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Breast cancer (BC) is classified based on the expression of histopathological markers, namely, estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). Carcinomas with apocrine differentiation (CAD) are classified based on morphology. Androgen receptor (AR) is highly expressed in CAD; however, no study has comprehensively examined AR-related proteins in CAD. Therefore, we examined the expression of AR-related proteins and AR, compared protein expression patterns between morphologically identified CAD and other BC subtypes, and investigated CAD characteristics. We performed immunohistochemistry for AR and various AR-related proteins in 66 invasive ductal carcinoma (32 ER+/PgR+/HER2−, 8 ER+/PgR+/HER2+, 12 ER−/PgR−/HER2+, and 14 ER−/PgR−/HER2− [triple-negative breast cancer)), 21 invasive lobular carcinoma, and 27 CAD cases. In the CAD group, all cases were AR-positive; some AR-related proteins were highly expressed. Nuclear phosphorylated-mammalian target of rapamycin was highly expressed in CAD cases compared with that in other BC groups, with a 33.3% sensitivity and 97.7% specificity. AR-expressing CAD cases exhibited high expression of other AR-related proteins. Specifically, the combination of AR+, GCDFP15+, and ER − or AR+, FOXA1+, and ER − may be useful for the diagnosis and treatment of AR-positive BC and CAD. These results may assist in androgen-related molecular targeted therapy research.

In recent years, several immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) or PD-1 have been developed for cancer therapy. The genetic background of tumors and factors that influence PD-L1 expression in tumor tissues are not yet elucidated in cutaneous squamous cell carcinoma (cSCC). CD8-positive tumor-infiltrating lymphocytes (TILs) are known to be related to tumor immunity. Here, we aimed to study the relationship between CD8/PD-L1 immunohistochemical reactivity and gene alterations in cSCC. Tumorigenic genes were examined to identify gene alterations using next-generation sequencing (NGS). We collected 27 cSCC tissue samples (from 13 metastatic and 14 non-metastatic patients at primary diagnosis). We performed immunohistochemical staining for CD8 and PD-L1, and NGS using a commercially available sequencing panel (Illumina Cancer Hotspot Panel V2) that targets 50 cancer-associated genes. Immunohistochemically, CD8-positive TILs showed a high positive score in cSCC without metastasis; in these cases, cSCC occurred predominantly in sun-exposed areas, the tumor size was smaller, and the total gene variation numbers were notably low. The tumor depth, PD-L1 positivity, and gene variation number with or without tumor metastasis were not related, but the gene variation number tended to be higher in cSCCs arising in non-sun-exposed areas. Tumor metastasis was more common in cSCC arising in non-sun-exposed areas, which decreased the number of TILs or CD8-positive cells. From a genetic perspective, the total gene alterations were higher in cSCC with metastasis. Among them, ERBB4 and NPM1 are presumably involved in cSCC tumorigenesis; in addition, GNAQ , GNAS , JAK2 , NRAS , IDH2 , and CTNNB1 may be related to tumor metastasis. These results provide information on potential genes that can be targeted for cSCC therapy and on immune checkpoint inhibitors that may be used for cSCC therapy.

Background We aimed to clarify the existence and pathological features of obesity cardiomyopathy (OCM) in Japan using our series of autopsy cases. Methods In this retrospective autopsy study, OCM was defined as cardiac hypertrophy (≥ 400 g in men, ≥ 320 g in women) of unknown aetiology in individuals with obesity (body mass index [BMI] ≥ 25 kg/m 2 according to the Japanese definition of obesity). We compared cases of OCM with those with obesity without cardiac hypertrophy (OB) and normal weight without cardiac hypertrophy (normal control). Macroscopically, heart weight and cardiac parameters, including epicardial adipose tissue, were measured. Fibrosis, cardiomyocyte diameter, and adipose tissue infiltration were analysed microscopically. Results Of the 294 cases, we identified 19 cases of OCM (6.5%) and compared them with the OB and normal control groups. Patients with OCM were slightly younger than non-OCM patients ( p  = 0.081). The median heart weight was significantly heavier in OCM cases than in OB cases (435 g, interquartile range [IQR] 408–515 g vs. 360 g, IQR 341–385 g). Macroscopically, OCM hearts had a “globoid” appearance with a thickened right ventricular outflow tract. Some OCM cases showed focal interstitial fibrosis in the left ventricle. Approximately half the OCM cases were diagnosed with sudden cardiac death (SCD), with significant differences. Conclusions The prevalence of OCM may be higher than expected in Japan, and this may be a specific pathological finding. Given that approximately half the cases of OCM were due to SCD, OCM may cause SCD, emphasizing the need to recognise and diagnose OCM.

