Ghossein RA, Roy D, Shaha A
… +2 more, Tuttle RM, Xu B
Histopathology
· 2026 Feb · PMID 41171100
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AIMS: Papillary thyroid carcinoma (PTC) with blood vessel invasion (BVI) is classified as intermediate risk by the American Thyroid Association (ATA). However, no publications have adequately distinguished between encaps...AIMS: Papillary thyroid carcinoma (PTC) with blood vessel invasion (BVI) is classified as intermediate risk by the American Thyroid Association (ATA). However, no publications have adequately distinguished between encapsulated follicular variant (EFV) of PTC and infiltrative PTC with regard to BVI. Recently, the WHO classification reclassified EFV of PTC, a RAS-like tumour, as a distinct entity from PTC. In this study, we aimed to investigate the prognostic impact of BVI in infiltrative PTC. METHODS AND RESULTS: This retrospective matched case-control study included 134 cases of infiltrative PTC with BVI and at least 1 year of follow-up. A 1:1 matched control group of 134 infiltrative PTC without BVI, matched for PTC subtype and AJCC stage, was also included. CD31 and D2-40 immunohistochemistry were performed on 195 blocks to distinguish BVI from lymphatic vessel invasion (LI). BVI was defined as a CD31-positive/D2-40-negative endothelium-lined tumour embolus within a vessel wall, whereas LI was defined as a free-floating tumour plug lacking an endothelial lining within a CD31/D2-40-positive vessel. The median follow-up period was 5.3 years. Extensive BVI was the only independent adverse prognostic factor for disease-free survival (hazard ratio = 3.531) on multivariate survival analysis. On univariate analysis, infiltrative PTC with extensive BVI was associated with significantly decreased distant metastasis-free survival compared with those without BVI or with focal BVI. CONCLUSIONS: Using CD31 and D2-40 as gold standard ancillary tools, we established reliable histologic criteria to differentiate BVI from LI. Extensive BVI is an independent adverse prognostic factor in infiltrative BRAF V600E-like PTC and should therefore be considered in initial risk stratification for infiltrative PTC.
Greenland NY, Cowan JE, Ding CC
… +7 more, Sirohi D, Cooperberg MR, Carroll PR, Simko JP, Stohr BA, Zhang L, Chan E
Histopathology
· 2026 Feb · PMID 41171098
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INTRODUCTION: A recent study proposed a system of unfavourable and favourable histology categories to risk-stratify prostate cancer patients. We hypothesized that unfavourable histology would be associated with higher De...INTRODUCTION: A recent study proposed a system of unfavourable and favourable histology categories to risk-stratify prostate cancer patients. We hypothesized that unfavourable histology would be associated with higher Decipher radical prostatectomy (RP) scores and would improve biochemical recurrence (BCR) prediction. MATERIALS AND METHODS: The RP slide with Decipher testing was classified as having either unfavourable or favourable histology, with unfavourable histology defined as the presence of Gleason pattern 5, large cribriform (diameter >0.25 mm), intraductal carcinoma, complex intraluminal papillary architecture, anastomosing cords of epithelium with or without cribriform spaces and/or grade 3 stromogenic carcinoma. Favourable histology was defined as the absence of unfavourable histology patterns. The association between favourable/unfavourable histology and Decipher RP score was evaluated using the Mann-Whitney test. Univariable and multivariable analyses to test for a statistically significant association between the predictors favourable/unfavourable histology, age, PSA at diagnosis, race, RP grade group, pT and pN stage and margin status and the risk of BCR were performed. RESULTS: Four hundred and eleven RP cases from 2014 to 2020 were classified as 306 (74.5%) unfavourable and 105 (25.5%) favourable. Median Decipher scores were 0.7 for unfavourable and 0.52 for favourable (P < 0.001), corresponding to Decipher assay high and intermediate risk categories, respectively. On univariate analysis, unfavourable histology compared to favourable histology was significantly associated with decreased time to BCR, which remained significant in a multivariable model (HR 1.65; 95% CI 1.04-2.64, P = 0.035). CONCLUSIONS: Unfavourable histology was associated with higher Decipher scores and increased BCR risk. The addition of the histology category improved BCR prediction in a multivariable model.
