A case of unilateral adrenal medullary hyperplasia

We report a case of unilateral hyperplasia of the adrenal medulla. The patient showed clinical features suggestive of pheochromocytoma. Removal of the hyperplastic adrenal gland resulted in complete disappearance of all prior symptoms, decrease of the plasma and urinary catecolamine levels and no high uptake in [133I] metaiodobenzylguanidine scintigraphy. A histological study revealed diffuse hyperplasia of the adrenal medulla. Up to now, there are relatively few reports of adrenal medullary hyperplasia in English literatures.     

Adrenal medullary hyperplasia. Hyperplasia-pheochromocytoma sequence

We present a case of unilateral adrenal medullary hyperplasia in a 63-year-old woman with clinical signs and symptoms of pheochromocytoma unassociated with multiple endocrine neoplasia. The surgically removed adrenal gland revealed diffuse medullary hyperplasia with multiple micronodules measuring up to 2 mm. The micronodules were composed of enlarged chromaffin cells with atypia, histologically similar to those of pheochromocytoma, forming small solid alveolar patterns separated by a fibrovascular stroma. Removal of the hyperplastic adrenal gland resulted in disappearance of paroxysmal nocturnal hypertension and palpitation. These results suggest that diffuse and nodular medullary hyperplasia is the precursor of pheochromocytoma.     

Adrenal Medullary Hyperplasia: Hyperplasia-pheochromocytoma Sequence

We present a case of unilateral adrenal medullary hyperplasia in a 63-year-old woman with-clinical signs and symptoms of pheochromocytoma unassociated with multiple endocrine neoplasia. The surgically removed adrenal gland revealed diffuse medullary hyperplasia with multiple micronodules measuring up to 2 mm. The micronodules were composed of enlarged chromaffin cells with atypia, histologically similar to those of pheochromocytoma, forming small solid alveolar patterns separated by a fibrovascular stroma. Removal of the hyperplastic adrenal gland resulted in disappearance of paroxysmal nocturnal hypertension and palpitation. These results suggest that diffuse and nodular medullary hyperplasia is the precursor of pheochromocytoma.     

Adrenal medullary hyperplasia. A morphometric analysis in patients with familial medullary thyroid carcinoma.

The syndrome of familial medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia is inherited as an autosomal dominant trait, and is characterized by development of bilateral and multicentric thyroidal and adrenal medullary tumors. One of the earliest manifestations of adrenal medullary hyperfunction in patients with this syndrome is an increased ratio of epinephrine to norepinephrine in urine. In order to define the morphologic correlates of these early catecholamine abnormalities in a large kindred with familial MTC, a morphometric analysis based on a point-counting system to asses adrenal medullary volume was undertaken. These studies clearly revealed adrenal medullary hyperplasia as reflected by a two- to three-fold increase in medullary volume and weight as compared to age- and sex-matched controls. The increase in total medullary mass resulted from diffuse and multifocal modular proliferations of adrenal medullary cells primarily within the head and body regions of the glands. These results support the hypothesis that the pheochromocytomas in patients with familial MTC may, in fact, represent extreme degrees of nodular hyperplasia of the medulla.     

Mixed pheochromocytoma and ganglioneuroma of the adrenal medulla: a case report with electron microscopic examination

The combination of pheochromocytoma and ganglioneuroma is a rare tumor within the adrenal medulla. This report describes a 37-year-old woman with a 5-year history of paroxysmal attacks of hypertension, headache, and palpitation. No elevated catecholamine levels could be detected. Angiography showed the tumor in the right adrenal gland; the gland was surgically removed. The patient has remained well and free of hypertensive attacks for more than 2 years. Light and electron microscopic findings of the tumor are described.     

Weight and shape of the human adrenal medulla in various age groups

Summary The weight and shape of the adrenal medulla were studied in 118 adrenal glands obtained at autopsies of 62 patients (38 males and 24 females) between 0 and 52 years of age. In adolescents 15 years and older and adults cases of sudden death only were entered in this study. The weight was calculated using morphometric measurements done on serial sections of the glands. In the new-born, the medulla accounts for less than 1% of the total volume of the adrenal gland. Though there is a rapid growth of the adrenal medulla after birth, the percentage of adrenal medullary volume at all age levels during childhood and adolescence is lower than in adults where it constitutes 9% of the total adrenal volume on the average. This corresponds to an average medullary weight of 0.43 g. In the new-born, the medulla consists of a thin plate made up of immature medulloblasts. Within a few months these are transformed into mature medullary cells; the shape of the medulla soon approaches that of the adult gland: an increase in thickness around the central vein and flat processes into the alae. With increasing age the cortico-medullary border becomes irregular and ragged. Especially in the vicinity of the central vein an intermingling of medullary and cortical cell complexes is found. An unequivocal diagnosis of genuine adrenal medullary hyperplasia can be established only by weighing the dissected medulla or by applying morphometric methods.     

Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency

BACKGROUND: Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known. METHODS: We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically. RESULTS: Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P<0.05), and the values were lowest in the patients with the most severe deficits in cortisol production. Urinary epinephrine excretion and plasma epinephrine concentrations were at or below the limit of detection of the assay in 8 (21 percent) of the patients with congenital adrenal hyperplasia and in 19 (95 percent) of the patients who had undergone adrenalectomy. In the group of patients with congenital adrenal hyperplasia, plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50 percent lower in those who had been hospitalized for adrenal crises than in those who had not. In three patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopical studies revealed a depletion of secretory vesicles in chromaffin cells. CONCLUSIONS: Congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system.     

Spontaneous proliferative lesions of the adrenal medulla in aging Long-Evans rats. Comparison to PC12 cells, small granule-containing cells, and human adrenal medullary hyperplasia

Aging rats of the Long-Evans strain spontaneously develop diffuse and nodular hyperplasia of the adrenal medulla in association with other abnormalities commonly encountered in human multiple endocrine neoplasia syndromes. The cells which comprise the adrenal nodules resemble those in the parent tumor of the rat PC12 pheochromocytoma cell line in that they show varying degrees of spontaneous or nerve growth factor-induced neurite outgrowth in culture and they contain little or no epinephrine. In addition, cells from at least some of the nodules contain immunoreactive neurotensin and neuropeptide-Y, which are also found in PC12 cells. There are a number of striking resemblances between the cells in adrenal nodules and the small granule-containing cells in the normal rodent adrenal. The findings suggest that spontaneous rat adrenal medullary nodules and PC12 cells might be derived from small granule-containing cells, or that cells within the nodules might regain properties of immature chromaffin cells and acquire characteristics of small granule-containing cells and of PC12 cells in the course of neoplastic progression. They further suggest a possible relationship between proliferative capacity and neurotransmitter phenotype in the adult rat adrenal medulla. By virtue of their sparse epinephrine content and their small granules, the cells in adrenal medullary nodules of Long-Evans rats differ from those in adrenal medullary nodules of humans with multiple endocrine neoplasia syndromes.     

Pheochromocytoma: Rediscovery as a catecholamine-metabolizing tumor

Catecholamine-producing tumors are rare neoplasms derived mainly from chromaffin cells of the adrenal medulla (pheochromocytomas) or, in about 10% of cases, from paraganglia (paragangliomas). Diagnosis of these tumors relies heavily on measurements of urinary or plasma catecholamines or catecholamine metabolites. The metabolites are usually thought to be produced after release of catecholamines into the bloodstream. This, however, ignores observations of over 40 yr ago that catecholamines are metabolized within pheochromocytoma tumor cells. Development of improved methods for measurement of catecholamine metabolites, in particular, plasma concentrations of free normetanephrine and metanephrine, has reestablished the importance of intratumoral catecholamine metabolism. In patients with pheochromocytoma, over 90% of the elevations in plasma free normetanephrine and metanephrine result from metabolism of catecholamines within pheochromocytoma tumor cells. This process occurs continuously and independently of variations in catecholamine release. As a consequence, measurements of plasma concentrations and urinary outputs of normetanephrine and metanephrine provide more reliable methods for diagnosis of pheochromocytoma than measurements of the parent amines. Rediscovery of the importance of intratumoral catecholamine metabolism is leading to a reevaluation of the procedures used to diagnose pheochromocytoma. This review provides an update on the diagnosis of pheochromocytoma, with emphasis on identifying and correcting relevant misconceptions about catecholamine metabolism.     

