Epithelial ovarian tumors origin of neoplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]

The origin of neoplasia in epithelial ovarian cancer: A mystery to solve

  • The previous proposition regarding the origin of epithelial ovarian cancers was that these tumors originated from surface epithelium of the ovaries and the neoplastic and metaplastic changes led to their differentiation into various histological subtypes such as serous tumors, clear cell carcinoma and endometrioid tumors.[1][2][3][4][5]
  • However the surface epithelium of ovaries is derived from mesothelium and ovarian carcinoma resembled more closely to tissues derived from Mullerian ducts rather than ovarian mesothelium derived surface epithelium. For example serous cancer histology resembles fallopian tube epithelium and that of transitional cells tumor resembles urinary bladder. Likewise endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis, and Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives.[1][2][3][4][5][6]
  • Secondly the genetic profile also overcasts shadows of doubt about origin of these neoplasms from ovarian surface epithelium. The presence of identical TP53 mutations in serous tubal intra-epithelial tumors and ovarian serous tumors puts a question mark on ovarian origin theory. Gene expression profiling also demonstrated the presence of similarities between serous tubal intra-epithelial tumors and ovarian serous tumors. The various theories of origin of epithelial ovarian cancers have been discussed below.[3][4][5][7][8]

Ovarian origin of ovarian epithelial tumors

  • This simple theory states that ovarian epithelial tumors simply originate from surface epithelium of ovaries through various neoplastic changes. But recent data has highlighted the numerous inconsistencies in the theory that was once highly regarded as accurate.[3][4][5]
  • Firstly surface epithelium of ovaries is derived from mesothelium and ovarian carcinoma resembled more closely to tissues derived from Mullerian ducts rather than ovarian mesothelium derived surface epithelium. For example serous cancer histology resembles fallopian tube epithelium and that of transitional cells tumor resembles urinary bladder. Likewise endometrioid, and sero-mucinous carcinomas are thought to have their origin in endometriosis, and Walthard nests potentially give rise to mucinous and Brenner malignant tumors, at least partially. All of these precursors are Müllerian system derivatives.[1][2][3][4][5][6]
  • Secondly the presence of identical TP53 mutations in serous tubal intra-epithelial tumors and ovarian serous tumors puts a question mark on ovarian origin theory. Gene expression profiling also demonstrated the presence of similarities between serous tubal intra-epithelial tumors and ovarian serous tumors.[3][4][5][7][8]
  • The expression of PAX8 and absence of calretinin in high grade serous tumors presents another problem with theory of ovarian origin because PAX8 is a Müllerian marker and calretinin is a mesothelium marker.[9][4][5]
  • In 2001, a Dutch study revealed the presence of high grade serous carcinomas in fallopian tubes of women with genetic susceptibility to hereditary ovarian cancers with no evidence of such lesions in ovaries of same women. These lesions were termed as serous tubal intra-epithelial tumors.[3][4][5][10][7][11]
  • Additional studies demonstrated the presence of similar lesions in fallopian tubes of women without genetic susceptibility to ovarian cancer. In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.[3][4][5][10][7][11]
  • In an attempt to explain these apparent discrepancies it was postulated that invagination of ovarian epithelium into ovarian stroma creates “cortical inclusion cysts”. These cysts then undergo various metaplastic changes (coelomic metaplasia hypothesis) due to hormonal influence and repair mechanisms to give rise to ovarian epithelial cancer. Although these cysts are present but no such neoplastic and metaplastic transformation has been reported or observed until now. Additionally the observed cysts could dimply be the transplants from the fallopian tubes.[3][4][5][12]
  • Another proposed theory is the implantation of tubal epithelium from fimbria into ovarian inclusion cysts due to their close contact during the ovulation process. This may explain the origin of serous tumor of the ovaries but unable to explain other tumor sub-types.[3][4][5]

Secondary Müllerian system

  • This theory tries to explain this apparent enigma of existence of Müllerian epithelial lesions in locations not derived from Müllerian ducts such as ovaries and peritoneal cavity. Secondary Müllerian system consists of müllerian-type tissue lined cysts that are located in close proximity to the ovaries.[13][3][4][5]
  • According to this hypothesis Müllerian tissues, considered by some as vestigial, are found in locations such as para-tubal and para-ovarian locations and these tissues or cysts, not the ovarian epithelium itself, give rise to epithelial ovarian neoplasms. These tumors, arising outside ovaries, then enlarge and become implants/or compress ovaries and present as ovarian tumors.[1][3][4][5]
  • But there are number of problems this theory fails to explain. For example mucinous epithelial tumors of ovaries resemble intestinal epithelium rather than endocervical epithelium. Also transitional cell tumor resemble morphologically to bladder epithelium that is not a derivative of Müllerian system.[3][4][5][6]
  • Another apparent flaw is that transition of these cysts lined by Müllerian-type epithelium, although present, to carcinoma has been very rare.[3][4][5]

