Controversies surrounding ovarian
tumors of low malignant
potential (LMP) largely arise
from gaps in our understanding of
their etiology and biology, as well as
the lack of effective adjuvant therapy
for the small proportion of patients
who experience progressive disease.
These gaps in knowledge have also led
to confusion in nomenclature.
These tumors have been called "ovarian
tumors of low malignant potential,"
based on the observation that
most are associated with a benign
prognosis, "borderline ovarian tumors,"
based on the faulty premise that
they represent an intermediate stage
between benign ovarian tumors and
frank epithelial carcinoma, and "atypical
proliferating tumors," a more recent
title introduced to escape from the
cancer mindset associated with the
terms "borderline" and "malignant."
Recent developments in molecular
biology suggest that what we call "epithelial
ovarian carcinoma" really represents
a potpourri of different histologies,
each with a differing etiology,
molecular biology, prognosis, and response
to therapy.[2,3] Similarly, both
clinical and laboratory reports suggest
that ovarian tumors of LMP represent
a "grab bag" of tumors, again with
different etiologies, molecular biologies,
and prognoses. LMP tumors
do not appear to represent an intermediate
stage between benign ovarian
epithelium and carcinoma. To date,
however, the lack of consensus among
gynecologic pathologists as to the appropriate
nomenclature of the various
subtypes has hampered communication
among investigators. In addition,
in many reports, the diagnoses have
been based on light microscopy, with
variable use of molecular biology for
more specific characterization.
Another pathologic controversy
centers on the role of "invasive" vs
"noninvasive" peritoneal implants. Several
retrospective reports suggest that
the presence of "invasive" implants
conveys a worse prognosis.[6-10] To
date, however, gynecologic pathologists
have not been able to reach a consensus
as to what histopathologic features
denote invasion. We would argue
that the presence of invasion signifies
a primary peritoneal carcinoma,
rather than a tumor of LMP.
Yet another controversy swirls around the origin of mucinous ovarian
tumors associated with pseudomyxoma
peritonei. Recent developments
suggest that the majority of these cases
are associated with a primary tumor
in the appendix or elsewhere in the
gastrointestinal tract.[11,12] We concur,
and would recommend removing
this group of intra-abdominal tumors
from the larger classification of ovarian
Several groups have also argued
that certain ovarian tumors with
"micropapillary"features are associated
with a higher rate of disease progression.[
13-15] The term "micropapillary
serous carcinoma" has been
proposed for this subset of tumors,
again removing them from the category
of ovarian LMP tumors. To
date, however, this delineation has not
been universally accepted.
Data on the incidence of LMP tumors
should not be considered particularly
reliable. Published incidence data
stems from both population-based tumor
registries and single-institution series.
In most cases, the reports from
population-based registries have not
included central pathology review. We
do not know whether changes in
awareness of this entity may have affected
reported changes in incidence,
nor how reliable pathologists are in
making this diagnosis.
Moreover, cancer registries have
not routinely collected information on
benign ovarian tumors, a category in
which ovarian tumors of LMP are
sometimes included. The Surveillance,
Epidemiology, and End Results
(SEER) Program of the National Cancer
Institute (NCI), for example,
stopped collecting data on LMP tumors
in 1997. Comparison between
institutional series has been difficult,
as individual pathologists have often
used different diagnostic criteria for
different subtypes of LMP tumors.
Ovarian tumors of LMP have been
reported among Caucasian, black African,
Chinese, Japanese, and Indian
populations. Among populations
that are predominantly Caucasian, they
appear to comprise from 4% to 14% of
all ovarian neoplasms. Shi et al have
reported that the ratio of borderline epithelial
ovarian tumors to epithelial carcinomas
in China is 1:5.9, with a similar
incidence of mucinous and serous
tumors of LMP. Harlow et al
survyeyed ovarian tumors in western
Washington State between 1975 and
1983. They found that the incidence
of ovarian tumors of LMP was 26.2 per
million women per year in the white
population and 16.5 per million women
per year in the nonwhite population.
They also noted an increase in the incidence
of serous and mucinous tumors
of LMP from 7.1 per million women
per year to 39 per million women per
year between 1975 and 1983.
