Epithelial tumors

Epithelial tumors-overview / molecular

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Last staff update: 7 July 2023

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PubMed Search: Ovarian epithelial tumors

Ayse Ayhan, M.D., Ph.D.
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Cite this page: Kuhn E, Ayhan A. Epithelial tumors-overview / molecular. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/ovarytumorsurfacegeneral.html. Accessed April 14th, 2024.
Definition / general
  • The ovary is a highly specialized organ physiologically dedicated to ovum production
  • It is composed mainly of stromal cells that support maturing germ cells, covered by a monolayer modified mesothelium (so called ovarian surface epithelium)
  • Most ovarian cancers are epithelial, but most testicular tumors derive from germ cells or sex cord stroma
Essential features
  • Ovarian carcinoma (previously called ovarian surface epithelial malignant tumors) is not a single entity, but a group of neoplasms with different histotypes, immunohistochemical characteristics, origins and biology
  • Although the WHO classification has not substantially changed from the first edition, recent molecular knowledge combined with epidemiological data has caused a considerable reevaluation of the pathogenesis, cell of origin and precursor lesions of ovarian carcinoma
  • Serous / Endometrioid / Clear cell / Seromucinous / Mucinous / Brenner / Undifferentiated

Tumor type Acronym Prevalence
High grade serous carcinoma HGSC 70%
Low grade serous carcinoma LGSC 5 %
Endometrioid carcinoma EMC 10%
Clear cell carcinoma CCC 10%
Seromucinous carcinoma SMT rare
Mucinous carcinoma MC 3%
Malignant Brenner tumor Malignant BT rare
Undifferentiated carcinoma UC rare
Traditional pathogenetic view:
  • Cells of origin: ovarian surface epithelium (OSE)
  • Primary site of origin: ovary
  • Mechanism: OSE is a modified mesothelium which undergoes metaplasia, acquiring a Müllerian or non-Müllerian epithelial phenotype and successively undergoes neoplastic transformation
  • In 1925, Sampson hypothesized that ovarian carcinoma may arise from malignant transformation of endometriosis, thought to derive from OSE metaplasia or embryonic residuals
  • Fathalla’s theory of “incessant ovulation” identifies recurrent ovulation as a transforming event for OSE through direct damage, inflammation and exposure to sex hormone-rich follicular fluid (Lancet 1971;2:163)
    • Therefore, incessant ovulation constitutes an index for individual ovarian cancer risk
    • This theory assumes that all ovarian surface epithelial tumors have the same origin
  • For many years, pathologists diagnosed and classified ovarian epithelial tumors based on histological similarity, size, clinical information and apparent cell of origin; fallopian tubes were inadequately sampled and ignored

Controversies with the traditional view
  • No ovarian surface epithelial carcinomas (serous, endometrioid, clear cell, mucinous, seromucinous, transitional) resemble OSE
  • Metaplasia of OSE is difficult to demonstrate and almost never observed
  • There are no intermediate / hybrid phenotypes of OSE metaplasia tumors
  • Real mesotheliomas are rare
  • Most ovarian tumors do not express OSE molecular markers
  • In the testis, analogous surface (tunica albuginea) tumors are rare

Realities to consider
  • Recent advances in molecular genetics have found mutations in BRCA1 and BRCA2 tumor suppressor genes responsible for most hereditary ovarian cancer
  • When patients with mutations underwent prophylactic salpingo-oophorectomy, dysplastic precursor lesions were found in fallopian tubes (later named Serous Tubal Intraepithelial Carcinoma, STIC), but not in ovaries
  • Tubal ligation reduces the incidence of ovarian endometrioid, clear cell carcinoma and high grade serous carcinoma (Cancer Epidemiol Biomarkers Prev 1996;5:933, Int J Cancer 2016;138:1076)
  • Thorough examination of fallopian tubes using the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbriated end), revealed early fallopian tube cancer in sporadic high grade serous carcinomas
    • There are overlapping molecular alterations with STIC and high grade serous carcinoma regarding p53, p16, FAS, RSF1, CCNE1 and centrosome amplification, suggesting a clonal relationship (Mod Pathol 2016;29:1254)
  • Endometrioid (40%) and clear cell carcinoma (50-90%) are commonly associated with endometriosis, and patients with endometriosis have a 3-10x increased risk of developing ovarian endometrioid and clear cell carcinomas
    • Molecular genetic alterations reveal a clonal relationship between endometriosis and endometrioid and clear cell carcinomas (ARID1A, KRAS, MET) (Int J Gynecol Cancer 2012;22:1310)
  • Primary mucinous ovarian carcinomas are uncommon: the real incidence of mucinous carcinomas is less than previously thought

