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Serous Tubal Intraepithelial Carcinoma or Not? Metastases to Fallopian Tube Mucosa Can Masquerade as In Situ Lesions.

Worldwide, ovarian carcinoma is the seventh most common cancer and the eighth most common cause of death from cancer in women. (1) High-grade serous carcinoma (HGSC) is the most common and most lethal type of ovarian carcinoma. For many decades it was assumed that HGSCs arise from the ovarian surface epithelium, but in 2001 this line of thinking was challenged by the identification of presumptive HGSC precursors--that is, serous tubal intraepithelial carcinomas (STICs), and occult HGSCs in the fallopian tubes of patients with germline BRCA1 mutations who were undergoing prophylactic surgery. (2, 3) Detailed examination of prophylactic specimens in this patient population implicated the tubal fimbriae as the origin of HGSC. (4) Additional evidence of tubal origin of HGSC was provided by several subsequent studies showing STIC with invasive carcinoma confined to the fallopian tube in women without hereditary predisposition to ovarian cancer. (5-7) Consequently, a recent consensus statement on primary site assignment of tubo-ovarian HGSCs recommends assigning cases as tubal in origin if STIC or invasive mucosal carcinoma is identified in the fallopian tube. (8)

Morphologically, STICs are characterized by a proliferation of nonciliated epithelium showing nuclear stratification, marked nuclear pleomorphism, prominent nucleoli, and mitotic figures. Immunohistochemical staining demonstrates aberrant p53 protein expression (either diffuse nuclear overexpression or complete absence of staining) and an increased Ki-67 proliferation index in the lesional epithelium. (9,10) Both BRCA1/2 mutation-positive and sporadic cases of nonuterine HGSC have been shown to be associated with concomitant STIC, with matched pairs of STIC-HGSC harboring identical TP53 mutations. (11-13) Additional molecular data provide further support for tubal rather than ovarian origin of most HGSCs. For example, the gene expression profiles of HGSCs are more similar to fallopian tube epithelium (FTE) than to the ovarian surface epithelium. (14) Furthermore, HGSCs express protein markers characteristic of Mullerian epithelium (eg, PAX-8) and do not express calretinin, a mesothelial marker that is also expressed by the ovarian surface epithelium but not the FTE. (15) Finally, FTE-specific inactivation of tumor suppressor genes recurrently mutated in human HGSCs results in tubal STICs and HGSCs in genetically engineered mice. (16,17)

Note: Illustration(s) are not available due to copyright restrictions.

Given the extensive support for tubal origin of HGSC, investigators have recently used advanced technologies to characterize the molecular relationship between STIC and HGSC in detail. McDaniel et al (18) performed targeted next-generation sequencing from 4 cases diagnosed as STIC with matched synchronous carcinoma. Two of the STICs were thought to be incidental findings in women undergoing total hysterectomy and bilateral salpingo-oophorectomy for surgical management of endometrial carcinoma, while the other 2 STICs were identified in women with nonuterine HGSC. All 4 STICs strongly overexpressed p53. As expected, both of the STICs associated with HGSCs harbored the identical TP53 mutations found in the matched HGSC. TP53 mutations were also identified in the 2 STICs associated with endometrial carcinoma. In 1 case, the matched endometrial carcinoma lacked TP53 mutation but contained mutations of several genes characteristically mutated in uterine endometrioid carcinomas, including PTEN, KRAS, PIK3CA, MTOR, and ATM. As all of these mutations were absent in the matched STIC, the STIC in this patient was confirmed to be an incidental finding, unrelated to the endometrial cancer. In the fourth case (Figure, A through D), a missense TP53 mutation was identified in the tubal lesion that was not present in the endometrial cancer. However, the tubal lesion also contained mutations of PTEN and CTNNB1, both of which are uncommon in HGSCs. The endometrial carcinoma contained the identical PTEN mutation, confirming a clonal relationship between the tubal and endometrial neoplasms. Interestingly, the endometrial carcinoma harbored a different CTNNB1 mutation than the one present in the tubal lesion. This finding likely represents an example of "convergent evolution" in which mutations of certain genes are recurrently selected for, because they provide affected cells with a strong fitness advantage and/or they cooperate with other preexisting mutations. (19,20) The findings described above provide compelling molecular evidence that the tubal lesion in the fourth case represents a mucosal micrometastasis from the endometrial carcinoma that mimics STIC. Even more recently, Eckert et al (21) used whole exome sequencing to analyze tumor samples from 8 women who presented with advanced-stage, sporadic HGSC and underwent primary debulking surgery without having received neoadjuvant chemotherapy. Phylogenetic clustering based on whole exome sequencing data from germline DNA, STIC, and HGSC from 3 sites (fallopian tube, ovary, and omentum) demonstrated STIC to be the HGSC precursor lesion in half of the cases. However, in 2 cases the STICs were identified as mucosal metastases to the fallopian tube rather than HGSC precursors.

