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D D
James M. Church
INTRODUCTION
Desmoid disease is a benign proliferation of broblasts that produces
a spectrum of manifestations from rapidly growing tumors to indolent nodules and at sheets of tissue that distort surrounding organs.
Although desmoid disease occurs in the general population, it is rare and
generally aects limbs and limb girdles. Colorectal surgeons encounter
it in the abdomen, where it is usually associated with familial adenomatous polyposis (FAP). In this context, desmoid disease can cause many
dierent problems because of its eects on surrounding organs and its
mass eect. In this chapter, desmoid disease in FAP will be discussed.
BIOLOGY
e abnormal proliferation of broblasts that is desmoid disease
occurs because the growth-controlling function of the wnt/wingless
signal transduction pathway has been lost. In sporadic desmoids, this
phenomenon is related to a mutation in CTNNB1, the gene coding for
β catenin. β catenin is a cytoplasmic protein that enters the cell nucleus
and stimulates downstream activation of a series of genes that produce
growth-stimulating proteins. APC is a cytoplasmic protein that acts as
a complex with other proteins (GSK and Axin) to degrade β catenin
and prevent activation of nuclear growth pathways. In FAP, one allele
of APC is dysfunctional because of a germline mutation. e stimulus
for the loss of the second allele in the broblasts of patients with FAP
seems to be surgical trauma, which also activates the scarring process.
Uncontrolled broblast growth initiates desmoid tumors.
EPIDEMIOLOGY
Desmoid disease is more common in women than in men by a two
to one margin. is characteristic suggests a role for estrogen is the
development and growth of desmoid disease, a suggestion that is
reinforced by the ndings that estrogen-modifying agents have some
success in treating desmoids and that pregnancy ameliorates the clinical course of desmoid disease.
e true incidence of desmoid disease in patients with FAP is dicult to estimate because desmoid reaction—the at, sheetlike desmoids
that occur in the mesentery—are dicult to detect on a computed
tomography (CT) scan and may even escape detection at laparotomy.
However, in a series of patients undergoing abdominal surgery for FAP
at the Cleveland Clinic, 3% had intra-abdominal desmoids at index surgery, whereas 31% had desmoid disease at a repeat operation. Approxi-
asymptomatic tumors and desmoid reaction had a similar risk of the
later development of clinically signicant desmoid disease.
In general, about 45% of FAP desmoid disease occurs in the
abdominal wall, 50% is intra-abdominal (mostly mesenteric or retroperitoneal), and 5% is extra-abdominal. Most desmoid disease arises
within 4 years of an abdominal surgery (80% of desmoids occur aer
abdominal surgery).
GENETICS AND DESMOID RISK
Quite an extensive body of literature maintains that desmoid disease
is more common in patients with 3′ mutations in APC. However,
recent data show that although desmoid incidence is independent of
genotype, desmoid severity is not independent of genotype. Desmoid
disease is more severe in patients with APC mutations 3′ (higher
than) of codon 1399.
Other risk factors for desmoid disease in FAP are a family history
of desmoid disease, female gender, and extracolonic manifestations
of Gardner syndrome (epidermoid cysts, osteomas, and extra teeth).
ese risk factors can be combined into a risk score that informs specialists about the advisability and timing of surgery (Table 58-1).
DESMOID SEVERITY: A STAGING SYSTEM
Desmoid disease varies in the eects it has on patients, from none
(asymptomatic, incidental) to lethal. Symptoms include pain and
pressure, and complications include bowel obstruction, ureteric
obstruction, tumor necrosis with abscess, erosion of the intestinal
wall with enteric stula, ureteric stula, and a superior mesenteric
artery aneurysm. e presentation and symptomatology of desmoid
disease varies from patient to patient and within each aected patient.
A staging system has been developed to allow easier comparison of
TABLE 58-1: Desmoid Risk Index
Factor 1 Point 2 Points 3 Points
Gender Male Female
Family history of
desmoid disease
Extracolonic mani-
festations (Gardner
syndrome)
Genotype 5′ of codon
4-6 points: low risk (5%)
6-8 points: medium risk (21%)
8-10 points: high risk (40%)
10-12 points: very high risk (>80%)
None 1 relative >1 relative
None 1 >1
400
Codon 400
to 1399
3′ of codon
1399
281
DesmoiD Disease282
patients and their disease, easier documentation of the disease progress, and rationalization of treatment (Table 58-2). is staging sys-
tem correlates with survival. Most patients with desmoid disease have
multiple tumors or multiple plaques. In any patient, the staging system is applied to the worst manifestation.
MANAGEMENT
Setting Expectations
Although some desmoids completely disappear, this outcome is not
a realistic expectation in most patients. Acceptable outcomes are
stabilization of previously growing tumors, shrinkage, or even just
resolution of symptoms. Medical treatment may soen tumors without aecting their dimensions, but this soening may be enough to
relieve a bowel or ureteric obstruction. Overall, about 12% of desmoid tumors resolve, about 7% grow relentlessly and are fatal, and
80% show variable or stable growth. Most patients live with their
desmoids. A pattern of decreasing symptoms with age is noticeable,
along with a denite benecial eect of pregnancy.
A Philosophy of Care
Because desmoid disease is not curable and no predictably eective
treatment is available, the management strategy is to use the least
toxic approach that has a realistic chance of working. Close followup, with scans every 3 to 6 months, allows new agents to be added
or substituted as necessary. Because repeated CT scans over time can
build up a signicant radiation dose, magnetic resonance imaging
scans should be used in young patients.
