3.4.2: Ovarian Tumors (WHO Classification)

3.4.2.1 Overview

Ovarian cancer is one of the gynecological cancers detected all over the world and is the fifth most common cause of death in the female population. It is associated with high mortality rates as it is usually diagnosed in advanced stages. The current screening tests are not very useful in detecting this cancer. The keys to the detection of this cancer are vaginal ultrasound and a biomarker known as CA-125; however, they couldn’t prevent the high rates of deaths caused by this cancer. Histologic and molecular subtyping are critical for management of ovarian cancer. The preferred treatment for this malignancy is chemotherapy, with cisplatin as the drug of choice. Antiangiogenic bevacizumab and poly ADP-ribose polymerase inhibitors resulted in a better cure. Recurrences and relapses are not uncommon.⁶

Ovarian tumors encompass a diverse group of neoplasms classified by their cell of origin. The WHO 2020 classification divides these into four broad categories: surface epithelial tumors, germ cell tumors, sex cord–stromal tumors, and metastatic tumors. This section elaborates on the major subtypes, focusing on their definition, etiology, pathogenesis, morphology, clinical presentation, diagnosis, and treatment.⁷

3.4.2.2 Surface Epithelial Tumors

• Etiology & Epidemiology

Surface epithelial tumors originate from the ovarian surface epithelium or inclusion cysts and represent approximately 70% of all ovarian neoplasms. Risk factors include age, ovulatory cycles, endometriosis, hormone replacement therapy, and inherited mutations (e.g., BRCA1/2). These tumors are more common in peri- and postmenopausal women.⁸

• Pathogenesis

These tumors arise from mesothelial cells that undergo müllerian-type differentiation. The pathogenesis may be influenced by repeated ovulatory injury and inflammation. Malignant transformation involves specific mutations: TP53 in high-grade serous carcinoma, KRAS/BRAF in low-grade serous and mucinous tumors, and ARID1A/PIK3CA in endometrioid and clear cell carcinomas.

• Molecular Profile

Characteristic molecular alterations include mutations in TP53 and BRCA genes. Please refer to the cited publications for more details on specific molecular profiles.

• Pathophysiology

Malignant transformation leads to local invasion and potential peritoneal spread. High-grade tumors often present at an advanced stage with ascites and omental metastases.

• Clinical Picture & Diagnosis

Patients may present with abdominal distension, pelvic pain, ascites, and/or mass effect. Imaging (ultrasound, CT, MRI), tumor markers (CA-125, HE4), and histopathology are used for diagnosis.

• Treatment

Surgery is the mainstay. Adjuvant chemotherapy is used in malignant tumors, particularly high-grade serous carcinoma. Targeted therapies such as PARP inhibitors are also used.⁹

• Subtypes

  • Serous Tumors

Serous tumors are epithelial neoplasms with serous (fallopian tube-like) differentiation. They are classified into two distinct subtypes: High-grade serous carcinoma (HGSC) and low-grade serous carcinoma (LGSC) based on morphology, molecular profile and prognosis. HGSC is the most common and deadliest subtype; low-grade serous carcinoma (LGSC) is less frequent. HGSC arises from the distal fimbrial end of the fallopian tube from a precursor lesion known as serous tubal intraepithelial carcinoma (STIC). They are associated with TP53, BRCA1/2 mutations. LGSC arise within the ovary from serous benign and borderline tumors and involves KRAS and BRAF mutations.¹⁰

Serous tumors often present as bilateral cystic masses with papillary projections. HGSC shows variable features, including papillary, micropapillary, and solid growth patterns. Microscopically, two histological types have been described: classical and SET (Solid, pseudoEndometroid and Transitional) (Figure 3.4.1). In classical HGSC, the tumor cells typically exhibit marked nuclear pleomorphism with prominent nucleoli, high mitotic activity (typically > 12 mitoses per 10 high‐power fields), including atypical mitoses. SET variant is characterized by solid sheets of cells simulating endometrioid and/or transitional cell carcinomas.¹¹

Figure 3.4.1. (A)Histologic appearance of classic high-grade serous carcinoma (HGSC) (hematoxylin and eosin, H&E, ×100); (B) Solid, pseudoendometrioid, transitional cell carcinoma-like (SET) variant of HGSC (hematoxylin and eosin, H&E, ×100).
Image Source: De Leo, Antonio, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, and et al. 2021. "What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors" Diagnostics 11, no. 4: 697 (2021). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Available from: https://doi.org/10.3390/diagnostics11040697.

