Segmental Adrenal Venous Sampling in Unilateral Primary Aldosteronism With Apparent Bilateral Aldosterone Suppression.

Apparent bilateral adrenal suppression (ABAS), where aldosterone/cortisol ratios in both adrenal veins are lower than in the inferior vena cava, yields uninterpretable adrenal venous sampling (AVS) results and is poorly understood. A 57-year-old male with hypertension and spontaneous hypokalemia was admitted to our hospital. Confirmatory tests established a diagnosis of primary aldosteronism (PA). Initial AVS indicated ABAS, but unilateral PA remained possible due to elevated aldosterone, low renin, hypokalemia, and a right adrenal nodule (8 × 7 mm) on computed tomography. Subsequently, a second, super-selective AVS identified tributaries from areas of aldosterone hypersecretion, enabling accurate localization of unilateral PA. ABAS may occur due to anatomical factors such as dilution by tributaries from nonaldosterone-producing adenoma (APA) areas with suppressed aldosterone production. Super-selective AVS proves beneficial in diagnosing unilateral PA concealed within ABAS by pinpointing tributaries from APA regions.

Right atrial cardiac myxoma with malignant transformation to undifferentiated sarcoma: A case report.

Generally, sarcomas arising from benign soft tissue are rare. Cardiac myxoma (CM) is a benign tumor, and few reports have described its malignant transformation. Herein, we documented a case of an 89-year-old man with prostate cancer and a 5-year history of a right atrium tumor without Carney complex. The tumor was resected surgically and had a myxomatous or gelatinous appearance. Microscopically, the tumor had two components: a sarcomatous area and myxomatous area. In the myxomatous area, typical myxoma cells were demonstrable and were strongly immunoreactive for immunohistochemistry (IHC) of calretinin. In the sarcomatous area, the epithelioid- to spindle-shaped cells with prominent atypia proliferated densely. The IHC profile of cells in the sarcomatous area was different from that of cells in the myxomatous area; MDM2-positive cells were found only in the sarcomatous area. Especially, the Ki-67 index and number of p53-positive cells in the sarcomatous area were higher than those in the myxomatous area. The transition of the two components was seamless. Thus, we made a diagnosis of CM with malignant transformation corresponding to undifferentiated pleomorphic sarcomas. This case suggests that CM may transform into sarcoma, albeit rarely.

The relationship between tumor immunity and the cGAS-STING pathway in breast cancer: An immunohistochemical study.

Breast cancer (BC) is classified into four major histological subtypes, namely luminal A, luminal B, HER2, and basal-like, and its treatment is based on these subtypes. The use of immune checkpoint inhibitors against BC depends on the expression of PD-1/PD-L1. Another tumor immune system-the cGAS-STING pathway-is a potential target for cancer immunotherapy. However, the status of the cGAS-STING pathway in BC has not been fully established. Therefore, we investigated the expression status of the cGAS-STING pathway and immune-related proteins in BC. We classified 111 BCs into six groups-29 hormone receptor-positive carcinomas, 12 HER2+ carcinomas (HER2), 8 luminal-HER2 carcinomas, 26 triple-negative breast carcinomas (TNBCs), 21 lobular carcinomas (LC), and 15 carcinomas with apocrine differentiation (CAD)-and investigated the relationship between BC and tumor immunity via the cGAS-STING pathway using histopathological and immunohistochemical methods. Expression of cGAS was high in CADs (100%) and low in TNBCs (35%); STING-positive lymphocytes were high in TNBC (85%, P = 0.0054). Expression of pSTAT3 was significantly high in patients with TNBC (≥10%, 88%). The proportion of PD-L1-positive tumor cells was higher in TNBCs (54%) than in other BCs (30%). SRGN expression was significantly higher in the TNBC group than in the other BC groups (58%). Tumor immune responses may differ among tumor subtypes. The cGAS-STING pathway may be functional in TNBC and CAD but not in LC. Therefore, targeting the cGAS-STING pathway might be useful in BC, particularly TNBC and CAD.

[Giant Coronary Artery Aneurysm in the Main Trunk of the Coronary Artery].

The case is a 76-year-old woman. She was admitted to the hospital because of chest and back pain. Coronary angiography revealed a 62-mm giant coronary artery aneurysm originating from the left main trunk( LMT), and urgent surgery was performed. Coronary artery-pulmonary artery fistula along with coronary artery aneurysm was completely removed by surgery. In this case, the reconstruction strategy for the LMT was crucial. The aneurysm wall was completely resected, allowing the coronary artery to return to its original course, and the length of the LMT defect was <2 cm. We determined that anatomical reconstruction of the LMT was optimal and succeeded in replacing a short great saphenous vein corresponding to the length of the defect. The patient was discharged without any complications.

