American Journal of Surgical Pathology最新文献

We developed a nuclear grading system for melanoma, the UNC Chapel Hill Method, akin to McGovern's 1970 classification, to evaluate its correlation with disease progression and adverse histologic features, including thickness, mitotic rate, and ulceration. This retrospective study analyzed 544 melanomas diagnosed from 2020 to 2023, with a median follow-up of 411 days; 89 patients experienced progression, and 22 died of disease. A dermatopathologist assigned nuclear grades based on nuclear size, membrane contour, nucleolar features, and chromatin arrangement. Grade 1 resembled nevus nuclei, Grade 3 exhibited marked nuclear abnormalities, and Grade 2 was intermediate. Kaplan-Meier survival analysis demonstrated significantly worse progression-free survival for Grade 3 lesions compared with grades 1 and 2 (P<0.003). Statistical analyses (Student t test, χ2, and Kruskal-Wallis) revealed that grade 3 melanomas were associated with increased age, Breslow thickness, mitotic rate, ulceration, advanced AJCC stage, and mortality (each P<0.05). In a univariate Cox model, grade 2 (HR: 1.7; 95% CI: 0.7-4.0) and grade 3 (HR: 3.6; 95% CI: 1.5-8.4) lesions had an increased risk of progression relative to grade 1. After adjusting for covariates, hazard ratios were attenuated for grade 2 (HR: 1.2; 95% CI: 0.5-2.9) and grade 3 (HR: 1.7; 95% CI: 0.7-4.2). These findings show nuclear grade is associated with melanoma progression, but increased statistical power with longer follow-up and additional cases are needed to assess its independent prognostic value.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with a predilection for children and adolescents. Data regarding IMTs in adulthood is limited, and evidence suggests that ALK expression/rearrangement rate decreases with age. We sought to better characterize IMT in patients ≥40 years. IMT cases in this age group were retrieved and re-reviewed. Various histomorphologic data were reported, and ALK status was documented. A total of 34 tumors were identified (21 females, 13 males; 40 to 77 y; median age 54 y), and tumor size ranged from 0.7 to 10 cm (median 2.5 cm). Predominant disease sites included the lung (12), followed by the urinary bladder (9), the uterus (4), and the head and neck (4). Morphologically, tumors exhibited loose fascicles of spindled fibroblasts with inflammatory infiltrate, with the majority being myxoid (25). Mild cytologic atypia was appreciated in 12 cases, and 6 cases showed focal necrosis. ALK expression was identified in 91% of cases through immunohistochemistry (28) and/or molecularly (24). Most common ALK fusion partners, identified by next-generation sequencing, included FN1 , TIMP3 , and EML4 . Follow-up data on 28 patients (3 to 165 mo; median 42) revealed mostly indolent behavior, but one ALK -negative patient had lung metastasis, and another ALK -positive patient had a recurrence. IMTs may arise in adulthood and mostly manifest in visceral sites. Despite earlier reports, ALK is frequently expressed/rearranged in tumors in this age group.

We report a case of mesothelioma in situ giving rise to invasive mesothelioma and associated with a long in-frame TP53 deletion. Tumor arose in the peritoneal cavity in a 55-year-old man. BAP1, MTAP, and NF2/merlin were retained by immunohistochemistry, but p53 was overexpressed by immunohistochemistry in the flat mesothelioma in situ, papillary mesothelioma in situ, and invasive mesothelioma. Almost all cases of mesothelioma in situ that have been previously described have a BAP1 mutation/deletion; this is the first example of mesothelioma in situ associated with a TP53 mutation, and suggests that staining for p53 may be useful in evaluating potential mesothelioma in situ cases.

