typically seen in patients in their second and third decades of life who present with symptoms/signs related to a fast-growing pelvic mass. It is typically associated with high serum alpha-fetoprotein (AFP) levels. Although in most cases it is pure, it may be a component of a mixed malignant germ cell tumor. On gross examination it is most frequently solid or solid and cystic with extensive areas of hemorrhage and necrosis. Histologically, multiple architectural patterns are seen, including reticular, micro- or macrocystic, solid, endodermal sinus (characterized by multiple Schiller-Duval bodies, composed of papillary structures lined by tumor cells with a central vessel free-floating within spaces), glandular, hepatoid, and polyvesicular vitelline, among others (Figure 13B). Tumor cells show clear cytoplasm and variable cytologic atypia and primitive appearance.¹⁴⁸ Yolk sac tumors are positive for SALL4, glypican 3, GATA3, and AFP.¹⁴³^,¹⁴⁹ Prognosis is dependent on stage with reported 5-year disease-free survival ≥95% for patients with Stage I–II, 71% for Stage III and 52% for Stage-IV tumors.¹⁵⁰ Yolk sac tumors or other malignant germ cell tumors can be seen in older patients in association with Müllerian carcinomas and are considered of somatic derivation as they show the same molecular alterations of the carcinoma component and are distinct from the yolk sac tumors discussed in this section (germ cell origin).¹⁵¹^,¹⁵²^,¹⁵³^,¹⁵⁴^,¹⁵⁵

Immature teratoma

Immature teratoma is the third most common malignant germ cell tumor. It may rarely be associated with a variety of paraneoplastic manifestations including neurologic syndromes (anti-NMDA receptor encephalitis).¹⁵⁶ It differs from mature cystic teratomas in its gross and microscopic characteristics as it is typically larger (median size of 16–20 cm; typically >8 cm) and presents as a solid or solid-cystic mass.¹⁵⁷ Although a variety of ectodermal, mesodermal and endodermal tissues can be seen, many are similar to those seen in mature teratomas. The defining and prognostic histologic feature is the presence and extent of immature neuroepithelium, characterized by primitive, mitotically active, hyperchromatic cells forming tubules and rosettes (Figure 13C). Grading is established by quantifying the number of microscopic low-power fields occupied by immature neuroepithelium (Grade 1: ≤1 low-power field in any one slide; Grade 2: >1 and ≤3; Grade 3: >3).¹⁵⁸^,¹⁵⁹ Currently these tumors are classified as low- (Grade 1) or high-grade (Grade 2 and 3). When the primitive neuroepithelium shows an expansile growth pattern without other intervening elements, the tumor is classified as an embryonic-type neuroectodermal tumor/primitive neuroectodermal tumor (ENT/PNET) (Figure 13D), which is associated with aggressive behavior.¹⁶⁰ Both mature and immature teratomas may be associated with mature glial tissue in the peritoneum (gliomatosis peritonei).¹⁶¹ Grade and stage of immature teratomas play a major role in their prognosis, with the 5-year disease-specific survival being 90% with almost 100% survival in Grade-1 tumors and Stage-I disease¹⁶²^,¹⁶³

Non-gestational choriocarcinoma

Non-gestational choriocarcinoma is rare and patients present with highly elevated serum hCG levels. It is grossly hemorrhagic and microscopically characterized by a biphasic population of highly atypical multinucleated (syncytiotrophoblast) and mononuclear (cytotrophoblast and less commonly intermediate trophoblast) cells associated with necrosis and hemorrhage (Figure 13E). Choriocarcinomas are positive for SALL4, hCG and inhibin.¹⁴³^,¹⁶⁴ As the histologic features of non-gestational and gestational choriocarcinoma are identical, their differentiation is based on the clinical scenario and molecular findings by short-tandem repeat analysis, which compares alleles in the tumor with the patient’s non-neoplastic tissue to establish its origin.¹⁶⁵

Embryonal carcinoma

Embryonal carcinoma is almost never seen in pure form but rather as a component of a malignant mixed germ cell tumor. It may show diffuse, glandular or papillary growth patterns composed of primitive cells with abundant amphophilic to clear cytoplasm, high-grade nuclear atypia, brisk mitotic activity and apoptosis (Figure 13F).¹⁶⁶^,¹⁶⁷ Embryonal carcinoma is positive for SALL4, OCT3/4, CD30, and SOX2.¹⁴³