Recurrent cardiac tamponade following coronavirus disease 2019 mRNA vaccination: A case report.

A 64-year-old woman with a history of subarachnoid hemorrhage, breast cancer, cervical spine tumor, and syringomyelia developed recurrent pericardial effusion and cardiac tamponade after receiving the third dose of coronavirus disease 2019 mRNA vaccine, mRNA-1273 (Spikevax, Moderna). The cardiac tamponade of unknown etiology was intractable with nonsteroidal anti-inflammatory drugs, colchicine, and prednisolone. She underwent thoracoscopic pericardiectomy, and microthrombi were detected in the pericardial tissue. Although the exact causal relationship between vaccination and recurrent cardiac tamponade was unclear, the vaccine possibly caused or triggered the microthrombi formation, resulting in recurrent cardiac tamponade. Because of the potential for cardiovascular side effects such as thrombosis and myocarditis following vaccination, it was deemed necessary to accumulate and analyze such cases.

Genetic Profiling of Sebaceous Carcinoma Arising from an Ovarian Mature Teratoma: A Case Report.

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1-2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event.

Multiple Somatic Mutations of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: A Case Report.

Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by germline and/or somatic SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) mutations. Here, we report a case of SCCOHT harboring multiple previously unreported somatic mutations in SMARCA4 (c.2866_2867delC>T; c.3543del). A 28-year-old breastfeeding Japanese female presented to a previous hospital with nausea and vomiting. She had no family history of relevant malignancies, including ovarian cancer. Based on an evaluation performed at another institution, she was referred to a gynecologist for suspected ovarian cancer. Imaging studies revealed a 16×15 cm heterogenous enhancing mass within the right ovary without lymph node or distant metastasis. She had mild ascites without peritoneal dissemination, but there was an elevation in the serum calcium level (15.1 mg/dL). The patient underwent cytoreductive surgery and was pathologically diagnosed with SCCOHT. Auxiliary immunohistochemical staining confirmed the loss of SMARCA4 protein expression. The patient was diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IA (pT1a pN0 M0). The serum calcium levels returned to normal post-surgery. Matched-pair analysis using tumor tissue and peripheral blood revealed multiple somatic mutations in SMARCA4, but no deleterious germline mutations were present. Microsatellite instability was not significant, and the patients had a heterozygous mutation of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1)*6. She underwent six cycles of irinotecan hydrochloride plus cisplatin chemotherapy and achieved complete remission. The patient was finally examined and evaluated 45 months postoperatively; there was no evidence of the disease. Overall, the genetic findings will not aid in the SCCOHT diagnosis and relevant genetic counseling; however, they may have implications for the treatment of this disease in the future.

Intractable Nocardial mycetoma with possible colonisation by Candida species.

A Japanese male in his 30s with no underlying medical condition presented with painless nodules after being bitten by a dog during a stay in Bali, Indonesia, 7 years earlier. He was referred to our department with multiple ulcers, nodules, and masses on the right leg. The final diagnosis was mycetoma caused by Nocardia vulneris, which may have been exacerbated by colonization of Candida parapsilosis and C. tropicalis as these yeasts were isolated by culture from the tissue. Treatment with minocycline hydrochloride and sulfamethoxazole trimethoprim showed partial efficacy, but the addition of posaconazole achieved significant efficacy. This suggests that the surmised coexistence of pathogenic yeasts of lower virulency may have made mycetoma in this case intractable.

Clinical characteristics, proteins, and genes related to interstitial pneumonia-associated squamous cell carcinoma of the lungs.

Squamous cell carcinoma (SCC) is a common histological type of lung carcinoma that is associated with interstitial pneumonia (IP). We hypothesized that identifying specific genetic alterations or molecular markers of SCC with IP may aid the development of novel therapeutic strategies for the same. Therefore, in the present study, we aimed to identify tumorigenic genetic alterations and molecular markers in cases of SCC with IP. We included 28 lung SCC cases (14 cases with IP and 14 cases without IP). We performed immunohistochemistry for STAT3, STAT5, and TLE1, and next-generation sequencing was performed using an iSeq 100 system. The panel used in this study targeted 50 cancer-associated genes. Immunohistochemically, the rate of TLE1 positivity was higher in the SCC without IP group (93 %) than in the SCC with IP group (29 %), while that of STAT5 was higher in the SCC with IP group (79 %) than in the SCC without IP group (14 %). STAT3 expression was high in both the groups (SCC with IP, 64 %; SCC without IP, 71 %). Eighteen genes were mutated in more than six samples, and FBXW7 mutation was mainly observed in the SCC with IP group (p < 0.01). Mechanisms underlying tumorigenesis in SCC with IP included STAT5 activation via inflammation, while that in SCC without IP included squamous TLE1-mediated metaplasia. These findings are based on smoking-induced STAT3 activation; therefore, patients with IP who smoke are more likely to have progressive SCC. We also found that FBXW7 mutations may be associated with SCC with IP and keratinization. ERBB4 and KDR mutations were observed in both with or without IP, and these genes may be tumor-related genes in SCC. These molecular markers may help determine the prognoses of patients with SCC with IP and direct the development of treatment approaches.