As with incidence, collective data
on prognosis is hardly robust, as it is
largely based on population-based
cancer registries without central pathology
review or predominantly retrospective
institutional series with inconsistent
pathologic criteria between
institutions. In addition, some reports
lump all LMP patients together, while
others split off the most common subtypes
(serous and mucinous). Nonetheless,
the vast majority of reports
indicate that most of these tumors convey
a benign prognosis, particularly if
patients with mucinous tumors of gastrointestinal
origin or primary peritoneal
cancers are excluded.
Data from the NCI's SEER program,
for example, which tracked
2,818 women, showed a 10-year relative
survival of 97% for women with
stage I ovarian tumors of LMP, 90%
for those with stage II, 88% for those
with stage III, and 69% for those with
stage IV. Similarly, Bjorge et al
found 93% 5-year survival for women
diagnosed with LMP tumors in Norway
between 1970 and 1993.
Seidman and Kurman summarized 97
reports, which included 4,129 serous
tumors of LMP. They calculated
the overall disease-specfic survival
rate, with a mean follow-up of 7 years,
to be 99% for women with stage I disease and 95% for women with stage III
disease. Zanetta and colleagues found
disease-free survival to be 99% for 277
women with stage I disease, 96% for
24 women with stage II disease, and
89% for 28 women with stage III
disease, with a mean follow-up of
We observe different patterns in epidemiology
between ovarian tumors of
LMP and epithelial ovarian cancer.
The most common inherited predilections
for epitheial ovarian cancer-
namely BRCA1 and BRCA2 mutations,
and hereditary nonpolyposis colorectal
cancer (HNPCC)-do not appear to increase
the risk of LMP tumors. The
use of fertility drugs appears to increase
the risk of LMP tumors but not ovarian
carcinomas.[25,26] LMP tumors
are more common among younger
women, whereas epithelial ovarian
tumors are more common among
older women. On the other hand,
factors that reduce the number of ovulations
and increase exposure to
progestins-ie, pregnancy, lactation,
and the use of oral contraceptives-do
decrease the risk of both LMP tumors
and epithelial ovarian carcinomas.
The absence of an effective screening
test or algorithm for epithelial ovarian
cancer is well known. Similarly, no
pattern of tumor marker expression or
imaging study has been shown to reliably
predict ovarian tumors of LMP or
to distinguish between ovarian cancer
and LMP tumors. CA-125 can be elevated
in serous tumors of LMP but is
generally not elevated with mucinous
tumors of LMP. Ovarian tumors of LMP
share the same presenting symptoms as
those of any ovarian enlargement, benign
or malignant. In general, the most
commly reported symptoms are abdominal
discomfort, abdominal pain,
and/or a feeling of abdominal enlargement
or sensation of a mass.
The diagnosis of an ovarian tumor
of LMP is best made on permanent
section, after inspection of representative
slides prepared from an ovarian
tumor as well as other intra-abdominal
and retroperitoneal samples. Consultation
with a pathologist with expertise
in the diagnosis of ovarian
malignancies may be helpful. Frozen-
section diagnosis of an LMP tumor
is often unreliable.[30-33] The
operating surgeon, therefore, is often
told that a tumor is "at least LMP." He
or she must then make intraoperative
decisions with the knowledge that the
final diagnosis may be LMP or invasive
Preoperative counseling remains
critically important. One must explore
with a patient and her family her desire
for future fertility and to retain
normal tissue. As noted above, LMP
tumors are more common among
younger women. The gynecologic surgeon
should, therefore, consider conservative
management for LMP tumors.
A review of treatment patterns
in the US found that half of women
less than 40 years of age undergo conservative,
when diagnosed with an ovarian tumor
It may be appropriate in certain instances
to plan a second surgical procedure
once final pathology is available.[
34] If an individual with appropriate
training in the operative and
clinical management of ovarian cancer
is not available when an LMP tumor
is diagnosed, then a second operation
should be scheduled when a
gynecologic surgeon with the relevant
expertise is available.
expertise is available.
Nonetheless, certain principles of
gynecologic oncology should be observed.
