Pre- and peri-operative characteristics, complications and outcomes of patients with biochemically silent pheochromocytomas; a case series.

PURPOSE: Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are poorly investigated. We aimed to systematically assess the pre- and peri-operative characteristics and the outcomes of patients with these tumors who had been treated and followed-up in 2 tertiary centers. METHODS: Clinical, laboratory and imaging data, treatment outcomes and follow-up of biochemically silent pheochromocytoma patients were recorded. RESULTS: Ten patients (5 men) [median age at diagnosis 52.5 years (24-72)] were included. Adrenal masses were incidentally discovered in all patients except from one who presented with pheochromocytoma-related manifestations. Twenty-four-hour urine metanephrine and normetanephrine levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. Tumors were unilateral [median size 46 mm (17-125)] and high density on pre-contrast CT imaging or high signal intensity on T2-weighted MRI scans were found in all cases. Pre-operatively, 5 patients were treated with phenoxybenzamine [median total daily dose 70 mg (20-100)]. Intra-operatively, 4 patients developed hypertension requiring vasodilator administration and 8 developed hypotension; vasoconstrictors were required in 5 cases. One patient, not pre-operatively treated with phenoxybenzamine, developed Takotsubo cardiomyopathy. During a median 24-month (12-88) follow-up period, one patient had disease progression. CONCLUSIONS: The majority (90%) of patients with biochemically silent pheochromocytomas developed hemodynamic instability during adrenal surgery. In patients with biochemically silent adrenal lesions and a high suspicion index for pheochromocytoma based on tumor imaging characteristics, pre-operative alpha-blockade treatment may be advisable.

Thyroid Paraganglioma With Medullary Carcinoma: A Unique Combination in a Patient in Association With Multiple Endocrine Neoplasia Type 2B Syndrome With Prolonged Survival.

Head and neck paragangliomas (PGLs) most commonly derive from the carotid body, jugulotympanic, vagal, and laryngeal paraganglia. Thyroid PGLs originate in the inferior laryngeal paraganglion, which may lie inside the thyroid parenchyma. Intrathyroid PGLs are rare with approximately 75 cases reported to date, mostly as solitary lesions. The coexistence of thyroid PGL with medullary thyroid carcinoma (MTC) has not been reported. Here, we report a unique case of intrathyroid PGL concomitant with MTC in the context of multiple endocrine neoplasia type 2B syndrome. Interestingly, the patient showed a prolonged survival with good clinical response to tyrosine kinase inhibitors, despite her advanced metastatic MTC. We discuss the challenges in pathology, differential diagnosis, and genetic background for the development of these thyroid lesions.

A very rare case of extranodal B-cell non-Hodgkin lymphoma presenting with adrenal and heart involvement.

We report an extremely rare case of extranodal B-cell NHL: DLBCL (diffuse large B-cell non-Hodgkin lymphoma), stage IVE, presenting with heart and bilateral adrenal involvement. On admission, adrenal and thorax imaging identified large bilateral adrenal masses and a 4.6 cm mass in the right atrium wall. An adrenal biopsy revealed the presence of a DLBCL, with triple expression of bcl2, bcl6, C-MYC(+70%). Following six cycles of systemic immunochemotherapy with R-DA-EPOCH, and high methotrexate dose for CNS prophylaxis a marked decrease of lymphoma infiltration was observed. The selection of the appropriate treatment modality can lead to profound response and improve patient's outcome.

Juxtaglomerular cell tumour of the kidney: a rare cause of resistant hypertension.

