Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia.

Ectopic ACTH syndrome (EAS) accounts for 10-20% of endogenous Cushing's syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing's syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing's syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.

Adrenal medullary hyperplasia mimicking pheochromocytoma.

A 59-year-old woman, a known case of hypertension, was incidentally diagnosed with a large right-sided adrenal mass. Investigations for a functional adrenal lesion resulted in very high preoperative norepinephrine levels. A right adrenalectomy was performed. Histology showed adrenal medullary hyperplasia (AMH). AMH is a rare diagnosis and its incidence is poorly documented in the literature. This is a benign entity which resembles pheochromocytoma (PCC) in both clinical and biochemical manner. AMH is usually bilateral and may occur in isolation or in association with PCC. In fact, some authors consider it to be a precursor to PCC. Thus, these patients need long-term follow-up in view of the risk of development of PCC later.

Expression of Extracellular Signal-regulated Kinase 5 and Ankyrin Repeat Domain 1 in Composite Pheochromocytoma and Ganglioneuroblastoma Detected Incidentally in the Adult Adrenal Gland.

Composite pheochromocytoma (cPC) is extremely rare, arising in the adrenal medulla as a mixture of PC and other tumors of neural origin. We herein report on a case of adrenal incidentaloma post-operatively diagnosed as cPC with ganglioneuroblastoma (GNBL). The PC component had 7 points on the PASS, a Ki-67 index of 5.1%, a focal absence of sustentacular cells, and no genetic aberrations in succinate dehydrogenase subunit B. The GNBL component exhibited no N-myc amplification. Tumor cells of both components were stained positively for extracellular signal-regulated kinase 5 and ankyrin repeat domain 1. The aberrant activation of growth signaling may play a role in the marginal malignancy of cPC.

Pentazocine inhibits norepinephrine transporter function by reducing its surface expression in bovine adrenal medullary cells.

(±)-Pentazocine (PTZ), a non-narcotic analgesic, is used for the clinical management of moderate to severe pain. To study the effect of PTZ on the descending noradrenergic inhibitory system, in the present study we examined the effect of [(3)H]norepinephrine (NE) uptake by cultured bovine adrenal medullary cells and human neuroblastoma SK-N-SH cells. (-)-PTZ and (+)-PTZ inhibited [(3)H]NE uptake by adrenal medullary cells in a concentration-dependent (3-100 µM) manner. Eadie-Hofstee analysis of [(3)H]NE uptake showed that both PTZs caused a significant decrease in the V(max) with little change in the apparent K(m), suggesting non-competitive inhibition. Nor-Binaltorphimine and BD-1047, κ-opioid and σ-receptor antagonists, respectively, did not affect the inhibition of [(3)H]NE uptake induced by (-)-PTZ and (+)-PTZ, respectively. PTZs suppressed specific [(3)H]nisoxetine binding to intact SK-N-SH cells, but not directly to the plasma membranes isolated from the bovine adrenal medulla. Scatchard analysis of [(3)H]nisoxetine binding to SK-N-SH cells revealed that PTZs reduced the B(max) without changing the apparent K(d). Western blot analysis showed a decrease in biotinylated cell-surface NE transporter (NET) expression after the treatment with (-)-PTZ. These findings suggest that PTZ inhibits the NET function by reducing the amount of NET in the cell surface membranes through an opioid and σ-receptor-independent pathway.

An uncommon type of adrenal incidentaloma: a case report of a schwannoma of the adrenal medulla with cytological, histological, and ultrastructural correlation.

Benign nerve sheath tumors of the adrenal gland are an extremely uncommon cause of an incidentaloma. We report a case of a schwannoma of the adrenal medulla in an asymptomatic 51-year-old woman, which was discovered incidentally on a computed tomography scan after routine workup for her degenerative joint diseases of the lumbar spine. Because of the large size and unknown biologic nature of the tumor by clinical and radiographic studies alone, an adrenalectomy was performed. The gross specimen featured a well-circumscribed medullary based tumor with cystic degeneration. The diagnosis of a nerve sheath tumor was based on classic histological findings, supported by S-100 positivity, and ultrastructurally by the finding of typical Schwann cells. The cytological diagnosis from the fine-needle aspiration biopsy material obtained at the time of gross examination was much more challenging on retrospective review. The aspirated material showed a round- to oval-cell predominant smear with occasional striking anisonucleosis, intranuclear inclusions (so-called ancient change), and pigment deposition. A review of the histogenesis and differential diagnosis of this common nerve sheath tumor in this unusual location is discussed.

Low-density pheochromocytoma on CT: a mimicker of adrenal adenoma.

