Publications by authors named "Yuto Yamazaki"

75 Publications

Quantitative digital image analysis of somatostatin receptor 2 immunohistochemistry in pancreatic neuroendocrine tumors.

Med Mol Morphol 2021 Jul 10. Epub 2021 Jul 10.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan.

Immunohistochemical analysis of somatostatin receptor 2 (SSTR2) provides important information regarding the potential therapeutic efficacy of somatostatin analogues (SSAs) in patients with neuroendocrine tumors. HER2 scoring has been proposed to interpret SSTR2 immunoreactivity but their reproducibility was relatively low because of its intrinsic subjective nature. Digital image analysis (DIA) has recently been proposed as an objective and more precise method of evaluating immunoreactivity. Therefore, in this study, we used DIA for analyzing SSTR2 immunoreactivity in pancreatic neuroendocrine tumors (PanNETs) to obtain its H score and "(%) strong positive cells" and compared the results with those of manually obtained HER2 scores. Membranous SSTR2 immunoreactivity evaluated by DIA was calculated by two scales as: "Membrane Optical Density" and "Minimum Membrane Completeness". PanNETs with HER2 score of > 2 demonstrated the highest concordance with results of "(%) strong positive cells" obtained by DIA when "Minimum Membrane Completeness" was tentatively set at 80%. The SSTR2 immunoreactivity, evaluated based on all scoring systems, was different between grades G1 and G2 in insulinoma but not in non-functional PanNETs. DIA provided reproducible results of SSTR2 immunoreactivity in PanNETs and yielded important information as to the potential application of SSAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00795-021-00294-6DOI Listing
July 2021

ACTH Stimulation Maximizes the Accuracy of Peripheral Steroid Profiling in Primary Aldosteronism Subtyping.

J Clin Endocrinol Metab 2021 Jun 12. Epub 2021 Jun 12.

Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA.

Background: ACTH can contribute to aldosterone excess in primary aldosteronism (PA) via increased melanocortin type 2 receptor expression. Dynamic manipulation of the hypothalamic-pituitary-adrenal axis could assist PA subtyping, but a direct comparison of dynamic tests is lacking.

Methods: We conducted comprehensive dynamic testing in 80 patients: 40 with aldosterone-producing adenoma (APA) and 40 bilateral PA (BPA). Peripheral plasma was collected from each patient at 6 time-points: morning; midnight; after 1 mg dexamethasone suppression; and 15, 30, and 60 minutes after ACTH stimulation. We quantified 17 steroids by mass spectrometry in response to ACTH variations in all patients, and compared their discriminative power between the two PA subtypes.

Results: Patients with APA had higher morning and midnight concentrations of 18-hydroxycortisol, 18-oxocortisol, aldosterone, and 18-hydroxycorticosterone than those with BPA (p<0.001 for all). In response to cosyntropin stimulation, the APA group had larger increments of aldosterone, 18-oxocortisol, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol (p<0.05 for all). Following dexamethasone suppression, the APA group had larger decrements of aldosterone, 18-hydroxycortisol, and 18-oxocortisol (p<0.05 for all), but their concentrations remained higher than in the BPA group (p<0.01 for all). The highest discriminatory performance between the PA subtypes was achieved using steroids measured 15 minutes post-ACTH stimulation (area under receiver operating characteristic curve 0.957).

Conclusion: Steroid differences between APA and BPA are enhanced by dynamic hypothalamic-pituitary-adrenal testing; such non-invasive tests could circumvent the need for adrenal vein sampling in a subset of patients with PA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab420DOI Listing
June 2021

Cellular Senescence in Human Aldosterone-Producing Adrenocortical Cells and Related Disorders.

Biomedicines 2021 May 18;9(5). Epub 2021 May 18.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

In situ cortisol excess was previously reported to promote cellular senescence, a cell response to stress, in cortisol-producing adenomas (CPA). The aim of this study was to explore senescence pathways in aldosterone-producing cells and related disorders, and the influence of aldosterone overproduction on in situ senescence. We analyzed 30 surgical cases of aldosterone-producing adenoma (APA), 10 idiopathic hyperaldosteronism (IHA) and 19 normal adrenals (NA). CYP11B2 and senescence markers p16 and p21 were immunolocalized in all those cases above and results were correlated with histological/endocrinological findings. In the three cohorts examined, the zona glomerulosa (ZG) was significantly more senescent than other corticosteroid-producing cells. In addition, the ZG of adjacent non-pathological adrenal glands of APA and IHA had significantly higher p16 expression than adjacent non-pathological zona fasciculata (ZF), reticularis (ZR) and ZG of NA. In addition, laboratory findings of primary aldosteronism (PA) were significantly correlated with p21 status in -mutated tumors. Results of our present study firstly demonstrated that non-aldosterone-producing cells in the ZG were the most senescent compared to other cortical zones and aldosterone-producing cells in PA. Therefore, aldosterone production, whether physiological or pathological, could be maintained by suppression of cell senescence in human adrenal cortex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9050567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158118PMC
May 2021

Dysgerminoma with Estrogen-Producing Functioning Stroma Presenting Precocious Puberty.

Case Rep Pathol 2021 22;2021:5545645. Epub 2021 Apr 22.

Department of Diagnostic Pathology, Juntendo University Nerima Hospital, Tokyo, Japan.

