Malignant Sex Cord-Stromal Tumor Classification
The WHO 2014 classification divides malignant sex cord-stromal tumors into three main categories: pure sex cord tumors (adult and juvenile granulosa cell tumors being the most common malignant types), mixed sex cord-stromal tumors (primarily Sertoli-Leydig cell tumors), and pure stromal tumors (fibrosarcoma and malignant steroid cell tumor). 1
Pure Sex Cord Tumors (Malignant Types)
The malignant entities within this category include:
- Adult granulosa cell tumor - the most frequent malignant sex cord-stromal tumor, typically oestrogenic and characterized by FOXL2 (402C-G) mutations in the majority of cases 1
- Juvenile granulosa cell tumor - occurs in adolescents and young females, with distinct morphology from the adult type 1
These tumors express inhibin alpha, calretinin, and FOXL2 on immunohistochemistry, which aids in diagnosis 1. Adult granulosa cell tumors are associated with estrogen production and may present with various clinical syndromes depending on patient age 1.
Mixed Sex Cord-Stromal Tumors (Malignant Types)
Sertoli-Leydig cell tumors represent the primary malignant entity in this category and are subclassified by differentiation level 1:
- Well differentiated
- Moderately differentiated (with or without heterologous elements)
- Poorly differentiated (with or without heterologous elements)
- Retiform (with or without heterologous elements)
These tumors typically produce androgens, with clinical virilization observed in 70-85% of patients 1. The retiform and poorly differentiated variants may be negative for FOXL2 on immunostaining but usually express inhibin alpha and/or calretinin 1.
Pure Stromal Tumors (Malignant Types)
The malignant stromal tumors include:
- Fibrosarcoma - rare malignant counterpart to the common benign fibroma 1
- Steroid cell tumor, malignant - designated as malignant subtype within the steroid cell tumor category 1
Most pure ovarian stromal neoplasms are benign, with over 50% being fibromas 1.
Sex Cord-Stromal Tumors, Not Otherwise Specified (NOS)
This category encompasses tumors that cannot be further classified into specific subtypes based on morphology 1.
Key Diagnostic Considerations
Immunohistochemical panels are essential for accurate diagnosis in morphologically ambiguous cases. An immunopanel of inhibin alpha, calretinin, and FOXL2, combined with FOXL2 (402C-G) mutational analysis, confirms the diagnosis of adult granulosa cell tumors 1. DICER1 mutations have been identified in a subset of sex cord-stromal tumors and may aid in diagnosis 1.
Clinical Behavior and Prognosis
Malignant sex cord-stromal tumors are rare, accounting for approximately 3-5% of ovarian malignancies 1. Granulosa cell tumors are the most common malignant histological type and are typically associated with good prognosis, particularly when presenting at early stages 1. Stage remains the most important prognostic factor, with FIGO stage and intraperitoneal tumor rupture being the most frequently reported prognostic factors 1. Advanced-stage disease can still have favorable outcomes due to chemotherapy sensitivity 1.
Granulosa cell tumors have an indolent course but can recur decades after initial diagnosis, requiring prolonged surveillance 1. Approximately 20% of these tumors relapse or develop metastases that can be fatal 1.