Genetic Evaluation and Management of Lynch Syndrome
Genetic Evaluation and Management of Lynch Syndrome
In 1966, Dr Henry T. Lynch and colleagues reported familial aggregation of CRC with stomach and endometrial tumors in 2 extended pedigrees and designated this condition cancer family syndrome. Later, to differentiate this syndrome from the other well-known inherited form of CRC, familial adenomatous polyposis, the appellation hereditary nonpolyposis colorectal cancer was utilized. In 1984, the term Lynch syndrome was coined by Boland and Troncale to refer to this disorder. Today this condition is called Lynch syndrome. This designation is correctly applied to families and patients with a germline mutation in an MMR gene or loss of expression of the MSH2 gene due to deletion in the EPCAM gene. Also, this name is more appropriate than HNPCC because most LS patients will develop one or several adenomatous polyps, which makes the term nonpolyposis misleading.
LS is an autosomal dominant disorder with colorectal malignancy as the major clinical consequence. The lifetime risk of CRC in LS has been variably estimated and appears dependent on sex and the MMR gene mutated. Most reports of lifetime risks of CRC for MLH1 and MSH2 gene mutation carriers range from 30 to 74% (Table 3). Lower cumulative lifetime risk for colorectal malignancy ranging from 10 to 22% has been found in patients with MSH6 mutations and 15%–20% in those with PMS2 mutations. Mean age at CRC diagnosis in LS patients is 44–61 years compared with 69 years in sporadic cases of CRC. In LS, colorectal tumors arise primarily (60%–80%) on the right side of the colon (proximal to the splenic flexure) compared with 30% in sporadic CRC. A high rate of metachronous CRC (16% at 10 years; 41% at 20 years) is noted in LS patients with segmental surgical resection of the initial CRC. The precursor lesion for LS appears to be a discrete colonic adenoma, which can occasionally be flat rather than elevated/polypoid. Compared with patients with attenuated polyposis syndromes, LS patients develop fewer colorectal adenomas by age 50 years (usually <3 neoplasms). LS colorectal adenomas typically demonstrate features of increased risk of cancer, including villous histology and high-grade dysplasia. The adenoma–carcinoma sequence appears more rapid in LS with polyp to cancer dwell times estimated at 35 months compared with 10–15 years in sporadic cancer. This phenomenon is likely related to dysfunction of the MMR genes, leaving frequent DNA mismatches in multiple genes leading to malfunction of these genes. The histopathology of LS CRC is more frequently poorly differentiated, can be signet cell histology, abundant in extracellular mucin, with tumor infiltrating lymphocytes, and distinguished by a lymphoid (Crohn's-like pattern and/or peritumoral lymphocytes) host response to tumor. LS patients have improved survival from CRC stage for stage compared with those with sporadic cancer.
In addition to CRC, LS patients have a significantly increased risk for a wide variety of extracolonic malignancies (Table 4). The highest risk is for endometrial cancer (EC), which occurs in up to 54% of women with MLH1 and MSH2 mutations, with lower risk in those with PMS2 (15%) mutations and much higher risk in persons with MSH6 mutations (71%). LS caused by MSH6 mutation is also characterized by later onset of colorectal and endometrial cancers than with other MMR gene alternations. Increased lifetime risk of transitional cell carcinoma of the ureter, renal pelvis, and bladder; adenocarcinomas of the ovary, stomach, hepatobiliary tract, and small bowel; brain cancer (glioblastoma); and cutaneous sebaceous neoplasms also occur in LS families. An increased risk of pancreas cancer in LS has been described by some investigators but not others. The relationship between LS and breast cancer is unclear. Although a small increase in absolute risk of breast cancer (18%) has been found, most registry reports have not demonstrated this consistently. However, there are early-onset breast cancers in some LS kindreds in which tumors have the microsatellite instability (MSI) phenotype. In several studies, the relative risk of prostate cancer is 2.0– to 2.5–fold higher than the general population risk. Also, an excess of laryngeal and hematologic malignancies has been described, but a definite association to LS has not been established. An association between sarcoma and LS probably exists, but the magnitude of risk is unclear.
