{"title":"Effects of Nicotine on Urinary Bladder Carcinogenesis.","authors":"Shugo Suzuki, Samuel M Cohen","doi":"10.1111/pin.70151","DOIUrl":"10.1111/pin.70151","url":null,"abstract":"<p><p>Epidemiological evidence has consistently demonstrated an association between tobacco smoking and an increased risk of urinary bladder cancer. However, the specific role of nicotine, independent from established genotoxic carcinogens such as aromatic amines, has not been clarified. This review summarises experimental evidence regarding the carcinogenic effects of nicotine and the underlying molecular mechanisms in urinary bladder carcinogenesis. In a two-stage rat carcinogenesis model, nicotine administration significantly increased the incidence and multiplicity of invasive urothelial carcinoma. In contrast, nicotine treatment alone increased hyperplasia but did not induce the formation of tumors, suggesting that nicotine functions as an enhancing agent for tumorigenesis, rather than as a DNA reactive agent. Mechanistically, nicotine has been shown to induce cell proliferation through two distinct pathways. One involves the activation of nicotinic acetylcholine receptors (nAChRs), particularly the α7 subunit, leading to activation of STAT3 and ERK1/2 signalling pathway. The other involves urothelial cytotoxicity followed by regenerative increased cell proliferation. In addition, cotinine, the major urinary metabolite of nicotine, was found to induce proliferation via nAChRs, without inducing cytotoxicity. These findings indicate that nicotine exposure may contribute to bladder cancer risk through mechanisms involving increased cell proliferation, either due to direct mitogenesis or secondary to cytotoxicity and regeneration.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70151"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13373482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Furkan Aknar, Tuce Soylemez-Akkurt, Pinar Engin Zerk, Basak Atalay, Mehmet Sabri Gürbüz, Numan Karaarslan
{"title":"RB1 Loss as a Diagnostic Clue in a High-Grade Glioma With Pleomorphic and Pseudopapillary Features (HPAP): The First Reported Case With Spinal Metastasis and a Review of the Literature.","authors":"Furkan Aknar, Tuce Soylemez-Akkurt, Pinar Engin Zerk, Basak Atalay, Mehmet Sabri Gürbüz, Numan Karaarslan","doi":"10.1111/pin.70150","DOIUrl":"10.1111/pin.70150","url":null,"abstract":"<p><p>High-grade glioma with pleomorphic and pseudopapillary features (HPAP) is a recently described entity defined by a distinct DNA methylation signature, recurrent monosomy 13, and mutations in TP53, RB1, and NF1. Most cases are supratentorial with a relatively favorable prognosis. We report a 45-year-old woman who presented with a right cerebellar mass exhibiting striking histopathological heterogeneity comprising low-grade and high-grade components. The high-grade component demonstrated a p53 null immunophenotype and complete loss of RB1 expression, contrasting with wild-type staining in the low-grade areas. Molecular analysis confirmed pathogenic variants in TP53 (p.Pro27LeufsTer17), NF1, and NF2, with losses of chromosomes 13 and 17. Despite gross total resection and adjuvant chemoradiotherapy, the patient developed spinal intradural metastasis 26 months postoperatively. The metastatic lesion mirrored the high-grade primary component immunohistochemically and harbored a newly acquired TERT promoter mutation. DNA methylation profiling of the spinal metastasis classified the tumor as HPAP. This case represents the first documented spinal metastasis and the first p53 null phenotype in HPAP, suggesting a potential role for combined RB1 and p53 immunohistochemistry in the diagnostic workup and highlighting the capacity for neuraxis dissemination in this emerging entity.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70150"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13389336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pulmonary Metastasizing Ameloblastomas Can Masquerade as Certain Bronchiolar Adenoma-Like Tumor With Squamous Epithelial Metaplasia.","authors":"Shengnan Zhao, Jianjun Li, Likun Hou, Yan Huang, Zhengwei Dong, Wei Wu, Wei Zhang, Chunyan Wu, Huikang Xie","doi":"10.1111/pin.70155","DOIUrl":"10.1111/pin.70155","url":null,"abstract":"<p><p>Bronchiolar adenoma (BA) is a generally benign peripheral lung neoplasm with a bilayered structure of basal and luminal cells. Recently, an increasing number of bronchiolar adenoma-like tumor with squamous epithelial metaplasia (BATSM) have been reported, raising the question of whether they represent variant subtypes of BA or potentially novel tumor entities. Pulmonary metastasis of ameloblastoma (MA) shares morphological similarities with BATSM, exhibiting TTF-1/Napsin A-positive luminal cells and P40/P63-positive basal cells; this overlap can lead to misdiagnosis of MA as BATSM. We collected 5 MA and 10 BATSM cases, analyzing their morphology, immunohistochemistry, elastic fiber staining and molecular pathology. MA presents as well-circumscribed bronchiole-unrelated nodules with alveolar destruction, intraluminal serous secretions, and Calretinin-positive stellate reticulum-like cells. BATSM is bronchiole-associated, preserves alveolar architecture, and is Calretinin-negative with weak basal TTF-1 positivity. 