Microsatellite instability in sporadic mucinous colorectal carcinomas: relationship to clinico‐pathological variables

Messerini, Luca; Vitelli, Francesca; Vitis, Lucia Rosaria De; Mori, Simona Maria Frances; Calzolari, Anna; Palmirotta, Raffaele; Calabrò, Antonino; Papi, Laura

doi:10.1002/(sici)1096-9896(199708)182:4<380::aid-path871>3.3.co;2-l

Cited by 35 publications

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“…Tumors with defective MMR tend to occur in younger patients, more often occur in the proximal colon, are more often mucinous, and frequently show a Crohn's-like lymphoid infiltrate or tumor-infiltrating lymphocytes. [8][9][10][11][12][13][14][15][16][17][18][19][20] In our study, none of the mucinous carcinomas or LAMNs with extra-appendiceal spread (considered well-differentiated mucinous carcinoma by some) demonstrated defective MMR. Our results are similar to those of Kabbani et al 40 who were unable to demonstrate MSI in 30 appendiceal adenocarcinomas.…”

Section: Discussionmentioning

confidence: 74%

“…7 Several investigators have reported that colorectal carcinomas with defective MMR often show distinctive clinicopathologic features including location in the proximal colon, younger patient age, mucinous differentiation, and a host-immune response characterized by a Crohn's-like lymphoid reaction or tumor infiltrating lymphocytes. [8][9][10][11][12][13][14][15][16][17][18][19][20] Serrated colonic polyps (hyperplastic polyps, mixed hyperplastic and adenomatous polyps, and serrated adenomas), particularly right-sided ones, are also associated with defective MMR 2,21 and are regarded as the precursor lesions for colorectal carcinomas with MSI, thus forming the basis of a 'serrated pathway' of colorectal tumorigenesis. 21 Appendiceal carcinomas, in contrast to 'generic colorectal carcinoma', often show mucinous differentiation and are per-force right-sided.…”

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confidence: 99%

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Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

2004

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Defective DNA mismatch repair has been proposed as a second pathway for colonic carcinogenesis, particularly in tumors arising in the right colon. We investigated whether tumors arising in the appendix are associated with defective DNA mismatch repair using immunohistochemistry for mismatch repair enzymes hMLH-1, hMSH-2, hMSH-6, and hPMS-2. These immunoassays have been shown to be highly sensitive and specific for defective DNA mismatch repair in sporadic and familial adenocarcinomas. Sporadic adenocarcinomas with defective DNA mismatch repair essentially always show loss of hMLH-1, while loss of hMSH-2, hMSH-6, or hPMS-2 is almost always due to germline mutation. In all, 35 cases of appendiceal epithelial neoplasms were evaluated, comprising 18 low-grade appendiceal mucinous neoplasms confined to the appendix; eight low-grade appendiceal mucinous neoplasms with extra-appendiceal spread (five peritoneum and ovaries, two peritoneum, one ovaries only); and nine invasive adenocarcinomas (three with metastatic disease). All immunohistochemical slides were reviewed by two pathologists. One (11%) invasive adenocarcinoma showed absent expression of hMSH-2 and hMSH-6, but preserved hMLH-1 and hPMS-2 expression. This case was a 26-year-old female with a history of synovial sarcoma who presented with acute appendicitis and appendiceal perforation (median age for other invasive carcinomas, 62 years; range 38-76 years). The appendiceal tumor was a moderately differentiated, colonic-type adenocarcinoma without significant extracellular mucin or tumor-infiltrating lymphocytes. The remaining invasive carcinomas and low-grade appendiceal mucinous neoplasms demonstrated preserved expression of all mismatch repair enzymes, including the seven cases in which extra-appendiceal tumor was also evaluated. We conclude that defective DNA mismatch repair does not play a role in the pathogenesis of low-grade appendiceal mucinous neoplasms. Defective DNA mismatch was found in 11% of invasive carcinomas, likely due to a germline mutation. These findings suggest that sporadic appendiceal neoplasia rarely arises through the defective DNA mismatch repair (mutator) pathway.