Ovarian Adrenal Rest Tumors Undetected by Imaging Studies and Identified at Surgery in Three Females with Congenital Adrenal Hyperplasia Unresponsive to Increased Hormone Therapy Dosage

Patients with congenital adrenal hyperplasia have a predisposition for developing adrenal rest tumors. In contrast to testicular adrenal rest tumors, ovarian adrenal rest tumors are less common, and only a few cases have been reported in the literature. This report presents three Chinese female congenital adrenal hyperplasia patients (9 to 15 years of age) with small ectopic adrenal cortical nodules that were not detected by imaging but were diagnosed at surgery. All three patients developed virilization with elevation of 17- hydroxyprogesterone, androstenedione, and androgen levels despite receiving maximum adrenal hormone replacement therapy. Ultrasound and magnetic resonance imaging of the abdomen and pelvis suggested bilateral expansion of the adrenal glands, but no lesions of the ovaries were observed. Laparoscopy and/or laparotomy revealed small nodular lesions surrounding the pelvic gonad in all three cases. Histopathological examination of the resected tissue in all cases revealed hyperplasic nodules of cells surrounded by fibrous tissue. The cells were arranged as nests with abundant cytoplasm, which were partially lightly stained with a small centered nucleus. Immunohistochemistry staining revealed the cells to be synaptophysin positive, melan-A positive, and chromogranin A negative, indicating the cells were adrenocortical tissue and not adrenal medullary cells. Thus, the findings of the histopathological examination were consistent with ovarian adrenal rest tumors. Female congenital adrenal hyperplasia patients with virilization who showed an inadequate response to hormone therapy and had negative imaging results may benefit from laparoscopic examination or laparotomy in order to confirm the diagnosis of ovarian adrenal rest tumors while receiving unilateral subtotal adrenalectomy or subtotal bilateral adrenalectomy.     

Neurogenic signals regulate chromaffin cell proliferation and mediate the mitogenic effect of reserpine in the adult rat adrenal medulla

The adrenal medulla is innervated by nerve fibers from several sources, which synapse on chromaffin cells and stimulate the secretion of catecholamines. The antihypertensive agent reserpine is known to reflexively increase this neurogenic stimulation by depleting catecholamine stores, and long-term administration of reserpine is associated with adrenal medullary hyperplasia and neoplasia. To determine the role of neurogenic signals in regulating normal and reserpine-stimulated proliferation of chromaffin cells, the incorporation of 5-bromo-2'-deoxyuridine (BrdU) into replicating nuclei was assessed in the adrenal medulla of adult rats. Unilateral adrenal denervation caused a 4-5 fold decrease in chromaffin cell labeling by 5-bromo-2'-deoxyuridine during a 2-week labeling period. Denervation also prevented stimulation of labeling in animals receiving reserpine in their diet. These findings suggest that neurogenic control of cell proliferation may play an important role in the pathogenesis of adrenal medullary hyperplasia and neoplasia, and in the normal development of the peripheral and central nervous systems.     

Catecholamine-synthesizing enzymes and chromogranin proteins in drug-induced proliferative lesions of the rat adrenal medulla.

Both epinephrine (E) and norepinephrine (NE) cells in the rat adrenal medulla are able to proliferate in response to pharmacologic stimulation. However, previous biochemical studies have suggested that drug-induced or spontaneous pheochromocytomas in rats are almost invariably NE-producing. To resolve these apparently conflicting data, immunocytochemical techniques were utilized to establish functional profiles of adrenal medullary lesions classified as pheochromocytoma or nodular hyperplasia in rats treated chronically with a phosphodiesterase inhibitor which induced pheochromocytomas. Sixteen of 17 pheochromocytomas and all hyperplastic nodules stained positively for tyrosine hydroxylase and dopamine beta-hydroxylase, consistent with an ability to produce NE. No lesion of either type stained for phenylethanolamine N-methyltransferase, consistent with an inability to produce epinephrine. Lesions of both types showed variable staining for chromogranin proteins. The findings indicate that qualitative functional differences cannot be used to discriminate hyperplastic nodules from small pheochromocytomas in rats. Some lesions currently classified as hyperplastic nodules might in fact be small pheochromocytomas. Others might represent diffuse hyperplasia within pre-existing islands of NE-cells in a background of hyperplastic epinephrine-cells.     

Disparate urinary catecholamine patterns in secondary hypertension due to unique sequential development of pheochromocytoma and neuroblastoma

A 43-year-old white woman had a pheochromocytoma removed from her left adrenal gland, and one year later she developed a new left upper abdominal mass that was found to be a neuroblastoma. On both occasions, urinary vanillylmandelic acid level was elevated. However, urinary norepinephrine and epinephrine levels were increased only during the pheochromocytoma episode, while the urinary homovanillic acid level was elevated only when neuroblastoma developed. Despite a high suspicion of pheochromocytoma recurrence, the urinary catecholamine profile was suggestive of neuroblastoma, which was revealed by histopathologic analysis of the tumor tissue.     