We report a case of alpha-fetoprotein-producing endometrioid carcinoma (AFP-EC) that originated within an adenomyoma of the uterine corpus. A 76-year-old Japanese woman was incidentally discovered to have a uterine tumor along with multiple lung nodules. Upon surgical removal of the uterus, it was revealed that the tumor was situated within the adenomyoma. The tumor exhibited microfollicular structures and solid growth patterns, with hyaline globules, clear cell glands, and primitive tumor cells. Immunohistochemical analysis indicated the presence of germ cell markers, including AFP, SALL4, and glypican3, leading to final diagnosis of AFP-EC. Histopathologically, AFP-ECs exhibit characteristics similar to those of AFP-producing neoplasms in other organs. Furthermore, a nomenclature issue arises when distinguishing AFP-ECs from yolk sac tumors of the endometrium in older patients due to their shared features. The concept of retrodifferentiation or neometaplasia suggests that “endometrioid carcinoma with yolk sac tumor differentiation” or “endometrioid carcinoma with a primitive phenotype” may serve as more fitting terms for the diverse spectrum of AFP-producing neoplasms in the endometrium. In conclusion, this case underscores the diagnostic challenges posed by AFP-ECs arising from adenomyomas and emphasizes the need for refining the nomenclature and classification of AFP-producing neoplasms within the endometrium.

Background Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). Methods We investigated the clinicopathological characteristics, Epstein–Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. Results Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4− CD8− nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival ( p  < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs ( p  = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). Conclusions OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Recent clinical evidence has suggested that interatrial septal (IAS) adiposity contributes to atrial fibrillation (AF). The present study aimed to confirm the usefulness of transesophageal echocardiography (TEE) to estimate IAS adiposity in patients with AF. The histological IAS analysis based on autopsy samples sought to clarify characteristics that underlie the contribution of IAS adiposity to AF. The imaging study analyzed the TEE results in patients with AF ( n  = 184) in comparison with transthoracic echocardiography (TTE) and computed tomography (CT) results. The autopsy study histologically analyzed IAS in subjects with ( n  = 5) and without ( n  = 5) history of AF. In the imaging study, the ratio of interatrial septum adipose tissue (IAS-AT) volume per epicardial adipose tissue (EpAT) volume was greater in patients with persistent AF compared (PerAF) to those with paroxysmal AF (PAF). Multivariable analysis revealed that both TEE-assessed IAS thickness and TTE-assessed left atrial dimension were predicted by CT-assessed IAS-AT volume. In the autopsy study, the histologically-assessed IAS section thickness was greater in the AF group than that in the non-AF group and was positively correlated with the IAS-AT area percentage. In addition, the size of adipocytes in IAS-AT was smaller, compared to EpAT and subcutaneous adipose tissue (SAT). IAS-AT infiltrated into the IAS myocardium, as if adipose tissue split the myocardium (designated as myocardial splitting by IAS-AT). The number of island-like myocardium pieces as a result of myocardial splitting by IAS-AT was greater in the AF group than in the non-AF group and was positively correlated with the IAS-AT area percentage. The present imaging study confirmed the usefulness of TEE to estimate IAS adiposity in patients with AF without radiation exposure. The autopsy study suggested that the myocardial splitting by IAS-AT may contribute to atrial cardiomyopathy leading to AF.

Previously, we reported that genomic loss of 14q occurs more frequently in high‐grade than in low‐grade clear cell renal cell carcinomas (ccRCCs), and has a significant impact on the levels of expression of genes located in this region, suggesting that such genes may be involved in the malignant transformation of ccRCCs. Here, we found that six of the genes located in the minimal common region of 14q loss were significantly downregulated in high‐grade ccRCCs due to copy number loss. Using a dataset from The Cancer Genome Atlas Research Network, we found that downregulation of one of these six genes, WDR20, was significantly associated with poorer outcome in patients with ccRCC, suggesting that WDR20 downregulation may be involved in the malignant transformation of ccRCCs. In functional assays, exogenous WDR20 significantly inhibited the growth of RCC cell lines and induced apoptosis. Interestingly, the phosphorylation levels of ERK and protein kinase B/AKT, which reportedly contribute to the malignant phenotype of RCC cells, were clearly reduced by exogenous expression of WDR20. Thus, our data suggest that downregulation of WDR20 due to 14q loss may be involved in the malignant transformation of ccRCCs, in part through activation of the ERK and protein kinase B/AKT pathways. WDR20 downregulation and copy number loss are associated with a poorer outcome in patients with clear cell renal cell carcinoma.

