Author Affiliations: Department of
Surgery, Indiana University School of Medicine, and Surgical Service,
Roudebush Veterans Affairs Medical Center, Indianapolis.
Risk-reducing bilateral salpingo-oophorectomy (RRBSO) and risk-reducing
mastectomy are widely used for BRCA1 and BRCA2 mutation carriers to reduce the risk of ovarian
and breast cancer. To our knowledge, no risk-reduction therapy has
addressed the BCRA1/2 carrier lifetime risk
of intra-abdominal peritoneal carcinoma from an appendix source. We
identified a BRCA1 carrier in a hereditary
breast and ovarian cancer kindred who developed a low-grade malignant
appendiceal mucocele 2 years after risk-reducing salpingo-oophorectomy.
Our retrospective meta-analysis assessed the risk of intraperitoneal
appendiceal cancer in BRCA1/2 carriers after
RRBSO to determine whether elective risk-reduction appendectomy could
reduce the incidence of intraperitoneal cancer. Data sources included
the case report and 12 reports of BRCA1 and BRCA2 carriers after RRBSO with ovarian, fallopian
tube, breast, and peritoneal cancer published from January 1, 1985,
through April 30, 2012. Main outcome measures were nonovarian, non–fallopian
tube, nonbreast, positive intra-abdominal peritoneal carcinoma in
previously cancer-free BRCA1/2 carriers after
RRBSO. The source of intraperitoneal cancer in BRCA1/2 carriers after risk-reducing salpingo-oophorectomy is highly likely
the appendix. Use of risk-reduction appendectomy with RRBSO in younger BRCA1/2 carriers may reduce lifetime risk of malignant
tumor and eliminate intraperitoneal cancer.
The well-documented penetrance of ovarian cancer (OC) in BRCA1 (OMIM 113705) mutation carriers is 11% to 54%, and the OC penetrance
in BRCA2 (OMIM 600185) carriers is 11% to 23%.1- 5 Clinical therapy for OC prevention has progressed to routine use
of risk-reducing bilateral salpingo-oophorectomy (RRBSO) in women
with hereditary breast cancer and OC (HBOC) kindred.3,4 Risk-reduction operative
ablative procedures have been reported in more than 8000 women resulting
in reduction of risk of OC in HBOC kindreds by 80%.6 Multiple studies have noted that BRCA1/2 carriers after BSO retain a lifetime risk
of intraperitoneal cancer from 1% to 10%.7,8 The peritoneal cancer occurrence
in BRCA1/2 cohorts presents an unknown, unanswered
mortality question related to the pathologic origin site of the intraperitoneal
tumor: ovarian or fallopian tube or gastrointestinal (GI) intra-abdominal
primary sites remain the most common suggested sources.
An element of diagnostic difficulty is using only histologic
examination in determining the primary organ source of malignant tumor
intraperitoneal carcinomatosis. On the basis of the histology of intraperitoneal
cancers, the primary site has been reported to be an ovary, a fallopian
tube, or the appendix and other possible GI sources, such as the colon,
stomach,bile duct, or pancreas.9 All
the peritoneal cancers from GI sources have been documented to produce
histologically quite similar serous intraepithelial mucoid cells.
The appendiceal source of low-grade mucoid tumor follows a clinical
course of origin and growth within the appendix progressing to appendiceal
rupture and peritoneal surface dissemination with carcinomatosis,
which has been called pseudomyxoma peritonei (PMP) for decades.10- 16 Many published reports17- 20 of intraperitoneal cancer occurrence in BRCA1/2 cohorts suggest that after RRBSO a pathology laboratory analysis
error has occurred.
The multiple primary cancer sites associated with BRCA1/2 carriers result in lifetime cancer risk for HBOC kindred
of 85% compared with 38% in the general population.21,22
The current case report of BRCA1 HBOC
kindred developing a low-grade malignant appendiceal mucocele 2 years
after RRBSO is notable. The clinical presentation reveals an unsuspected
malignant appendiceal mucocele before rupture without intraperitoneal
dissemination. This case is an example of a potential major cause
of intraperitoneal cancer in BRCA1 mutation
carriers in which rupture of the appendix results in PMP. This clinical
case prompted a retrospective meta-analysis literature review to assess
the relationship of BRCA1/2 mutation carriers
after RRBSO and risk-reducing bilateral mastectomy (RRBM) who develop
intraperitoneal cancer and to determine whether elective risk-reduction
appendectomy would reduce the residual intraperitoneal cancer risk
in female BRCA1/2 carriers.
