Aberrant GATA3 reactivity in a clear cell renal cell carcinoma with clear cell papillary renal cell tumor-like features: a case reportPopescu, Miruna C.; Akgul, Mahmut; Williamson, Sean R.; Sangoi, Ankur R.
doi: 10.1007/s00428-026-04538-7pmid: 42068355
Clear cell papillary renal cell tumor (CCPRCT) has been reclassified from “carcinoma” to “tumor” in the latest World Health Organization (WHO) Classification in 2022 to better reflect its excellent outcome. Therefore, its distinction from its closest mimic, clear cell renal cell carcinoma (CCRCC), is now more clinically relevant than ever. The well-documented occurrence of tumors with significant overlapping morphologic and immunohistochemical features between CCPRCT and CCRCC has sparked a search for additional immunohistochemical markers that may aid in this distinction. Based on the putative distal nephron origin of CCPRCT, GATA binding protein 3 (GATA3) has been proposed as a sensitive and specific marker for this diagnosis, with only exceptional cases of CCRCC reported to show GATA3 reactivity. To the best of our knowledge, this is the first report of a molecularly-confirmed, low-stage, low-grade CCRCC showing overlapping histology with CCPRCT and an exceptional CCPRCT-like immunohistochemical profile, including diffuse nuclear expression of GATA3.
Stromal-only endometriosis catamenial pneumothorax: A diagnostic algorithm with potential pitfallsPapa, Riccardo; Meroni, Alberto; Incarbone, Matteo; Pelosi, Giuseppe
doi: 10.1007/s00428-026-04585-0pmid: 42151596
Catamenial pneumothorax (CP) is a rare form of recurrent spontaneous pneumothorax occurring synchronously with menstruation and represents the most common manifestation of thoracic endometriosis. CP predominantly involves the right hemithorax as a result of the transdiaphragmatic migration of endometrial tissue through congenital or acquired diaphragmatic defects, a phenomenon thought to be facilitated by the clockwise circulation of peritoneal fluid and by the absence of an effective anatomical barrier on the right side to limit transdiaphragmatic spread. Diagnosis may be particularly challenging when endometrial implants are composed exclusively of stromal cells without identifiable glands, are focal in distribution, and minute in size. We herein describe two challenging cases of recurrent right-sided pneumothorax in women of reproductive age, in whom paucifocal endometrial deposits were consistent with stromal-only endometriosis in the absence of endometrial glands. Based on these cases, we propose a practical diagnostic flowchart addressing the major pitfalls in the recognition of stromal-only thoracic endometriosis and highlighting the critical importance of close clinicopathologic correlation, particularly in gland-deficient lesions.
The critical role of accurate neoplastic cell percentage (NCP) assessment: investigating targeted training strategies for pulmonary biopsy and cytology specimensPham, Thi Mai Phuong; Peeters, Dieter; von der Thüsen, Jan; Remmelink, Myriam; Weynand, Birgit; Dequeker, Elisabeth
doi: 10.1007/s00428-026-04505-2pmid: N/A
Cancer diagnostics and therapeutics have widely changed, and in advanced non-small cell lung cancer (aNSCLC), molecular analysis is crucial to identify actionable biomarkers. Targeted therapies specifically interfere with molecular mechanisms involved in tumor growth and proliferation to improve clinical outcomes and quality of life compared to conventional chemotherapy. However, suboptimal testing practices, including errors in neoplastic cell percentage (NCP) assessment, limit reliable downstream analyses, and therefore, hinder accurate targeted therapy decisions for NSCLC patients. This study conducted two assessment rounds in which participants evaluated cytology or biopsy cases to examine NCP assessment accuracy and molecular testing decisions among pathologists and non-pathologists. No evidence was found for changes in NCP assessment performance across rounds (OR = 1.996, 95% CI = [0.600;6.644], p = 0.260) and they were also not influenced by professional background (OR = 0.932, 95% CI = [0.611;1.421], p = 0.743). However, prior training in NCP assessment showed potential benefit for accurate NCP estimation. Additionally, incorrect NCP assessments were significantly linked to subsequent molecular testing decision errors (OR = 2.327, 95% CI = [1.286;4.212], p = 0.005), and the inter-observer agreement for cytology cases was poor with higher error rates for cytology cases compared to biopsy cases (OR = 2.389, 95% CI = [0.967;5.906], p = 0.059). In conclusion, a continuing need for training focusing on harmonization of NCP assessment and molecular testing decision-making remains. Ultimately, such assessment improvements will enhance accuracy of downstream precision medicine for NSCLC patients.