The origin of epithelial ovarian tumors from fallopian tubes and endometrium, and not from ovaries

  • The evidence from recent studies indicate that majority of epithelial ovarian cancers have their origin outside ovaries, especially from fallopian tubes and endometrium. This idea is supported by several observations in a number of studies.[3][4][5]
  • The histology of serous, endometrioid and clear cell carcinoma demonstrates that their morphology is similar to that fallopian tubes, and endometrium rather than ovarian epithelium.[3][4][5][14][15]
  • Presence of PAX8, a Müllerian marker, and absence of calretinin, a mestothelial marker, further supports the theory. Moreover the genetic profile expression similarities and presence of similar TP53 mutation signatures in serous tubal intra-epithelial tumors and epithelial ovarian cancers also supports the extra-ovarian origin of epithelial ovarian cancer.[3][4][5][7][8].
  • In 2001, a Dutch study revealed the presence of high grade serous carcinomas in fallopian tubes of women with genetic susceptibility to hereditary ovarian cancers with no evidence of such lesions in ovaries of same women. These lesions were termed as serous tubal intra-epithelial tumors.[3][4][5][7][11][10]
  • Additional studies demonstrated the presence of similar lesions in fallopian tubes of women without genetic susceptibility to ovarian cancer. In cases when fallopian tubes were removed carefully along with ovarian and/or peritoneal serous cancer, the involvement of mucosa of the tubes were found to be involved in about 70% of the cases.[3][4][5][7][11][10]
  • These tubal serous lesions were located in fimbria in almost all of the cases, giving rise to the proposition that serous tumors originated in fallopian tubes and then implantation into ovaries.[3][4][5][16][7][17]
  • The association between adnexal malignant mixed mesodermal tumors and serous tubal intraepithelial tumors pints further in direction of tubal origin of these epithelial ovarian tumors.[3][4][5][18][19]
  • Similarly morphologic and molecular studies have indicated that endometrioid and clear cell carcinoma of the ovaries have their origin in endometriosis. These studies suggest that these tumors arise from endometriomas, the endometriotic cysts that are present outside the normal endometrium.[3][4][5][14][15]
  • This theory regarding the origin of endometrioid and clear cell carcinoma of the ovary is supported by the fact that tubal ligation that prevents endometriotic implants into ovary and peritoneum in endometriosis has a protective effect on endometrioid and clear cell type cancers but not on the serous cancer of the ovary because it doesn't occlude the connection between fimbria and the ovaries.[3][4][5][20][21]

The origin of mucinous tumors of gastrointestinal type and transitional cell (Brenner) tumors: Still a mystery to solve

  • Mucinous and the transitional tumors of ovaries are two of the least common types of the epithelial ovarian tumors. In fact, most of the mucinous tumors in ovaries are secondary and primary tumors only form about 3% of all epithelial ovarian cancers. Mucinous epithelium in mucinous tumors of ovaries resemble more to intestinal mucinous epithelium rather than that of endocervix as was previously argued. Transitional cell tumors, on the other hand, are closer to bladder epithelium in histological studies.[5][3][4][6][22][23]
  • Another study demonstrated the presence of Brenner tumor foci in mucinous cystadenoma in almost one fifth of the cases. Alternatively the association of mucinous tumors with Walthard cell nests, which are composed of transitional-type epithelium, also indicates the connection between mucinous and transitional tumors.[5][3][4][22][23]


References

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  2. 2.0 2.1 2.2 Lauchlan SC (July 1984). "Metaplasias and neoplasias of Müllerian epithelium". Histopathology. 8 (4): 543–57. PMID 6090303.
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  19. Gupta AJ, Singh M, Rani P, Jain S, Khurana N, Sahu L (2017). "Malignant mixed mullerian tumor of ovary-scrape cytology: Findings with review of literature". J Cytol. 34 (2): 125–126. doi:10.4103/0970-9371.203568. PMC 5398022. PMID 28469326.
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