Virchows Archiv最新文献

The reliable diagnosis of one of the many types of B-cell lymphoma (BCL) currently requires an integrated approach comprising morphological expertise, immunophenotyping, and inclusion of clinical data, but may also incorporate flow cytometry, cytogenetics, and clonality analysis. In recent years, several studies have elucidated the mutational landscape of BCL, which may also serve as a complementary diagnostic tool. We have developed a custom next-generation sequencing panel for application in the routine diagnosis of BCL based on available literature and our diagnostic questions. We applied this panel to 160 cases of BCL or with this differential diagnosis (DD) in our routine workflow to gain further diagnostic support or on clinical request. Evaluable results were obtained in all but two cases of the entire cohort. Diagnostically informative molecular genetic profiles were identified in 72% of the evaluable cases. Focusing on 21 challenging cases with the DD of Burkitt lymphoma (BL) and the germinal center B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL), we detected at least one mutation in all cases, and in 18/21 (86%) cases, panel sequencing provided significant decision guidance. In conclusion, although morphology and immunohistochemistry remain the backbone of diagnosis, panel sequencing provided substantial diagnostic assistance in many cases. It has been particularly useful in providing additional arguments to clarify the clinically important DD between BL and DLBCL in challenging cases.

Proliferative verrucous leukoplakia (PVL) is a rare yet aggressive oral potentially malignant disease (OPMD) with the greatest rate of malignant transformation. Its pathophysiology is poorly understood despite much histopathological and molecular research. Particularly, Telomerase reverse transcriptase (TERT) promoter mutations at C228T and C250T have been linked to many epithelial malignancies; however, their significance in PVL is yet unknown in the Indian population. The aim of this study was to assess frequency of TERT promoter mutations (C228T, C250T) and rs2853669 single nucleotide polymorphism (SNP) in PVL, oral leukoplakia (OL), oral squamous cell carcinoma (OSCC) and healthy controls. 120 fresh frozen tissue specimens (30 each of OL, PVL, OSCC and controls) were tested for presence of C228T and C250T mutation in TERT promoter gene region and SNP at rs2853669, using Sanger sequencing on genomic DNA. TERT C228T mutation was found in 6.7%, 0% and 20% cases in PVL, OL and OSCC group (p = 0.03) respectively. TERT C250T mutation was present only in OSCC group (6.7% cases). None of the two mutations were present in controls. Both the mutations were mutually exclusive of each other. A significant association was found between rs2853669 SNP and epithelial dysplasia in OL, specifically with CC genotype (p = 0.04). Molecular signature of PVL shows limited evidence of TERT promoter mutations. The findings of this study suggest that the genetic underpinnings of PVL are distinct from those commonly observed in other forms of cancerous lesions.

We report a case of GALT-associated carcinoma, a rare morphological variant of colorectal adenocarcinoma characterised by cystic glands containing eosinophilic material, set within dense lymphoid stroma with germinal centres. Since its first description in 1999, only 26 cases have been documented. Its association with lymphoid tissue, the presence of intraepithelial lymphocytes, and the absence of goblet cells led to the hypothesis that it may originate from M-cells located in the dome epithelium of gut-associated lymphoid tissue, hence the alternative term "dome-type carcinoma". Through detailed histological, immunohistochemical, ultrastructural and molecular analyses of our case, supported by a comprehensive literature review, we found no evidence supporting M-cell differentiation: intraepithelial B lymphocytes were absent, GP2 immunostaining was negative and ultrastructural features were inconsistent with M-cell morphology. Nevertheless, the lesion's pushing growth pattern, lack of high-risk histopathological features and indolent behaviour justify its recognition as a distinct morphological subtype of colorectal cancer.

Adenoid cystic carcinoma (ACC) is the second most common malignancy of salivary glands with a poor long-term prognosis. The presence of mutually exclusive t(6;9)/MYB::NFIB and t(8;9)/MYBL1::NFIB chromosomal translocations has been used as diagnostic markers for ACC. In this study, we report a non-MYB/MYBL1 fusion gene NFIB::PHACTR2 in a palate ACC of a 66-year-old male. The excised 1.7 cm partially encapsulated tumor featured focal invasion into the adjacent mucinous minor salivary glands. By light microscopy, the tumor showed cribriform and tubular patterns with obvious perineural and intraneural invasion. The findings remind us that salivary gland tumors without MYB/MYBL1 fusion genes could still be ACC if they have a rearrangement involving genes adjacent to MYB/MYBL1 genes.