Dysgerminoma is a malignant ovarian germ cell tumor, and unlike sex-cord stromal tumors, endocrine manifestation is considered rare. Here, we report the first case of dysgerminoma presenting precocious puberty. The patient is a 7-year-old girl who presented with a breast development in Tanner stage 3. Serum estradiol (E) was markedly elevated while luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were suppressed below the detection limit. Microscopically, the right ovarian mass displayed nests of large polygonal cells and fibrous septa which were focally concentrated by theca-like plump spindle cells. Immunohistochemistry revealed that the spindle cells expressed various steroidogenic enzymes involved in estrogen biosynthesis including P450 aromatase. The tumor was diagnosed with pure dysgerminoma with estrogen-producing functioning stroma. After the operation, serum E declined below the detection limit; LH and FSH returned within the normal range. This case demonstrates that even a conventional dysgerminoma can present endocrine manifestation through functioning stroma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/5545645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112997PMC
April 2021

Pathology of Aldosterone Biosynthesis and its Action.

Tohoku J Exp Med 2021 ;254(1):1-15

Department of Pathology, Tohoku University, Graduate School of Medicine.

Aldosterone plays pivotal roles in renin-angiotensin-aldosterone system in order to maintain the equilibrium of liquid volume and electrolyte metabolism. Aldosterone action is mediated by both mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Its excessive actions directly induced tissue injuries in its target organs such as myocardial and vascular fibrosis in addition to chronic kidney diseases. Excessive aldosterone actions were also reported to be involved in unbalanced electrolyte metabolism in inflammatory bowel disease and development of pulmonary diseases. Hyperaldosteronism is tentatively classified into primary and secondary types. Primary aldosteronism is more frequent and has been well known to result in secondary hypertension with subsequent cardiovascular damages. Primary aldosteronism is also further classified into distinctive subtypes and among those, aldosterone-producing adenoma is the most frequent one accounting for the great majority of unilateral primary aldosteronism cases. In bilateral hyperaldosteronism, aldosterone-producing diffuse hyperplasia and aldosterone-producing micronodules or nodules are the major subtypes. All these aldosterone-producing lesions were reported to harbor somatic mutations including KCNJ5, CACNA1D, ATP1A1 and ATP2B3, which were all related to excessive aldosterone production. Among those mutations above, somatic mutation of KCNJ5 is the most frequent in aldosterone-producing adenoma and mostly composed of clear cells harboring abundant aldosterone synthase expression. In contrast, CACNA1D-mutated aldosterone-producing micronodules or aldosterone-producing nodules were frequently detected not only in primary aldosteronism patients but also in the zona glomerulosa of normal adrenal glands, which could eventually lead to an autonomous aldosterone production resulting in normotensive or overt primary aldosteronism, but their details have remained unknown.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1620/tjem.254.1DOI Listing
January 2021

Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.

Endocr J 2021 May 18. Epub 2021 May 18.

Department of Health Promotion and Medicine of the Future, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa 920-8641, Japan.

The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis. In the first case, back pain was the trigger; while in the second case, the triggers were low fever and weight loss. Metabolic abnormalities such as hypertension and obesity were not detected in either case. Neither patient had relevant previous medical histories, including malignancy. However, both had a long-term history of smoking. Systemic imaging studies revealed only adrenal tumors and surrounding lesions. Primary adrenocortical carcinoma was initially suspected, and chemotherapy including mitotane was considered. However, due to difficulty in complete resection of the tumor, core needle tumor biopsies were performed. Histopathological examination of biopsy specimens led to the diagnosis of carcinoma of unknown primary origin with isolated adrenal metastasis. In both cases, additional laboratory testing showed high levels of serum squamous cell carcinoma-related antigen and serum cytokeratin fragment. Malignant lesions confined to the adrenal glands are rare. As in our cases, it could be occasionally difficult to differentiate non-functioning primary adrenocortical carcinoma from metastatic adrenal carcinoma of unknown primary origin localized to the adrenal gland. If the lesion is unresectable and there are elevated levels of several tumor markers with no apparent hormonal excess, core needle tumor biopsy should be considered to differentiate the primary tumor from the metastatic tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.EJ21-0141DOI Listing
May 2021

Recent Development toward the Next Clinical Practice of Primary Aldosteronism: A Literature Review.

Biomedicines 2021 Mar 17;9(3). Epub 2021 Mar 17.

Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.

For the last seven decades, primary aldosteronism (PA) has been gradually recognized as a leading cause of secondary hypertension harboring increased risks of cardiovascular incidents compared to essential hypertension. Clinically, PA consists of two major subtypes, surgically curable and uncurable phenotypes, determined as unilateral or bilateral PA by adrenal venous sampling. In order to further optimize the treatment, surgery or medications, diagnostic procedures from screening to subtype differentiation is indispensable, while in the general clinical practice, the work-up rate is extremely low even in the patients with refractory hypertension because of the time-consuming and labor-intensive nature of the procedures. Therefore, a novel tool to simplify the diagnostic flow has been recently in enormous demand. In this review, we focus on recent progress in the following clinically important topics of PA: prevalence of PA and its subtypes, newly revealed histopathological classification of aldosterone-producing lesions, novel diagnostic biomarkers and prediction scores. More effective strategy to diagnose PA based on better understanding of its epidemiology and pathology should lead to early detection of PA and could decrease the cardiovascular and renal complications of the patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines9030310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002562PMC
March 2021

Steroidogenic Activity in Unresected Adrenals Associated With Surgical Outcomes in Primary Aldosteronism.

