Clinical Characteristics

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant colon cancer syndrome. The first description of a cancer-prone family with HNPCC dates back to the late 1800s.1 However, it was not until the work of Lynch in the 1970s that a more complete clinical picture of this disorder began to emerge.2,3 The diagnosis of HNPCC has, until recently, been based primarily on family history. As a result, reliably differentiating patients with HNPCC from those with sporadic cancer has been difficult. However, the constellation of several clinical characteristics, in addition to family history, may raise suspicion of HNPCC.

One of the primary clinical characteristics of HNPCC is the early age at which tumors develop. The average age of colon cancer diagnosis in individuals with HNPCC is in the early to mid-40s, although many tumors may occur in the 20s or even in teenage years. This is in contrast to a mean age of diagnosis of the mid-60s for sporadic colorectal cancer (CRC).4 In addition to CRC, several other tumor types are also observed at an increased frequency in families with HNPCC. These include endometrial, ovarian, gastric, small intestine, brain, and urinary and biliary tract tumors.5 In addition, the Muir-Torre variant is associated with the typical extracolonic features of HNPCC in addition to sebaceous gland tumors and keratoacanthomas.6

Individuals with HNPCC also have a high rate of synchronous and metachronous tumors. Although HNPCC patients do not develop colon polyps more frequently than the general population, their polyps tend to be larger, to be more villous, and to contain more high-grade dysplasia.7 These observations are consistent with an "aggressive adenoma" theory, in which, although polyps are not more common, they progress to carcinoma more frequently and more quickly than sporadic polyps.8 Thus, the increased rate of tumor progression may be the major factor accounting for the cancer predisposition in HNPCC.

Several histologic features of the colon tumors are characteristic of a particular subgroup of HNPCC patients

(those with defective DNA mismatch repair). These features include high histologic grade, mucinous or signet ring cell differentiation, medullary features, and a host immune response characterized by a Crohn's-like lymphoid reaction and an excess of tumor-infiltrating lymphocytes.9 Although many of the histologic features of HNPCC would be considered aggressive (e.g., high grade and signet ring differentiation), HNPCC is paradoxically associated with a more favorable prognosis. In one study, the 5-year survival rate after CRC in individuals with HNPCC was reported to be 86% versus 59% for those with sporadic CRC.10 Possible biologic explanations for the favorable prognosis include a decreased propensity of these tumors to metastasize, the high frequency of diploid DNA content, wild-type TP53 status, and enhanced immune surveillance.11-14

In 1991, a set of guidelines (the Amsterdam criteria) was established to aid in the identification of families with HNPCC and to make the process of defining families for research purposes more uniform (Table 19-1a).15 These criteria were based primarily on an extended family history of CRC and were instrumental in helping to identify the genes responsible for a majority of families with HNPCC. However, from a clinical perspective, several shortcomings of the Amsterdam criteria were subsequently identified. First, although many individuals with HNPCC have affected relatives in multiple generations, this is not always the case, because of small family size, variable pen-etrance, new mutations, or incomplete pedigree information. Second, these criteria did not consider the many extracolonic tumors frequently associated with HNPCC. Thus, use of the Amsterdam criteria for clinical purposes likely leads to an underdiagnosis of HNPCC.As a result, the true incidence of HNPCC and the underlying molecular defects have been difficult to establish. The estimates of the incidence of HNPCC vary widely, but population-based studies indicate that the diagnosis accounts for approximately 2% of all CRC.16,17

To address the limitations of the initial Amsterdam crite-ria,the Amsterdam criteria II18 and the Bethesda guidelines19 were proposed (Table 19-1b and c). These criteria

Table 19-1. Minimum Criteria for Clinical Diagnosis of HNPCC

a. Amsterdam criteria I

1. At least three relatives should have histologically verified CRC;one of them should be a first-degree relative to the other two.

2. At least two successive generations should be affected.

3. In one of the relatives colorectal cancer should be diagnosed before age 50.

4. Familial adenomatous polyposis should be excluded.

b. Amsterdam criteria II

1. At least three relatives should have an HNPCC-associated cancer (CRC;cancer of the endometrium, small bowel, ureter, or renal pelvis).

2. One should be a first-degree relative of the other two.

3. At least two successive generations should be affected.

4. At least one should be diagnosed before age 50.

5. Familial adenomatous polyposis should be excluded in the CRC case(s), if any.

6. Tumors should be verified by pathologic examination.

c. Bethesda criteria

1. Individuals with cancer in families that meet the Amsterdam criteria.

2. Individuals with two HNPCC-related cancers including synchronous and metachronous CRC, or associated extracolonic cancers.*

3. Individuals with CRC and a first-degree relative with CRC and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed before age 45, and the adenoma before age 40.

4. Individuals with CRC or endometrial cancer diagnosed before age 45.

5. Individuals with right-sided CRC showing undifferentiated pattern on histopathology.f

6. Individuals with signet ring cell type CRC.t

7. Individuals with adenomas diagnosed before age 40.

*Endometrial, ovarian, gastric, hepatobiliary, small bowel, transitional cell carcinoma of the renal pelvis or ureter. fSolid cribriform defined as a poorly undifferentiated carcinoma composed of irregular solid sheets of large eosinophilic cells and containing small glandlike spaces. t Composed of more than 50% signet ring cells.

allow for a more liberal definition of HNPCC and include individuals with HNPCC-associated tumors as well as patients with early onset or multiple primary tumors, or both, whose family history is either incomplete or for whom the pedigree is small. These guidelines also include criteria based on the common histologic presentations of the tumors and make recommendations for germline DNA testing.

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