Pleomorphic carcinoma is a rare, aggressive subtype of non-small cell lung cancer (NSCLC). Invasion into the left atrium and dissemination to cerebral arteries are exceptionally uncommon, and the role of cardiopulmonary bypass (CPB)-assisted resection remains debated. We report two surgically treated cases with left atrial invasion. Case 1: A 57-year-old man underwent left lower lobectomy with partial atrial resection under CPB. One month later, he developed subarachnoid hemorrhage caused by rupture of a cerebral aneurysm secondary to metastasis; histology of the aneurysmal wall confirmed carcinoma. He remains recurrence-free at 21 months. Case 2: A 62-year-old woman underwent extended left upper lobectomy with partial atrial resection under CPB. Although adrenal metastasis was suspected radiologically, pathological confirmation was lacking preoperatively; surgery was pursued because of symptomatic disease and atrial involvement. She developed postoperative cerebral infarction and rapid adrenal progression and died at 4 months despite chemotherapy. These cases illustrate both the technical feasibility of CPB-assisted atrial resection and the aggressive biology of pleomorphic carcinoma, including atypical vascular metastasis to cerebral arteries. Careful staging, patient selection, and early multidisciplinary planning (thoracic surgery, cardiac surgery, neurosurgery, oncology, and radiology) are essential. Surgery can be justified in selected patients with atrial invasion; however, pleomorphic histology portends poor outcomes and unusual metastatic tropism. Vigilant postoperative surveillance and integration of systemic therapy are required.

Differentiating tuberculous (TB) pleurisy from malignant pleural mesothelioma is challenging due to similar clinical presentations. We report an 83-year-old man with sarcomatoid mesothelioma initially treated for TB pleurisy. He presented with lymphocyte-predominant exudative pleural effusion and a positive Interferon-Gamma Release Assay. Thoracoscopy revealed purulent effusion, but biopsies were non-diagnostic. Despite empiric anti-tuberculosis therapy, the effusion persisted. A subsequent surgical biopsy showed fibrosis and scattered spindle cells. However, 2 months later, a rapidly growing chest wall mass with bone invasion appeared. A CT-guided percutaneous biopsy showed proliferation of atypical spindle cells and fluorescence in situ hybridization (FISH) analysis allowed for the diagnosis of sarcomatoid mesothelioma. This case highlights the aggressive nature of sarcomatoid mesothelioma and its diagnostic difficulty. For treatment-refractory pleurisy, clinicians must maintain high suspicion, ensuring vigilant follow-up and prompt repeat biopsies despite negative initial results, while consulting pathologists to consider additional FISH testing.

BACKGROUND:Mesothelioma is an aggressive malignancy with limited therapeutic options. Genetic alterations involving the Hippo pathway are commonly observed. O-GlcNAcylation is frequently elevated in cancer and drives tumour progression. However, its relationship with Hippo pathway dysfunction in mesothelioma remains unclear. METHODS:O-GlcNAcylation levels were examined in mesothelioma samples and cell lines, and O-GlcNAcylated proteins were detected by mass spectrometry. The functional impact of O-GlcNAcylation was determined by quantifying nuclear transport dynamics using light-induced live-cell imaging. Genetic and pharmacological inhibition of O-GlcNAcylation was evaluated in vitro. Treatment with the nuclear export inhibitor KPT-330 (Selinexor) was assessed in vitro and in a mouse xenograft model. RESULTS:O-GlcNAcylation was markedly increased in mesothelioma cells with Hippo pathway inactivation. This modification primarily targeted nuclear pore complex proteins, including NUP214 and NUP62, and significantly accelerated nuclear export rates. Suppression of O-GlcNAcylation diminished nuclear export and inhibited cell proliferation. Importantly, pharmacological blockade of nuclear export using KPT-330 suppressed cell growth in vitro and produced significant antitumour effects in vivo. CONCLUSIONS:These findings demonstrate O-GlcNAcylation-driven enhancement of nuclear export as a therapeutically actionable vulnerability in mesothelioma with inactivation of the Hippo pathway.