Phenotypic stigmata of LS are found rarely on physical examination, but can include café au lait spots, cutaneous sebaceous gland tumors, and keratoacanthomas. Café au lait spots are found in patients with biallelic mutations of the MMR genes. This variant of LS is referred to as constitutional MMR deficiency syndrome and will be described here.
In 1990, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer established criteria (Amsterdam I Criteria) for HNPCC (Table 5). All of the following are required to diagnose HNPCC: 3 or more relatives with histologically verified colorectal cancer, 1 of which is a first-degree relative of the other 2 (familial adenomatous polyposis should be excluded); CRC involving at least 2 generations; and 1 or more CRC cases diagnosed before the age of 50 years. In response to concern that these standards were too stringent for clinical and research application, more sensitive criteria (Amsterdam II criteria) were established in 1999 (Table 5). Amsterdam II criteria include some extracolonic tumors commonly seen in LS as qualifying cancers—in particular, cancer of the endometrium, small bowel, ureter, or renal pelvis. Most experts today expand the spectrum of LS-related tumors to also include cancer of the ovary, stomach, hepatobiliary tract, and brain.
The Revised Bethesda Guidelines are a third set of clinicopathologic criteria developed to identify individuals who deserve investigation for LS by evaluation of MSI and/or immunohistochemistry (IHC) testing of their tumors (Table 6).
HNPCC designates patients and/or families who fulfill the Amsterdam I or II criteria. LS is applied to patients and families in which the genetic basis can be linked to a germline mutation in one of the DNA MMR genes or the EPCAM gene. Lynch-like syndrome describes patients and/or families in which molecular testing demonstrates the presence of MSI and/or abnormalities in the expression of MMR gene proteins on IHC testing of tumor tissue expression, but no pathogenic germline mutation can be found in the patient (eg, in the absence of a BRAF mutation and/or MLH1 promoter hypermethylation when there is loss of tumor expression of the MLH1 protein). In a recent publication, about half of LLS patients had biallelic somatic mutations of MLH1 or MSH2 to explain the MMR deficient tumors without having causal germline or promotor mutations.
Familial colorectal cancer type X (FCRCTX) refers to patients and/or families that meet Amsterdam I criteria, but, when tumors are tested, lack the MSI characteristic of LS. Studies suggest that the age at diagnosis of CRC in these pedigrees is slightly older than in families with LS. Also, the lifetime risk of CRC appears substantially lower in FCRCTX families than in LS; the standardized incidence ratio for CRC in FCRCTX pedigrees was 2.3 (95% CL: 1.7–3.0) compared with 6.1 (95% CL: 5.7–7.2) for individuals in pedigrees with LS. In addition, in FCRCTX families, risk of extracolonic cancers found in LS is not significantly higher than the general population.
Muir-Torre syndrome, a rare variant of LS, is diagnosed in patients and/or families with LS and skin sebaceous gland neoplasms (sebaceous adenomas and carcinomas) and/or neoplasms of the hair follicle (keratoacanthomas). Mutations in any of the MMR genes can be found in these patients, but MSH2 mutation appears most common. MSI can be identified in the skin neoplasms and colorectal tumors of affected patients.
Turcot's syndrome is defined as patients and/or families with colorectal neoplasia and brain tumors. However, these families can be cases of LS (associated with glioblastomas) or familial adenomatous polyposis (associated with medulloblastomas), so Turcot's syndrome is not an independent entity.
Constitutional mismatch repair deficiency syndrome is the term applied to patients and/or families with biallelic mutations of the DNA MMR genes. These patients are characterized by café au lait spots, early (in childhood and teenage years) onset of colorectal neoplasia or other LS cancers, oligopolyposis in the small bowel and/or colon, brain tumors, and hematologic malignancies.