Szalai F, Pápay J, Dezső K
… +4 more, Kuthi L, Sebestyén A, Khoór A, Krencz I
Histopathology
· 2026 Feb · PMID 41171076
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AIMS: Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histol...AIMS: Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non-metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. METHODS AND RESULTS: Immunohistochemistry for GPNMB was performed on cases of LAM (N = 15), potential differential diagnostic mimics (N = 30) and normal lung tissue (N = 2). Immunohistochemistry was assessed using the H-score method; an H-score above 100 was considered 'high'. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak-to-moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only 'high' positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. CONCLUSIONS: Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody-drug conjugate targeting GPNMB.
Machuca-Aguado J, Catherwood M, Gonzalez D
… +1 more, McCluggage WG
Histopathology
· 2026 Feb · PMID 41171033
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AIMS: The 2013 Cancer Genome Atlas (TCGA) study identified four molecular types of endometrial carcinoma (EC) that are prognostic and predictive of therapy response. The p53 abnormal (p53abn) group of tumours is associat...AIMS: The 2013 Cancer Genome Atlas (TCGA) study identified four molecular types of endometrial carcinoma (EC) that are prognostic and predictive of therapy response. The p53 abnormal (p53abn) group of tumours is associated with aggressive clinical behaviour, chemoresponsiveness and generally high-grade histology. p53abn tumours may be identified by p53 immunohistochemical staining (a surrogate marker) or molecular testing. In this study, we evaluated the concordance between p53 immunohistochemistry and TP53 molecular testing in a consecutive cohort of ECs from a population-based setting. Our aim was to investigate the rate of concordance and reasons for discordance between the immunohistochemistry and molecular testing and to provide recommendations for pathologists and clinicians dealing with these discordant cases. METHODS AND RESULTS: A total of 386 ECs were included where all biopsy specimens underwent molecular testing using a next-generation sequencing (NGS) panel (including POLE and TP53 genes and MSI testing) and immunohistochemistry for oestrogen receptor (ER), p53 and mismatch repair (MMR) proteins. Concordance between p53 immunohistochemistry and TP53 NGS was initially 88.6% (discordance of 11.4%) following review of the pathology and molecular reports; most of the discordant cases comprised carcinomas with wild-type p53 immunohistochemistry but TP53 mutations identified on NGS. The discordance reduced to 6.5% after review of the p53 stained slides, which revealed subclonal mutation-type staining in some tumours, and to 5% after excluding POLE mutated and mismatch repair deficient carcinomas. However, there remained a small cohort of 19 POLE wild-type/MMR proficient carcinomas (8 low-grade endometrioid, 9 high-grade endometrioid, 2 carcinosarcomas), with wild-type p53 staining but with TP53 mutations on NGS. Altogether, there were 12 POLE wild-type/MMR proficient low-grade endometrioid carcinomas with TP53 mutations on NGS; all were stage I (11 IA, 1 IB). CONCLUSIONS: Our study demonstrated a good overall concordance between p53 immunohistochemical staining and TP53 molecular results. The concordance can be increased by reviewing the p53 stained slides in discrepant cases but there remains a small cohort of cases, mostly low-grade endometrioid carcinomas (POLE wild-type/MMR proficient), where TP53 mutations are present on NGS but p53 immunohistochemistry is wild-type. Such cases present a dilemma for the pathologist (which TCGA group should they be placed into) and the clinician (should adjuvant therapy be instigated based on the presence of a TP53 mutation alone with no other adverse features). For now, we advise classifying such cases as p53abn but not to administer adjuvant therapy based on the presence of a TP53 mutation alone without other adverse pathological factors. The significance of TP53 mutations in such cases should be determined by larger studies with long-term follow-up.
