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A rare subset of somatic tumors shows a striking resemblance to yolk sac tumors (YSTs) of germ cell origin, including somatic carcinomas with YST/enteroblastic differentiation, fetal lung adenocarcinomas (FLACs), and YSTs in older (≥ 40 years) females. These somatic tumors express markers such as SALL4, glypican 3 (GPC 3) and alpha-fetoprotein (αFP). However, it is currently unclear to what extent they express FOXA2, HNF1β, and SOX17, which are pioneer transcription factors and key drivers of YST differentiation and stain the vast majority of chemotherapy-naïve YSTs of germ cell origin. Therefore, a multi-institutional series of seven somatically derived "YST-like" tumors was assembled and evaluated with a comprehensive panel of YST related markers (SALL4, FOXA2, HNF1β, SOX17, αFP, GATA3, and CDX2), to evaluate the potential involvement of FOXA2, HNF1β, and SOX17 in the biology of these tumors. FOXA2 and HNF1β were positive in all (7/7, 100%) YST-like tumors, followed by CDX2 (6/7, 85.7%) and SALL4 (5/7, 71.4%). In contrast, SOX17, GATA3, αFP, and GPC3 were positive in fewer cases, and showed lower percentages and intensities. Four of seven (57.1%) YST-like tumors showed synchronous/accompanying somatic neoplastic components: one clear cell carcinoma of the ovary, two urothelial carcinomas of the bladder, and one invasive non-mucinous (conventional) adenocarcinoma of the lung. HNF1β stained all these components (4/4, 100%), and all of them (4/4, 100%) stained for at least two of the YST markers evaluated (range: 2-4). In conclusion, our results support the use of an immunohistochemical panel to diagnose YST-like tumors, considering not only the most frequently expressed makers (FOXA2 and HNF1β), but also the potential expression (particularly of HNF1β) by the associated somatic neoplastic components lacking an overt YST phenotype. The consistent expression of FOXA2 and HNF1β (but not SOX17) in our cohort underscores the phenotypic overlap between YST-like tumors and YSTs of germ cell origin (type II), including shared expression of multiple pioneer transcription factors which drive the YST phenotype.
Endometrial carcinoma (EC) is a common gynecological cancer with rising incidence driven by obesity and aging populations. Accurate and timely molecular classification is critical for guiding personalized oncology treatment, especially in early-stage high-grade endometrioid carcinoma. Here we present a large scale, retrospective multicenter validation of a novel POLE-POLD1 mutation assay for use in molecular characterization of EC. We evaluated the analytical performance and robustness of the novel Idylla™ POLE-POLD1 Mutation Assay, a cartridge-based PCR platform optimized for FFPE tissue. Performance comparators were established NGS reference methods. Overall, 544 formalin-fixed, paraffin embedded (FFPE) EC cases from diagnostic pathology of ten centers in Europe and North America were included. Of 544 samples, 520 revealed POLE-POLD1 test and comparator results, yielding an overall concordance of 97% (PPA of 0.96 and NPA of 0.98). Discordance was limited to a small number of variants and was often associated with low input material or the detection of multiple concurrent variants. The assay demonstrated robust performance across variable FFPE slice thickness (4-10 μm), number of Sects. (1-6), and tumor cell percentage (from 10% to 100%), with an assay invalid rate of only 2.76%. Moreover, the Idylla™ platform offers rapid results (~ 2 h) with minimal workflow complexity. The Idylla™ POLE-POLD1 Mutation Assay is a reliable and rapid diagnostic assay for clinically relevant molecular classification of EC, demonstrating high concordance with NGS and robust performance under routine pathology conditions. Whereas NGS provides comprehensive genomic profiling, including rare variants of unknown pathogenic significance, the Idylla™ assay targets treatment relevant pathogenic variants with rapid turnaround time, supporting timely, individualized treatment decisions.