Detailed molecular analyses are not necessarily required to demonstrate that the fallopian tube can harbor metastases from other sites in an apparent intraepithelial fashion. For example, Rabban et al (22) characterized the features of 100 nongynecologic cancers that metastasized to the fallopian tubes. Nearly 90% were adenocarcinomas, most often colonic, upper gastrointestinal tract/pancreaticobiliary, or breast. Several had features mimicking STIC or HGSC, including location in the fimbriae, unilaterality, high-grade morphology, and p53 protein overexpression. Importantly, routinely used immunohistochemical stains can usually establish when a tubal lesion represents a STIC rather than a metastasis from a nongynecologic primary. For example, lack of immunoreactivity for PAX-8, WT-1, CK7, and hormone receptors in association with CK20 and CDX-2 positivity can aid in the recognition of a colon carcinoma metastasis. Because many types of cancers acquire TP53 mutations, reliance on p53 immunostaining alone is insufficient to confirm tubal origin.

Nontubal gynecologic carcinomas can also metastasize to the fallopian tube. A study by Reyes et al (23) found that cervical carcinomas can colonize the tubal mucosa and mimic a primary tubal process. At low power, metastatic endocervical adenocarcinoma can share the hyperchromatic appearance of STIC. Unilateral involvement can further add to diagnostic confusion. However, at higher magnification metastatic endocervical adenocarcinoma is characterized by apical mitoses and apoptotic bodies, will generally be positive for high-risk human papillomavirus by in situ hybridization, and usually does not overexpress p53. (23) Importantly, p16 is not useful for distinguishing STIC from metastatic endocervical adenocarcinoma because p16 is likely to be overexpressed in both. (24) Finally, Kommoss et al (25) used histopathology and immunohistochemistry to clarify the relationship between STIC-like lesions and uterine serous carcinoma in 32 cases. On the basis of the histologic and immunohistochemical features, the tubal lesion was considered to represent metastasis from the uterine HGSC in most cases. Only 3 were considered likely to represent an independent tubal primary.

In conclusion, STICs are appropriately considered HGSC precursors, but some apparent STICs actually represent mucosal metastases from tumors arising elsewhere, either within or outside of the female genital tract. The possibility that a tubal intraepithelial carcinoma could represent a metastasis should be considered by practicing pathologists even in the context of HGSC. The accumulated evidence thus far suggests that the presence of STIC in 1 or both fallopian tubes does not provide sufficient evidence for tubal origin of advanced-stage HGSC in a given patient. In many cases, careful attention to morphology and routinely used immunohistochemical stains can be used to distinguish between true STIC and metastases from nontubal primaries.

References

(1.) Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5):E359-E386.

(2.) Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 2001; 195(4):451-456.

(3.) Paley PJ, Swisher EM, Garcia RL, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol. 2001; 80(2):176-180.

(4.) Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006; 30(2):230-236.

(5.) Gilks CB, Irving J, Kobel M, et al. Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas. Am J Surg Pathol. 2015; 39(3):357-364.

(6.) Morrison JC, Blanco LZ Jr, Vang R, Ronnett BM. Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series. Am J Surg Pathol. 2015; 39(4):442-453.

(7.) Rabban JT, Garg K, Crawford B, Chen LM, Zaloudek CJ. Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery. Am J Surg Pathol. 2014; 38(6):729-742.

(8.) Singh N, Gilks CB, Hirschowitz L, et al. Primary site assignment in tuboovarian high-grade serous carcinoma: Consensus statement on unifying practice worldwide. Gynecol Oncol. 2016; 141 (2):195-198.

(9.) Kurman RJ, Carcanglu ML, Herrington CS, Young RH, International Agency for Research on Cancer. WHO Classification of Tumours of Female Reproductive Organs. 4th ed. Lyon, France: International Agency for Research on Cancer; 2014. World Health Organization Classification of Tumours; vol 6.

