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Abstract
Modern Pathology , (20 January 2017)
In
recent years it has become clear that many extra-uterine (pelvic)
high-grade serous carcinomas (serous carcinomas) are preceded by a
precursor lesion in the distal fallopian tube. Precursors range from
small self-limited ‘p53 signatures’ to expansile serous tubal
intraepithelial neoplasms that include both serous tubal epithelial
proliferations (or lesions) of uncertain significance and serous tubal
intraepithelial carcinomas. These precursors can be considered from
three perspectives. The first is biologic underpinnings, which are
multifactorial, and include the intersection of DNA damage with Tp53
mutations and disturbances in transcriptional regulation that increase
with age. The second perspective is the morphologic discovery and
classification of intraepithelial neoplasms that are intercepted early
in their natural history, either incidentally or in risk-reduction
surgeries for germline mutations. For the practicing pathologist, as
well as the investigators, a distinction between a primary
intraepithelial neoplasm and an intramucosal carcinoma must be made to
avoid misinterpreting (or underestimating) the significance of these
proliferations. The third perspective is the application of this
information to intervention, devising strategies that will actually
lower the ovarian cancer death rate by opportunistic salpingectomy,
widespread comprehensive genetic screening and early detection. Central
to this issue are the questions of (1) whether some STICs are
metastatic, (2) whether lower-grade epithelial proliferations can invade
prior to evolving into intraepithelial carcinoma, or (3) metastasize
and become malignant elsewhere (‘precursor escape’). An important caveat
is the persistent and unsettling reality that many high-grade serous
carcinomas are not associated with an obvious point of initiation in the
fallopian tube. The pathologist sits squarely in the midst of all of
these issues, and has a pivotal role in managing expectations for
stemming the death rate from this lethal disease.
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