Lynch Syndrome Characteristics
Clinical Manifestations
In 1966, Dr Henry T. Lynch and colleagues reported familial aggregation of CRC with stomach and endometrial tumors in 2 extended pedigrees and designated this condition cancer family syndrome. Later, to differentiate this syndrome from the other well-known inherited form of CRC, familial adenomatous polyposis, the appellation hereditary nonpolyposis colorectal cancer was utilized. In 1984, the term Lynch syndrome was coined by Boland and Troncale to refer to this disorder. Today this condition is called Lynch syndrome. This designation is correctly applied to families and patients with a germline mutation in an MMR gene or loss of expression of the MSH2 gene due to deletion in the EPCAM gene. Also, this name is more appropriate than HNPCC because most LS patients will develop one or several adenomatous polyps, which makes the term nonpolyposis misleading.
LS is an autosomal dominant disorder with colorectal malignancy as the major clinical consequence. The lifetime risk of CRC in LS has been variably estimated and appears dependent on sex and the MMR gene mutated. Most reports of lifetime risks of CRC for MLH1 and MSH2 gene mutation carriers range from 30 to 74% (Table 3). Lower cumulative lifetime risk for colorectal malignancy ranging from 10 to 22% has been found in patients with MSH6 mutations and 15%–20% in those with PMS2 mutations. Mean age at CRC diagnosis in LS patients is 44–61 years compared with 69 years in sporadic cases of CRC. In LS, colorectal tumors arise primarily (60%–80%) on the right side of the colon (proximal to the splenic flexure) compared with 30% in sporadic CRC. A high rate of metachronous CRC (16% at 10 years; 41% at 20 years) is noted in LS patients with segmental surgical resection of the initial CRC. The precursor lesion for LS appears to be a discrete colonic adenoma, which can occasionally be flat rather than elevated/polypoid. Compared with patients with attenuated polyposis syndromes, LS patients develop fewer colorectal adenomas by age 50 years (usually <3 neoplasms). LS colorectal adenomas typically demonstrate features of increased risk of cancer, including villous histology and high-grade dysplasia. The adenoma–carcinoma sequence appears more rapid in LS with polyp to cancer dwell times estimated at 35 months compared with 10–15 years in sporadic cancer. This phenomenon is likely related to dysfunction of the MMR genes, leaving frequent DNA mismatches in multiple genes leading to malfunction of these genes. The histopathology of LS CRC is more frequently poorly differentiated, can be signet cell histology, abundant in extracellular mucin, with tumor infiltrating lymphocytes, and distinguished by a lymphoid (Crohn's-like pattern and/or peritumoral lymphocytes) host response to tumor. LS patients have improved survival from CRC stage for stage compared with those with sporadic cancer.
In addition to CRC, LS patients have a significantly increased risk for a wide variety of extracolonic malignancies (Table 4). The highest risk is for endometrial cancer (EC), which occurs in up to 54% of women with MLH1 and MSH2 mutations, with lower risk in those with PMS2 (15%) mutations and much higher risk in persons with MSH6 mutations (71%). LS caused by MSH6 mutation is also characterized by later onset of colorectal and endometrial cancers than with other MMR gene alternations. Increased lifetime risk of transitional cell carcinoma of the ureter, renal pelvis, and bladder; adenocarcinomas of the ovary, stomach, hepatobiliary tract, and small bowel; brain cancer (glioblastoma); and cutaneous sebaceous neoplasms also occur in LS families. An increased risk of pancreas cancer in LS has been described by some investigators but not others. The relationship between LS and breast cancer is unclear. Although a small increase in absolute risk of breast cancer (18%) has been found, most registry reports have not demonstrated this consistently. However, there are early-onset breast cancers in some LS kindreds in which tumors have the microsatellite instability (MSI) phenotype. In several studies, the relative risk of prostate cancer is 2.0– to 2.5–fold higher than the general population risk. Also, an excess of laryngeal and hematologic malignancies has been described, but a definite association to LS has not been established. An association between sarcoma and LS probably exists, but the magnitude of risk is unclear.
