In

Committed neuroblast

Sympathetic neuron

SCG10++

SCG10++

Chromaffin precursor

High glucocorticoid

PNMT+

High glucocorticoid

PNMT+

Adrenergic chromaffin cell chromaffin-specific gene expression minimi neuron-specific gene expression

FIGURE 64-2. Progressive stages in the development of sympathoadrenal (SA) lineage. Changes in marker expression that correlate with these stages are shown. Cross-hatched lines in the bipotential SA progenitor indicate that both neuron-specific and chromaffin-specific genes are coexpressed. Monoclonal antibodies (HNK-1) are used to isolate bipotential SA progenitors from rat adrenal glands. SA-1 antigen is a chromaffin cell marker and B2 antigen is specific for neuronal precursors. High levels of glucocorticoids induce differentiation of chromaffin cells. SA progenitor cells initiate neuronal differentiation in response to basic fibroblast growth factor (FGF), lose competence to respond to glucocorticoids, subsequently develop a dependence on nerve growth factor (NGF) for further maturation and survival, and when maniré, can be identified with the use of antineurofilament (NF+) antibodies. PNMT = phenylethanolamine iV-methyltransferase. (Adapted from Anderson DJ. Molecular control of cell fate in the neural crest: The sympathoadrenal lineage. Annu Rev Neurosci 1993;16:129.)

acetate and cholesterol. The placenta then removes sulfate from DHEA-S, which is further transformed by 3(i-hydroxy-steroid dehydrogenase (3|i-HSD) (an enzyme not present in the fetal adrenal cortex) and used in the estrogenic pathway. The availability of DHEA-S for placental estrogen production is controlled by a positive feedback loop in which estrogen enhances production of precursor DHEA-S from fetal adrenal cells. The large amounts of estrogen produced by the placenta indicate the presence of an intact and functional fetoplacental unit.

The fetal adrenal does not develop the enzymatic capacity to produce Cortisol de novo (i.e., from endogenous cholesterol) until very late in gestation because of a lack of key rate-limiting steroidogenic enzymes (as 3|}-HSD). At midgestation, essentially 100% of Cortisol in fetal serum is of maternal origin. The increased placental oxidation of Cortisol to cortisone provides the stimulus for fetal hypothalamic-pituitary axis function and the timely onset of de novo Cortisol production. It is postulated that because the fetal production of corticosteroids is reduced, the adrenals are stimulated continuously by high levels of corticotropin and become enlarged.29 At term, less than 50% of fetal Cortisol originates from hormone produced by the maternal adrenal.

Clinical Aspects

At birth, the gland is about one third the size of the kidney, whereas in the adult, it is only about one thirtieth. This change in proportions is due not only to renal growth but also to involution of the fetal cortex after birth, so that by the end of the second postnatal month its weight is only half that at birth. In the latter half of the second year, the gland begins to increase in size and gradually attains its birth weight at or just before puberty, after which it only increases slightly in weight in adult life.

ACCESSORY TISSUE

Small accessory suprarenal glands, which may consist of cortical tissue only, often occur in the areolar tissue around the principal glands. They are sometimes present in relation to the sympathetic plexus and in relation to structures derived from the urogenital ridge: epididymis, vas deferens, broad ligament of the uterus, ovarian pedicle, or within the ovary or testis.

Adrenocortical rests may occur in 50% of newborn infants but tend to atrophy and disappear after a few weeks. They persist and enlarge in the adrenogenital syndrome or any condition of continued corticotropin stimulation. Those within the scrotum may be misinterpreted as testicular tumors.

Ectopic medullary tissue also occurs, occasionally in conjunction with cortical tissue but more often alone, as isolated masses along the abdominal aorta or in association with the sympathetic chain and the plexus (the retroperitoneal celiac plexus). These have been described by Zuckerkandl,30 whose name is associated with an especially large mass that may occur anterior to the aorta and distal to the origin of the superior mesenteric artery. Coupland characterized these masses as paraganglia or chromaffin bodies.

Ten percent of pheochromocytomas develop in "accessory" sites, particularly in ganglia around the aorta at the level of the kidney, anterior to the inferior aorta (at the level of the organ of Zuckerkandl), in the mediastinum, or in the bladder. Occasionally, they have been reported in the neck, sacrococcygeal, anal, or vaginal areas. The incidence of extra-adrenal pheochromocytoma is higher in children than adults.

Tumors of sympathoadrenal lineage (affecting mainly children) correspond to discrete stages of differentiation in this lineage and are derived from the neural crest cells. They can be located in the adrenal medulla and sympathetic ganglia and are often associated with excessive production of catecholamines and catecholamine metabolites. Neuroblastoma, the most immature and malignant of these tumors, can be considered derivatives of primitive sympathogonia or neuroblasts. Ganglioneuroblastomas are partially differentiated neuroblastomas, and ganglioneuroma is the benign form, derived from sympathetic ganglion cells. Tumors showing an immature (neuroblast) phenotype appear to have a latent capacity to differentiate into more mature tissue and have a much higher probability of spontaneous remission than those of chromaffin type. Potential therapy for the more malignant chromaffin-like tumors might involve in situ conversion to neuroblastic-type tumors using nerve growth factor or glucocorticoid antagonists.25

Chromaffin cells are included in the amine precursor uptake and decarboxylation (APUD) cell group described by Pearse31 on the basis of functional characteristics and embryologic origin. Tumors of the chromaffin tissue can occur in association with tumors of other cells of the APUD system, such as medullary carcinoma of the thyroid and hyperparathyroidism (as in MEN 2 syndrome).

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