Gynecologic Pathology

Tubal Intraepithelial Carcinoma

Christopher P. Crum
Brigham & Women's Hospital
Boston, MA


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Clinical History
This is a fallopian tube from a 44 year old woman with a history of BRCA mutation who underwent a prophylactic salpingo-oophorectomy. A single plica is lined by a population of abnormal tubal epithelial cells.


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Case 4 - Figure 1 - Lower power photomicrograph
Case 4 - Figure 2 - Higher power magnification of one plica
Case 4 - Figure 3 - Cuboidal cell population

Case 4 - Figure 4 - Higher magnification
Case 4 - Figure 5 - Higher magnification
Case 4 - Figure 6 - Higher magnification

Case 4 - Figure 7 - Some epithelial stratification
Case 4 - Figure 8 - Immunostaining for p53


Introduction
Prophylactic salpingo-oophorectomies or their equivalent are performed when patients either have a hereditary BRCA mutation (BRCA+) or a perceived increase risk of breast or ovarian cancer based on personal or family history. The objective is to bot prevent ovarian cancer and exclude an occult or unsuspected malignancy. The pathologist must do the following:

1) Ensure that the tubes and ovaries are examined in their entirety.

2) Exclude benign mimics of early Mullerian neoplasia during the histologic exam.

3) Determine if a malignancy is present. The earliest form is a tubal intraepithelial carcinoma (TIC) Most of these are serous but a minority exhibit other patterns, including endometrioid histology.

Differential Diagnosis
1) The fallopian tube hosts a wider range of mucosal variations, including secretory cell hyperplasias, papillary hyperplasias, and benign proliferations of predominately ciliated epithelium. An important finding in most of these is the presence of relatively mild nuclear enlargement, preservation of cell polarity, conspicuous cilia, and strong cell-cell cohesion.

2) Serous carcinogenesis in the fimbria. Excluding occasional endometrioid tumors, components of this carcinogenic sequence share one or more features that characterize a clonally derived population with a common genetic abnormality (p53 mutation). These include p53 positivity resulting from a p53 mutation, cellular proliferation, atypia and ultimately the capacity to spread to adjacent organs without invading. They fall into the following categories.

a) Step I, "Latent precursors", characterized byp53 mutations but lacking either appreciable atypia or increased proliferative index. These small clonal expansions of p53 mutated epithelium are the result of un-repaired DNA damage, possibly resulting from the release of oxidants at the time of ovulation. We term these latent precursors "p53 signatures." We do not classify P53 signatures as either malignant or neoplastic because they do not exhibit increased proliferation and cannot be distinguished from the adjacent mucosa by morphologic inspection alone. Nevertheless, the p53 signature is an entity that shares many characteristics with tubal carcinoma, hence the designation as a latent precursor. P53 signatures are strongly p53 positive (80% of 12 or more consecutive nuclei), involve secretory cells, localize principally to the fimbria, exhibit evidence of DNA damage, frequently co-exist with TIC and often contain p53 mutations. However, like many precursors at other sites, p53 signatures are common and presumed unlikely to progress to malignancy. Because of this and because they are not recognizable without p53 immunostaining, p53 signatures are not relevant to patient management. They are probably, however, a critical link in the pathway to pelvic serous carcinoma that may provide clues to the pathogenesis of many of these cancers.

b) Step II, Tubal intraepithelial lesions in transition (TILTs). Most of the p53 positive entities we have identified in the fallopian tubes consist of either non-proliferating p53 signatures or frank intraepithelial carcinomas. However, we have occasionally identified strongly p53-positive epithelia – most commonly in BRCA+ women or women with existing tubal cancer - that contain p53 mutations and moderately increased proliferative activity but do not grow as a dominant population of disorganized epithelial cells. In contrast to tubal intraepithelial carcinomas, these lesions exhibit features that indicate a less aggressive growth process, including: 1) Incomplete replacement of the ciliated cell population; 2) preserved cell polarity and cell-cell adhesion, and 3) lower proliferative index relative to TIC, ranging between 30 and 50% of cells. We approach these as tubal intraepithelial lesions in transition to distinguish them from both p53 signatures (which are not proliferative) and TICs (which are malignant).