Westerdorf J, Tretiakova M, Weiten R
… +16 more, Pryalukhin A, Quaas A, Reis H, Gaisa NT, Fahoum I, Pham H, Bismar TA, Lima JF, Eich ML, Lasnitschka NA, Hulla W, Heidenreich A, Netto GJ, Büttner R, Paffenholz P, Tolkach Y
Histopathology
· 2026 Feb · PMID 41171031
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BACKGROUND AND AIMS: Histological grading of renal cell carcinoma (RCC) is an important part of diagnostic evaluation. Reproducibility of RCC grading using whole-slide imaging (WSI) compared to glass-slide microscopy is...BACKGROUND AND AIMS: Histological grading of renal cell carcinoma (RCC) is an important part of diagnostic evaluation. Reproducibility of RCC grading using whole-slide imaging (WSI) compared to glass-slide microscopy is understudied. The aim of the study was a head-to-head evaluation of WSI-based and glass-based grading approaches in clear-cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC) subtypes. METHODS: Four cohorts of patient cases with glass slides and corresponding digitized WSI were included from two institutions (cases n, Institution 1 (I-1): ccRCC 100, pRCC 89; Institution 2 (I-2): ccRCC 97, pRCC 50). Nine board-certified pathologists provided grades, with some pathologists evaluating both glass-based and WSI-based slides in the same cohorts. An interobserver and intraobserver (different modalities) analysis was carried out, including comparisons to majority vote and consensus grades using kappa statistics. Information on prognostic endpoint (overall survival) was available for cases from Institution 1. RESULTS: In ccRCC cases, interobserver pairwise comparison among pathologists showed low to moderate agreement, similar for glass-based (kappa range 0.14-0.77) and WSI-based (0.12-0.83) approaches, with in general similar results for pRCC subtype. Significant differences could be observed for datasets stemming from two institutions: ccRCC kappa average 0.73 and 0.54 for I-1 and I-2, respectively, for glass-based, and 0.66 and 0.48 for the WSI-based approach, revealing staining differences as a potential important confounder. Intraobserver (same pathologist, same cases, glass-based vs. WSI-based) analyses revealed significant differences in assigned grades with trends to both under-grading and over-grading. For ccRCC (I-1: pathologists n = 5, I-2: n = 3), the kappa range was 0.47-0.90 for I-1 and 0.43-0.70 for I-2. In the majority vote/consensus grade analysis, there was a clear general trend to over-grading using the WSI-based approach, with more cases scored as G4. Prognostic analysis showed the value of both WSI-based and glass-based approaches. CONCLUSIONS: WSI-based grading approach for RCC results in divergent grading outcomes, with a trend to over-grading. The interobserver and especially intraobserver agreement present in low to moderate areas for both modalities warrants more standardization and exploring the potential of artificial intelligence for grading objectivization. Institute-specific staining differences might be a confounder for less reproducible RCC grading. We open-source all digital datasets and grades for education and research purposes.
Histopathology
· 2026 Jan · PMID 41117504
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Soft tissue tumours of the genitourinary tract are both rare and encompass a diverse range of mesenchymal neoplasms with varied histogenesis and clinical behaviour. This review provides an up-to-date overview of these tu...Soft tissue tumours of the genitourinary tract are both rare and encompass a diverse range of mesenchymal neoplasms with varied histogenesis and clinical behaviour. This review provides an up-to-date overview of these tumours, incorporating recent updates in classification, grading and molecular diagnostics.
Xu Y, Xia Q, Wang X
… +8 more, Fang R, Tong Q, Wang Y, Chen J, Chen J, Fu Y, Shi J, Rao Q
Histopathology
· 2026 Feb · PMID 41099277
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AIMS: The molecular characteristics and intricate relationships between tumours exhibiting overlapping features of metanephric adenoma (MA) and epithelial Wilms tumour (WT), as well as their pure forms, remain largely en...AIMS: The molecular characteristics and intricate relationships between tumours exhibiting overlapping features of metanephric adenoma (MA) and epithelial Wilms tumour (WT), as well as their pure forms, remain largely enigmatic. METHODS AND RESULTS: Herein, we conducted a comprehensive genetic analysis of nine epithelial-predominant Wilms tumours, focusing on genetic alterations through expanded targeted sequencing and RNA sequencing (RNA-seq) methodologies. The patients ranged in age from 13 to 61 years, with a mean and median age of 43 and 48 years, respectively. The cohort included seven males and two females. These tumours exhibited immune reactivity for BRAF, WT1, and CD57, and harboured frequent TERT promoter mutations (7/9) and BRAF V600E mutations (8/9). RNA sequencing-based clustering revealed a close similarity between the tumours and MAs, suggesting that they may represent a distinct subset within the Wilms tumour spectrum. Two patients were lost to follow-up, while the remaining seven (7/7) were alive without tumour recurrences or metastases at the time of analysis, with a mean follow-up duration of 78.1 months. CONCLUSIONS: Our research supports the notion previously described that epithelial-predominant Wilms tumours, characterized by frequent TERT promoter and BRAF V600E mutations, represent a distinct subset within the Wilms tumour spectrum. These tumours display an expression profile closely resembling that of metanephric adenomas and are associated with a favourable prognosis.
