The terms HNPCC and Lynch syndrome have often been used synonymously; however, a greater understanding of the molecular mechanisms underlying cancer development in this disease has led to more precise definitions. In 1985, Henry Lynch introduced the term HNPCC to describe a syndrome that he thought was characterized by an autosomal dominant inheritance pattern, early onset of cancers, multiple colorectal cancers, and extracolonic cancers, most notably those of the endometrium and ovaries [2,3]. As clinical cancer registries began to form, the need for standardized definitions to facilitate communication and clinical research became apparent. Subsequently, the Amsterdam I criteria (Box 1) were proposed in 1991 to define families that were considered to have HNPCC [4]. These criteria did not capture the full extent of the syndrome and were later revised in 1999 (Amsterdam II) to include extracolonic cancers in an effort to improve sensitivity [5]. More recently, some groups have broadened the clinical criteria (Amsterdam-like) to allow for inclusion of high-risk adenomas as a surrogate for colorectal cancer to correct for the phenotype attenuation secondary to the increasing use of colonoscopic surveillance and polypectomy [6].

Box 1 Amsterdam criteria that define HNPCC

• Amsterdam I (1991)

Three or more family members diagnosed with colorectal cancer, 1 of whom is a first-degree relative of the other 2

Two successive affected generations

One or more of the cancers diagnosed before 50 years of age

Familial adenomatous polyposis has been excluded

• Amsterdam II (1999)

Three or more family members diagnosed with an HNPCC-related cancer, 1 of whom is a first-degree relative of the other 2

Two successive affected generations

One or more of the HNPCC-related cancers diagnosed before 50 years of age

Familial adenomatous polyposis has been excluded

The underlying genetic cause of cancers associated with HNPCC was identified in 1993 as a heritable mutation in the DNA mismatch repair (MMR) mechanism [7–9]. As genetic and molecular laboratory techniques developed, this finding allowed for a more accurate identification of kindred with truly increased risk of developing malignancy. Importantly, among patients with known hereditary MMR deficiency, only approximately 40% meet the Amsterdam criteria [1]. Conversely, only approximately 50% to 60% of patients that meet the Amsterdam criteria will carry a known MMR defect [10]. Therefore, to be more precise, it has been suggested that Lynch syndrome moniker be reserved for patients with an MMR gene mutation [11]. In lieu of genetic testing, patients meeting the Amsterdam criteria who develop a cancer that is microsatellite unstable are putatively considered to have Lynch syndrome because MMR deficiency results in tumor microsatellite instability. Thus, the Amsterdam criteria are used to define HNPCC and can, then, be used as a guide to help clinicians determine those who may benefit from genetic counseling and testing to identify true Lynch syndrome, defined as a family that harbors a germline defect in the MMR mechanism. Patients who meet the Amsterdam criteria (and thus HNPCC) but have microsatellite stable tumors have been coined as familial colorectal cancer type X [12], which is briefly discussed later.

The late pathologist Jeremy Jass clarified the confusing nomenclature in the following way: “The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. If present, these are merely useful clinical pointers that have been accorded undue importance when considered in isolation of other facts. No simple set of clinical criteria can serve as a diagnostic label for Lynch syndrome. At the same time, the careful appraisal of clinical, pathologic and molecular features can achieve an accurate working diagnosis before the demonstration of a pathogenic germline mutation in a DNA mismatch repair gene” [11].

It is well-known that patients with Lynch syndrome are at increased risk for developing cancer compared with the general population. For MMR mutation carriers, the incidence of colorectal cancer is approximately 60% to 80% and the incidence of uterine cancer is approximately 40% to 60% [13–17]. Cancers of the stomach and ovaries are the next most common, with incidence of approximately 7% to 19% and 9% to 13%, respectively [14,18]. Less common tumors but still with increased incidence compared with the general population include those of the hepatobiliary tract (2%–7%), urinary epithelium (4%–5%), small bowel (1%–4%), pancreas (3%–4%), and brain or central nervous system (1%–3%).

The goal of surveillance is to detect precursor lesions before they develop into cancer and thus prevent cancer-related deaths. Multiple studies have shown that surveillance by colonoscopy in patients with Lynch syndrome decreases the development of, and the number of deaths from, colorectal cancer [15,19–21]. Patients with cancer before 20 years of age are extremely rare, and thus, the first colonoscopy is recommended at age 20 to 25 or 10 years younger than the earliest cancer in the family with subsequent surveillance every 1 to 2 years [19,22,23].

Surgery for Lynch syndrome may be considered therapeutic or prophylactic. Therapeutic resection, such as a right hemicolectomy for an ascending colon cancer or a hysterectomy for uterine cancer, is done to treat the disease. On the other hand, prophylactic surgery may be performed as an intervention done to prevent the development of disease by removing the organ at risk before the development of cancer. Both therapeutic and prophylactic practices are used in the treatment of patients with Lynch syndrome.