To comprehensively investigate the clinicopathological characteristics, immunohistochemical (IHC) profiles and HPV status of "synchronous" endocervical and ovarian adenocarcinoma. Retrospective analysis of 21 cases of "synchronous" endocervical and ovarian adenocarcinoma was conducted. HE staining was used for morphological observation. IHC staining was performed to detect expression of p16, Mucin 6, Claudin18.2, NapsinA, and P504S. Testing for human papillomavirus (HPV) infection was carried out using the RNAscope method. Among the 21 cervical cancer cases, eight exhibited pseudostratified nuclear arrangement with prominent apical mitotic figures and apoptotic bodies, 11 had cells with clear cytoplasm and distinct cell borders, while the remaining two displayed hobnail cells. The ovarian tumors recapitulated the morphological spectrum of primary ovarian epithelial tumors and demonstrated invasive growth patterns. Endometrial/myometrial and fallopian tube involvement was observed in some cases, while others presented with lymphovascular space invasion and lymph node metastasis. IHC analysis revealed that all eight cases of both cervical and ovarian adenocarcinoma exhibited diffuse and strong positivity for p16, 11 cases co-expressed Claudin18.2 and Mucin 6, and two cases were positive for both NapsinA and P504S. RNAscope testing results were positive for all eight endocervical and ovarian adenocarcinoma cases. The final classification of eight cases was ovarian metastasis of HPV-associated (HPVA) endocervical adenocarcinoma (EAC) and the remaining 13 as metastasis of HPV independent (HPVI) EAC. The diagnosis of ovarian metastasis from EAC requires careful integration of morphological features with other clinicopathological characteristics. The markers p16, Claudin18.2 and Mucin 6 are useful for diagnosis, with HPV RNAscope testing recommended when necessary. Ovarian metastasis may involve intraepithelial spread along the endometrium/fallopian tube, traditional lymphovascular invasion, and invasive growth patterns.
The workshop on 'Reactive and therapy induced BM changes linked to systemic infectious and non-infectious disorders including MAS/HLH' of the 22nd meeting of the European Association for Haematopathology held in Dubrovnik, 2024, included 58 cases. These encompassed a broad range of infections, autoimmune disorders, malignancies and therapy-effects, or a combination of these factors, of which 28 had an associated Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage Activation Syndrome (MAS). Histoplasmosis, the infection mostly associated with HLH, showed a wide variability of BM changes, with or without focal lesions. Leishmaniasis, less often associated with HLH, induced BM changes that mimic myelodysplastic syndrome. BM changes after COVID-19 infection included myeloid and megakaryocytic hypoplasia, erythroid hyperplasia, dyserythropoiesis, hemophagocytosis, and possibly ring granulomas. Other infectious causes included viruses (HHV-8, EBV, Parvovirus B19), mycobacterial infections, and human granulocytic anaplasmosis. HLH may arise in association with the full spectrum of EBV-related disorders, including acute infection, systemic chronic active EBV disease, viral reactivation, and EBV-associated malignancies. BM changes associated with autoimmune diseases included plasmacytosis, myeloid hyperplasia and hemophagocytosis, with or without meeting the criteria of MAS/HLH, the latter often triggered by a secondary infection or exacerbation of the disease. Haematologic malignancies (EBV-positive and negative) with HLH encompassed B-cell, T-/NK-cell, and myeloid neoplasms. In addition, the workshop included therapy-induced BM changes, such as differentiation syndrome, lenalidomide-associated B-ALL, therapy-related dysplasia, gelatinous transformation, CAR-T-induced BM hypoplasia, and CAR-T-associated HLH. Finally, the workshop demonstrated the presence of T-cell expansions in a variety of conditions, which should not be misinterpreted as T-cell malignancy.
Autoimmune Hepatitis (AIH) is a liver disease with a wide clinical spectrum, driven by an abnormal immune response against the liver parenchyma. Challenges persist especially in terms of accurate diagnosis of acute onsets and differential diagnosis, outlined by the European Association for the Study of Liver guidelines. Our training cohort comprised 170 untreated AIH and 232 control cases with a variety of differential diagnosis. Ground Truth was the integrative diagnosis of the clinical, histological, biological and treatment response data. We trained a multiple-instance deep-learning model (DLM) from Whole Slide Images alone for the initial diagnosis of AIH. The model was then tested on an external dataset of 61 AIH and 124 controls. Prospective real-life testing of the model was conducted between January and June 2025. Our DLM "Artificial Intelligence On Liver Immunity (AIOLI)" achieved an AUC of 0,92 ± 0,02 on the training dataset and an AUC of 0,74 on the external dataset; in detail, it achieved an AUC of 0,89 for the differential diagnosis of AIH vs. acute alcoholic hepatitis, 0,98 vs. MASH, 0,42 vs. Hepatitis B Virus and 0,76 vs. drug-induced liver injuries. Retrieval of the five most predictive tiles allowed to identify patterns used by the model for prediction and provided interpretability. In the prospective setting, AIOLI achieved a Sensibility of 0.86, a Specificity of 0.76, a F1-score of 0.69 and an AUC of 0.73. AIOLI is an interpretable DLM able to segregate AIH from a variety of control cases with performances comparable to those of an expert liver pathologist, setting a benchmark for future research. We plan to enhance our performances by enriching our dataset, and to validate this approach with a multicentric deployment.
