Perianal Intestinal-Type Paget Disease With and Without Invasion, Unassociated With Internal Malignancy: A Distinct Form of Primary Perianal Adenocarcinoma.

Primary perianal adenocarcinoma of intestinal type (PPAI) has been described in recent literature and proposed as a subtype of extramucosal anal adenocarcinoma. Whether this represents a unique entity remains to be elucidated. Herein, we analyzed the clinicopathologic and genomic features of 14 cases of PPAI. Fourteen patients, predominantly older adults with a median age of 73 years (range, 50-85), with a slight woman predilection (5 men and 9 women) were identified. All cases presented with pagetoid intraepithelial growth, and 9 were eventually found to have underlying invasive carcinoma at the site of the Paget disease. Clinical and radiographic evaluation failed to detect another primary site, either in the anorectal region or elsewhere, in all patients. By immunohistochemistry, all but 1 case showed an intestinal phenotype with cytokeratin 20 and caudal-related homeobox transcription factor 2 (CDX2) positivity and variable cytokeratin 7. Metastasis developed in 4 of 14 patients, including regional lymph node and distant bone metastasis. Patient survival for localized disease ranged from 29 to 176 months (median, 62 months), whereas for metastatic disease, it ranged from 13 to 75 months (mean, 31 months). Genomic profiling revealed a high frequency of TP53 mutations (86%, 12/14), ERBB2 alterations (57%, 8/14), and MYC amplification (36%, 5/14), with absence of genetic alterations typically seen in rectal adenocarcinomas, such as APC, KRAS, and BRAF. In contrast, a control group of primary extramammary Paget disease cases displayed distinct genomic features, including recurrent PIKC3A and KMT2C mutations. Treatment included surgical excision, radiation therapy, and systemic chemotherapy in metastatic cases, with radiation proving effective in preventing local recurrence among those with localized disease. In metastatic cases, chemotherapeutic regimens including capecitabine/oxaliplatin and folinic acid, fluorouracil, and oxaliplatin were employed. The absence of anorectal or other visceral adenocarcinomas along with distinct genomic findings supports the classification of PPAI as a distinct clinicopathologic entity.