To estimate the risk of nonovarian, non–fallopian tube,
primary appendix origin of intraperitoneal cancer in BRCA1/2 mutation carriers, a review of published studies of BRCA1/2 cohorts was conducted. The review yielded
12 nonoverlapping studies reporting the incidence of intraperitoneal
cancer. These studies23- 34 included BRCA1/2 carriers after RRBSO
and RRBM with no history of breast, ovarian, fallopian tube, or uterine
cancer. These studies form the basis of a meta-analysis estimate of
intraperitoneal cancer risk from a suspected primary appendiceal source
in BRCA1/2 carriers who were documented to
be free of all other primary cancer sites.
The Indiana University institutional review board provided expedited
approval of the study (full review of case studies and meta-analyses
is not required by this board). Methods and case report clinical data
were obtained, de-identified from hospital records of the BRCA1 patient and her HBOC kindred.
Intraperitoneal cancer primary site of origin is a diagnosis
of exclusion reached by a process of elimination, which is the method
used to identify the intraperitoneal cancer source of the highest
probability. The method of elimination is iterative. The possible
primary site of origin of intraperitoneal cancer in every patient
considered for enrollment in this meta-analysis was identified. Every
case enrolled from published cohorts into the present meta-analysis
had established resections of several primary sites (breast, ovary,
fallopian tube, and uterus), thus eliminating these as primary site
possibilities. This left only 4 intra-abdominal sites of intraperitoneal
cancer: appendix, colon, GI tract, or pancreas. The latter GI sources
(colon, GI tract, and pancreas) cannot be accepted as probable primary
sites with no primary organ mass and no symptoms, which leads to greater
than 99.99% diagnosis before classification as intraperitoneal cancer.
Any BRCA1/2 mutation carrier reported to
have colon, gastric, or pancreatic cancer was excluded from the analysis.
Meta-analysis patient-specific clinical data were extracted
from the case report, and 12 reports published from January 1, 1985,
through April 30, 2012, were obtained from a PubMed search23- 34 of BRCA1/2 mutation carriers followed
up after RRBSO and/or RRBM who developed peritoneal cancer.
Cohort studies and prospective studies with retrospective elements
were reviewed, and the case familial series report was included. The
basic design of the 12 published studies used to extract data was
that of a prospective cohort study of BRCA1 and BRCA2 female carriers. The case report
qualified as a familial cohort series. Randomized control trials were
excluded. The major effect of pathologic determination within any
reported cohort series was derived from specific data on individual
patient cancer site identification, and there was no overlap with
Length of follow-up by definition was more than 5 years after
RRBSO and/or RRBM in order to have a patient develop intraperitoneal
cancer with no risk of peritoneal metastatic cancer from these common
sources. This study used process of elimination to lead to a conclusion.
All other consensus primary-origin sites of intraperitoneal cancer
(of the breast, uterus, fallopian tube, ovary, pancreas, colon, and
stomach) were methodically excluded from any patient included in this
The method used an extensive limitation of inclusion criteria.
The “extraction criteria” eliminated all other consensus-accepted
primary pathologic sources of reported intraperitoneal cancers in
female patients. This method assumes that breast, ovarian, fallopian
tube, uterine, pancreatic, colon, or stomach primary cancer had been
identified and reported in the manuscripts used in the meta-analysis.
For the published studies to be accepted in this meta-analysis, all
cancer sources in all patients had to be reported. In publications
accepted into the meta-analysis, all breast, ovarian, and fallopian
tube cancers found in resected tissues in the patients were reported,
and these specific patients were excluded from the analysis. Only
previously cancer-free patients and those with intraperitoneal cancer
with no other primary-site cancer identified were extracted from series
for inclusion in this study. All reports of any other cancer site
or mortality from all other causes resulted in exclusion of the patient
from the current meta-analysis.
A meta-analysis estimate of risk and mortality reduction was
stratified by BRCA1 and BRCA2 mutation status, intraperitoneal carcinoma incidence,
sex, OC status, breast cancer status, other cancer site status, and
age to evaluate the risk and benefit of a novel intraperitoneal cancer
risk-reduction strategy: elective appendectomy. The analysis cohort
was restricted to women, and all cases of OC or breast cancer of any
stage identified before or after RRBSO were excluded. Also, all patients
with any other cancer present before or at the time of RRBSO and/or
RRBM were excluded. Therefore, all patients with extraperitoneal cancer
or with intraperitoneal cancer that could represent OC or breast cancer
or fallopian tube cancer progression were excluded.