Since the histogenesis of heterologous elements within Sertoli-Leydig cell tumors (SLCTs) is poorly understood, we aimed to study the molecular relationship between Sertoli cells and the heterologous elements in 16 ovarian SLCTs. We performed a comprehensive molecular study on both SLCT and heterologous components, separately. Eleven tumors (68.7%) had one heterologous element and 5/16 (31.3%) had 2. Heterologous elements were epithelial (7/21 [81%]) (benign mucinous epithelium [9/21, 42.9%], borderline mucinous tumor [1/21, 4.8%], infiltrative mucinous adenocarcinoma [3/21, 14.3%], carcinoid tumor [3/21, 14.3%], and hepatocytes [1/21,4.8%]) or mesenchymal (4/21, 19%) (rhabdomyosarcoma [3/21,14.3%] and chondrosarcoma [1/21, 4.8%]). A DICER1 pathogenic variant was shared between SLCT and the heterologous elements in all cases with interpretable results (15/15), and other common likely-pathogenic/pathogenic variants were shared between SLCTs and heterologous components (3/16, 18.75%), favoring a clonal relationship. In contrast, the identification of distinct variants between components favored a different evolution. The molecular profile of heterologous elements differed from that of their ovarian counterparts occurring without SLCT (eg, mucinous heterologous elements were KRAS wild-type). Chromosome 8 gains, TERT and NRAS/KRAS variants, and absence of fusion transcript, were the hallmark of rhabdomyosarcoma components (3/3, 100%). The progression-free survival rate was significantly shorter for patients with TERT pathogenic variant ( P =0.0029). One patient had pleomorphic Sertoli cells associated with TP53 variants and very poor prognosis with early recurrence after complete initial surgery of a stage IA tumor. These data highlight the biological relationship between SLCTs and their heterologous elements, and the clinical usefulness of identifying pathogenic variants (ie, TERT and TP53 ), although this last point needs to be confirmed in a larger series.

True lipomas involving the joints are rare. In this study, we investigated 18 intra-articular and juxta-articular lipomas of the knee. The tumor occurred in middle-aged or older patients (median age: 63 years) with a strong female predilection (3 males and 15 females), and most presented with palpable masses without associated pain. Four tumors were entirely intra-articular, whereas 11 involved both intra-articular and extra-articular compartments, consistent with herniation from the joint. The herniation commonly occurred through the space between the patellar tendon and either the lateral or medial patellar retinaculum, with the extra-articular masses being located anterolaterally or anteromedially to the joint. All tumors analyzed at least focally involved or abutted the infrapatellar fat pad. The relationship with the joint was not recognized at diagnosis in most of the herniated cases. The remaining 3 were juxta-articular lipomas that were firmly fixed to the joint. All 18 lipomas revealed distinct histology, and included fine lobulation, fibrosis with spindle cells, conspicuous presence of medium-caliber vessels and slivers of dense, tendon-like fibrous tissue. Myxoid changes, chondro-osseous metaplasia, and fat necrosis were commonly observed. These findings led to a suspicion of atypical lipomatous tumors, other benign lipomatous tumors, malformation, or hamartoma, and originally prevented a definitive diagnosis in the majority of cases. HMGA2 immunoreactivity was observed in all 18 tumors, whereas all were negative for MDM2 expression and RB1 loss. RNA sequencing revealed HMGA2 fusions in 8 of the 12 tumors tested. Intra-articular and juxta-articular lipomas of the knee, particularly the herniated intra-articular subset, are likely under-recognized and can be a source of diagnostic concern because of peculiar histology and unawareness of the relationship with the joint.

Diffuse adult-type gliomas are delineated based on their molecular composition including the presence or absence of mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2), a key enzyme in the citric acid cycle. IDH-mutant tumors are associated with better survival than IDH-wildtype counterparts and can be further subdivided into astrocytoma or oligodendroglioma. Rare gliomas with fumarate hydratase (FH) deficiency have been reported. Given that FH is also a critical enzyme in the citric acid cycle, such tumors seem to be epigenetically similar to IDH-mutant tumors and, despite meeting criteria as IDH-wildtype gliomas per the current recommendations set forth by the World Health Organization, may behave in a manner akin to IDH-mutant neoplasms. Hereditary leiomyoma and renal cell cancer syndrome is associated with cutaneous and uterine leiomyomas and renal cell carcinoma caused by a germline FH alteration. To date, only rare examples of patients with known germline FH mutation subsequently diagnosed with a glioma have been reported. We report a case of a young patient with a glioma harboring features of IDH-mutant astrocytoma without evidence of IDH1/2 alterations. After the identification of cutaneous FH-deficient leiomyomas, a retrospective analysis of his brain tumor revealed FH deficiency and a germline FH alteration was ultimately identified after further molecular studies. Although rare, we conclude that FH mutations seem to be part of the spectrum of alterations in diffuse gliomas.

Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive subtype of bladder cancer. We retrospectively analyzed 136 patients diagnosed between 1993 and 2025. Clinicopathologic features, immunophenotype, PD-L1 expression, molecular alterations, and survival outcomes were assessed, with a focus on patients presenting with local low-stage (pT1) disease. The cohort included 96 males and 40 females (median age: 72). Most tumors (77%) were mixed with conventional urothelial carcinoma (UC), and 10% demonstrated heterologous differentiation. Tumor stage, lymphovascular invasion (LVI), and nodal metastasis were significantly associated with poor overall survival (OS; P <0.05). Fifty-four cases had CK5/6 and GATA3 immunohistochemical stains available; a mixed basal-luminal phenotype (CK5/6+/GATA3+) was most common (43%), though immunophenotypic grouping did not significantly impact survival. Twenty-two patients had PD-L1 immunostain performed at diagnosis, and most patients (82%) were PD-L1(+) with a CPS ≥10. Patients with CPS ≥50 trended toward improved OS. Panel-based sequencing was available for 6 patients and revealed heterogeneous mutations with few recurrent alterations. In our cohort, 10 patients had local low-stage (LLS/pT1) SUC, which is rare in SUC. The metastatic rate was 30%, and mortality was 40%. Findings in LLS patients with poor outcomes included large tumor, extensive invasion, tumor necrosis, and heterologous elements. LLS patients who underwent radical cystectomy (RC) had longer OS compared with those treated with transurethral resection of bladder tumor (TURBT) alone ( P =0.0269). 3/6 survival LLS patients had no residual tumor at RC. Our findings highlight the variable clinical courses of SUC, and call for more attention on this unique group of patients. The absence of residual disease in several pT1 patients following RC suggests that timely RC can have a favorable outcome in a subset of patients.

Point mutations in genes of the mitogen-activated protein kinase (MAPK) pathway are the most frequent oncogenic drivers of melanocytic neoplasms, whereas gene fusions are comparatively rare. Kinase fusions are among the molecular alterations that characterize Spitz neoplasms; however, not all melanocytic tumors that harbor one as the main oncogenic driver conform to clinical and/or histomorphologic parameters associated with Spitz neoplasms. In this study, we describe the clinical, histopathologic, and molecular characteristics of 7 RAF1 and 23 BRAF fusion-positive melanomas of patients who presented with or later developed regional and/or distant metastases. We report that most tumors in this series arose in adult patients and lacked Spitz-like microscopic features. Awareness of the varied clinical and histopathologic presentation of RAF1 and BRAF fusion-positive melanomas is important as the protein products of these kinase gene fusions constitute potentially actionable therapeutic targets.

Ten anaplastic juvenile granulosa cell tumors (JGCT) with architectural and cytologic features that differ from those seen in conventional JGCTs were identified from patients who ranged from 7 to 44 (median 13) years. The tumors measured from 8.3 to 28 (median 21) cm. FIGO stage was IA (n=3), IC3 (n=2), II (n=1), IIIA (n=3), or unknown (n=1). All tumors had conventional areas with solid/nodular growth usually punctuated by follicles. However, all demonstrated areas (median 50%, range: 10% to 90%) with effacement of this architecture, characterized by diffuse growth, marked cytologic atypia, and brisk mitoses (up to 40/10 HPFs). In contrast, the conventional component exhibited significantly less atypia and mitoses. Next-generation sequencing was performed in 7 tumors and all harbored TP53 mutations; the remaining 3 showed aberrant p53 expression by immunohistochemistry. MYC family ( MYC and MYCN ) amplifications were identified in 4 tumors, while other alterations included AKT1 in-frame duplications (n=4) and DICER1 mutations (n=2). Follow-up was available for 9 patients (median 22 mo); 4 died of disease (all stage II/III with MYC/MYCN amplifications), one was alive with disease (stage IA), and 4 were alive and well (stages IA/IC). Anaplastic JGCTs have a distinct morphologic appearance and consistently demonstrate TP53 inactivation, with MYC family amplification evident in advanced-stage tumors. Although it cannot be determined whether MYC family amplifications are an independent predictor of behavior, they are important to recognize as such patients may benefit from MYC inhibitors. Tumors with the features described herein should be distinguished from conventional JGCTs because of the prognostic implications. In addition, the architectural deviations from that usually encountered and pleomorphism further add to diagnostic challenges in evaluating JGCTs.