OBJECTIVE: Attenuation values on CT of less than 10 H are considered characteristic of adrenal adenomas. Adrenal pheochromocytomas can infrequently contain fat that could result in low attenuation on CT. The purpose of our study was to determine if pheochromocytomas could be confused with adenomas by virtue of their attenuation values on unenhanced CT. MATERIALS AND METHODS: CT attenuation and size of nine adrenal nodules producing pheochromocytoma syndrome were measured on unenhanced CT in nine patients. For five patients who received IV contrast material, washout profiles were also calculated. RESULTS: Two of the nine patients had adrenal lesions with attenuation values of less than 10 H; one had a pheochromocytoma with an attentuation of 9.0 H, and the other had a medullary hyperplasia with an attenuation of 1.8 H. These two nodules showed evidence of microscopic fat at histologic examination. No macroscopic fat was seen on the CT scans. The remaining seven patients had lesions with attenuation values exceeding 10 H (mean value, 25.6 H; range, 1.8-41 H). Mean diameter of the nine tumors (including the hyperplastic nodule) was 3.2 cm (range, 0.8-6.7 cm; SD, +/- 2.3 cm). The two low-attenuation lesions also mimicked adenomas by displaying more than 60% contrast washout on 10-min-delayed contrast-enhanced scans, unlike the other three pheochromocytomas for which we had washout data. CONCLUSION: On CT, pheochromocytomas may have attenuation values less than 10 H and also may display more than 60% washout of contrast agents on delayed scanning. Adrenal pheochromocytomas should be included with adenomas in the differential diagnosis both for masses with low attenuation on unenhanced CT and for lesions exhibiting a high percentage of contrast washout.

Radioisotope diagnosis and therapy of malignant pheochromocytoma.

The availability of radiopharmaceuticals to depict primary malignant pheochromocytoma and its metastases has markedly changed the approach to these unusual cancers. Whole body screening afforded by scintigraphy allows remote tumor involvement to be identified and provides staging information necessary to guide subsequent therapy. The avid accumulation by malignant pheochromocytoma of some radiopharmaceuticals used for scanning has shown promise in therapeutic trials. In this paper, we discuss radiopharmaceuticals presently employed in malignant pheochromocytoma for both diagnostic and therapeutic uses and potential future compounds that may find their way into clinical practice in the approach to these and other related neoplasms.

Sporadic bilateral adrenal medullary hyperplasia: apparent false positive MIBG scan and expected MRI findings.

Adrenal medullary hyperplasia is a rare cause of clinical symptoms and biochemical findings identical to pheochromocytoma occurring mostly in multiple endocrine neoplasia patients. The scenario of positive MIBG scan, but no focal lesion found on CT and MRI led to diagnostic and management difficulties. Like pheochromocytoma, surgical excision can lead to clinical and biochemical recovery. We report this unusual case of sporadic bilateral adrenal medullary hyperplasia, with hypertension and biochemical abnormalities alleviated after surgical adrenalectomy. Based on T2 values reported in literature, high signal focal lesions may not appear on T2-weighted MRI images until development of frank pheochromocytoma. MIBG scan remains the most sensitive imaging modality for this condition.

Iodine-131-MIBG scintigraphy in adults: interpretation revisited?

UNLABELLED: Iodine-131-metaiodobenzylguanidine (MIBG) scintigraphy is a reliable method used to diagnose pheochromocytoma. Although the adrenal medulla usually is not visualized, faint uptake can be observed in 16% of the patients 48-72 hr after injection of 18.5-37 MBq 131I-MIBG. We recently observed an increase in the frequency of visualization of the adrenal medulla in patients injected with 74 MBq 131I-MIBG. Therefore, we retrospectively evaluated the pattern of uptake and potential changes between 1984 and 1994. METHODS: Scintigraphic data from 103 patients referred for suspected pheochromocytoma were reviewed randomly. Data from 19 patients with medullary thyroid carcinoma were analyzed separately. Patients were injected with 74 MBq 131I-MIBG and imaged at 24 hr postinjection, 48 hr postinjection, or both. Adrenal uptake was scored visually as 0 (no visible uptake) and 1 (uptake just visible) to 4 (most intense activity in the picture). Semiquantitative indicies were evaluated for discriminating between normal adrenal medullae and pheochromocytomas. Twenty-seven pheochromocytomas were surgically proven in 25 patients. RESULTS: A visual score > or =3 was noted in 81% and 90% of the pheochromocytomas at 24 hr and 48 hr postinjection, respectively. From 1984 to 1988, 16% and 31% of adrenal medullae were seen at 24 and 48 hr postinjection, respectively, whereas from 1989 to 1994, 56% and 73% were visualized at 24 and 48 hr postinjection, respectively. Before 1989, the best cutoff criterion to identify a pheochromocytoma, determined from receiver operating characteristic curve analysis, was a score > or =1 at 24 hr and > or =3 at 48 hr postinjection, with a sensitivity and specificity of 92% and 84% at 24 hr and 92% and 99% at 48 hr postinjection. From 1989, the best cutoff was a score > or =3 at both imaging sessions, with a sensitivity and specificity of 82% and 100% at 24 hr and 100% and 97% at 48 hr postinjection. Among the semiquantitative indicies, the adrenal-to-liver and adrenal-to-heart ratios were the best discriminators between normal and pathological adrenals. They were, however, of little use because of the overlap between normal adrenal medullae and pheochromocytomas. CONCLUSION: The high rate of visualization of the normal adrenal medulla in this study was related to the larger-than-usual injected dose (74 MBq). Over recent years, however, this rate has been increasing, possibly because of the increased specific activity of 31I-MIBG. Adequate interpretation should take into account that a faint or definite uptake may be visible in more than 50% of normal adrenal medullae.

