Virchows Archiv最新文献

Neoplasms with inactivating mutations in SWI/SNF chromatin remodeling complex subunits gained attention in the head and neck (H&N) region due to their poor clinical outcomes. The sinonasal tract is a recognized "hot-spot" for SMARCA4-deficient cancers, including SMARCA4-deficient sinonasal carcinomas, and most sinonasal teratocarcinosarcomas. To date, only two H&N SMARCA4-deficient carcinomas have been reported outside the sinonasal region. We identified eight cases of SMARCA4-deficient H&N carcinomas from the authors' files and reviewed their clinicopathological features. All cases with available tissue blocks were investigated by molecular genetic methods using next-generation sequencing (NGS). The cohort included four sinonasal and four non-sinonasal tumors involving the tongue, oral floor, the upper jaw submucosa, and the hypopharynx. The extra-sinonasal cases affected three males and one female (ages 61-81). Histologically, two cases showed poorly differentiated small cell morphology, one case resembled salivary duct carcinoma, and one case had a dedifferentiated squamous cell carcinoma phenotype. Regional lymph node metastases were documented in two cases. Sinonasal tumors showed spindle cell morphology, olfactory neuroblastoma-like features with glandular or squamoid differentiation areas, and an undifferentiated small cell pattern. This study expands the known anatomical distribution and histological spectrum of SMARCA4-deficient H&N carcinomas. Their occurrence outside the sinonasal tract is rare and poses a diagnostic challenge. These tumors are highly aggressive and often present at advanced stages. In the sinonasal region, they can mimic olfactory neuroblastoma, while in other H&N sites, they can resemble neuroendocrine carcinoma.

Follicular lymphoma (FL) spans both nodal and extranodal sites, with molecular characteristics that may vary by anatomical location. While nodal FL typically shows BCL2 rearrangement and frequent chromatin-modifying gene mutations (CREBBP, KMT2D), some extranodal FLs lack t(14;18)(q32:q21) and harbour distinct alterations, such as TNFRSF14 mutations. In our retrospective series of 23 ocular adnexal FL (OA FL) cases that include both primary and secondary involvement, an approximately equal distribution of BCL2-rearranged and non-rearranged cases was observed, underlining that the ocular localisation displays features of both conventional nodal and extranodal FL. Mutational analysis revealed a mix of mutations commonly seen in nodal and extranodal FL, with strong CD23 expression correlating with JAK/STAT pathway gene mutations. Most OA FLs followed an indolent course with good outcomes after local therapy, though transformation to diffuse large B-cell lymphoma occurred in a subset of two cases. Our results suggest that OA FL exhibits genetic heterogeneity, combining molecular features from both subtypes, and highlight the importance of thorough staging and individualised therapeutic and surveillance strategies for each patient.

Intraoperative evaluation of sentinel lymph nodes (SLNs) in breast cancer patients after neoadjuvant therapy (NAT) is challenged by treatment-related fibrosis and scarring, leading to high false-negative rates with conventional frozen-section hematoxylin-eosin (FS-HE) analysis. We prospectively validated whether cytokeratin rapid immunohistochemistry (CK-RIHC) could improve the accuracy of intraoperative SLN diagnosis in this setting. This prospective study included 204 breast cancer patients undergoing SLN biopsy after NAT. The SLN was the unit of analysis. Intraoperatively, paired adjacent frozen sections were evaluated by FS-HE and CK-RIHC (FS-HE first, followed by CK-RIHC), and results were compared with definitive postoperative paraffin histopathology as the reference standard. The primary endpoint was per-node sensitivity for residual nodal involvement. Definitive pathology confirmed nodal involvement in 140 of 693 evaluable SLNs (20.2%). One additional SLN was uncertain (non-verifiable) and excluded from the primary performance analyses. CK-RIHC demonstrated higher sensitivity than FS-HE (98.6% vs 84.3%, p < 0.05) and increased per-node diagnostic accuracy from 96.8% to 99.7%. FS-HE missed 22 involved SLNs, including 1 macrometastasis and 13 micrometastases. CK-RIHC detected all macrometastases and micrometastases in the evaluable cohort, whereas detection of ITCs remained less complete. Intraoperative CK-RIHC is significantly superior to FS-HE in the evaluation of intraoperative SLNs. By enhancing the detection of epithelial cells within therapy-modified tissue, this method reduces false-negative diagnoses of clinically relevant metastatic SLNs. CK-RIHC represents a valuable pathological tool for optimizing intraoperative diagnostic accuracy in post-NAT breast cancer specimens.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms characterized by myomelanocytic differentiation and dichotomic molecular pathogenesis (mTOR-activating mutations versus TFE3 gene rearrangements). A recently recognized subset harboring YAP1::TFE3 gene fusion, termed inflammatory spindle cell PEComa, has been described predominantly in the lungs of adults showing significant morphologic and molecular overlap with YAP1::TFE3-fused clear cell stromal tumor of the lung (CCST-L). We report the first pediatric case of YAP1::TFE3-rearranged inflammatory spindle cell PEComa arising in the anterior mediastinum of a 5-year-old child. The tumor, largely enclosed by a thick fibrous capsule, was composed of plump ovoid to spindle cells with a prominent chronic mononuclear inflammatory infiltrate and strikingly extensive multifocal stromal dystrophic calcifications that were radiologically conspicuous. Worrisome features included large size (8 cm) and multifocal necrosis. Tumor cells showed diffuse expression of melanocytic markers (HMB45 and melanoma cocktail), cathepsin K and TFE3 in the absence of smooth muscle markers. The C-terminal YAP1 staining revealed complete loss limited to the neoplastic cells. This case expands the clinicopathologic and age spectrum of YAP1::TFE3-rearranged PEComa which needs to be distinguished from other overlapping neoplasms carrying the same gene fusion.