MESENCHYMAL AND MIXED EPITHELIAL-MESENCHYMAL TUMORS

Primary ovarian, tubal and peritoneal mesenchymal or mixed epithelial-mesenchymal tumors are rare.¹⁶⁸ Primary adnexal or peritoneal endometrioid stromal sarcoma and adenosarcoma are typically associated with endometriosis and are morphologically similar to their uterine counterparts with adenosarcomas being associated with a more aggressive behavior compared to their uterine counterpart.¹⁶⁹^,¹⁷⁰^,¹⁷¹ Leiomyosarcoma can arise in the adnexa and peritoneum from ligaments, smooth muscle metaplasia or vessel muscle wall.¹⁷²^,¹⁷³^,¹⁷⁴ They exhibit marked nuclear atypia, brisk mitotic activity and/or tumor necrosis, similar to their uterine counterpart. Ovarian leiomyosarcoma shows aggressive behavior with frequent recurrent disease and poor clinical outcomes.¹⁷³ Other less common malignant mesenchymal tumors that may occur in the ovary include perivascular epithelioid cell tumor (PEComa),¹⁷⁵ inflammatory myofibroblastic tumor,¹⁷⁶ solitary fibrous tumor,¹⁷⁷ rhabdomyosarcoma,¹⁷⁸ angiosarcoma,¹⁷⁹ and liposarcoma,¹⁸⁰ among others. Extra-gastrointestinal stromal tumor and desmoplastic small round cell tumor may involve secondarily the ovary.¹⁸¹^,¹⁸² Carcinosarcoma is considered an epithelial neoplasm, in which a component undergoes transdifferentiation to a mesenchymal phenotype; therefore, it is discussed in the section above (epithelial malignancies – carcinomas).

OTHER MALIGNANT OVARIAN NEOPLASMS

Small cell carcinoma of ovary, hypercalcemic type

Small cell carcinoma of ovary, hypercalcemic type is a very aggressive neoplasm, first described by Dr Robert E. Scully.¹⁸³ It typically affects young patients, predominantly in the second and third decades of life, presenting with hypercalcemia in approximately 60% and often with advanced stage. It is composed of small undifferentiated cells with scant cytoplasm and brisk mitotic activity that grow in sheets, nests, cords, clusters, or single cells with variable numbers of follicle-like spaces (Figure 14A–C). Some tumors may contain a component of large cells with moderate to abundant eosinophilic cytoplasm, variable rhabdoid morphology and prominent nucleoli that, when predominant, has been named large cell variant. Rarely, mucinous epithelium may be seen.¹⁸⁴ The lineage of differentiation is still unclear; however, molecular alterations in SMARCA4 (BRG) and SMARCA2 (BRM), components of SWI/SNF complex, have been uncovered as driver events in these tumors.¹⁸⁵^,¹⁸⁶^,¹⁸⁷ Patients with rhabdoid tumor predisposition syndrome type 2, caused by germline loss-of-function mutations in SMARCA4, are at increased risk of developing small cell carcinoma of ovary, hypercalcemic type.¹⁸⁵^,¹⁸⁶ This tumor is associated with a very poor prognosis even in patients with tumor confined to the ovary at presentation.

Small cell carcinoma of ovary, hypercalcemic type. (A) Cells arranged in nests and sheets. (B) Follicle-like spaces. (C) Small, undifferentiated cells with scant cytoplasm and brisk mitotic activity.

STK11 adnexal tumor

STK11 adnexal tumor has been recently described as a distinctive neoplasm characterized by STK11 alterations often centered in a paratubal location (Figure 15A) and seen in patients with Peutz–Jeghers syndrome in approximately 50% of cases..¹⁸⁸ This tumor was misdiagnosed in the past as female adnexal tumor of probable wolffian origin (FATWO), endometrioid carcinoma, mesothelioma and sex-cord stromal tumor. It is characterized by interanastomosing cords and trabeculae of epithelioid and spindled cells in a myxoid to edematous stroma (Figure 15B–D). A variety of other patterns, such as tubular, cystic, cribriform, and microacinar can be seen. This tumor is associated with frequent recurrences and metastases.¹⁸⁹

STK11 adnexal tumor. (A) Paratubal location (arrows indicating adjacent Fallopian tube). (B) Interanastomosing nests and trabeculae set in a myxoid background. (C) Microacini, small nests and cords resembling a salivary-type tumor. (D) Diffuse and spindled patterns.

Mesothelioma

Mesothelioma may rarely present as a predominant ovarian mass¹⁹⁰ or as diffuse peritoneal involvement with nodules or masses of varying size and secondary adnexal involvement. Epithelioid morphology is the most prevalent and is characterized by a variety of architectural patterns, including tubular, papillary and solid, which can mimic Müllerian serous or clear cell neoplasms. Less commonly, it shows sarcomatoid or spindled cells and a biphasic appearance.¹⁹¹^,¹⁹² These tumors are positive for calretinin, WT1 and D2–40, and may also express PAX8, a known Müllerian marker.¹⁹³ The link between asbestos exposure and peritoneal mesothelioma is weaker than that observed for pleural mesothelioma.¹⁹⁴ Common molecular alterations include BAP1 (inactivating mutations and deletion), CDKN2A (deletion) and NF2 (inactivating mutations and deletion).¹⁹⁵^,¹⁹⁶ A subset of mesotheliomas arise in patients with BAP1 tumor predisposition syndrome.¹⁹⁷

