Elsevier

Gynecologic Oncology

Volume 113, Issue 3, June 2009, Pages 391-396
Gynecologic Oncology

Review
Precursors to pelvic serous carcinoma and their clinical implications

https://doi.org/10.1016/j.ygyno.2009.01.013Get rights and content

Abstract

Pelvic serous carcinoma has traditionally been viewed as a rapidly evolving malignancy, due principally to its late stage at diagnosis and tendency for poor outcome, both in the endometrium and the upper genital tract. Recently, studies of women with BRCA1 or BRCA2 mutations (BRCA+) undergoing risk reducing salpingo-oophorectomy have highlighted the distal fallopian tube as a common (80%) site of tumor origin and additional studies of unselected women with pelvic serous carcinoma have demonstrated that serous tubal intraepithelial carcinoma may precede a significant percentage of these tumors. This review examines the serous carcinogenic spectrum in the fallopian tube, highlighting recent evidence that these tumors may follow a defined precursor that has been present for a prolonged interval. The data supporting a candidate precursor, the implications of these findings for early detection and prevention of pelvic serous carcinoma and the caveats, are discussed.

Introduction

The majority of epithelial cancers, whether they arise in the lung, colon, stomach, pancreas, uterus, ovary, cervix or other sites, arise via a sequence of events that progressively evolve into a malignant phenotype. In most cases, this pathway begins in a biologically normal epithelium, which, for a period of time, is vulnerable to intervention (or spontaneous resolution) relative to later stages of the neoplastic continuum. A classic example is the cervix, where infection by oncogenic human papillomaviruses initiates as a precancerous lesion (CIN). Interruption of this process by colposcopic exam and lesion ablation prevents cervical cancer. Similarly, immunization with viral-like particles that duplicate the antigenic determinants of these cancer-related HPV types prevents CIN from developing. Hence, cervical cancer is prevented by blocking the development of the earliest phase of tumor development [1]. If by analogy, cancer is viewed as a forest fire, the precursor is a lit match. The vaccine effectively prevents the match from being struck or extinguishes it before it can ignite the forest fire.

Prevention of ovarian carcinoma, the most common of which is serous carcinoma, has been complicated by factors that are not present in the cervical cancer model. First, the ovary is not sufficiently accessible to permit frequent inspection. Second, serous carcinomas of the ovary typically spread early in their clinical course, and third, the source of the tumor – by analogy the place and mechanism by which the match is struck – has until recently been a mystery. Ovarian cancer accounts for approximately 3% of malignancies in women but is the leading cause of death from gynecologic cancers with an estimated 15, 280 deaths in 2007 [2]. The lifetime risk of developing an ovarian cancer is much higher for women with hereditary mutations in BRCA1 or BRCA2 [3]. Because serous carcinoma is usually discovered at a late clinical stage after spreading to the ovarian surface and peritoneum, it has a poor outcome.

Recent molecular studies have suggested that epithelial ovarian malignancies can be divided into two groups based on shared genetic mutations and observed progression from precursor lesions [4], [5]. The type I tumors show mutations in a variety of pathways including mismatch repair genes, BRAF, KRAS, Beta-catenin, and PTEN. This family includes clear cell, endometrioid, mucinous, and low-grade serous carcinomas as well as the borderline (serous, mucinous, endometrioid) tumors. Type I tumors seem to evolve in a stepwise fashion from cortical inclusion cysts and endometriosis to borderline tumors to invasive malignancies. Low-grade serous carcinomas, for instance, are more likely to have mutations in BRAF and KRAS similar to their borderline mucinous and endometrioid counterparts. Conversely, high-grade serous carcinomas (type II tumors) commonly show mutations in p53 and are usually not found in association with adjacent borderline serous tumors. High-grade serous malignancies are usually discovered at an advanced stage, which has made identification of a precursor lesion elusive in the past due to the extensive tumor distribution when detected.

Section snippets

The BRCA+ model and serous tubal intraepithelial carcinoma (STIC)

Historically, primary fallopian tube malignancies have been considered rare relative to conventional ovarian carcinomas, approximately one fiftieth as common [6], [7]. Part of this disparity was attributed to the stringent criteria for the diagnosis of a primary tubal malignancy. Criteria include the presence of a mass lesion in the fallopian tube that contrasts with other candidate sites, such as the ovaries and the presence of an intraepithelial component, identical to serous intraepithelial

Tubal intraepithelial carcinomas, ovarian and peritoneal serous cancer

The association of STIC with BRCA+ status has strongly endorsed the concept that this entity is the more common early malignancy in women with this genetic risk factor. This association raised the obvious question of whether pelvic serous malignancies without a documented history of BRCA+ could be linked to the distal fallopian tube. Three recent studies have supported this pathway as an explanation for a significant proportion of pelvic serous carcinomas, including many fulfilling the criteria

A new candidate precursor for serous cancer in the fallopian tube (the “p53 signature”)

Important features of early serous cancer (STIC) in the distal fallopian tube are cytologic atypia, high proliferative index and nuclear staining for p53. The latter is strongly linked to accumulation of mutant p53 protein. Staining for p53 is negative in 10–15% of these cases because mutations in the gene can occur upstream of the protein segment targeted by the immunohistochemical analysis and such truncated mutated protein products will go undetected. In our experience with early serous

Clinical implications of early serous carcinogenesis

One of the greatest accomplishments in gynecologic cancer prevention in the past 50 years has been the widespread use of the Papanicolaou smear and more recently, the discovery and development of a vaccine that promises to significantly reduce the incidence of high grade cervical cancer precursors and their malignant counterparts. The past and future success of this venture has depended heavily on two characteristics of cervical carcinogenesis: first, these tumors are preceded by precursor

Caveats

Despite the above advances, two realities must be emphasized. 1) The origin of a significant percentage of pelvic serous carcinomas remains unknown, even with protocols that focus on extensive pathologic analysis of fallopian tube. 2) The proportion of symptomatic pelvic serous carcinomas in women with a family history of BRCA mutations that are assigned to the ovary is much higher than that assumed from the evaluation of prophylactic salpingo-oophorectomies in this population, which show a

Conflict of interest statement

The authors have no conflict of interest to declare.

Acknowledgments

This work was supported by grants from the NCI (P50 CA105009 [SPORE]: D. Cramer, PI), NCI 1R21CA124688-01A1 (CP Crum, PI), The Charlotte Geyer Foundation (CP Crum, PI), The Columbia Hospital For Women Research Foundation (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.

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