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4 Lynch Syndrome, HNPCC or Familial Cancer?

4 Lynch Syndrome, HNPCC or Familial Cancer?

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17.5 Clinical Identification


Table 17.3 MMR-gene mutation analysis in relation to clinical

criteria and results of MSI- and IH-analysis in populationbased or consecutive series of unselected colorectal cancer.


Primary test used





Total no.

of CRC








Aaltonen 1998





Debniak 2000






6 (3.5 %)

Solavaara 2000





18 (3.3%)

Cunningham 2001






Hampel 2005








Pinol 2005






Proportion of mutation

carriers that meet the

clinical criteria

10 (1.9%)

5 (1.95%)












23 (2.1%)




11 (0.9%)




111 (24%)

30/73 (41%)

a Communicated with authors.

b The original number of consecutive CRCs was 168, including 143 sporadic cases and

25 suspected cases. A total of 43 of the sporadic cases and 25 suspected cases were analyzed.

Currently, the Amsterdam II or the revised Bethesda criteria are used to select

patients with suspected familial CRC for molecular genetic and/or IH analysis of

the tumor, and those with evidence of MSI or loss of MMR expression are offered

mutation analysis. There are six studies in which either MSI- or IH-analysis or

both tests were performed as the primary screening tool in prospective and

unselected series of CRC patients (Table 17.3) [16–21].

Previous studies have shown that the yield of mutation analysis (positive predictive value) in families that meet the Amsterdam criteria is approximately 50% and

the yield in families that meet the Bethesda criteria between 10 and 20% [22] These

55/62 (89%)


17 Lynch Syndrome (HNPCC)

six studies showed that the sensitivity of the Amsterdam criteria for the detection

of mutations was 40% and that of the Bethesda guidelines was about 90%. This

means that if the revised Bethesda guidelines had been used, about 10% of the

mutation carriers would have been missed, mostly patients with CRC diagnosed

between ages 50 and 60.

Is performing both MSI and IH necessary as a prescreening tool, or is one of

both sufficient, and if so, which one is more recommendable? Most studies

addressing this issue have been retrospective and methodology applied varied

greatly. For IH-analysis, mostly only two antibodies (MLH1, MSH2) were

employed; other studies used three or four antibodies (MLH1, MSH2, MSH6,

PMS2). In the studies in which both MSI analysis and IH analysis have been performed prospectively, the sensitivity of MSI analysis was slightly better than that

of IH analysis [17, 19–21, 23–27]. In one large (German) study, the outcome of

both methods was tested prospectively in families that meet the Amsterdam,

Bethesda, or age-independent modified criteria. MSI analysis (using the Bethesda

set of 5 markers) and IH analysis (2 antibodies) was performed in 1119 index

patients [24]. Two hundred and thirty pathogenic MMR gene mutations were

identified, the sensitivity of MSI analysis being 100% and that of IH analysis 94%.

A Dutch study demonstrated increased detection by including an antibody against

PMS2 [28].

IH is broadly available, less cost-intensive, and pinpoints towards the specific

underlying gene defect. Most authors prioritize the use of IH for these reasons,

especially in families with a high probability for an MMR mutation (e.g. families

that meet the Amsterdam criteria, or families with a high predicted probability

based on calculations using the Wijnen [22] or Engel model). MSI may be recommended in addition, if IH is unconclusive.


Surveillance Colorectum

The term HNPCC is misleading, since the adenoma-carcinoma sequence applies

to development of CRC in Lynch syndrome families. Due to the increased occurrence of CRC and the availability of a precursor lesion, colonoscopic surveillance

has been recommended since the 1980s. The question to be raised is: does colonoscopic surveillance translate to a reduction in mortality?

Several studies address this issue [29–37]. All studies demonstrate a benefit of

surveillance in detecting CRC at an earlier stage compared to historical controls.

The only prospective controlled trial (Järvinen 1995/2000) showed that surveillance led to a 63% reduction in CRC. Two studies assessed the effect of surveillance on CRC-associated mortality. A Finnish study showed that colonoscopic

surveillance significantly decreased the mortality associated with CRC [34, 38]. A

study from The Netherlands evaluated the relative mortality in a large series of

families over a period of 45 years and demonstrated a reduction in mortality [31].

The protocols that have been used in studies of surveillance have varied with

17.8 Surveillance of the Endometrium/Ovary

respect to the surveillance intervals. Some studies advised a 3-yearly colonoscopy

and others colonoscopy every year – the data available so far does not allow a

clear-cut recommendation; however, the surveillance interval will lie between 1

and 3 years.


