American Journal of Surgical Pathology最新文献

Uterine placental site trophoblastic tumors (PSTTs) are rare trophoblastic neoplasms, presumed to be of gestational origin. Herein, using a comprehensive morphologic, immunohistochemical, and molecular approach, we describe 5 cases of primary uterine nongestational PSTTs. The median age at presentation was 32 years (range 25 to 45). All tumors were initially expected to be of gestational origin as all were located in the uterus and all patients had a history of pregnancy (5/5, 100%). The median size of the primary uterine tumors was 6.3 cm (range 4.8 to 7.5). Three patients (3/5, 60%) had metastatic disease at presentation or revealed during initial workup (1/5 [20%] patients with lymph node metastasis only and 2/5 [40%] with distant metastases). All tumors showed similar histopathologic and immunohistochemical features to those of gestational PSTTs. The tumor cells expressed hPL in 5/5 (100%) tumors, hCG in 5/5 (100%; focal in all tumors), and GATA3 in 5/5 (100%). However, short tandem repeat (STR) genotyping did not identify any nonpatient alleles in the tumors, indicating a nongestational origin. The median progression-free survival was 18 months (range: 0 to 85) and 2/5 (40%) patients died from disease, highlighting the potential poor prognosis of this nongestational tumor. Thus, in the same way as gestational and nongestational choriocarcinomas are recognized as different entities, nongestational PSTTs could be viewed as a distinct entity from their gestational counterparts, although further investigation and more cases are needed. Furthermore, we propose recommendations for diagnosing and staging of nongestational PSTTs to improve patient stratification and management.

Inflammatory spindle cell PEComa is a rare PEComa variant with rare cases harboring YAP1::TFE3 fusion recently reported in the lungs. These tumors share identical YAP1::TFE3 fusion breakpoints and overlapping morphology with clear cell stromal tumor of the lung ( CCST-L ), but differ by demonstrating a myomelanocytic immunophenotype. We report the first 3 nonvisceral cases of inflammatory spindle cell PEComa with YAP1::TFE3 fusion. All occurred in female patients, aged 51 to 76 years, involving the vulva, presacral region, and thigh, and ranged from 3.8 to 5.0 cm (median: 4.0 cm). Histologically, all were well circumscribed with a fibrous capsule containing lymphoid cuffs, and were composed of fusiform to plump spindle cells arranged in short fascicles and vaguely storiform patterns, admixed with prominent inflammatory infiltrates. Extensive stromal calcifications, focal necrosis and occasional mitotic figures, including one atypical mitosis, were present in one case. Immunohistochemically, all cases were positive for smooth muscle actin and HMB45, and negative for cytokeratins, ERG, CD31, S100, and ALK. Targeted RNA sequencing identified YAP1::TFE3 fusions in all tumors, with 2 showing identical breakpoints to CCST-L ( YAP1 exon 4- TFE3 exon 7), and 1 showing a breakpoint involving YAP1 exon 3- TFE3 exon 7. We report the first 3 cases of YAP1::TFE3 -rearranged, nonvisceral inflammatory spindle cell PEComa occurring in somatic soft tissue sites, expanding the anatomic spectrum of this recently characterized entity. Inflammatory spindle cell PEComa should be considered in the differential diagnosis of spindle cell neoplasms with prominent admixed inflammation.

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 SMARCB 1 -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.

Most primary retroperitoneal soft tissue tumors are malignant, with liposarcomas and leiomyosarcomas being the most common. However, other sarcomas and benign tumors can also occur in this location. Pathologic evaluation of retroperitoneal sarcomas (RPS) presents unique challenges. Sarcomas are a heterogeneous group with overlapping microscopic features, making accurate classification essential for prognosis and evolving targeted therapies. Core biopsies often capture only a small portion of the tumor, which may result in underestimation of key features such as differentiation, necrosis, and proliferation, leading to undergrading. Surgical management is complicated by the RPS's tendency to involve adjacent organs. Resections are often large and en bloc, and formalin fixation can obscure anatomic landmarks, making it difficult to identify and assess true surgical margins. In addition to the standard data elements required for cancer staging, specific pathologic features of RPS should be reported to aid in prognosis and treatment planning. This position paper/consensus statement was developed by members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) based on evidence and expert opinion. A detailed description of specimen handling, specimen sampling, and the inclusion of the key diagnostic elements required for an accurate pathology report are provided. The aim of this manuscript is to offer a comprehensive critical reappraisal of the role of pathologic evaluation of surgical specimens in RPS surgery, as well as to propose a standard pathology report to harmonize reporting and facilitate future data collection and interpretation for future research development.