Extra-abdominal Desmoid Tumors
Extra-abdominal desmoids can occur anywhere and sometimes are
found in unusual sites such as the jaw, back, neck, and chest wall. When
they are found in children, treatment depends on the rate of growth
and symptoms. Asymptomatic tumors and those that are growing
slowly can be observed, although if they can be easily resected, this
option is reasonable. Large or rapidly growing tumors tend to be symptomatic and should be treated either with chemotherapy or surgery—
whichever seems to be less morbid and more likely to be eective. e
presence of extra-abdominal desmoid tumors in patients with FAP is
an indicator of risk for intra-abdominal tumors aer elective colectomy.
The earlier they are resected, the smaller the defect. The defect
can be closed with mesh. Sometimes portions of small intestine
have adhered to abdominal wall desmoids, and at times a segment
of intestine needs to be removed with the desmoid (Fig. 58-1).
Histologic margins are not always clearly definable, and there is
no evidence that an R1 margin leads to a higher risk of recurrence.
Resection with a gross margin of 1 cm is adequate. Abdominal
wall desmoids can be treated with medications, chemotherapy,
brachytherapy, external beam radiotherapy, or cryotherapy. However, when they can be excised without difficulty, what is the point
in using these other modalities?
Occasionally an abdominal wall tumor is continuous with a mesenteric desmoid (“transabdominal”). In this dicult situation, surgery should be avoided.
Intra-abdominal Desmoid Disease
Intra-abdominal desmoid disease is the most dicult problem in
patients with FAP. e disease tends to occur on or within the small
bowel mesentery or retroperitoneum, where it can be seen as a hard
white plaque or tumor that tethers and distorts the adjacent tissues,
including mesenteric vessels, bowel, and ureter. Desmoid disease
oen surrounds the superior mesenteric artery, making resection
impossible without depriving large amounts of small intestine of its
blood supply.
Workup
An abdominal CT scan or magnetic resonance imaging will show a
desmoid tumor and may even show whorls in the small bowel mesentery indicative of desmoid reaction (plaques). e appearance is
typical, and in a patient with FAP, a biopsy is not needed. Desmoid
disease oen occurs in multiple places within the abdomen, and
small desmoids may also be seen in the abdominal wall. One should
check for hydroureter and stage the desmoid (the initial stage relies
on history for estimation of the growth rate). In a person with multiple desmoids, the tumor with the worst stage represents the patient.
Medical Treatment
As a means of general support, nutrition should be optimized. If
the patient has nutritional decits, intravenous nutrition may be
needed. One should ensure that the gastrointestinal tract is free of
threatening lesions.
Stage I: No treatment or sulindac, 150 to 200 mg twice a day with
food.
Abdominal Wall Tumors
Abdominal wall desmoids usually can be resected without
sequelae other than the creation of a defect in the abdominal wall.
TABLE 58-2: Desmoid Staging System
Stage Size Growth Symptoms
I <10 cm None None
II <10 cm Slow (<50% in
3 mo)
III 10-20 cm Slow Moderate (e.g., small bowel/
IV >20 cm Rapid (>50%
in 3 mo)
Mild (e.g., some pain)
ureteric obstruction)
Life threatening (e.g., sepsis,
stula)
FIGURE 58-1 A resected mesenteric desmoid tumor with a loop of
small bowel attached. The superior mesenteric artery was preserved.
COLON 283
Stage II: Sulindac, 150 to 200 mg twice a day with food plus ralox-
ifene, 60 mg twice a day. Continue this treatment for 3 months
and then perform a repeat scan. If stabilization or shrinkage is
found, along with lessening of symptoms, the patient should
stay on the regimen for another 3 months and then a repeat
scan should be performed. If there is no response, chemotherapy should be considered.
Stage III: Administer chemotherapy with methotrexate and vi-
norelbine for one course and reassess the patient’s condition.
Continue treatment for 6 months if there is a response, and
then consider changing to sulindac and raloxifene. If no response occurs, consider administration of doxil, imatinib, or
sorenib.
Stage IV. Administer chemotherapy with doxil. If no response oc-
curs, consider administration of bevacizumab or cetuximab.
Role of Surgery
Surgery is a realistic option for many patients with intra-abdominal
desmoid disease. Patients who have a tumor distal in the mesentery
and away from the superior mesenteric artery are potential candidates. Such a tumor may be seen on a CT scan and may be able to
be judged by physical examination of the tumor, which should be
ballotable. A tumor can sometimes be removed with minimal loss of
small bowel. At laparotomy, if the tumor involves the superior mesenteric artery, resection must be abandoned and the default option
of medical treatment must be chosen. Recent data suggest that
recurrence rates aer an R0 or R1 resection of an intra-abdominal
desmoid tumor can be less than 50%. Some cases and small series
describe a successful small bowel transplant in patients with abdominal desmoid disease. As small bowel transplantation becomes more
routine, this option can be considered in severely symptomatic
patients whose tumors envelop the superior mesenteric artery. e
algorithms in Figures 58-2 and 58-3 provide a summary of desmoid
treatment pathways.
to desmoid-related adhesions, or to adhesions and internal hernias
unrelated to the desmoid disease. If the obstruction is symptomatic
or does not resolve with antidesmoid medications such as sulindac and raloxifene, a laparotomy is indicated. All obstructions can
be relieved by using the options of adhesiolysis, desmoid resection,
bowel resection, strictureplasty, bypass, or stoma. Patients unsuitable
for surgery may need total parenteral nutrition until more aggressive medical therapy has a chance to shrink the tumors or soen the
reaction.
Ureteric Obstruction
Ureteric obstruction occurs in about 30% of patients with intraabdominal desmoids. It is not easily correctable surgically because
the ureters become encased in retroperitoneal desmoid reaction
that is dicult to remove or liberate without loss of a segment of
ureter. erefore, the option of ureteric stents is best, with medical treatment of the desmoids in the hope that they will soen or
shrink. Progressive hydronephrosis with thinning of the renal
tissue can be managed by nephrostomy, nephrectomy, or renal
autotransplantation.
