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.

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.

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.

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.

Immunohistochemical negativity of AID and MUM1 identifies a prognostically favorable subgroup of diffuse large B-cell lymphoma/high-grade B-cell lymphoma with double-hit MYC and BCL2 or BCL6 and triple hit, and a gene set and enrichment analysis showed that genes belonged to PI3K-Akt, matrix remodeling and metastasis, cell adhesion and migration, myeloid compartment, and metabolic stress were up-regulated in the AID-negative/MUM1-negative subgroup.

Glomerular capillary microaneurysm (GCM) is a pathological lesion defined by aneurysmal dilatation of glomerular capillaries resulting from mesangiolysis with severe endothelial damage and is commonly observed in diabetic nephropathy and thrombotic microangiopathy. However, its clinicopathological significance in membranoproliferative glomerulonephritis (MPGN)-pattern glomerular diseases remains unclear. We retrospectively reviewed 50 renal biopsy cases diagnosed as MPGN or MPGN-like glomerulopathy and identified 12 GCM-positive cases for clinicopathological analysis, including Pathologische Anatomie Leiden Endothelium (PAL-E) staining and CD34 immunohistochemistry to assess endothelial injury. Among GCM-positive cases, proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) was significantly enriched; however, exclusive glomerular IgG3 positivity was consistently observed across other diagnostic categories, irrespective of light-chain restriction. Electron microscopy revealed continuous, irregularly shaped, fine granular subendothelial electron-dense materials with endothelial denudation. PAL-E staining was positive in all evaluable cases, with ultrastructurally identified diaphragmed endothelial fenestrae. Furthermore, CD34 staining demonstrated loss of continuous lining in GCM lesions, suggesting severe endothelial injury. Clinically, all patients presented with nephrotic-range proteinuria, and more than half progressed to end-stage kidney disease or died within 3 years. These findings indicate that GCM-positive MPGN-pattern glomerular diseases represent an aggressive subset associated with IgG3-dominant deposition and severe endothelial injury, with important diagnostic implications.

Homology is a mathematical concept involving two Betti numbers-b0, representing the number of independent objects, and b1, representing the number of holes formed by surrounding objects-which can be used to quantify the contact degree. We previously demonstrated the use of a homology-based method to diagnose advanced colorectal cancer. It is clinically important to discriminate adenoma, especially high-grade adenoma, and early-stage cancer from non-cancerous tissue; thus, it was of interest to evaluate whether our homology-based method could also diagnose adenoma and early-stage cancer. In the present study, we developed a homology-based application to calculate b1 values for a region of interest, and used it to analyze normal tissue, adenoma, and early-stage cancer from the colorectum. Area correction was required for proper comparison of b1 values. We found that area-corrected b1 values were significantly higher in high-grade adenoma and early-stage cancer, compared to normal tissue. Although there remains a need for further development of the algorithm to discriminate low-grade adenoma and inflammatory regions, our present findings indicate that our homology-based method using Betti numbers can be useful for distinguishing high-grade adenoma and early-stage cancer from normal tissue, as well as advanced colorectal cancer.

Prostate cancer is a common cancer in males and there is an urgent unmet clinical need to identify new therapies for advanced disease. Aberrant glycosylation is a hallmark of prostate cancer and plays a functional role in disease progression. The sialyl-Tn antigen (sTn) has been widely studied in cancer, yet its involvement in prostate cancer remains relatively unexplored. Here, we utilise a novel anti-sTn antibody (L2A5) to comprehensively monitor sTn expression levels in clinical prostate cancer tissues encompassing normal, benign, primary, metastatic castration-resistant prostate cancer (CRPC), and in patient-derived xenograft (PDX) tissues. We show that while sTn is detected at low or negligible levels in normal prostate tissues, it is expressed in 44% of prostate tumours, and prostate cancer patients with high sTn levels have significantly poorer survival times. Analysis of metastatic therapy-resistant prostate-derived tumours growing in the liver and bone shows sTn is expressed in 37.5% of cases. Furthermore, sTn is expressed in nearly half of the PDX models tested and was found to be broadly androgen-regulated. These findings identify sTn as a potential prognostic biomarker and therapeutic target in prostate cancer and lay the groundwork for the development of sTn-targeted precision therapies for advanced disease.