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.

Penile squamous cell carcinoma (PSCC) and its established precursor, penile intraepithelial neoplasia (PeIN), are classified as HPV-associated and HPV-independent. However, there is a spectrum of precursor lesions, which presents diagnostic challenges due to morphologic overlap. Immunohistochemical loss of GATA3, a tumor suppressor gene, has recently been reported in vulvar neoplasia. In this study, we evaluate the expression and diagnostic utility of GATA3 immunohistochemistry (IHC) in penile neoplasia. GATA3, p53, and p16 IHC was performed on 97 penile lesions, including lichen sclerosus (LS, N=14), condyloma acuminatum (N=11), squamous hyperplasia (SH, N=9), verrucous lesions (N=3), HPV-independent (N=12) and HPV-associated (N=18) PeIN, invasive HPV-independent, (N=19) and HPV-associated (N=11) PSCC, and normal skin (NL, N=41). GATA3 expression was scored as >75% basal/parabasal staining (pattern 0), 25% to 75% (pattern 1), 5% to 25% (pattern 2), and <5% (pattern 3). GATA3 was retained in NL (90%) and condyloma (73%) ( P =0.15). LS and SH combined had significant GATA3 loss (44% pattern 0, 17% pattern 1, and 39% patterns 2 to 3) ( P <0.001 vs. NL). HPV-independent PeIN had decreased GATA3 expression compared to NL (100% patterns 1 to 3, 87% patterns 2 to 3) ( P <0.001), and LS-SH ( P =0.003), but had similar expression to HPV-independent PSCC ( P =1.00). HPV-associated PeIN and invasive PSCC had similar GATA3 loss (patterns 1 to 3, P =0.096). HPV-associated PSCC had a more severe loss (91%) than HPV-associated PeIN (39%) ( P =0.008). These findings suggest that GATA3 alterations may be an early event during tumorigenesis, and that this marker may represent a useful complement to p16 and p53 in the differential diagnosis of HPV-independent PeIN from benign mimickers.

A distinct type of pancreatic carcinoma (n=31; 6% of adenocarcinomas) is described, distinguished from conventional pancreatic ductal adenocarcinoma (PDAC) by: (1) solid/undifferentiated (sheet-like, stroma-poor) carcinomas lacking features of other entities (no osteoclasts, microsatellite stable, INI-1 retained, nonkeratinizing squamous <30%), often admixed with ordinary PDAC; (2) radiology/gross showing central necrosis/demarcation mimicking nonductal neoplasms, not scirrhous like PDAC; (3) marked intratumoral heterogeneity with divergent patterns, including basal/squamoid (81%), solid sheets punctuated with megavacuoles (77%), clear cell (68%), mucoepidermoid-like (36%), sarcomatoid (36%), and occasional choriocarcinomatous or angiosarcomatous patterns, and some with carcinomatous vasculitis; (4) cellular anaplasia with pleomorphic giant cells (55%), multinucleated nonosteoclastic (32%), and rhabdoid-like (32%); (5) immunohistochemically (n=16) consistently showing a basal phenotype with common GATA6 loss/depletion and/or CK5/6, p40, or p63 expression; (6) molecular-genetic profile (n=13) showing altered frequencies: ARID1A (31% vs. 4%) and CDKN2A/p16 (92% vs. 30%) alterations, universal KRAS mutations with enrichment in KRAS G12D, frequent TP53, and lower SMAD4 loss (8% vs. 55%). Limited follow-up suggests comparable or more favorable outcomes. In conclusion, this is a distinct type of carcinoma in the pancreas that is prone to being misdiagnosed as nonductal/non-PDAC cancers. It is the first pancreatic carcinoma type in which a basal molecular phenotype can be indicated clinically by both imaging and histopathology, with major potential management implications (as it is also enriched in actionable targets like ARID1A). Recognition of this category is critical for cancer research, as it offers an invaluable group to study plasticity, stroma versatility, necrosis mechanisms, and the basal type in pancreatic cancer.