Accurate assessment of human epidermal growth factor receptor 2 (HER2) expression is foundational for targeted therapy in breast cancer (BC). The recent expansion of treatment eligibility to include HER2-ultralow poses a significant diagnostic challenge due to poor inter-observer reproducibility. We developed and validated a whole-slide image (WSI)-based deep learning (DL) model to standardize the identification and quantification of HER2-ultralow expression. A DL model was developed using a single-center training set. For external validation, an initial pool of 180 cases (originally archived as HER2 IHC 0 or 1+) was screened across 20 medical centers. Following rigorous quality control and expert consensus re-evaluation, a high-quality validation cohort of 89 cases (66 primary, 23 metastatic) was selected. The final consensus labels for this cohort included 65 cases of IHC 0, 19 of IHC 1+, and 5 of IHC 2+ (all ISH-negative). To address inter-pathologist variability, a reference standard was established through consensus review by expert breast pathologists, supplemented by Gaussian kernel density estimation (KDE) for continuous quantification of ultralow signals. Performance was benchmarked against participating pathologists using recall, F1 score, and mean absolute error (MAE). The AI model demonstrated superior diagnostic performance in IHC 0 classification compared to pathologists, with higher overall recall (0.862 vs. 0.828) and F1 score (0.761 vs. 0.755). Critically, the model achieved a 93.8% detection rate for HER2-ultralow cases, higher than the pathologist consensus rate (84.6%). Within the IHC 0 subset (n = 65), the AI model yielded a lower MAE, indicating enhanced quantitative precision. The model maintained high generalizability across primary and metastatic sites while accurately excluding non-neoplastic and non-invasive tissue components. To overcome the subjectivity of HER2-ultralow evaluation, particularly the visual challenge of quantifying faint staining, AI demonstrates reproducibility. By providing a robust and objective reference, this quantitative framework shows strong potential to serve as a clinical auxiliary tool, which may help practicing pathologists match expert-level concordance within this highly challenging diagnostic range. AI-based tools have the potential to augment HER2-ultralow scoring possibly in combination with dedicated pathologist training.
Ampullary cancer is a rare malignancy, histologically divided into intestinal and pancreatobiliary subtypes based on histomorphological and immunophenotypic features as they arise from different epithelial origins and exhibit distinct biological behavior, treatment responses, and clinical outcomes. However, current histomorphological and immunohistochemical classification often remains ambiguous, complicating accurate subtype assignment to guide therapeutic approaches. In this retrospective study of 125 ampullary carcinoma cases, we performed immunohistochemical profiling using a panel of markers including CDX2, CK20, mucins (MUC1, MUC2, MUC5AC), and claudins (CLDN1-4, CLDN7, CLDN18) to refine subtype classification and identify prognostic biomarkers. Hierarchical clustering based on marker expression H-scores revealed two molecular subtypes corresponding to intestinal and pancreatobiliary differentiation. While CDX2 and CK20 are routinely used in combination for diagnosis, other markers, particularly CLDN3, CLDN7, and MUC5AC, demonstrated superior diagnostic and prognostic performance to CDX2. CK20, by contrast, remained a robust marker of intestinal differentiation and favorable outcome. Pancreatobiliary-type tumors exhibited elevated MUC1, MUC5AC, and CLDN18 expression, and were associated with advanced stage, invasive features, and significantly worse survival. Multivariate analysis showed high MUC5AC and apical MUC1 expression to be associated with adverse outcomes, whereas CLDN1, CLDN3 and CLDN4 expression were linked to improved survival. Membranous CLDN18 expression was more common in pancreatobiliary-type ampullary cancer, making it a potential therapeutic target. These findings underscore the diagnostic and prognostic value of multiplex immunohistochemical profiling. We propose retaining CK20 but replacing CDX2 with a more informative marker, namely CLDN3, to enhance classification and therapeutic stratification.