Statistical modeling used data censoring and Cox proportional
analysis and has been widely used in BRCA studies.35 Data censoring was performed
to remove variables and narrowed to a specific variable (intraperitoneal
cancer) assessment over time variable before applying Cox proportional
Hazard ratio estimates were identified directly from data extracted
from the original articles. Pooled results were computed from nonconcurrent
studies by fixed-effects meta-analysis.37 Intraperitoneal cancer incidence was calculated directly from extracted
data by age, mutation-type cohort, and other-site “cancer-free”
status. The hazard ratio analysis using Cox proportional hazard risk
was performed comparing risk of intraperitoneal cancer occurrence
in each specific group: all BRCA1 carriers
and all BRCA2 carriers, and all female BRCA1 plus BRCA2 carriers.
Also, hazard ratio analysis of censored longitudinal data of intraperitoneal
cancer in patients with BRCA1, BRCA2, and BRCA1/2 was determined
by unpaired t test.38
A 44-year-old woman presented with a 40-day history of increasing
right lower quadrant abdominal pain. Her medical history was significant
for RRBSO and risk-reducing mastectomy as a carrier of BRCA1 mutation 2 years before this presentation. Both her
mother and sister were kindred BRCA1/2 carriers
who had developed OC. The patient did well after RRBSO. Subsequently,
evaluation of the new abdominal pain included a computed tomographic
scan that demonstrated a large appendiceal mass. At exploratory laparotomy,
she was found to have an appendiceal mass, which was resected with
appendectomy and partial cecectomy. This was malignant. Pathologic
evaluation revealed a nonperforated, low-grade, mucinous appendiceal
neoplasm with negative colonic margins and no nodal involvement in
the 5 lymph nodes evaluated. The patient was discharged 24 hours after
the operation and has done well in 1 year of follow-up. The case reveals
the clinical presentation of an unsuspected appendiceal mucocele before
progression to intraperitoneal cancer in a BRCA1 mutation carrier from a well-documented HBOC kindred.
The meta-analysis estimates of risk of primary peritoneal cancers
for HBOC kindred women with no breast, no ovarian, and no fallopian
tube cancers after RRBSO, by age and mutation type, are presented
in Table 1. The risk of peritoneal
cancer following RRBSO was significantly higher for BRCA1 mutation carriers than for BRCA2 mutation carriers (11.6% vs 0.9%; P < .01)
(Table 1). Also notable is
that intraperitoneal cancer incidence increased with age. There was
0% risk before age 40 years. No case of intraperitoneal cancer in BRCA1/2 cohorts younger than 40 years was reported.
The annualized BRCA1 carrier intraperitoneal
cancer hazard risk of 0.06% rose from the youngest reported case (age
42 years) in a cumulative fashion, which summed to 5% per decade after
the fifth decade of life (40-49 years of age). The cumulative hazard
rate reached 11.6% penetrance after the seventh decade (Figure). This represents 30 years of
exposure after age 40. This steady increase in intraperitoneal cancer
correlation with age may relate to increased occurrence due to timeline
exposure or due to years' delay in clinical presentation. Hazard risk
analysis revealed 6.8% annualized risk in BRCA1 carriers older than 40 years and 0.5% risk in BRCA2 carriers older than 40 years. Total BRCA1/2 carriers have 6.7% annual hazard risk of intraperitoneal
cancer (Table 2).
Figure. Intraperitoneal cancer cumulative
incidence in BRCA1 carriers.
Statistical modeling predicts that widespread use of elective
risk-reduction appendectomy in HBOC kindred BCRA1 mutation carriers combined with early RRBSO would result in 99%
reduction of the lifetime risk for intraperitoneal cancer. Risk-reduction
appendectomy would not reduce peritoneal cancer if the source were
gastric, biliary, pancreatic, or other colonic sites as typically
found in other familial cancer cohorts, such as familial adenomatous
polyposis. Risk-reduction appendectomy, when combined with RRBSO and
risk-reducing mastectomy, may also complete a “trifecta”
resulting in an 80% reduction of total lifetime cancer risk.
The BRCA1/2 mutation carries a 1000-fold
increased risk of peritoneal cancer compared with the risk in the
general population. Also, BCRA1 mutation
carries a specific 11.6% lifetime risk of intra-abdominal peritoneal
cancer. Aging increases the risk of peritoneal cancer in BRCA1/2 mutation carriers. This study indicates
that age greater than 40 years carries a 1000-fold increased risk
of mucinous peritoneal cancer in HBOC kindred women. In BRCA1 carriers, aging steadily increased the risk of intraperitoneal
cancer by 0.5% per year after the age of 40 years was reached (Figure). The cohort of women with BRCA1 mutations who are older than 40 years have
a significantly increased incidence of intraperitoneal cancer compared
with the general population.