Abscess/Enterocutaneous Fistula
Sepsis arises in association with mesenteric or retroperitoneal desmoids and represents either erosion of the desmoid into a loop of
bowel, bowel ischemia due to obliteration of mesenteric vessels, or
desmoid necrosis, which also subsequently erodes into the bowel.
Bowel erosion can also cause hemorrhage from a deep mucosal ulcer. e sepsis must be controlled, usually by percutaneous
drains, bowel rest, and antibiotics. Once the situation is stabilized,
elective surgery can proceed. Usually the bowel is outlined preoperatively via a CT scan or contrast studies to ensure that there is no
distal obstruction and to get a sense of the place from which the
stula is originating.
Complications of Desmoid Disease
Small Bowel Obstruction
Small bowel obstruction is the most common complication of desmoid disease. is complication can be due to the desmoid itself,
Abdominal wall Intra-abdominal
Observe Sulindac
Stable Enlarging Stable Enlarging
Resect Resectable?
No Yes
Raloxifene Resect
FIGURE 58-2 An algorithm for approaching asymptomatic desmoid
disease in familial adenomatous polyposis.
Symptomatic desmoid disease
Abdominal wall Intra-abdominal
Resect Stage
II III IV
Resectable?
Yes No
Resect II Sulindac/raloxifene
III Methotrexate/vinorelbine
IV Doxil/Adriamycin
FIGURE 58-3 An algorithm for approaching symptomatic desmoid
disease in familial adenomatous polyposis.
DesmoiD Disease284
Superior Mesenteric Artery Aneurysm
A superior mesenteric artery aneurysm is a rare situation that is a
result of erosion of the arterial wall by the desmoid tumor. It can
present acutely with intraperitoneal bleeding. Sometimes the leaking
aneurysm can be stented; otherwise, surgery and a partial enterectomy are required.
Points about Operating on Persons with Desmoid Disease
1. Patient and tumor selection are key. For intra-abdominal disease,
one must ensure that the superior mesenteric artery is away from
the tumor to be resected. If not, a bypass can be performed, as
long as unobstructed downstream bowel is available.
2. Develop a sense for the anatomy of the gastrointestinal tract, especially relative to the desmoid disease. e anatomy must be clearly
dened before surgery.
3. Avoid an enterotomy, especially if you cannot be sure that the patient does not have a distal obstruction.
4. Be careful when dissecting at the site of the adhesion between the
mesentery and the desmoid. Dissecting too deep into the mesentery can cause bleeding and ischemic bowel, and dissecting too
deep into the desmoid can cause bleeding from the tumor.
5. Kinks in the bowel due to problematic and “unfreeable” adhesions
can be bypassed.
SUMMARY AND GENERAL COMMENTS ABOUT THE EFFECT OF DESMOID DISEASE ON SURGICAL STRATEGY IN FAMILIAL ADENOMATOUS POLYPOSIS
Desmoid disease is the second most common cause of death in
patients with FAP and causes symptoms in 15% of patients. No predictably eective medical treatment is available, and because of the
variety of presentations and its location in the abdomen, surgery is
dicult. Sometimes management of FAP in general is determined
by a “desmoidophobia”—that is, “What if a desmoid happens?” is
apprehension should be resisted because oen a desmoid doesn’t
arise, or when a desmoid does occur, it is relatively asymptomatic.
e primary goal of FAP treatment should be to prevent or treat
colorectal cancer and upper gastrointestinal cancer, with a secondary goal of preventing or managing desmoids. However, in a patient
with a high risk of desmoid disease, deferring prophylactic surgery
makes sense. Such high-risk patients oen have mild or attenuated
polyposis. Some data suggest that desmoids are more common
aer restorative proctocolectomy than aer ileorectal anastomosis, especially if the surgery is performed laparoscopically. is
nding is a consideration in patients who need a colectomy. However, the choice of operation is primarily made on the basis of the
polyp count in the colon and rectum rather than a concern about
desmoids.
S u g g e S t e d R e a d i n g
Church J, Lynch C, Neary P, LaGuardia L, Elayi E. A desmoid tumor-staging
system separates patients with intra-abdominal, familial adenomatous
polyposis-associated desmoid disease by behavior and prognosis. Dis Co-
lon Rectum. 2008;51:897–901.
Elayi E, Manilich E, Church J. Polishing the crystal ball: knowing geno-
type improves ability to predict desmoid disease. Dis Colon Rectum.
2008;51:802–803.
Hartley JE, Church JM, Gupta S, McGannon E, Fazio VW. Signicance of
incidental desmoids identied during surgery for familial adenomatous
polyposis. Dis Colon Rectum. 2004;47:334–338.
Latchford AR, Sturt NJ, Neale K, Rogers PA, Phillips RK. A 10-year review of
surgery for desmoid disease associated with familial adenomatous polyposis. Br J Surg. 2006;93(10):1258.
Lips DJ, Barker N, Clevers H, Hennipman A. e role of APC and beta-
catenin in the aetiology of aggressive bromatosis (desmoid tumors). Eur
J Surg Oncol. 2009;35(1):3–10.
Poritz LS, Blackstein M, Berk T, etal. Extended follow-up of patients treated
with cytotoxic chemotherapy for intra-abdominal desmoid tumors. Dis
Colon Rectum. 2001;44:1268–1273.