Acinar cell carcinomas (ACCs) of the pancreas are rare neoplasms composed of cells showing acinar cell differentiation demonstrated by the immunoreactivity for acinar cells markers including trypsin, chymotrypsin, and BCL10. The differential diagnosis with more common pancreatic neuroendocrine tumors (PanNETs) may be difficult due to some overlapping morphological features and the expression of general neuroendocrine markers (synaptophysin and chromogranin A) by acinar cells, a phenomenon observed in about 35% of cases. These tumors showing a dual acinar and neuroendocrine differentiation need to be separated from PanNETs since their clinical management and prognosis are different. Little is known about the possible diagnostic role of INSM1, a highly specific and sensitive "second generation" neuroendocrine marker recently identified. With this aim we investigated INSM1 expression in 58 ACCs that, based on the expression of synaptophysin and chromogranin A, were separated into 36 pure ACCs lacking any neuroendocrine marker expression, 21 ACCs with divergent acinar and neuroendocrine differentiation, and one mixed neuroendocrine/non-neuroendocrine neoplasm (MiNEN) consisting of two separate acinar and neuroendocrine components. INSM1 expression overlapped that of synaptophysin and chromogranin A, although in several cases the number of INSM1 positive cells was less than that of chromogranin A. In conclusion, our results show that INSM1 expression in a pancreatic neoplasm should be carefully considered and interpreted in conjunction with morphology and a comprehensive immunohistochemical panel and does not give any diagnostic advantage respect to "traditional" neuroendocrine markers.
The evaluation of tumors is increasingly becoming an integrated diagnosis based on combined histologic and genomic evaluations. As more tumors are subjected to genomic analyses, discrepancies between the histologic diagnosis and molecular findings surface. Pathologic review of genomic-directed specimens plays a vital role in understanding and resolving these discrepancies. We aim to assess the frequency of and reasons for discrepant diagnoses in genomic-directed specimens from a precision genomics program. A retrospective review of genomic-directed specimens analyzed through a precision genomics program was performed. We assessed the frequency of discrepancies between the histologic diagnosis and molecular findings. The discrepant cases were further studied to uncover the reasons behind the discrepancy. 381 patients referred to the program had their tumors sequenced. Nine cases (2.4%) had discrepancies between the original histologic diagnosis and molecular findings. These discrepancies were related to a combination of nonspecific morphology, nonconclusive immunophenotypes, and misleading immunophenotypes. While infrequent, diagnostic discrepancies do occur in genomic-directed specimens. These cases are often diagnostically challenging to begin with. Integrated diagnostics (histology, immunohistochemistry, and molecular) and collaborative discussions are critical for resolving and reducing discrepancies.
ASPSCR1::TFE3-rearranged renal cell carcinoma (RCC) represents the most common subtype of TFE3-rearranged RCC, yet clinicopathologic and prognostic data remain limited. We analyzed 30 cases confirmed by fluorescence in situ hybridization or RNA-based next-generation sequencing, representing the largest single-center series to date. The cohort demonstrated an overwhelming female predominance, with a median age of 23.6 years. Microscopically, tumors exhibited diverse histological patterns, including papillary, nested, or tubular architectures, with papillary structure being the most prevalent. Tumor cells characteristically showed abundant clear to eosinophilic cytoplasm with discrete cell borders. Psammoma bodies were frequently present. Rare morphologic patterns included TFEB-rearranged RCC-like and cystic changes that, to our knowledge, have not been reported previously. Immunohistochemically, all tested tumors showed nuclear TFE3 positivity, with variable PAX8 expression, weak or absent staining for epithelial markers (CK7 and EMA), and negativity for melanocytic markers (HMB45 and Melan-A). PD-L1 was positive in 4 of 18 cases. Over 5-173 months of follow-up, the 5-year disease-free survival (DFS) rate was 37.9%, while the corresponding overall survival (OS) rate was 61.4%, with 3 patients developing recurrences and 16 developing metastases. Univariate analysis linked larger tumor size (> 4 cm), grossly solid appearance, tumor necrosis, psammoma bodies, microvascular tumor thrombi, high Ki-67 (≥ 5%), advanced stage (≥ III), and synchronous metastasis to worse prognosis. On multivariate analysis, tumor necrosis was independently associated with shorter DFS. Our findings expanded the clinicopathologic, immunohistochemical, molecular, and prognostic spectrum of ASPSCR1::TFE3-rearranged RCC and underscored the importance of precise morphologic and molecular assessment for risk stratification.
