The article by Trimble and
Trimble nicely summarizes the
state of knowledge on ovarian
tumors of low malignant potential
(LMP) and underscores the fact that
gaps in that knowledge have led to
confusion and controversy regarding
several issues related to these interesting
neoplasms. Many of these controversies
can be characterized as debates
between the "lumpers" and the "splitters."
The Johns Hopkins group has
long been at the forefront of research
on ovarian LMP tumors. In this review,
I will attempt to place some of the
authors'comments into perspective
and, at times, present a different point
and Molecular Biology
Since the original description of
"semimalignant tumors" by Taylor in
1929, no consensus has been reached
about the nomenclature for ovarian
LMP tumors. Although we have
generally used the term "borderline"
in numerous publications, it has been
used simply because it is less cumbersome
than "tumor of low malignant
potential." However, I actually prefer
the latter. I totally agree with the
Trimbles that the term "borderline"
sends the wrong message-that the
tumor is intermediate between benign
and malignant. Most of the molecular
biology studies of these tumors
strongly suggest that they are quite
distinct from frankly malignant ovarian
cancers and have a very different
On the other hand, I strongly disagree
with the use of the term "atypical
proliferating tumors," which has
been advanced by the Johns Hopkins
group to imply that these tumors almost
always behave in a benign fashion.
This paradigm fundamentally fits
the biology associated with stage I
LMP tumors but breaks down when
one considers stage II-IV tumors. The
Trimbles suggest that peritoneal implants
associated with ovarian LMP
tumors, particularly invasive peritoneal
implants, are, in fact, primary
peritoneal cancers and not somehow
related to the primary ovarian tumor.
However, this statement is speculative
and not clearly supported by molecular
and genetic data. I do agree, however,
that the ultimate answer to these
types of theories will emerge from further molecular and clonal investigations
The Trimbles also briefly discuss
the introduction of the term "micropapillary,"
which designates a proliferative
histopathologic pattern distinct
from the typical serous borderline pattern.
The Johns Hopkins group has
proposed that so-called micropapillary
serous carcinomas be split from tumors
with the typical serous borderline
pattern, but, as mentioned in
their article, this "splitting" has not
been universally accepted by either
the gynecologic pathology community
or the gynecologic oncology
community. In fact, most prominent
gynecologic pathology groups have
advocated maintaining the micropapillary
pattern as a subset of serous
LMP tumors based on their clinicopathologic
Surgical Management Issues
Because of the imprecise clinical
findings associated with ovarian LMP
tumors, general obstetrician/gynecologists
(rather than gynecologic
oncologists) are more likely to encounter
these neoplasms while operating for
an adnexal mass. Approximately 50%
of serous tumors and 80% to 90% of
mucinous LMP tumors are confined to
one ovary at diagnosis. Therefore, in a
high proportion of these patients who
have not completed childbearing, fertility-
sparing surgery-ovarian cystectomy,
or some combination thereof-
is feasible and highly desirable.
After resection of the ovarian
tumor(s), a frozen-section examination
is recommended, whenever possible.
Most expert gynecologic pathologists
should be able to diagnose
serous ovarian LMP tumors, but mucinous
tumors are more problematic.
I agree with the Trimbles that many
pathologists may be able to state only
that the tumor is "at least LMP." The
diagnosis of either an ovarian LMP
tumor or a frankly malignant tumor on
frozen section has implications for
comprehensive surgical staging.
The issue of surgical staging is also
controversial, even among expert gynecologic
oncologists. Because these
tumors, particularly those that are
stage I, are associated with an excellent
prognosis, and because no evidence
suggests that postoperative
treatment is warranted, some advocate
that surgical staging is unnecessary.
However, I would submit that comprehensive
surgical staging is indicated
when an ovarian LMP tumor is
diagnosed, for the following reasons:
(1) The information gained will further
elucidate the biologic behavior of
these tumors; (2) precise staging information
will allow patients and their
families to better understand their
prognosis, because the risk of recurrence
and death is higher in patients
with extraovarian spread; (3) in some
cases in which frozen-section examination
suggests the diagnosis of an
ovarian LMP tumor, the final diagnosis
will indicate invasive ovarian cancer.
In addition, once effective therapy
for advanced-stage ovarian LMP
tumors has been developed, there
will be even more compelling reasons
to justify comprehensive surgical
Postoperative Therapy, Prognosis,
and Use of Biomarkers
The Trimbles are correct-no postoperative
therapy has been shown to be
effective in reducing the relapse rate or
improving survival in women with advanced-
stage disease. However, essentially
all of these studies are retrospective,
and many suffer from small numbers.
Approximately 30% of women
with serous tumors have disease spread
beyond the ovary in the form of peritoneal
implants. In reported studies, approximately
18% of patients with
noninvasive peritoneal implants relapse,
and approximately 6% have died of tumor.[
2,6-14] Among patients with invasive
peritoneal implants, approximately
36% relapse, and 25% have died
Zanetta and colleagues have suggested
that the prognosis of patients
with advanced-stage tumors may be
better than previously reported.
However, longer follow-up may be
necessary to demonstrate relapse rates
reflected in the prior studies, particularly
the M. D. Anderson series.[13,15]
The studies from M. D. Anderson indicate
that, of all patients who relapse,
approximately 75% have low-grade
serous carcinomas, and 25% have recurrent
Several clinical or clinicopathologic
factors appear to be prognostic.
These include FIGO stage, age at diagnosis,
and residual disease at
completion of primary surgery. Although
ploidy, p53 overexpression, K-ras, and
so forth-have been studied in an effort
to identify patients at high risk of
relapse, none have been validated in
The Trimbles' contention that socalled
recurrent LMP tumors represent
either a primary peritoneal cancer
missed at initial diagnosis or a new
ovarian or primary peritoneal cancer
is, once again, speculative. They may
be correct, but the data are thus far
inconclusive. The molecular biology
of this phenomenon has not yet been
resolved. Although studies of ovarian
LMP tumors and their peritoneal implants
suggest multifocality or
polyclonality rather than monoclonality,
the numbers of patients in
these studies were small and the techniques
used were few.[17,18] In addition,
mutational analysis of advancedstage
serous LMP tumors that subsequently
"recurred" suggested a second
primary tumor rather than a true recurrence. Further study is clearly
Future research that will allow us
to bridge the gaps in our knowledge
of ovarian LMP tumors should focus
on the following: (1) causative factors
in the pathogenesis of these tumors;
(2) the value of comprehensive surgical
staging; (3) elucidation of clinical,
pathologic, and molecular predictive
and prognostic factors to select patients
who are at high risk of relapse
and who may benefit from postoperative
therapy; (4) a search for more effective
systemic therapies for advanced-
stage tumors and for subsequent
low-grade serous carcinomas;
(5) the role of microinvasion and
micropapillary pattern in prognosis
and in determining optimal treatment;
and (6) the clonality of the primary ovarian tumors, their peritoneal implants,
and subsequent low-grade carcinomas.
Such information will begin
to blur the differences between the
"splitters" and the "lumpers."
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