H
N
C C
L S
INTRODUCTION
Approximately 5% of all colorectal cancers (CRCs) are associated with
a hereditary syndrome, where a germline mutation in a key tumor suppressor or DNA repair gene produces a cancer predisposition that can
be inherited. Hereditary nonpolyposis colorectal cancer (HNPCC) is
the most common of the hereditary CRC syndromes, accounting for
about 3% of all CRC cases. HNPCC includes many families aected by
Lynch syndrome, but overlap exists between these two terms. HNPCC
is dened clinically by family history criteria, whereas Lynch syndrome
is diagnosed genetically by the presence of an inherited mutation in a
DNA mismatch repair (MMR) gene. Not all patients with Lynch syndrome fulll HNPCC criteria, and not all HNPCC families have Lynch
syndrome. Both syndromes confer an increased risk for colorectal and
extracolonic cancers starting at an early age, and because they are
both autosomal dominantly inherited, each rst-degree relative of an
aected person carries a 50% chance of having the disease. Physicians
need to understand these syndromes to appropriately identify, diagnose, and educate aected families. Surgical decision making is based
on knowledge of cancer risk, the natural history of the disease, risks
of surgery, and the eects of the proposed surgery on quality of life.
is chapter presents an overview of HNPCC/Lynch syndrome and
provides a practical approach to its clinical management.
HISTORICAL PERSPECTIVE AND CLARIFICATION OF TERMS
In 1913, Alfred Warthin presented a large pedigree of a family in
Michigan that had a predominance of colorectal and extracolonic
cancers, many occurring at a young age. is report of “Family
G” supported the concept that cancers can occur in families as an
inherited condition and set the stage for study of inherited cancers.
In 1966, Henry Lynch used the term “cancer family syndrome” in a
report on two Midwestern families with an abundance of colorectal, endometrial, and gastric cancers. To distinguish this syndrome
from familial adenomatous polyposis, which was the only recognized hereditary colorectal cancer syndrome at the time, the term
hereditary nonpolyposis colorectal cancer (HNPCC) was introduced.
HNPCC was dened by clinical criteria to facilitate research into the
syndrome. e Amsterdam criteria were established in 1991 by the
International Collaborative Group on HNPCC (Table 59-1). In 1999,
the Amsterdam criteria were revised to include extracolonic cancers
as qualifying criteria, and these Amsterdam II criteria have become
the way to dene HNPCC (see Table 59-1).
In 1993, germline mutations in DNA MMR genes were found
to be the genetic cause of HNPCC in many families. However, it
became apparent that only about 60% of HNPCC families carry a
germline MMR gene mutation. ese genetically dened patients are
diagnosed as having Lynch syndrome. Only about 80% of Lynch syndrome families t the Amsterdam criteria, and thus at least 20% of
Matthew F. Kalady
cases are missed with reliance on these criteria to screen for Lynch
syndrome. In families that fulll the Amsterdam II criteria, the suspicion of Lynch syndrome is raised and genetic counseling and testing
are indicated; however, Amsterdam II criteria in themselves do not
dene Lynch syndrome. at is a genetic denition. Patients from
families who meet Amsterdam criteria but have microsatellite stable
tumors (i.e., intact MMR) have familial colorectal cancer type X (FCC
X), which carries a lower cancer risk than does Lynch syndrome. is
distinction is important for appropriate clinical management. When
discussing Lynch syndrome and HNPCC, it is important to use the
correct denitions to allow for the proper classications of the dierent phenotypes and genotypes.
GENETIC AND MOLECULAR CAUSE OF LYNCH SYNDROME
Lynch syndrome is caused by inactivation of one of four DNA mismatch repair genes: MLH1, MSH2, MSH6, or PMS2. ese genes
encode proteins that function as heterodimers (MLH1/PMS2 and
MSH2/MSH6) to recognize and repair nucleotide mismatches that
occur during DNA replication. Approximately 90% of Lynch syndrome cases are caused by an inherited mutation in MLH1 or MSH2.
Rarely, Lynch syndrome can also result from an inherited deletion
in the EPCAM gene, which silences expression of MSH2. Inherited
germline hypermethylation of MLH1, resulting in silencing of its
expression, has also been reported but is very rare.
Lynch syndrome is inherited in an autosomal-dominant pattern.
When a child inherits the mutated allele from the aected parent,
normal MMR function is maintained by the wild-type allele inherited from the unaected parent. However, with sporadic loss of the
wild-type allele, MMR function is lost. Because DNA mismatch
errors tend to occur in areas of repeating nucleotide bases called
microsatellites, unrepaired errors accumulate in these regions and
lead to microsatellite instability in tumors. Panels of microsatellite
markers have been established to assess tumor DNA microsatellite
stability, the most common of which includes ve markers. If two or
more are unstable, the tumor is considered microsatellite instability
high (MSI-H)—evidence of DNA MMR deciency. About 90% of all
Lynch syndrome tumors are MSI-H. In contrast, about 15% of sporadic colorectal tumors are MSI-H, resulting from epigenetic loss of
MLH1 via DNA promoter hypermethylation.
HISTOLOGIC FEATURES OF LYNCH TUMORS
Colorectal cancers arising within Lynch syndrome have distinct
histologic characteristics that, when recognized in a tumor, suggest
defective MMR. ese characteristics include the presence of tumorinltrating lymphocytes, a Crohn-like lymphoid reaction, signet ring
285
Hereditary NoNpolyposis ColoreCtal CaNCer aNd lyNCH syNdrome286
TABLE 59-1: Amsterdam Criteria for Clinical Diagnosis of Hereditary Nonpolyposis Colorectal Cancer
Amsterdam I Amsterdam II Amsterdam-like
3 or more family members, one of whom is a
rst-degree relative of the other two, with
colorectal cancer
2 or more successive aected generations
1 or more of the colorectal cancers diagnosed
before age 50 years
Familial adenomatous polyposis is excluded
Same criteria as for Amsterdam I, but cancers
not limited to colorectal cancer
Qualifying lesions also include hereditary non-
polyposis colorectal cancer–related cancers:
endometrial, ovarian, gastric, small bowel,
ureter, renal pelvis, pancreas, biliary tract,
brain, sebaceous adenomas/adenocarcinomas
BOX 59-1: Revised Bethesda Guidelines
Colorectal cancer diagnosed before age 50 years
Presence of synchronous or metachronous colorectal cancer or
Lynch syndrome–associated tumors*
Microsatellite instability high–type histologic features: tumor-
inltrating lymphocytes, Crohn-like reaction, mucinous tumor,
signet cell dierentiation, medullary growth pattern in tumor
from a patient younger than 60 years
Patient with colorectal cancer and a rst-degree relative with colo-
rectal cancer or a Lynch syndrome–associated tumor* before
age 50 years
Patient with colorectal cancer and two rst- or second-degree
relatives with colorectal cancer or a Lynch syndrome–
associated tumor* at any age
*Lynch syndrome–associated tumors include tumors of the colorectum, endometrium,
stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, and
sebaceous glands, along with keratoacanthomas.