80% of MA cases harbored BRAF V600E mutations; 30% of BATSM cases exhibited EGFR exon 20 insertions. This study highlights the need for integrating clinical history, morphology, immunohistochemistry and molecular testing to avoid misdiagnosing MA as BATSM.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70155"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148592938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Three Rare Cases of Pulmonary Squamous Cell Carcinoma Harboring a KRAS Mutation, Including the Actionable G12C Variant.","authors":"Daiji Ohba, Masafumi Hiratsuka, Hironori Ninomiya","doi":"10.1111/pin.70148","DOIUrl":"10.1111/pin.70148","url":null,"abstract":"<p><p>KRAS mutations are far less frequent in lung squamous cell carcinoma than in adenocarcinoma. In our institutional series of 136 pulmonary squamous cell carcinomas analyzed using Oncomine Dx Target Test, KRAS G12C mutations were identified only one case (0.8%). Although rare, identification of KRAS G12C mutations in LUSC may expand therapeutic options and support the role of comprehensive molecular profiling in the era of precision oncology.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70148"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13376999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148471834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Latent Vasculopathy of a Peripheral Pulmonary Artery in FBN1-Related Marfan Syndrome.","authors":"Masato Aragaki, Noriyuki Otsuka, Mitsuko Furuya, Hirokuni Yamazawa, Hiroko Morisaki, Takayuki Morisaki, Tatsuya Kato, Yukio Nakatani","doi":"10.1111/pin.70153","DOIUrl":"10.1111/pin.70153","url":null,"abstract":"<p><p>Marfan syndrome (MFS) is a hereditary connective tissue disorder characterized by cardiovascular and skeletal abnormalities. While cardiovascular pathology is well described, the microscopic features of peripheral vasculature remain poorly characterized. We report a case of perioperative pulmonary arterial rupture in a patient with FBN1-related MFS. A 17-year-old woman underwent bullectomy for spontaneous pneumothorax. Although the procedure was initially uneventful, unexpected bleeding developed beneath the staple line immediately after reinflation for the post-bullectomy air-leak test, necessitating additional wedge resection. Histologically, a ruptured pulmonary arterial branch was identified adjacent to the staple line. Patchy foci of hyperacute vascular injury with hemostatic plugs were identified on the luminal surface, and the surrounding airspaces were filled with fresh blood. The affected arterial wall showed mucoid extracellular matrix accumulation and disorganization of smooth muscle bundles. Furthermore, the medial layer demonstrated an aberrant distribution of elastic fibers, deviating from the normal architecture of muscular arteries. These findings highlight previously underrecognized microscopic features of peripheral arterial involvement in FBN1-related MFS, characterized by latent structural fragility associated with abnormal vascular patterning. Surgery-associated hemodynamic changes, including perioperative reinflation for an air-leak test, which would be tolerated under normal conditions, may precipitate vascular injury and rupture.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70153"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13373479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Marked Anaplasia Obscuring the Diagnosis of Clear Cell Sarcoma of the Kidney in Pretreatment Needle Biopsy.","authors":"Masahiro Fukuhara, Kenichi Kohashi, Amane Kamouchi, Takumi Tomonaga, Yoshiki Yamaguchi, Kenta Ishimoto, Yuko Hino, Junnosuke Maniwa, Naonori Kawakubo, Shunsuke Yamamoto, Utako Oba, Kentaro Nakashima, Yasunari Sakai, Tatsuro Tajiri, Yoshinao Oda","doi":"10.1111/pin.70149","DOIUrl":"10.1111/pin.70149","url":null,"abstract":"<p><p>Clear cell sarcoma of the kidney is an uncommon pediatric renal malignancy with metastatic potential and marked morphologic heterogeneity. The anaplastic variant is rare and may mimic other high-grade pediatric renal tumors, resulting in diagnostic challenges in limited pretreatment biopsy specimens. A 3-year-old girl presented with progressive abdominal distension. Imaging showed a 15-cm right retroperitoneal mass with tumor thrombus in the inferior vena cava and no distant metastasis. Pretreatment core needle biopsy showed a highly pleomorphic malignant neoplasm