Mesothelioma has characteristic genetic changes including inactivation of neurofibromatosis type 2 (NF2) and deletion of the INK4A/ARF region. Cells deficient of NF2 protein (MERLIN) depend on focal adhesion kinase (FAK) for cell adhesion and FAK inhibitors suppress the cell growth. The INK4A/ARF deletion activates MDM2 functions which ubiquitinate and degrade p53, and consequently the cellular p53 levels decrease. The deletion therefore induces loss of p53 functions although a majority of mesothelioma has wild-type TP53 genotype. An MDM2 inhibitor which blocked the ubiquitination increased p53 levels, restored p53 functions and facilitated cell growth arrest. Moreover, FAK and p53 expressions were reciprocally regulated. We examined growth suppressive effects of a FAK inhibitor, defactinib, and MDM2 inhibitors, nutlin-3a and reactivation of p53 and induction of tumor cell apoptosis (RITA), with representative wild-type and mutated TP53 mesothelioma and investigated molecular changes induced by the agents. We analyzed possible combinatory effects of the inhibitors and molecular changes caused by the combination. Our study showed that defactinib inhibited cell growth and induced FAK dephosphorylation irrespective of the TP53 genotype, and that the inhibited FAK phosphorylation was not associated with MERLIN levels or with p53 up-regulation, but linked with AKT dephosphorylation. Nutlin-3a preferentially suppressed growth of wild-type TP53 cells and augment p53 expression without DNA damage, whereas RITA-mediated p53 up-regulation was linked with the damage. A combination of defactinib and the MDM2 inhibitors showed that nutlin-3a showed synergistic/additive effects in wild-type and antagonistic effects in mutated TP53 cells, whereas RITA retained synergistic activity in mutated TP53 cells. These results suggest that the therapeutic success of combined FAK and MDM2 inhibition in mesothelioma depends on the precise matching of MDM2 inhibitors with the TP53 genotypes, and highlight the need for genotype-based selection of MDM2 inhibitors.

NUT midline carcinoma family number 1 (NUTM1)-rearranged sarcoma is extremely rare and characterized by NUTM1 gene rearrangement with variable morphological features. The gastrointestinal tract is one of the most common sites. These sarcomas showing similar histopathological findings have yielded poor clinical outcomes. A healthy 52-year-old Japanese man presented with a solitary, localized submucosal mass, 3 cm in size, in the descending colon. Microscopically, the sarcoma comprised sheet-like proliferation of plump epithelioid/rhabdoid cells, fibrosarcoma-like spindle cells showing an intersecting fascicular pattern, and neoplastic cell nests in hyalinized stroma. Immunohistochemistry (IHC) revealed that sarcoma cells were diffusely positive for NUT. Fluorescence in situ hybridization (FISH) confirmed NUTM1 gene rearrangement. Recurrences in the retroperitoneum at 9 and 21 months after initial surgery were surgically excised. The histopathological features and the results of IHC and FISH for the sarcoma coincided with those of previously reported NUTM1-rearranged sarcoma occurring in the colon. The sarcoma recurred three times within a short time after the initial surgery. Therefore, the behavioral aggressiveness and site in which the sarcoma arose were also consistent with those of NUTM1-rearranged sarcoma in the colon. Of note, these recurrent sarcomas comprised only a plump epithelioid/rhabdoid cell component. We reported here an unusual sarcoma with unexpected poor outcomes. Our case may provide additional useful information regarding this extremely rare sarcoma of colonic submucosal origin.

Wolffian tumors of the female adnexa are rare with only few cases reported. Their benign or malignant nature is not clearly defined in the literature and many of the malignant cases are probably misdiagnoses. The description of similar tumors harboring STK11 mutations has opened new pathways in understanding these tumors. In this review, we sought to present in detail the reported FATWO and STK11 adnexal tumors to understand their clinical and pathological features, and to discuss their differential diagnosis.

IgG4-related disease (IgG4-RD) rarely presents as an anterior mediastinal mass and may radiologically resemble thymic neoplasms. We report a 70-year-old man with an incidentally detected anterior mediastinal tumour on chest CT. The lesion measured 33 mm, was well-circumscribed, homogeneous and partially calcified. Tumour markers and serum IgG4 were within the normal range. The patient underwent thoracoscopic resection under the diagnosis of thymoma. Histopathological examination revealed dense lymphoplasmacytic infiltration and abundant IgG4-positive plasma cells, confirming IgG4-related sclerosing mediastinitis. No corticosteroid therapy was administered, and the patient remained disease-free over 3 years of follow-up. This case highlights the diagnostic challenge of mediastinal IgG4-RD and the importance of considering it in the differential diagnosis of thymic tumours, even when serum IgG4 is normal.