SUMMARY: Juxtaglomerular cell tumour (JGCT) is an unusually encountered clinical entity. A 33-year-old man with severe long-standing hypertension and hypokalaemia is described. The patient also suffered from polyuria, polydipsia, nocturia and severe headaches. On admission, laboratory investigation revealed hypokalaemia, kaliuresis, high aldosterone and renin levels, and the abdomen CT identified a mass of 4 cm at the right kidney. Kidney function was normal. Following nephrectomy, the histological investigation revealed the presence of a JGCT. Immunostaining was positive for CD34 as well as for smooth muscle actin and vimentin. Following surgery, a marked control of his hypertension with calcium channel blockers and normalization of the serum potassium, renin or aldosterone levels were reached. According to our findings, JGCT could be included in the differential diagnosis of secondary hypertension as it consists of a curable cause. The association of JGCT with hypertension and hypokalaemia focusing on the clinical presentation, diagnostic evaluation and management is herein discussed and a brief review of the existing literature is provided. LEARNING POINTS: Juxtaglomerular cell tumours (JGCT), despite their rarity, should be included in the differential diagnosis of secondary hypertension as they consist of a curable cause of hypertension. JGCT could be presented with resistant hypertension along with hypokalaemia, kaliuresis and metabolic alkalosis. Early recognition and management can help to prevent cardiovascular complications. Imaging (enhanced CT scans) may be considered as the primary diagnostic tool for the detection of renal or JGCT. For the confirmation of the diagnosis, a histopathologic examination is needed.

Diabetic ketoacidosis in patients treated with SGLT2 inhibitors: experience at a tertiary hospital.

PURPOSE: Diabetic ketoacidosis (DKA) is a rare and life-threatening complication in patients with diabetes. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have rarely been associated with ketoacidosis. The aim of this retrospective study was to investigate DKA episodes occurring after SGLT2i treatment and to compare them to DKA episodes due to other causes. METHODS: The medical records of the years 2018-2020 related to clinical and biochemical characteristics and to treatment of six patients with DKA due to SGLT2i were reviewed. They were compared to those of 12 patients with DKA due to other causes. RESULTS: On admission, the most common symptom was abdominal pain. Glucose levels (median, min-max) were lower in patients with SGLT2i-induced DKA compared to those with DKA due to other causes (229 (150-481) vs. 458.5 (332-695) mg/dl, p = 0.007), whereas no statistical difference was observed in HbA1c and in the severity of DKA (pH, HCO3, CO2, and anion gap). The duration of insulin infusion (41 (33-124) vs. 21.50 (11-32) h, p < 0.001) and the time required until DKA resolution (39 (31-120) vs. 19 (9-28) h, p < 0.001) were higher in patients with SGLT2i-induced DKA than those with DKA due to other causes. In addition, there were increased fluid requirements (14 (8-22.75) vs. 5.5 (2-24) L, p = 0.013) and longer hospitalization time (11 (6-22) vs. 5.5 (2-14) days, p = 0.024) in patients with SGLT2i-induced DKA. No statistically significant differences were observed in total intravenous insulin and potassium administration until DKA resolution. CONCLUSIONS: Patients with SGLT2i-induced DKA had lower serum glucose levels on admission and required increased fluid administration and longer time to recover from acidosis compared to patients with DKA from other causes.

Effectiveness of intramuscular ergocalciferol treatment in a patient with osteomalacia and insufficiency fractures due to severe vitamin D deficiency after bariatric surgery.

Vitamin D (vitD) deficiency and bone loss may occur after bariatric surgery and hence, supplementation with high oral doses of vitD may be required. Alternatively, intramuscular depot ergocalciferol, which slowly releases vitD and bypasses the gastrointestinal tract, could be administrated. We present a case of severe vitD deficiency-osteomalacia after gastric bypass operation for morbid obesity, treated with ergocalciferol intramuscularly. A 45-year-old woman was presented with hip pain and muscle weakness, which led ultimately to immobilization in a wheelchair. Fifteen years ago, she underwent roux-en-Y gastric by-pass for morbid obesity. Occasionally, she was treated with multivitamin supplements. On admission, iron deficiency anaemia, vitD deficiency (25OHD: 3.7 ng/ml) and secondary hyperparathyroidism were revealed. Bone turnover markers (BTM) were elevated. Radiological evaluation demonstrated insufficiency fractures on the pubic and left femur and reduced BMD. Osteomalacia due to vitD deficiency and calcium malabsorption were diagnosed. Calcium citrate 500 mg qid and intramuscular ergocalciferol 600,000 IU every 20 days were initiated. One month later, musculoskeletal pain and weakness were resolved and the patient was mobilized. Few months later, vitD, BTM and BMD showed substantial improvement. Intramuscular ergocalciferol administration can improve the clinical and biochemical status and thus, is suggested to prevent and/or treat osteomalacia in such patients.

Expression of clock-related genes in benign and malignant adrenal tumors.

