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Gynaecological Oncology
Rare Epithelial Ovarian Tumours
David M Gershenson
Professor and J Taylor Wharton, MD, Distinguished Chair in Gynecologic Oncology, Department of Gynecologic Oncology,
University of Texas MD Anderson Cancer Center
Abstract
Epithelial ovarian cancer is not a single homogeneous tumour type but rather comprises many distinct phenotypes. Historically, all types
of epithelial ovarian cancer have been ‘lumped’ together in phase II and III trials worldwide. Emerging clinical, molecular and genetic
information indicates that certain types of rare epithelial ovarian cancers – low-grade serous carcinoma, clear-cell carcinoma and
mucinous carcinoma – have molecular signatures and clinical behaviour patterns and outcomes that are quite distinct from those of the
typical high-grade serous carcinomas. Clinically, low-grade serous carcinomas appear to be on a continuum with serous ovarian tumours
of low malignant potential and are associated with young age at diagnosis and prolonged overall survival. Both clear-cell and mucinous
carcinomas are more aggressive and associated with a worse prognosis. All three subtypes appear to be relatively chemoresistant.
Therefore, in future clinical trials each of these three subtypes should be studied separately using targeted agents based on pathways and
genes identified in molecular and genomic studies.
Keywords
Ovarian cancer, rare tumours, chemotherapy, clear-cell, mucinous, low-grade serous
Disclosure: The author has no conflicts of interest to declare.
Received: 17 December 2008 Accepted: 9 February 2009
Correspondence: David M Gershenson, Professor and Chair, Department of Gynecologic Oncology, Unit 1362, The University of Texas MD Anderson Cancer Center, PO Box
301439, Houston, TX 77230-1439, US. E:
dgershen@mdanderson.org
For several years, we have known that epithelial ovarian cancer is not highly reproducible in a multi-institutional setting, with excellent
a single homogeneous tumour type but rather comprises many interobserver and intraobserver agreement, and that it may be
distinct phenotypes. Nevertheless, for the past several decades superior to other grading systems, including that of the International
conventional clinical trial design has dictated that all types of Federation of Gynecology and Obstetrics (FIGO).
5,6
Further support for
epithelial ovarian cancer be ‘lumped’ together in phase II and III trials a two-tier grading system for serous carcinoma arises from a recent
worldwide. However, with the emergence of recent clinical, molecular report that suggests that subclassification of high-grade serous
and genetic information, we now know that certain types of rare carcinoma into moderately and poorly differentiated (grades 2 and 3)
epithelial ovarian cancer, specifically low-grade serous carcinoma, is not relevant based on molecular genetic and in vitro drug
clear-cell carcinoma and mucinous carcinoma, have molecular resistance data.
7
signatures and clinical behaviour patterns and outcomes quite
distinct from those of the typical high-grade serous carcinomas. In Molecular Studies
this article, a case will be made, based on available evidence, that Over the past few years, it has become increasingly clear that
future clinical trials should be designed to develop separate studies serous tumours of low malignant potential (LMP) and low-grade serous
for women with these three histological types in both the first-line carcinomas exist on a continuum quite distinct from high-grade
and recurrent disease settings. serous carcinomas. A number of reports have suggested that the ras-
raf-MEK-ERK pathway may play a prominent role in the pathogenesis of
Low-grade Serous Ovarian Carcinoma serous LMP and low-grade ovarian carcinomas, but not in the
Pathology pathogenesis of high-grade serous carcinomas.
8–11
Singer and colleagues
Although histological grade has emerged in several studies as one of reported that either BRAF or K-ras mutations occurred in 68% of low-
the most important prognostic factors for epithelial ovarian cancer, no grade serous carcinomas and in 61% of serous tumours of LMP, but in
universal grading system exists.
1–3
In the early 1990s, in an effort to none of the 72 high-grade serous carcinomas.
9
In addition, studies of p53
develop a simpler, more reproducible, more clinically meaningful mutational analysis and overexpression by immunohistochemical
grading system, the MD Anderson Cancer Center designed and staining indicate that high-grade serous carcinomas have a high level of
refined a two-tier grading system – low- and high-grade – for invasive p53 mutations/overexpression compared with serous LMP tumours and
serous ovarian carcinoma. After more than a decade of clinical use, low-grade serous carcinomas.
7,12,13
In addition, there appears to be a
the details of this proposed grading system were published.
4
significantly higher expression of oestrogen and progesterone receptors
Subsequent reports revealed that this two-tier grading system is by immunostaining in low-grade serous carcinomas compared with
62 © TOUCH BRIEFINGS 2009
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