Hypertension 2021 May 29;77(5):1638-1646. Epub 2021 Mar 29.

Endocrinology and Diabetes Center (K.N., Y.T., K.I., J.S., T.N.), Yokohama Rosai Hospital, Japan.

[Figure: see text].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16335DOI Listing
May 2021

Coincidence of Large Adrenal Cyst and Prominent Hyporeninemic Hyperaldosteronism.

Case Rep Endocrinol 2021 20;2021:8860498. Epub 2021 Feb 20.

Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism. Histological examination of the resected tumor with anti-CYP11B2 antibody indicated that she had a vascular endothelial cyst with primary aldosteronism (PA) due to multiple adrenocortical micronodules. This report implicates the pathological interaction between adrenal vascular cysts and PA-mediated vascular damage of the adrenal vein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/8860498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914103PMC
February 2021

The Genotype-Based Morphology of Aldosterone-Producing Adrenocortical Disorders and Their Association with Aging.

Endocrinol Metab (Seoul) 2021 Feb 24;36(1):12-21. Epub 2021 Feb 24.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosteroneproducing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3803/EnM.2021.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937858PMC
February 2021

Physical and Chemical Relationships in Accelerated Carbonation Conditions of Alkali-Activated Cement Based on Type of Binder and Alkali Activator.

Polymers (Basel) 2021 Feb 23;13(4). Epub 2021 Feb 23.

Department of Civil Engineering and Architecture, Muroran Institute of Technology, Hokkaido 050-8585, Japan.

Alkali-activated cements prepared from aluminosilicate powders, such as blast furnace slag and fly ash, are rapidly attracting attention as alternatives to cement because they can significantly reduce CO emissions compared to conventional cement concrete. In this study, we investigated the relationship between the physical and chemical changes by accelerated carbonation conditions of alkali-activated cements. Alkali-activated cements were prepared from binders composed of blast furnace slag and fly ash as well as alkali activators sodium silicate and sodium hydroxide. Physical changes were analyzed from compressive strength, pH, and neutralization depth, and chemical changes were analyzed from XRD, TG-DTG, and Si MAS NMR. The C-(N)-A-S-H structure is noted to change via carbonation, and the compressive strength is observed to decrease. However, in the case of Na-rich specimens, the compressive strength does not decrease by accelerated carbonation. This work is expected to contribute to the field of alkali-activated cements in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/polym13040671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926754PMC
February 2021

The Potential of Computed Tomography Volumetry for the Surgical Treatment in Bilateral Macronodular Adrenal Hyperplasia: A Case Report.

Tohoku J Exp Med 2021 02;253(2):143-150

Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Hospital.

Although adrenal resection is a major option to control hypercortisolemia in patients with bilateral macronodular adrenal hyperplasia, a predictive method for postoperative cortisol production has not been established. A 53-year-old man with ulcerative colitis was referred to our hospital for bilateral multiple adrenal nodules and hypertension. Physical and endocrinological examination revealed inappropriate cortisol production and suppressed secretion of adrenocorticotropic hormone with no typical signs of Cushing's syndrome. Imaging analysis revealed bilateral adrenal nodular enlargement, the nodules of which had the radiological features of adrenocortical adenomas without inter-nodular heterogeneity. In addition, computed tomography volumetry demonstrated that the left adrenal gland (70 mL) accounts for three quarters of the total adrenal volume (93 mL). The patient was diagnosed as subclinical Cushing's syndrome due to bilateral macronodular adrenal hyperplasia, and subsequently underwent a left laparoscopic adrenalectomy with the estimation of 75% decrease in the cortisol level based on the adrenal volume. The surgical treatment ultimately resulted in control of the cortisol level within the normal range, which was compatible to our preoperative prediction. However, regardless of the sufficient cortisol level, ulcerative colitis was exacerbated after the surgery, which needed a systemic therapy for remission. This case indicates successful surgical control of hypercortisolemia based on computed tomography volumetry in bilateral macronodular adrenal hyperplasia, as well as the perioperative exacerbation risk for inflammatory diseases in Cushing's syndrome. We report the potential utility of computed tomography volumetry as a quantitative method with retrospective evaluation of our historical cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1620/tjem.253.143DOI Listing
February 2021

A case of adrenocortical adenoma harboring venous thrombus mimicking adrenal malignancy.

Endocr J 2021 Mar 4. Epub 2021 Mar 4.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.