More than 20 years have passed since the distinct definition of undifferentiated endometrial carcinoma (UEC) was proposed in 2005. Based on its distinguishing clinicopathological features, the fourth and fifth editions of the World Health Organization classification of gynecological tumors recognized UEC as a distinct subtype of endometrial carcinoma. An accurate diagnosis of UEC is crucial due to its aggressive clinical behavior and for ensuring appropriate patient management. Many investigators have elucidated clinicopathological and molecular characteristics that are useful for its diagnosis; however, a number of differential diagnoses need to be considered before the final pathological diagnosis. This review summarizes the pathological characteristics of UEC, with a focus on its histological, molecular, and immunophenotypic features, as well as key points for a differential diagnosis. UEC shows diverse immunophenotypes. In addition to the loss of or a marked reduction in epithelial and gynecological markers, UEC frequently expresses ZEB1 and cyclin D1, and occasionally expresses neuroendocrine and germ cell tumor markers. Approximately 60% of UECs show the loss of SMARCA4, SMARCB1, or ARID1A/1B, which may contribute to tumor pathogenesis. These immunophenotypes are not specific because other epithelial and non-epithelial uterine tumors may exhibit overlapping features. Therefore, a comprehensive pathological understanding of UEC is essential for avoiding diagnostic pitfalls and improving diagnostic accuracy.

Leptomeningeal metastases (LM) is a rare but clinically important subtype in central nervous system (CNS) metastasis. Multicentre data was reviewed to detail the epidemiology, clinicopathological associations among patients with positive cerebrospinal fluid cytology (CSF) cytology. Patients with CNS metastasis and clinical data were identified through the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (CDARS). In total, through 1st January 2000 to 31st December 2024, 38,893 patients with CNS metastasis were retrieved, 1503 had CSF cytology. The most common primary malignancies were lung (54.16%), breast (11.18%) and gastrointestinal (5.66%; colonic: 3.33%, gastric: 1.86%, esophageal: 0.47%). There were 220 (14.64%) patients with positive CSF, they were younger (57.72 years vs. 60.03, p = 0.005), and likely with breast (20.84%, p = 0.016) and lung primaries (16.47%, p = 0.030). The median overall survival (OS) was 113 days. Positive CSF, age > 60 and gastrointestinal primary were correlated with shorter OS (p < 0.05). The inclusion of brain radiotherapy (260 day vs. 82, p < 0.001) and systemic therapy (496 days vs. 61, p < 0.001) for treatment of leptomeningeal metastases was independently associated with longer OS. Positive CSF cytology is a strong independent indicator of poor outcomes. Radiotherapy and systemic therapy improve overall survival for the medium term (6-12 months).

The molecular mechanisms underlying metastasis still remain unclear. We previously established a suspension culture using low-attachment culture dishes and demonstrated that cell lines adapted through 2 months suspension culture (termed FL sublines) exhibited higher metastatic potential than their parental counterparts. In this study, we identified the molecules involved in acquiring these phenotypes under low-adhesion conditions. We showed that detached tumor cells in suspension culture formed spheroids that recapitulated tumor cells in the spread-through-air space (STAS), and demonstrated that the anti-adhesion molecule mucin 21 was upregulated in detached lung cancer cells independent of driver mutations. Analyses of both cell lines and primary tumors revealed that mucin 21 is overexpressed in terminal respiratory unit-type lung adenocarcinomas. Mucin 21-knockout cells showed reduced viability and proliferation under adherent and low-attachment conditions, accompanied by enhanced anoikis. Transmission electron microscopy revealed that the intercellular spaces observed in FL sublines during suspension culture were reduced in mucin 21-knockout cells, suggesting impaired acquisition of low adhesive properties. Thus, mucin 21 appears crucial for the survival of terminal respiratory unit-type lung adenocarcinoma cells under both adherent and low-adhesion conditions.

