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.
In testicular germ cell tumors (TGCTs), staging is a major determinant of disease-specific outcomes and dictates clinical management. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual recommends that tumor deposits in the spermatic cord that are discontinuous with the primary tumor be considered pathologic stage M1 (clinical stage [CS] III). This recommendation is controversial because, if patients do not show other metastases, it results in upstaging from CS I to III. This is relevant because CSI patients are candidates for active surveillance, whereas chemotherapy represents the standard treatment of CSIII patients. In this study, we describe the clinicopathologic findings and disease outcomes of TGCT patients presenting with discontinuous cord involvement no other concurrent metastases (ie, otherwise CS I). A total of 19 patients were assessed: 16 nonseminomas and 3 seminomas. When the focus of discontinuous spermatic cord invasion was excluded from staging, 10 tumors were pT3, 8 were pT2, and 1 was pT1. Adjuvant chemotherapy was given to 15 patients, 10 of whom developed disease recurrence (8 of them showing metastases in the retroperitoneum). None of the 4 patients kept on active surveillance showed evidence of recurrence at last follow-up, which is incompatible with the natural history of untreated CS III TGCTs. If the focus of discontinuous cord involvement was excluded from staging, these 4 cases were all pT2. Our data support that discontinuous cord invasion should not be considered pM1, since this practice may result in overtreatment of patients that could be kept on surveillance. We suggest staging these tumors as pT3(disc), considering this finding a risk factor for recurrence.
High-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS), is defined by morphologic features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL). Lymphomas with a complex 11q aberration or concurrent MYC- and BCL2- or BCL6-rearrangements are excluded from this category. However, the reproducibility of the diagnosis of HGBCL, NOS is unknown to date. Expert hematopathologists of the Lymphoma/Leukemia Molecular Profiling Project reviewed 92 cases submitted as HGBCL, NOS. At least 3/4 hematopathologists reviewing cases independently confirmed the diagnosis in 30/92 (33%) cases, while 13 cases (14%) were reclassified as DLBCL. The remaining 49 cases were jointly reviewed by the consensus panel of 10 to 15 pathologists, confirming an additional 9 HGBCL, NOS. The remaining cases were reclassified as DLBCL or other aggressive B-cell lymphomas or were excluded due to insufficient material. In aggregate, only 39/92 (42%) of initially submitted cases were confirmed as HGBCL, NOS, demonstrating poor interobserver agreement. Interestingly, however, there were no significant differences between the initially submitted cohort and those ultimately confirmed by the pathology review panel concerning dark zone signature (DZsig) expression, frequency of MYC-rearrangements and cell of origin, among others. Despite the finding that pathologists can identify cytomorphological features associated with adverse biological characteristics, the poor reproducibility of high-grade morphology and molecular heterogeneity suggests that HGBCL, NOS does not represent a distinct clinicopathologic entity and that more objective markers of distinct biologic features, such as the DZsig, may better separate cases into relevant diagnostic categories than morphology alone.
This study reports 6 cases of low-grade nasopharyngeal papillary adenocarcinoma (LGNPPA) reviewed by the REFCOR network, integrating clinicopathological, genetic, and epigenetic analyses to refine our understanding of its histogenesis and biological behavior. Our 6 cases were located in the nasopharynx. Histologically, 5 cases had a frank papillary architecture, whereas 1 case showed a mixed papillary and tubular architecture. Papillary and tubular structures were covered by a single layer of epithelium of nonciliated cuboidal or columnar neoplastic cells. Squamous differentiation foci were present in 2 cases. Neither desmoplastic stroma, vascular invasion, nor perineural invasion was seen. All cases expressed TTF1. Neither local recurrence nor metastasis occurred in any of our cases, nor in the literature when only TTF1-positive cases are considered. At the molecular level, in the 3 cases that underwent CGH array and RNA sequencing, we did not find significant molecular anomalies. Our 3 LGNPPAs with DNA methylation analysis were closely grouped on the UMAP with posterior pituitary tumors. Furthermore, comparison of LGNPPA and low-grade non-ITAC sinonasal adenocarcinoma transcriptomes highlighted CNS-related genes as significantly upregulated in LGNPPAs. In conclusion, our transcriptomic and epigenetic data suggest a putative link to a shared progenitor with pituicyte-derived tumors. Our clinicopathological findings are consistent with the literature, highlighting a very indolent behavior.
Mesenchymal spindle cell tumors represent a heterogeneous group of neoplasms defined by distinct clinicopathologic features and diverse molecular alterations. While USP6 rearrangements are well-established in nodular fasciitis and related entities, fusions involving other ubiquitin-specific proteases, such as USP2 and USP8, have only recently emerged. Prompted by sporadic reports of USP8 fusions in matrix-rich neoplasms, we aimed to characterize the clinicopathologic and molecular spectrum of USP2/USP8-rearranged mesenchymal tumors. We retrospectively analyzed 19 tumors, evaluating clinical, histopathologic features, immunohistochemical profiles, whole-transcriptome RNA sequencing, and DNA methylation profiling. Nineteen tumors were identified, harboring either USP8 (n=12) or USP2 (n=7) fusions. The cohort included patients aged 3 to 70 years (median: 32). Tumors primarily affected the distal extremities, with the notable exception of 2 intracardiac cases in pediatric patients, harboring USP8 fusions (CBLB::USP8 and SPPL2A::USP8). Histologically, all cases were composed of bland spindle cells arranged in either a myofibromatous or an inflammatory pattern; notably, USP2-fused tumors exhibited an exclusively myofibromatous morphology. Immunohistochemically, SMA was frequently expressed, while desmin, h-caldesmon, ALK, ROS1, panTRK, and CD34 were consistently negative. Transcriptomic analysis demonstrated proximity to myofibroma and nodular fasciitis profiles, rather than forming a distinct USP2/8-specific cluster. No cases showed malignant behavior or recurrence during the available follow-up period. USP2/8-rearranged neoplasms represent a morphologically diverse but biologically indolent subset of myofibroblastic tumors. They exhibit significant overlap with USP6-associated lesions and PDGFR-altered myofibromas. Recognizing these fusions is critical to avoid diagnostic pitfalls and overtreatment, particularly when they present in unusual sites, such as the heart.