Advances in imaging technology and its widespread use have increased the number of identified patients with bilateral adrenal incidentalomas. The pathology of bilateral adrenal incidentalomas is gradually elucidated by its increased frequency. Although there is no consensus regarding the optimal management of bilateral adrenal lesions, adrenal lesions that are a suspected adrenocortical carcinoma on the basis of radiological imaging require surgical resection. We report a clinically interesting case of a 59-year-old female with adrenocortical adenoma harboring venous thrombus that mimicked adrenal malignancy. She was referred for evaluation of asymptomatic asymmetric lesions on both adrenal glands. Abdominal computed tomography and magnetic resonance imaging showed a 4.7-cm-diameter heterogenous lesion with peripheral enhancement in the right adrenal gland and a 2.0-cm-diameter homogenous lesion in the left adrenal gland. Adrenal scintigraphy with I-adosterol exhibited marked accumulation in the left lesion and slight accumulation in the middle inferior portion of the right lesion. Endocrine data revealed subclinical Cushing syndrome, and the patient underwent right laparoscopic adrenalectomy. The serum cortisol level was not suppressed on an overnight dexamethasone suppression test after the adrenalectomy. The resected tumor revealed a cortisol-producing adrenocortical adenoma harboring an organized and re-canalized venous thrombus, which was associated with focal papillary endothelial hyperplasia. This case illustrates the difficulty with preoperatively diagnosing this heterogeneously enhanced large benign adrenal lesion and differentiating it from adrenocortical carcinoma or angiosarcoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1507/endocrj.EJ20-0667DOI Listing
March 2021

Primary aldosteronism due to bilateral micronodular hyperplasia and concomitant subclinical Cushing's syndrome: A case report.

World J Clin Cases 2021 Feb;9(5):1119-1126

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.

Background: Adrenal incidentaloma (AI) has been frequently encountered in the clinical setting. It has been shown that primary aldosteronism (PA) or subclinical Cushing's syndrome (SCS) are the representative causative diseases of AI. However, the coexistence of PA and SCS has been reportedly observed. Recently, we encountered a case of AI, in which PA and SCS coexisted, confirmed by histopathological examinations after a laparoscopic adrenalectomy. We believe that there were some clinical implications in the diagnosis of the present case.

Case Summary: A 58-year-old man presented with lower right abdominal pain with a blood pressure of 170/100 mmHg. A subsequent computed tomography scan revealed right ureterolithiasis, which was the cause of right abdominal pain, and right AI measuring 22 mm × 25 mm. After the disappearance of right abdominal pain, subsequent endocrinological examinations were performed. Aldosterone-related evaluations, including adrenal venous sampling, revealed the presence of bilateral PA. In addition, several cortisol-related evaluations showed the presence of SCS on the right adrenal adenoma. A laparoscopic right adrenalectomy was then performed. The histopathological examination of the resected right adrenal revealed the presence of a cortisol-producing adenoma, while CYP11B2 immunoreactivity was absent in this adenoma. However, in the adjacent non-neoplastic adrenal, multiple CYP11B2-positive adrenocortical micronodules were detected, showing the presence of aldosterone-producing adrenocortical micronodules.

Conclusion: Careful clinical and pathological examination should be performed when a patient harboring AI presents with concomitant SCS and PA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12998/wjcc.v9.i5.1119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896658PMC
February 2021

Gender differences in human adrenal cortex and its disorders.

Mol Cell Endocrinol 2021 04 11;526:111177. Epub 2021 Feb 11.

Department of Pathology, Tohoku University Graduate School of Medicine, Japan. Electronic address:

The adrenal cortex plays pivotal roles in the maintenance of blood volume, responsiveness to stress and the development of gender characteristics. Gender differences of human adrenal cortex have been recently reported and attracted increasing interests. Gender differences occur from the developing stage of the adrenal, in which female subjects had more activated stem cells with higher renewal capacity resulting in gender-associated divergent structures and functions of cortical zonations of human adrenal. Female subjects generally have the lower blood pressure with the lower renin levels and ACE activities than male subjects. In addition, HPA axis was more activated in female than male, which could possibly contribute to gender differences in coping with various stressful events in our life. Of particular interest, estrogens were reported to suppress RAAS but activate HPA axis, whereas androgens had opposite effects. In addition, adrenocortical disorders in general occur more frequently in female with more pronounced adrenocortical hormonal abnormalities possibly due to their more activated WNT and PRK signaling pathways with more abundant activated adrenocortical stem cells present in female adrenal glands. Therefore, it has become pivotal to clarify the gender influence on both clinical and biological features of adrenocortical disorders. We herein reviewed recent advances in these fields.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mce.2021.111177DOI Listing
April 2021

Novel genetic characteristics of multifocal micronodular pneumocyte hyperplasia (MMPH): a case report with frequent BRAF mutations analyzed by next-generation sequencing supporting benign behaviors of MMPH.

Virchows Arch 2021 Jan 14. Epub 2021 Jan 14.

Department of Anatomic Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

A woman in her 30s, who was clinically diagnosed with tuberous sclerosis complex, underwent lung transplantation due to lymphangioleiomyomatosis with concomitant multifocal micronodular pneumocyte hyperplasia (MMPH). Histologically, MMPH lesions demonstrated variety in histology; some showed homogenous cells with mild nuclear atypia and elastic fibers proliferation, and the others showed enlarged nuclei without elastic fibers. Because the natural history of MMPH is not well characterized, we used next-generation sequencing to perform a comprehensive genetic analysis for the MMPH lesions to explore their malignant potential. Regardless of their histological variety, three of four lesions had BRAF missense mutations, especially the types frequently detected in atypical adenomatous hyperplasia that is considered to be benign rather than a precursor of adenocarcinoma. None of them had major driver mutations of lung adenocarcinoma, except for BRAF mutations. In conclusion, our study of the lesions from this patient indicated the benign characteristic of MMPH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-020-03013-1DOI Listing
January 2021

A case of renovascular hypertension with incidental primary bilateral macronodular adrenocortical hyperplasia.

