Recent Advances in the Pathology of Functional Ovarian Tumors

Classification (WHO Framework)

• Berek & Novak's Gynecology, p. 2399

1. Granulosa Cell Tumors (GCT)

Morphology & Subtypes

• Adult GCT (95%): Postmenopausal predominance; bilateral in only ~2%. Classic "coffee bean" grooved nuclei, Call-Exner bodies (rosettes around central eosinophilic material), macrofollicular/microfollicular/trabecular/sarcomatoid patterns.
• Juvenile GCT (5%): Younger patients (under 30); rounder hyperchromatic nuclei, large irregular follicle spaces, frequent mitoses, often cystic with luteinized cells. Associated with sexual pseudoprecocity in ~75% of prepubertal cases.

Granulosa cell tumor with classic Call-Exner bodies (H&E). - Berek & Novak's Gynecology, p. 2400

Key Molecular Advance: FOXL2 c.402C>G (p.C134W)

• A Norwegian study found ~30% of adult GCTs were initially misdiagnosed; FOXL2 testing corrected these errors. Of 477 cases in the Emil Novak Registry, 15% were reclassified after histologic review.
• FOXL2 molecular testing is now routine to distinguish adult GCT from carcinomas, poorly differentiated mesothelial tumors, teratoid tumors, and small cell carcinoma.

Additional Somatic Alterations (2024-2025 Data)

• FOXL2 c.402C>G: 97% (only common driver mutation)
• TERT promoter mutation: ~41% - significantly more frequent in recurrent tumors (p<0.01), suggesting a role in clonal evolution at relapse
• KMT2D truncating mutations: ~14% - earlier reports suggested association with recurrence; this larger review found no significant difference between primary and recurrent tumors
• TP53 pathogenic variants: ~4%
• Tumor mutational burden (TMB) is consistently low across all studies - implications for immunotherapy remain limited

Prognostic IHC Markers (2023 Review)

• Unfavorable prognosis associated with: FOXL2 mRNA loss (paradoxically), and positive CD56, GATA-4, SMAD3 expression
• No prognostic value established for: ER, Anti-Müllerian hormone (AMH), inhibin
• Inconsistent data for: Ki-67, p53, beta-catenin, HER2

Serum Markers

• Inhibin B is more frequently elevated than inhibin A; useful for monitoring recurrence with ~12-month lead time before clinical relapse
• AMH has >90% sensitivity for detecting recurrence; elevated in ~75% of patients preoperatively
• About 70% of GCTs secrete estrogen or androgens. GCTs express ER in ~30% and progesterone receptors in nearly 100%, forming the basis for hormonal therapy in recurrent disease (aromatase inhibitors, GnRH agonists, progestins).

2. Sertoli-Leydig Cell Tumors (SLCTs / Androblastomas)

Morphology

• Third to fourth decade predominance; <0.2% of ovarian cancers; rarely bilateral (<1%)
• Tubules of Sertoli cells adjacent to clusters of eosinophilic Leydig cells in stroma
• Graded as well-/moderately-/poorly differentiated (sarcomatoid); heterologous elements (e.g., mucinous epithelium, carcinoid) occur in ~20% and raise the differential of a primary GI mucinous tumor
• Virilization in 70-85% (oligomenorrhea → amenorrhea, hirsutism, clitoromegaly, deepening voice)

Key Molecular Advance: DICER1

• Hotspot mutations in the RNase IIIb domain (exons 24-25) are most common
• DICER1 syndrome (germline DICER1 mutation) confers risk for bilateral SLCTs, pleuropulmonary blastoma, cystic nephroma, thyroid tumors, and other lesions - the pathologist is often the first to raise syndromic suspicion
• DICER1 mutation is associated with moderately to poorly differentiated SLCTs and a worse prognosis
• A 2024 review (Muscat & Calleja-Agius, Discov Med, PMID 38409829) highlights that DICER1 and FOXL2 mutations can coexist in rare cases, and that differentiation level correlates with mutation status and degree of virilization

• Immunophenotype alone is often nonspecific between stromal and sex cord tumors
• Molecular testing (FOXL2, DICER1) is now indispensable for accurate subclassification
• This molecular triage has important downstream implications for genetic counseling

3. Sex Cord Tumor with Annular Tubules (SCTAT)

• Peutz-Jeghers syndrome (PJS)-associated: bilateral, multifocal, benign; linked to germline STK11/LKB1 mutation. STK11 IHC loss is a reliable surrogate marker for PJS-related tumors.
• Non-PJS (sporadic): usually unilateral, larger, may have malignant potential (~20%)

• Monosomy 22: 8/12 sporadic cases (novel recurrent finding)
• FOXL2 copy number gain: 10/12 cases (not the typical point mutation of adult GCT)
• WT1 and GATA4 gains also recurrent
• TERT promoter mutations: 6/12
• High-grade transformation (previously undescribed): 1 case with TP53 biallelic inactivation, cytologic atypia, necrosis - a newly recognized rare event
• STK11 was mutated in only 1/13 sporadic tumors, confirming that most sporadic SCTATs are STK11 wild-type

4. Steroid Cell Tumors

• Comprise <1% of ovarian neoplasms; most produce androgens causing virilization; rare cases secrete cortisol (Cushing's) or estrogen
• Subtypes: stromal luteoma (benign, within ovarian stroma), Leydig cell tumor/hilus cell tumor (positive for inhibin, calretinin; Reinke crystals on EM), steroid cell NOS (most common, ~20% malignant - especially those >8 cm)
• About 20% metastasize, predominantly intraperitoneally
• IHC: inhibin+, calretinin+, SF-1+; SALL4/PLAP negative

5. IHC Panel Summary for SCSTs

6. Emerging Therapeutic Targets

• Granulosa cell tumors: paclitaxel ± bevacizumab (Alienor trial results awaited); aromatase inhibitors for recurrent disease (case series showing durable responses)
• DICER1-mutant SLCTs: potential for targeted therapy given the specific molecular pathway
• Hormonal agents (GnRH agonists, progestins) remain viable in hormone-receptor-positive GCTs

Key References