A. Munro Neville

The clinical and pathologic featurfs of “non‐hormonal” adrenocortical tumors. Report of twenty new cases and review of the literature

The clinicopathologic features of 178 patients with “non‐hormonal” or “nonfunctioning” adrenocortical tumors are presented. Such tumors usually affect patients in the 5th, 6th, and 7th decades and occur in males twice as often as females. The prognosis is poor, most patients succumbing during the 1st year after diagnosis. The most helpful radiographic diagnostic test is the intravenous pyelogram, although arteriography and pre‐sacral air insuffiation may also aid in the diagnosis. Lymphangiography was found to be of value in assessing the lymph nodes during treatment and at subsequent followup examination. No reliable, definite indication of the functional or metastatic potential of these tumors can be made from histopathologic examination; all should be viewed as malignant. The tumors are capable of forming precursor steroids without hormonal activity. Hence they are not in fact “non‐functioning.” Their treatment should be primarily surgical, but postoperative radiotherapy should be administered if there is residual tumor. All chemotherapeutic agents are relatively ineffective but some form of combination chemotherapy may be beneficial.

Functional Activity of the Adrenal Cortex

All known hormones synthesised and secreted by the adult human adrenal cortex are steroids (Fig. 8.1) which in man are derived by a series of enzymatic steps from cholesterol. The most important and/or quantitatively dominant hormones produced are illustrated in Fig. 8.1.

Origin and Development of the Adrenal Gland

The adrenal cortex is of mesodermal origin with its parenchymal steroidogenic cells arising from the coelomic mesothelium. The most extensive study of human adrenal embryogenesis is that of Crowder, based on the Carnegie Embryological Collection (Crowder 1957). The following resume is taken largely from his descriptions which must supersede, by virtue of their completeness, the earlier but still widely quoted studies of Keene and Hewer (1927), Uotila (1940), and Velican (1948).

The Distinction Between Benign and Malignant Adrenocortical Tumours causing Cushing’s and/or the Adrenogenital Syndromes: Structural and Functional Criteria

One of the principal problems facing the diagnostic histopathologist is the differentiation of benign from malignant adrenocortical neoplasms. Such a prognostic problem is not unique to the adrenal but is common to all endocrine tumours. From the foregoing account, it is clear that many of the classical histological criteria of malignancy such as capsular and vascular invasion and prominent mitotic activity are not present, or are not prominent, in adrenocortical tumours causing hypercorticalism and which were subsequently shown to be carcinomas by their ability to metastasise. In this section we will describe and discuss some alternative approaches to assist reaching a more precise distinction of benign from malignant based on in vitro functional assessments of such lesions and their relationship to tumour structure.

Hyperaldosteronism and Related Syndromes of Mineralocorticoid Excess

The syndrome of hyperaldosteronism with low plasma renin (so-called ‘primary’ aldosteronism) was recognised as a specific clinicopathological entity by Conn in 1955. It is typified by hypokalaemic alkalosis, hypertension and muscle weakness, and is usually referred to as Conn’s syndrome, particularly when associated with a solitary aldosterone-secreting adrenal adenoma. Similar symptoms also occur when steroids, other than aldosterone, with mineralocorticoid activity are secreted in excess, as sometimes occurs in association with malignant adrenocortical tumours (p. 231).

Functional Zonation of the Adrenal Cortex

The concept of functional zonation of the adrenal cortex, and the mechanisms of intraglandular regulation of steroidogenesis that underlie it, are important both for an understanding of the normal gland, and to explain certain hitherto puzzling or paradoxical aspects of its pathology. We believe that functional zonation stems, in part at least, from different steroid concentration gradients across the cortex, and have proposed that it is the responses of the individual cortical cells to this aspect of their local microenvironment that creates and sustains some zonal differences in their steroidogenic functions (Hornsby and O’Hare 1977; O’Hare et al. 1978; Neville and O’Hare 1979).

Myelolipoma and Related Changes

The term myelolipoma was first coined by Oberling (1929) to denote a rare benign lesion of the adrenal gland which consists of admixtures of adipose, bone marrow and lymphocyte-like elements, whose first description is usually credited to Gierke in 1905. Nearly 200 examples of this rare entity have now been described in the world literature, and the review and analysis by Plaut (1958) is by far the most comprehensive. There does not appear to be either sex or side predilection and there is no correlation with anaemia in the adult, unlike extra-adrenal myelolipomas. Although normal fatty marrow will aromatise androgens to oestrogens (Frisch et al. 1980), these lesions are not associated with detectable aberrations of steroidogenesis or haematopoeisis in the vast majority of cases and hence present as ‘non-functioning’ tumours. Most are asymptomatic and are detected as incidental autopsy findings. However, some of the larger lesions may cause pain, haematuria or present as abdominal masses. With recent advances in radiological technology and sonography (Gee et al. 1975; Behan et al. 1977) an increasing number have been detected during life and removed successfully at operation (Newman and Silen 1968; Whittaker 1968; Olsson et al. 1973; Desai et al. 1979) the first successful example being recorded by Dyckman and Freedman (1957). According to Desai et al. (1979), an adrenal myelolipoma should be suspected when a biochemically non-functioning radiolucent, solid adrenal mass without neovascularity on angiography is detected.

Structure of the Adult Adrenal Cortex

The overall dimensions of the adult adrenal glands are similar; they measure on average, 5.0 cm by 2.5 cm along their major axes with the left gland tending to be slightly (2-3 mm) wider. The right gland is pyramidal in outline and is often described as resembling a cocked-hat; the left gland is crescentic in shape. Both have a concave posterior surface where they abut onto the kidneys, with a ridge-like crest that increases in prominence laterally (Fig. 4.1). The anterior surface of both glands is flat, except for the anterior groove from which the main adrenal vein emerges, and which is more prominent on the left adrenal. Computerised tomography (CT) of the adrenal glands tends to give linear or V-shaped profiles of the right gland with Y-shaped triradiate shapes formed by the left (Wilms et al. 1979).

Regulation of Growth of the Adrenal Cortex

Many experiments in animals, and pathological observations in man, have demonstrated an association between physiologically, pharmacologically and pathologically elevated levels of ACTH and enhanced protein synthesis, cellular hypertrophy, and eventually hyperplasia or conversely varying degrees of atrophy in the absence of ACTH (see Gill 1976 for review). It is clear, therefore, that ACTH, or some closely related factor, plays an important role in the regulation of growth of the human adrenal cortex. However, the simplistic view that growth takes place by the same mechanism as stimulation of steroidogenesis, i.e. with cyclic AMP as an intracellular effector, has been seriously challenged by recent observations on cultured adrenocortical cells.

‘Non-Functioning’ (Non-Hormonal) Adrenocortical Tumours

A variety of tumours, or tumour-like lesions, not associated with signs and symptoms of overt clinical hormonal excess, may involve the adrenal cortex. These include myelolipomas (p. 290), cysts (p. 294) and tumours derived from the stroma. However by far the commonest example is the so-called ‘non-functioning’ nodule, often wrongly referred to as an adenoma. These have been previously discussed in detail (p. 53).