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 [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR


[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

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 [disease/malignancy] 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:[1][2][3][4][5][6][7]

  • 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 tuomrs 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:[2][8][9][10][1][11]

  • 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[9][5]
  • Somatic mosaic mutations in IDH1 and IDH2 are observed
  • Ollier disease includes enchondromatosis, whereas Mafucci syndrome includes enchondromatosis and hemangiomas

Gross and Microscopic Pathology

The gross and microscopic features of the most common tumors are described below:[5][12][13][14][15][16][17][6][18][19][20]

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 oedematous 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 tumours
  • They are solid, lobulated, yellow on cut surfaces
  • Retiform tumours have a spongy sectioned surface
  • Poorly differentiated tumours may be extensively haemorrhagic and necrotic
  • Well differentiated tumours are characterised by Sertoli cells in a predominantly tubular pattern, and Leydig cells in the intervening stroma
  • Tumours 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 tumour
  • 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
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
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:[21][22][23][24][25][26][27]

  • 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:[18][19][28]

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

References

  1. Jump up to: 1.0 1.1 Lim, Diana; Oliva, Esther (2018). "Ovarian sex cord-stromal tumours: an update in recent molecular advances". Pathology. 50 (2): 178–189. doi:10.1016/j.pathol.2017.10.008. ISSN 0031-3025.
  2. Jump up to: 2.0 2.1 Fuller PJ, Leung D, Chu S (February 2017). "Genetics and genomics of ovarian sex cord-stromal tumors". Clin. Genet. 91 (2): 285–291. doi:10.1111/cge.12917. PMID 27813081.
  3. Li, Jiaheng; Bao, Riqiang; Peng, Shiwei; Zhang, Chunping (2018). "The molecular mechanism of ovarian granulosa cell tumors". Journal of Ovarian Research. 11 (1). doi:10.1186/s13048-018-0384-1. ISSN 1757-2215.
  4. Li J, Bao R, Peng S, Zhang C (February 2018). "The molecular mechanism of ovarian granulosa cell tumors". J Ovarian Res. 11 (1): 13. doi:10.1186/s13048-018-0384-1. PMC 5802052. PMID 29409506.
  5. Jump up to: 5.0 5.1 5.2 Schultz KA, Harris AK, Schneider DT, Young RH, Brown J, Gershenson DM, Dehner LP, Hill DA, Messinger YH, Frazier AL (October 2016). "Ovarian Sex Cord-Stromal Tumors". J Oncol Pract. 12 (10): 940–946. doi:10.1200/JOP.2016.016261. PMC 5063189. PMID 27858560.
  6. Jump up to: 6.0 6.1 Boussios, Stergios; Moschetta, Michele; Zarkavelis, George; Papadaki, Alexandra; Kefas, Aristides; Tatsi, Konstantina (2017). "Ovarian sex-cord stromal tumours and small cell tumours: Pathological, genetic and management aspects". Critical Reviews in Oncology/Hematology. 120: 43–51. doi:10.1016/j.critrevonc.2017.10.007. ISSN 1040-8428.
  7. Leung, Dilys T.H.; Fuller, Peter J.; Chu, Simon (2016). "Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors". The International Journal of Biochemistry & Cell Biology. 72: 51–54. doi:10.1016/j.biocel.2016.01.003. ISSN 1357-2725.
  8. Goulvent T, Ray-Coquard I, Borel S, Haddad V, Devouassoux-Shisheboran M, Vacher-Lavenu MC, Pujade-Laurraine E, Savina A, Maillet D, Gillet G, Treilleux I, Rimokh R (January 2016). "DICER1 and FOXL2 mutations in ovarian sex cord-stromal tumours: a GINECO Group study". Histopathology. 68 (2): 279–85. doi:10.1111/his.12747. PMID 26033501.
  9. Jump up to: 9.0 9.1 Stewart CJ, Charles A, Foulkes WD (June 2016). "Gynecologic Manifestations of the DICER1 Syndrome". Surg Pathol Clin. 9 (2): 227–41. doi:10.1016/j.path.2016.01.002. PMID 27241106.
  10. Wang Y, Karnezis AN, Magrill J, Tessier-Cloutier B, Lum A, Senz J, Gilks CB, McCluggage WG, Huntsman DG, Kommoss F (August 2018). "DICER1 hot-spot mutations in ovarian gynandroblastoma". Histopathology. 73 (2): 306–313. doi:10.1111/his.13630. PMID 29660837.
  11. Xu Q, Zou Y, Zhang XF (October 2018). "Sertoli-Leydig cell tumors of ovary: A case series". Medicine (Baltimore). 97 (42): e12865. doi:10.1097/MD.0000000000012865. PMC 6211859. PMID 30334998.
