The pathology of HNPCC tumours is similar to that of sporadic colorectal carcinoma showing high levels of instability at short tandem repeat sequences, microsatellites (MSI-H). Many studies make no distinction between familial and non-familial MSI-H carcinomas. The following descriptions apply to all MSI-H carcinomas, but highlight subtle differences between HNPCC cancers and their sporadic counterparts where these are known.

Fig. 6.64 Immunohistochemistry for the MLH1 gene product in a patient with HNPCC. Normal expression is seen in the non-neoplastic epithelium (left). Expression is lost in the adenocarcinoma (right).


HNPCC cancers show a predilection for the proximal colon including caecum, ascending colon, hepatic flexure and transverse colon {1130}. At least 60% occur in the proximal colon. The gross appearances have not been studied in detail. However, since HNPCC and MSI-H colorectal carcinomas show a consistent trend towards good circumscription {842, 1723}, they are more likely to present as polypoid growths, plaques, ulcers or bulky masses and less likely to present as diffuse growths or tight strictures.

Adenomas are not numerous but are likely to be more frequent in HNPCC subjects than age-matched controls {846}. Colonoscopic studies indicate that the distribution of adenomas in HNPCC may not mirror the proximal colonic predilection of carcinoma {846}. This could be

Table 6.02

Revised diagnostic criteria for HNPCC (Amsterdam criteria II)

due to the occurrence of sporadic distal adenomas in older HNPCC subjects or because proximal adenomas are more likely to progress to cancer.


No individual microscopic feature is specific to HNPCC, but particular groups of features are diagnostically useful {1723}. Identical features are found in the 10 to 15% of sporadic colorectal cancers that show high levels of DNA microsatellite instability (MSI-H) {842}. However, sporadic MSI-H cancers present in older subjects lacking a family history of bowel cancer. HNPCC and sporadic MSI-H col-orectal cancers fall into three groups based on site and microscopic criteria: Proximally located mucinous adenocarcinomas. These are usually well circumscribed and well or moderately differentiated. Lymphocytic infiltration is not prominent but tumour infiltrating (intra-epithelial) lymphocytes (TIL) may be evident in non-mucinous areas. Tubulo-vil-lous or villous adenomatous remnants adjacent to the cancer may be present. Mucin production may be more common in subjects with an MSH2germline mutation {1723}.

Proximally located, poorly differentiated adenocarcinomas. Poor differentation indicates a failure of gland formation, the malignant epithelium being arranged in small clusters, irregular trabeculae or large aggregates. Tumours are well circumscribed and lack an abundant desmoplastic stroma. Some are peppered with TIL. A Crohn-like lymphocytic reaction may be present. This subtype has been described as medullary or 'undifferentiated', though the majority contains subclones in which glandular differentiation is evident. This subtype may be more common in subjects with an MSH2 mutation {1723}. In general, colorectal cancers showing TIL and/or a Crohn-like lymphocytic reaction appear to be more common in subjects with an MLH1 germline mutation {1723}. Adenomas in HNPCC. These are more likely to show features indicative of increased cancer risk including villosity and high-grade intraepithelial neoplasia {846}. Immunohistochemical staining to demonstrate loss of expression of MLH1 or MSH2 may assist in pinpointing the underlying germline mutation. However, antigenicity may be retained in the case of MLH1, even if genetic changes have resulted in a non-functioning protein {1924A: 1924B}. Virtually all sporadic MSI-H carcinomas lose MLH1 through methylation.

Immunohistochemical staining of MSI-H colorectal cancers confirms that the majority of TIL are CD3 positive T-cells and most, in turn, are cytotoxic (CD8 positive) {423}. In H&E sections, lymphocytes are difficult to discern when the percentage of CD3 positive lymphocytes (out of all epithelial nuclei) is less than about 5%. CD3 counts in excess of 5% occur in around 70% of MSI-H cancers. CD3 counts in excess of 10% are highly specific for MSI-H cancers. The nodular arrangements of lymphocytes occurring peri-tumourally or within the serosa (Crohn-like reaction) are B-lymphocytes surrounded by T-lymphocytes.


Acquired genetic changes in HNPCC cancers

The demonstration of DNA microsatellite instability serves as an important bio-marker for HNPCC cancers. Bandshifts in BAT26 are highly sensitive for both familial and sporadic MSI-H cancers {3}, though some cases may be missed {548}.