Tumor budding is an established adverse prognostic factor in colorectal cancer (CRC), based on the number of isolated single tumor cells or small tumor cell clusters at the invasive front. While bud counts are well studied, the prognostic significance of the spatial distribution and distance of tumor buds away from the tumor bulk is unclear. We defined TB-distance as the average distance from the tumor bulk to the three farthest tumor buds and evaluated its clinicopathologic and prognostic associations in two independent CRC cohorts (N = 776 and N = 1,100). Using a cohort-derived cutoff, high TB-distance (≥ 123 µm) was significantly associated with adverse tumor characteristics, including high grade, advanced disease stage, lymphovascular invasion, high conventional tumor budding grade, and MMR proficient status (p < 0.003 for all). High TB-distance was also associated with shorter cancer-specific survival (Cohort 1: multivariable HR (high vs. low) 1.47, 95% CI 1.04-2.09, p = 0.030; Cohort 2: multivariable HR 1.34 95% CI 1.04-1.74, p = 0.026). However, TB-distance did not provide additional prognostic information within conventional tumor budding grade strata or when modeled alongside tumor budding. These findings indicate that high TB-distance is associated with aggressive tumor morphology and worse outcome but does not improve prognostication beyond standard tumor budding assessment. TB-distance may still be useful as a visual aid in routine pathology and a quantifiable spatial feature for computational pathology.

TFEB-altered renal cell carcinomas (RCCs) display a wide range of morphological features and variable immunohistochemical profiles, often overlapping with other RCC subtypes. This variability poses significant diagnostic challenges. Consequently, there is an ongoing search for reliable ancillary tests that can aid in identifying cases that warrant molecular testing. In this study, we focused on GPNMB immunohistochemistry expression in TFEB-rearranged and TFEB-amplified RCCs. A total of 25 TFEB-altered RCCs, including 16 TFEB-amplified RCCs and nine TFEB-rearranged RCCs, were included in the study. GPNMB immunohistochemistry was positive in all nine TFEB-rearranged RCCs, demonstrating strong, diffuse cytoplasmic staining. In the TFEB-amplified RCC cohort, GPNMB expression was also detected in all 16 tumors; however, the staining pattern differed from that seen in TFEB-rearranged RCCs. Diffuse staining was observed in eight tumors (50%), four of which showed variable staining intensity, while the remaining eight tumors (50%) exhibited focal GPNMB reactivity, with intervening negative areas. GPNMB was therefore positive in all 25/25 (100%) TFEB-altered RCCs by IHC, supporting its potential role as a sensitive screening marker for such RCCs. TFEB-rearranged RCCs typically exhibited strong, diffuse GPNMB immunoreactivity, whereas TFEB-amplified RCCs more often showed patchy or focal staining of lower intensity, interspersed with areas of GPNMB negativity. Variability of staining in TFEB-amplified RCCs underscores the need for cautious interpretation, particularly in limited biopsy specimens, taking into account the morphologic findings and other immunohistochemistry stains, such as Melan A and Cathepsin K.

Breast cancer (BC) consists of several subtypes that vary regionally by incidence and mortality rates. The study population consisted of 1411 incident BCs diagnosed in Sulaimania, Iraq, in the years 2009-2014. Based upon positive (p) or negative (n) reactions, hormone receptor (HR)pHER2n tumors were divided into low recurrence risk (HRp low-risk) and high recurrence risk (HRp high-risk) subtypes with the Magee 2 equation that uses pathological data, without a Ki67 index. The 5-, 10-, and 13-year distant disease-free survival (DDFS) rates for the subtypes were estimated using proportional hazards models. The median age of patients for all subtypes was < 50 years. The proportion of subtypes was 29.6% for HRp low-risk, 36.2% for HRp high-risk, 11.8% for HRpHER2p, 11.7% for HRnHERp, and 10.6% for triple-negative (TN) BC. The 5-, 10-, and 13-year DDFS rates were as follows: HRp low-risk (n = 418, 85.5%, 74.4%, 71.7%), HRp high-risk (n = 511, 76.2%, 62.8%, 58.7%), HRpHER2p (n = 167; 77.7%, 58.6%, not reached), HRnHER2p (n = 165; 60.4%, 46.6%, not reached), and TNBC (n = 150; 61.4%, 54.2%, not reached). The difference in DDFS between HRp low-risk vs HRp high-risk was significant, p < 0.001, as were the differences between HRp high-risk vs HRnHER2p and HRp high-risk vs TNBC, both p < 0.001. The difference in DDFS between HRp high-risk vs HRpHER2p BC was not significant, p = 0.83, nor was the difference between HRnHER2p vs TNBC, p = 0.91. Distant disease or death from breast cancer was identified for 395 patients, 86 with HRp low-risk, 137 with HRp high-risk, 50 with HRpHERp, 69 with HRnHER2p, and 53 with TNBC. Iraqi HRpHER2n BCs can be separated into low and high risk using the Magee 2 risk assessment equation. The HRp low-risk BC has a favorable outcome. HRp high-risk was the most common subtype and the major cause of recurrent distant disease.

