Lynch syndrome is caused by germline mutations in DNA mismatch repair (MMR) genes. Both microsatellite instability (MSI) testing and immunohistochemical analyses (IHC) of colon cancers are valuable diagnostic strategies for Lynch syndrome. We sought to determine whether these markers of MMR deficiency were also detectable in pre-cancerous colorectal adenomas. Fifteen subjects with a germline MMR gene mutation who had 44 adenomas removed during surveillance colonoscopy were identified. MSI testing and IHC for MLH1 , MSH2 , and MSH6 were performed. MSI was detected in 23 adenomas. There was a significant association between MSI and high-grade dysplasia (P ؍ 0.006) and distal location (P ؍ 0.0008). Loss of MMR protein by IHC was detected in 31 adenomas. A significant association was observed between loss of staining by IHC and high-grade dysplasia (P ؍ 0.04). Among the 40 adenomas in which both MSI tests and IHC were performed , the presence of a germline mutation correlated with an abnormal MSI result in 58% of cases , an abnormal IHC result in 70% of cases , and either an abnormal MSI or IHC result in 73% of cases. The combination of MSI and IHC testing in colorectal adenomas is a sensitive screen for the detection of Lynch syndrome and may be particularly useful when Lynch syndrome is suspected and adenomatous polyps are the only tissues available for
One of the most vexing issues in diagnostic neuropathology relates to the distinction of diffuse astrocytomas (and other diffuse gliomas) from astrocytosis (gliosis) on biopsies, particularly small biopsies. This challenging differential diagnosis arises in two general situations: (1) low cellularity edges of infiltrating astrocytomas versus mild astrocytosis from a nearby reactive condition; and (2) florid astrocytosis (e.g., near a vascular malformation) versus more cellular astrocytomas.The "holy grail" sought in such diagnostic dilemmas is a tumor-specific marker. To date, the most widely used marker for this purpose has been p53 detection by immunohistochemistry; since mutant p53 has a longer half-life than wild-type p53, it can be more readily detected immunohistochemically than wild-type protein [3,9]. However, p53 immunohistochemistry is not an entirely accurate marker since: (1) it may show light labeling of non-neoplastic cells; (2) not all TP53 gene mutations result in immunohistochemically detectable p53; and (3) some reactive conditions (notably progressive multifocal leukoencephalopathy) may be strongly positive [8]. Another immunohistochemical marker of tumor cells is the vIII mutant of the epidermal growth factor receptor (EGFR) protein. However, this marker is not of diagnostic utility in the above differential diagnosis, since EGFRvIII is primarily expressed in glioblastomas rather than lower-grade astrocytomas. Moreover, antibodies are not widely available or readily optimized for standard immunohistochemistry, again limiting its differential diagnostic utility.Recently, isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations have been demonstrated in a variety of diffuse gliomas, with IDH1 mutations occurring commonly in lower-grade gliomas [1,2,10,12]. Notably, nearly all IDH1 mutations are the same, with CGT-CAT transition causing a specific amino acid change from arginine to histidine at codon 132 (R132H). As a result, the detection of IDH1 mutations may be a specific means to aid in differentiating between glioma and gliosis. Indeed, one recent paper utilized a PCR-based assay to show that IDH mutations are found in astrocytomas but not in reactive conditions [6]. Of 57 nonneoplastic conditions, none showed IDH1/2 mutations. In contrast, 67.3% of grade II and grade
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