Case 1 -

Serous Tubal Intraepithelial Carcinoma of Tubal Fimbria, Bilateral, with: - Multifocal Microscopic Metastatic Deposits of High Grade Serous Carcinoma on Surface of Both Ovaries Patricia A. Shaw Toronto General Hospital Toronto, Ontario, Canada

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Clinical History: Modified radical hysterectomy, bilateral salpingo- oophorectomy and lymph node dissection is performed on a 56 year old woman with adenocarcinoma diagnosed on Pap smear and endocervical curettage. Case 1 - Figure 1 Striking multifocal epithelial proliferation Case 1 - Figure 2 Stratification with tufting and budding Case 1 - Figure 3 Marked nuclear atypia Case 1 - Figure 4 Carcinoma metastasis on ovarian surface Case 1 - Figure 5 High grade serous carcinoma Case 1 - Figure 6 Carcinoma with focal ovarian stromal invasion Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Extensive epithelial proliferation and stratification of distal tubal epithelium involving both tubes was readily evident at low power magnification. The cellular stratification was characterized by tufting and budding of small tumour clusters. Nuclear atypia and pleomorphism was marked. Microscopic metastases of high grade serous carcinoma involved the surface of both ovaries. Differential Diagnoses: non-neoplastic epithelial proliferation metastatic carcinoma to tubal mucosa synchronous carcinomas of tube and ovary Final Diagnosis: Serous Tubal Intraepithelial Carcinoma of Tubal Fimbria, Bilateral, with: - Multifocal Microscopic Metastatic Deposits of High Grade Serous Carcinoma on Surface of Both Ovaries Case Discussion: Clinical During surgery, which included palpation of the upper abdomen, there was no macroscopic evidence of malignancy. Extensive serous Tubal Intraepithelial Carcinoma (TIC) involved bilateral tubal fimbria. Multiple deposits of high grade serous carcinoma involved the ovarian surfaces with focal stromal invasion. Peritoneal washings were positive for adenocarcinoma. The patient was treated with six cycles combined platinum/taxol, but was diagnosed with recurrent disease 3 months following completion of first line chemotherapy. Microscopic This is an unusually prominent and extensive example of Tubal Intraepithelial Carcinoma (TIC). TICs are identified only on microscopic examination, and are found in the tubal fimbria, infundibulum, and distal ampulla. Rarely, TICs are identified in the mid-isthmus, and are not seen in the proximal or intramural tube. TICs may be multifocal [1]. Many TICs are recognizable as lesions at low power magnification, particularly in post-menopausal women, but may be missed without careful histological examination of pre-menopausal women, because the normal and hormonally responsive tubal epithelium has varying degrees of stratification and proliferation throughout the ovarian cycle. TIC is characterized by an increased nuclear/cytoplasmic ratio, nuclear pleomorphism, significant nuclear atypia with hyperchromasia, loss of polarity, and, usually, by cellular stratification. Mitoses are identified only occasionally, and nucleoli may be prominent. TICs are composed of cells without cilia, although occasional residual ciliated cells may be scattered through the lesion. Nuclear atypia, pleomorphism, crowding, stratification are all features common to TICs, but there is also variation in the microscopic appearance of TIC lesions [2]. Most TICs have a uniform luminal border, but occasionally TICs also have cellular tufting, formation of slit like spaces, and even detachment of surface cells, representing an exophytic growth pattern in the absence of stromal invasion. Immunohistochemistry is not necessarily required to diagnose a clinically significant lesion of the fallopian tube, but is useful in confirming the diagnosis of TIC. Ki67 is usually expressed in greater than 50% of TIC nuclei. Diffuse nuclear overexpression of p53 is seen in at least 70% of TICs, similar to the finding in the invasive counterpart. It should be noted however that p53 positivity is not a requirement of diagnosis. Differential Diagnosis: The tubal epithelium is hormonally responsive and the preponderance of the differentiated cell types of the normal tube, ciliated and secretory types, varies under hormonal influence. The normal premenopausal tubal epithelium has varying degrees of stratification and proliferation, and these changes are not necessarily uniform in the tube [3]. Alterations in the pattern of cell-cell arrangement may suggest the possibility of a lesion, but in the absence of significant nuclear atypia, these foci are unlikely to represent lesions of clinical significance. Immunohistochemistry for ki67 is helpful in distinguishing non-neoplastic findings and neoplastic lesions. Significant abnormalities should have increased ki67 expression compared to the background epithelium. Other putative serous cancer precursor lesions have been reported. The p53 signature is a lesion which by definition is only identified with the use of immunohistochemistry for p53 and ki67. As defined by Crum and his colleagues, the p53 signature is a focus of at least 12 consecutive cells with intense nuclear staining with p53, but without other abnormal morphology, although usually these small lesions are composed of secretory cells only, with no intervening ciliated cells [4, 5]. There is no stratification and no increased proliferation. Most lesions are small, and are usually composed of less than 100 cells. P53 signatures may be multifocal, and bilateral. Like TICs, they are found in the distal fallopian tube epithelium, usually the fimbriated end, and may co-exist with TICs. The biological significance of this lesion is uncertain, particularly as it is seen commonly in women at low genetic risk of carcinoma [1]. Mutations of p53 have been documented in at least some p53 signatures, suggesting that the p53 signature may be a latent precursor of TIC and tubal serous carcinoma [4]. They may also demonstrate evidence of DNA damage as documented by γ-H2AX immunohistochemistry [2] . The p53 signature however should be considered as a benign non-neoplastic lesion. There are uncommon tubal lesions which do not fulfill the histological criteria for a diagnosis of malignancy but may have any or a combination of the following histological features - atypia, stratification, p53 nuclear positivity, and increased cellular proliferation [1]. The significance, the classification, and the diagnostic reproducibility of these lesions is as yet uncertain. Histological atypia and p53 overexpression may co-exist in a focus with no or minimally increased Ki67. This is a poorly described and poorly understood entity which may represent a lesion transitional between the p53 signature and Tubal Intraepithelial Carcinoma. The differential diagnosis of TIC may also include transitional cell metaplasia of the tubal epithelium [6]. The lack of nuclear atypia, the lack of proliferation and the presence of nuclear grooves are features which readily distinguish this common entity from the malignant precursors. Processing of Risk- Reducing Salpingo-oophorectomy Specimens: TICs are identified most frequently in prophylactically resected tubes in BRCA1/2 mutation carriers. When mutation carriers undergo risk-reducing surgery, the pathologist is key in their multi-disciplinary care. The reason for the surgery must be communicated to the pathologist at the time of surgery, and strict grossing protocols must be in place to preserve the delicate and exposed epithelium of the tubal fimbria and the ovarian surface, and ensure careful histological examination of the maximum surface area of the tubal fimbria and the ovarian surface epithelium. One approach to sectioning the tube is described by Medeiros et al, the SEE-FIMS protocol [7]. Briefly, after formalin fixation, the fimbriated end of the tube is amputated and sectioned serially longitudinally to maximize histological examination of fimbrial plicae. The remaining tube is serially sectioned at 2-3 mm intervals. All tissue is submitted for microscopic examination. There is no evidence to suggest that multiple levels are required for the detection of clinically significant lesions, but the sectioning protocol might include additional unstained sections adjacent to the H&E-stained section which may be used to further classify any lesion identified on histology [8]. The ovaries should be handled with care and sectioned at 2-3 mm intervals after fixation. Review of the Literature/Treatment Options: Women at high genetic risk of ovarian/tubal carcinoma identified by family history or genetic testing for mutations of BRCA1 or BRCA2 are advised to undergo risk-reducing salpingo-oophorectomy. Careful histopathological examination of the ovaries and fallopian tubes has led to the recognition that clinically undetectable carcinomas are more frequently identified in the tubes than ovaries in mutation carriers, and that histological serous carcinoma precursors exist in the distal tube and fimbria. The frequency of occult carcinoma in mutation carriers undergoing prophylactic surgery is about 4%, and Tubal Intraepithelial Carcinoma about 8% [9, 1]. TIC is also seen frequently in association with clinically evident and advanced stage serous carcinoma [10]. It is likely that malignant transformation of tubal epithelium is key in the serous carcinogenesis whether the carcinoma is clinically diagnosed in the ovary, fallopian tube, or peritoneum. Conclusion(s): This case is unusual but it also highlights an important feature of TIC. These lesions are intraepithelial and lack stromal invasion, but they should not be necessarily considered as in situ lesions without the capacity to spread. In this example, the malignant cells have detached and implanted onto the ipsilateral ovarian surface, with invasion. This suggests that at least some TICs may metastasize before invasion is established in the tube. The natural history of TICs is not yet well understood. TICs are not only identified in mutation carriers, but, as in this case, may also be found in women not known to be at genetic risk. When identified, the ovarian and adnexal tissue must be examined carefully to exclude the possibility of microscopic peritoneal spread. References: Shaw PA, Rouzbahman M, Pizer ES, Pintilie M, Begley H. Candidate serous cancer precursors in fallopian tube epithelium of BRCA1/2 mutation carriers. Mod Pathol. 2009 Sep;22(9):1133-8. Jarboe E, Folkins A, Nucci MR, Kindelberger D, Drapkin R, Miron A, Lee Y, Crum, CP. Serous carcinogenesis in the fallopian tube: A descriptive classification. Int J Gynecol Pathol. 2007 Jan;27(1):1-9. Yanai-Inbar I, Silverberg SG. Mucosal epithelial proliferation of the fallopian tube: prevalence, clinical associations, and optimal strategy for histopathologic assessment. Int J Gynecol Pathol. 2000 Apr;19(2):139-44. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J of Pathol. 2007 Jan;211(1):26-35. Lee Y, Medeiros F, Kindelberger D, Callahan MJ, Muto MG, Crum CP. Advances in the recognition of tubal intraepithelial carcinoma: applications to cancer screening and the pathogenesis of ovarian cancer. Advances in Anatomic Pathology. 2006 Jan;13(1):1-7. Rabban JT, Crawford B, Chen LM, Powell CB, Zaloudek CJ. Transitional cell metaplasia of fallopian tube fimbriae: a potential mimic of early tubal carcinoma in risk reduction salpingo-oophorectomies from women With BRCA mutations. Am J of Surg Pathol. 2009 Jan;33(1):111-9. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J of Surg Pathol. 2006 Feb;30(2):230-6. Rabban JT, Krasik E, Chen LM, Powell CB, Crawford B, Zaloudek CJ. Multistep level sections to detect occult fallopian tube carcinoma in risk-reducing salpingo- oophorectomies from women with BRCA mutations: implications for defining an optimal specimen dissection protocol. Am J of Surg Pathol. 2009 Dec;33(12):1878-85. Finch A, Shaw P, Rosen B, Murphy J, Narod SA, Colgan TJ. Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol. 2006 Jan;100(1):58-64. Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J of Surg Pathol. 2007 Feb;31 (2):161-9.