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Anal squamous cell carcinomas (ASCCs) frequently harbor human papillomavirus (HPV), most commonly high-risk (HR-) HPV type 16. While p16 immunohistochemistry (IHC) is typically used as a surrogate for HR-HPV status in the oropharynx and cervix, its overexpression can also occur as a result of oncogenic stress and sometimes prove nonspecific. There have been recent investigations into the use of HPV RNA in situ hybridization (RISH) assays as an alternative method, which have shown robust results for squamous cell carcinomas of the oropharynx and cervix. Our study evaluated HPV RISH and p16 IHC in 50 ASCCs, as well as the clinicopathologic features of ASCC relative to HPV status. We found that HPV RISH and p16 IHC were closely in agreement with 96% concordance. Using the 2 methodologies, 78% of ASCCs were HR-HPV positive, 10% were low-risk HPV positive, and 12% were HPV-negative. None of our cases showed co-infection across HR-HPV and low-risk HPV. ASCCs that were not related to HR-HPV were more likely to have a typical keratinizing morphology (P=0.05) and more likely to involve the perianal area (P=0.006). HPV-negative cases were particularly aggressive with high rates of metastases and patient death within 2 years of diagnosis. Overall, HPV RISH appears to be a reliable methodology for testing, and HPV status may have implications for prognostication of ASCCs.

Lynch syndrome (LS) is defined by germline mutations in DNA mismatch repair (MMR) genes, and affected patients are at high risk for multiple cancers. Reflexive testing for MMR protein loss by immunohistochemistry (IHC) is currently only recommended for colorectal and endometrial cancers, although upper tract urothelial carcinoma (UTUC) is the third-most common malignancy in patients with LS. To study the suitability of universal MMR IHC screening for UTUC, we investigated MMR expression and microsatellite status in UTUC in comparison to bladder UC (BUC), and evaluated the clinicopathologic features of UTUC. We found that 9% of UTUC showed MMR IHC loss (8 MSH6 alone; 1 MSH2 and MSH6; 1 MLH1 and PMS2; n=117) compared with 1% of BUC (1 MSH6 alone; n=160) (P=0.001). Of these, 4/10 (40%) of UTUC (3% overall; 3 MSH6 alone; 1 MLH1 and PMS2) and none (0%) of BUC had high microsatellite instability on molecular testing (P=0.03). The only predictive clinicopathologic feature for MMR loss was a personal history of colorectal cancer (P=0.0003). However, UTUC presents at a similar age to colon carcinoma in LS and thus UTUC may be the sentinel event in some patients. Combining our results with those of other studies suggests that 1% to 3% of all UTUC cases may represent LS-associated carcinoma. LS accounts for 2% to 6% of both colorectal and endometrial cancers. As LS likely accounts for a similar percentage of UTUC, we suggest that reflexive MMR IHC screening followed by microsatellite instability testing be included in diagnostic guidelines for all UTUC.