Diagnosis of early mycosis fungoides (MF) is hindered by overlap with benign dermatoses and by the variable sensitivity of conventional polymerase chain reaction–based molecular clonality assays in paucicellular specimens. We demonstrate that T-cell receptor β-chain constant region 1 (TRBC1) immunohistochemistry (IHC) provides a spatially resolved assessment of T-cell clonality that may aid the evaluation of early MF. In early MF, we identified a characteristic “spatial clonal discordance,” where monotypic TRBC1 expression is confined to intraepidermal T cells while dermal infiltrates remain polytypic. This compartment-specific pattern reflects neoplastic epidermotropism and may help explain discordant clonality results obtained by bulk molecular assays in paucicellular lesions. Conversely, tumor-stage MF and Sézary syndrome exhibited spatially concordant, pan-compartmental restriction. Digital image analysis showed high concordance between single-stain IHC and multiplex immunofluorescence, establishing TRBC1+ thresholds of ≤25% or ≥75% for defining clonality. Although this study is limited by its retrospective, single-center design and relatively small cohort, the findings establish TRBC1 IHC as a powerful, spatially informative tool. It effectively overcomes the “dilution effect” of reactive cells in early MF, serving as a high-sensitivity adjunct to conventional molecular testing for accurate, compartment-specific clonal evaluation.
Human papillomavirus (HPV)-associated non-salivary adenocarcinoma of the oropharynx is exceptionally rare and poorly defined. We report a multi-institutional series of 12 cases from 6 tertiary centers. Histologic, immunohistochemical, HPV testing, molecular, and follow-up data were reviewed. Among 11 patients with available sex data, all were men; the median age was 62 years (range: 46 to 70 y). The cohort comprised 9 primary oropharyngeal adenocarcinomas and 3 metastatic adenocarcinomas, including a right neck metastasis of presumed oropharyngeal origin and 2 distant metastases in patients with previously documented HPV-associated oropharyngeal squamous cell carcinoma. Primary sites included the palatine tonsil or tonsil-palate region (n=7), base of tongue (n=1), and oropharynx, not otherwise specified (n=1). Among cases with available T-category, 5 of 6 were T3/T4. All tumors showed high-grade adenocarcinoma morphology without a recognizable squamous component, with infiltrative glandular, ductal, or cribriform architecture. Diffuse p16 expression was present in all cases, and high-risk HPV was confirmed by polymerase chain reaction or in situ hybridization. p40 was negative in the tumor cell population in cases 1 to 6, 8, 9, 11, and 12, whereas case 7 showed p40 and CK5/6 expression confined to abluminal cells. Molecular profiling in 2 cases identified alterations or variants involving PIK3CA and PIK3R1 . Follow-up in 6 patients with primary tumors showed distant metastases in 3 and disease-specific death in 1. HPV-associated nonsalivary adenocarcinoma of the oropharynx is a diagnostically challenging tumor that expands the morphologic spectrum of HPV-related oropharyngeal carcinoma. Recognition requires exclusion of salivary-type and metastatic adenocarcinoma and confirmation of HPV association.
Fibroblastic connective tissue nevus is an uncommon benign cutaneous lesion first described in 2012. It is characterized by an irregularly disposed intradermal spindle cell proliferation and is sometimes associated with papillomatous epidermal hyperplasia and/or admixed adipose tissue. Fibroblastic connective tissue nevus shows some morphologic overlap with a second benign cutaneous lesion known as dermatomyofibroma, and some authors have speculated that the 2 lesions might represent a morphologic spectrum of a single entity. Recurrent activating mutations in the cell-surface receptor tyrosine kinase PDGFRB have recently been identified in dermatomyofibroma. Here, we identified similar recurrent activating PDGFRB mutations in fibroblastic connective tissue nevus, supporting the notion that the 2 lesions are indeed closely related. Direct comparison of the 2 lesions suggests that the most reliable distinguishing characteristics are the lesional architecture and immunoprofile. Whereas fibroblastic connective tissue nevus typically shows an irregular or haphazard architecture, dermatomyofibroma typically shows a horizontal band-like arrangement relative to the overlying epidermis. Immunohistochemically, fibroblastic connective tissue nevus shows frequent expression of CD34 with relative lack of SMA, while dermatomyofibroma shows frequent SMA expression with much less frequent CD34. These results provide insight into the relationship between fibroblastic connective tissue nevus and dermatomyofibroma, and place fibroblastic connective tissue nevus in the broader context of dermal spindle cell neoplasms characterized by activation of the PDGFB pathway.
Chromophobe renal cell carcinoma (chRCC) is generally considered an indolent malignancy; however, studies have produced conflicting results regarding the differences among its histologic patterns. The prognostic significance of eosinophilic morphology in chRCC remains controversial, in part due to inconsistent diagnostic criteria and inclusion of morphologic mimickers. Cases were classified by 3 expert genitourinary pathologists into eosinophilic, classic, and mixed chRCC patterns based on strict morphologic and immunohistochemical criteria (n=110). Clinicopathologic features, copy number variations (CNVs), and targeted sequencing of TP53, PTEN, and RB1 were assessed, along with pathway analyses using RNAseq and multiplex gene expression profiling. Clinicopathological and survival analysis were assessed using GraphPad Prism. The final cohort included 24 eosinophilic, 47 classic, and 39 mixed chRCC. CNV frequencies were similar across patterns, while RB1 aberrations and enrichment of oncogenic pathways (TP53, PTEN, RB1, DNA repair, mTOR, and cell cycle) were increased in both mixed and eosinophilic chRCC, with the greatest prominence in eosinophilic chRCC. Clinically, eosinophilic chRCC and mixed chRCC were associated with larger tumour size, more advanced clinical stage, and significantly worse disease-free survival (DFS) and overall survival (OS) compared with classic chRCC. On multivariate analysis, histologic pattern and stage remained prognostic of DFS. Therefore, eosinophilic chRCC showed a distinct molecular phenotype with enriched oncogenic pathways and poorer outcomes, while mixed chRCC displayed an intermediate but similarly aggressive profile. These findings indicate that eosinophilic morphology has potentially more aggressive biology than classic chRCC, underscoring the need for the introduction of specific diagnostic criteria for eosinophilic chRCC and its differentiation clinically.
