Digital pathology has rapidly expanded over the past decade, driven by advances in whole-slide imaging and increasing demand for remote and data-integrated diagnostic workflows. However, many implementations remain limited to partial digitization, without fundamentally transforming laboratory and diagnostic processes. In this review, we examine digital transformation in pathology as a systems-level redesign encompassing workflow optimization, digital infrastructure, and networked diagnostic services. Using the implementation at International University of Health and Welfare (IUHW) Narita Hospital as an illustrative example, we describe how a digital-first approach can be integrated into routine clinical practice. Key elements include continuous laboratory workflows aligned with slide digitization, comprehensive digital infrastructure enabling seamless access to diagnostic data, and networked systems that support multi-institutional collaboration and subspecialty consultation. We further discuss how digital pathology extends beyond clinical diagnosis to support education and research, transforming traditional slide archives into accessible data resources, and outline practical considerations for implementation, including workflow redesign, user adoption, and institutional coordination. Finally, by comparing the IUHW Narita experience with other large-scale implementations, we discuss generalizable principles for digital transformation in pathology, including workflow-driven design, data integration, interoperability, and network-based diagnostic models.
Adipose tissue has traditionally been regarded as an energy-storage organ; however, accumulating evidence indicates that adipocytes actively regulate cancer biology through local and systemic mechanisms. These findings have contributed to the emergence of adipo-oncology, an interdisciplinary field focused on interactions between adipose tissue and cancer. This review summarizes current evidence on the local and systemic roles of adipocytes in tumor progression and discusses how tissue heterogeneity and plasticity may influence these processes. Locally, adipocytes adjacent to tumors may be reprogrammed into cancer-associated adipocytes that promote tumor progression through enhanced lipolysis and inflammatory signaling, paracrine adipokine and cytokine secretion, local lipid transfer, and modulation of stromal and immune cell populations within the tumor microenvironment. Systematically, adipocytes may influence metabolic remodeling, epithelial-mesenchymal transition, invasion, metastasis, therapeutic resistance, and establishment of tumor-promoting niches. Additionally, adipocyte plasticity and epigenetic reprogramming have emerged as important determinants of adipocyte function during cancer progression. Collectively, these findings support a model in which adipocytes function as central regulators of cancer biology at local and systemic levels. A deeper understanding of the molecular basis of adipo-oncology may provide new insights into tumor progression and facilitate the development of metabolic, immunological, and epigenetic therapeutic strategies targeting adipose tissue.
Tumors exhibiting mismatch repair deficiency without detectable germline mutations via standard multigene panel testing are often classified as Lynch-like syndrome. In the present report, we describe the case of a 47-year-old man presenting with synchronous axillary sebaceous carcinoma and colonic medullary carcinoma. Although initial germline multigene panel testing failed to identify pathogenic variants, a high degree of pathological suspicion for Muir-Torre syndrome remained. Immunohistochemistry revealed a concordant loss of MSH2 and MSH6 expression in both the extraocular sebaceous carcinoma and the colonic medullary carcinoma. This identical protein-loss pattern detected across anatomically distinct tumors served as decisive pathological evidence of an underlying germline defect rather than independent biallelic somatic mutations. Consequently, whole-genome sequencing was performed to resolve the discrepancy between the pathological findings and multigene panel testing results, successfully identifying a germline intronic MSH2 variant (NM_000251.3:c.2459-12A>G). Subsequent RNA analysis confirmed aberrant splicing with an 11-bp insertion. In conclusion, the present case illustrates that concordant mismatch repair protein loss across multiple tumors provides compelling morphological evidence to guide pathologists in reconsidering negative panel results and pursuing comprehensive genomic investigation to identify pathogenic intronic variants.
DNA methylation-based classification is a key adjunct to histopathology in CNS tumor diagnostics. Although both fresh-frozen and FFPE tissues are used, the impact of sampling strategy on classifier performance remains insufficiently characterized. We analyzed 179 CNS specimens (162 tumors and 17 controls), including 42 FFPE and 137 fresh-frozen samples with ≥ 50% tumor cellularity. Fresh-frozen cases were stratified into histology-validated and blind sampling groups. Genome-wide DNA methylation profiling was performed using Illumina EPIC/EPIC v2.0 arrays and classified using the DKFZ Brain Tumor Classifier, with independent validation using the NIH Methylscape platform. Results were categorized as confirmed, refined, changed, or unclassified and correlated with histopathological diagnoses. FFPE samples showed high diagnostic yield with minimal unclassified results (2%). Among fresh-frozen specimens, histology-validated samples demonstrated robust classification, whereas blind sampling showed higher discordance and unclassified rates (22%). Discordant results were confined to the blind-sampling group and were most consistent with sampling bias and variable tumor representation rather than technical limitations. Methylation profiling confirmed or refined diagnoses in most cases and led to clinically relevant reclassification in a subset. Classifier performance appeared to be influenced more by sampling strategy rather than preservation method, with histology-guided sampling associated with the most reliable diagnostic outcomes.
The Japanese General Rules of Clinical and Pathological Reporting of Cancers (Kiyaku) are unique standardized systems for cancer handling and documentation used by professionals involved in cancer care in Japan. The Japanese Society of Pathology (JSP) conducted a questionnaire survey among practicing pathologists regarding the utilization and awareness of Kiyaku. We analyzed 1083 valid responses, representing 22.4% of the JSP members and 33.8% of the board-certified pathologists. Kiyaku, with > 90% latest-edition ownership, covered approximately 90% of all cancers in Japan. The timing of the implementation of the new editions varied not only across institutions but also among individuals in each institution. Among department directors, 46.1% reported implementing new editions at their discretion without prior notice. Item-level responses were collected for the stomach, lung, and breast as representative Kiyaku; histological classification and descriptive symbols were widely considered useful and frequently used across the three cancers, whereas biopsy-related items in the lung and breast were used less frequently. In conclusion, Kiyaku is broadly embedded in daily practice and facilitates standardized cancer documentation in Japan, although several challenges remain. The JSP should clearly articulate the purpose of Kiyaku and promote coordinated adoption to standardize its use in pathology practice.
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-1neg/p40neg 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-1neg/p40neg tumors and support accurate diagnosis and optimal clinical management.
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.
Clusters of epithelial cells of the fallopian tube exhibiting aberrant p53 expression, termed "p53 signatures," are detected at a relatively high frequency and have been regarded as putative precursors of high-grade serous carcinoma (HGSC). In contrast, the recently proposed "β-catenin signature" represents a distinct tubal epithelial alteration characterized by the aberrant expression of β-catenin, the biological significance of which remains unclear. To clarify the frequency and spatial relationship between the two lesions, we analyzed 30 consecutive risk-reducing salpingo-oophorectomy specimens from BRCA1/2 mutation carriers using the sectioning and extensively examining the fimbriated end protocol and performed immunohistochemical evaluation for p53, β-catenin, and Ki-67. p53 signatures and β-catenin signatures were each identified in seven cases (23%). Two cases (6.7%) harbored both lesions; however, no spatial overlap or histological continuity was observed. Neither lesion demonstrated significant associations with BRCA mutation subtype, age, body mass index, or parity. Furthermore, no cases showed serous tubal intraepithelial lesion, serous tubal intraepithelial carcinoma, or HGSC. These findings suggest that p53 signatures and β-catenin signatures may represent distinct localized epithelial alterations in the fallopian tube, although further molecular and spatial analyses are required to clarify their biological relationship.
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.
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-b 0, representing the number of independent objects, and b 1, 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 b 1 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 b 1 values. We found that area-corrected b 1 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.
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.