Emerging pathogenetic views
  • Ovarian carcinoma (so called ovarian surface epithelial tumors) is not a single entity
  • Cells of origin: extra-ovarian Müllerian epithelia (endometrium or fallopian tube epithelium)
  • Primary site of origin: extra-ovarian Müllerian epithelia (endometrium or fallopian tube epithelium) or ovary (endometriosis or fallopian tube epithelium seeded on the ovary as inclusion cysts)
  • Mechanism: genetically normal or initially transformed epithelial cells from fallopian tube or endometrium seed the ovary, whose microenvironment promotes their neoplastic transformation
  • Mucinous carcinomas are composed of tumors with different genesis, including mature cystic teratoma and extra-ovarian Müllerian epithelium (Brenner tumors or endometriosis)
  • The most significant risk factor is family history (Bethesda (MD): National Cancer Institute (US); 2002)
  • Contributing factors: excessive gonadotropins, androgen stimulation, pelvic inflammation, ovarian exposure to contaminants and carcinogens (talc and asbestos), nulliparity, refractory infertility, obesity
  • Protective factors: multiparity, tubal ligation, hysterectomy, oral contraceptives (use for 5+ years reduces risk 50% even for those with a family history, Cancer Epidemiol Biomarkers Prev. 2009 Feb;18:601)
Clinical features
Genetic syndromes and germline alterations
  • Hereditary Breast and Ovary Cancer syndrome from germline mutations in BRCA1 and BRCA2
  • Lynch syndrome from germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2)
  • Peutz-Jeghers syndrome from germline mutations in STK11
  • Cowden syndrome from germline mutations in PTEN
  • Coffin-Siris Syndrome from germline mutations in ARID1A
  • Li-Fraumeni syndrome from germline mutations in TP53 / p53
  • Other germline mutations that are correlated to ovarian carcinoma affect BRIP1, CHEK2, RAD51
    Gross images

    Contributed by Ayse Ayhan, M.D.

    Clear cell carcinoma, case 1:


    Outer appearance

    Fixed pictures of surgical material

    Cut surface

    Clear cell carcinoma, case 2:

    Outer appearance

    Cut surface

    Fixed cut surface

    Bilateral endometrioid cancer:

    Left, 730g, 14.5x12.6cm

    Left, 730g, 14.5x12.6cm

    Ovarian tumor:

    Right, 70g, 7.5x3.5cm

    Microscopic (histologic) description
    Putative precursor lesions
    • Serous tubal intraepithelial carcinoma / low grade serous carcinoma: for high grade serous carcinoma
    • Serous borderline tumor: for low grade serous carcinoma and a few high grade serous carcinomas
    • Endometriosis / adenofibroma / borderline tumor: for endometrioid carcinoma, clear cell carcinoma, seromucinous carcinoma, mixed endometrioid-clear cell carcinoma
    • Endometriosis / mucinous borderline tumor: for mucinous carcinoma
    • Teratoma / Brenner tumor / mucinous borderline tumor: for mucinous carcinoma
    • Benign Brenner tumor: for borderline Brenner tumor
    Positive stains
    • p53 (high grade serous carcinoma, high grade endometrioid carcinoma, mucinous carcinoma)
    • nuclear β catenin (endometrioid carcinoma)
    • HER2 (mucinous carcinoma)
    • Refer to histopathology for lineage specific markers
    Negative stains
    Molecular / cytogenetics description
    Common mutations
    Tumor type Acronym Prevalence
    High grade serous carcinoma BRCA1 12%
    BRCA2 11%
    CSMD3 6%
    FAT3 6%
    TP53 95%
    Low grade serous carcinoma BRAF 38%
    KRAS 19%
    Endometrioid carcinoma ARID1A 55%
    CTNNB1 60%
    KRAS 7%
    MLH1/MSH2/MSH6/PMS2 20%
    PIK3CA 35%
    PTEN 16%
    PPP2R1A 10-15%
    TP53 7%
    Clear cell carcinoma ARID1A 75%
    KRAS 10%
    PIK3CA 35%
    PPP2R1A 10%
    TERT 16%
    Seromucinous tumor ARID1A 33%
    KRAS 69%
    Mucinous carcinoma BRAF 12%
    HER2 50%
    KRAS 54%
    RNF43 20%
    TP53 50%
    Borderline Brenner tumors KRAS 14%
    PIK3CA 28%

    NOTE: High grade serous carcinoma and low grade serous carcinomas have a mutually exclusive mutational signature

    • Germline/somatic mutations in BRCA1, BRCA2 and other genes predict:
      • Platinum sensitivity and longer survival in women with high grade serous carcinoma
      • Benefit from PARP inhibitors (Journal of Cancer 2016;7:1441)
    Additional references
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