Clinicopathologic characterization of primary anal canal mucosal melanomas: a single institution studyFeng, Yan; Zhang, Steven; Dehner, Carina A.; Umphress, Brandon A.; Saeed, Omer; González, Iván A.
doi: 10.1007/s00428-026-04595-ypmid: N/A
Primary anorectal melanomas are relatively rare, and it is recommended to staged them based on the American Joint Committee on Cancer (AJCC) melanoma staging system which relies primarily on tumor size. To date, no studies have characterized the clinicopathologic features of primary anal canal melanomas. Twenty cases of primary anal canal melanomas were included. Patients presented with a median age of 67.4 years (range: 47–88) and the male to female ratio was 1:1. Most of the patients presented with rectal bleeding (80%) and/or with a hemorrhoid-like mass (60%). The median tumor size was 2.0 cm (range: 0.8–9.7) and all were considered pT4 per the melanoma staging system whereas using the anal cancer staging system cases were considered as pT1 (9 cases, 45%), pT2 (6 cases, 30%) and pT3 (4 cases, 20%). The median depth of invasion was 9 mm (range: 1.6–3.5) and the median mitotic rate/1mm2 was 11 (range: 1–31). Most tumors only extended to the submucosa (68.4%), followed by muscularis propria (15.8%) and peri-anorectal tissue (15.8%). PRAME was positive in 91% of the cases. 1 case had a BRAF D594G variant and 1 case had a KIT V560A variant. After a median follow-up of 14.9 months (range: 3.6–119), 19 patients (95%) were deceased. Only tumor extension was independently associated with disease-free survival (HR: 7.325, 95%CI: 1.316–40.779) but a trend was seen for tumor size (p = 0.078). Our data shows that for primary anal canal melanoma, the anal cancer staging system in combination with the extent of tumor invasion is more adequate for patient stratification.
FOXL2 expression in dysgenetic gonads supports the diagnostic possibility of ovotesticular differences of sex developmentBahmad, Hisham F.; Gestrich, Catherine K.; Salgado, Claudia M.; Baskin, Laurence S.; Reyes-Múgica, Miguel
doi: 10.1007/s00428-026-04591-2pmid: 42168620
Ovotesticular disorders of sex development (DSD) are variations in sex development characterized by the presence of both ovarian and testicular parenchyma in the same individual, with histopathologic confirmation being mandatory for accurate diagnosis. FOXL2, a transcription factor involved in ovarian differentiation and maintenance, has emerged as a potential immunohistochemical marker for ovarian tissue. However, its diagnostic utility in pediatric DSD patients, particularly in identifying ovotesticular cords (OVTCs), remains underexplored. This study aims to evaluate the immunohistochemical expression of FOXL2 in gonadal tissues of patients with ovotesticular DSD and gonadal dysgenesis to determine its value in identifying ovotesticular cords (OVTCs) and support the diagnosis of ovotestis. A retrospective histopathological analysis was conducted on 19 gonadal specimens from 14 pediatric patients diagnosed with ovotesticular DSD or gonadal dysgenesis. Cases were retrieved from the surgical pathology archives of the University of Pittsburgh Medical Center – Children’s Hospital of Pittsburgh and the consultation files of Miguel Reyes-Múgica. Formalin-fixed, paraffin-embedded tissue sections underwent hematoxylin and eosin staining and immunohistochemical analysis for FOXL2 and additional gonadal markers. FOXL2 expression was assessed for nuclear localization, and distribution within stromal and cordal compartments, with staining intensity semi-quantitatively scored as 0 (no positive cells), 1+ (few-to-moderate, < 50%), or 2+ (numerous, ≥ 50%). Among the 19 gonads examined, histologic diagnoses included 4 ovaries, 11 ovotestes (among which 3 were classified as bipolar ovotestis, 2 as streak-type ovotestis), and 4 dysgenetic testes, and streak gonads. FOXL2 showed strong and diffuse nuclear expression in ovarian stroma and was consistently positive in ovotestes, including focal intracordal staining within OVTCs, even in gonads with predominantly testicular histology. Of the 12 gonads with ovotesticular DSD (including 11 ovotestes and 1 ovary with OVTCs), 11 (92%) demonstrated FOXL2 expression in testicular components. All gonads classified as ovaries were FOXL2-positive, while dysgenetic testes lacking histologic evidence of ovarian differentiation were either negative or showed only rare positive stromal cells without intracordal expression. FOXL2 staining correlated with histologic and clinical findings, confirming its value in identifying ovarian differentiation and supporting the diagnosis of ovotesticular DSD. FOXL2 immunohistochemistry is a reliable marker of ovarian differentiation and can aid in the diagnosis of ovotesticular DSD. Its expression in ovarian stroma and OVTCs enhances the histological evaluation of ambiguous gonads and supports its routine use in the diagnostic workup of pediatric DSD patients.
