Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; S. Emily Bachert, MD, associate pathologist, Brigham and Women’s Hospital, Boston; Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Divya Sharma, MD, associate professor, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center; and Paula Toro, MD, gastrointestinal and hepatobiliary fellow, Cleveland Clinic.
Perianal intestinal-type Paget disease with and without invasion and unassociated with internal malignancy
August 2026—Primary perianal adenocarcinoma of intestinal type 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. The authors conducted a study in which they analyzed the clinicopathologic and genomic features of 14 cases of primary perianal adenocarcinoma of intestinal type (PPAI). They identified for the study 14 patients who were predominantly older adults (median age, 73 years [range, 50–85 years]). All cases (five men and nine women) presented with pagetoid intraepithelial growth, and nine 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 in all patients. With the exception of one case, for which caudal-related homeobox transcription factor 2 (CDX2) staining was unavailable, all tumors demonstrated cytokeratin 20 and CDX2 expression. Metastasis developed in four of 14 patients, including regional lymph node and distant bone metastases. Patient survival for localized disease ranged from 29 to 176 months (median, 62 months) and for metastatic disease ranged from 13 to 75 months (mean, 31 months). Genomic profiling revealed a high frequency of TP53 mutations (86 percent, 12 of 14), ERBB2 alterations (57 percent, eight of 14), and MYC amplification (36 percent, five of 14), with an absence of genetic alterations typically seen in rectal adenocarcinomas, such as those involving 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. Chemotherapeutic regimens, including capecitabine/oxaliplatin, folinic acid, fluorouracil, and oxaliplatin, were employed in metastatic cases. The authors concluded that the absence of anorectal or other visceral adenocarcinomas, along with distinct genomic findings, supports the classification of PPAI as a distinct clinicopathologic entity.
Bahceci D, Saoud C, Isidro RA, et al. Perianal intestinal-type Paget disease with and without invasion, unassociated with internal malignancy: a distinct form of primary perianal adenocarcinoma. Mod Pathol. doi.org/10.1016/j.modpat.2025.100917
Correspondence: Dr. Jinru Shia at jshia@mskcc.org or Dr. Dorukhan Bahceci at bahcecd1@mskcc.org
Cutaneous plasmablastic lymphoma: a study of primary and secondary skin involvement
Cutaneous plasmablastic lymphoma is a rare and aggressive neoplasm that presents as skin nodules. Despite occurring in approximately five percent of plasmablastic lymphoma (PBL) cases, the World Health Organization does not distinguish primary cutaneous PBL (pcPBL) from secondary cutaneous PBL (scPBL), and their clinical differences remain poorly defined. To determine whether pcPBL represents a distinct clinical entity, the authors compared the clinicopathologic features, IHC profiles, and survival outcomes of pcPBL and scPBL. Their retrospective comparative study analyzed 40 cases of cPBL (six newly identified institutional cases and 34 cases from the literature) categorized as pcPBL (n = 25; no extracutaneous disease at diagnosis) or scPBL (n = 15; concurrent extracutaneous disease). Patients with pcPBL were older than those with scPBL (median, 62 versus 43 years; Mann-Whitney test, P = .018). Leg involvement was significantly associated with pcPBL (odds ratio [OR] = 6.22; 95 percent confidence interval [CI], 1.21–31.9; P = .031). Disease-specific survival (DSS) analysis included 17 evaluable cases (pcPBL, n = 11; scPBL, n = 6). Median DSS was 42 months for pcPBL and eight months for scPBL (log-rank χ2 = 3.98; P = .046). Median follow-up (reverse Kaplan-Meier) was 20 months for pcPBL and was not reached for scPBL. Cox models were directionally consistent but underpowered. The authors concluded that in this pooled analysis, cases presenting with primary cutaneous involvement tended to occur in older patients and more often involved the legs. However, these observations should be interpreted cautiously given the small numbers and heterogeneity of the available data. Within pcPBL, Epstein-Barr virus positivity correlated with better survival. These hypothesis-generating findings provide a basis for prospective, multi-center studies to clarify the classification, staging implications, and management approach for this rare lymphoma.