ABA
Same criteria as for Amsterdam II, but
qualifying lesions also include highrisk adenomas: high-grade dysplasia,
>1 cm, and/or 3 or more adenomas
found upon a single endoscopic
examination
cells, mucinous components, and a lack of dirty necrosis. Some of
these histologic factors have been incorporated into the revised
Bethesda criteria (Box 59-1) as a tool to identify which patients should
undergo testing for the presence of MSI (Figs. 59-1, 59-2, and 59-3.)
DIAGNOSING LYNCH SYNDROME
e rst step in managing Lynch syndrome in a family is to diagnose
it. Several strategies can be used to select patients for genetic testing,
including clinical criteria, prediction models, and tumor testing.
Clinical Criteria
Amsterdam I criteria (see Table 59-1) require three relatives aected
with colorectal cancer, with two being rst degree to the other one,
in at least two consecutive generations, with one relative younger
than 50 years and polyposis excluded. Amsterdam II criteria are
more inclusive than Amsterdam I criteria because they include any
Lynch-related cancers as qualifying events. Amsterdam II criteria
are highly sensitive (85%) but poorly specic (20%). However, the
shrinking size of families and the attenuation of phenotype caused
by increasingly widespread colonoscopic screening is decreasing
the sensitivity of family-based criteria. erefore, we have adopted
“Amsterdam-like” criteria, in which high-risk adenomas count as a
qualifying lesion (see Table 59-1). e revised Bethesda guidelines
include details of the cancers, as well as family history and age at
diagnosis, and are aimed at identifying tumors suitable for MSI testing (see Box 59-1).
Models
In an eort to improve the predictive accuracy of clinical criteria,
several clinical computational prediction models have recently been
B
FIGURE 59-1 A, Poorly differentiated (medullary) adenocarcinoma
composed of irregular, solid sheets of large eosinophilic cells containing
small glandlike spaces. B, Signet-ring adenocarcinoma.
developed and validated to determine a person’s risk for Lynch syndrome. ese models include MMRpro, MMRpredict, and PREMM.
ey include factors such as age, gender, location of tumor, and the
presence of multiple tumors or endometrial cancer, and they are
available for use as Internet-based programs. Although they seem to
outperform traditional clinical criteria, they do not replace a comprehensive family history and clinical acumen.
Tumor Testing
For patients who have a cancer or a large adenoma, tumor testing
for MMR deciency is a more accurate and cost-eective way of
identifying potential patients with Lynch syndrome than are clinical
criteria or prediction models alone. MMR deciency is evaluated
by MSI or by immunohistochemistry for expression of MMR proteins. About 90% of Lynch syndrome CRCs will be MSI-H and lack
MMR protein expression. Lack of expression of a specic protein
COLON 287
d
can direct germline testing for mutations to a specic gene. If MSH2
is mutated, both MSH2 and MSH6 are lost; if MSH6 is mutated, only
MSH6 is lost. If MLH1 is mutated, both MLH1 and PMS2 expression
are lost, but if PMS2 is mutated, then only PMS2 is lost. Depending
on the ndings of immunohistochemistry, the appropriate gene(s)
FIGURE 59-2 Crohn-like lymphoid aggregation within a germinal
center in the stroma inferior to the tumor.
is/are sequenced. About 15% to 18% of all colorectal cancers are
MSI-H, and approximately 85% of these are attributable to acquired
methylation of the MLH1 promoter not associated with Lynch syndrome. erefore, if MLH1 expression is lost, results should be
taken within the context of age and family history. Most tumors
with methylation of MLH1 will have mutations in BRAF, whereas
these are almost never found in Lynch tumors. erefore, testing
for BRAF mutations and MLH1 methylation can dierentiate most
tumors with absent MLH1 expression into Lynch syndrome and not
Lynch syndrome.
Although tumor testing is the best way to identify patients for
genetic testing, selection criteria for testing are debated. Limiting
tumor testing by age or clinical criteria would lead to a signicant
number of Lynch syndrome cases being missed, and thus there is a
move toward testing of all resected CRCs. In 2009, the Evaluation
of Genomic Applications in Practice and Prevention Working Group
recommended that samples of all newly diagnosed CRC undergo
MSI and/or immunohistochemistry for MMR protein expression.
ese guidelines are endorsed by the Collaborative Group of the
Americas on Inherited Colorectal Cancer. Recently, the National
Comprehensive Cancer Network recommended universal screening
of all colorectal cancers for persons younger than 70 years and for
those older than 70 years who meet revised Bethesda guidelines. e
Cleveland Clinic approach to universal tumor testing is summarized
in Figure 59-4.
Ideally, tumor testing is performed using the colonoscopic biopsy
specimen taken at the time of diagnosis, before surgery. is testing allows preoperative identication of Lynch syndrome and aords
an opportunity for patient education and a more informed choice
regarding surgical strategy.
FIGURE 59-3 Tumor-infiltrating lymphocytes. (Courtesy Tom C.
Smyrk, MD, Associate Professor of Pathology, University of Nebraska
College of Medicine.)