Although the effect of the central clock system on adrenal function has been extensively studied, the role of the peripheral clock system in adrenal tumorigenesis remains largely unexplored. In this study we investigated the expression of clock-related genes in normal adrenocortical tissue and adrenocortical tumors. Twenty-seven fresh frozen human adrenal tissues including 13 cortisol secreting adenomas (CSA), seven aldosterone producing adenomas (APA), and seven adrenocortical carcinomas (ACC) were collected. CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα mRNA and protein expression were determined by qPCR and immunoblotting in pathological tissues and compared with the adjacent normal adrenal tissues. A significant downregulation of PER1, CRY1, and Rev-ERB compared with their normal tissue was demonstrated in CSA. All clock-related genes were overexpressed in APA compared with their normal tissue, albeit not significantly. A significant upregulation of CRY1 and PER1 and downregulation of BMAL1, RORα, and Rev-ERB compared with normal adrenal tissue was observed in ACC. BMAL1 and PER1 were significantly downregulated in APA compared with CSA. CLOCK, CRY1, and PER1 were upregulated, whereas BMAL1, RORα, and Rev-ERB were downregulated in ACC compared with CSA. Our study demonstrated the expression of CLOCK, BMAL1, PER1, CRY1, Rev-ERB, and RORα in normal and pathological human adrenal tissues. Adrenal tumors exhibited altered expression of these genes compared with normal tissue, with specific differences between benign and malignant lesions and between benign tumors arising from glomerulosa vs fasciculata zone. Further studies should clarify whether these alterations could be implicated in adrenocortical tumorigenesis.

Salt intake in mineralocorticoid receptor antagonist-treated primary aldosteronism: foe or ally?

Mild hyperkalemia is a common side effect of mineralocorticoid receptor antagonist (MRA) treatment of patients with primary aldosteronism (PA), which can be worsened by instructions to minimize salt intake. Our objective was to evaluate the effect of salt consumption on serum potassium levels and mean, mean minimal, and mean maximal systolic and diastolic blood pressure (BP) in MRA-treated hyperkalemic PA patients under relative salt restriction. Seventeen consecutive mildly hyperkalemic MRA-treated PA patients aged 66.3 ± 8.37 years were recruited. Body mass index (BMI) and BP were assessed, and serum and 24-h urinary sodium and potassium levels, plasma renin, and serum aldosterone were measured, while patients followed a relatively salt-restricted diet, after 1 month of controlled salt supplementation (usual salt-restricted diet plus 4 g salt/day) and after 6 months on instructions for free dietary salt consumption. Baseline salt consumption was additionally evaluated in two more patient groups (normotensive subjects and normokalemic MRA-treated PA patients). One month of controlled salt supplementation (24-h urine sodium (median, min, max): 195.2 (120.30-275.20) vs 110.13 (34.30-139.20) mEq/day, p < 0.001) resulted in increased kaliuresis (62.25 (40.69-97.0) vs 54.0 (23.28-79.60) mEq/day, p = 0.001) and a decrease of serum potassium (5.2 (5-5.70) vs 4.6 (3.8-5.1) mEq/L, p < 0.001), while serum sodium (139 (133-141) vs 1 39 (135-144) mEq/L) and mean systolic (130 (105-141 vs. 130 (106-141) mmHg) and diastolic (76 (53-85) vs75 (53-84) mmHg) BP remained stable. These findings were unchanged after 6 months of free salt consumption. BMI remained constant, while plasma renin and serum aldosterone decreased following salt repletion. Adequate salt consumption attenuates MRA-induced hyperkalemia in relatively salt-restricted PA patients without affecting BP or BMI.

Concomitant alterations of metabolic parameters, cardiovascular risk factors and altered cortisol secretion in patients with adrenal incidentalomas during prolonged follow-up.