A subset of epithelioid-to-spindle cell sarcomas remains difficult to classify due to lack of defining molecular alterations or pathologic features that do not fit neatly into a single tumor class. After identification of a primary mesenchymal neoplasm with EPS15L1::KLF17 gene fusion, we retrospectively collected 4 additional soft tissue tumors with EPS15L1 :: KLF17 or EPS15 :: KLF17 fusions. The cohort comprised 4 males and one female with age range of 5 to 64 years. The tumors arose in soft tissue of the extremities, head/neck, paraspinal region, and intra-abdominal mesentery. Two patients developed metastatic disease with one death from disease at 62 months; one showed late metastases at 5 and 11 years. Histologically, these were cellular neoplasms composed of epithelioid and spindled tumor cells with prominent cystic spaces and focal stromal sclerosis. All tumors demonstrated diffuse, strong MUC4 positivity (5/5) with cytokeratin (3/3), EMA (4/4), and S100 (3/4) expression. Whole transcriptome RNA sequencing identified EPS15L1 :: KLF17 fusions in 2 cases and EPS15 :: KLF17 fusions in 3 cases. RNA expression profiles, available in 2 cases, showed high expression of MUC4 and CD24. DNA methylation profiling revealed distinct epigenetic clustering, separate from EWSR1 :: KLF15 -rearranged soft tissue myoepithelial tumor, sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and other mesenchymal neoplasms. EPS15/EPS15L1 :: KLF17 -rearranged sarcoma has distinctive histologic findings, including diffuse MUC4 expression. Recognition is clinically important given its potential for late recurrence and metastasis.

Nonampullary duodenal neoplasms of gastric phenotype include pyloric gland adenoma, foveolar-type adenoma, and duodenal neoplasm of uncertain malignant potential. In addition, previously undesignated epithelial tumors have been observed in the duodenum. Their clinicopathological and molecular characteristics, as well as their pathologic classification, remain incompletely defined due to their rarity. In this study, we examined a total of 105 lesions from 100 patients for histopathologic and immunohistochemical features and analyzed genomic alterations in 20 representative cases using next-generation sequencing (NGS). All 105 cases were classified by a combination of growth pattern (exophytic, dumbbell, and inverted), nuclear grade (low- and high-grade), and predominant gastric phenotype (foveolar, pyloric gland, intermediate mucous cell, fundic gland, and not otherwise specified). Among the 105 tumors, 97 (92%) were low-grade and 8 (8%) were high-grade. Intratumoral heterogeneity in nuclear grade and/or immunophenotype was frequently observed. NGS revealed mutations in GNAS (75%), KRAS (45%), and APC (30%) across the histopathologic subgroups. In addition, 6 of 8 high-grade tumors (75%) harbored MDM2 gene amplification, which was associated with diffuse and strong expression of MDM2 protein and high Ki-67 index. In contrast, low-grade tumors exhibited rare MDM2 amplification (6%), and immunoreactivity for MDM2 and Ki-67 was generally sparse. The patients showed an extremely favorable prognosis without metastases, irrespective of nuclear grade. These findings suggest that nonampullary duodenal neoplasms of gastric phenotype can be reclassified as "gastric-type adenomas" based on excellent prognosis and common genetic alterations, albeit a wide spectrum of morphology and gastric phenotypic expression. MDM2 amplification may contribute to histologic progression.

The assessment of micronests in tumor stroma has been introduced recently for the prognostication of human malignancies. In this multicenter study, we included a total of 110 patients treated for nasopharyngeal carcinoma (NPC) at one of the Finnish University Hospitals. All available hematoxylin and eosin (H&E)-stained slides were scanned. Assessment of micronests in tumor stroma was conducted on scanned HE-stained slides. Presence of micronests in tumor stroma had a significant prognostic value in predicting overall survival in the multivariable analysis with a hazard ratio (HR) of 1.92 (95% CI: 1.14-3.24, P=0.01). Similarly, in the multivariable analysis of disease-specific survival, micronests in tumor stroma had a significant prognostic value with an HR of 1.87 (95% CI: 1.00-3.48, P=0.04). In addition, the presence of micronests in tumor stroma showed a significant association with keratinizing and EBV-negative tumors (P<0.001). In conclusion, the evaluation of micronests in tumor stroma can be used as a prognostic classifier in NPC and they can be assessed in routine H&E-stained sections.