Anderson WJ, Kolin DL, Gonzalez IA
… +9 more, Vargas SO, Gonzalez-Peramato P, Cornejo KM, Maclean F, Sangoi AR, Colecchia M, Hirsch MS, Ulbright TM, Acosta AM
Histopathology
· 2025 Nov · PMID 41090222
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AIMS: Intratubular large cell hyalinizing Sertoli cell neoplasia (ILCHSCN) is a rare testicular sex cord stromal tumour that occurs in paediatric patients in the context of Peutz-Jeghers syndrome, a condition caused by g...AIMS: Intratubular large cell hyalinizing Sertoli cell neoplasia (ILCHSCN) is a rare testicular sex cord stromal tumour that occurs in paediatric patients in the context of Peutz-Jeghers syndrome, a condition caused by germline STK11 alterations. The diagnosis of ILCHSCN and its distinction from large cell calcifying Sertoli cell tumour (LCCSCT), a neoplasm associated with loss of function PRKAR1A mutations, can be challenging. We therefore aimed to assess the immunohistochemical expression of STK11 in a cohort of ILCHSCN and LCCSCT to investigate its diagnostic utility. METHODS AND RESULTS: Immunohistochemistry (IHC) for STK11 was assessed in 7 ILCHSCN and 9 LCCSCT. Six ILCHSCN were also stained for PRKAR1A, a biomarker known to be lost in LCCSCT. The majority of ILCHSCN (4/7; 57%), including one case with invasion, showed complete loss of expression of STK11. All LCCSCT (9/9) showed retained STK11 expression. All ILCHSCN assessed with PRKAR1A (6/6) showed retained expression. CONCLUSIONS: The majority of ILCHSCN demonstrate loss of expression of STK11, while LCCSCT shows retained expression. Our findings support that STK11 IHC is highly specific and moderately sensitive in distinguishing between these two tumours. The combination of STK11 and PRKAR1A IHC has even greater utility for distinguishing ILCHSCN and LCCSCT.
Zhou Y, Perez-Atayde AR, Zhang X
… +3 more, O'Neill AF, Church AJ, Putra J
Histopathology
· 2026 Feb · PMID 41064934
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AIMS: Hepatocellular adenomas (HCAs) are rare in children and often arise in distinct clinical contexts, despite sharing classification frameworks with adult cases. This series evaluates the clinicopathologic features of...AIMS: Hepatocellular adenomas (HCAs) are rare in children and often arise in distinct clinical contexts, despite sharing classification frameworks with adult cases. This series evaluates the clinicopathologic features of HCAs in patients 21 years or younger, highlighting phenotype-genotype correlations and the clinical relevance of molecular testing. METHODS AND RESULTS: 27 HCAs from 26 patients (69% female; mean age: 16.2 years) were analyzed. Based on morphology and immunohistochemistry (IHC), most cases were unclassified (46%), followed by inflammatory (35%), HNF1A-inactivated (15%) and β-catenin-activated (4%) subtypes. Most patients (69%) had multifocal disease. In addition to classic risk factors such as oral contraceptive use and obesity, 35% had a history of neoplasm and 15% had glycogen storage disease. Next-generation sequencing was performed on 13 HCAs; germline testing was available in 1 patient with familial adenomatous polyposis. While molecular testing had limited impact on reclassification, it was valuable in cases with ambiguous IHC profiles and in guiding management of patients with atypical or syndromic presentations by excluding variants associated with malignant potential. CONCLUSIONS: Paediatric HCAs arise in diverse clinical contexts and may require individualized treatment planning. While histologic and immunophenotypic evaluation is sufficient in most cases, molecular profiling adds value in diagnostically challenging scenarios and may help guide management decisions.
