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Recent evidence indicates that the distal fallopian tube is the principal site of early serous cancer in women with a hereditary risk for ovarian cancer. Moreover, the fimbria is involved by early cancer in a significant minority of pelvic serous carcinomas, irrespective of whether the patient has a hereditary BRCA1 or BRCA2 mutation. In addition, the distal tube has been occasionally identified as a site of concurrent endometrioid tumors in women with endometrial carcinoma. Although the risk of sporadic fimbrial tumors in otherwise healthy women without genetic risk is unknown, routine histologic examination of the fimbria provides the opportunity to determine the risk of such an event. A case is presented to illustrate this point, of a woman who underwent surgery for an ovarian fibroma. The distal tube was submitted, and found to harbor a focus of serous tubal intraepithelial carcinoma (STIC) with a 2mm invasive tumor. Incidentally discovered carcinomas underscore the potential risk, albeit low, of concurrent unsuspected malignancy in the distal fallopian tube and emphasize the importance of routine pathologic examination of the fimbria in all salpingectomies. The rationale for this strategy, and its potential impact on early detection and in uncovering persons or families potentially at risk for ovarian cancer, is discussed.
Routine pathologic examination of the uterus and adnexae entails sampling of the cervix, endo-myometrium, fallopian tubes and ovaries, ostensibly to confirm the presence of these tissues and exclude incidental disease, specifically neoplasia. The cervix is routinely submitted to display the cervical transformation zone, inasmuch as this is the site of origin of HPV-related squamous and glandular neoplasia. Similarly, sections of anterior and posterior endometrium are examined to exclude an occult neoplasia (endometrial intraepithelial neoplasia and/or adenocarcinoma), which although rare, will be encountered periodically in a presumably normal uterus. Leiomyomata are sampled, albeit variably, primarily to exclude a grossly unappreciated leiomyosarcoma.
The ovaries and fallopian tubes are typically sectioned to document their presence, excepting rare instances when neoplasia is discovered. In particular, the fallopian tubes have been given the most limited examination, often limited to a single cross section in the center of the tube, or a cross section combined with a fragment of the fimbriated end. Irrespective of the sampling strategy, invariably only a portion of the fallopian tube is submitted for histopathologic analysis. This protocol changes however, in the woman with a BRCA mutation who is undergoing risk-reducing surgery with removal of the tubes and ovaries. In these specimens and those from women with a family history of ovarian cancer, the entire tubes and ovaries are histologically submitted for pathology review. Recent reports indicate that in BRCA+ women over age 40, the odds of discovering an early serous or endometrioid carcinoma are approximately 5 per 100 cases examined.
When an early serous carcinoma is detected in the fallopian tube, either in a woman with or without a family history, the majority are in the distal (fimbria) segment.1 Interestingly, occult endometrioid carcinomas of the fallopian tube associated with endometrial carcinomas are also typically fimbrial.2 Moreover, some common benign tumors, specifically adenofibromas, are unique to the fimbria relative to the more proximal tube.3 Thus, the distal fallopian tube has emerged as an important locale for early serous and endometrioid carcinomas in BRCA+ women as well as women undergoing surgery for ovarian cancers.4, 5, 6, 7
Although close scrutiny of the distal tube will uncover tumors in women considered at high risk for pelvic serous carcinoma, specifically those with BRCA1 or BRCA2 mutations, the notion that the tube could harbor clinically occult neoplasia has not been addressed in a systematic fashion. The low expectations on the part of pathologists for such an event are evident in the manner by which fallopian tubes are processed in routine salpingo-oophorectomy specimens. However, one case recently seen in our consultation files calls to question this strategy and argues for a more detailed exam of the distal tube in routine practice.
A 69 year-old woman with a history of a prior vaginal hysterectomy presented with complaints of bloating and alternating episodes of constipation followed by diarrhea. There were no other abnormal findings on her pre-operative evaluation. An abdominal ultrasound revealed a left adnexal mass. The patient underwent a bilateral salpingo-oophorectomy which confirmed a left ovarian mass and no other pelvic abnormality.
The ovary contained a 7 cm smooth mass which revealed a homogeneous tan surface on sectioning. Both fallopian tubes and the right ovary appeared grossly unremarkable.
A pelvic washing at the time of surgery was negative. Sections of the ovary received in consultation revealed a left ovarian fibrothecoma. However, the primary pathologist submitted the fallopian tubes in their entirety according to the previously described SEE-FIM (sectioning and entirely examining the fimbria) protocol. In one section of the fimbriated end of the left fallopian tube, a 2 mm invasive serous adenocarcinoma was discovered in association with a serous tubal intraepithelial carcinoma (STIC, Figure 1A&B). The latter was strongly positive with immunostains for MIB-1 and p53, staining over 70% of the cell nuclei (Figure 1C&D). A portion of the STIC stained negative for p53 (Figure 1D, boxed area), consistent with a second truncating mutation in the p53 gene leading to deletion of the antigenic target.
