Serous Tubal Intraepithelial Carcinoma or Not? Metastases to Fallopian Tube Mucosa Can Masquerade as In Situ Lesions.
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.
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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: firstname.lastname@example.org).
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|
|Date:||Oct 1, 2017|
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