Background Segmental absence of intestinal musculature (SAIM) is a partial defect of the intrinsic muscular layer of the intestinal tract. In this report, we describe a case of perforation of the sigmoid colon due to SAIM accompanied by vascular Ehlers–Danlos syndrome (vEDS), which was successfully treated by surgical therapy. Case presentation A male in his 30 s was being followed up for vEDS diagnosed by genetic testing. He had undergone two major vascular surgeries, abdominal aortic artery revascularization and thoracic endovascular aortic repair for a residual dissection and enlarging abdominal aortic aneurysm. On postoperative day 11, the patient developed perforation of the sigmoid colon for which intraperitoneal lavage and drainage, Hartmann surgery, and transverse colostomy were performed. Histological findings showed no disturbance of blood flow or diverticulum but did show a defect in the intrinsic muscular layer around the perforation site, leading to the pathological diagnosis of SAIM and associated perforation of the sigmoid colon. Postoperatively, the patient had no complications and was discharged on postoperative day 18. The patient is being followed as an outpatient and has experienced no relapse. Conclusions Both SAIM and vEDS, which may be related diseases, are associated with the presence of tissue fragility and have a high potential to cause intestinal perforation Caution should be exercised during surveillance in patients with constipation and examinations that cause increased intestinal pressure.

INTRODUCTION: Alectinib, a 2nd-generation anaplastic lymphoma kinase–tyrosine kinase inhibitor (ALK-TKI), is an established 1st-line therapy for advanced ALK fusion gene–positive non–small cell lung cancer (NSCLC). However, the role of salvage surgery following alectinib for locally advanced disease remains uncertain.CASE PRESENTATION: A 41-year-old woman was diagnosed in the postpartum period with Stage IIIA (cT1cN2M0) ALK fusion gene–positive lung adenocarcinoma. She received 1st-line alectinib, achieving a 55.3% reduction in tumor size over 11 months. Subsequent salvage surgery revealed a pathological complete response with no residual tumor cells. During postoperative follow-up off alectinib, recurrence was observed 20 months after surgery, with new brain and pulmonary metastases. Reintroduction of alectinib achieved renewed disease control, and the patient has remained progression-free for 23 months since restarting therapy.CONCLUSIONS: This case highlights the potential role of salvage surgery following alectinib in locally advanced ALK fusion gene–positive NSCLC. Furthermore, it suggests that maintenance ALK-TKI therapy after salvage surgery might be associated with a reduced risk of recurrence. Further studies are warranted to optimize perioperative ALK-targeted strategies.

Background It is very rare for clear cell sarcomas (CCS) to arise in the bone. During diagnosis, it is important to distinguish primary CCS of bone from bone metastasis of melanoma because this difference fundamentally changes the therapeutic options. Recently, characteristic fusion genes of CCS have been detected using reverse transcription polymerase chain reaction (RT-PCR) or direct sequencing which allowed to distinguish CCS from melanoma. However, there was no study applying these analyses with positive results. In this case, we describe the use of fusion gene analysis to diagnose a primary CCS of the bone. Case presentation A 36-year-old male presented with a four-months history of left knee pain. Magnetic resonance imaging showed a lesion in the left femoral medial epicondyle. Histological examination of the biopsy specimen revealed proliferating oval or rounded cells. These cells had clear cytoplasm arranged in fascicles or compact nests with frequent deposits of brown pigment. Furthermore, immunohistochemistry analysis revealed that tumor cells were positive for S-100 protein, HMB-45, Melan-A, and SOX10. It stained negative for CD34 and BRAF v600e. Conclusively, detection of the EWSR1/ATF1 fusion gene using RT-PCR and direct sequencing confirmed that the lesion was a primary CCS of the bone. Wide-margin resection and reconstruction with a tumor endoprosthesis were performed. Conclusions Herein, we diagnosed a rare case of primary CCS of the bone by detecting EWSR1/ATF1 fusion gene using RT-PCR and direct sequencing. Since fluorescence-in situ hybridization (FISH) and RT-PCR could show false positive by mainly due to technical problems, it is better to perform direct sequencing to confidently diagnose the tumor as a primary CCS especially at very rare site such as bone.