Sexcord/ stromal ovarian tumors pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

The exact pathogenesis of sexcord/ stromal ovarian tumors is not fully understood. Mutations mainly involving FOXL2, DICER1, STK11 are involved. They are associated with ollier disease and maffucci syndrome.The microscopic pathology varies with the individual subtype of sexcord stromal ovarian tumors.

Pathophysiology

Pathogenesis

• The exact pathogenesis of sexcord/ stromal ovarian tumors is not completely understood.
• However genetic factors attribute to the pathogenesis of some subtypes of the tumors
• The pathophysiology of sexcord/ stromal ovarian tumors depends on the histological subtype.

Genetics

• The recent advancing analyses have made us understand the pathophysiology of some of these tumor subtypes
• Mutations mainly involving DICER1, STK11, and FOXL2 influence the development of some of these neoplasms

FOXL2:

• FOXL2 is a tumor suppressor gene
• It is a member of the forkhead box (FOX) family of evolutionarily conserved transcription factors
• It plays a fundamental and crucial role in ovarian development
• It regulates the ovarian granulosa cell proliferation, follicle development and ovarian hormones synthesis
• Almost all like 97% of adult granulosa cell tumors are characterized by missense somatic point mutations (402 C→G) in FOXL2 gene
• Infact this mutation is a sensitive and specific biomarker for adult granulosa cell tumors making it a pathognomonic feature
• The phosphorylation modification of FOXL2 in particular is responsible to the growth of granulosa cell tumors
• Importantly this mutation alter's antiproliferative pathways and also limit the apoptosis, as a result contributing to the pathogenesis of adult granulosa cell tumors
• Other factors that play an important role in the pathogenesis of granulosa cell tumors are PI3K/AKT (phosphatidylinositol-3-kinase; serine/threonine kinase), TGF-β (Transforming growth factor beta) signaling pathway, Notch signaling pathway, GATA4 and VEGF (vascular endothelial growth factor)

Schematic representation of the cell signaling pathways in GCT development. PI3K, phosphatidylinositol-3-kinase; AKT, serine/threonine kinase; FOXO 1/3, forkhead box O1/3; AMH, Source:Li J, Bao R, Peng S, Zhang C. The molecular mechanism of ovarian granulosa cell tumors. J Ovarian Res. 2018;11(1):13. Published 2018 Feb 6. doi:10.1186/s13048-018-0384-1

DICER1:

• DICER1 mutations are associated with leydig cell tumors and gynandroblastomas
• Although both germ line and somatic mutations play a role, approximately 60% of sexcord leydig cell tumors have somatic DICER1 mutations
• This particular gene DICER1 encodes for a RNA endoribonuclease that helps to cleave precursor miRNA into mature miRNAs
• DICER1 mutations are associated with a lot of tumors of which pleuropulmonary blastoma, is the most common lung tumor of infancy and early childhood
• Others are embryonal rhabdomyosarcoma of the uterine cervix, renal tumors, thyroid nodules and carcinoma, nasal chondromesenchymal hamartoma, ciliary body medulloepithelioma, pineoblastoma, and pituitary blastoma
• The above mentioned tumors typically have biallelic DICER1 mutations that are composed of a loss of function in one allele and a missense mutation in the RNase IIIb domain

STK11:

• Mutations in the STK11 gene is associated with sex cord-stromal tumors with annular tubules

Associated Conditions

• Patients with ollier disease and maffucci syndrome are associated with an increased risk of juvenile granulosa cell tumors
• Somatic mosaic mutations in IDH1 and IDH2 are observed
• Ollier disease includes enchondromatosis, whereas maffucci syndrome includes enchondromatosis and hemangiomas

Gross and Microscopic Pathology

The gross and microscopic features of the most common tumors are described below:

