Evaluating the usefulness of plasma chromogranin A measurement in cyclic ACTH-dependent Cushing's syndrome.

Cushing's syndrome, a clinical condition characterized by hypercortisolemia, exhibits distinct clinical signs and is associated with cyclic cortisol secretion in some patients. The clinical presentation of cyclic Cushing's syndrome can be ambiguous and its diagnosis is often challenging. We experienced a 72-year-old woman with cyclic ACTH-dependent Cushing's syndrome caused by a pulmonary carcinoid tumor. Diagnosis was challenging because of the extended trough periods, and the responsible lesion was initially unidentified. A subsequent follow-up computed tomography revealed a pulmonary lesion, and ectopic ACTH secretion from this lesion was confirmed by pulmonary artery sampling. Despite the short peak secretion period of ACTH (approximately one week), immunostaining of the surgically removed tumor confirmed ACTH positivity. Interestingly, stored plasma chromogranin A levels were elevated during both peak and trough periods. The experience in evaluating this patient prompted us to investigate the potential use of plasma chromogranin A as a diagnostic marker of ACTH-dependent Cushing's syndrome. A retrospective study was conducted to determine the efficacy of plasma chromogranin A in three patients with ectopic ACTH syndrome (EAS), including the present case, and six patients with Cushing's disease (CD) who visited our hospital between 2018 and 2021. Notably, plasma chromogranin A levels were higher in patients with EAS than in those with CD. Additionally, a chromogranin A level in the present case during the trough phase was lower than that in the peak phase, and was similar to those in CD patients. The measurement of plasma chromogranin A levels could aid in differentiating EAS from CD.

A Case of 17α-hydroxylase/17,20-lyase Deficiency Diagnosed at 45 Years of Age with Hyperaldosteronism.

17α-hydroxylase deficiency is a type of congenital adrenocortical hyperplasia that is typically diagnosed in childhood or adolescence. It manifests as hypertension with gonadal dysfunction as the primary symptom. We herein report 17α-hydroxylase/17,20-lyase deficiency (17OHD) diagnosed at the age of 45 years. The patient presented with hypertension, irregular menstruation, and hyperaldosteronism. The clinical manifestations of 17OHD vary based on the specific variant pattern of CYP17A1. In this case, the variant was c.157_159 TCC del p. Phe53del, which has been frequently reported in Japan. The enzymatic deficiency due to this variant is partial, leading to a delay in making a correct diagnosis.

Histopathological analysis of tumor microenvironment in adrenocortical carcinoma: Possible effects of in situ disorganized glucocorticoid production on tumor immunity.

Adrenocortical carcinoma (ACC) patients with glucocorticoid excess have been reported to be associated with decreased tumor-infiltrating immune cells, but the effects of in situ glucocorticoid production on tumor immunity have remained unknown. In addition, ACC was also known to harbor marked intra-tumoral heterogeneity of steroidogenesis or disorganized steroidogenesis. Therefore, in this study, we immune-profiled tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) and pivotal steroidogenic enzymes of glucocorticoid biosynthesis (CYP17A and CYP11B1) to explore the potential effects of in situ glucocorticoid production and intra-tumoral heterogeneity/disorganized steroidogenesis on tumor immunity of ACC. We also studied the correlations of the status of tumor immunity with that of angiogenesis and tumor grade to further explore the tumor tissue microenvironment of ACC. TILs (CD3, CD4, CD8, and FOXP3), TAMs (CD68 and CD163), key steroidogenic enzymes of glucocorticoid (CYP17A and CYP11B1), angiogenesis (CD31 and vasohibin-1 (VASH-1)), tumor grade (Ki-67 and Weiss score) were immunohistochemically evaluated in 34 ACCs. Increased CYP17A immunoreactivity in the whole tumor area was significantly positively correlated with FOXP3-positive TILs (p = 0.021) and negatively with CD4/CD3 ratio (p = 0.001). Increased CYP11B1 immunoreactivity in the whole tumor area was significantly positively correlated with CD8/CD3 (p = 0.039) and CD163/CD68 ratios (p = 0.006) and negatively with CD4-positive TILs (p = 0.036) and CD4/CD3 ratio (p = 0.001). There were also significant positive correlations between CYP17A and CD8 (r = 0.334, p < 0.001) and FOXP3-positive TILs (r = 0.414, p < 0.001), CD8/CD3 ratio (r = 0.421, p < 0.001), and CD68-positive TAMs (r = 0.298, p < 0.001) in randomly selected areas. Significant positive correlations were also detected between CYP11B1 and CD8/CD3 ratio (r = 0.276, p = 0.001) and negative ones detected between CYP11B1 and CD3- (r = -0.259, p = 0.002) and CD4-positive TILs (r = -0.312, p < 0.001) in those areas above. Increased micro-vessel density (MVD) -VASH-1 was significantly positively correlated with CD68- (p = 0.015) and CD163-positive TAMs (p = 0.009) and CD163/CD68 ratio and the high VASH-1 with CD163-positive TAMs (p = 0.042). Ki-67 labeling index was significantly positively correlated with MAD-VASH-1 (p = 0.006) and VASH-1 (p = 0.006) status. Results of our present study indicated that in situ glucocorticoid production did influence the status of tumor immunity in ACC. In particular, increased levels of CYP17A and CYP11B1, both involved in glucocorticoid producing immunoreactivity played different effects on tumor immunity, i.e., reflecting the involvement of intra-tumoral heterogeneity and disorganized steroidogenesis of ACC, which also did indicate the importance of in situ approaches when analyzing tumor immunity of ACC.

