Diagnosis of Surgical Lesions and Diseases of the Adrenal Glands

Diagnosis of Surgical Lesions and Diseases of the Adrenal Glands LOUIS T. PALUMBO, M.D., F.A.C.S.* I. SAM TASHIMA, M.D.

THE adrenal gland has finally assumed the prominence in the present horizon of medicine and surgery that it rightly deserves. This has come about in a slow but progressive manner over many decades. The developments in this field have resulted in a more thorough knowledge of the physiologic role played by both portions of the gland in our very existence. This knowledge has come from clinical evaluation, laboratory studies, isolation of hormones and chemicals from the gland, and from the studies of the effects of synthesized chemical agents upon patients with deficient or abnormal functions of the gland. As a result of this progress, both the surgical and medical management of many diseases and conditions of the adrenal glands and associated glands of internal secretion can be approached today with much better prospect of success than was true ten years ago. With the aid of chemical and other ancillary diagnostic methods or procedures, we can with reasonable accuracy establish a diagnosis and outline a positive program in patient care. Through a critical analysis of clinical material and the effects on the physiologic changes occurring as a result of the disease per se or the changes following extirpative surgery of the adrenals, an understanding of the normal and disturbed functions of these glands has been obtained. ADRENAL CORTEX

The adrenal cortex is esselltial to life. To date, 28 crystalline steroids have been isolated from the adrenal gland, but it is uncertain as to which of these are produced by the cortex itself or which, individually or in combination, are the essential ones. The functions of the cortex are associated with the (1) electrolyte metabolism, (2) carbohydrate metaFrflm the Department of Surgery, Veterans Administration Center, Des Moines, Iowa * Chief of Surgical Service. 193

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bolism and certain aspects of the metabolism of protein and fats, (3) renal activity, (4) growth, (5) resistance to stress, (6) blood pressure, (7) muscular response and (8) activities similar to these produced by certain gonadal hormones. In adrenal insufficiency, either acquired or after adrenalectomy, a marked reduction in the total base occurs; this is due to loss of sodium. This loss is a result of diminished reabsorption by the renal tubules and an increase in water excretion. Dehydration then occurs producing an increase in serum potassium as a result of a reduced urinary excretion rate and loss from the extracellular fluid compartment. The deficiency in adrenal cortical function may produce hypoglycemia, muscular weakness and hypotension and a poor response to any experienced stress. The cortical steroids also contain estrogenic, androgenic and progestational factors; these are known as 17-ketosteroids. The daily urinary excretion rate is 14 mg. per 24 hours in men and 9 mg. in women. The adrenal cortex secretes 9 mg. in both sexes; in man the other 5 mg. is derived from testicular function. Lesions and TUIllors of the Adrenal Cortex

The tumors of this portion of the gland may be malignant or benign. Some may be asymptomatic and found only at autopsy. The inactive tumors are usually nonhormonal in character and manifest themselves by signs and symptoms referable to a large retroperitoneal mass. Pain in the upper abdomen or flank, becoming worse after exercise, is usually the first symptom. Symptoms of malaise, fatigue and diminution of appetite are often present. Metastasis may occur to the lungs, heart and adjacent viscera. Examination of the abdomen may reveal a large mass in the loin. A roentgenogram (flat film) of the abdomen may show a large dense shadow beneath the diaphragm with displacement of the kidney downward. Perirenal air insufflation will usually outline the tumor and its relation to the adjoining structures. The prognosis of most nonhormonal tumors is not good; because of lack of symptoms an early diagnosis is not established and therefore the tumor usually reaches a large size before treatment is instituted. The hormonally active cortical tumors or changes usually manifest themselves by the adrenogenital or the Cushing syndrome. The adrenogenital syndrome may result from overactivity of a normal gland, from hyperplasia and more rarely from an adenoma or carcinoma. It is seen more frequently in the female, in whom the changes consist in the appearance of male secondary sex characteristics and the repression of female characteristics and function (Fig. 45). In general, the earlier in life the lesion develops, the more pronounced is the masculinization;

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hence in very young children the changes are those of pseudohermaphroditism. If the changes occur in prepubertal life, the masculinization is less complete. In males, the juvenile form of the syndrome causes precocious sexual development with genital enlargement and hirsutism, often associated with rapid increase in stature and muscular development, or with obesity. In the adult male the disease is rare and then the tendency- is more toward feminization than toward virility.

B A Fig. 45. A, Characteristics of adrenogenital syndrome in a girl of 16 with a tumor of the left adrenal with marked androgenic changes for 2 years. Taken before operation, the photograph shows a male torso and marked hirsuties. B, Changes 1 month after tumor was removed. In this picture the girl's figure is feminine, the breasts have hypertrophied and hirsuties is less. (Courtesy Cahill et al.: Adrenal Cortical Tumors. Burg., Gynec. & Obst. 74: 281-305,1942.) .