with necrosis and fibrous-to-myxoid stroma; however, a definitive diagnosis could not be established. The patient was clinically managed as a nephroblastoma and received preoperative chemotherapy followed by surgical resection. The resected specimen showed features characteristic of clear cell sarcoma of the kidney. Immunoreactivity of BCL6 corepressor and cyclin D1 was observed, whereas Wilms tumor 1 was negative. Molecular testing further identified an in-frame internal tandem duplication of BCOR. Retrospective immunohistochemistry on the pretreatment biopsy demonstrated concordant BCOR and cyclin D1 expression. Marked anaplasia can obscure the typical morphology of clear cell sarcoma of the kidney. Immunohistochemistry for BCL6 corepressor and cyclin D1 at an early diagnostic stage, with molecular confirmation may facilitate accurate diagnosis and timely treatment.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70149"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13416797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148606120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Re-appraisal of the Diagnostic Value of PAS-D Staining in TTF-1-NEGATIVE NSCLC Subclassification: A Large Real-World Cohort Study.","authors":"Dogu Vuralli Bakkaloglu, Hafize Ozdemir, Melek Buyuk, Dilek Yilmazbayhan, Yasemin Ozluk","doi":"10.1111/pin.70154","DOIUrl":"10.1111/pin.70154","url":null,"abstract":"<p><p>Subclassification of NSCLC is critical for therapeutic decision-making, particularly in small biopsies and cytology specimens where ancillary testing must be limited. Although the TTF-1/p40 panel is widely used to distinguish adenocarcinoma (ADC) from squamous cell carcinoma, a subset of NSCLCs remains unclassified, highlighting the need for adjunctive markers. Periodic acid-Schiff with diastase (PAS-D) is readily available but underutilized. We retrospectively reviewed 2611 NSCLC specimens from 2298 patients. Diagnosis was based on morphology alone in 38.6% of cases, while ancillary testing was required in 57.7%. Among 287 TTF-1<sub>neg</sub>/p40<sub>neg</sub> tumors, 30.3% were classified as ADC using PAS-D and/or Napsin A. PAS-D demonstrated higher sensitivity than Napsin A (71.8% vs. 69.3%), and markedly outperformed Napsin A in TTF-1-negative ADCs (89.7% vs. 25.9%, p < 0.001). This finding reflects biological differences between terminal respiratory unit-derived ADCs and non-terminal airway tumors, in which PAS-D positivity is more diagnostically informative. Combined testing improved sensitivity, with the TTF-1/PAS-D panel achieving 97.5%. This study highlights the underappreciated diagnostic value of PAS-D, particularly in TTF-1-negative tumors. PAS-D represents a simple, effective adjunct to routine diagnostic panels. Therefore, incorporating PAS-D into routine panels can enhance NSCLC subclassification, particularly in TTF-1<sub>neg</sub>/p40<sub>neg</sub> tumors and support accurate diagnosis and optimal clinical management.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70154"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148593077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A Rare Case of Extramammary Paget Disease With Concurrent Herpes Simplex Virus Infection: Three-Color Immunohistochemical Analysis for Re-Evaluating Previous Hypotheses.","authors":"Yoshikazu Senda, Hayato Kimura, Shoichiro Minami, Masaharu Kohara, Eiichi Morii","doi":"10.1111/pin.70146","DOIUrl":"10.1111/pin.70146","url":null,"abstract":"<p><p>The coexistence of extramammary Paget disease and clinically apparent herpes simplex virus (HSV) infection is extremely uncommon, with only two cases previously described in detail. Herein, we present the case of an elderly woman with an extensive vulvar lesion showing concurrent extramammary Paget disease and HSV infection. Triple immunohistochemical staining for cytokeratin 7, cytokeratin 10, and HSV antigen was performed to re-evaluate the hypothesis that HSV-mediated fusion between Paget cells and keratinocytes contributes to multinucleated giant cell formation. HSV antigen was detected in both Paget cells and keratinocytes. HSV-positive multinucleated giant cells displayed a cytoplasmic staining pattern similar to that of keratinocytes, whereas no Paget cell-like cytoplasmic staining pattern was observed. These findings indicate that HSV can directly infect Paget cells and that the multinucleated giant cells in this case were of keratinocytic origin. No definitive evidence of cell fusion-either among Paget cells or between Paget cells and keratinocytes-was observed in the examined sections. However, the possibility of rare fusion events in unexamined tissue cannot be entirely excluded.</p>","PeriodicalId":19806,"journal":{"name":"Pathology International","volume":"76 7","pages":"e70146"},"PeriodicalIF":1.9,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}