Endocrinol Diabetes Metab Case Rep 2020 Aug 6;2020. Epub 2020 Aug 6.

Division of Endocrinology and Hypertension, Department of Cardiovascular and Internal Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.

Summary: Renovascular hypertension (RVHT) is an important and potentially treatable form of resistant hypertension. Hypercortisolemia could also cause hypertension and diabetes mellitus. We experienced a case wherein adrenalectomy markedly improved blood pressure and plasma glucose levels in a patient with RVHT and low-level autonomous cortisol secretion. A 62-year-old Japanese man had been treated for hypertension and diabetes mellitus for 10 years. He was hospitalized because of a disturbance in consciousness. His blood pressure (BP) was 236/118 mmHg, pulse rate was 132 beats/min, and plasma glucose level was 712 mg/dL. Abdominal CT scanning revealed the presence of bilateral adrenal masses and left atrophic kidney. Abdominal magnetic resonance angiography demonstrated marked stenosis of the left main renal artery. The patient was subsequently diagnosed with atherosclerotic RVHT with left renal artery stenosis. His left adrenal lobular mass was over 40 mm and it was clinically suspected the potential for cortisol overproduction. Therefore, laparoscopic left nephrectomy and adrenalectomy were simultaneously performed, resulting in improved BP and glucose levels. Pathological studies revealed the presence of multiple cortisol-producing adrenal nodules and aldosterone-producing cell clusters in the adjacent left adrenal cortex. In the present case, the activated renin-angiotensin-aldosterone system and cortisol overproduction resulted in severe hypertension, which was managed with simultaneous unilateral nephrectomy and adrenalectomy.

Learning Points: Concomitant activation of the renin-angiotensin-aldosterone system and cortisol overproduction may contribute to the development of severe hypertension and lead to lethal cardiovascular complications. Treatment with simultaneous unilateral nephrectomy and adrenalectomy markedly improves BP and blood glucose levels. CYP11B2 immunohistochemistry staining revealed the existence of aldosterone-producing cell clusters (APCCs) in the adjacent non-nodular adrenal gland, suggesting that APCCs may contribute to aldosterone overproduction in patients with RVHT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EDM-19-0163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424347PMC
August 2020

A case of Williams syndrome with suspected coexisting ectopic aldosterone-producing tumor in the liver.

Endocrinol Diabetes Metab Case Rep 2020 Sep 23;2020. Epub 2020 Sep 23.

Departments of Diabetes and Endocrinology, Sapporo City General Hospital, Sapporo, Japan.

Summary: A 31-year-old man with Williams syndrome (WS) was referred to our hospital because of a 9-year history of hypertension, hypokalemia, and high plasma aldosterone concentration to renin activity ratio. A diagnosis of primary aldosteronism (PA) was clinically confirmed but an abdominal CT scan showed no abnormal findings in his adrenal glands. However, a 13-mm hypervascular tumor in the posterosuperior segment of the right hepatic lobe was detected. Adrenal venous sampling (AVS) subsequently revealed the presence of an extended tributary of the right adrenal vein to the liver surrounding the tumor. Segmental AVS further demonstrated a high plasma aldosterone concentration (PAC) in the right superior tributary vein draining the tumor. Laparoscopic partial hepatectomy was performed. The resected tumor histologically separated from the liver was composed of clear cells, immunohistochemically positive for aldesterone synthase (CYP11B2), and subsequently diagnosed as aldosterone-producing adrenal adenoma. After surgery, his blood pressure, serum potassium level, plasma renin activity and PAC were normalized. To the best of our knowledge, this is the first report of WS associated with PA. WS harbors a high prevalence of hypertension and therefore PA should be considered when managing the patients with WS and hypertension. In this case, the CT findings alone could not differentiate the adrenal rest tumor. Our case, therefore, highlights the usefulness of segmental AVS to distinguish adrenal tumors from hepatic adrenal rest tumors.

Learning Points: Williams syndrome (WS) is a rare genetic disorder, characterized by a constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension. WS is a disease with a high frequency of hypertension but the renin-aldosterone system in WS cases has not been studied at all. If a patient with WS had hypertension and severe hypokalemia, low PRA and high ARR, the coexistence of primary aldosteronism (PA) should be considered. Adrenal rest tumors are thought to arise from aberrant adrenal tissues and are a rare cause of PA. Hepatic adrenal rest tumor (HART) should be considered in the differential diagnosis when detecting a mass in the right hepatic lobe. Segmental adrenal venous sampling could contribute to distinguish adrenal tumors from HART.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EDM-20-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576637PMC
September 2020

A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.

J Endocr Soc 2021 Feb 27;5(2):bvaa184. Epub 2020 Nov 27.

Department of Endocrinology, Metabolism and Diabetes, Kindai University Faculty of Medicine, Osaka, Japan.

Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvaa184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751009PMC
February 2021

O-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms.

BMC Cancer 2020 Dec 7;20(1):1195. Epub 2020 Dec 7.

Department of Pathology, Tohoku University, Graduate School of Medicine, Sendai, Miyagi, 980-8575, Japan.

Background: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ.

Methods: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs).

Results: In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = - 0.4570; MGMT score: P = 0.0064, ρ = - 0.4399; H-score: P = 0.0110, ρ = - 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy.