The processing of a specific organ or specimen submitted for pathologic evaluation is governed by the disorders that are unique to that organ. When confronted with a specific tumor, the pathologist follows a protocol appropriate to that neoplasm, which ensures the recovery of all clinically and biologically relevant information. In the case of an early cervical cancer, the entire cervix is submitted to determine the extent of disease and guide subsequent management, and additional tissues (lymph nodes, etc) are examined with this in mind. When a uterus and cervix are submitted for benign disease (e.g. leiomyomata) or for a non-cervical neoplasm (i.e., endometrial carcinoma, etc.) the cervix examination is governed by 1) its gross appearance, 2) the odds that, if grossly negative, the cervix harbors clinically insignificant disease and 3) the presumed location of disease if it were to be unexpectedly encountered histologically at this site. As a rule, a normal appearing cervix that has been received for reasons other than suspected cervical cancer or precancer is not extensively sectioned due to the very low risk of unsuspected malignancy. If the cervix is grossly normal, a single histologic section is taken from each of the anterior and posterior surfaces, including the squamo-columnar junction, corresponding to the geographic distribution and mucosal location of most cervical neoplasms. The expectation is that a neoplasm will not be found, but if one is present, this strategy maximizes the odds of detection.8
Currently, the Association of Directors of Anatomic and Surgical Pathology have recommended a two-tiered approach to the fallopian tube, depending on the level of suspicion for an occult invasive or intraepithelial carcinoma. Fallopian tubes removed for pelvic cancer risk reduction should be extensively sampled, with attention to the fimbria, similar to the SEE-FIM protocol proposed by Medeiros et al.9 Fallopian tubes removed from low risk women undergoing procedures for benign conditions are to be sectioned at “2- to 3-mm intervals and submit 3 sections to represent isthmus, ampulla and infundibulum/fimbria (1 block).” 10 Other publications recommend a single central section from the fallopian tube. 8
Although the inclusion of the fimbria in the tubal analysis is important, submission of the entire infundibulum and fimbria is recommended by these authors for the following reasons:
The strongest theoretical argument for this sampling procedure is the emerging data that implicate the distal fallopian tube in the pathogenesis of a significant – albeit unknown – percentage of pelvic serous carcinomas in women with BRCA1 and BRCA2 mutations.4, 5 The current assessment of risk for familial cancer is predicated on a series of parameters that, as currently defined, will not invariably identify women at genetic risk until either they or their close family members, or both, have developed a breast or ovarian malignancy. If fimbrial exam uncovered even a small number of at-risk women in this category and did so at no additional cost, the benefit to cost ratio would be extremely high. A second advantage from this strategy would be, in a relatively short time, a realistic estimation of the frequency of fimbrial carcinoma in the low risk population would be attainable.
The principal arguments against submitting the entire fimbria for routine exam in salpingectomies removed for benign disease include the following:
The interruption of pelvic serous carcinoma in its earliest stages remains a paramount goal in the quest to reduce the number of deaths attributed to this disease. Prophylactic salpingo-oophorectomy reduces the risk of pelvic serous carcinoma in women with BRCA1 or BRCA2 mutations by approximately 85%.14 Accordingly, salpingo-oophorectomy in low-risk women presumably has a significant impact on the frequency of subsequent pelvic cancer.15 The number of early cancers encountered in the fimbria in the latter group would be expected to be extremely low. Nevertheless, based on the case presented in this report, routine examination of the fimbria will occasionally uncover cases of early serous or endometrioid carcinoma, and a cost-effective strategy to determine the frequency of this phenomenon should be employed. The fundamental principal of ovarian cancer death reduction is early detection. As early malignancies detected in these low risk women accumulate, the proof of this principal will be tested and value of the distal tube as a target for intercepting early serous carcinoma will come into sharper focus. Accordingly, our understanding of the natural history of Stage IA non invasive tubal carcinomas will be enhanced.
This work was supported by grants from the NCI (P50 CA105009 [SPORE]: D. Cramer, PI), NCI 1R21CA124688-01A1 (CP Crum, PI), the Francis Ward Paine and TSA Pemberton Funds from the Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital and a gift in memory of Elizabeth Ford Smith. The authors are grateful to Dr. Catrina Readingfor contributing this case and for helpful discussions.