Cushing's syndrome is a term now used to describe a symptom complex without regard to etiology. It may occur at any age; however, it is most common up to and including early adult life. The incidence is four times greater in the female. Such a syndrome is often associated with a basophilic adenoma of the pituitary gland, or it may be due to an adrenal tumor, either benign or malignant, or caused by bilateral adrenal cortical hyperplasia. The nature of the clinical manifestations will depend largely on the sex and age of the individual at the time of onset of the disease. They include rapidly developing obesity, moon face, buffalo hump (accumula-

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Fig. 46. A, Photograph of J. E. 0., aged 26, during military service and prior to illness. Picture taken sometime in 1945. B, C, Same patient on January 9, 1951, at age of 31. Cushing's syndrome has developed. D, Eight weeks after bilateral adrenalectomy; revealing progressive changes back to normal.

tion of fat at base of neck and shoulder regions), purplish striae on lower abdomen and thighs, acne; amenorrhea and hirsutism in the female; and impairment of sexual functions in the male (see Fig. 46.) In

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addition, hypertension, frank or latent diabetes, disturbances of nitrogenous metabolism and osteoporosis are frequently present. In order to complete the picture, the following should be included: polycythemia, cyanosis, purpura or ecchymosis, asthenia, polyphagia, polydipsia, polyuria, mental changes and occasional pigmentation of the skin. The following diagnostic guide for the surgical management of Cushing's syndrome has been suggested by others: (1) If the first adrenal gland explored is atrophic, it is almost certain that the other gland contains a tumor. (2) If the first adrenal gland explored is large, the patient has adrenal hyperplasia and the other gland will be large also. (3) If the first adrenal gland explored is normal in size, this adrenal and its opposite are probably hyperfunctioning though not hyperplastic and a tumor in the other gland is unlikely. Diagnosis

The identification of syndromes due to adrenal cortical diseases or conditions depends primarily on the clinical picture. Further investigation should include a well documented history, a thorough physical examination and specific laboratory and roentgenologic studies. The age of onset of the symptoms and changes, the duration of the disease, the presence or absence of the external phenomena described above, the presence or absence of abdominal and pelvic masses a\fl in establishing a preliminary diagnosis and will provide the initial direction for further study. The significant laboratory studies include the determination of the urinary 17-ketosteroids, salt tolerance tests, blood electrolyte determinations, glucose tolerance curve, and the presence or absence of anemia or polycythemia. The x-ray studies should include views of the sella turcica for enlargement or destruction indicative of pituitary tumor, films taken of the long bones for osteoporosis, pyelography and perirenal insufflation of air for visualization of an adrenal tumor or adrenal cortical hypertrophy. When the diagnosis of adrenal cortical hyperfunction is established, the determination of the presence of absence of an adrenal tumor is dependent upon the following findings: (1) palpation of an abdominal mass, (2) perirenal insufflation studies demonstrating the existence of an adrenal mass by x-rays, (3) pyelographic evidence of a suprarenal mass, (4) excessive urinary excretion of neutral 17-ketosteroids or estrogens. Finally, (5) it may be necessary to explore the adrenals for evidence of a tumor or hypertrophy. Differential Diagnosis

The differential diagnosis includes pituitary basophil ism , arrhenoblastoma of the ovary, thymic and pineal tumors, hyperostosis frontalis

t Louis T. Palumbo, I. Sam Tashirr.a 198 interna and intersti tial or Leydig cell tumors of the ovary, and Addiso n's disease. Generally, Cushing's syndro me in children is associated with the presence of an adrena l tumor. In the adult, however, unless laborat ory or clinical findings point to the adrena l gland, the probab ility is that the condition is not caused by an adrena l cortical tumor.

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Fig. 47. Carcino ma of thymus, showing the fatness of the face, neck and trunk and the striae atrophicae, all similar to body changes seen in Cushing's syndrom e. (Compare .with Figure 46, B, C.) (Courtes y Leyton, 0., Turnbul l, H. M. and Bratton , A. B.: Primary Cancer of the Thymus with Plurigla ndular Disturba nce. J. Path. & Bact. 34: 635-660, 1931.) .

Arrhenoblastoma of the ovary is a solid tumor produc ing virilism . The patient develops amenorrhea, hirsutism, hypert rophy of the clitoris and in general becomes masculine. The metabo lic disturb!1nces charact eristic of Cushing's disease do not develop. Urinar y excretion of the neutral 17-ketosteroids is within normal limits. Despite the laborat ory and x-ray studies, the diagnosis is often settled by an explora tory laparot omy.