Iodine-131 MIBG imaging in multiple endocrine neoplasia type 2B.

A 16-year-old boy had a swollen neck that was a result of multiple endocrine neoplasia Type 2B (MEN 2B). CT revealed bilateral thyroid tumors, swelling of right cervical lymph nodes, and slight enlargement of the right adrenal gland. I-131 metaiodobenzylguanidine (MIBG) scintigraphy demonstrated increased uptake in the right adrenal gland and the left thyroid tumor, but no abnormal uptake in the right thyroid tumor and the right cervical lymph nodes. Postoperative pathologic findings were consistent with the diagnosis of right adrenal medullary hyperplasia, which is a precursor of pheochromocytoma. In patients with MEN 2B, I-131 MIBG scintigraphy in conjunction with CT of the adrenal glands should be performed to determine the disease stage of the adrenal medullae. In the cervical region, the diagnosis was medullary thyroid carcinoma (MTC) in both thyroid tumors and metastases in the right cervical lymph nodes. The right MTC was more aggressive than the left MTC. It is interesting that not all sites of known MTC take up I-131 MIBG to the same degree.

[Imaging of adrenal glands]. / Imagerie des glandes surrénales.

The technical choice in imaging the adrenal gland will depend on several factors discussed in the review. CT and MRI are achieving increasingly high accuracy in the investigation of patients suspected to present adrenal pathology. Scintigraphy evaluates functional patterns of both adrenal cortex and medulla, depending on the radiopharmaceutical that is used. Non invasive characterization of adrenal lesions is very important in cases of incidental discovery of adrenal masses. This review concentrates on new techniques for evaluating the incidentally discovered adrenal masses and differentiating between adrenal adenomas and metastases.

Location of adrenal medullary pheochromocytoma by I-123 metaiodobenzylguanidine SPECT.

This is a retrospective study evaluating the efficacy of SPECT in the location of pheochromocytoma. Thirty patients with a suspected pheochromocytoma underwent I-123 metaiodobenzylguanidine (I-123 MIBG) SPECT 4 and 22 hours after intravenous injection of 370 MBq I-123 MIBG. SPECT was compared with planar scintigraphy, CT scanning, histology, and clinical course. Twenty-two-hour I-123 MIBG SPECT correctly identified 10 patients with adrenal medullary pheochromocytoma and correctly excluded pheochromocytoma in 19 patients. The sensitivity of the 22-hour MIBG SPECT was 1.00 and the specificity was 0.95. The positive predictive value was 0.95 and the negative predictive value was 1.00. In 16 patients, planar scintigraphy was compared with SPECT. SPECT located normal adrenal glands and tumors with greater confidence in three dimensions, but the patients with adrenal medullary pheochromocytoma were all correctly identified by planar scintigraphy. The results of SPECT and CT agreed in 29 of 30 patients (96.7%). I-123 MIBG SPECT for the location of pheochromocytoma has a high sensitivity, specificity, and positive and negative predictive values. I-123 MIBG SPECT or CT scanning alone were equally good for locating adrenal medullary pheochromocytoma but the combination of MIBG SPECT and CT makes it possible to distinguish between functioning and nonfunctioning adenomas. I-123 MIBG SPECT may be used alone or in combination with planar scintigraphy when three-dimensional location of a lesion is wanted.

Adrenal cortical and medullary imaging.