Types	Gross pathology	Microscopic pathology	Images
Adult granulosa cell tumours	They show yellowish solid or solid-cystic appearance on cut surface	It is characterised by densely cellular sheets of cells with scant cytoplasm imparting a ‘small blue cell tumour’ appearance Small cavities called Call–Exner bodies that may contain eosinophilic fluid, degenerating nuclei, hyalinised basement membrane material, or rarely basophilic fluid are seen The presence of nuclear grooves and Call–Exner bodies are often considered to be pathognomonic of AGCTs	Mikael Häggström and Nephron [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)],https://upload.wikimedia.org/wikipedia/commons/9/9b/Call-Exner_bodies.png
Juvenile granulosa cell tumours	They are solid/cystic on cut sections The solid areas show a tan-yellow or greyish appearance with foci of haemorrhage and/or necrosis The cysts have serous or haemorrhagic contents	Shows a nodular or diffuse proliferation of cells embedded in an edematous or myxoid stroma Follicle-like spaces of varying sizes and shapes, containing eosinophilic or basophilic secretions, is a characteristic feature Call–Exner bodies are almost never seen	Microcystic spaces, cuboidal-to-polygonal cells in sheets or stands or cords, with moderate-to-marked nuclear atypia, and basophilic cytoplasm https://librepathology.org/wiki/File:Juvenile_granulosa_cell_tumour_-_very_high_mag.jpg
Sex cord tumour with annular tubules	They are usually solid and yellow	They are characterized by simple and complex annular (ring-shaped) tubules often with calcification They show tubules with sertoli cells arranged around one or more hyaline bodies These tubules may be scattered and admixed with normal ovarian tissue rather than forming a distinct mass especially, in patients with Peutz-Jegher syndrome	well-circumscribed nests of cells with nuclei at the periphery, annular tubules (ring-shaped tubules) with dense hyaline material,https://librepathology.org/wiki/Sex_cord_tumour_with_annular_tubules
Sertoli–leydig cell tumors	They are solid, lobulated, yellow on cut surfaces Retiform tumors have a spongy sectioned surface Poorly differentiated tumors may be extensively haemorrhagic and necrotic	Well differentiated tumors are characterised by sertoli cells in a predominantly tubular pattern, and leydig cells in the intervening stroma Tumors of intermediate differentiation often show a striking so-called alveolar pattern of sertoli cells with pale cytoplasm Poorly differentiated tumors are usually dominantly sarcomatoid Retiform tumors shows elongated tubules and the stroma is focally somewhat hyalinised Heterologous elements include mucinous epithelial glands or rhabdomyosarcomatous and/or chondrosarcomatous elements	https://librepathology.org/wiki/File:Ovary_SertoliLeydigCellTumor_4_PA.jpg
Sclerosing stromal tumor	They are mostly solid masses with yellowish foci, edema, and cystic areas	A pseudolobular pattern, admixed spindled and rounded weakly luteinised cells, Prominent typically ectatic branching staghorn-like blood vessels	Pseudolobular pattern showing hypo and hypercellular areas seperated by oedematous fibrous strands://openi.nlm.nih.gov/detailedresult?img=PMC4175603_ogs-57-405-g001&query=sclerosing%20stromal%20tumour%20of%20ovary&it=xg&req=4&npos=5
Luteinised thecomas with sclerosing peritonitis	They are bilateral with abnormal in appearance due to a hypercerebriform contour often large masses having a beefy appearance with oedema and cyst formation	Microcytic change within the cellular neoplasm composed of admixed, spindled, and weakly luteinised cells Normal ovarian elements are often present between the proliferating spindle cells	https://openi.nlm.nih.gov/detailedresult?img=PMC4264285_JMH-5-198-g001&query=Luteinised%20thecomas%20with%20sclerosing%20peritonitis&it=xg&req=4&npos=2
Microcystic stromal tumour	They are solid and cystic with solid tissue that is tan to white to rarely yellow.	The microscopic appearance consists of three components: Microcysts (present in 60% of cases) Solid cellular areas Hyalinised fibrous stroma The microcystic pattern is characterised by small round to oval cystic spaces, focally coalescing into larger irregular channels; intracytoplasmic vacuoles are also common The solid cellular areas are usually intersected by fibrous bands and hyalineplaques
Fibroma	They are solid ovarian tumors	Spindle-shaped fibroblasts are seen	Fibroma showing ischemic necrosis,https://openi.nlm.nih.gov/detailedresult?img=PMC4491469_PAMJ-20-322-g007&query=fibroma%20ovarian%20tumor&it=xg&req=4&npos=22
Thecoma	They appear yellow on solid sectioned surface	Lipid-laden stromal cells with pale, vaculolated cytoplasm	Bland oval or spindled nuclei, abundant cytoplasm that is pale and vaculolated,https://librepathology.org/wiki/Thecoma
Fibrosarcoma	They are large unilateral masses, often with necrosis and hemorrhage	Fibromas with increased cellularity and cell proliferation (mitotic activity) They follow a malignant course

Immunohistochemistry

Adult granulosa cell tumors stain Positive for:

• Inhibin
• Calretinin
• FOXL2 and
• SF-1
• WT1
• CD56

They are negative for:

• Epithelial markers CK7 and EMA
• SALL4
• CD20
• CD45

Sertoli–stromal cell tumors are positive for:

• Calretinin
• Inhibin
• SF-1
• WT1

Microcystic Stromal Tumor:

• CD10+
• Vimentin+
• Cyclin D1+
• Nuclear β-catenin-positive
• Inhibin-
• Calretinin-