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.

Ameloblastomas are locally aggressive odontogenic tumors that most commonly arise in the mandible and maxilla and often harbor BRAF V600E mutations. While rare extragnathic ameloblastomas have been reported, primary pulmonary cases have not been documented. We identified 3 pulmonary neoplasms with features of ameloblastoma that were submitted for consultation between 2022 and 2025 at 3 academic institutions and performed detailed clinicopathologic and molecular analysis. The tumors presented as 5.4 to 7.3 cm peribronchial solitary lung masses. All resected tumors exhibited a predominant stellate reticulum-like component composed of loosely arranged p40-reactive bland squamoid-to-spindled cells with long intercellular bridges, and streaming and swirling architecture, surrounded by palisaded columnar cells with focal reverse nuclear polarity at the interface with myxoid stroma. All tumors were immunoreactive for BRAF V600E IHC, and BRAF V600E mutations were confirmed by molecular assays, including broad next-generation sequencing on 2 cases. Florid hyperplasia of entrapped pneumocytes initially suggested a biphasic neoplasm, but the absence of BRAF V600E IHC labeling confirmed pneumocyte entrapment. Occult gnathic primary tumors were excluded by subsequent clinical examination, including negative panoramic dental x-rays. No recurrences or metastases have been observed to date. This first series of primary pulmonary ameloblastomas highlights a distinctive tumor with histologic and molecular features identical to gnathic counterparts. We discuss the potential histogenesis of these unusual tumors.

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.

The College of American Pathologists recognizes "intraductal papillary neoplasm of the bile ducts (IPNB) with an associated invasive carcinoma" in its protocols for the pancreas and intrahepatic bile ducts, but not for the perihilar or distal bile ducts. We aimed to investigate the clinicopathologic and molecular features of 27 surgically resected perihilar IPNB cases. The cohort included 14 males and 13 females, with a median age of 70 years. Six IPNBs were noninvasive, while 21 had associated invasive carcinoma. The median overall tumor size was 2.8 cm, and the median invasive tumor size was 1.2 cm. Eight of 16 patients had elevated CA19-9. Immunohistochemistry as a surrogate of molecular analysis was performed in 19 cases with invasive carcinoma. Among them, positive PD-L1 expression was found in 3 cases (15.8%, all had low expression, CPS<5). DNA mismatch repair deficiency (loss of MSH2 and MSH6) and p53 overexpression were each identified in 1 case (5.3%). All cases were negative for HER2 and pan-TRK. After a median follow-up of 38 months, 11 patients died of disease. Next-generation sequencing revealed genetic alterations impacting multiple signaling pathways, including MAPK/ERK, WNT/β-catenin, TGF-β, DNA damage response, and PI3K/AKT. Our case series suggests that IPNB with associated invasive carcinoma may be included in CAP protocols as one of the carcinoma types of perihilar bile ducts. Future studies are warranted to compare perihilar IPNB with those originating in other biliary tract sites. We expect our molecular findings to help guide the selection of potential therapeutic targets.

Cancers of the endometrium, cervix, and anus are frequently treated with radiation therapy (RT), which carries a risk for secondary malignancies. RT causes vaginal atrophy, dryness, and increased mucosal friability, predisposing to ulcers. Here, we describe "atypical vulvovaginal postradiation vascular lesion" (AVPRVL), a benign post-RT vascular lesion that histologically mimics angiosarcoma. Fifteen cases were retrospectively identified in patients aged 44 to 77 years (median: 70 y) who presented 3 to 23 years post-RT (median: 14 y), usually with vaginal bleeding. Histologically, AVPRVL demonstrated papillary endothelial hyperplasia (Masson change), mild-to-moderate nuclear atypia, and direct juxtaposition to squamous epithelium. Atypical vessels were located in fibrin and were not distributed in the native lamina propria. MYC immunohistochemistry demonstrated only scattered, weak expression in 5 tested lesions. Fluorescence in situ hybridization was negative for MYC amplification in 11 tested lesions. Five sequenced lesions lacked recurrent pathogenic alterations or copy number changes. Clinical follow-up was available for 11 patients (73%; median length: 3.3 y; range: 1 to 21.7 y). None developed metastases. Six patients (55%) experienced persistent or recurrent lesions, although sometimes it was not possible to distinguish true recurrence from new lesions developing in the RT field. At the most recent follow-up, 9 patients were alive with no evidence of disease, and 2 were alive with recurrent lesions. Ultimately, most lesions resolved with excision or cautery. Unlike RT-associated angiosarcoma, AVPRVL lacked MYC amplification, showed indolent clinical behavior, and usually resolved with conservative management. Unlike cutaneous atypical postradiation vascular proliferation, AVPRVL did not show vessels distributed within native subepithelial tissue. Instead, it more closely resembled a Masson change with nuclear atypia. We conclude that AVPRVL represents a distinctive, benign, possibly reactive vascular proliferation of the vulvovaginal mucosa occurring years after pelvic RT. The distinction between AVPRVL and angiosarcoma is critical to avoid overtreatment.