OBJECTIVE: Adrenal incidentalomas (AI) are associated with metabolic and hormonal abnormalities, most commonly autonomous cortisol secretion (ACS). Data regarding alterations of insulin resistance (IR) and ACS after prolonged follow-up are limited. We investigated the evolution of IR, cortisol secretion and ACS development in patients with AI during prolonged follow-up. DESIGN: Prospective study in a tertiary hospital. PATIENTS AND MEASUREMENTS: Seventy-one patients with AI [51 nonfunctioning (NFAI) and 20 ACS] and 5·54 ± 1·7 years follow-up underwent testing for ACS and oral glucose tolerance test to determine IR indices and adrenal imaging. RESULTS: At follow-up, 16/51 (31%) NFAI patients converted to ACS, while two with previous ACS reverted to NFAI; 21% (7/33) of patients who did not covert to ACS exhibited high urinary-free cortisol (H-UFC) levels. All AI patients developed deterioration of IR irrespective of their cortisol secretory status. Eight patients developed newly diagnosed type 2 diabetes (9·8% NFAI and 15% ACS, respectively) and 14 IR (17·6% NFAI and 25% ACS, respectively). Adenoma size increased from 2·1 ± 0·8 to 2·3 ± 0·8 cm, whereas IR correlated with postdexamethasone cortisol level and adenoma size increase. IR showed an incremental continuum trend from normal UFC (Ν-UFC), to H-UFC, C-ACS and ACS patients. CONCLUSIONS: New-onset ACS developed in 31% patients with NFAI, whereas 21% of NFAI patients had H-UFC levels. All AI patients as a group and the subgroups of N-UFC, H-UFC, C-ACS and ACS patients developed deterioration of metabolic parameters during follow-up that was more prominent in ACS patients.

Surgery for pheochromocytoma: A 20-year experience of a single institution.

OBJECTIVE: Resection of pheochromocytomas is a challenging procedure due to hemodynamic lability. Our aim was to evaluate surgical outcomes in 67 patients with pheochromocytoma and to validate the role of laparoscopic surgery in the treatment of these tumors. DESIGN: This study is a retrospective review. A total of 68 procedures for pheochromocytoma were performed between June 1997 and February 2017. All patients were investigated and operated on using an established departmental protocol. Relevant data were retrieved from the hospital records of 533 patients who underwent 541 adrenalectomies for benign and malignant adrenal tumors in the same period. RESULTS: Sixty-nine tumors were removed from 67 patients. One patient with/MEN2A underwent bilateral resection of pheochromocytomas in two stages. Tumor size in laparoscopic procedures ranged from 1.2 cm to 11.0 cm (mean 5.87 cm). Thirty-seven patients had benign disease, 31 potentially malignant (based on PASS) and 1 malignant with metastasis. Eight were in the context of a familial syndrome. Forty-nine patients underwent laparoscopic adrenalectomy, 8 patients had open approach from the start for recurrent pheochromocytoma or large benign tumor, 1 patient had open approach due to inoperable malignant pheochromocytoma and 10 patients had conversions from laparoscopic to open procedure. Nine patients received sodium nitroprusside intraoperatively to treat hypertension. One patient developed pulmonary embolism and succumbed 1 month later. There were no recurrences of the benign or potentially malignant tumors during the follow-up period. CONCLUSIONS: Laparoscopic resection of pheochromocytomas, despite its increased level of difficulty compared to that of other adrenal tumors, is a safe and effective procedure.

A complicated case of primary hypophysitis with bilateral intracavernous carotid artery occlusion.

UNLABELLED: Primary hypophysitis (PH) is a rare clinical entity characterized by inflammatory infiltration of the pituitary gland with various degrees of pituitary dysfunction. OBJECTIVE: To present a complicated case of aggressive PH with bilateral cavernous sinuses infiltration, successfully treated with azathioprine after failure of corticosteroid treatment. METHODS AND RESULTS: A 48-year-old woman presented with episodes of recurrent headache and progressively worsening muscle weakness. Magnetic resonance imaging (MRI) identified an intrasellar pituitary lesion with thickened pituitary stalk extending to the cavernous sinuses and causing asymptomatic occlusion of both internal carotid arteries (ICAs). Hormonal investigation showed severe anterior pituitary deficiency. The diagnosis of PH, and more specifically of lymphocytic hypophysitis (LYH), was suspected and glucocorticoid treatment was initiated. Because of the patient's susceptibility to infections, the attempt to gradually reduce glucocorticoid dosage induced a relapse of PH. Immunosuppressive therapy with azathioprine was administered. Significant pituitary mass reduction with regression of the inflammation to the cavernous sinuses was documented. At follow-up the pituitary function was normal, while the patient was on the minimum dose of azathioprine. Thereafter, azathioprine was discontinued without any clinical/biochemical or radiological evidence of PH except for the permanent ICA occlusion. CONCLUSIONS: Despite its rarity, PH should be included in the differential diagnosis of pituitary masses and involvement of ICAs occlusion should not be underestimated. Azathioprine, applied as an alternative treatment, was shown to result in remarkable PH improvement.

