Elsevier

Gynecologic Oncology

Volume 127, Issue 3, December 2012, Pages 645-650
Gynecologic Oncology

Clinical Commentary
New views on the pathogenesis of high-grade pelvic serous carcinoma with suggestions for advancing future research

https://doi.org/10.1016/j.ygyno.2012.08.023Get rights and content

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Background

High-grade serous carcinomas (HSCs) of the gynecological tract typically present with advanced stage disease, which often proves fatal despite treatment [1]. Effective approaches for early detection or prevention of HSCs have not been developed [2]; however, the emergence of new insights into the pathogenesis of these tumors raises hopes that achieving this goal may be possible in the future [3], [4], [5], [6].

Historically HSCs were widely presumed to arise from ovarian surface epithelium

Prevalence of HSC precursors in fallopian tubes

Our knowledge of the prevalence of HSC precursors is based mainly on pathological studies of RRSOs, in which precursors are undoubtedly more frequent than in the general population, because this procedure is generally restricted to women at markedly elevated risk of ovarian and fallopian tube cancer. Nonetheless, published estimates of HSC prevalence, even in this group, are almost certainly too low, for several reasons:

  • (1)

    Many tubes removed as part of RRSOs are not entirely submitted for

Ovarian surface epithelium (OSE)

Historically, studies of OSE have been limited by difficulties in collecting sufficient, representative OSE samples for histologic examination and molecular analysis. OSE consists of a single cell layer, which exfoliates readily with minimal handling. Consequently, histological studies of OSE have been limited by sparse, patchy, cellular representation of the entire OSE and potentially preferential loss of rare cancer precursors during intra-operative and post-resection handling. Thus,

Ovarian surface epithelium (OSE) brushings

Laboratory scientists have typically prepared immortalized cultures of OSE from oophorectomy specimens for in vitro experimentation (reviewed in [7]). These procedures overcome limitations related to insufficient cellularity, but immortalization may alter cell biology, limiting the relevance of these studies for human pathophysiology. We have tried to develop methods to collect specimens that are adequate for histological and molecular analyses without undergoing prior culture.

Initially, we

Challenges to evaluating fallopian tube epithelium and ovarian stroma

The interpretation of subtle cytological changes in tubal epithelium is challenging; poor preservation and suboptimal fixation can render this task difficult at best, unreliable at worst. A recent inter-observer study found that agreement among expert gynecological pathologists in the diagnosis of fallopian tubal in situ carcinoma was poor, although results were improved in a repeat review of the same cases when aided by immunohistochemical stains for p53 and Ki67 [23]. These challenges are

The sojourn time for progression of HSC precursors to clinical cancer: data supporting a two-phase model

Few models have been developed to estimate the sojourn time of HSC from cancer initiation to symptomatic clinical detection. Using published data related to the prevalence and size of occult and clinically-evident HSCs, Brown proposed that HSC may remain clinically occult for more than 5 years, on average, prior to detection [33]. However, such analyses are limited by the quality and scarcity of data regarding the characteristics of occult HSC and cannot readily account for the natural history

Ovarian surface epithelium (OSE) and subjacent stroma: fertile soil for the pathogenesis of high-grade serous carcinoma (HSC)?

Historically, pelvic HSCs have been classified as ovarian cancers because the bulk of disease in most women is located in the ovaries and peritoneum. As recently highlighted [35], even when early HSCs are detected, the majority of the tumor volume consists of multiple nodules involving the ovarian surface and subjacent stroma, a pattern more consistent with metastatic spread to the ovary than with primary origin. Given that few high-stage HSCs occur without ovarian involvement, and that primary

Conclusion

Progress towards understanding the pathogenesis of HSC has been slow. Until recently, research has focused on the biology of OSE, once presumed to represent the epithelial source of HSC and its precursors. A new paradigm in which HSC arises from the tube rather than the ovary sheds light on the pathogenesis of this disease, and thus on prospects of developing effective methods for early detection and prevention. The development of models using cultured fallopian tube cells may provide increased

Conflict of interest statement

No conflict of interest.

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