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Thymic tumors, particularly certain malignant lesions, are associated with virilism and the metabolic disturbances as seen in a Cushing's syndrome (Fig. 47). The clinical manifestations as such are probably due to an associated adrenal hyperplasia. Pineal tumors occasionally result in premature puberty in young boys but they lack the typical obesity, hypertension and striae. However, the tumor produces signs and symptoms characteristic of an intracranial lesion. Hyperostosis frontalis interna usually occurs in women during the fifth decade. The systemic and metabolic changes are similar to those of Cushing's syndrome. The bony changes in the skull are characteristic for this disease; there is a symmetrical hyperostosis with an increased thickness of the frontal, parietal and occipital portions. In addition there is absence of a diffuse osteoporosis, normal blood electrolyte levels, and a normal urinary 17-ketosteroid excretion rate. Interstitial or Leydig cell tumors of the ovary are extremely rare. They produce masculinization without metabolic disturbances as seen in Cushing's syndrome. The urinary excretion of 17-ketosteroids is greatly increased. Addison's disease is due to atrophy of the adrenal cortex or destruction of this portion of the adrenal by tuberculosis or some other disease. It occurs usually in the adult between the ages of 30 and 50 and is associated with local and systemic manifestations without the principal primary androgenic or estrogenic changes seen in the Cushing or adrenogenital syndrome. Pigmentation of the skin and mucous membranes occurs, usually of a "bronzing" type (Fig. 48). Hypotension, dyspnea and palpitation, x-ray evidence of a small heart and low voltage as seen on the electrocardiogram are characteristic of the cardiovascular changes associated with the disease. Anorexia, nausea and vomiting and bowel disturbances are common complaints. In association with these are asthenia, weight loss, muscular wasting, fatigue, and in some nervousness and irritability. The 17ketosteroids excretion in the urine is low; the carbohydrate metabolism is disturbed, generally resulting in a fasting hypoglycemic state. Diuresis does not usually develop following intake of water in fairly large amounts. A roentgenogram (flat plate) of the abdomen may show calcification oLthe adrenal glands. The "water test" may be employed as a simple screening test. If the volume of night urine exceeds that of any of the hourly specimens following water ingestion, Addison's disease is suggested. The Thorn (eosinophil) test, glucose tolerance test and a trial use of desoxycorticosterone will aid in confirming the diagnosis of Addison's disease.

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Louis T. Palumbo, I. Sam Tashima ADRENAL MEDULLA

The medullary portion of the adrenal gland is mainly concerned with the production and systemic physiologic action of epinephrine and

Fig 48. Pigmentation in Addison's disease. Female showing absence of pubic hair, pigmentation of areolae, thighs, knees and legs. Patient usually had normal menses, occasionally interrupted by menorrhagica. Note deep pigmentation of appendectomy scar. (Courtesy Selye, Textbook of Endocrinology, Acta Endocrinologica, University of Montreal, Montreal, Canada, 1947.)

norepinephrine. Epinephrine causes both excitatory and inhibitory effects. Norepinephrine is entirely a vasoconstrictor. The functions of the adrenal gland are thus closely related and influence many of the functions of the sympathetic portion of the autonomic nervous system. Upon stimulation

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of this adrenosympathetic system the following actions occur: (1) rise in systemic blood pressure, accompanied by dilatation of vessels of the skeletal muscles; (2) hyperglycemia by mobilization of the carbohydrate stores of the liver; (3) increase in the number of red blood cells by splenic contracture; (4) bronchiolar dilatation; (5) inhibition of tone and movement of muscles of the intestine and excitation of the pyloric, ileocolic and internal anal sphincter; (6) excitation of muscles of the gallbladder, ureter, trigone and sphincter of the bladder; and (7) dilatation of the pupil. Lesions and Tum.ors of the Adrenal Medulla

These tumors are divided into those hormonally active and inactive. The inactive hormonal tumors are sympathogonioma, neuroblastoma and ganglioneuroma; they may be benign or malignant. They are manifested by a large mass in the abdomen and evidence of distant metastasis. The hormonally active tumors are pheochromocytoma and chromaffinoma. The latter may be located anywhere in the abdomen, chest and neck. The effects produced by these tumors are based on the release of excessive amounts of epinephrine and norepinephrine. Pheochromocytoma gives rise to paroxysms of hypertension accompanied by anxiety, headache, precordial and epigastric distress, palpitation, sweating, pallor, coldness Qf the extremities, nausea and vomiting. It is a disease which occurs mainly in the adult in about an equal sex ratio. The attacks increase in frequency and duration; the cause of death may be cerebral hemorrhage, chronic congestive heart failure, acute ventricular failure, Addison's disease or adrenal hemorrhage. The tumor occurs bilaterally in 20 per cent of cases. Diagnosis of Pheochrom.ocytom.a