Initial screen: DNA testing for MSI or IHC for MMR proteins
Test for
MSI
MSS
No further
evaluation
MSI-H
MMR IHC
GENETIC COUNSELING AND TESTING
Identication of a specic mutation as the underlying cause of Lynch
syndrome benets the patient in terms of personalized risk assessment and facilitates testing of at-risk family members. Indications
for referral to a genetic counselor are listed in Box 59-2. For patients
with a diagnosis of cancer, genetic counseling and testing should
be initiated at the time of diagnosis. Working with the clinician,
the genetic counselor uses tumor test results to guide which gene
should be sequenced. Germline genetic testing is most commonly
conducted with a blood sample but also may be conducted with
material from a buccal swab. When tumor testing is not available to
BRAF testing
MLH1
MLH1 methylation
BRAF WT and
MLH1 not methylate
Genetic counseling
Germline testing for
specific MMR mutation
MMR protein loss
FIGURE 59-4 Universal testing of colorectal cancers for Lynch syndrome. IHC, Immunohistochemistry;
MMR, mismatch repair; MSI-H, microsatellite instability high; MSS, microsatellite stable; W T, wild type.
(From Kalady MF, Heald B. Diagnostic Approach to Hereditary Colorectal Cancer Syndromes. Clin Colon Rect
Cancer Surg 2015;28:205-214.)
MSH2, MSH6, PMS2MSH2, MSH6, PMS2
Hereditary NoNpolyposis ColoreCtal CaNCer aNd lyNCH syNdrome288
BOX 59-2: Indications for Referral to Genetic Counseling
and Testing for Lynch Syndrome
Family meets Amsterdam I or II or Amsterdam-like criteria
Colorectal or endometrial cancer before age 50 years
Patient/family satises revised Bethesda guidelines
First-degree relative of a known patient with Lynch syndrome
>5% chance of mutation by computed prediction models
Molecular and genetic tumor testing consistent with Lynch syn-
drome
TABLE 59-2: Lifetime Colorectal Cancer Risk by
Age 70 Years in Persons with Lynch Syndrome by
Gene
Gene Colorectal Cancer Risk, %
MLH1/MSH2
Male 27-74
Female 22-53
MSH6
Male 22
Female 10
PMS2
Male 20
Female 15
Modied from Giardiello FM, Allen JI, Axilbund JE, etal. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement
by the US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum.
2014;57:1025-1048.
suggest the particular gene for testing, other strategies are employed.
Some counselors sequence all four MMR genes, and recently, commercial gene panel tests have become available for patients with suggestive phenotypes. e use of a panel of 18 to 25 genes promises
to reveal unsuspected germline mutations in patients with atypical
clinical presentations, which may lead to quandaries in management. Because of the complexity of interpreting results, genetic testing should be performed within the context of appropriate patient
education and counseling both before and aer testing. For at-risk
relatives of a person with Lynch syndrome, testing should be considered around the age when cancer surveillance would commence.
ese patients can be screened for the family mutation, which is a
much cheaper and easier process than nding the mutation in the
rst place.
CLINICAL MANIFESTATIONS AND MANAGEMENT
Lynch syndrome aects multiple organs, although colorectal cancer
is the most common manifestation. CRCs within patients with Lynch
syndrome are characterized by onset at an early age (mean age, 44 to
61 years), right-sided location, and a high incidence of synchronous
and metachronous colorectal neoplasms. e lifetime risk of developing CRC is associated with gender and genotype and is listed in
Table 59-2. Other organs have a substantial cancer risk and are listed
in Table 59-3.
TABLE 59-3: Lifetime Extracolonic Cancer Risk by
Age 70 Years in Persons with Lynch Syndrome
Risk in General
Cancer
Population, %
Endometrial 2.7
MLH1/MSH2 14-54
MSH6 17-71
PMS2 15
Gastric <1 0.2-13
Ovarian 1.6 4-20
Urinary tract <1 0.2-25
Small bowel <1 0.4-12
Pancreas 1.5 0.4-4
Hepatobiliary tract <1 0.02-4
Brain/central nervous
<1 1-4
system
Sebaceous neoplasm <1 1-9
Prostate 16.2 9-30
Breast 12.4 5-18
Modied from Giardiello FM, Allen JI, Axilbund JE, etal. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement
by the US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum.
2014;57:1025-1048.
Risk in Lynch
Syndrome, %
COLORECTAL CANCER RISK MANAGEMENT
Surveillance Colonoscopy and Polypectomy
e goals of managing patients and families with Lynch syndrome
are to reduce the incidence of colorectal and other cancers and minimize deaths from cancer when it does occur. For the colon and rectum, colonoscopic surveillance helps achieve this goal. Colonoscopy
screening at 3-year intervals has been shown to reduce the risk of
CRC by 62% and overall mortality by 65%, with interval cancers due
to the aggressive carcinogenesis that is part of the syndrome. e
ideal interval between colonoscopies that balances screening eectiveness with inconvenience, potential morbidity, and cost is debated,
but most guidelines recommend surveillance colonoscopy every 1
to 2 years, starting at age 20 to 25 years. Surveillance colonoscopy
must be uncompromising and requires excellent bowel preparation
to permit meticulous inspection of the mucosa. Some consideration
is given to delaying the rst colonoscopy until age 25 to 30 years for
patients with MSH6 and PMS2 mutations, respectively, because the
overall risk of colorectal cancer is lower and age of onset is older than
in persons with MSH2 or MLH1 mutations.
Chemoprevention
e Concerted Action Polyp Prevention 2 (CAPP2) trial was a multicenter, double-blinded, randomized study evaluating the eects of
a 600-mg dose of aspirin daily versus placebo on CRC formation in
COLON 289
patients with Lynch syndrome. Patients who took aspirin for at least
2 years experienced a 60% decrease in the incidence of CRC. CAPP3
is under way to help establish the most eective dose and treatment
duration.