Adrenal disease can be manifested by endocrine dysfunction or anatomic abnormalities detected by cross-sectional imaging modalities. With the advent of newer and more reliable in vitro assays and a better understanding of the spectrum of adrenal pathology, the physician can now adopt a more accurate and cost-effective approach to the diagnosis of adrenal disease. Both functional and anatomic imaging modalities can play an important role in the evaluation of the incidental adrenal mass, the early detection of adrenal metastases, differentiation of the various causes of Cushings's syndrome, selection of patients for potentially curative surgery in primary aldosteronism and adrenal hyperandrogenism, and localization of pheochromocytomas and neuroblastomas. The usefulness of the adrenal cortical radiopharmaceutical, 131I-6-beta-iodomethylnorcholesterol (NP-59), and the adrenal medullary radiopharmaceuticals, 131I and 123I-metaiodobenzylguanidine (MIBG), is detailed for these various clinical settings and the role of NP-59 and MIBG is contrasted to that of the cross-sectional modalities, computed tomography and magnetic resonance imaging (MRI). Incidental adrenal masses are common, but malignancies are few. Imaging studies select those patients who require a further evaluation by biopsy examination or adrenalectomy. In the hyperfunctioning endocrine states, such as Cushing's syndrome, primary aldosteronism, adrenal androgenism, and pheochromocytoma, correlation of biochemical findings with both functional and anatomic imaging is necessary to avoid inappropriate and ineffective surgical intervention, yet not miss an opportunity for curative resection. Lastly, MIBG and MRI are complementary in the detection and staging of neuroblastoma.

[Nuclear medicine methods for the diagnosis of adrenal tumors]. / Metodiche medico-nucleari per la diagnosi dei tumori surrenalici.

Adrenal scintigraphy using 131I-6-beta-iodomethyl-19-norcholesterol or 6-methyl-75Se-methyl-19-norcholesterol is a function-dependent imaging method which, in association with high-resolution spatial imaging techniques, plays an essential role in the study of adrenocortical hyperfunction. It can distinguish between bilateral cortical hyperplasia and monolateral adenoma or carcinoma and can lateralise the adenoma. In patients with Cushing syndrome, in addition to allowing a distinction to be made between ACTH-dependent forms and independent forms, adrenocortical scintigraphy is particularly appropriate to identify non-common forms of adenomatous hyperplasia. Adrenocortical scintigraphy, performed during dexamethasone administration, is an accurate mean of differentiating bilateral adrenal hyperplasia from monolateral forms (adenoma or carcinoma) in patients with Conn's syndrome. Owing to the gradual spread of high-resolution spatial imaging techniques, the problem of the diagnostic classification of so-called "incidentalomas" (clinically silent masses discovered by chance) is a subject of considerable interest. Adreno-cortical scintigraphy appears to be able to provide an important contribution to identifying the functional behaviour of these tumours. Since the early 80s meta-iodobenzyl-guanidine (MIBG), marked with 131I or 123I, with a structure similar to norepinephrine and characterized by selective tropism for sympathetic and chromaffin tissue, has been used for the scintigraphic study of adrenal medulla. MIBG scintigraphy has been found to be particularly appropriate for the study of intra- and extra-adrenal, single and multiple, benign and malignant pheochromocytomas. This method has a high overall sensitivity and specificity. Lastly, MIBG scintigraphy is useful in the study of neuroblastoma.

Detection of norepinephrine distribution in rats with adrenal medulla autotransplants using 125I-meta-iodobenzyl guanidine.

The viability of autologous adrenal medullary transplants was evaluated using 125I-meta-iodobenzyl guanidine (MIBG), an adrenal medullary scanning agent. Bilateral cavities in the caudate nuclei were made stereotaxically in Wistar rats. One week later, the left adrenal medulla was resected by microsurgery, followed by reoperation of the cranium and implantation of a 0.5-1.0 mm diameter fragment of the adrenal medulla into the right caudate nucleus. Six weeks after the second operation, MIBG was administered intravenously. Specimens from both cerebral hemispheres, from the right adrenal medulla and blood were analysed by radioactivity counting. The radioactivity present in the blood of the transplanted group of 11.40 +/- 2.35 cpm mg-1 (mean +/- S.E.M.) was significantly higher than in the control group of 4.97 +/- 1.16 cpm mg-1 (P < 0.05). Radioactivity present in the right hemisphere of the transplanted group was 0.66 +/- 0.03 cpm mg-1, also significantly higher than in the control group which was 0.47 +/- 0.04 cpm mg-1 (P < 0.01). Autoradiography revealed increased radioactivity in the area of the transplants, which was also confirmed histologically.