American Journal of Surgical Pathology最新文献

Artificial intelligence diagnostic tools show promise for improving histotype classification in epithelial ovarian cancer but face challenges due to slide variability across institutions. To address this domain shift, the adversarial Fourier-based domain adaptation (AIDA) model was developed. This retrospective study evaluates AIDA's performance in classifying the 5 major ovarian cancer subtypes using an independent cohort. Surgically treated patients diagnosed with clear cell (CCC), endometrioid (EC), high-grade serous (HGSC), low-grade serous (LGSC), or mucinous (MC) ovarian cancer at Amsterdam University Medical Center (1985-2022) were included in the study. The deep learning method AIDA, trained on data from Vancouver General Hospital, was applied to all cases. Final histotype predictions were made through majority voting across 15 independently trained models. For misclassified cases, up to 3 additional slides were scanned, and the AIDA model was retrained. Classification was then assessed using single-slide and majority voting approaches. The AIDA algorithm achieved an overall balanced accuracy of 79.7% across all histotypes. Accuracy was highest for CCC (90.9%) and LGSC (89.8%), and lowest for EC (62.4%). Common misclassifications included MC as EC and EC as HGSC or LGSC. Retraining with additional slides improved balanced accuracy to 85.8% based on single-slide voting and 82.6% based on majority voting. This study highlights the future potential of the AIDA model in classifying epithelial ovarian cancer histotypes. With further refinement to improve performance on more challenging cases, the model could enhance diagnostic accuracy in clinical practice.

Distinguishing endometrial hyperplasia from endometrial adenocarcinoma remains a histopathologic challenge. Several retrospective studies have reported high interobserver variability when assessing the progestin-naive endometrium, while only one study has assessed interobserver variability of postprogestin endometrial biopsies. This study quantified the interobserver variability between trial site pathologists and central pathology review of endometrial specimens taken before treatment with the levonorgestrel intrauterine device (LNG-IUD), 3 months and 6 months post-treatment as part of the feMMe phase 2 randomized clinical trial (NCT01686126). Interobserver agreement was 73% (105/143, κ=0.50) at baseline, 80% (107/134, κ=0.72) at 3 months and 77% (98/127, κ=0.64) at 6 months post-LNG-IUD treatment. Overall, 42% (45/107) site-reported diagnoses of endometrial hyperplasia and 13% (21/161) site-reported diagnoses of endometrial adenocarcinoma were discordant. Site-reported diagnoses were upgraded to higher risk pathology on central review for 77% (72/94) discordant cases. This study confirms the high rate of interobserver variability when diagnosing endometrial hyperplasia or endometrial adenocarcinoma both before and after progestin treatment in specimens collected as part of a clinical trial. It emphasizes the value of confirming diagnosis by a gynecologic pathologist and comparing specimens from the progestin-treated endometrium with the pretreatment biopsy. This study highlights the importance of central pathology review for clinical trial reporting and when deciding on treatment options and assessing response, particularly in the context of progestin treatment.

Increasing availability and utilisation of high-throughput sequencing techniques has resulted in a rapidly expanding range of uterine mesenchymal lesions harbouring recurrent and nonrecurrent gene rearrangements. Within the literature, 3 molecularly confirmed FOXO1 -rearranged uterine corpus tumors have been reported, all representing alveolar rhabdomyosarcomas (ARMS). We report 5 cases of non-ARMS uterine mesenchymal tumors, in patients aged 36 to 71, harbouring novel FOXO1 rearrangements with different fusion partners ( JRK , PIK3R4, MEIS1 , and ATP7B); in the fifth case, FISH revealed a FOXO1 gene rearrangement with an unknown fusion partner. Although morphologically heterogenous, all 5 cases had a low-grade spindle cell component with 3 cases showing prominent myxoid stroma. Two cases were originally diagnosed as myxoid leiomyosarcoma, one as high-grade endometrial stromal sarcoma, one as an undifferentiated sarcoma with a fibrosarcoma-like appearance, and the other as a myxoid neoplasm of uncertain malignant potential. In 3 cases, the rearrangements showed similar breakpoints to known recurrent FOXO1 gene fusions; 2 rearrangements ( JRK::FOXO1 and MEIS1::FOXO1 ) incorporate both an intact transactivation domain and a DNA-binding domain akin to the rearrangements seen in ARMS, likely representing true oncogenic driver events. Although all 5 cases were confined to the uterine corpus at presentation, recurrences occurred in 2 patients indicating a potential for malignant behaviour and justifying the designation of sarcoma. These cases expand the landscape of FOXO1 -rearranged neoplasms and describe a potential new uterine mesenchymal entity. Further study of additional cases is needed to establish whether these rearrangements truly represent an initiating event for a distinct subset of uterine sarcomas, or whether FOXO1 rearrangements simply represent an additional noninitiating/nondriver event within other established tumor types.

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.

Mutations in genes encoding proteins of the SWI/SNF complex are highly recurrent in select tumor entities. Among primary cutaneous tumors, only 4 SMARCA4-deficient undifferentiated neoplasms and 3 primary cutaneous SMARCB1-deficient carcinomas have been documented. In this report, we describe the morphologic, immunohistochemical, genomic, and methylation profile features of 5 additional SMARCA4-deficient undifferentiated neoplasms and 2 SMARCB1-deficient carcinomas of the skin. The patients (6M;1F) had a median age of 82 years (range: 60 to 94). Morphologically, all lesions showed poorly differentiated, dermal-based neoplasms, 5 of which were associated with subcutaneous involvement. The tumor cells were organized into nests, strands, and solid sheets. These cells displayed moderate to abundant cytoplasm, large, round vesicular nuclei, and prominent nucleoli. Immunohistochemical analysis revealed expression of cytokeratin AE1/AE3 in all cases, along with loss of SMARCA4 expression in 5 cases. Loss of SMARCB1 expression was identified in 2 cases and was mutually exclusive with SMARCA4 alterations. DNA sequencing revealed a high tumor mutation burden and a prominent UV signature in 4 of the 5 analyzed cases. Methylation analysis, in which tumors were compared with a control group of 68 SNF/SWI-deficient neoplasms and 18 cutaneous squamous cell carcinomas, revealed that primary cutaneous SMARCA4-deficient and SMARCB1-deficient neoplasms, along with SMARCA4-deficient carcinomas of other organs, constitute a unique group of neoplasms, distinct from other analyzed tumor entities. These results support the theory that these primary cutaneous SWI/SNF-deficient tumors represent a distinctive group of morphologically undifferentiated cutaneous carcinoma.