Background: CD276 is an immune checkpoint, and immune checkpoint inhibitors (ICIs) targeting CD276 have been tested against various cancers. However, the precise role of CD276 in mesothelioma subtypes is unknown. This study aimed to reveal the prognostic significance of CD276 in various cancers and explore CD276 as a target for ICIs in different mesothelioma subtypes. Methods: We evaluated data from The Cancer Genome Atlas (TCGA) database retrospectively. The Wilcoxon rank-sum test was used to assess CD276 mRNA expression between cancer tissues and the adjacent normal tissues in the context of various cancers. The study involved 86 patients with mesothelioma. The mean number of patients was set as the cutoff value for comparing CD276 mRNA expression. The overall survival (OS) of patients with each mesothelioma subtype was estimated using the Kaplan-Meier method with CD276 mRNA expression. The factors affecting the correlation between OS and high/low CD276 expression in combination with/without a current existing molecular targets of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and vascular endothelial growth factor A (VEGFA) were assessed using a multivariate Cox proportional hazards model. The correlation between the mRNA expression of CD276 and expression of gene markers of tumor-infiltrating immune cells and those of different pathways was evaluated using Spearman's correlation. The factors affecting correlations of CD276 mRNA expression were confirmed using a multivariate linear regression model. Results: Upregulated CD276 mRNA expression was associated with a poor prognosis in various cancers, including epithelioid mesothelioma. The multivariate Cox proportional hazards model demonstrated that upregulated CD276 mRNA expression indicated the worst prognosis, including the combination of CD276 and PD-1, CTLA4, and VEGFA. In addition, using a multivariate linear regression model, CD276 mRNA expression was found to correlate with multiple glycolytic pathway mRNAs in epithelioid mesothelioma, Conclusions: CD276 is an independent prognostic biomarker in patients with epithelioid mesothelioma. It is associated with the glycolytic pathway and may contribute to ATP generation in epithelioid mesothelioma. CD276 inhibitors might contribute to better prognosis in patients with epithelioid mesothelioma.

Amniotic lesions provide useful information regarding the conditions of the fetus and mother in the gestational period. We noticed a characteristic papillary, branching or ramifying structure of the amnion on the fetal membrane that we termed "amniotic papillary folding" (APF), which was identifiable on microscopic observation, but not macroscopically. Based on the morphological features, APF entirely comprises preexisting amnion and seems to result from misalignment of the amnion. Among 201 placentas submitted for histopathological examination, 88 placentas (43.8 %) displayed APF. From a clinical perspective, APF appeared more frequently in placentas from mothers with hypertensive disorders of pregnancy (HDP). Conversely, APF was significantly less frequent in mothers with gestational diabetes mellitus (GDM). APF tended to be infrequent among mothers with threatened miscarriage, non-reassuring fetal status (NRFS) or fetal growth restriction (FGR). Regarding the relevance to other pathological diagnoses, chorioamnionitis was significantly associated with a reduced frequency of APF, whereas placental infarction was associated with an increased frequency. Our results may imply that the histogenesis of APF is positively associated with retained activity of the fetus in the uterus. APF might be infrequently encountered under conditions in which the fetus is weakened with attenuated mobility, including threatened miscarriage, NRFS, FGR, and most prominently GDM. Although the mechanisms involved remain unclear, this unique amniotic structure may offer a marker for the status of fetal dynamics and abnormal maternal conditions.