HER2-targeted therapy is increasingly used in colorectal cancer (CRC). However, discrepancies between conventional detection methods (immunohistochemistry [IHC]/fluorescence in situ hybridization [FISH]) and next-generation sequencing (NGS) remain to be elucidated. Furthermore, the impact of spatial intratumoral heterogeneity (SIH) in HER2 overexpression on both the methodological concordance and therapeutic efficacy is still poorly understood. Two consecutive retrospective cohorts from Peking Union Medical College Hospital (2018-2024) were analyzed. In the NGS cohort (n = 1,343), HER2-amplified cases were identified based on NGS-derived gene copy number (GCN), and their clinicopathological and molecular features were characterized using stage-matched HER2-non-amplified controls. In the IHC cohort (n = 3,585), spatial HER2 expression heterogeneity was comprehensively assessed. Finally, treatment outcomes were reviewed in four HER2-amplified patients who received anti-HER2 therapy. HER2 amplification was detected in 2.53% (34/1,343) of tumors and defined a distinct molecular subset characterized by fewer RAS/KRAS mutations and more frequent CDK12 and TP53 alterations. Concordance between NGS and IHC was higher when applying ToGA criteria (κ = 0.85) compared to the HERACLES criteria, particularly in cases with high-level amplifications (GCN ≥ 10). Notably, intrablock heterogeneity accounted for 82% of discordant cases, underscoring a major biological source of testing variability. In the IHC cohort, HER-2 positivity was defined as ≥ 10% 3 + staining or 2 + in IHC with amplification confirmed by FISH. Overall, 1.62% of CRCs were HER2-positive, of which 24.14% exhibited intrablock heterogeneity, and 31.25% demonstrated SIH across tumor blocks or between primary and metastatic sites. Among four patients treated with anti-HER2 therapy, two with relatively limited HER2 expression heterogeneity showed sustained CEA decline and stable disease (SD), whereas the two with marked heterogeneity demonstrated fluctuating CEA levels and disease progression, even in the presence of high-level amplification. HER2-amplified/overexpressed CRC constitutes a biologically distinct entity frequently characterized by SIH. This heterogeneity represents a key determinant of inter-method discordance and may influence response to HER2-targeted therapy. These findings support integrating spatial assessment into HER2 testing algorithms and warrant prospective validation of its predictive value.
Borderline breast lesions (B3 lesions, also termed lesions of uncertain malignant potential or high-risk lesions) represent a heterogeneous group of entities associated with variable risks of malignancy. While the management of screen-detected B3 lesions has become increasingly standardised, no dedicated international recommendations exist for symptomatic B3 lesions, despite them posing a distinct clinical challenge. Symptomatic lesions differ from screen-detected lesions in their mode of presentation, lesion characteristics, biopsy techniques, and diagnostic objectives; consequently, management strategies derived from screening populations may not be directly applicable. This review summarises the current evidence and proposes a pragmatic management framework for B3 lesions encountered in the symptomatic setting (defined as those presenting with breast symptoms outside population-based screening programmes). This is particularly relevant for patients under 50 years of age, where the primary objective is to exclude malignancy at the index site rather than solely to stratify long-term cancer risk. Clinical-radiological-pathological concordance and multidisciplinary assessment are central to management decisions. Lesions presenting as palpable abnormalities (which are typically larger) or those demonstrating radiological-pathological discordance warrant a lower threshold for additional sampling or excision. Conversely, selected concordant lesions without atypia may be managed conservatively following adequate sampling. The long-term cancer risk associated with epithelial atypia should also be considered with subsequent risk-based surveillance implemented where appropriate. Overall, management requires a risk-adapted, multidisciplinary approach integrating pathological, radiological, and clinical factors alongside patient symptoms and quality-of-life considerations. Given the limited evidence, current recommendations rely on expert consensus and a proposed practical framework. They underscore the need for large-scale, high-quality studies with long-term follow-up to establish formal clinical guidelines.