Surgery
Colectomy in the Absence of Cancer
Prophylactic colectomy for unaected patients with Lynch syndrome
should be discussed as an option but is not generally recommended.
Statistical modeling suggests a 1.8-year survival benet for patients
undergoing a prophylactic subtotal colectomy at age 25 years compared with undergoing surveillance colonoscopy. e survival benet decreases when prophylactic surgery is performed at older ages.
A prophylactic colectomy may be considered in families with highly
penetrant CRC, in persons who are not compliant with screening recommendations, and in persons for whom colonoscopy examination
is dicult. Occasionally, patients request a colectomy to lessen their
fear of developing colon cancer. is request is reasonable, but the
risks, benets, and sequelae of the surgery need to be discussed with
the patient.
Treatment of Colon Cancer
Unlike sporadic CRC, which is routinely treated with a segmental
colectomy, the options for CRC in persons with Lynch syndrome
include consideration of an extended resection. e two main factors inuencing surgical strategy are the risk of metachronous CRC
and quality of life. Surgical options include a segmental resection (i.e.,
removal of only the aected segment of colon) or a total abdominal
colectomy with ileorectal anastomosis (TAC-IRA). TAC-IRA treats
the current cancer and prophylactically removes most of the remaining colon, which otherwise would be at risk for further development
of CRC.
Although no prospective trials have been performed to show
a survival benet for TAC-IRA compared with segmental colectomy, multiple retrospective studies with metachronous cancer as
an end point favor an extended approach. e risk of the development of metachronous CRC aer segmental colectomy is approximately 10% at 10 to 15 years. A study from the Colon Cancer
Family Registries demonstrates increasing cancer risk with time
and estimates the risk of a second colon cancer aer segmental
resection to be as high as 72% at 40 years. e risk of metachronous rectal cancer aer a TAC-IRA is approximately 5% to 10%
at 10 to 12 years, and annual rectal surveillance with removal of
polyps is warranted.
Data are limited regarding quality of life aer segmental or total
colectomy for cancer in persons with Lynch syndrome. Haanstra
et al published results from 104 patients with Lynch syndrome
who were treated either with TAC-IRA or a segmental colectomy.
Using quality of life and colorectal function questionnaires, these
investigators determined that patients who underwent an extended
resection had more frequent stooling, which had a greater increased
impact on life. However, this nding did not translate into any statistical dierence in quality of life. A small study from e Cleveland Clinic also showed that although stooling frequency was
greater for patients aer they underwent a total colectomy (four vs.
two bowel motions daily), there was no dierence in continence or
overall quality of life.
Based on this information, I favor extended resection for colon
cancer in persons with Lynch syndrome. However, the decision for
each patient is an individual one. Factors to consider in the discussion include medical comorbidities, the likely compliance of the
patient with postoperative surveillance, the penetrance of disease
in the family, the patient’s degree of risk aversion, and overall life
expectancy.
Rectal Cancer in Persons with Lynch Syndrome
Rectal cancer develops in approximately 25% of patients with Lynch
syndrome. Choice of treatment remains controversial, and decisions are inuenced by multiple factors. Options include a standard
anterior resection or abdominal perineal excision or a total proctocolectomy with an end ileostomy or restorative ileal pouch–anal
anastomosis (IPAA). e Colon Cancer Family Registries demonstrated increasing risk of metachronous colon cancer with time aer
a proctectomy: 19% at 10 years, 47% at 20 years, and 69% at 30 years.
A Cleveland Clinic study evaluated the risk of metachronous colon
cancers and high-risk adenomas and showed that cancer developed
in 15% of patients and high-risk adenomas developed in another 36%
at a median of 6 years aer a proctectomy.
Management of a metachronous colon cancer aer a primary
anterior resection of the rectum is dicult. Construction of an IPAA
at a secondary procedure entails resecting a coloanal anastomosis in
a repeat pelvis procedure, which is challenging and is associated with
increased morbidity compared with an initial IPAA. Of course, bowel
function aer an IPAA is dierent from that aer a proctectomy
and coloanal anastomosis (either with or without a colon pouch). A
patient with an IPAA will have more frequent bowel movements and
more liquid stool and be more prone to incontinence and seepage. e
morbidity associated with pelvic dissection is similar, but the issues
that can occur with ileal pouch construction must be considered.
is procedure is technically challenging and should only be performed by persons with specialized surgical training and expertise.
e “correct” approach is still controversial, and the choice is adapted
to individual patient circumstances. e younger the patient and the
more aggressive the family phenotype, the more the balance swings
toward a total proctocolectomy and IPAA. e older the patient, the
milder the phenotype, and the greater the number of adverse factors
for a pouch (e.g., obesity, poor sphincter function, and a history of
anal sepsis), the more the balance swings toward a proctectomy. In
addition, if the cancer is advanced and the likelihood of dying from
recurrent disease outweighs the likelihood of a metachronous second
primary cancer, a palliative proctectomy should be performed.
RISK MANAGEMENT OF EXTRACOLONIC MANIFESTIONS
Lynch syndrome is a multisystem disease, and multiple organ systems are at increased risk for malignancy (Table 59-3). Several expert
panels and societies have published guidelines for screening, mostly
based on expert opinion. It is important to note that these are general
guidelines. Specic tests and intervals vary depending on the individual and family genotype and phenotype. e extracolonic risks
and screening recommendations are described briey in the following sections. Table 59-4 lists general guidelines used by the Sanford R.
Weiss, M.D., Center for Colorectal Neoplasia at e Cleveland Clinic.
For a more detailed discussion regarding screening and surveillance
protocols, the reader is referred to the article by Giardiello etal on
behalf of the U.S. Multi-Society Task Force on Colorectal Cancer (see
Suggested Reading) and the National Comprehensive Cancer Net-
work Web site.
