Anatomic Pathology Abstracts

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Kwon CH, Kim YK, Lee S, et al. Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes. Histopathology. 2018;72:556–568.

Correspondence: Dr. D. Y. Park at pdy220@pusan.ac.kr

Distinguishing clear cell carcinoma from p16-positive squamous cell carcinoma

Clear cell carcinoma is a low-grade malignancy that commonly arises in minor salivary glands of the oropharynx and other sites. EWSR1-ATF1 gene fusions seem to be specific for this salivary neoplasm. Testing for EWSR1-ATF1 has expanded the histologic spectrum of clear cell carcinoma (CCC). For example, many CCCs have a predominantly squamous phenotype with few clear cells, a finding that can lead to it being confused with squamous cell carcinoma (SqCC). P16 immunohistochemical staining to determine human papillomavirus (HPV) status has become standard practice for all oropharyngeal carcinomas showing squamous differentiation. The authors conducted a study to determine whether this practice could contribute to the difficulty in distinguishing CCC from p16-positive SqCC. They searched their surgical pathology archives for cases of CCC and evaluated those cases using p16 immunohistochemistry, high-risk HPV RNA in situ hybridization (ISH), and EWSR1 gene break-apart fluorescence ISH. They identified 16 CCCs, all of which harbored an EWSR1 rearrangement, in 11 women and five men. The study subjects ranged in age from 30 to 85 years (mean, 58 years). The CCCs arose in the oropharynx (tongue base or tonsil: n = 8; 50 percent), oral cavity (n = 4; 25 percent), and nasopharynx (n = 4; 25 percent). Each case demonstrated clear cells, but the proportion was highly variable (10 to 90 percent; mean, 48 percent), with seven of 16 cases having fewer than 50 percent clear cells. Submitted diagnoses included SqCC (n = 3) and mucoepidermoid carcinoma (n = 2). Of the three patients diagnosed with SqCC, one was scheduled to undergo chemoradiation and one had already completed chemoradiation. All 16 CCCs demonstrated p16 staining, with the percentage of p16-positive cells categorized as 70 percent or more (n = 2), 50 to 69 percent (n = 3), and 10 to 49 percent (n = 11). Staining was cytoplasmic and nuclear. All cases were negative for high-risk HPV by RNA ISH. CCCs regularly show squamous features, often lack prominent clear cell changes, frequently arise in the oropharynx, and invariably show p16 staining. These features may cause confusion with SqCC, particularly HPV-related oropharyngeal SqCC. P16 staining is not to be taken as unequivocal evidence of an HPV-related SqCC, even for carcinomas showing squamous differentiation and originating in the oropharynx. Failure to recognize this pitfall could result in overly aggressive treatment of a low-grade carcinoma.

Bishop JA, Rooper LM, Chiosea SI, et al. Clear cell carcinoma of salivary glands is frequently p16 positive: a pitfall in the interpretation of oropharyngeal biopsies. Am J Surg Pathol. 2018;42(3):367–371.

Correspondence: Dr. J. A. Bishop at justin.bishop@utsouthwestern.edu

Frequency of KRAS mutations and high tumor budding in cecal adenocarcinoma

Recent literature indicates that adenocarcinomas of the cecum differ from noncecal proximal colon adenocarcinomas with respect to molecular alterations and that cecal tumor site may be a prognostically relevant variable. The authors compared molecular alterations, histopathologic features, and disease-specific survival in a series of 328 colonic adenocarcinomas identified during a two-year period and stratified by tumor location (cecum, right colon, and left colon). Overall, cecal adenocarcinomas demonstrated the highest frequency of molecular abnormalities, with 74 percent harboring a KRAS exon 2 or 3 mutation, BRAF mutation, or DNA mismatch repair protein deficiency. KRAS mutations were more frequently seen in the cecum than in all other tumor sites (P = .03). They were identified in 46 percent of cecal adenocarcinomas compared with only 25 percent of adenocarcinomas of the right colon (P = .004). Cecal adenocarcinomas more frequently displayed adverse histopathologic features—in particular, high tumor budding (31 percent)—compared with tumors of the right colon (18 percent; P = .04) and left colon (17 percent; P = .02). Overall stage was the most important independent predictor of disease-specific survival in the multivariable analysis. However, cecal tumor site and high tumor budding were also predictive of poor survival, particularly in patients with stage III or IV tumors. The authors concluded that cecal adenocarcinomas are characterized by a high frequency of KRAS mutations compared with noncecal right colon tumors, frequently display high tumor budding, and may be a prognostically relevant variable, particularly in patients with stage III or IV disease.

Landau MA, Zhu BS, Akwuole FN, et al. Site-specific differences in colonic adenocarcinoma: KRAS mutations and high tumor budding are more frequent in cecal adenocarcinoma. Am J Surg Pathol. 2018;42:351–358.

Correspondence: Dr. Reetesh K. Pai at pair@upmc.edu