Ultrastructure of the fetal rat adrenal gland at full-term and during prolonged gestation

The ultrastructure of the fetal rat adrenal gland is described at full-term (day 22) and during artificially prolonged gestation (days 23, 24, 25). The latter was achieved by daily subcutaneous injections of seven mg progesterone to gravid females from the twentieth through the twenty-fourth day. Cortical and medullary cells contained well developed organelles at all stages. Nonetheless, zonation of the gland was not yet distinct. Whereas the zona glomerulosa and zona fasciculata were fairly well delineated, the zona reticularis and medulla were as yet poorly defined. The latter regions were intermingled, and thus collectively referred to as the “zona reticulo-medullaris.” During prolonged gestation (days 24 and 25 only), many cells of the zona fasciculata and zona reticulo-medullaris contained dilated smooth endoplasmic reticulum and numerous enlarged mitochondria. Enlarged mitochondria were observed also in medullary cells concurrent with a paucity of catecholamine storage granules. Moreover, meconium staining, which is indicative of fetal stress, was also observed on days 24 and 25. The ultrastructural changes observed were interpreted to be an expression of response by the fetal adrenal gland to fetal stress produced by as yet undetermined factors arising during prolonged gestation.     

Adrenal gland: structure, function, and mechanisms of toxicity

The adrenal gland is one of the most common endocrine organs affected by chemically induced lesions. In the adrenal cortex, lesions are more frequent in the zona fasciculata and reticularis than in the zona glomerulosa. The adrenal cortex produces steroid hormones with a 17-carbon nucleus following a series of hydroxylation reactions that occur in the mitochondria and endoplasmic reticulum. Toxic agents for the adrenal cortex include short-chain aliphatic compounds, lipidosis inducers, amphiphilic compounds, natural and synthetic steroids, and chemicals that affect hydroxylation. Morphologic evaluation of cortical lesions provides insight into the sites of inhibition of steroidogenesis. The adrenal cortex response to injury is varied. Degeneration (vacuolar and granular), necrosis, and hemorrhage are common findings of acute injury. In contrast, chronic reparative processes are typically atrophy, fibrosis, and nodular hyperplasia. Chemically induced proliferative lesions are uncommon in the adrenal cortex. The adrenal medulla contains chromaffin cells (that produce epinephrine, norepinephrine, chromogranin, and neuropeptides) and ganglion cells. Proliferative lesions of the medulla are common in the rat and include diffuse or nodular hyperplasia and benign and malignant pheochromocytoma. Mechanisms of chromaffin cell proliferation in rats include excess growth hormone or prolactin, stimulation of cholinergic nerves, and diet-induced hypercalcemia. There often are species specificity and age dependence in the development of chemically induced adrenal lesions that should be considered when interpreting toxicity data.     

Brief and repeated noise exposure produces different morphological and biochemical effects in noradrenaline and adrenaline cells of adrenal medulla

Exposure to stressful stimuli is known to activate the peripheral sympathetic nervous system and the adrenal gland. In this study, we evaluated the effects of single or repeated bouts of exposure to a readily measurable stressful stimulus (loud noise) on the catecholamine content and ultrastructure of the rat adrenal medulla. In particular, we measured tissue levels of dopamine, noradrenaline, adrenaline and metabolites. In parallel studies, we evaluated the fine ultrastructure of catecholamine cells, including a detailed study of catecholamine granules and a morphometric analysis of adrenaline and noradrenaline medullary cells. Animals were exposed either to a single (6 h) session of loud (100 dBA) noise, or to this noise stimulus repeated every day for 21 consecutive days. There was a marked correlation between biochemical indexes of catecholamine activity and the ultrastructural morphometry of specific catecholamine granules. Exposure to loud noise for 6 h induced a parallel increase in dopamine, noradrenaline, adrenaline and their metabolites, a polarization and an increased numerical density of noradrenaline and adrenaline granules in the cells. After repeated noise exposure, noradrenaline levels were significantly higher than in controls, and adrenaline decreased significantly. In addition, adrenaline cells also exhibited ultrastructural alterations consisting of wide homogeneous cytoplasmic areas and large, pale vesicles.     