Rearrangements involving NFATC2 define a heterogeneous group of neoplasms, and NFATC2::NUTM2-associated tumors of the lung and salivary glands have recently emerged as a distinctive clinicopathologic entity. We report two primary pulmonary tumors that further refine the spectrum of this neoplastic group and highlight the diagnostic value of structural genomic analysis in morphologically characteristic but targeted sequencing-negative lesions. Both patients presented with small, slowly growing, contrast-enhancing pulmonary nodules and were free of disease at 12 and 18 months after resection. Histologically, both tumors were well circumscribed and composed of relatively monomorphic epithelioid to basaloid cells arranged in nests, cords, and trabeculae within densely sclerotic to hyalinized stroma, with a conspicuous peripheral lymphoid cuff. Immunohistochemically, both tumors showed an epithelial/basal phenotype with an atypical, non-lineage-definitive myoepithelial-like immunoprofile, expressing pan-cytokeratin, CK5/6, EMA, GATA3, calponin, and D2-40, while lacking S100, SOX10, p63, p40, and SMA. Targeted DNA- and RNA-based next-generation sequencing did not identify a driver alteration. Formalin-fixed paraffin-embedded Hi-C demonstrated the same recurrent t(10;20)(q22;q13) involving NUTM2E and NFATC2 in both cases. RNA-based analysis detected an NFATC2::NUTM2E fusion transcript in 1 case and additional breakpoint-level support in both. These findings expand the spectrum of primary pulmonary NFATC2::NUTM2-associated myoepithelial-like neoplasms and support morphology-guided structural genomic testing as a practical second-line diagnostic strategy.
Inverted follicular keratosis (IFK) is an uncommon benign skin epithelial neoplasm that microscopically consists of a superficial, sharply circumscribed tumor composed of bland keratinocytes associated with squamous eddies. Only a few examples of combined tumors associating IFK and either trichoblastoma or a sebaceous component have been reported in the literature. Herein, we report the clinicopathological and molecular characterization of 12 cases of combined tumor comprising IFK associated with an adnexal neoplasm, including trichoblastoma (n = 7), sebaceoma (n = 4), and tubular adenoma (n = 1). The age at presentation ranged from 26 to 79 years, with a mean of 55 years. The majority of the tumors were located on the head (n = 8) with a median size of 6 mm (Range: 3-14 mm). Microscopically, all cases showed a biphasic appearance with a prominent IFK component superficially, associated either with trichoblastoma, sebaceoma or tubular adenoma at the deeper aspect, with an abrupt transition between the two tumor components. There was no evidence of nevus sebaceus in the surrounding tissue. Molecular investigation revealed pathogenic HRAS or KRAS mutations in 3 of the 4 cases harboring a sebaceous component and also in the specimen with combined IFK and tubular adenoma. No mutations were detected in any of the 5 tested IFK-TB cases. To conclude, our series expands the spectrum of combined tumors associated with IFK. Genetic characterization suggests that pathogenic mutations of RAS might drive a subset of these cases, particularly when associated with sebaceoma, even in the absence of pre-existing nevus sebaceus.
Desmoplastic reaction (DR), characterised by myxoid stroma and keloid-like collagen, is a poor prognostic factor in several types of cancer. We investigated the impact of stromal DR status on recurrence and prognosis in patients with upper urinary tract urothelial carcinoma (UTUC). This study included 155 UTUC patients who underwent surgery between 1999 and 2021. The presence of myxoid stroma and keloid-like collagen at the invasive front of the tumour was evaluated. Patients were classified into three groups: mature-type, keloid-like, and myxoid-type DR. We analysed the associations between DR status and clinicopathological factors, tumour budding (BD), and tumour-associated immune cell status (TAICs), as well as its impact on extraurothelial recurrence-free survival (EUR-FS) and overall survival (OS). Among the 155 patients, 101 (65%), 15 (10%), and 39 (25%) were classified as mature-type, keloid-like, and myxoid-type DR, respectively. DR status was significantly associated with adverse pathological prognostic factors. In univariate analysis, higher pathological T category, lymphovascular invasion, lymph node metastasis, positive surgical margins, presence of subtype histology, myxoid-type DR, and high-grade BD were significantly associated with worse EUR-FS. Multivariate analysis revealed that myxoid-type DR (HR = 2.19, p = 0.0279) and high-grade BD (HR = 3.35, p = 0.0008) were independent predictors of EUR-FS. Regarding OS, age ≥ 70, lymphovascular invasion, and myxoid-type DR were independent predictors. The presence of myxoid stroma was associated with adverse prognostic factors and low TAICs and served as an independent predictor of EUR-FS and OS. These findings suggest that myxoid stroma in the invasive front represents a novel and useful pathological prognostic indicator for UTUC.
