Ovary tumors origin

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 A recent study provides morphologic and immunophenotypic evidence that ovarian Low Grade-Serous Carcinoma (LG-SC) is most likely originated from the tubal fimbria. In conjunction with evidence in the published literature, we propose a sequence of LG-SC development. First, fallopian tubal epithelia, mostly from fimbriated end, implants on the ovarian surface.

 


Two possibilities exist for how this detachment and implantation occurs:

·         Given the close relationship between the ovarian surface and the tubal fimbriated end, ovulation or non-ovulation induced disruption of the ovarian surface, may offer an opportunity for the adjacent tubal epithelium to detach and implant in the ovarian stroma.

·         Adhesion of tubal epithelium on the ovarian surface, from inflammation or other factors, and dynamic stromal growth around it may eventuate in tubal derived Ovarian Epithelial Inclusions (OEI) formation. Second, the acquisition of KRAS or BRAF mutations and possibly other mutations in tubal derived OEIs and serous cystadenomas result in their transformation to serous borderline tumors and ultimately to LG-SC

 

These findings may have significant implications for current “ovarian” cancer-prevention strategies. (1)

 


Immunophenotype of tubal fimbria and ovarian epithelial inclusions. Top panel shows morphologic appearance of tubal fimbria, M-OEl, and F-OEl, followed by immunohistochemical stainings of PAX8, calretinin, and tubulin, respectively. PAX8 (nuclear) and tubulin (apical border) staining was seen in tube and F-OEl, but not in M-OEl. Conversely, calretinin was positive in M-OEl and negative in tube and F-OEI: (original magnifications: left panel 200X).

 

 

P53 signature in Serous Tubal In-situ Carcinoma

Most of the epithelial malignancies arise through a sequence of genotypic events leading to malignant phenotypes, regardless of whether they occur. A representative illustration is cervical cancer, in which an infection by oncogenic human papillomavirus can cause the biological normal epithelium to develop into precancerous lesions and stepwise even to cancer.

Early diagnoses of these lesions and their appropriate treatment (lesion ablation) can prevent further progression to cancer. These models of tumor development became a paradigm for researchers in molecular oncology. Recent studies have begun to show similar explanations for the development of primary tubal cancer (TC), primary peritoneal cancer (PPC), and cases of prophylactic bilateral salpingo-oophorectomy (BSO) in women with BRCA-mutation-induced ovarian cancer. In fact, it has been suggested that epithelial cells in the fallopian tubes play a major role in the development of TC, PPC, and ovarian cancer.

To maximize the detection of early cancers localized to the fallopian tube in patients at risk for ovarian cancer, the protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM) has been established by Medeiros et al. Examination of prophylactically removed fallopian tubes has shown serous tubal in-situ carcinomas (STIC) of the fimbriated end between 57% and 100%.

Lee et al. were able to show that the p53 signatures of serous carcinomas, which represent one step within this process, were also mostly situated in the fimbriated end of the fallopian tubes.

Fascinatingly, 47% of tumors classified as ovarian serous carcinoma coexisted with STIC as reported by Kindelberger et al.(2)


Serous carcinogenic steps within the fallopian tube. (A–C) p53 signature: normal appearance of the epithelia of the fallopian tube (A) with strong nuclear p53 staining in more than 12 secretory cell nuclei (B) but very low proliferative activity, represented by Ki-67 staining (C). (D–F) Tubal intermediate lesion in transition: mild epithelial atypia within the fallopian tubal epithelium (D), strong nuclear p53 positivity (E), and low-to-moderate proliferative activity (F). (G–I) Serous tubal in-situ carcinoma: neoplastic tubal epithelium with atypical cells and architectural alterations (G), strong p53 staining (H), and high proliferative activity (I).

 References

1.          Kurman RJ, Shih IM. The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory. American Journal of Surgical Pathology. 2010 Mar;34(3):433–43.

2.            Leonhardt K, Einenkel J, Sohr S, Engeland K, Horn LC. p53 Signature and Serous Tubal In-situ Carcinoma in Cases of Primary Tubal and Peritoneal Carcinomas and Serous Borderline Tumors of the Ovary. International Journal of Gynecological Pathology. 2011 Sep;30(5):417–24.


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