c) Step III, Tubal intraepithelial carcinoma (TIC). TIC is a bona-fide malignancy that is confined to the mucosa of the fallopian tube. It originates in the secretory cell and like its counterpart in the endometrium has the capability to spread to the ovarian and peritoneal surfaces, and occasionally, the endometrium. The saliant morphologic features of TICs are the following: a) a dominant cell population without intervening normal cells. 2) variable epithelial thickness, c) nuclear stratification with loss of cell polarity; d) absence of cilia, e) a MiB1 index that may vary regionally and an absolute percentage of positive cells has not been established for this diagnosis. We have seen some TICs accompanied by distant spread that had lower levels of MiB1 positivity in the range of 50%. We have also encountered low MiB1 indices in endometrioid lesions in BRCA+ women, emphasizing further the primary role of histopathology; f) seams or fracture lines in the upper epithelial layers with loss of cell to cell cohesion. In our experience these lesions invariably contain a p53 mutation, which will be shared by coexisting ovarian or peritoneal tumors. A diagnosis of TIC is tantamount to a diagnosis of serous carcinoma.

The Role of the Tube in Pelvic Serous Carcinoma
Careful inspection of fallopian tubes from women with presumed serous ovarian cancer and primary peritoneal serous carcinomas has disclosed TIC in one half and two thirds respectively. This has led us to speculate that many of these tumors are actually arising in the distal fallopian tube. These tumors invariably share the same p53 mutation with the early tubal carcinomas. This fact combined with the existence of a serous carcinogenic sequence in the distal fallopian tube, supports this hypothesis.

Final Diagnosis
Tubal intraepithelial carcinoma. This is a challenging case because the morphologic heterogeneity and variable MiB1 index are consistent with a mixture of both a lesion in transition and TIC. However, in some serial sections the loss of polarity is conspicuous and accompanied by a MiB1 index exceeding 70%.

Practical Issues in Diagnosis
The Division of Women's and Perinatal Pathology at Brigham and Women's Hospital uses the following procedure for managing the distal fallopian tube in women at risk for or suspected to have pelvic serous carcinoma:

1) The tubes, including fimbria, are completely examined using a protocol that maximizes the exposure of the fimbriated end (SEE-FIM protocol).

2) The diagnosis of TIC is based principally on morphologic criteria; both p53 and MiB1 are helpful but are used for confirmation only. The MiB1 index may vary.

3) Once the diagnosis of TIC is made, it should be corroborated by a second pathologist.

The terminology used for diagnosis is the following.

1) For p53 signatures detected incidentally: No diagnosis is given. P53 signatures are not neoplasms and should not be diagnosed as such.

2) For lesions in transition: Descriptive diagnosis emphasizing that the lesion does not fulfill the criteria for TIC. We cannot specify the risk of subsequent pelvic serous cancer in this group, but based on the literature, assume it is low. Additional sectioning of the case is advised to exclude a more advanced lesion (TIC). Until further data are available, such patients should not receive chemotherapy if the pathologist cannot make a histologic diagnosis of TIC.

3) For TICs: Tubal intraepithelial carcinoma. The diagnosis implies a risk of spread to the ovary or mesothelial-lined surfaces. The actual risk is unclear, and a decision regarding (prophylactic) chemotherapy will be dictated by multiple factors, including the extent of the lesion, peritoneal cytology and other factors. A clear dialogue between pathologist and oncologist is important to this process.

Bibliography
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  6. 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. Adv Anat Pathol. 2006 Jan;13(1):1-7.

  7. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007 Jan;211(1):26-35.

  8. Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, Medeiros F, Callahan MJ, Garner EO, Gordon RW, Birch C, Berkowitz RS, Muto MG, Crum CP. Intraepithelial Carcinoma of the Fimbria and Pelvic Serous Carcinoma: Evidence for a Causal Relationship. Am J Surg Pathol. 2007 Feb;31(2):161-169.

  9. Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, Lee Y. The distal fallopian tube: a new model for pelvic serous carcinogenesis. Curr Opin Obstet Gynecol. 2007 Feb;19(1):3-9.