Retroperitoneal Paraganglioma With Asymptomatic Follicular Lymphoma: A Case Report.

Paraganglioma (PGL) is a rare tumor originating from extra-adrenal paraganglionic chromaffin tissues, and most sympathetic PGLs have excessive catecholamine secretion. However, nonfunctional PGLs are sometimes found. Although malignant PGL is defined by metastasis to nonchromaffin tissues, it is difficult to predict malignancies due to the lack of reliable markers of potential malignancies. We report the case of a 69-year-old Japanese woman with an incidental retroperitoneal tumor and multiple enlarged mesenteric lymph nodes simultaneously. The patient had no subjective symptoms and there were no laboratory findings suggesting catecholamine hypersecretion. Both the retroperitoneal tumor and the enlarged mesenteric lymph nodes showed high accumulation of fluorodeoxyglucose (FDG), whereas metaiodobenzylguanidine (MIBG) was accumulated only at the retroperitoneal tumor. Although a retroperitoneal tumor was diagnosed as nonfunctional PGL by examination including MIBG scintigraphy, the cause of enlarged mesenteric lymph nodes could not be diagnosed by imaging and biochemical tests. As a result of retroperitoneal tumor resection and mesenteric lymph nodes sampling, histopathological examination revealed that a retroperitoneal tumor was PGL and enlarged mesenteric lymph nodes were follicular lymphoma. To reveal an underlying genetic factor, we performed whole exome sequencing of genomic DNA, and we identified 2 possible candidate variants in SDHD and DLST, but the pathogenicity of these variants remains uncertain in the present case. This rare case reinforces the importance of histopathological diagnosis of nonchromaffin tissue lesions in patients with PGL for the appropriate treatment strategy.

Renal Injuries in Primary Aldosteronism: Quantitative Histopathological Analysis of 19 Patients With Primary Adosteronism.

[Figure: see text].

CCNB2 and AURKA overexpression may cause atypical mitosis in Japanese cortisol-producing adrenocortical carcinoma with TP53 somatic variant.

BACKGROUND: Many genomic analyses of cortisol-producing adrenocortical carcinoma (ACC) have been reported, but very few have come from East Asia. The first objective of this study is to verify the genetic difference with the previous reports by analyzing targeted deep sequencing of 7 Japanese ACC cases using next-generation sequencing (NGS). The second objective is to compare the somatic variant findings identified by NGS analysis with clinical and pathological findings, aiming to acquire new knowledge about the factors that contribute to the poor prognosis of ACC and to find new targets for the treatment of ACC. METHOD: DNA was extracted from ACC tissue of seven patients and two reference blood samples. Targeted deep sequencing was performed using the MiSeq system for 12 genes, and the obtained results were analyzed using MuTect2. The hypothesis was obtained by integrating the somatic variant findings with clinical and pathological data, and it was further verified using The Cancer Genome Atlas (TCGA) dataset for ACC. RESULTS: Six possible pathogenic and one uncertain significance somatic variants including a novel PRKAR1A (NM_002734.4):c.545C>A (p.T182K) variant were found in five of seven cases. By integrating these data with pathological findings, we hypothesized that cases with TP53 variants were more likely to show atypical mitotic figures. Using TCGA dataset, we found that atypical mitotic figures were associated with TP53 somatic variant, and mRNA expression of CCNB2 and AURKA was significantly high in TP53 mutated cases and atypical mitotic figure cases. CONCLUSION: We believe this is the first report that discusses the relationship between atypical mitotic figures and TP53 somatic variant in ACC. We presumed that overexpression of CCNB2 and AURKA mRNA may cause atypical mitosis in TP53 somatic mutated cases. Because AURKA is highly expressed in atypical mitotic cases, it may be an appropriate indicator for AURKA inhibitors.