Women who carry the BRCA1 and/or BRCA2 genetic mutations have a well-documented
increased risk of breast, ovarian, and fallopian tube cancers. Individual
lifetime OC risk is estimated to range from 36% to 63% but is elevated
to 95% if both maternal and sibling BRCA1 carriers have already developed OC.39 Additional cancer risk has also been reported to include an increased
association of intra-abdominal peritoneal malignant tumors with OC.40 Some highly selective BRCA1/2 cohort studies based on primary therapy RRBSO in young
patients and brief follow-up with or without chemotherapy report a
low incidence of intraperitoneal cancer.41 Other larger, longer-term studies have identified peritoneal carcinomatosis
in 2% to 3% of BRCA1/2 HBOC kindred cohorts
after RRBSO with no prior OC diagnosis.23- 34
Multiple studies have observed that female carriers of BRCA1 or BRCA2 germline
mutations are at an increased risk of developing breast, ovarian,
salpingo-fallopian tube, and/or peritoneal malignant tumors. Management
strategies for genetically susceptible women include genetic counseling,
chemoprevention, radiologic and tumor-marker surveillance, and risk-reducing
surgery, such as mastectomy and bilateral salpingo-oophorectomy.42
Identification of the source organ in intraperitoneal cancer
is frequently inaccurate because the pathology nomenclature classification
includes primary papillary serous carcinoma of the peritoneum with
no identification of the primary organ site. Papillary serous carcinoma
of the peritoneum is considered a rare tumor found predominantly in
elderly and postmenopausal women. Papillary serous carcinoma of the
peritoneum has histologic characteristics similar to serous ovarian
papillary carcinoma, serous fallopian tube cancer, and PMP arising
from the appendix.43- 45 These
histologic similarities render an extracorporeal pathologic identification
of organ origin site quite difficult, with primary site investigation
limited to radiologic imaging and histologic analysis without pathologic
examination of the primary organ site following excision or resection.
Although the pathogenesis of papillary serous carcinoma of the peritoneum
remains unclear, documentation or exclusion of GI sources has not
been complete. Several published familial studies46,47 have included peritoneal
carcinoma in the HBOC syndrome, which also includes breast, ovarian,
and fallopian tube neoplasms.
Many published reports16- 19 of intraperitoneal cancer in BRCA1/2 cohorts
suggest that occurrence after RRBSO indicates that a pathology laboratory
analysis error has occurred. The possible errors include that OC or
fallopian tube cancer was not found or that cancer was missed owing
to a sampling error or poor pathology processing. The diffuse peritoneal
cancer primary source of origin has commonly been suggested to be
an ovary, a fallopian tube, or the appendix (PMP) or to be a pancreatic
intraductal papillary mucinous neoplasm, or a low-grade colonic mucoid
epithelial tumor.48 The total cancer
risk for a BRCA HBOC kindred is increased
for gastric cancer, gallbladder and biliary tract cancer, and melanoma.
Multiple other primary sites of metastatic intraperitoneal mucoid
epithelial serous cancers may originate from GI sources. Low-grade,
mucinous, adenomatous, intraperitoneal colon cancer syndromes include
Lynch syndrome, familial adenomatous polyposis, attenuated familial
adenomatous polyposis, MYH -associated polyposis,
familial colon rectal cancer, Peutz-Jeghers syndrome, juvenile polyposis
syndrome, hereditary mixed polyposis syndrome, and hyperplastic polyposis
syndrome.49- 57 The BRCA1/2 gene mutations have never
been linked to any of these syndromes nor has BRCA1/2 been directly linked to colon cancer except in 1 case report.58 Also, no ovarian,breast, or fallopian tube
cancers have been reported in any of the colon cancer syndrome cohorts.
Many studies have identified multiple variable genetic expressions
in histologically similar or identical tumors in appendiceal and ovarian
tumors. The incidence of appendiceal cancer is rare, occurring in
less than 0.5% of all general population GI tumors.59 Appendiceal mucocele incidence is reported
to occur rarely, in less than 0.3% of all appendectomies, and occurs
in less than 0.0001% of the general population based on data about
lifetime risk from the Surveillance, Epidemiology, and End Results
program of the National Cancer Institute.60,61 These tumors may represent
appendiceal tumors, which progress to locoregional peritoneal carcinomatosis,
which is characteristic of PMP. Most intra-abdominal tumors in OC
patients are reported as low-grade, mucinous, intraperitoneal cancers.