Conclusion: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07579-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720403PMC
December 2020

Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma.

Front Endocrinol (Lausanne) 2020 10;11:587779. Epub 2020 Nov 10.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Pheochromocytomas (PHEOs) are relatively rare catecholamine-producing tumors derived from adrenal medulla. Tumor microenvironment (TME) including neoangiogenesis has been explored in many human neoplasms but not necessarily in PHEOs. Therefore, in this study, we examined tumor infiltrating lymphocytes (CD4 and CD8), tumor associated macrophages (CD68 and CD163), sustentacular cells (S100p), and angiogenic markers (CD31 and areas of intratumoral hemorrhage) in 39 cases of PHEOs in the quantitative fashion. We then compared the results with pheochromocytoma of the adrenal gland scaled score (PASS), grading system for pheochromocytoma and paraganglioma (GAPP) and the status of intra-tumoral catecholamine-synthesizing enzymes (TH, DDC, and PNMT) as well as their clinicopathological factors. Intratumoral CD8 (p = 0.0256), CD31 (p = 0.0400), and PNMT (p = 0.0498) status was significantly higher in PHEOs with PASS <4 than PASS ≧4. In addition, intratumoral CD8 lymphocytes were also significantly more abundant in well-than moderately differentiated PHEO according to GAPP score (p = 0.0108) and inversely correlated with tumor size (p = 0.0257). Intratumoral CD68 cells were significantly higher in PHEOs with regular or normal histological patterns than those not (p = 0.0370) and inversely correlated with tumor size (p = 0.0457). The status of CD163 was significantly positively correlated with that of CD8 positive cells (p = 0.0032). The proportion of intratumoral hemorrhage areas was significantly higher in PHEOs with PASS ≧4 (p = 0.0172). DDC immunoreactivity in tumor cells was significantly positively correlated with PASS score (p = 0.0356) and TH status was significantly higher in PHEOs harboring normal histological patterns (p = 0.0236) and cellular monotony (p = 0.0219) than those not. Results of our present study did demonstrate that abundant CD8 and CD68 cells could represent a histologically low-scored tumor. In particular, PHEOs with increased intratumoral hemorrhage should be considered rather malignant. In addition, abnormal catecholamine-producing status of tumor cells such as deficient PNMT and TH and increased DDC could also represent more aggressive PHEOs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.587779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685215PMC
May 2021

Steroid metabolites for diagnosing and predicting clinicopathological features in cortisol-producing adrenocortical carcinoma.

BMC Endocr Disord 2020 Nov 23;20(1):173. Epub 2020 Nov 23.

Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Approximately 60% of adrenocortical carcinomas (ACC) are functional, and Cushing's syndrome is the most frequent diagnosis that has been revealed to have a particularly poor prognosis. Since 30% of ACC present steroid hormone-producing disorganization, measurement of steroid metabolites in suspected ACC is recommended. Previous reports demonstrated that steroid hormone precursors or their urine metabolites, which can be assessed using liquid chromatography tandem mass spectrometry (LC-MS/MS) or gas chromatography mass spectrometry (GC-MS) respectively, are useful for distinguishing ACC from cortisol-producing adenomas (CPA); however, despite high precision, LC-MS/MS and GC-MS require a highly trained team, are expensive and have limited capacity.

Methods: Here, we examined 12 serum steroid metabolites using an immunoassay, which is a more rapid and less costly method than LC-MS/MS, in cortisol-producing ACC and CPA. Further, the correlation of each steroid metabolite to the classification stage and pathological status in ACC was analyzed.

Results: Reflecting disorganized steroidogenesis, the immunoassay revealed that all basal levels of steroid precursors were significantly increased in cortisol-producing ACC compared to CPA; in particular, 17-hydroxypregnenolone (glucocorticoid and androgen precursor) and 11-deoxycorticosterone (mineralocorticoid precursor) showed a large area under the ROC curve with high sensitivity and specificity when setting the cut-off at 1.78 ng/ml and 0.4 mg/ml, respectively. Additionally, a combination of androstenedione and DHEAS also showed high specificity with high accuracy. In cortisol-producing ACC, 11-deoxycortisol (glucocorticoid precursor) showed significant positive correlations with predictive prognostic factors used in ENSAT classification, while testosterone showed significant positive correlations to the Ki67-index in both men and women.

Conclusion: Less expensive and more widely available RIA and ECLIA may also biochemically distinguish ACC from CPA and may predict the clinicopathological features of ACC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12902-020-00652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686776PMC
November 2020

Recent Advances in Histopathological and Molecular Diagnosis in Pheochromocytoma and Paraganglioma: Challenges for Predicting Metastasis in Individual Patients.

Front Endocrinol (Lausanne) 2020 27;11:587769. Epub 2020 Oct 27.