Primary renal synovial sarcoma (PRSS) is an extremely rare neoplasm that presents considerable diagnostic challenges due to its morphological overlap with other renal tumors. In this multicenter study, 23 PRSS cases with confirmed SS18::SSX rearrangements and 112 non-PRSS renal tumors were included. Clinicopathological features and immunohistochemical expression were evaluated. Diagnostic performance of individual markers and their combinations was assessed using sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy, and a practical diagnostic approach for PRSS was proposed. The cohort (n = 23) had a median age of 42.3 years with slight male predominance (56.5%). Most presented with loin pain, and the mean tumor size was 8.7 cm. After a mean follow-up of 25 months, 41.2% (7/17) died of disease. Histologically, 87% (20/23) of cases showed intersecting monophasic spindle-cell morphology with oval‑to‑spindle hyperchromatic nuclei, while 13% (3/23) were biphasic. Key immunohistochemical findings included positivity for SS18-SSX (56.5%), TLE1 (82.4%), BCL2 (75%), and EMA (25%), with reduced/mosaic INI1 expression in 73.9% of cases. SS18-SSX, TLE1, and INI1 formed the optimal diagnostic panel. The criterion of at least two positive or aberrant markers achieved the highest performance: accuracy 94.8%, sensitivity 69.6%, specificity 100%, PPV 100% and NPV 94.1%. Based on these findings, a practical diagnostic approach integrating morphology with SS18-SSX, TLE1, and INI1 immunohistochemistry was proposed. PRSS is a rare malignant tumor with a poor prognosis that presents significant diagnostic challenges. Our immunohistochemical panel (SS18-SSX, TLE1, INI1) enhances diagnostic accuracy and may assist in the triage of cases requiring molecular confirmation.
Laryngeal squamous cell carcinoma (LSCC) frequently arises from premalignant dysplastic lesions, yet reliable predictors of malignant transformation remain limited. This study investigates the immune microenvironment of laryngeal dysplasia and its association with progression to invasive carcinoma. We conducted a retrospective cohort study of 110 patients with histologically confirmed laryngeal dysplasia excised between 2009 and 2022, reclassified according to the 2022 WHO two‑tier system. Clinical data, including tobacco and alcohol exposure, were collected, and outcomes included recurrence, progression to invasive carcinoma, and cancer‑free survival. Immunohistochemistry and digital image analysis were used to quantify intraepithelial and stromal immune markers (CD3+, CD4+, CD8+, CD68+, CD163+, PD-L1). High-grade dysplasia represented 68% of cases, and 33% progressed to invasive carcinoma. Intraepithelial T-cell and macrophage densities did not differ significantly between progressing and non-progressing lesions, whereas stromal immune characteristics showed prognostic value. In multivariate analysis, alcohol exposure, dysplasia grade, stromal CD8 + density, and PD-L1 expression were independently associated with progression. Former drinkers showed a higher risk than lifelong abstainers, while high-grade dysplasia carried a fourfold increased risk relative to low-grade lesions. Higher stromal CD8 + infiltration and lower stromal PD-L1 expression correlated with progression, though with modest effect sizes. Digital immune profiling validated distinct stromal immune signatures associated with progression in laryngeal dysplasia. These findings suggest that malignant transformation depends not only on histological grade and alcohol exposure but also on subtle immune alterations, supporting integration of stromal immune markers with WHO grading to refine risk stratification and guide surveillance strategies.