INTRODUCTION:Since no universal cytological classification system for lung cancer has been established, the Japanese Lung Cancer Society and the Japanese Society of Clinical Cytology (JSCC) jointly established and reported four cytological categories: negative for malignancy, atypical cells, suspicious for malignancy, and malignancy. In 2022, the WHO Reporting System for Lung Cytopathology was published. This system presented five cytological classifications, including the four cytological category classifications above and insufficient/inadequate/nondiagnostic. The creation of a classification alone is not practical in actual clinical practice. Thus, we evaluated the reproducibility of the classification through tutorials and identified the issues and problems involved in the wide dissemination of this classification. METHODS:Forty-two cases were selected from those used in previously published articles, and diagnosis and tutorial systems were created. The first diagnostic round and tutorial and the second diagnostic round were conducted on the web. Participants were recruited via the JSCC website and emails. Images (×100 and ×400) of the lesions to be diagnosed were categorizing by 4 cytological categories (benign, atypical, suspicious for malignancy, malignant), 7 suggestive pathological diagnoses, and 4 cytological features. The mean correct or incorrect answer rates for the 42 cases and the mean correct response rates for 105 participants were compared between the first and second rounds using McNemar's test and t tests to identify cases with diagnostic difficulties and high tutorial effects. RESULTS:Comparing the correct response to cytological categories, the results showed that 17 of 42 cases improved significantly. The mean number of correct answers for the four cytological categories increased significantly from 16.0 (38.1%) in the first round to 20.3 (48.3%) in the second round (p < 0.001). For the seven suggestive pathological diagnoses, the mean number of correct answers increased significantly from 20.3 (48.3%) in the first round to 25.1 (59.8%) in the second round (p < 0.001). The mean number of correct responses increased significantly from 40.2 (38%) in the first round to 51.5 (49%) in the second round (p = 0.0147). Four cases were difficult to match even after the tutorial and three cases were highly affected by the tutorial. The most important basis for diagnoses was nuclear findings in the first and second rounds. CONCLUSION:Comprehensive tutorials on diagnostic criteria are needed to effectively implement this system globally. In particular, devising ways to appropriately diagnose cancers with mild atypia or without characteristic morphology is important.

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm; pulmonary cases can become massive and hypervascular, increasing surgical risk. A 71-year-old woman with a giant pulmonary SFT underwent preoperative angiography, which identified the internal thoracic artery as the dominant feeder. Selective embolization was performed, followed by total left pneumonectomy without cardiopulmonary support. Pathology confirmed margin-negative (R0) resection without pulmonary infiltration or nodal involvement. The postoperative course was uneventful, and no recurrence has been observed for 2.5 years. Preoperative angiographic evaluation and embolization are effective strategies to enhance surgical safety in managing hypervascular giant pulmonary SFTs.

Background:Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine malignancy prone to late recurrence and distant metastasis, most commonly to the lungs. Bilateral multiple pulmonary metastases are exceedingly uncommon, and optimal management remains unclear. Case presentation:A 51-year-old woman underwent total abdominal hysterectomy for LG-ESS at age 43. Eight years later, routine chest radiography revealed multiple bilateral pulmonary nodules. Computed tomography showed three well-circumscribed nodules (7-9 mm) in the left S4, left S8, and right S8 segments. Positron emission tomography showed minimal fluorodeoxyglucose uptake. Bilateral video-assisted thoracoscopic wedge resections were performed, achieving complete removal of all lesions. Histopathology confirmed metastatic LG-ESS (CD10/ER/PR positive). The patient received oral medroxyprogesterone acetate for five years. The therapy was discontinued following subarachnoid hemorrhage due to a ruptured posterior-circulation intracranial aneurysm and treated by surgical clipping; she has no residual neurological deficits. She remains disease-free a total of eight years after metastasectomy. Conclusion:Complete resection of bilateral multiple pulmonary metastases from LG-ESS, combined with hormonal therapy, can achieve durable long-term disease control in carefully selected patients.

Background:Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a known but potentially fatal complication in patients with underlying interstitial lung disease (ILD). However, reports of ICI-P in the postoperative setting remain scarce. Case presentation:We present a 67-year-old man with unclassifiable interstitial pneumonia who underwent right upper lobectomy for stage IB squamous cell carcinoma. Two cycles of adjuvant nivolumab were administered. Ten days after the second cycle, the patient developed fever and progressive dyspnea. Chest CT revealed diffuse ground-glass opacities and consolidation in both lungs. Despite initial improvement with high-dose corticosteroids, respiratory failure recurred and progressed rapidly. The patient died 21 days after onset. Pathological review of the resected lung confirmed fibrosis compatible with unclassifiable interstitial pneumonia and squamous cell carcinoma. No autopsy was performed. Conclusion:This case highlights the potentially fatal risk of postoperative nivolumab therapy in patients with pre-existing ILD, even in the setting of unclassifiable interstitial pneumonia. Careful risk-benefit assessment is warranted when considering adjuvant immune checkpoint inhibitors in this population.