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Section: Discussionmentioning

confidence: 74%

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confidence: 99%

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

2004

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“…Thus, 53% of the MSI-H tumours were strong HLA-DR positive, vs 11% in the MSS/MSI-L group. Because of the strong association between MSI-H tumours and HLA-DR expression, significant correlation was also demonstrated between DR expression and tumours with right-sided location, poor differentiation and diploid DNA pattern, which are the characteristics typical for colorectal tumours following the MSI pathway (Lothe et al, 1993;Kim et al, 1994;Ruschoff et al, 1995;Messerini et al, 1997;Jass et al, 1998;Thibodeau et al, 1998). Strong HLA-DR positive tumours also had a higher TIL count than the other two groups.…”

Section: Discussionmentioning

confidence: 99%

“…MSI leads to the accumulation of deletion and insertion of nucleotides at simple repeat sequences. The clinical and pathological features of colorectal cancers showing high degree of MSI (MSI-H) are proximal location, poor differentiation, mucinous phenotype, high density of lymphocyte infiltration, diploid DNA content, reduced invasiveness, female preponderance and multiplicity (Lothe et al, 1993;Kim et al, 1994;Ruschoff et al, 1995;Messerini et al, 1997;Jass et al, 1998;Thibodeau et al, 1998). High density of tumour infiltrating lymphocytes (TIL) are found in MSI-H colorectal cancers, whereas it is only infrequently observed in MSI-L and MSS tumours (Jass et al, 1998;Smyrk et al, 2001).…”

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confidence: 99%

“…Furthermore, patients with MSI-H tumours and a high content of activated cytotoxic lymphocytes showed improved overall survival (Guidoboni et al, 2001). Some studies have reported improved survival among colorectal cancer patients with microsatellite unstable tumours (Lothe et al, 1993;Thibodeau et al, 1993;Bubb et al, 1996;Lukish et al, 1998;Halling et al, 1999;Johannsdottir et al, 1999;Massa et al, 1999;Elsaleh et al, 2000;Gryfe et al, 2000;Hemminki et al, 2000;Wright et al, 2000;Ward et al, 2001;Watanabe et al, 2001), while others have not (Messerini et al, 1997;Senba et al, 1998;Feeley et al, 1999;Salahshor et al, 1999;Curran et al, 2000).…”

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Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

et al. 2002

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Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival ( P <0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability ( P <0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients. British Journal of Cancer (2002) 87 , 756–762. doi: 10.1038/sj.bjc.6600507 www.bjcancer.com © 2002 Cancer Research UK

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p27 cell‐cycle inhibitor is inversely correlated with lymph node metastases in right‐sided colon cancer

Liu¹,

Ferguson²,

Cooper³

et al. 1999

J. Clin. Lab. Anal.

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p27, a cyclin-dependent kinase inhibitor, suppresses proliferation of normal and neoplastic cells. Expression of p27 is correlated with survival in colon cancer. To some degree, right-sided colon cancers differ biologically and clinically from left-sided colon cancers. We analyzed 41 patients with right-sided colon cancers, including 18 cases with regional lymph node metastases and 23 cases with negative lymph nodes. Immunostaining for p27 was performed on histologic sections of primary cancers and scored. Correlation of p27 protein expression with histologic parameters was performed by t-test and multivariate analysis. Decreased p27 protein expression was associated with large tumor size. As percentages of positively stained tumor cells decreased from 70 to 29%, the mean tumor size increased from 1.9 to 7.3 cm. p27 protein expression significantly decreased in primary cancers with angiolymphatic invasion or with positive lymph nodes in comparison with those without angiolymphatic invasion (26 +/- 6 vs. 44 +/- 5%, P < 0.03) or with negative lymph nodes (23 +/- 4 vs. 47 +/- 6%, P < 0.003). p27 expression was not statistically different in terms of depth of tumor invasion (T1/T2 vs. T3/T4), tumor type or tumor differentiation. Multivariate analysis revealed that low p27 expression in primary cancers was correlated with lymph node metastases (P = 0.01). However, it did not correlate with any other histologic parameters. In summary, decreased p27 expression was associated with an increased likelihood of lymph node metastases in colon cancers, independent of depth of tumor invasion. This implies that p27 is a potentially important predictor for tumor metastasis and patient's prognosis in right-sided colon cancers.

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Microsatellite instability in sporadic mucinous colorectal carcinomas: relationship to clinico‐pathological variables

Cited by 35 publications

References 0 publications

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

p27 cell‐cycle inhibitor is inversely correlated with lymph node metastases in right‐sided colon cancer

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