Familial Cancer

In a significant proportion (∼30%) of families that meet the Amsterdam criteria,

the results of MSI analysis and IH analysis of the colorectal tumor(s) are negative

[40]. Clustering of CRC by chance or genetic defects other than those of MMR may

be responsible for the disease in such families, and they do not have Lynch syndrome. These families are characterized by a more advanced age of onset of CRC

than in Lynch syndrome families and the absence of endometrial cancer and

multiple tumours. A recent study reported that the risk of developing CRC in such

families is only increased by a factor of 2.3 [40]. Another study compared the

results of surveillance in families with clustering of CRC with and without MSI

[41]. The results showed that the yield of adenomas was the same in both types of

families. However, CRC was only identified in the families with MSI tumors. In

families without evidence for MMR deficiency, a less intensive colonoscopic surveillance program (e.g. colonoscopy: 1x/3–5 years, starting 5–10 years before the

first diagnosis of CRC or >45 years) might be appropriate. In view of the absence

of endometrial cancer in such families, surveillance of the endometrium is not



Surveillance of the Endometrium/Ovary

The international studies in Lynch syndrome families have shown that carriers of

an MMR mutation have a high risk of developing endometrial cancer [7]. Though

it is known that the majority of (sporadic) endometrial cancers are detected at an

early stage, about 10 to 15% of patients with such tumors will ultimately die from

metastatic disease. Due to this significant mortality and the high risk of developing

endometrial cancer in Lynch syndrome families, specifically if the mutation is

located on MSH6, surveillance is advised.

British and Dutch investigators evaluated the outcome of surveillance of 269

women from families suspected of having Lynch syndrome [42, 43]. The surveillance program consisted of ultrasound every 1 to 2 years. It did not lead to the

detection of pre-malignant lesions or endometrial cancer. In another study from

The Netherlands, 41 women from Lynch families underwent surveillance by transvaginal ultrasound (TVU) followed by aspiration biopsy in suspected cases. After

a mean follow-up of 5 years, premalignant lesions, that is, complex atypia, were

detected in three patients. There was one early stage interval cancer diagnosed 8



17 Lynch Syndrome (HNPCC)

months after a normal ultrasound. A recent study of 175 subjects from Finland

reported the results of surveillance by TVU and aspiration biopsy [44]. Complex

atypia was found in 5 patients, endometrial cancer was found in 11, and there

were two interval cancers. Six of the 11 screen-detected cancers were only identified by aspiration biopsy and not by TVU. American investigators reported on a

retrospective cohort of 315 women, all mutation carriers, 61 of whom had prophylactic surgery and were then followed up for approximately 10 years. No endometrial cancer or ovarian cancer developed in those women who had prophylactic

surgery, whereas 33% of the women who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer [45].

In conclusion, two of the three available studies suggested that surveillance may

lead to the detection of pre-malignant lesions, and one study also to detection of

endometrial cancer at an early stage. Due to the higher risk of developing endometrial cancer in carriers of a MSH6 mutation, hysterectomy may be suggested

for these women at the time of CRC surgery or after menopause. This surgery

may also be considered for carriers of mutations in the other MMR genes, and for

women who require surgery for a CRC. In view of the risk of ovarian cancer and

the failure of early detection of such tumors by TVU and CA-125 estimation,

bilateral salpingo-oophorectomy might be considered in mutation carriers after

completion of family planning.


Surveillance for Other Related Cancers

Other cancers associated with Lynch syndrome include cancer of the stomach,

ureter, renal pelvis (see Chapter 15 on hereditary renal tumors of the adult), small

bowel, the bile ducts, and tumors of the brain. The life-time risk of developing one

of these cancers is relatively low (<10%), and may be associated with the underlying MMR defect. The risk of developing gastric cancer may be higher in some

countries, such as Germany. The International Society of Gastrointestinal Hereditary Tumours (InSiGHT) recommends surveillance for cancer of the stomach and

urinary tract, if the specific type of cancer clusters in the family (more than one

case) [46]. However, screening for urological cancers by cytology has not proven

to have any benefit.