Background/Aim:HER2-positive breast carcinomas (BCs) generally behave more aggressively and show higher cytological and histological grade than HER2-negative BCs. However, the clinical properties of HER2-positive early BCs have not been studied extensively. Hence, the therapeutic significance of neoadjuvant chemotherapy (NAC) for this BC remains debatable.Patients and Methods:We retrospectively examined the clinicopathological features of 94 HER2-positive early BCs who perioperatively received anti-HER2 drugs, without undergoing NAC prior to surgery.Results:The patients' five year-disease free survival (DFS) and overall survival (OS) rates were 95.6% and 100%, respectively. Univariate analysis demonstrated significant differences in distant metastasis-free survival (DMFS) between clinical and pathological tumor stages (T stages). Pathological T1 stage and clinical T1 stage tumors showed significantly higher DMSF than pT2-3 and cT2-3 (p=0.0002 and 0.0294). Multivariate analysis disclosed no significant differences in DFS, OS, and DMFS with respect to preoperative clinical tumor stage, patient age, type of surgery, postoperative therapy, and pathological factors. Recurrences occurred in nine patients: four (4.3%) and five (5.3%) patients showed local and distant recurrences, respectively. One patient with cT2 BC died of disease. Interestingly, four of the five BCs with distant recurrence pathologically demonstrated lymph vessel invasion. The prognoses of patients with HER2-positive stage cT1/2N0M0 BC were highly favorable.Conclusion:The indications for NAC in small, localized, and node-negative HER2-positive BC should be carefully assessed based on the presence of a larger tumor size, postoperative pathological evaluation of tumor size, and lymph vessel invasion.

Context.— Mesothelioma is an uncommon tumor that can be difficult to diagnose. Objective.— To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. Data Sources.— Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions.— There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.

Metaplastic breast carcinoma (MBC) is a heterogeneous group of invasive breast carcinomas (IBCs) characterized by the differentiation of the neoplastic epithelium toward squamous cells and/or mesenchymal-appearing elements. The present study describes the case of a 42-year-old woman who underwent a mastectomy and sentinel lymph node biopsy for two tumors in their left breast. One of the resected tumors was diagnosed as MBC with neuroendocrine (NE) differentiation and the other was diagnosed as IBC of no special type. The MBC tumor contained a matrix composed of basal lamina with a focal area of myxoid matrix and squamoid differentiation. To the best of our knowledge, the present study is the first report of MBC producing prominent basal lamina. The patient has remained alive and well for >10 years without recurrence, and has been treated with oral and injected anticancer drugs.

Background Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM. Methods We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan–Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed. Results LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM. Conclusions LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM. Trial registration This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022–0048) at Tokyo Women’s Medical University.

The World Health Organization (WHO), the International Academy of Cytology, and the International Agency for Research on Cancer have developed an approach to standardized reporting of pancreaticobiliary cytopathology. The WHO Reporting System for Pancreaticobiliary Cytopathology (WHO System) revises the Papanicolaou Society of Cytopathology (PSC) System for Reporting Pancreaticobiliary Cytology published in 2015 and replaces the 6 PSC categories with 7 categories: “Insufficient/Inadequate/Nondiagnostic”; “Benign/Negative for malignancy”; “Atypical”; “Pancreaticobiliary neoplasm, low risk/grade (PaN-low)”; “Pancreatic neoplasm, high risk/grade (PaN-High)”; “Suspicious for malignancy”; and “Malignant”. In the PSC system, there is a single category for “Neoplastic” lesions that includes 2 groups, 1 for benign neoplasms and 1 named “Neoplastic-other”, dominated by premalignant intraductal neoplasms primarily intraductal papillary mucinous neoplasms and low-grade malignant neoplasms (pancreatic neuroendocrine tumors (PanNET) and solid pseudopapillary neoplasms (SPN). In the WHO System, benign neoplasms with virtually no risk of malignancy are included in the “Benign” category and low-grade malignancies (PanNET and SPN) are included in the “Malignant” category, as per the 5th edition of the WHO Classification of Digestive System Tumors, while the non-invasive pre-malignant lesions of the ducts are divided by the cytomorphological grade of the epithelium into PaN-low and PaN-high with distinctly different risks of malignancy. Within each category, key diagnostic cytopathologic features and the ancillary studies for diagnostic and prognostic evaluation, as well as the implications of diagnosis for patient care and management, are outlined. Reporting and diagnostic management options recognize the variations in the availability of diagnostic and prognostic ancillary testing modalities in low- and middle-income countries.