These tumors often show geographical necrosis and are associated with a high count of tumor-infiltrating lymphocytes. Microscopically, LGSC is composed of a homogeneous population of small cells with scant cytoplasm arranged in small papillae (Figure 2). In contrast to HGSC, tumor cells show mild to moderate nuclear atypia without pleomorphism (<3_ variation in size) and may have prominent nucleoli. Mitoses are usually less than 12 per 10 high-power fields. Psammoma bodies are frequent. LGSC is differentiated from serious borderline tumors by the presence of stromal invasion greater than microinvasion (invasive foci measuring > 5 mm or 10 mm2) (Figure 3.4.2).¹²

Figure 3.4.2. (A) Histologic appearance of low-grade serous carcinoma showing tumor cells with uniform nuclei and inconspicuous mitotic activity (hematoxylin and eosin, H&E, ×100); (B) Psammoma bodies are frequent in low-grade serous carcinoma (hematoxylin and eosin, H&E, ×100).
Image Source: De Leo, Antonio, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, and et al. 2021. "What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors" Diagnostics 11, no. 4: 697 (2021). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Available from: https://doi.org/10.3390/diagnostics11040697.

• Mucinous Tumors

In recent years, there has been a significant shift in how ovarian mucinous tumors are classified. Many tumors previously diagnosed as primary ovarian mucinous carcinomas (MCs) are now recognized as secondary (metastatic) lesions, most commonly originating from the appendix, gastrointestinal tract, pancreas, or biliary system, especially when associated with pseudomyxoma peritonei. True primary mucinous tumors of the ovary are relatively uncommon. They account for 10–15% of all primary ovarian tumors, and the majority—over 80%—are benign or borderline. Mucinous carcinoma, the malignant form, comprises only 3–4% of ovarian carcinomas. The exact origin of primary MCs remains unclear. While a subset may arise from ovarian teratomas, most lack any identifiable teratomatous component.¹³

Clinically and pathologically, several features help distinguish primary ovarian MCs from metastatic mucinous tumors:

• Primary MCs are typically large (>13 cm), unilateral, and lack surface involvement.
• Metastatic lesions are usually bilateral, smaller, and often associated with pseudomyxoma peritonei.

Grossly, MCs appear as large, cystic masses (8–40 cm) often with multilocular or unilocular architecture, filled with mucinous fluid. They may contain papillary or solid areas, which vary in texture from mucoid to firm.

Microscopically, MCs show a mixture of benign, borderline, and malignant components, necessitating extensive sampling. Most display gastrointestinal-type differentiation, and less commonly, endocervical-type features. Two distinct growth patterns are recognized (Figure 3.4.3):

1. Expansile: Closely packed malignant glands with little stromal invasion—associated with better prognosis.
2. Infiltrative: Evident stromal invasion, often with desmoplastic response—linked to worse outcomes.¹⁴

Figure 3.4.3. Mucinous carcinoma of the ovary (MC). Infiltrative type of invasion with glandular and cribriform areas (a) (H&E, 100x). Expansile type of invasion with areas of complex glandular proliferation (b) (H&E, 40x). Diffuse expression of cytokeratin 7 (c) (100x) and focal expression of cytokeratin 20 (d) (200x). Focal and weak expression of PAX8 (e) (200x). Tumor cells showing retained expression of DPC4 (f) (200x).
Image Source: Dundr, Pavel, Naveena Singh, Barbora Nožičková, Kristýna Němejcová, Michaela Bártů, and Ivana Stružinská. “Primary Mucinous Ovarian Tumors vs. Ovarian Metastases from Gastrointestinal Tract, Pancreas and Biliary Tree: A Review of Current Problematics.” Diagnostic Pathology, 16, No. 20 (2021). This open access article is distributed under the terms of the Creative Commons Attribution License CC-BY 4.0. Available from: https://rdcu.be/emRz9.

• Endometrioid tumors

Ovarian endometrioid carcinoma (EC) is the second most common histologic subtype of ovarian carcinoma, accounting for 10–15% of cases. Its incidence has declined in recent years due to reclassification of many former “high-grade endometrioid carcinomas” as SET variants of high-grade serous carcinoma (HGSC). The median age at diagnosis is approximately 51 years, and most patients are diagnosed at an early stage (FIGO I or II). ECs are bilateral in 20% of cases and are synchronously associated with endometrial carcinoma in 15–20% of cases. A strong link exists between EC and endometriosis, with atypical endometriosis identified as a precursor lesion in up to 40% of cases. Molecular studies have shown shared mutations between the carcinoma and adjacent atypical endometriosis, supporting this precursor relationship.¹⁵

Grossly, ECs often appear as solid-cystic masses with soft tissue components and areas of hemorrhage. A residual endometriotic cyst may be found at the periphery. Microscopically, they resemble endometrial adenocarcinoma (Figure 3.4.4).