Distinct molecular pathogenesis in the two most common subtypes of cutaneous squamous cell carcinomaNeil, Alexander J.; Davis, Dale; Singer, Sean; Hanna, John
doi: 10.1007/s00428-026-04564-5pmid: 42086840
The Bowenoid subtype of cutaneous squamous cell carcinoma (SCC) has been distinguished from conventional SCC for over a century based on its different histopathologic appearance, clinical features, and biologic potential. While there has been extensive molecular analysis of conventional SCC, there has been comparatively little investigation of Bowenoid SCC. Here we show that loss of RB1 protein expression is a defining feature of Bowenoid SCC and reflects biallelic genetic inactivation which most commonly proceeds through mutation of one RB1 allele and copy number loss of the other allele. Neither RB1 protein loss nor RB1 mutations were seen in conventional SCC. A third, but much less common, form of cutaneous SCC is caused by human papillomavirus (HPV). This subtype showed similar morphologic features to Bowenoid SCC and also showed loss of RB1 protein expression. However, these tumors lacked RB1 mutation and likely inactivate RB1 through HPV’s known capacity to promote post-translational degradation of RB1 protein. These data suggest that the two most common subtypes of cutaneous SCC proceed through distinct pathways of molecular pathogenesis and highlight an unexpected relationship between Bowenoid and HPV-associated cutaneous SCC.
DICER1 alterations in thyroid lesions: a systematic review and meta-analysis with clinicopathologic implicationsStraccia, Patrizia; Fiorentino, Vincenzo; Piermattei, Alessia; Mulè, Antonino; Rossi, Esther Diana; Rossi, Esther
doi: 10.1007/s00428-026-04580-5pmid: N/A
DICER1 is a key RNase III endoribonuclease involved in microRNA biogenesis and is implicated in both constitutional DICER1-related tumor predisposition and sporadic thyroid tumorigenesis. In thyroid pathology, DICER1 alterations have been reported across a broad spectrum of lesions, but their reported frequency and clinicopathologic significance vary substantially across published series. We performed a systematic review of thyroid-focused studies published between 2020 and 2025. Studies were included in the quantitative synthesis only if they provided an interpretable lesion-level numerator and denominator for thyroid lesions harbouring DICER1 alterations. Additional thyroid-focused studies that refined the cytomorphologic, histologic, and lesion-spectrum interpretation of DICER1-associated thyroid disease, but lacked a suitable denominator for prevalence meta-analysis, were retained for qualitative clinicopathologic synthesis. Random-effects meta-analysis of logit-transformed proportions was used for the quantitative component. Seven studies met criteria for quantitative synthesis, comprising 16,831 thyroid lesions, of which 317 were reported as DICER1-altered. Study-level proportions ranged from 1.4% in a large adult consecutive molecular-testing cohort to 22.0% in a pediatric follicular-patterned tumor cohort. The pooled proportion of thyroid lesions harbouring DICER1 alterations was 5.76% (95% CI, 2.49%-12.78%), with substantial heterogeneity (I² = 96.94%). Exploratory stratification showed lower pooled proportions in predominantly adult cohorts and higher pooled proportions in pediatric or young-enriched cohorts. Qualitative synthesis showed that DICER1 alterations occur across a wide thyroid lesion spectrum, including multinodular and follicular nodular disease, follicular adenoma, NIFTP, follicular thyroid carcinoma, follicular-patterned papillary thyroid carcinoma, and rare higher-grade or primitive malignant tumors such as thyroblastoma. Cytologically and histologically, these lesions frequently show follicular-patterned architecture, often with macrofollicular or mixed follicular growth and relatively bland nuclear features.Seven studies met criteria for quantitative synthesis, comprising 16,831 thyroid lesions, of which 317 were reported as DICER1-altered. Study-level proportions ranged from 1.4% in a large adult consecutive molecular-testing cohort to 22.0% in a pediatric follicular-patterned tumor cohort. The pooled proportion of thyroid lesions harbouring DICER1 alterations was 5.76% (95% CI, 2.49%-12.78%), with substantial heterogeneity (I² = 96.94%). Exploratory stratification showed lower pooled proportions in predominantly adult cohorts and higher pooled proportions in pediatric or young-enriched cohorts. Qualitative synthesis showed that DICER1 alterations occur across a wide thyroid lesion spectrum, including multinodular and follicular nodular disease, follicular adenoma, NIFTP, follicular thyroid carcinoma, follicular-patterned papillary thyroid carcinoma, and rare higher-grade or primitive malignant tumors such as thyroblastoma. Cytologically and histologically, these lesions frequently show follicular-patterned architecture, often with macrofollicular or mixed follicular growth and relatively bland nuclear features. DICER1 alterations are uncommon in large unselected adult thyroid cohorts but enriched in pediatric, young-adult, and follicular-patterned settings. They should not be interpreted as isolated lesion-specific markers. Rather, their diagnostic significance lies in the integration of molecular findings with lesion type, cytomorphology, histology, patient age, and clinical context, including the selective recognition of cases in which constitutional DICER1-related tumor predisposition should be considered.