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Pheochromocytomas and paragangliomas (PHEO/PGL) are rare but occasionally life-threatening neoplasms, and are potentially malignant according to WHO classification in 2017. However, it is also well known that histopathological risk stratification to predict clinical outcome has not yet been established. The first histopathological diagnostic algorithm for PHEO, "PASS", was proposed in 2002 by Thompson et al. Another algorithm, GAPP, was then proposed by Kimura et al. in 2014. However, neither algorithm has necessarily been regarded a 'gold standard' for predicting post-operative clinical behavior of tumors. This is because the histopathological features of PHEO/PGL are rather diverse and independent of their hormonal activities, as well as the clinical course of patients. On the other hand, recent developments in wide-scale genetic analysis using next-generation sequencing have revealed the molecular characteristics of pheochromocytomas and paragangliomas. More than 30%-40% of PHEO/PGL are reported to be associated with hereditary genetic abnormalities involving > 20 genes, including , and others. Such genetic alterations are mainly involved in the pathogenesis of pseudohypoxia, , and kinase signaling, and other intracellular signaling cascades. In addition, recurrent somatic mutations are frequently detected and overlapped with the presence of genetic alterations associated with hereditary diseases. In addition, therapeutic strategies specifically targeting such genetic abnormalities have been proposed, but they are not clinically applicable at this time. Therefore, we herein review recent advances in relevant studies, including histopathological and molecular analyses, to summarize the current status of potential prognostic factors in patients with PHEO/PGL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.587769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652733PMC
May 2021

Intratumoral heterogeneity of the tumor cells based on in situ cortisol excess in cortisol-producing adenomas; ∼An association among morphometry, genotype and cellular senescence∼.

J Steroid Biochem Mol Biol 2020 11 28;204:105764. Epub 2020 Sep 28.

Department of Pathology, Tohoku University Graduate School of Medicine, Japan. Electronic address:

Cortisol-producing adrenocortical adenomas (CPAs) are associated with ACTH-independent Cushing's syndrome and histologically composed of two cellular subtypes: compact (lipid-poor) and clear (lipid-rich) tumor cells. However, the details of hormonal and biological activities of these tumor cells have remained unknown, especially in CPAs. CPAs frequently harbored unique histological features different from those of aldosterone-producing adenomas (APAs) including a senescent phenotype. Therefore, we explored the association between morphological features and the immunoreactivity of steroidogenic enzymes in CPAs with different genotypes and compared them with cellular senescence markers as well as clinicopathological factors of the cases. Hormonal activities (3βHSD, CYP21A, CYP17A1, CYP11B1 and DHEA-ST) and cellular senescence markers (p16, p21 and Ki-67) within different morphological features (clear and compact) were evaluated in 40 CPAs. CPA genotypes (PRKACA, GNAS and CTNNB1) were examined by Sanger sequencing and then compared them with the factors above. p21 immunoreactivity was significantly positively correlated with that of CYP21A (p = 0.0110), CYP17A1 (p = 0.0356) and DHEA-ST (p = 0.0420) but inversely with tumor size (p = 0.0015). CYP21A (p = 0.0016), CYP11B1 (p = 0.0001), CYP17A1 (p < 0.0001) and p16 (p = 0.0137) immunoreactivity were all significantly higher in compact cells than those in clear cells. CYP17A1 (p = 0.0056) and 3βHSD (p = 0.0437) immunoreactivity was significantly higher in PRKACA-mutated than wild type CPAs. p16 immunoreactivity and serum DHEA-S level were both significantly higher in GNAS-mutated than PRKACA-mutated (p = 0.0250) and wild type (p = 0.0180) CPAs. Results of our present study did demonstrate that compact tumor cells were hormonally active and more senescent than clear tumor cells in CPAs. PRKACA- and GNAS-mutated tumor cells were more hormonally active and senescent than those without mutations despite the similar morphological features. We herein proposed a novel histological classification of the tumor cell subtypes based on in situ cortisol excess, genotypes and the status of cell senescence in CPAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsbmb.2020.105764DOI Listing
November 2020

Epstein-Barr virus-associated enteritis with multiple ulcers: The first autopsy case.

Pathol Int 2020 Nov 7;70(11):899-905. Epub 2020 Sep 7.

Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Epstein-Barr virus (EBV)-associated enteritis is extremely rare and has not been well characterized. Herein, we present the first autopsy case of EBV-associated enteritis with multiple ulcers in a 73-year-old Japanese male. The patient had abdominal pain and was clinically diagnosed with enteritis. An endoscopic examination revealed multiple ulcers at the terminal ileum. His condition worsened due to serosanguinous bowel discharge and the patient was then admitted to the hospital. Ileocecal and subtotal small intestinal resection was performed for repetitive hemorrhage from ulcers. However, the patient died due to uncontrolled hemorrhage. An autopsy was then performed in order to explore the cause of ulcers in the small intestine. Macroscopic findings revealed multiple ulcers with occasional cobblestone-like appearance of the ileum. Histological analysis revealed marked infiltration of lymphocytes and plasma cells around the ulcer. EBV-encoded RNA in situ hybridization (EBER-ISH) revealed positive inflammatory cells. Cytomegalovirus was immunohistochemically negative. Macroscopic and microscopic findings obtained from autopsy specimens showed no foci of inflammation and EBER-ISH-positive stromal cells in the esophagus, stomach, and colorectum. EBV-associated enteritis can cause uncontrolled repetitive hemorrhage from ulcers and result in critical condition of the patient, which can be used for differential diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pin.13013DOI Listing
November 2020

Prevalence of Somatic Mutations in Aldosterone-Producing Adenomas in Japanese Patients.