  12. Bremmer F, Schweyer S (February 2016). "[Leydig cell, Sertoli cell and adult granulosa cell tumors]". Pathologe (in German). 37 (1): 71–7. doi:10.1007/s00292-015-0131-y. PMID 26782032.
  13. Bremmer F, Behnes CL, Radzun HJ, Bettstetter M, Schweyer S (May 2014). "[Sex cord gonadal stromal tumors]". Pathologe (in German). 35 (3): 245–51. doi:10.1007/s00292-014-1901-7. PMID 24819979.
  14. Roth LM, Czernobilsky B (March 2011). "Perspectives on pure ovarian stromal neoplasms and tumor-like proliferations of the ovarian stroma". Am. J. Surg. Pathol. 35 (3): e15–33. doi:10.1097/PAS.0b013e31820acb89. PMID 21317704.
  15. Young RH (January 2018). "Ovarian sex cord-stromal tumours and their mimics". Pathology. 50 (1): 5–15. doi:10.1016/j.pathol.2017.09.007. PMID 29132723.
  16. Zhang HY, Zhu JE, Huang W, Zhu J (2014). "Clinicopathologic features of ovarian Sertoli-Leydig cell tumors". Int J Clin Exp Pathol. 7 (10): 6956–64. PMC 4230071. PMID 25400781.
  17. Chen, Vivien W.; Ruiz, Bernardo; Killeen, Jeffrey L.; Cot�, Timothy R.; Wu, Xiao Cheng; Correa, Catherine N.; Howe, Holly L. (2003). "Pathology and classification of ovarian tumors". Cancer. 97 (S10): 2631–2642. doi:10.1002/cncr.11345. ISSN 0008-543X. replacement character in |last4= at position 4 (help)
  18. Jump up to: 18.0 18.1 Irving JA, Lee CH, Yip S, Oliva E, McCluggage WG, Young RH (October 2015). "Microcystic Stromal Tumor: A Distinctive Ovarian Sex Cord-Stromal Neoplasm Characterized by FOXL2, SF-1, WT-1, Cyclin D1, and β-catenin Nuclear Expression and CTNNB1 Mutations". Am. J. Surg. Pathol. 39 (10): 1420–6. doi:10.1097/PAS.0000000000000482. PMID 26200099.
  19. Jump up to: 19.0 19.1 Irving JA, Young RH (March 2009). "Microcystic stromal tumor of the ovary: report of 16 cases of a hitherto uncharacterized distinctive ovarian neoplasm". Am. J. Surg. Pathol. 33 (3): 367–75. doi:10.1097/PAS.0b013e31818479c3. PMID 18971779.
  20. Mathur A, Seth A, Pant L (2018). "Ovarian fibroma with luteinized thecal cells and minor sex cord element: A rare case report". Indian J Pathol Microbiol. 61 (2): 264–267. doi:10.4103/IJPM.IJPM_446_17. PMID 29676374.
  21. Kaspar, Hanna G.; Crum, Christopher P. (2015). "The Utility of Immunohistochemistry in the Differential Diagnosis of Gynecologic Disorders". Archives of Pathology & Laboratory Medicine. 139 (1): 39–54. doi:10.5858/arpa.2014-0057-RA. ISSN 0003-9985.
  22. Zhao C, Vinh TN, McManus K, Dabbs D, Barner R, Vang R (March 2009). "Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors". Am. J. Surg. Pathol. 33 (3): 354–66. doi:10.1097/PAS.0b013e318188373d. PMID 19033865.
  23. McCluggage WG, McKenna M, McBride HA (July 2007). "CD56 is a sensitive and diagnostically useful immunohistochemical marker of ovarian sex cord-stromal tumors". Int. J. Gynecol. Pathol. 26 (3): 322–7. doi:10.1097/01.pgp.0000236947.59463.87. PMID 17581419.
  24. Zhao C, Bratthauer GL, Barner R, Vang R (September 2007). "Diagnostic utility of WT1 immunostaining in ovarian sertoli cell tumor". Am. J. Surg. Pathol. 31 (9): 1378–86. doi:10.1097/PAS.0b013e3180339961. PMID 17721194.
  25. Zhao C, Barner R, Vinh TN, McManus K, Dabbs D, Vang R (October 2008). "SF-1 is a diagnostically useful immunohistochemical marker and comparable to other sex cord-stromal tumor markers for the differential diagnosis of ovarian sertoli cell tumor". Int. J. Gynecol. Pathol. 27 (4): 507–14. doi:10.1097/PGP.0b013e31817c1b0a. PMID 18753972.
  26. Deavers MT, Malpica A, Liu J, Broaddus R, Silva EG (June 2003). "Ovarian sex cord-stromal tumors: an immunohistochemical study including a comparison of calretinin and inhibin". Mod. Pathol. 16 (6): 584–90. doi:10.1097/01.MP.0000073133.79591.A1. PMID 12808064.
  27. Oliva E, Garcia-Miralles N, Vu Q, Young RH (October 2007). "CD10 expression in pure stromal and sex cord-stromal tumors of the ovary: an immunohistochemical analysis of 101 cases". Int. J. Gynecol. Pathol. 26 (4): 359–67. doi:10.1097/PGP.0b013e318064511c. PMID 17885484.
  28. Bi R, Bai QM, Yang F, Wu LJ, Cheng YF, Shen XX, Cai X, Zhou XY, Yang WT (December 2015). "Microcystic stromal tumour of the ovary: frequent mutations of β-catenin (CTNNB1) in six cases". Histopathology. 67 (6): 872–9. doi:10.1111/his.12722. PMID 25913412.

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