Reactive and clonal proliferations of histiocytes (macrophages/dendritic cells) represent a broad spectrum of disorders, which can affect virtually any organ of the body. The clinical spectrum ranges from benign, localized and self-limiting manifestations to severe multi-system disease. Hemophagocytic lymphohistiocytosis (HLH) is a frequently life-threatening, systemic hyperinflammatory process triggered by massive cytokine release by activated, reactive macrophages. Familial and secondary forms of HLH are discerned. Histiocytoses are clonal inflammatory myeloid disorders characterized by proliferations of mature histiocytes/macrophages and dendritic cells with recurrent kinase-activating mutations which result in constitutive activation of the ERK signaling pathway. Although traditionally subclassified according to the phenotype of the lesional cells, the clonal cells can show significant plasticity, and the occurrence of mixed histiocytoses is increasingly recognized. This is in part due to their derivation from a myeloid progenitor cell and explains the frequent association with clonal hematopoiesis or overt myeloid neoplasms in adults. At the joint Workshop of the Chinese Society of Hematopathology, the European Association for Haematopathology and the Society for Hematopathology on histiocytic/dendritic cell proliferations, neoplasms, and their mimics in Hefei, China, April 2024, in sessions 1 and 2 a total of 8 cases of HLH, 9 cases of reactive histiocytic proliferations and 40 cases of histiocytoses were submitted and reviewed by the panel. The latter included cases of LCH, indeterminate cell histiocytosis, Erdheim Chester disease, juvenile xanthogranuloma, Rosai Dorfman disease, multicentric reticulohistiocytosis, ALK-positive histiocytosis, and mixed histiocytoses. The present report summarizes important findings and open questions arising from discussing the workshop cases.

Chondroblastomas represent less than 1% of all bone tumors. They are currently classified as benign neoplasms and "benign lung implants" have been described. Exceedingly rare case of malignant chondroblastomas have been published, and only three of them have scalp metastases. We present the case of a 57-year-old healthy man who noticed a rapidly growing mass on his left chest. Radiological imaging revealed an 8 cm expansile and lytic lesion located in the anterior segment of the sixth costal arch with a thinned cortex without periosteal reaction. The tumor was removed with wide margins. Seven years later, he presented with multiple superficial movable lesions on the scalp that were surgically removed. The costal mass was histologically composed of fused nests of discohesive polygonal cells with grooved nuclei, and scattered osteoclast-like giant cells embedded in an eosinophilic chondroid matrix. It presented a permeative growth pattern with entrapped pre-existing bone trabeculae and focal soft tissue extension. Scanty "chicken-wire" calcifications were detected. Moderate atypia and necrotic foci were observed. Occasional non-atypical mitotic figures were also observed. The cutaneous lesions demonstrated the same histopathological findings. Both the metastases and the primary tumor showed diffuse immunoreactivity for anti-histone H3K36M. Molecular study of the H3 histone family member 3B gene demonstrated a p.K37M mutation in exon 2 in the original mass and in the metastasis. Next-generation sequencing did not detect any other molecular alterations in the metastases. Malignant chondroblastomas are extremely rare tumors that most commonly arise in unusual locations, such as the rib or scapula, and in older adults. Permeative growth pattern, soft tissue extension, greater atypia, and higher mitotic rates are histopathological features of malignancy. H3K36M immunoreactivity and H3F3B gene mutations are key to achieving correct diagnosis. Wide resection and close follow-up of patients should be recommended. There is currently no consensus regarding the administration of adjuvant chemotherapy.

Basal cell adenoma (BCA) is a benign salivary neoplasm that exhibits a divergent spectrum of growth patterns, including cribriform, tubular, trabecular, membranous, and solid. A subset of BCAs is characterized by the presence of abundant S100 protein-positive stroma, which makes this variant unique and potentially represents a hybrid lesion or an entity intermediate between BCA and pleomorphic adenoma (PA). From the authors' registry, we selected 17 cases of BCA with abundant S100 protein-positive stromal components and compared them with 7 cases of BCA without S100 protein-positive stroma, and 6 cases of myoepithelial cell-rich PAs. All cases were analyzed by immunohistochemistry (IHC) using antibodies to S100 protein, SOX10, PLAG1, HMGA2, p63/p40, cytokeratins, EMA, LEF1, and/or β-catenin. Next-generation sequencing (NGS), fluorescence in situ hybridization (FISH) for the rearrangement of PLAG1, and methylation analysis were performed. The BCA S100 protein stromal cell-rich group consisted of 7 males and 10 females with an average age of 62 years. Their tumors showed typical S100 protein-positive stroma, which was also positive for SOX10 in all cases. The stromal and/or epithelial components showed expression of LEF1 and β-catenin in 17 and 15 cases, respectively. HMGA2 IHC showed nuclear expression in one case while PLAG1 was negative in all cases. In 11 cases, one or more mutations were present, including CTNNB1 mutation (n = 11). The first control cohort of BCA without S100 protein-positive stroma consisted of 1 male and 6 females with an average age of 50 years. This group showed LEF1 and nuclear β-catenin expression in 1 and 2 cases, respectively. The second control group of PA (including 4 spindle-shaped cellular and 2 oncocytic PAs) was devoid of CTNNB1 mutations. Two cases presented with gene fusions, including MEG3::PLAG1 and ACTA2::PLAG1, and an additional two cases showed PLAG1 break. It has been proposed earlier that BCA is related to PA based on a shared biphasic nature and a divergent spectrum of growth patterns. Our findings suggest that BCAs with abundant S100 protein-positive stroma are tumors that morphologically display tricellular differentiation into inner (luminal) ductal epithelial cells, outer (abluminal) basaloid myoepithelial cells, and spindle-shaped stromal S100-positive cells (stromal abluminal). According to our investigation, BCAs with S100 protein-positive stroma represent a distinctive triphasic subset of BCA, which is substantially different from PA, both in immunoprofile and molecular underpinnings.