First, these patients need a
complete exploration of the pelvis and
abdomen. Any suspicious lesions
should be biopsied or removed. Surgical
staging should be performed,
with conservation of the uterus and
contralateral tube and ovary as indicated.[
35] Women who undergo ovarian
cystectomy are at greater risk for
tumor persistence or recurrence than
those who undergo oophorectomy. A
laparoscopic approach may be appropriate,
as long as the operator has expertise in both laparoscopic techniques
and the operative management of gynecologic
Postoperative Adjuvant Therapy
To date, no adjuvant therapy-
whether chemotherapy, hormonal
therapy, or radiation therapy-has been
shown to prolong survival in women
with LMP tumors. This observation has
held true both in the few prospective
trials completed as well as in the many
retrospective reports.[16,38,39] The 1994 National Institutes of
Health Consensus Statement on Ovarian
Cancer concluded that adjuvant
chemotherapy was not of benefit to
women with ovarian tumors of low
malignant potential. As mentioned
above, however, these women should
undergo complete surgical exploration
and staging to rule out the diagnosis
of a primary peritoneal cancer.
As noted earlier, several retrospective
reports suggest that women with
"micropapillary carcinoma"-a subset
of patients who have been grouped
with LMP tumor patients in the past-
are at high risk for recurrence and
progression.[13-15] Even these micropapillary
tumors, however, are relatively
indolent; they have limited response
to the standard chemotherapeutic
agents we use for epithelial ovarian
Several groups of investigators
have sought to identify progostic
markers that might identify LMP tumor
patients at high risk for disease
progression. Markers identified to date
in single-institution, retrospective
studies include DNA ploidy, p53
overexpression, MIB1, and histomorphometry.[
41-44] However, none
of these have been validated in prospective,
Risk of Malignant
The risk of malignant transformation
of LMP tumors is controversial.
Kurman and Trimble summarized 22
studies, including 953 women with
serous LMP tumors, and found a risk of malignant transforation of 0.7%,
similar to the risk of malignant transformation
of uterine leiomyomata.
They excluded from this analysis
women with invasive peritoneal implants
at time of diagnosis. Crispens
et al, however, found that 36 of 49
patients with recurrent LMP tumors
had low-grade serous carcinomas at
the time of recurrence. This
retrospective series ran from 1956 to
1997; many patients did not have
definitive surgical staging at the time
of initial diagnosis. We suspect that
the vast majority of cases in which the
malignant transformation of an LMP
tumor has been posited actually reflect
either a primary peritoneal cancer
missed at initial diagnosis or a
new ovarian or primary peritoneal
Therapy for Progressive Disease
Surgical debulking remains the
mainstay of treatment for the few
women who experience disease progression.
Ovarian tumors of LMP,
even those that progress, are generally
so indolent that they do not respond
to standard chemotherapeutic agents.
That said, experimental cytostatic or
biologic regimens should be considered
in this setting.
Women who undergo conservative
surgery are at risk for persistent or progressive
disease. They should be counseled
regarding this risk. Zanetta et al
have reported on a small series of 24
women who underwent conservative
surgery. They found that transvaginal
ultrasound was more sensitive
than physical examination or CA-125
in diagnosing recurrences. In their series,
18 of 19 women found to have
recurrences had an abnormal adnexal
mass on ultrasound.
Pregnancy After Diagnosis
Numerous retrospective reports
suggest that women who undergo
pregnancy after the diagnosis of an
LMP tumor do not increase the risk of
tumor progression.[48-52] We should note, however, that these women are
at risk for the presence of persistent
LMP disease at the time of cesarean
section, laparoscopy, or hysterectomy
after completion of childbearing.
There have also been case reports
documenting the use of in vitro fertilization
among women with a history
of an ovarian tumor of LMP.
Therapy After Diagnosis
We have scant data regarding the
safety of hormonal replacement
therapy (HRT) after the diagnosis of
an LMP tumor. Prospective clinical
trials evaluating the safety of HRT are
not feasible, given the low baseline
risk of progression, the relatively low
incidence of LMP tumors, and recent
studies demonstrating the limited
health benefits of HRT. A woman who
has acute menopausal symptoms as
well as a diagnosis of an LMP tumor
should be considered for HRT.
She should be counseled, however,
about the absence of data supporting
the safety of HRT in this clinical
Future Directions for Research
We need to go beyond light microscopy
to molecular biology to characterize
ovarian tumors of LMP. In this
instance, classifications will be more
useful with further "splitting" rather
than "lumping." Once we have defined
the molecular biology of these tumors,
then we need to identify both prognostic
markers, to help identify women
at risk for progression, and targets for
Once we have identified therapeutic
targets, then we need to develop and
test interventions in the appropriate
patient populations. Given the small
number of women who may benefit
from postoperative adjuvant therapy,
as well as the small number of women
who experience progression of
disease, we will need to set up multiinstitutional
phase II trials for such
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