Endometrial and Ovarian Cancer
Endometrial cancer is the second most common cancer that occurs
in persons with Lynch syndrome. e magnitude of risk varies with
the gene that is mutated, with an MSH6 mutation carrier having a
71% risk of having uterine cancer by age 70 years. Age of onset varies
but is younger than that of patients with sporadic endometrial cancer
by about 10 years. No evidence exists to indicate that endometrial
screening improves survival, perhaps partly because the majority of
endometrial cancers in persons with Lynch syndrome are early stage,
Hereditary NoNpolyposis ColoreCtal CaNCer aNd lyNCH syNdrome290
TABLE 59-4: The Cleveland Clinic Weiss Center
Guidelines for Screening Affected or At-Risk Persons
with Lynch Syndrome
Organ
System Intervention
Colorectum Colonoscopy 20-25 Every 1-2 yr until
Gynecologic Transvaginal
ultrasound
Pelvic exami-
nation with
endometrial
sampling
Urology Urinalysis 30-35 Annually
Stomach
and small
bowel
Skin Dermatologic
EGD, Esophagogastroduodenoscopy.
with a nearly 90% 5-year survival. Still, experts recommend annual
pelvic examination and transvaginal ultrasound. An endometrial
biopsy can identify premalignant lesions and asymptomatic cancers,
and experts recommend that this screening be performed annually
starting at age 30 to 35 years. No studies have been performed to
evaluate the eectiveness of screening for ovarian cancer, but transvaginal ultrasound is part of gynecologic screening. Prophylactic
removal of the uterus and ovaries eliminates the risk of developing
endometrial cancer and should be considered in women with Lynch
syndrome who have completed childbearing.
EGD 30-35 Every 2-3 yr
evaluation
Age at
Initiation, yr Interval
age 40 yr, then
annually
30-35 Annually
20-25 Annually
Upper Gastrointestinal Tract
e risk of gastric cancer is as high as 13%, and although no data exist
on the cost-eectiveness of screening for gastric cancers, experts recommend esophagogastroduodenoscopy with biopsy starting at age 30
to 35 years. Because gastric cancers are associated with Helicobacter
pylori, this infection should be treated. A repeat examination should
be performed every 2 to 3 years depending on the ndings and family history. e lifetime risk of small bowel cancer has been reported
to be as high as 12%, with most cancers located in the duodenum or
terminal ileum—areas that can be surveyed endoscopically. Conicting opinions exist about the place of capsule endoscopy as a screening
test. e U.S. Multi-Society Task Force on Colorectal Cancer and the
Mallorca Group do not recommend routine small bowel screening,
whereas the National Comprehensive Cancer Network suggests consideration of capsule endoscopy every 2 to 3 years beginning at age
30 to 35 years.
urinalysis for hematuria is recommended as an annual screening.
Patients with a positive test should be referred to a urologist for further evaluation.
Skin Neoplasms
Sebaceous adenomas or sebaceous adenocarcinomas will develop
in approximately 1% to 9% of persons with Lynch syndrome. ese
lesions are detectable on a simple skin examination. Although no evidence exists to indicate that screening prevents these lesions from
developing, our patients undergo annual screening by a dermatologist as part of their high-risk clinic visit.
Other Cancers
Multiple other cancers may occur in patients with Lynch syndrome,
but the risks are low (Table 59-3). No data show that screening for
these cancers is eective, and given the low incidence, routine screening is not recommended. Breast and prostate cancer have been extensively studied in recent years to determine if they are part of Lynch
syndrome, and data are conicting. Currently, routine screening
recommendations for breast and prostate cancer are the same for
patients with and without Lynch syndrome.
CLINICAL VARIATIONS OF HNPCC AND LYNCH SYNDROME
Patients and families do not always t neatly into a particular syndrome or diagnosis. Methods of diagnosis include family history,
tumor testing, and germline testing. Although a Lynch syndrome
family typically ts Amsterdam criteria and has MSI-H cancers with
loss of MMR protein expression and a detectable germline mutation
in the relevant gene, none of these characteristics is always present,
and some situations can be confusing.
Familial Colorectal Cancer Type X
Approximately 40% of patients whose families satisfy Amsterdam
criteria have microsatellite stable tumors and do not have an inherited MMR mutation. ey are categorized as having FCC X. is
group of patients is a heterogeneous population, some of whom have
germline mutations in APC (familial adenomatous polyposis), MYH
(MYH-associated polyposis), NTHL1 (NTHL1-associated polyposis)
and POLD1/POLE (polymerase proofreading associated polyposis).
ese patients are a minority, however, and most genotypes are not yet
fully appreciated. Overall, persons with FCC X have about a twofold
increased risk of CRC when compared with the general population—
less than the sixfold increased risk of Lynch syndrome. e mean age
of CRC diagnosis is 61 years, which is between that of patients with
Lynch syndrome and the general population. Screening guidelines
recommend colonoscopy every 5 years, starting at age 45 years, or
10 years younger than the earliest age at the appearance of CRC in a
relative. In the absence of any known mutation or clinical polyposis,
cancers are treated surgically in the same manner as sporadic cancers
while considering patient preferences and comorbidities.
Urinary Tract
Urinary tract cancers associated with Lynch syndrome include transitional cell carcinomas of the ureters, bladder, or renal pelvis. e
risk is as high as 25% and varies by gender and genotype. Men with
an MSH2 mutation have the highest risk. Simple screening tests
such as urinalysis and urine cytology are not particularly sensitive,
but because of its relative ease, noninvasive nature, and low cost,
Likely Lynch Syndrome: Amsterdam Criteria with a
Microsatellite Instability High Colorectal Cancer, but
Germline Testing Is Not Done
Occasionally, patients may not undergo genetic testing. Some patients
do not want to know if they have a genetic syndrome, others fear
being tested because of concerns about insurance discrimination,