This study aimed to investigate the molecular genetic characteristics and histomorphological spectrum of pseudomyogenic haemangioendothelioma (PHE) and to summarize its clinicopathological features, treatment, and prognosis. We retrospectively analyzed the clinical data, histological morphology, immunohistochemistry, and molecular findings from next-generation sequencing (NGS) in five PHE cases diagnosed at our institution. In addition, we conducted a systematic review of all PHE cases with detailed data reported in the literature worldwide since its reclassification in 2011. Molecular analysis confirmed FOSB gene rearrangements in all five cases. Three cases harbored novel, previously unreported FOSB fusion types (NEDD9::FOSB, ZFP36::FOSB, LGALS3::FOSB), thereby expanding the molecular spectrum of PHE. Histologically, the case with the NEDD9::FOSB fusion exhibited prominent vascular channels surrounded by tumor cells-a morphological feature not previously described in PHE. Our literature review incorporated 270 PHE cases (including our cohort). The median age at disease onset was approximately 32 years, with a male-to-female ratio of about 3.29:1. The primary tumor site was predominantly the extremities. Immunohistochemistry consistently showed expression of CD31, ERG, FLI1, FOSB, and keratins in tumor cells. Molecular testing confirmed the FOSB genetic alteration. Treatment mainly involved surgical resection, and the overall prognosis was relatively favorable. In conclusion, this study expands the molecular genetic spectrum and histomorphological spectrum of PHE. By integrating our data with a systematic literature review, this study provides a comprehensive overview of the clinicopathological features, immunophenotype, molecular genetics, treatment, and prognosis of PHE, offering valuable insights for accurate diagnosis and understanding of its biological behavior.

This case report describes a rare case of bi-phenotypic gastric cancer with two distinct, but clonally related, histological components. The first component, associated with Epstein-Barr virus (EBV) infection, exhibited the morphological features of gastric carcinoma with lymphoid stroma, suggesting that EBV, as an effective immunogenic factor, may trigger a prominent immune response within the tumour microenvironment. The second component, which was EBV-negative, displayed tubular/papillary morphology and features of increased biological aggressiveness, such as high-grade areas and lymphatic invasion. Immunohistochemical and molecular studies confirmed that, despite the differing morphologies and immunophenotypes, both components were clonally related, with the EBV-negative area showing more complex DNA aberrations, reminiscent of chromosomally instable (CIN) lesions. This case describes clonally related EBV-positive and -negative components within a single gastric cancer, contributing to a better understanding of EBV role in tumour heterogeneity and progression and highlights the impact of EBV loss on tumour behaviour.

Trichoblastoma (TB) is a benign primitive follicular neoplasm that can occur in the setting of Brooke-Spiegler syndrome (CYLD mutations), in association with nevus sebaceous (mosaic HRAS mutations), or sporadically. We studied the histopathologic and molecular features of 16 sporadic trichoblastic neoplasms, including a case of trichogerminoma and a case of trichoblastic carcinoma arising within a TB. Sixteen tumors were identified in nine males and seven females (median age 64 years, range 33-97 years) involving the scalp (4), back (2), nasolabial fold (1), cheek (1), skin overlying the parotid gland (1), nasal ala (1), ear (1), upper chest (1), gluteal region (1), thigh (1), leg (1), and ankle (1) with a median size of 1.6 cm (range 1.2-7.0 cm). Histologically, 16 cases consisted of a dermal multinodular growth of basaloid epithelial cells surrounded by fibrotic stroma without epidermal connection. Malignant transformation was observed in one case, characterized by increased atypia and mitotic activity. Another case exhibited focal areas of "cell balls," indicative of trichogerminoma. RNA sequencing of six tumors showed a high tumor mutational burden (TMB) and lacked a UV-related mutational signature, which may help distinguish trichoblastic tumors from potential mimics. Additionally, a FOXK1::GRHL1 fusion was found in the case of trichogerminoma. Clinical follow-up (15/16 patients; 94%; median: 65 months; range 2.5-106.5 months) showed no evidence of residual or metastatic disease.