Ovarian Cancer Under the Microscope: How the Pathologist Diagnoses and Classifies the Disease

From specimen to diagnosis

Ovarian cancer is not a single disease. By the time a tissue specimen reaches the pathology bench, the central task is no longer simply confirming that a cancer is present — it is determining which cancer, because the major types behave as biologically distinct illnesses with different origins, molecular drivers, prognoses, and treatment eligibilities.

The specimen itself may arrive in several forms: an intact ovary and fallopian tube removed at surgery, omental and peritoneal biopsies that document spread, or smaller diagnostic samples. Crucially, the fallopian tube is now examined with the same care as the ovary, because the most common and most lethal ovarian carcinoma frequently originates there rather than in the ovary itself. Tissue is fixed, embedded in paraffin, sectioned thinly, and stained with hematoxylin and eosin (H&E) — the foundational stain that colors nuclei blue-purple and cytoplasm pink, revealing architecture and cellular detail. The H&E slide drives the initial impression; immunohistochemistry (IHC) and, increasingly, molecular testing then confirm or refine it.

The H&E picture: reading architecture and nuclei

Under H&E, the pathologist reads two things in parallel: how the tumor is organized (architecture) and what the individual cells and their nuclei look like (cytology). The major ovarian carcinomas each carry a recognizable signature.

• High-grade serous carcinoma shows papillary, solid, and glandular growth with markedly atypical, pleomorphic nuclei and brisk mitotic activity. Psammoma bodies — small laminated calcifications — are a recurring clue, and the tumor is often traceable to a precursor lesion in the fallopian tube (serous tubal intraepithelial carcinoma, or STIC) [1].
• Low-grade serous carcinoma, by contrast, presents uniform, monotonous low-grade nuclei in micropapillary or papillary patterns with few mitoses, frequently arising on a background of a serous borderline tumor [1].
• Clear cell carcinoma displays cells with clear cytoplasm and characteristic "hobnail" nuclei bulging into tubulocystic, papillary, or solid spaces, often associated with endometriosis [1].
• Endometrioid carcinoma forms glands that recall the lining of the uterus, sometimes with squamous (morular) differentiation, and is likewise linked to endometriosis [1].
• Mucinous carcinoma is built from tall, mucin-filled gastrointestinal-type epithelium, with invasion that may be expansile or frankly infiltrative [1].

Because these patterns can overlap, H&E alone is rarely the final word. The evidence supports a small, powerful IHC panel as the master discriminator — discussed below.

The major categories: naming the subtypes

Histotype is the classification. The five major epithelial histotypes are best understood as five separate diseases rather than variations of one. Each is a hub for its own detailed discussion.

High-grade serous carcinoma (HGSC) is the most common and most lethal. Its IHC signature is WT1-positive with an aberrant (mutant-pattern) p53 — either complete loss ("null") or strong diffuse overexpression — alongside PAX8 positivity and block-positive p16. At the molecular level it is defined by near-universal TP53 mutation, with a large subset showing BRCA1/2 mutation or broader homologous-recombination deficiency (HRD) [1].

Low-grade serous carcinoma (LGSC) shares WT1 positivity with HGSC but is separated by a wild-type p53 pattern — the single most useful distinction between the two. It is driven by MAPK-pathway mutations (KRAS, BRAF, NRAS) and is TP53 wild-type. It is biologically distinct from HGSC: more indolent in tempo yet relatively resistant to conventional chemotherapy [1].

Clear cell carcinoma is endometriosis-associated and IHC-distinct: Napsin A and HNF1-beta positive, WT1 negative, usually p53 wild-type, and frequently ER-negative. Recurrent ARID1A loss and PIK3CA mutations characterize it. It is treated as high-grade by default [1].

Endometrioid carcinoma is typically WT1-negative and ER/PR-positive, with p53 wild-type in low-grade tumors. Its molecular landscape includes ARID1A, PTEN, CTNNB1, and PIK3CA alterations, plus mismatch-repair deficiency in a subset — relevant to Lynch syndrome [1].

Mucinous carcinoma is a rare primary ovarian cancer, and its defining diagnostic challenge is exclusion of a metastasis from the gastrointestinal tract, appendix, or pancreaticobiliary system. It is typically CK7-positive with variable CK20, often PAX8-negative, WT1-negative, and SATB2-negative (helping exclude lower-GI origin). KRAS mutation is common, and a subset shows HER2 amplification [1].

The unifying logic is the WT1 + p53 pair: HGSC is WT1+/p53-aberrant; LGSC is WT1+/p53 wild-type; clear cell and endometrioid carcinomas are WT1-negative. This compact panel, read against the H&E architecture, resolves the majority of cases.

How grading and staging work

Grading does not apply uniformly across histotypes, because histotype already encodes much of the biology. Serous carcinoma uses a binary system: HGSC is high-grade by definition, and LGSC is a separate entity, not merely a low grade of the same tumor. Clear cell carcinoma is considered high-grade by default, and conventional grading is not applied. Endometrioid carcinoma, by contrast, is graded FIGO 1–3, paralleling its uterine counterpart, and mucinous carcinoma is assessed by architecture and atypia [1].

Staging is a separate axis from histotype and grade. It describes anatomic extent — confinement to the ovary, spread to the pelvis, peritoneal and omental involvement, and distant disease — and is determined surgically and pathologically across the submitted specimens. Histotype tells you what the disease is; stage tells you how far it has traveled.

Why classification matters

Accurate classification is not academic taxonomy — it changes what the disease means and what therapy classes are even applicable. Distinguishing HGSC from LGSC matters because the former is often HRD/BRCA-associated, making patients eligible to be considered for PARP-inhibitor–class therapy, while the latter is MAPK-driven and raises the relevance of MEK-inhibitor–class agents. Endometrioid carcinoma triggers mismatch-repair testing with its Lynch-syndrome implications. Mucinous carcinoma demands a rigorous search for an extra-ovarian primary before any ovarian diagnosis is finalized, and HER2 testing may become relevant. (Eligibility for a drug class is a population-level statement and is not individual treatment advice.)

What's current: recent reclassification

The framework summarized here reflects the WHO Classification of Female Genital Tumours, 5th edition (2020) [1]. Its central modern shift is the firm recognition that the five major epithelial histotypes are distinct diseases rather than grades along a continuum, and the formal embrace of the fallopian tube — via STIC — as the origin of much HGSC. The serous category in particular has been clarified: LGSC and HGSC are now understood as separate entities with separate molecular drivers, not two grades of one tumor. IHC and molecular signatures evolve, and specific marker patterns should always be verified against current standards at the time of reporting; the evidence in this fast-moving area continues to be refined.

References

1. WHO Classification of Tumours Editorial Board. Female Genital Tumours, 5th ed. IARC, Lyon, 2020. ISBN 978-92-832-4504-9.