Papillary thyroid microcarcinoma (PTMC) is generally considered low risk due to its favourable prognosis; however, in some cases, it presents aggressive features such as lymph node metastasis and extrathyroidal extension (ETE). The aim of this study was to investigate the pathological factors that influence prognosis in PTMC with the purpose of refining risk stratification based on our cohort of 311 cases. We performed a retrospective analysis based on anonymous data from 311 PTMC samples (tumours ≤ 1.0 cm in size) collected between 2016 and 2024. We examined several variables, including gender, histological subtype, tumour size, ETE, lymph node metastasis, and thyroiditis. The evaluations followed the eighth edition of the American Joint Committee on Cancer (AJCC) staging system. We used Pearson's chi-square test for univariate analysis and binary logistic regression for multivariate analysis. A p-value less than 0.05 was considered statistically significant. In our cohort, 45 patients (14.5%) had lymph node metastases. Male sex (OR = 3.3132; 95% CI = 1.5554-7.0574; p = 0.002), age < 45 years (OR = 2.4974; 95% CI = 1.2228-5.1006; p = 0.012), multicentricity (OR = 2.9351; 95% CI = 1.4314-6.0182; p = 0.003) and vascular invasion (OR = 3.5184; 95% CI = 1.3044-9.4905; p = 0.013) are found to be independent risk factors for lymph node metastases. The tall cell histological subtype (OR = 3.897; 95% CI = 1.6649-9.122; p = 0.002) emerged as an independent predictor of ETE. Although PTMC is commonly considered an indolent neoplasm, some cases may present aggressive features that require careful prognostic evaluation. The identification of independent risk factors may improve clinical decision-making and therapeutic strategies for patients with PTMC.

The advent of next-generation sequencing (NGS) has significantly advanced the classification of mesenchymal neoplasms, allowing for the identification of novel gene fusion-driven entities, also in the cutaneous setting. These molecular discoveries are redefining diagnostic criteria and shedding light on tumors previously misclassified or poorly understood. This review aims to provide an updated overview of cutaneous mesenchymal neoplasms characterized by recurrent gene fusions, with special attention to recently described and emerging entities. Following a molecularly oriented classification, we examine the histopathologic, immunohistochemical, and genetic profiles of key entities, including MITF pathway-activated tumors (e.g., CRTC1::TRIM11, MITF::CREM, ACTIN::MITF), small round blue cell sarcomas (e.g., EWSR1::ETS, CIC::DUX4, BCOR-fused tumors), and several distinctive fibroblastic and spindle cell neoplasms (e.g., EWSR1::SMAD3, ALK-rearranged tumors, NTRK-rearranged spindle cell neoplasms, and keratin-positive giant cell tumor). For each, we highlight diagnostic challenges, relevant differential diagnoses, and prognostic implications. The integration of molecular diagnostics into routine dermatopathology practice is essential for the accurate classification and clinical management of cutaneous mesenchymal tumors. Recognition of gene fusion signatures not only enhances diagnostic precision but also opens avenues for targeted therapy in selected cases. Continued molecular investigation and case accumulation are necessary to validate the biological behavior and therapeutic implications of many of these newly recognized entities.

Tubo-ovarian high-grade serous carcinoma (HGSC) with proficient homologous recombination (HR) DNA repair (HRP) accounts for approximately 50% of cases and is associated with platinum-resistance and poor prognosis. We hypothesize that the acquisition of hybrid phenotypes displaying both epithelial and mesenchymal (E/M) features may be involved in the malignant transformation and tumour dissemination in this subgroup. Therefore, we analysed, by digital pathology, the expression and prognostic significance of 3 classic cadherins (E-cadherin, epithelial marker; N-cadherin, mesenchymal marker; and P-cadherin, candidate marker of hybrid E/M) in 577 formalin-fixed paraffin-embedded human samples representing the putative stepwise serous carcinogenesis in the Fallopian tube epithelium (FTE). We observed a non-canonical N-to-P-cadherin switch along the carcinogenic progression, with a statistically significant overexpression of P-cadherin in pre-malignant and malignant samples, compared to the control FTE. Interestingly, this overexpression was most pronounced in precursor lesions and HGSC cells from malignant ascites. Tumours with high P-cadherin expression were significantly associated with worse overall survival, especially in the subgroup without BRCA1/2 mutations. Transient P-cadherin knock-down resulted in in vitro significant reduction of functional hybrid E/M hallmarks, namely decreased anoikis resistance, reduced collective migration and invasion in a representative platinum-resistant HRP cell line. Taken together, our results suggest that P-cadherin overexpression is an early event in the serous carcinogenesis and may be involved in hybrid E/M activation in HRP-HGSC, further supporting this adhesion molecule as a promising biomarker for this poor prognostic subgroup.