Repetto F, Cornejo KM, O’Donnell P, et al. Cutaneous plasmablastic lymphoma: retrospective comparative study of primary and secondary skin involvement. Histopathology. 2026. doi.org/10.1111/his.70095
Correspondence: Dr. Frederico Repetto at frepetto@bwh.harvard.edu
High-grade colorectal adenocarcinomas with SMAD4 deficiency
Poor prognosis has been reported for patients with SMAD4-deficient colorectal adenocarcinomas. However, it is not yet clear whether unique tumor morphologies or other advanced disease signatures stratify those patients. To reappraise this possibility across a homogeneous cohort of colorectal carcinoma (CRC) patients with advanced-stage disease, the authors leveraged next-generation sequencing (NGS) data to identify 50 SMAD4-deficient (dSMAD4) CRCs at their institution. An equal number of NGS-verified SMAD4-proficient (pSMAD4) CRCs were identified in parallel, yielding a control group in which demographics, clinicopathologic parameters, and background genetic drivers were similar to those for the dSMAD4 test group. Although both groups progressed to American Joint Committee on Cancer stage IV metastatic disease at high rates (dSMAD4: 90 percent; pSMAD4: 86 percent), the dSMAD4 CRC specimens were enriched with overtly high-grade mucinous and nonmucinous histomorphologies (dSMAD4: 44 percent; pSMAD4: 12 percent; p=.0007). The high-grade subset drove poor prognosis in dSMAD4 CRCs, as those patients developed widely metastatic disease (p=.0048) with short overall and progression-free survival (p≤.0001). Metastasis of unknown primary was not uncommon for high-grade dSMAD4 CRCs, posing diagnostic challenges in those instances. However, all dSMAD4 CRCs retained positive immunolabeling for CDX2 or SATB2 irrespective of grade, thereby aiding diagnosis and distinguishing the high-grade subset from other high-grade CRCs that lose these biomarkers. The authors’ reappraisal identified an underappreciated class of high-grade dSMAD4 CRCs that progresses rapidly to widely metastatic disease with a dismal prognosis. Although high-grade morphologies may mask the origins of CRC, immunohistochemistry retains diagnostic utility for dSMAD4 CRCs.
Mirzabeigi Y, Shah N, Schwartz KR, et al. High grade colorectal adenocarcinomas with SMAD4 deficiency. Mod Pathol. 2026. doi.org/10.1016/j.modpat.2025.100957
Correspondence: Dr. Oliver G. McDonald at ogm443@miami.edu
Ability to detect hepatocellular adenomas with high-risk molecular alterations using specific staining patterns
Beta-catenin–mutated hepatocellular adenomas carry an increased malignant transformation risk, and staining for glutamine synthetase and β-catenin by IHC is used to screen for the tumor. The authors conducted a study to assess glutamine synthetase (GS) and β-catenin interpretation guidelines for their applicability and reproducibility in predicting high-risk β-catenin–mutated hepatocellular adenomas (HCA) and other relevant molecular alterations. Three pathologists interpreted hematoxylin and eosin, β-catenin, GS, and CD34 stains from 75 HCA using method A (GS interpretation: negative, perivenular patchy, map like, diffuse, and indeterminate) and method B (a similar GS interpretation scheme based on a recent publication, with and without CD34 expression patterns). They assessed ease of application and interpretation confidence level. High-risk IHC was defined as nuclear β-catenin or diffuse homogeneous GS, or both. Molecular testing was performed on a subset of HCA and controls. Fifty-seven resections and 18 biopsy specimens were examined. Methods A and B (GS only) were rated as easy to apply, with high interpretation confidence (90 percent or more using both methods). The consensus rate was comparable in biopsy specimens (100 percent for both methods) and resections (88 percent for method A, 93 percent for method B). While the same cases were stratified into high-risk GS categories using both systems, clinically significant genetic alterations (TERT promoter, EGFR, MTOR, and TP53) were identified in 25 percent of cases stratified by IHC as not high risk. The authors concluded that both methods have a similar ease of application and level of interpretation confidence, and they detected β-catenin mutations as expected. Other relevant molecular alterations associated with risk of neoplastic progression or bleeding, or both, were detected in 25 percent of HCA with the non-high–risk IHC phenotype, suggesting the value of molecular testing in this subset.
Gosnell HL, Roberts DE, Zhang X, et al. Hepatocellular adenomas with high-risk molecular alterations undetected by “high-risk” β-catenin and/or glutamine synthetase staining patterns. Am J Clin Pathol. 2025. doi.org/10.1093/ajcp/aqaf115
Correspondence: Dr. Hailey Gosnell at gosnelh@ccf.org