Identification of a novel mutation of the PRKAR1A gene in a patient with Carney complex with significant osteoporosis and recurrent fractures.

OBJECTIVE: Carney complex (CNC) is a rare autosomal dominant multiple neoplasia syndrome characterized by the presence of endocrine and non-endocrine tumors. More than 125 different germline mutations of the protein Kinase A type 1-α regulatory subunit (PRKAR1A) gene have been reported. We present a novel PRKAR1A gene germline mutation in a patient with severe osteoporosis and recurrent vertebral fractures. DESIGN: Clinical case report. CASE REPORT: A 53-year-old male with a medical history of surgically removed recurrent cardiac myxomas was evaluated for repeated low-pressure vertebral fractures and severe osteoporosis. Physical examination revealed spotty skin pigmentation of the lower extremities and papules in the nuchal and thoracic region. The presence of hypercortisolism due to micronodular adrenal disease and the history of cardiac myxomas suggested the diagnosis of CNC; the patient underwent detailed imaging investigation and genetic testing. METHODS: Standard imaging and clinical testing; DNA was sequenced by the Sanger method. RESULTS: Sequence analysis from peripheral lymphocytes DNA revealed a novel heterozygous point mutation at codon 172 of exon 2 (c.172G>T) of the PRKAR1A gene, resulting in early termination of the PRKAR1A transcript [p.Glu58Ter (E58X)]. CONCLUSION: We report a novel point mutation of the PRKAR1A gene in a patient with CNC who presented with significant osteoporosis and fractures. Low bone mineral density along with recurrent myxomas should point to the diagnosis of CNC.

A new highly sensitive and specific overnight combined screening and diagnostic test for primary aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most common cause of endocrine hypertension that is diagnosed following a two-step process: an initial screening test, based on the serum aldosterone-to-renin ratio (ARR), followed by a relatively laborious and time-consuming confirmatory test to document autonomous aldosterone (ALD) secretion. OBJECTIVE: The aim of this study is to develop a simple overnight test for the early and definite diagnosis of PA. PATIENTS AND METHODS: Totally, 148 hypertensive patients underwent a fludrocortisone-dexamethasone suppression test (FDST) and the new overnight diagnostic test (DCVT) using pharmaceutical RAAS (renin-angiotensin-aldosterone system) blockade with dexamethasone, captopril and valsartan. RESULTS: Of the 148 patients, 45 were diagnosed as having PA and they all normalized their elevated blood pressure (BP) after administration of spironolactone or eplerenone. The remaining 103 patients were considered as having essential hypertension and served as controls. Using ROC analysis, the estimated sensitivity and specificity were 91 and 100%, respectively, for the post-FDST ARR, whereas 98% and 89% and 100% and 82% for the post-DCVT ARR and post-DCVT ALD, respectively, with selected cutoffs of 0.32ng/dL/µU/mL and 3ng/dL respectively. However, considering these cutoffs simultaneously, the estimated sensitivity and specificity were 98 and 100% respectively. Applying these cutoffs, the diagnosis of PA was confirmed in 44 (98%) of the 45 patients who were considered to have the disease. CONCLUSIONS: In this study, a highly sensitive and specific, low-cost, rapid, safe, and easy-to-perform diagnostic test (DCVT) for PA is described, which could be utilized on an outpatient basis potentially substituting conventional laborious testing.

Primary aldosteronism in hypertensive patients: clinical implications and target therapy.