Soft tissue leiomyosarcoma (STLMS) remains a challenging malignancy with variable clinical outcomes, highlighting the need for reliable prognostic biomarkers. Recent genomic studies have proposed risk stratification models based on RB1 and ATRX alterations; however, the utility of corresponding immunohistochemical (IHC) surrogates has not been fully explored. In this study, we analyzed clinicopathological features and ATRX/Rb IHC expression in a cohort of 70 STLMS cases to identify correlates of aggressive behavior and assess their prognostic value. Metastasis was significantly associated with female sex (p = 0.004), age ≤ 60 years (p = 0.022), internal cavity location (p = 0.014), necrosis (p = 0.032), elevated mitotic rate (p = 0.01), high FNCLCC grade (p < 0.001), larger tumor size (p = 0.03), and deep/internal origin. Loss of ATRX staining (44% of cases) correlated significantly with larger tumor size (p = 0.003), deep location (p = 0.015), and internal cavity site (p = 0.007), linking ATRX deficiency to more extensive local disease. Rb loss was frequent (74%) but lacked strong associations with most clinicopathological variables. Although ATRX, Rb, and combined IHC patterns did not significantly stratify overall survival (OS), disease-free survival (DFS), or disease-specific survival (DSS), FNCLCC grade robustly differentiated outcomes, particularly for DFS (p = 0.000741) and DSS (p = 0.0206), with a clear trend in OS (p = 0.0711). Low-grade tumors exhibited no metastases and favorable survival. These findings validate FNCLCC grading as a cornerstone prognostic tool and demonstrate that ATRX IHC identifies clinically relevant subsets with aggressive local features. The observed discordance between IHC and genomic classifiers underscores the complexity of translating molecular alterations to protein-level surrogates, likely due to regulatory mechanisms beyond mutation. This work provides practical insights for risk assessment in STLMS and supports the integration of traditional grading with targeted IHC and molecular profiling for refined patient management.
NTRK-rearranged neoplasms may occur at many body sites. In the female genital tract, they are most common in the uterus with a predilection for the cervix where they often exhibit aggressive behaviour, justifying the designation sarcoma. Typically, these sarcomas are composed of monomorphic spindled cells arranged in fascicular or herringbone patterns. We report two cases of uterine sarcoma (1 cervix, 1 corpus) with next generation sequencing-detected NTRK rearrangements and novel "aberrant" morphologic and immunohistochemical features, including heterologous rhabdomyoblastic and cartilaginous differentiation, negative staining with panTRK and loss of H3K27me3 expression. One case harbored a AKAP13::NTRK3 rearrangement, which has not been previously reported in NTRK-rearranged sarcomas, with co-occurring LZTR1 and TP53 variants. The other case contained hotspot and nonsense variants in DICER1, and was ultimately classified as a DICER1 sarcoma. Our findings expand the morphological and immunohistochemical spectrum of NTRK-rearranged uterine sarcomas, highlight important diagnostic pitfalls and raise the important question of driver versus passenger molecular events. Recognition of tumours with these unusual features is crucial, as NTRK-rearranged sarcomas frequently show aggressive clinical behaviour but are potentially amenable to targeted therapy with selective TRK inhibitors.
Structured reporting in pathology can enhance data quality and interoperability through standardized terminologies; however, its integration into routine practice remains limited as structured reporting systems are frequently perceived as disruptive to established workflows. Although synoptic templates are widely implemented, they represent only an intermediate stage of digital maturity and do not ensure interoperable data. Evidence regarding real-world implementation and usability remains scarce. This study evaluates the impact of structured reporting on data completeness, reporting accuracy, and user adoption in routine lung cancer pathology reporting. A structured pathology reporting tool (SynReport, Celerato AG) was evaluated in two phases. In the validation phase, data from 123 conventional (synoptic) lung cancer resection reports were retrospectively re-entered into the tool. In the implementation phase, the tool was integrated into routine diagnostics with optional use over one year (n = 151). Report completeness was evaluated against ICCR core elements and adoption was measured by voluntary usage rates. Retrospective analysis identified 33 missing or inconsistent data elements (98.4% completeness) in the re-entered conventional reports, including six TNM classification errors, none of which occurred when using the tool. During routine implementation (n = 151), pathologists used the structured reporting tool in 90.1% of the cases (n = 136), achieving 99.9% completeness, whereas the remaining conventional reports contained multiple omissions (n = 11). Structured reporting achieved high voluntary adoption in routine practice while improving data completeness and reducing errors. This study demonstrates that structured reporting can be integrated into daily workflows and represents a practical step toward interoperable and data-driven pathology.