A mucocele is characterized by the accumulation of mucoid material
in the appendiceal lumen. The designation of mucocele has been proposed for a neoplasm that is pathologically benign,
premalignant, or malignant. Epithelial appendiceal tumor histology
has been classed as 4 types: (1) a simple appendiceal mucocele, (2)
a mucocele with epithelial hyperplasia, (3) a cystadenoma, and (4)
a cystadenocarcinoma.62,63 The latter 2 are more aggressive neoplasms. Dissemination of neoplastic
cells producing mucoid material in the abdominal cavity typically
occurs following appendiceal perforation, which results in PMP. This
has been reported in 10% to 15% of appendiceal epithelial tumors.
Metastatic dissemination of appendiceal low-grade epithelial tumors
by vascular or lymphatic invasion has not been reported. These appendiceal
benign or malignant proliferative pathologic features either can remain
asymptomatic for a lifetime or present clinically with abdominal pain
associated with intraperitoneal volume space reduction due to increasing
tumor volume. The most common initial clinical manifestation is pain
in the right iliac fossa. The appendiceal epithelial proliferative
pathology diagnosis is most frequently based on intraoperative observation
without histologic evaluation.
To our knowledge, this report presents the first case of a documented
HBOC kindred BRCA1 carrier presenting with
an appendiceal mucocele tumor 2 years after RRBSO before developing
PMP. This analysis provides strong clinical evidence that BRCA1 mutation carriers older than 40 years carry
an additional 11% lifetime risk of appendiceal mucinous neoplasm,
which is the most likely source of reported intraperitoneal cancer
in BRCA1 and BRCA2 carriers. The data also strongly suggest that appendiceal tumors
are the predominant source of intraperitoneal cancer in BRCA1/2 mutation carriers who have undergone RRBSO and have
no fallopian tube cancer or OC.
Treatment of appendiceal tumor is excision appendectomy. Appendectomy
is curative for a simple appendiceal mucocele, for an appendiceal
mucocele with epithelial hyperplasia, and for cystadenoma with an
intact appendiceal base; cecal resection is indicated for cystadenoma
with appendiceal base involvement or invasion.64 Right hemicolectomy remains the elective
oncologic staging and treatment for appendiceal cyst adenocarcinoma.
Elective appendectomy carries no risk of functional loss and total
operative risk of less than 0.01%.62,65 Elective appendectomy
performed during RRBSO would not result in significant complications
specifically related to appendectomy.66
These facts, the strong statistical correlation of appendiceal
mucinous peritoneal malignant tumor with OC, and the increased risk
of intra-abdominal carcinomatosis in BRCA1 carriers support the proposed clinical treatment mandate of risk-reduction
surgery to include prophylactic elective appendectomy with RRBSO in
all BRCA1 carriers older than 40 years.
This meta-analysis confirms that BRCA1/2 mutation carrier cohorts older than 40 years have significantly
increased incidence and risk of intraperitoneal cancer compared with
the general population. The BRCA1 mutation
carrier has a 6.8% annualized cumulative hazard risk of intraperitoneal
cancer compared with a 1% risk in BRCA2 carriers.
The BRCA1 risk of 11.6% is increased 1000-fold
above that of PMP or other intraperitoneal cancer risk in the general
population, whose risk is 1 in 100 000 (0.001%). Based on the
hazard risk assessment, the addition of risk-reduction appendectomy
to RRBSO and RRBM in the cohort of women older than 40 years with BRCA1 or BRCA2 mutations
is predicted to reduce the annual 6.7% risk of intraperitoneal cancer.
This may also contribute a 12% total reduction in lifetime malignant
tumor risk after eliminating the breast, fallopian tube, ovary, and
appendix as intraperitoneal cancer primary source risks. The statistical
model predicts that widespread use of risk-reduction appendectomy
with RRBSO and risk-reducing mastectomy in HBOC kindred BCRA1 mutation carriers would result in a 99% reduction of
the lifetime risk for peritoneal cancer and also lower total lifetime
cancer risk from 95% to 20%.
Correspondence: James V. Sitzmann,
MD, Surgical Service (112), Indianapolis Veterans Affairs Medical
Center, 1001 W 10th St, Indianapolis, IN 46202 (email@example.com).
Accepted for Publication: September
Author Contributions:Study concept and design: Sitzmann. Acquisition
of data: Sitzmann. Analysis and interpretation
of data: Sitzmann and Wiebke. Drafting of
the manuscript: Sitzmann and Wiebke. Critical
revision of the manuscript for important intellectual content: Sitzmann and Wiebke. Statistical analysis: Sitzmann. Administrative, technical, and material
support: Sitzmann and Wiebke. Study supervision: Wiebke.
Conflict of Interest Disclosures: None
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