Table 6.03

Summary of clinical, pathological and genetic features of HNPCC (Lynch syndrome)

- Familial clustering of colorectal and/or endometrial cancer

- Excess risk of cancer of the ovary, ureter/renal pelvis, small bowel, stomach, brain, hepatobiliary tract, and skin (sebaceous tumours)

- Development of multiple cancers at an early age

- Features of colorectal adenoma include: (1) variable numbers from one to a few; (2) increased proportion of adenomas with a villous growth pattern (3) a high degree of dysplasia; (4) rapid progression from adenoma to carcinoma and (5) high frequency of microsatellite instability (MSI-H)

- Features of colorectal cancer include: (1) predilection for proximal colon; (2) improved survival; (3) multiple colorectal cancers (4) increased proportion of muci-nous tumours, poorly differentiated tumours, and tumours with marked host-lymphocytic infiltration and lymphoid aggregation at the tumour margin.

There should be at least three relatives with an

HNPCC-associated cancer: colorectal cancer

(CRC), or cancer of the endometrium, small bowel, ureter or renal pelvis.

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

- At least two successive generations should be affected.

- At least one tumour should be diagnosed before age 50.

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

- Tumours should be verified by histopatho-logical examination.


Fig. 6.65 Tubular adenoma from a patient with HNPCC immunostained for (A) MLH and (B) MSH2 . The neoplastic epithelium shows loss of MSH2 expression (upper portion of B)

A panel of five markers (BAT25, BAT26, D2S123, D5S346 and D17S250) has been recommended for screening purposes {164}. Bandshifts at two or more microsatellite loci are indicative of MSI-H. Around 60% of HNPCC adenomas are MSI-H {2}.

Most MSI-H cancers are diploid or near diploid and the frequency of loss of heterozygosity (LOH) is low for the traditional loci 5q, 17p and 18q {962, 841}. The frequency of APC, KRAS and TP53 mutation is reduced {962, 841}. Conversely, mutations are encountered in TGFRII, IGF2R, BAX, E2F-4, MSH3, MSH6 and caspase 5 {548, 1165, 1699, 1793, 2156, 1558}. In general, the driving force for colorectal cancer development and progression may be DNA instability (mutator pathway) or chromosomal instability (suppressor pathway). HNPCC cancers and sporadic MSI-H cancers share the mutator pathway.

Mode of inheritance, chromosomal location, and structure

HNPCC is transmitted as an autosomal dominant trait. It is associated with germline mutations in five genes with verified or putative DNA mismatch repair function, namely MSH2 (MutS homologue 2), MLH1 (MutL homologue 1), PMS1 (Postmeiotic segregation 1), PMS2

(Postmeiotic segregation 2), and MSH6 (MutS homologue 6). Structural characteristics of these genes are given in Table 6.04. Homozygous MLH1 mutations confer to a neurofibromatosis 1 like pheno-type {2048, 1580}.

Gene product

HNPCC genes are ubiquitously expressed in adult human tissues, and therefore, the expression pattern does not seem to explain the selective organ involvement in this syndrome. Expression is particularly prominent in the epithelium of the digestive tract as well as in testis and ovary {505, 1030, 2120}. In the intestine, expression is confined to the replicating compartment, i.e. the bottom half of the crypts. Immunohistochemical staining against these proteins is nuclear.


The protein products of HNPCC genes are key players in the correction of mismatches that arise during DNA replication {957}. Two different MutS-related het-erodimeric complexes are responsible for mismatch recognition: MSH2-MSH3 and MSH2-MSH6. While the presence of MSH2 in the complex is mandatory, MSH3 can replace MSH6 in the correction of insertion-deletion mismatches, but not single-base mispairs. Following mis-

Fig. 6.66 Microsatellite instability in HNPCC. Shifts of allele size are evident in dinucleotide and mononucleotide markers. N = normal tissue, T = tumour.

match binding, a heterodimeric complex of MutL-related proteins, MLH1-PMS2 (and possibly another alternative complex formed by MLH1-MLH3) is recruited, and this larger complex, together with numerous other proteins, accomplishes mismatch repair. The observed functional redundancy in the DNA mismatch repair protein family may help explain why mutations in MSH2 and MLH1 are prevalent in HNPCC families, while mutations in PMS1, PMS2, and MSH6 are much less frequent, and no germline mutations in MSH3 or MLH3 have been reported, so far (see below). Mismatch repair deficiency gives rise to microsatellite instability, and as such may aid in the diagnosis of this syndrome {3}.

Table 6.04

Characteristics of HNPCC-associated human DNA mismatch repair genes.

Table 6.04

Characteristics of HNPCC-associated human DNA mismatch repair genes.


Chromosomal location

Length of cDNA (kb)

Number of exons

Genomic size (kb)


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