PRACTICE RECOMMENDATIONS

High-grade serous carcinoma is typically aggressive, characterized by TP53 mutations and, in most cases, arises from the fimbriated end of the Fallopian tube.
Fallopian tubes of patients with high-grade serous carcinoma should be examined microscopically following the SEE-FIM (sectioning and extensively examining the fimbriated end) protocol to detect serous tubal intraepithelial carcinoma (STIC) and assign primary site.
High-grade serous carcinoma with solid, pseudo-endometrioid and transitional-like (SET) pattern is often seen in association with homologous recombination deficiency (HRD), which predicts sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors.
Chemotherapy response score (CRS) should be assigned based on the amount of residual tumor involving the omentum in patients with advanced-stage high-grade serous carcinomas receiving neoadjuvant chemotherapy.
Folate receptor alpha (FOLR1) immunohistochemistry has emerged as a companion predictive biomarker test to assess eligibility for the antibody drug conjugate mirvetuximab soravtansine.
Low-grade serous carcinoma commonly arises from serous borderline tumors and harbors molecular alterations involving RAS and RAF pathways (KRAS, NRAS and BRAF) and lacking TP53
Endometrioid carcinoma is often seen in association with endometriosis or adenofibroma and can exhibit a wide morphologic spectrum that may closely mimic other ovarian tumors, including sex-cord stromal tumors, carcinosarcoma or squamous cell carcinoma.
Ovarian endometrioid carcinoma can co-occur with an endometrial endometrioid carcinoma and, based on pathologic criteria, is classified as low-risk (synchronous or independent primaries) or high-risk (advanced stage metastatic tumor).
Clear cell carcinoma is also frequently associated with endometriosis and is considered by definition a high-grade malignancy. It may be associated with paraneoplastic syndromes.
Endometrioid and clear cell carcinomas may exhibit mismatch repair protein deficiency and can be associated with Lynch syndrome.
Undifferentiated and dedifferentiated carcinoma frequently show abnormal expression of SWI/SNF (SWItch/Sucrose Non-Fermentable) complex components (ARID1A/B, SMARCA2/BRM, SMARCA4/BRG and SMARCB1/INI1) and may also be a manifestation of Lynch syndrome.
Comprehensive sampling guided by careful gross examination and clinical findings is key to the evaluation of ovarian tumors, in particular, mucinous neoplasms due to their remarkable intratumoral heterogeneity and frequent differential diagnosis with metastases.
Ovarian involvement may be the first manifestation of an extra-ovarian mucinous carcinoma, especially in pancreatobiliary tumors, in which the primary may be very small and difficult to identify.
The pattern of invasion of primary ovarian mucinous carcinoma is a better predictor of behavior than the traditional grading classifications with infiltrative/destructive growth being associated with worse prognosis when compared to expansile.
Mesonephric-like carcinoma is a newly reported subtype of carcinoma associated with aggressive behavior and tendency to metastasize to the lungs, and is often misdiagnosed as low-grade endometrioid adenocarcinoma.
Adult type granulosa cell tumor is associated with elevated serum inhibin and can present with estrogenic manifestations with increased risk of developing endometrial hyperplasia and carcinoma. Most adult-type granulosa cell tumors reveal FOXL2.
Juvenile granulosa cell tumor lacks FOXL2. Patients with Ollier disease and Maffucci syndrome are at increased risk of developing this tumor.
Sertoli-Leydig cell tumors are typically associated with androgenic manifestations and classified based on the appearance of the Sertoli cell component. Well-differentiated tumors are considered benign and lack DICER1 mutations. Moderately and poorly differentiated tumors can show malignant behavior and may be associated with DICER1 tumor predisposing syndrome. Rhabdomyosarcomatous differentiation may be responsible for more aggressive behavior.
Patients with Peutz–Jeghers syndrome can present with a variety of uncommon gynecologic tract neoplasms, including sex cord tumor with annular tubules (SCTAT), STK11 adnexal tumor, Sertoli cell tumor, and gastric-type proliferations (endocervical adenocarcinoma, lobular endocervical hyperplasia, ovarian neoplasms, multifocal lesions).
Most malignant germ cell tumors are associated with isochromosome 12p or 12p amplifications, except for pure immature teratomas.
Serum markers can be helpful in the differential diagnosis of germ cell tumors: lactose dehydrogenase (dysgerminoma), alpha-fetoprotein (yolk sac tumor) and human chorionic gonadotropin (choriocarcinoma).
Germ cell component (most common yolk sac) associated with Müllerian carcinomas is considered of somatic derivation not of germ cell origin.
Immature teratoma is diagnosed and graded based on the presence and amount of immature neuroepithelium. Grading and stage predict outcomes in these tumors, in contrast to other malignant germ cell tumor, which are not graded and stage is the most important prognostic factor.
Small cell carcinoma of ovary, hypercalcemic type is a highly aggressive malignancy that typically affects young patients (second and third decades of life) and is characterized by SMARCA4 (BRG) and SMARCA2 (BRM) mutations. Patients with rhabdoid tumor predisposition syndrome type 2 (germline loss-of-function germline mutations in SMARCA4) are at increased risk of developing this tumor.
It is important to recognize the association between distinctive adnexal neoplasms (benign, borderline or malignant) and specific tumor-predisposition genetic syndromes, including hereditary breast and ovarian cancer syndrome, Lynch syndrome, Peutz–Jeghers syndrome and DICER1 syndrome.

CONFLICTS OF INTEREST

The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.

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