Figure 3.4.4. (A) and (B) Histologic appearance (hematoxylin and eosin, H&E) of low-grade endometrioid carcinoma with squamous differentiation (×100 and ×200, respectively).
Image Source: De Leo, Antonio, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, and et al. 2021. "What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors" Diagnostics 11, no. 4: 697 (2021). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Available from: https://doi.org/10.3390/diagnostics11040697.

Low-grade ECs typically display glandular, cribriform, or villoglandular patterns, with tall columnar epithelial cells, scant eosinophilic cytoplasm, and squamous differentiation, a characteristic and helpful diagnostic feature. High-grade ECs show solid architecture, marked nuclear atypia, and high mitotic activity, requiring careful distinction from SET-type HGSC.

Three histologic clues—termed “confirmatory endometrioid features”—support the diagnosis in ambiguous cases:

1. Metaplastic changes, including squamous, mucinous, hobnail, or eosinophilic differentiation.
2. Association with endometriosis, endometrioid adenofibroma, or endometrioid borderline tumors.
3. Presence of synchronous uterine endometrioid carcinoma.

Grading follows the same system used for uterine EC:

• Grade 1: <5% solid growth
• Grade 2: 5–50% solid growth
• Grade 3: >50% solid growth

(Note: squamous areas are excluded from grading)

Two invasion patterns are recognized:

1. Expansile invasion: confluent glandular growth with minimal stromal response—associated with low-stage disease and favorable prognosis.
2. Destructive invasion: irregular infiltration into stroma with a desmoplastic reaction—linked to a more aggressive course.

Immunohistochemistry: Ovarian ECs commonly express

• PAX8
• Vimentin
• Estrogen (ER) and Progesterone (PR) receptors
• Nuclear β-catenin (in some cases)

They are generally negative or only focally positive for WT1, p53, and p16, unlike HGSC. High-grade ECs, however, may show aberrant p53 staining patterns, reflecting underlying mutations.They harbor molecular alterations such as PTEN, POLE mutations, microsatellite instability (MSI), and ARID1A mutations.¹⁶

• Clear Cell Carcinoma

Ovarian clear cell carcinoma (CCC) accounts for approximately 10% of ovarian carcinomas and is notable for presenting at early stages (FIGO I–II) in about 25% of such cases. These tumors are typically unilateral and have a strong association with endometriosis, similar to the endometrioid subtype. Some CCCs also contain adenofibromatous or borderline components, which have been linked to a better prognosis—with studies showing significantly improved 5-year survival in tumors with adenofibromatous areas (≈79%) compared to those without (≈49%).

While CCC is generally considered a high-grade malignancy, early-stage disease—especially FIGO stage I, including cases with positive peritoneal cytology or capsular involvement (stage IC)—often has a favorable outcome, with 5-year survival rates between 80–90%. However, advanced-stage CCC carries a poor prognosis, often worse than that of high-grade serous carcinoma (HGSC), largely due to its limited response to platinum-based chemotherapy. Notably, mismatch repair (MMR) deficiency or association with Lynch syndrome may indicate better long-term survival, possibly due to increased tumor immunogenicity and potential for response to immunotherapy.¹⁷

Grossly, CCCs usually appear as large, unilateral, mixed solid and cystic masses, often with foci of endometriosis and superficial adhesions. Histologically (Figure 3.4.5), CCCs are characterized by a variety of architectural patterns, most commonly:

• Papillary
• Tubulocystic
• 

Figure 3.4.5. (A) Histologic appearance of clear cell carcinoma with tubulocystic pattern, tumor cells are polygonal to cuboidal and flattened with clear cytoplasm; (hematoxylin and eosin, H&E, ×200); (B) Papillary pattern shows small and regular papillae, frequently hyalinized (hematoxylin and eosin, H&E ×100).
Image Source: De Leo, Antonio, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, and et al. 2021. "What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors" Diagnostics 11, no. 4: 697 (2021). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Available from: https://doi.org/10.3390/diagnostics11040697.