Factors underlying differential colonization by human intestinal spirochetosis (HIS) of various colorectal neoplastic lesions remain unclear. We compared HIS positivity and colonization patterns between sessile serrated lesions (SSLs) and tubular adenomas (TAs) and examined the relationship between spirochetal distribution and epithelial differentiation. HIS positivity was significantly higher in SSLs than TAs at both lesion (26/590 [4.4%] vs. 3/536 [0.6%], p < 0.001) and case (16/421 [3.8%] vs. 1/171 [0.6%], p = 0.03) levels. Because the SSL and TA main cohorts covered different periods, nine HIS-positive SSL cases harboring TAs diagnosed outside the TA cohort period were separately analyzed for within-case comparison, confirming significantly higher HIS positivity in SSLs than TAs (11/12 [91.7%] vs. 6/23 [26.1%], p = 0.003). Among HIS-positive lesions, both SSLs and TAs showed reduced colonization at lesion sites compared to surrounding mucosa, with greater reduction in TAs. GS-II staining demonstrated reduced terminal βGlcNAc on HIS bacterial bodies at SSL lesion sites. HIS preferentially colonized absorptive epithelium, although less evidently in TAs with limited absorptive differentiation. All cases harbored only Brachyspira aalborgi. These results indicate that HIS exhibits universal affinity for absorptive epithelium and that higher HIS positivity in SSLs reflects their greater abundance of absorptive epithelium.

Penile squamous cell carcinoma (pSCC) is a rare cancer associated with a relatively poor prognosis. The WHO classifies pSCC into HPV-associated and HPV-independent subtypes, with HPV-positive pSCCs showing slightly better outcomes. A key negative prognostic marker is TP53 mutation. The aim of this study was to evaluate the concordance of (1) p16 immunohistochemistry with HPV status determined by PCR, (2) p53 immunohistochemistry with TP53 mutational status obtained by NGS, and (3) prognostic impact of overexpression and null phenotype p53 immunohistochemistry profiles. Analyzing invasive pSCC from 209 patients, we assessed concordance between p16 immunohistochemistry and HPV status (n = 132) determined by quantitative PCR, obtaining Cohen's kappa Κ = 0.62 (p < 0.0001). For p53 immunohistochemistry versus TP53 status by NGS (n = 145), Cohen's kappa reached Κ = 0.693 (p < 0.0001). We found worse overall survival (Hazard ratio = 3.33, 95% CIs 1.92-5.56, p < 0.0001) in p53 mutated cases (n = 38, both overexpression and null phenotype) compared to wild type (n = 171), but without a significant difference between both mutated profiles. Both HPV status and p53 profile can be reliably assessed by immunohistochemistry with substantial agreement. Patients with a mutated p53 profile showed significantly worse survival, irrespective of the mutated profile variant.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are clinically heterogeneous, making prediction of metastatic behavior challenging. This study examined Cell Adhesion Molecule 1 (CADM1) and the differentially expressed in adenocarcinoma of the lung-1 expression in 75 resected GEP-NETs and evaluated their associations with clinicopathological features, tumor grade, and established adhesion- or prognosis-related markers, including E-cadherin (ECAD), CD56, progesterone receptor (PgR), and cytokeratin 19 (CK19). CADM1 promoter methylation was assessed using methylation-specific PCR, and the miR-214 and miR-375 expressions were analyzed by quantitative real-time PCR. The expression of CADM1 was significantly lower in tumors with lymph node and/or distant metastasis (p = 0.01), and a low CADM1 expression was independently associated with metastatic disease (p = 0.0004; OR = 4.63). Additionally, low PgR (p = 0.014; OR = 4.13) and a high CK19 (p = 0.0002; OR = 4.83) expression, as reported previously, were linked to poor outcomes. In contrast, neither ECAD nor CD56 showed any notable associations with aggressive features in a univariable assessment. No significant relationship was observed between CADM1 promoter methylation and the CADM1 expression. These findings suggest that a reduced CADM1 expression may be associated with lymph node and distant metastasis in GEP-NETs and could be a potential prognostic marker.