Surgical Management

Several studies showed that Lynch syndrome patients have an increased risk of

developing multiple (synchronous and metachronous) CRCs. A Dutch study

reported that the risk of developing a second colon tumor after treatment of a

primary CRC in Lynch syndrome was 16% after 10 years of follow-up [37]. In view

of this substantial risk, the question arises whether a subtotal colectomy instead

17.11 Chemotherapy

of a segmental resection might be the preferred treatment in patients from Lynch

syndrome families with a primary tumor. In a recent study, a decision analysis

was performed to compare the life expectancy for patients undergoing subtotal

colectomy or partial resection for a primary screen-detected CRC [47]. The results

indicated that subtotal colectomy performed at a young age (<47 years) would lead

to an increased life expectancy of up to 2.3 years. Unfortunately, the authors were

not able to use quality of life (QOL) adjusted life expectance because studies on

QOL that specifically consider Lynch syndrome patients are not available in the

literature. Although for sporadic CRC, QOL after segmental resection has been

reported to be better than after subtotal colectomy, in Lynch syndrome families

QOL after segmental resection may be decreased by the need for colonoscopy

(vs. sigmoidoscopy after subtotal colectomy) and increase of fear of a second


Based on these findings and taking into account the substantial risk of developing a second tumor, subtotal colectomy with ileorectal anastomosis can be discussed if colon cancer is detected in a young patient participating in a surveillance

program. A prospective study that also addresses QOL should evaluate which

surgical option is the most appropriate in Lynch syndrome. Until the outcome of

such studies is available, the Mallorca group recommends discussing the pros and

cons of both options with a patient from a Lynch syndrome family who develops




Currently, at least three chemotherapeutic agents have been proven to be effective

in the treatment of CRC, that is, 5FU with or without leucovorin, oxaliplatin, and

irinotecan (CPT11). In vitro studies suggested that MMR-deficient colon cancer

cells might not respond to 5FU-based chemotherapy [48]. On the other hand, CRC

cell lines defective of MMR exhibit increased sensitivity to CPT11 (irinotecan)


The effect of chemotherapy in patients with MSI-H or HNPCC tumors has been

reported in only a few studies [50–54]. Most studies showed that there was no

benefit of 5FU treatment in such patients. One small study on Stage IV CRC

patients reported complete or partial responses to treatment with irinotecan in 4

out of 7 patients with MSI-H tumors compared to 7 out of 65 patients with MSIL/MSS tumors [55].

Because most studies are retrospective, all authors urge caution in implementing these findings in clinical practice until they are confirmed by prospective

studies. Because it may be unethical to withhold chemotherapy in a clinical trial

for potentially curable advanced-stage colon cancer, the best format of such studies

is to compare effective drugs such as CPT11 or oxalaplatin with 5FU. These

approaches require validation in large patient cohorts before routine integration

into clinical recommendations.



17 Lynch Syndrome (HNPCC)


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Gastrointestinal Stromal Tumors (GISTs)

Maria Debiec-Rychter


Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors

of the gastrointestinal tract (GI), evolve from a progenitor related to the interstitial

cells of Cajal (ICC). Oncogenic mutations in the KIT or PDGFRA gene are detected

in approximately 85% of sporadic GISTs.

Familial GIST syndrome is an autosomal dominant genetic disorder with

germline mutations of the KIT or PDFGRA gene as an underlying cause of the

disease. Familial GIST syndrome associated with a germline KIT mutation is

characterized by multiple GISTs associated with hyperplasia of ICCs, and other

clinicopathologic features, such as skin hyperpigmentation, GI motility dysfunctions, or mast cell abnormalities. Symptoms associated with GI bleeding are

common, and may be the only manifestation of the disease. Germline PDGFRA

mutations result in multiple GISTs, diffuse hyperplasia of ICCs, and GI dysmotility symptoms, but affected kindreds lack pigmentation or mast cells


Hereditary forms of the disease also arise in the settings of other hereditary

syndromes, such as neurofibromatosis type 1 (NF1), the Carney–Stratakis syndrome, and the Carney triad. GIST development in patients with NF1 is caused

by a somatic inactivation of the wildtype NF1 allele in the tumor and the absence

of neurofibromin, resulting in hyperactivation of the signaling pathway downstream of KIT. Familial Carney–Stratakis syndrome is the dyad of multifocal,

gastric GISTs and paragangliomas, transmitted as an autosomal-dominant trait

with incomplete penetrance. The condition is caused by germline “loss-of function” mutations in the succinate dehydrogenase subunit B (SDHB), C (SDHC),

or D (SDHD) genes. The association of gastric, multiple GISTs, with pulmonary

chondromas and functional paragangliomas is known as the Carney triad. The

genetic basis of the association is yet unknown.

Familial GISTs usually have a milder clinical course than sporadic cases. Imatinib mesylate may be effective in the prevention of development as well as in the

treatment of hereditary GISTs.

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