(10.) Visvanathan K, Vang R, Shaw P, et al. Diagnosis of serous tubal intraepithelial carcinoma based on morphologic and immunohistochemical features: a reproducibility study. Am J Surg Pathol. 2011; 35(12):1766-1775.

(11.) Kindelberger DW, Lee Y, Miron A, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol. 2007; 31(2):161-169.

(12.) Przybycin CG, Kurman RJ, Ronnett BM, Shih Ie M, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol. 2010; 34(10): 1407-1416.

(13.) Kuhn E, Kurman RJ, Vang R, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma-evidence supporting the clonal relationship of the two lesions. J Pathol. 2012; 226(3):421-426.

(14.) Marquez RT, Baggerly KA, Patterson AP, et al. Patterns of gene expression in different histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube, endometrium, and colon. Clin Cancer Res. 2005; 11(17):6116-6126.

(15.) Kurman RJ, Shih IeM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010; 34(3):433-443.

(16.) Perets R, Wyant GA, Muto KW, et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in brca;tp53;pten models. Cancer Cell. 2013; 24(6):751-765.

(17.) Kim J, Coffey DM, Creighton CJ, Yu Z, Hawkins SM, Matzuk MM. Highgrade serous ovarian cancer arises from fallopian tube in a mouse model. Proc Natl Acad Sci USA. 2012; 109(10):3921-3926.

(18.) McDaniel AS, Stall JN, Hovelson DH, et al. Next-generation sequencing of tubal intraepithelial carcinomas. JAMA Oncol. 2015; 1(8):1128-1132.

(19.) Grove CS, Vassiliou GS. Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Dis Model Mech. 2014; 7(8):941-951.

(20.) Cunningham JJ, Brown JS, Vincent TL, Gatenby RA. Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites. Evol Med Public Health. 2015; 201 5(1):76-87.

(21.) Eckert MA, Pan S, Hernandez KM, et al. Genomics of ovarian cancer progression reveals diverse metastatic trajectories including intraepithelial metastasis to the fallopian tube. Cancer Discov. 2016; 6(12):1342-1351.

(22.) Rabban JT, Vohra P, Zaloudek CJ. Nongynecologic metastases to fallopian tube mucosa: a potential mimic of tubal high-grade serous carcinoma and benign tubal mucinous metaplasia or nonmucinous hyperplasia. Am J Surg Pathol. 2015; 39(1):35-51.

(23.) Reyes C, Murali R, Park KJ. Secondary involvement of the adnexa and uterine corpus by carcinomas of the uterine cervix: a detailed morphologic description. Int J Gynecol Pathol. 2015; 34(6):551-563.

(24.) Chiesa-Vottero AG, Malpica A, Deavers MT, Broaddus R, Nuovo GJ, Silva EG. Immunohistochemical overexpression of p16 and p53 in uterine serous carcinoma and ovarian high-grade serous carcinoma. Int J Gynecol Pathol. 2007; 26(3):328-333.

(25.) Kommoss F, Faruqi A, Gilks CB. et al. Uterine serous carcinomas frequently metastasize to the fallopian tube and can mimic serous tubal intraepithelial carcinoma. Am J Surg Pathol. 2016; 41(2):161-170.

Reena Singh, MD; Kathleen R. Cho, MD

Accepted for publication May 23, 2017.

From the Department of Pathology, University of Michigan Medical School, Ann Arbor.

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the New Frontiers in Pathology meeting; October 13-15, 2016;Ann Arbor, Michigan.

Reprints: Kathleen R. Cho, MD, Department of Pathology, University of Michigan, 1506 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200 (email: kathcho@umich.edu).

Caption: Hematoxylin-eosin-stained sections of serous tubal intraepithelial carcinoma (STIC)-like lesion in fallopian tube (A) with concomitant endometrial endometrioid carcinoma (B). The tubal lesion was shown to be a metastasis from the endometrial carcinoma by targeted next-generation sequencing. Immunohistochemical staining for p53 shows p53 overexpression in the STIC-like tubal lesion (C), but not in the matched endometrial carcinoma (D) (original magnifications X400 [A, C, and D] and X200 [B]).
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Author:Singh, Reena; Cho, Kathleen R.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Oct 1, 2017
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