J Clin Endocrinol Metab 2020 11;105(11)

Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Context: Results of previous studies demonstrated clear racial differences in the prevalence of somatic mutations among patients with aldosterone-producing adenoma (APA). For instance, those in East Asian countries have a high prevalence of somatic mutations in KCNJ5, whereas somatic mutations in other aldosterone-driving genes are rare.

Objectives: To determine somatic mutation prevalence in Japanese APA patients using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach.

Method: Patients with a unilateral form of primary aldosteronism who underwent adrenalectomy at the Tohoku University Hospital were studied. Based on CYP11B2 immunolocalization of resected adrenals, genomic DNA was isolated from the relevant positive area of 10% formalin-fixed, paraffin-embedded tissue of the APAs. Somatic mutations in aldosterone-driving genes were studied in APAs by direct Sanger sequencing and targeted next-generation sequencing.

Results: CYP11B2 IHC-guided sequencing determined APA-related somatic mutations in 102 out of 106 APAs (96%). Somatic KCNJ5 mutation was the most frequent genetic alteration (73%) in this cohort of Japanese patients. Somatic mutations in other aldosterone-driving genes were also identified: CACNA1D (14%), ATP1A1 (5%), ATP2B3 (4%), and CACNA1H (1%), including 2 previously unreported mutations. KCNJ5 mutations were more often detected in APAs from female patients compared with those from male patients [95% (36/38) vs 60% (41/68); P < 0.0001].

Conclusion: IHC-guided sequencing defined somatic mutations in over 95% of Japanese APAs. While the dominance of KCNJ5 mutations in this particular cohort was confirmed, a significantly higher KCNJ5 prevalence was detected in female patients. This study provides a better understanding of genetic spectrum of Japanese APA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947976PMC
November 2020

International Histopathology Consensus for Unilateral Primary Aldosteronism.

J Clin Endocrinol Metab 2021 Jan;106(1):42-54

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Germany.

Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA).

Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals.

Patients And Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists.

Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists.

Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765663PMC
January 2021

-Mediated Gene Deletion and Loss of Heterozygosity in a Patient with Multiple Endocrine Neoplasia Type 1.

J Endocr Soc 2020 Aug 9;4(8):bvaa051. Epub 2020 May 9.

Department of Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder caused by mutations of the tumor suppressor gene . Most of the germline gene mutations have been small mutations, and the whole gene deletion is rarely observed. In the present study, we revealed retrotransposon-mediated germline deletion of the whole gene and somatic copy-neutral loss of heterozygosity (LOH) in a patient with MEN1. The patient is a 39-year-old woman who was referred to our department for the management of prolactinoma. She was also diagnosed with primary hyperparathyroidism and suspected of MEN1. Although nucleotide sequencing did not detect any gene mutations, multiplex ligation-dependent probe amplification (MLPA) revealed a large germline deletion of the gene. Subsequent quantitative polymerase chain reaction (qPCR)-based copy number mapping showed a monoallelic loss of approximately 18.5-kilobase region containing the whole gene. Intriguingly, the 2 breakpoints were flanked by repetitive elements, suggesting the contribution of /-mediated rearrangements (AAMR) to the whole gene deletion. Furthermore, copy number mapping using MLPA and qPCR in combination with single nucleotide polymorphism analysis revealed copy-neutral LOH as a somatic event for parathyroid tumorigenesis. In conclusion, copy number mapping revealed a novel combination of /-mediated germline deletion of the gene and somatic copy-neutral LOH as a cytogenetic basis for the MEN1 pathogenesis. Moreover, subsequent in silico analysis highlighted the possible predisposition of the gene to retrotransposon-mediated genomic deletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jendso/bvaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371388PMC
August 2020

Expression of Key Androgen-Activating Enzymes in Ovarian Steroid Cell Tumor, Not Otherwise Specified.

J Investig Med High Impact Case Rep 2020 Jan-Dec;8:2324709620933416

Tidelands Health Group, Myrtle Beach, SC, USA.

To characterize the expression of steroidogenic enzymes implicated in the development of ovarian steroid cell tumors, not otherwise specified (SCT-NOS). We present 4 ovarian SCT-NOS evaluated by immunohistochemical staining of steroidogenic enzymes as an approach to define this entity pathologically. All 4 ovarian SCT-NOS showed increased expression for cholesterol side-chain cleavage enzyme (CYP11A1), 17α-hydroxylase (CYP17A1), 17β-hydroxysteroid dehydrogenase 1 (HSD17B1), aldo-ketoreductase type 1 C3 (AKR1C3), 3β-hydroxysteroid dehydrogenase 2 (HSD3B2), 5α-reductase type 2 (SRD5A2), steroid sulfatase (SULT2A1), estrogen sulfotransferase (EST), and aromatase (CYP19A1). Expression was negative for 21-hydroxylase (CYP21A2) and 17β-hydroxysteroid dehydrogenase 2 (HSD17B2). 17β-hydroxysteroid dehydrogenase 3 (HSD17B3) and 5α-reductase type 1 (SRD5A1) showed variable expression. Our analysis reveals a novel finding of increased expression of AKR1C3, HSD17B1, SRD5A2, SULT2A1, and EST in ovarian SCT-NOS, which is clinically associated with androgen excess and virilization. Further studies are needed to validate these enzymes as new markers in the evaluation of hyperandrogenic ovarian conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2324709620933416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323262PMC
June 2021