Teich T, Hu R, Nagy A
… +6 more, Shago M, Ko YCK, Ren C, Seethala RR, Purgina B, Hahn E
Histopathology
· 2026 Feb · PMID 41064927
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AIMS: Immunohistochemistry (IHC) for p16 is widely used as a surrogate marker for HPV involvement in oropharyngeal squamous cell carcinoma (OPSCC), among other tumours. Confirming HPV status in OPSCC is critical, as HPV-...AIMS: Immunohistochemistry (IHC) for p16 is widely used as a surrogate marker for HPV involvement in oropharyngeal squamous cell carcinoma (OPSCC), among other tumours. Confirming HPV status in OPSCC is critical, as HPV-positive tumours have better overall survival and may require de-escalated therapy compared to HPV-independent OPSCC in the future. However, discordance exists between p16 and HPV, and direct HPV testing is occasionally required to ensure an accurate diagnosis. The aim of this study is to highlight the genomic basis behind the limitation of relying on p16 IHC as a surrogate marker for HPV involvement. METHODS AND RESULTS: Through a multi-institutional collaboration, this case series compiled four patients with a 'false' negative p16 staining pattern in HPV-positive non-keratinizing head and neck squamous cell carcinoma. All cases demonstrated minimal to no p16 IHC staining and were positive for HPV by direct RNA in situ hybridization. Through CDKN2A fluorescence in situ hybridization testing, three patients demonstrated a homozygous deletion of CDKN2A and one demonstrated a heterozygous deletion. CONCLUSIONS: This series highlights the genomic basis for the 'false' negative p16 results, raising awareness of a significant diagnostic pitfall while emphasizing the importance of careful consideration of clinicopathologic parameters in the clinical workup of these cases.
Choudhry MFK, Caires D, Gamallat Y
… +4 more, Yilmaz A, Brimo F, Argiropoulos B, Bismar TA
Histopathology
· 2026 Feb · PMID 41064901
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AIMS: To investigate histological and copy number variations (CNVs) in Leydig cell tumours (LCTs) of the testis. Although usually benign, a small minority of cases can be associated with a poor prognosis and metastasis....AIMS: To investigate histological and copy number variations (CNVs) in Leydig cell tumours (LCTs) of the testis. Although usually benign, a small minority of cases can be associated with a poor prognosis and metastasis. METHODS: We performed whole copy number analysis to compare the genomic profile of atypical (defined by the presence of any atypical features) versus benign LCTs. Our sample consisted of one malignant (with biopsy-proven metastasis), five atypical and five benign cases. RESULTS: We found increased genomic instability in the malignant tumour and within two out of five (40%) atypical cases. One benign case revealed a likely pathogenic mutation in the neurofibromatosis type 2 gene, but all benign cases lacked genomic instability. Apart from the malignant case (which had metastatic spread to the scrotal skin), all remaining atypical cases did not reveal evidence of recurrence or metastatic spread. CONCLUSION: CNVs by themselves are not sufficient to discriminate between cases that are benign versus those with malignant potential, without the use of histomorphological parameters. Genomic instability was only detected in the malignant and atypical cases, and not in any of the benign tumours. Thus, genomic instability may represent an early step in malignant progression. The presence of metastasis remains the only malignant criterion for LCTs.
Histopathology
· 2026 Feb · PMID 41037018
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AIMS: Since there is currently limited data regarding the risk of malignancy that radial scars/complex sclerosing lesions (RS/CSL) or papillary lesions without atypia carry, we reviewed all such cases treated at King's C...AIMS: Since there is currently limited data regarding the risk of malignancy that radial scars/complex sclerosing lesions (RS/CSL) or papillary lesions without atypia carry, we reviewed all such cases treated at King's College Hospital between January 2017 and June 2023 to determine the upgrade rates following immediate excision and longer follow-up. METHODS AND RESULTS: Patients were identified using electronic database searches. An 'upgrade' was defined as the presence of ductal carcinoma in situ (DCIS) or invasive breast carcinoma (IBC) on excision at the biopsy site. One hundred and two patients had RS/CSL (85% screen-detected; 15% symptomatic). Only one (1%) of the 90 patients who underwent excision was upgraded to DCIS; none to IBC. On longer follow-up, four patients (4%) developed ipsilateral DCIS/IBC, while one patient developed contralateral DCIS with microinvasion. Two hundred and twenty-six patients had papillary lesions without atypia (42% screen-detected; 58% symptomatic). Eight (4%) of the 179 patients who underwent excision were upgraded to DCIS; none to IBC. On longer follow-up, one patient developed ipsilateral DCIS; another patient developed contralateral IBC. For both lesions, radiological size was not significantly associated with atypia/upgrade (P > 0.05; Mann-Whitney U-test). CONCLUSION: Since RS/CSL without atypia carry a low upgrade risk (1%), these patients could avoid excision and be followed up with mammographic surveillance. However, further data are needed for this change in practice to be considered. Papillary lesions without atypia appear to be more heterogeneous in behaviour, carrying an upgrade risk of 4%. Current treatment guidelines should not change until we better understand the biology of these lesions.