The tumor cells typically have clear, eosinophilic, or flattened cytoplasm, and large atypical nuclei with prominent nucleoli, but the cytologic atypia is relatively uniform, lacking significant pleomorphism. Mitoses are usually sparse (<5 per 10 high-power fields), which helps distinguish CCC from more proliferative ovarian carcinomas. Importantly, the presence of clear cytoplasm alone is not diagnostic, as clear cells may be seen in other ovarian tumors (e.g., endometrioid or serous carcinoma). However, three histologic features are particularly suggestive of CCC:

1. Multiple complex papillae
2. Hyaline basement membrane or mucoid stroma in papillary cores
3. Hyaline globules (bodies)

Immunohistochemical Profile

CCC has a distinct immunophenotype:

• Positive for hepatocyte nuclear factor 1-beta (HNF-1β)
• Negative for WT1, ER, and PR
• Wild-type p53 expression

This profile aids in distinguishing CCC from other ovarian carcinoma subtypes, especially in morphologically ambiguous cases.Key molecular features include ARID1A and PIK3CA mutations.¹⁸

• Brenner Tumors

Brenner tumors typically present as solid, fibrous masses composed microscopically of transitional epithelium-like cells embedded within a fibrous stroma^.19

3.4.2.3 Germ Cell Tumors

Germ cell tumors primarily affect younger women, typically under 20 years of age.²⁰

• Etiology

Arise from aberrant differentiation of primitive germ cells.

• Pathogenesis

Stem from genetic abnormalities during germ cell differentiation.

• Molecular Profile

Frequently involve genetic abnormalities such as isochromosome 12p (i(12p)). (Refer to "Integrated Morphologic and Molecular Analysis").

• Clinical Picture

Common symptoms include abdominal pain, palpable masses, or hormonal symptoms related to tumor-produced substances.

• Treatment Options

Fertility-sparing surgery combined with chemotherapy is often curative.

• Subtypes

  • Dysgerminoma

Grossly, dysgerminomas are solid, lobulated masses resembling seminomas microscopically, with uniform cells and a characteristic lymphocytic infiltrate.²¹

• Endodermal Sinus (Yolk Sac) Tumor

Endodermal sinus tumors present grossly as hemorrhagic and necrotic masses. Microscopically, they exhibit Schiller-Duval bodies and secrete α-fetoprotein, aiding diagnosis and monitoring.²⁵

• Teratomas

Teratomas range from benign cystic dermoid (mature) containing differentiated tissues such as hair, cartilage, and teeth to malignant immature teratomas composed of primitive neural elements (neuroectodermal tissue).²²

• Choriocarcinoma

Choriocarcinomas are aggressive, rapidly growing tumors presenting with extensive hemorrhage and necrosis, microscopically composed of syncytiotrophoblast and cytotrophoblast, producing human chorionic gonadotropin (hCG).²³

3.4.2.4 Sex Cord-Stroma Tumors

Sex Cord-Stroma Tumors are derived from the ovarian stroma and sex cord derivatives, including granulosa, theca, Sertoli, and Leydig cells.²⁴

• Etiology & Epidemiology

Account for ~5–8% of ovarian neoplasms. Most common in peri- and postmenopausal women (for granulosa cell tumors) or younger patients (for juvenile variants).

• Pathogenesis

Thought to originate from primitive sex cord-stromal elements. Granulosa cell tumors commonly harbor FOXL2 mutations (adult type). Sertoli–Leydig tumors may involve DICER1 mutations.

• Clinical Picture & Diagnosis

May produce estrogen (granulosa) or androgens (Sertoli–Leydig), causing abnormal bleeding or virilization. Elevated inhibin, anti-Müllerian hormone (AMH) may be present. Diagnosis confirmed via histology and immunostains (e.g., inhibin+, calretinin+).

• Treatment

Surgical excision is curative in early-stage disease. Advanced or recurrent disease may require chemotherapy or hormonal therapy.²⁵

• Subtypes

• Fibroma

Characterized grossly as solid, firm tumors with spindle cells in a dense collagenous stroma microscopically, occasionally associated with Meigs syndrome.

• Thecoma

Thecomas appear yellowish grossly due to high lipid content, microscopically showing lipid-laden thecal cells.

• Granulosa Cell Tumor

Granulosa cell tumors present grossly as solid-cystic lesions with hemorrhagic regions. Microscopically, they feature characteristic Call-Exner bodies and coffee bean-shaped nuclei, often harboring FOXL2 mutations.