BACKGROUND: The prevalence of primary aldosteronism (PA) in hypertensive patients varies according to diagnostic testing and ascertained normal cut-offs. The aim of this case-control study was to confirm the high prevalence of PA in a large hypertensive population and evaluate the antihypertensive effect of mineralocorticoid receptor antagonists (MRA) treatment. MATERIAL AND METHODS: We investigated 327 hypertensive and 90 matched normotensive subjects with normal adrenal imaging. Serum aldosterone (ALD), active renin (REN) levels and aldosterone/active renin (ALD/REN) ratio were measured before and after a combined sodium chloride, fludrocortisone and dexamethasone suppression test (FDST). Post-FDST values were compared to cut-offs obtained from controls (post-FDST ALD 2·96 ng/dL and post-FDST ALD/REN 0·93 ng/dL/µU/mL). PA patients received MRA treatment. RESULTS: By applying the combination of post-FDST ALD levels and ALD/REN ratio, 28·7% of the hypertensive patients had PA. There was a positive, albeit weak, correlation between systolic (SBP) and diastolic blood pressure (DBP) and ALD levels and/or ALD/REN ratio after the FDST (P < 0·0001). SBP was associated with a post-FDST ALD of 3·24 ng/dL and ALD/REN ratio of 0·90 ng/dL/µU/mL, whereas post-FDST ALD had an inverse association at serum K+ values of less than 3·9 mEq/L. MRA treatment in 69 PA patients, resulted in a significant reduction in the maximum SBP and DBP values (28 ± 15 and 14 ± 7 mmHg, respectively, P < 0·0001). CONCLUSIONS: Using the FDST, an increased prevalence of PA in hypertensives was observed. Α significant blood pressure lowering effect was obtained with MRA treatment, implying that these agents may be beneficial in a significant number of hypertensive patients.

A unique case of a benign adrenocortical tumor with triple secretion of cortisol, androgens, and aldosterone: development of multiple sclerosis after surgical removal of the tumor.

We present a 39-year old female with a benign adrenal tumor characterized by autonomous secretion of cortisol, androgens, and aldosterone. The patient presented with a 4-year history of hypertension and severe hirsutism. Baseline investigations revealed elevated testosterone, androstendione, and 17OH progesterone with normal levels of dehydroepi androsterone sulfate. CT of the adrenals revealed a 2.5 x 3.0 cm tumor with characteristics of an adenoma on the left adrenal gland. Pelvic ultrasound was normal. Further investigations revealed suppressed basal ACTH levels, loss of diurnal rhythm of cortisol, and failure to suppress on low dose dexamethasone suppression test, suggesting autonomous cortisol secretion by the tumor. She had an exaggerated response of 17OH progesterone to ACTH, implying reduced 21-hydroxylase activity. An elevated plasma aldosterone concentration to plasma renin activity ratio was suggestive of hyperaldosteronism, which was confirmed by failure of aldosterone to suppress to a formal saline infusion test. Complete clinical and biochemical remission of the disease was observed after left adrenalectomy. Histology confirmed the presence of an adrenocortical adenoma. The patient developed multiple sclerosis 6 months after the operation. The flare-up of an autoimmune disease (multiple sclerosis) postoperatively could be coincidental or possibly related to the high normalization of the high cortisol levels acting as a precipitating factor.

ACTH-Producing Cholangiocarcinoma Associated with Cushing's Syndrome.

A 61-year~old woman was admitted to the hospital with clinical manifestations of Cushing's syndrome. The ACTH level was 1340 pglmL, the urinary free cortisol level > 900 pg/mL, and the serum K+ levels 21 meqlL. The brain/pituitary MRI and thoracic CT scan were normal. Gastroscopy, colonoscopy, and small bowel follow through were normal. Abdominal CT and MRI showed normal adrenals, but dilated gallbladder with numerous gallstones, as well as peripancreatic and hepatoduodenal lymphadenopathy. A large meta-static deposit and three smaller lesions were also seen in the liver. Because of the poor respiratory function tests and the severe hypokalaemia, laparoscopy under local anaesthesia was performed. Following the procedure the patient became gradually jaundiced and thus underwent exploratory laparotomy. Locally advanced cholangiocarcinoma was found, infiltrating the liver hilum, with multiple small bilateral liver metastatic deposits. Acute cholecystitis with pericholecystic abscess was also found. Cholecystostomy as well as gallbladder, liver and hilar node biopsies were performed. Histopathology showed liver adenocarcinoma of bile duct origin, while immunocytochemistry revealed scattered, chromogranin A positive cells, some of them strongly immunoreactive for ACTH. Small clusters of chromogranin A positive cells were also found to be immunoreactive for CRH, but not for ACTH.