The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience

An important question facing physicians who care for families with multiple endocrine neoplasia type 2a is whether prospective screening to detect early abnormalities of the thyroid, parathyroid, or adrenal glands favorably influences the ultimate course of the disease. An 18-year study of a large family has allowed us to examine the effect of early treatment on the clinical course of the disease. Of 22 patients who underwent thyroidectomy for early C-cell abnormalities, 19 remained free of detectable medullary thyroid carcinoma according to all criteria, at a mean of 11 years after thyroidectomy. None of the 22 patients had evidence of parathyroid disease either at the time of surgery or after a mean follow-up of 10 years. Prospective screening for adrenal medullary abnormalities by means of measurement of 24-hour urinary epinephrine excretion and the ratio of urinary epinephrine to norepinephrine was predictive of pheochromocytoma in 10 of 11 patients (with a false negative result in one patient) but was not useful in diagnosing adrenal medullary hyperplasia. We conclude that regular, prospective screening and early treatment of the manifestations of multiple endocrine neoplasia can prevent metastasis of medullary thyroid carcinoma and the morbidity and mortality caused by pheochromocytoma.     

Extra-adrenal pheochromocytoma associated with bilateral diffuse-nodular hyperplasia of the adrenal cortex and micro-macrofollicular goiter]

At autopsy there was found extra-adrenal pheochromocytoma, bilateral diffuse-nodulous and adenomatous hyperplasia of the adrenal cortex in a female patient who had suffered for a long time from high arterial pressure. In the enlarged thyroid gland there was revealed micro-macrofollicular colloid goiter with basedowification. The morphological changes and results of an investigation of the liquor (drop in the content of potassium) justify the assumption that in this case there is a combination of extra-adrenal pheochromocytoma with hormonally active rearrangement of the adrenal cortex--primary hyperaldosteronism and basedowified goiter.     

Up-regulation of ret by reserpine in the adult rat adrenal medulla

The receptor tyrosine kinase, ret, is activated by glial cell line-derived neurotrophic factor, neurturin and related ligands that bind to glycosylphosphatidylinositol-tailed receptors GFRalpha1-4. Ret expression is developmentally regulated and detectable only at very low levels in adult adrenal medulla. However, mutations of ret that cause constitutive activation or alter signal transduction give rise to adrenal medullary hyperplasia and pheochromocytomas in humans with hereditary multiple endocrine neoplasia (MEN) syndromes 2A and 2B and in animal models. These discordant observations pose the conundrum of how a molecule barely detectable in the adult adrenal can contribute to development of adrenal medullary pathology that typically occurs in adults. We recently reported that depolarization and phorbol esters that activate protein kinase C act synergistically with neurturin to up-regulate ret protein and mRNA expression in adult rat chromaffin cell cultures. Those findings suggested that ret expression in vivo is not static and might be regulated in part by neurally derived signals. We show here that the anti-hypertensive agent reserpine, which is known to cause a reflex increase in trans-synaptic stimulation of chromaffin cells, increases expression of ret mRNA and protein in adult rat adrenal medullary tissue in vivo. Elevated ret protein levels are detectable both by immunoblots and immunohistochemistry, which shows immunoreactive ret in chromaffin cells and neurons after reserpine administration. The finding that ret expression is subject to up-regulation by environmental signals in vivo suggests that epigenetic factors might influence the development of adrenal medullary disease by affecting the expression of ret. It is known that long-term administration of reserpine leads to the development of adrenal medullary hyperplasia and pheochromocytomas in rats. Our findings suggest potential utility of the rat model for studying the roles of ret in the adrenal medulla and the mechanisms of its involvement in MEN 2 and other pheochromocytoma syndromes.     

Synchronous renal and adrenal masses: an analysis of 80 cases

Synchronous renal and adrenal masses are uncommon. Although adrenal masses in the context of renal cell carcinoma (RCC) are often suspected as metastasis, other adrenal lesions with different therapeutic and prognostic implications may coexist with RCC. In a retrospective review of 550 radical nephrectomies with ipsilateral adrenalectomy, 80 cases of coexisting renal and adrenal masses were identified. The renal masses included 76 RCCs, 3 oncocytomas, and 1 malignant pheochromocytoma of adrenal gland involving the kidney. Although the gross pathologic impression of adrenal masses in the presence of RCC was metastasis, on histologic examination, 56% of them were found to be benign lesions (mostly adrenal adenoma/hyperplasia), whereas malignant involvement from RCC was seen in 43%. The benign and malignant nature of the adrenal lesions in the context of RCC could not be discriminated based on the size of adrenal mass. Because of the prognostic implication of direct or metastatic involvement of adrenal gland in the setting of RCC and the possibility of finding small metastatic foci, a meticulous gross and microscopic examination of adrenal glands is emphasized. Rare unusual combinations of renal and adrenal lesions such as RCC and adrenal histoplasmosis, RCC and adrenal myelolipoma, renal oncocytoma, and adrenal pheochromocytoma are also described.