Huang CY, Wang YJ, Hsieh MS
… +2 more, Lin PY, Lee YH
Histopathology
· 2026 Jan · PMID 41037016
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AIMS: We aimed to evaluate tumour-infiltrating lymphocytes (TILs), tertiary lymphoid structures (TLSs) and myxoid stroma in breast biopsies diagnosed with atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (D...AIMS: We aimed to evaluate tumour-infiltrating lymphocytes (TILs), tertiary lymphoid structures (TLSs) and myxoid stroma in breast biopsies diagnosed with atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). We hypothesized that these stromal features may help identify patients at high risk for upstaging to invasive carcinoma. METHODS AND RESULTS: Analysis included 592 patients diagnosed with ADH or DCIS via breast biopsy. TILs, TLSs and myxoid stroma were correlated with high-risk features, including larger lesion size, higher BIRADS scores, higher nuclear grade, comedonecrosis, oestrogen receptor (ER) negativity and HER2 overexpression, and were associated with an increased risk of upstaging. In a multivariate logistic regression model incorporating stromal TILs or TLSs, myxoid stroma and basic pathological factors, both stromal TILs or TLSs and myxoid stroma showed independent predictive value, with an AUC of 0.77. The AUC further increased to 0.87 when clinical factors and immunohistochemistry (ER and HER2) were included. Both stromal TILs or TLSs and myxoid stroma demonstrated predictive power exceeding that of comedonecrosis and comparable with nuclear grade. The two pathologists showed moderate to high interobserver agreement in evaluating these stromal and immune features. A simplified scoring system based on six clinicopathological variables retained strong discriminative ability (AUC 0.84). CONCLUSIONS: Stromal TILs, TLSs and myxoid stroma are robust predictors of upstaging to invasive carcinoma in patients diagnosed with ADH/DCIS on biopsy. These features can be readily assessed by pathologists using only H&E staining and should be considered in future risk stratification models to inform clinical decision-making.
Histopathology
· 2026 Jan · PMID 41025914
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AIMS: Dermatofibrosarcoma protuberans (DFSP) is a superficial, locally aggressive spindle cell neoplasm, characterised by diffuse CD34 expression and the presence of COL1A1::PDGFB or related fusions. S100 expression is n...AIMS: Dermatofibrosarcoma protuberans (DFSP) is a superficial, locally aggressive spindle cell neoplasm, characterised by diffuse CD34 expression and the presence of COL1A1::PDGFB or related fusions. S100 expression is not a feature of DFSP. Prompted by a recent case of classic DFSP with significant S100 expression, we sought to explore the prevalence of S100 expression in DFSP, including its fibrosarcomatous variants. METHODS AND RESULTS: We reviewed our institutional and consultation archives for cases of DFSP that had undergone S100 immunohistochemical staining. A total of 176 cases were identified. Pigmented DFSP (Bednar tumour) cases were excluded from this study. S100 positivity expression was observed in 9 of 176 cases (5.1%), all of which lacked SOX10 expression. The mean patient age was 46.2 years, and there was a male predominance (M:F 3.5:1). The majority of tumours were located in the head and neck region (6/9), with the scalp being the most common location (n = 4). Pan-TRK staining was variably positive in 5 of the 7 cases tested. Fibrosarcomatous transformation was present in 7 of the 9 cases. Molecular confirmation was achieved in all 9 cases. CONCLUSION: S100 expression occurs in a small subset of DFSP, with a notable association with fibrosarcomatous transformation and head and neck location. The co-expression of CD34 and S100, in the absence of SOX10, mirrors the immunoprofile of emerging 'NTRK-rearranged spindle cell tumours'. Awareness of this unexpected immunophenotypic finding is essential to avoid misdiagnosis and to ensure appropriate molecular workup, which carries important prognostic and therapeutic implications.