Phenotypic stigmata of LS are found rarely on physical examination, but can include café au lait spots, cutaneous sebaceous gland tumors, and keratoacanthomas. Café au lait spots are found in patients with biallelic mutations of the MMR genes. This variant of LS is referred to as constitutional MMR deficiency syndrome and will be described here.
Clinical Criteria
In 1990, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer established criteria (Amsterdam I Criteria) for HNPCC (Table 5). All of the following are required to diagnose HNPCC: 3 or more relatives with histologically verified colorectal cancer, 1 of which is a first-degree relative of the other 2 (familial adenomatous polyposis should be excluded); CRC involving at least 2 generations; and 1 or more CRC cases diagnosed before the age of 50 years. In response to concern that these standards were too stringent for clinical and research application, more sensitive criteria (Amsterdam II criteria) were established in 1999 (Table 5). Amsterdam II criteria include some extracolonic tumors commonly seen in LS as qualifying cancers—in particular, cancer of the endometrium, small bowel, ureter, or renal pelvis. Most experts today expand the spectrum of LS-related tumors to also include cancer of the ovary, stomach, hepatobiliary tract, and brain.
The Revised Bethesda Guidelines are a third set of clinicopathologic criteria developed to identify individuals who deserve investigation for LS by evaluation of MSI and/or immunohistochemistry (IHC) testing of their tumors (Table 6).
Terminology/Differential Diagnosis
HNPCC designates patients and/or families who fulfill the Amsterdam I or II criteria. LS is applied to patients and families in which the genetic basis can be linked to a germline mutation in one of the DNA MMR genes or the EPCAM gene. Lynch-like syndrome describes patients and/or families in which molecular testing demonstrates the presence of MSI and/or abnormalities in the expression of MMR gene proteins on IHC testing of tumor tissue expression, but no pathogenic germline mutation can be found in the patient (eg, in the absence of a BRAF mutation and/or MLH1 promoter hypermethylation when there is loss of tumor expression of the MLH1 protein). In a recent publication, about half of LLS patients had biallelic somatic mutations of MLH1 or MSH2 to explain the MMR deficient tumors without having causal germline or promotor mutations.
Familial colorectal cancer type X (FCRCTX) refers to patients and/or families that meet Amsterdam I criteria, but, when tumors are tested, lack the MSI characteristic of LS. Studies suggest that the age at diagnosis of CRC in these pedigrees is slightly older than in families with LS. Also, the lifetime risk of CRC appears substantially lower in FCRCTX families than in LS; the standardized incidence ratio for CRC in FCRCTX pedigrees was 2.3 (95% CL: 1.7–3.0) compared with 6.1 (95% CL: 5.7–7.2) for individuals in pedigrees with LS. In addition, in FCRCTX families, risk of extracolonic cancers found in LS is not significantly higher than the general population.
Muir-Torre syndrome, a rare variant of LS, is diagnosed in patients and/or families with LS and skin sebaceous gland neoplasms (sebaceous adenomas and carcinomas) and/or neoplasms of the hair follicle (keratoacanthomas). Mutations in any of the MMR genes can be found in these patients, but MSH2 mutation appears most common. MSI can be identified in the skin neoplasms and colorectal tumors of affected patients.
Turcot's syndrome is defined as patients and/or families with colorectal neoplasia and brain tumors. However, these families can be cases of LS (associated with glioblastomas) or familial adenomatous polyposis (associated with medulloblastomas), so Turcot's syndrome is not an independent entity.
Constitutional mismatch repair deficiency syndrome is the term applied to patients and/or families with biallelic mutations of the DNA MMR genes. These patients are characterized by café au lait spots, early (in childhood and teenage years) onset of colorectal neoplasia or other LS cancers, oligopolyposis in the small bowel and/or colon, brain tumors, and hematologic malignancies.
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