• Sertoli-Leydig Cell Tumor

Grossly solid and lobulated, these tumors are composed of Sertoli and Leydig cells microscopically, often associated with androgenic symptoms and DICER1 mutations.²⁶

3.4.2.5 Metastatic Tumors

Metastatic tumors are secondary ovarian tumors originating from extragenital primaries. Ovarian metastases commonly originate from gastrointestinal, breast, or endometrial cancers. Krukenberg tumors specifically refer to bilateral ovarian involvement characterized histologically by mucin-producing signet-ring cells.²⁷

• Pathogenesis

Tumor cells spread hematogenously, via lymphatics, or transcoelomically. Bilateral involvement is common.

• • Gross

Often bilateral, solid with a nodular surface.

• Microscopic

Depends on primary—Krukenberg: mucin-filled signet-ring cells; colorectal metastases: dirty necrosis, glandular patterns.

• Clinical Picture & Diagnosis

Abdominal pain or distension. CA-125 may be elevated but nonspecific. IHC critical for differentiation:

• CK7+/CK20–: primary ovarian
• CK7–/CK20+: GI origin
• CDX2+, MUC2+: colorectal

• Treatment

Depends on primary site. Oophorectomy may be performed for symptom control. Systemic therapy is based on the primary tumor.²⁸

• Common Mistakes

  • Confusing primary mucinous carcinoma with metastatic colorectal cancer—look for bilaterality and IHC profile.
  • Assuming all germ cell tumors are malignant—mature teratomas are usually benign.
  • Overlooking STIC lesions in the fallopian tube during assessment for high-grade serous carcinoma.
  • Misclassifying borderline tumors as invasive carcinoma without thorough histologic sampling.

Clinical Pearls

• Psammoma bodies are commonly seen in serous tumors and can be a diagnostic clue.
• Bilateral ovarian masses should raise suspicion for metastatic disease.
• Consider struma ovarii or other monodermal teratomas when evaluating hormonally active tumors.
• Meigs syndrome (ovarian fibroma, ascites, pleural effusion) resolves with tumor resection.

Footnotes

6. Zamwar, Udit M, and Ashish P Anjankar. “Aetiology, Epidemiology, Histopathology, Classification, Detailed Evaluation, and Treatment of Ovarian Cancer.” Cureus, 14, No. 10: e30561 (October 21, 2022). This open access article is distributed under the terms of the Creative Commons Attribution License CC-BY 4.0. Available from: https://doi.org/10.7759/cureus.30561.
7. Zamwar & Anjankar, 2022.
8. De Leo, Antonio, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, and et al. 2021. "What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors" Diagnostics 11, no. 4: 697 (2021). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Available from: https://doi.org/10.3390/diagnostics11040697.
9. De Leo et al, 2021.
10. De Leo et al, 2021.
11. De Leo et al, 2021.
12. De Leo et al, 2021.
13. De Leo et al, 2021.
14. De Leo et al, 2021.
15. De Leo et al, 2021.
16. De Leo et al, 2021.
17. De Leo et al, 2021.
18. De Leo et al, 2021.
19. De Leo et al, 2021.
20. De Leo et al, 2021.
21. De Leo et al, 2021.
22. De Leo et al, 2021.
23. De Leo et al, 2021.
24. De Leo et al, 2021.
25. De Leo et al, 2021.
26. De Leo et al, 2021.
27. De Leo et al, 2021.
28. De Leo et al, 2021.

Image Acknowledgements

• De Leo, Antonio, Donatella Santini, Claudio Ceccarelli, Giacomo Santandrea, Andrea Palicelli, Giorgia Acquaviva, Federico Chiarucci, Francesca Rosini, Gloria Ravegnini, Annalisa Pession, and et al. 2021. "What Is New on Ovarian Carcinoma: Integrated Morphologic and Molecular Analysis Following the New 2020 World Health Organization Classification of Female Genital Tumors" Diagnostics 11, no. 4: 697 (2021). This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Available from: https://doi.org/10.3390/diagnostics11040697.
• Dundr, Pavel, Naveena Singh, Barbora Nožičková, Kristýna Němejcová, Michaela Bártů, and Ivana Stružinská. “Primary Mucinous Ovarian Tumors vs. Ovarian Metastases from Gastrointestinal Tract, Pancreas and Biliary Tree: A Review of Current Problematics.” Diagnostic Pathology, 16, No. 20 (2021). This open access article is distributed under the terms of the Creative Commons Attribution License CC-BY 4.0. Available from: https://rdcu.be/emRz9.