Alpha-fetoprotein producing endometrioid carcinoma arising in an adenomyoma of the uterus.

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.

SOX10-Internal Tandem Duplications and PLAG1 or HMGA2 Fusions Segregate Eccrine-Type and Apocrine-Type Cutaneous Mixed Tumors.

Cutaneous mixed tumors exhibit a wide morphologic diversity and are currently classified into apocrine and eccrine types based on their morphologic differentiation. Some cases of apocrine-type cutaneous mixed tumors (ACMT), namely, hyaline cell-rich apocrine cutaneous mixed tumors (HCR-ACMT) show a prominent or exclusive plasmacytoid myoepithelial component. Although recurrent fusions of PLAG1 have been observed in ACMT, the oncogenic driver of eccrine-type cutaneous mixed tumors (ECMT) is still unknown. The aim of the study was to provide a comprehensive morphologic, immunohistochemical, and molecular characterization of these tumors. Forty-one cases were included in this study: 28 cases of ACMT/HCR-ACMT and 13 cases of ECMT. After morphologic and immunohistochemical characterization, all specimens were analyzed by RNA sequencing. By immunohistochemistry, all cases showed expression of SOX10, but only ACMT/HCR-ACMT showed expression of PLAG1 and HMGA2. RNA sequencing confirmed the presence of recurrent fusion of PLAG1 or HMGA2 in all cases of ACMT/HCR-ACMT, with a perfect correlation with PLAG1/HMGA2 immunohistochemical status, and revealed internal tandem duplications of SOX10 (SOX10-ITD) in all cases of ECMT. Although TRPS1::PLAG1 was the most frequent fusion, HMGA2::WIF1 and HMGA2::NFIB were detected in ACMT cases. Clustering analysis based on gene expression profiling of 110 tumors, including numerous histotypes, showed that ECMT formed a distinct group compared with all other tumors. ACMT, HCR-ACMT, and salivary gland pleomorphic adenoma clustered together, whereas myoepithelioma with fusions of EWSR1, FUS, PBX1, PBX3, POU5F1, and KLF17 formed another cluster. Follow-up showed no evidence of disease in 23 cases across all 3 tumor types. In conclusion, our study demonstrated for the first time SOX10-ITD in ECMT and HMGA2 fusions in ACMT and further refined the prevalence of PLAG1 fusions in ACMT. Clustering analyses revealed the transcriptomic distance between these different tumors, especially in the heterogenous group of myoepitheliomas.

Immunohistochemical staining of versican as a potential marker for predicting lymph node metastasis in gastric cancer.

Gastric cancer is one of the most common cancers and has a high mortality rate. Lymph node metastasis is a key determinant of prognosis, and an essential mechanism involved in metastasis is the epithelial-mesenchymal transition. In this study, we aimed to assess the diagnostic role of versican (VCAN), a molecule participating in the epithelial-mesenchymal transition, on the detection of metastatic cancer. The expression of VCAN was evaluated using immunohistochemistry, and its biological activity was examined using gastric cancer cell lines. In patients with lymph node metastasis, VCAN expression was more prominent at primary tumor sites. In addition, VCAN was found to promote cell migration in vitro, thus potentially facilitating the distribution of metastases. Overall, increased expression of VCAN at the primary site may signify the development of metastases in lymph nodes because this protein is recognized as contributing to the migration of cancer cells into lymph nodes.

Apoptosis-related factors are relevant to progression of pancreatic neuroendocrine tumors.

BACKGROUND: Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection. METHODS: Forty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan-Meier method and compared with the log-rank test. RESULTS: GLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044). CONCLUSIONS: Survivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.

Clinicopathological correlations of endometrioid and clear cell carcinomas in the uterus and ovary.

Endometrioid carcinoma (EC) and clear cell carcinoma (CC) are associated with endometrial tissue hyperplasia and endometriosis, and they occur in the endometrium and ovaries. However, detailed differences between these tumors based on immunostaining are unclear; therefore, in this study, we aimed to analyze the clinicopathological correlations between these tumors using immunostaining and to develop new treatments based on histological subtypes. Immunohistochemistry was used to investigate differentially expressed hypoxia-associated molecules (hypoxia-inducible factor-1 subunit alpha [HIF-1α], forkhead box O1, prostate-specific membrane antigen, signal transducer and activator of transcription 3 [STAT3], hepatocyte nuclear factor 1ß [HNF-1ß], aquaporin-3, and vimentin [VIM]) between these carcinomas because of the reported association between CC and ischemia. Immunostaining and clinicopathological data from 70 patients (21 uterine endometrioid carcinomas [UECs], 9 uterine cell carcinomas, 20 ovarian endometrioid carcinomas [OECs], and 20 ovarian cell carcinomas [OCCs]) were compared. HIF-1α and prostate-specific membrane antigen expression levels were higher in UEC and OCC than in uterine cell carcinomas and OEC. STAT3 was slightly overexpressed in UEC. Additionally, forkhead box O1 expression was either absent or significantly attenuated in all ECs. VIM and AQ3 were highly expressed in UEC, whereas HNF-1ß expression was higher in OCC. UEC, OEC, and OCC were more common in the uterine fundus, left ovary, and right ovary, respectively. Ovarian endometriosis was strongly associated with EC. Our findings suggest that UEC and OCC share a carcinogenic pathway that involves HIF-1α induction under hypoxic conditions via STAT3 expression, resulting in angiogenesis. Furthermore, the anatomical position of carcinomas may contribute to their carcinogenesis. Finally, aquaporin-3 and VIM demonstrate strong potential as biomarkers for UEC, whereas HNF-1ß expression is a crucial factor in CC development. These differences in tumor site and histological subtypes shown in this study will lead to the establishment of treatment based on histological and immunohistological classification.

Uncommon case of cytopathological features of sialadenoma papilliferum.

Sialadenoma papilliferum, a benign and rare salivary gland neoplasm, accounts for 0.4%-1.2% of all salivary gland tumors and occurs primarily in minor salivary glands of the oral cavity. Here, we report a case of sialadenoma papilliferum and its associated cytological findings. A papillary tumor was incidentally detected on the palate of an 86-year-old Japanese man. Conventional oral exfoliative cytology was performed; the cytology smear exhibited epithelial clusters composed of atypical epithelial cells with a high nuclear/cytoplasm ratio and arranged in sheet or small papillary-like projections. Cytoplasmic vacuoles were also observed in the papillae. It was difficult to make a definitive diagnosis due to the presence of uncommon cytological features. The excisional biopsy specimen revealed histological features characteristic of sialadenoma papilliferum. Mutational analysis detected BRAFV600E mutation, which confirmed the diagnosis of sialadenoma papilliferum. To the best of our knowledge, no prior cytomorphological evaluations of sialadenoma papilliferum have been reported in detail. Oral exfoliative cytology specimens from salivary gland tumors can demonstrate uncommon cytomorphological features. A differential diagnosis of sialadenoma papilliferum can be based on the observation of mildly atypical epithelial cells that form small papillary-like structures.

Histopathological Aspects of the Prognostic Factors for Salivary Gland Cancers.

Salivary gland cancers (SGCs) are diagnosed using histopathological examination, which significantly contributes to their progression, including lymph node/distant metastasis or local recurrence. In the current World Health Organization (WHO) Classification of Head and Neck Tumors: Salivary Glands (5th edition), malignant and benign epithelial tumors are classified into 21 and 15 tumor types, respectively. All malignant tumors have the potential for lymph node/distant metastasis or local recurrence. In particular, mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (AdCC), salivary duct carcinoma, salivary carcinoma, not otherwise specified (NOS, formerly known as adenocarcinoma, NOS), myoepithelial carcinoma, epithelial-myoepithelial carcinoma, and carcinoma ex pleomorphic adenoma (PA) are relatively prevalent. High-grade transformation is an important aspect of tumor progression in SGCs. MEC, AdCC, salivary carcinoma, and NOS have a distinct grading system; however, a universal histological grading system for SGCs has not yet been recommended. Conversely, PA is considered benign; nonetheless, it should be cautiously treated to avoid the development of metastasizing/recurrent PA. The aim of this review is to describe the current histopathological aspects of the prognostic factors for SGCs and discuss the genes or molecules used as diagnostic tools that might have treatment target potential in the future.

CD8/PD-L1 immunohistochemical reactivity and gene alterations in cutaneous squamous cell carcinoma.

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.