The diagnosis of pheochromocytoma depends upon an awareness on the part of the physician of the existence of this clinical entity. A careful history with meticulous attention to details is important. When the clinical picture is strongly suggestive of a benign tumor of this type, the following procedures will aid in the diagnosis: (1) palpation for a mass in the abdomen, (2) x-rays of the abdomen, (3) intravenous pyelography, (4) perirenal insufflation of air and (5) pharmacologic tests. Procedures 2, 3 and 4 may reveal a tumor above the kidney. However, small lesions may not be shown by any of these methods. The following pharmacologic tests have been employed: (1) those designed to stimulate discharge of pressor compounds from the tumor and (2) those designed to lower blood pressure by inhibition of the pressor compounds. The histamine test belongs to group 1 above. However, a negative test does not eliminate the possibility of a tumor. A rapid elevation of blood

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pressure occurs within one to three minutes after the administration of histamine intravenously. This peak may be 100 mm. above the patient's elevated pressure. If the patient's pressure is already very high this test is dangerous for it may result in a cerebral hemorrhage, therefore it is recommended for use only in those patients in whom the resting blood pressure does not exceed 150 mm. systolic and 110 mm. diastolic. No sedatives or narcotics of any kind should be used for 24 hours prior to the test. After the patient has been lying in a quiet room for 15 minutes and his pressure has become stabilized, 0.025 to 0.25 mg. of histamine is injected rapidly intravenously. The blood pressure is recorded every 30 seconds for the next four minutes and at one minute intervals for the remaining 15 minutes. In the second group, inhibitors of pressor compounds are such drugs as dibenamine, Regitine and benzodioxane; they produce a significant drop in blood pressure, a depressor response. Not all patients with pheochromocytoma give positive results and false positive values have been found in patients with uremia and hypertensive vascular diseases. These three depressor agents are used in suspected cases of pheochromocytoma with sustained hypertension with the resting control blood pressure level greater than 150/110. Of these three agents, benzodioxane is the most reliable and results in less false positive tests. None of the above agents and pharmacologic tests is infallible. More than a single test may be necessary to establish the diagnosis. The use of dibenamine as a diagnostic test should be discouraged because it gives too many false positive results in patients with essential hypertension. Regitine is a safe drug from the standpoint of freedom of unpleasant side reactions and it does not produce the alarming rise in blood pressure sometimes noted after benzodioxane administration. Final evaluation of this agent will have to"await further experience in its use. A complete elaboration of the details of these tests may be found elsewhere; space does not permit a detailed presentation. For those interested in a more complete survey a study of the reports by Chapman and Singh listed in the references will prove invaluable. Differential Diagnosis of Adrenal Medullary Lesions

Neuroblastoma may be compared with a Wilms tumor of the kidney. The latter produces renal symptoms with hematuria and pyelographic changes. Chloroma may simulate neuroblastoma, but it differs in producing an exophthalmos and lesions in the bone of the orbit and other evidence of leukemia. The classical picture of hyperadrenalism of pheochromocytoma is not simulated by any other disease. A painstaking history of previous

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paroxysmal attacks, x-rays and perirenal insufHations usually will lead to a correct diagnosis. REFERENCES Bartels, E. C. and Cattell, R. B.: Pheochromocytoma; Its Diagnosis and Treatment. Ann. Surg. 131: 903, 1950. Cahill, C. F.: Hormonal Tumors of Adrena!' Surgery 16:233, 1944. Cahill, G. F.: Physiology of the Adrenal. J. Urol. 73: 437, 1955. Cahill, G. F. amd Melicow, N. M.: Tumors of the Adrenal Gland. J. Urol. 64: 1, 1950. Chapman, W. P. and Singh, M.: Evaluation of Tests Used in the Diagnosis of Pheochromocytoma. I. Modern Concepts of Cardiovascular Diseases. Bul!. Am. Heart A. 23: 22, 1954. Chapman, W. P. and Singh, M.: Evaluation of Tests Used in the Diagnosis of Pheochromocytoma. II. Modern Concepts of Cardiovascular Diseases. Bull. Am. Heart A. 23: 225, 1954. Crooke, A. C.: The Endocrine Disorders Associated with Cushing's Syndrome and Virilism. J. Clin. Endocrino!. 7: 787, 1947. Galante, M., Rukes, M., Forsham, P. H. and Bell, H. G.: The Use of Corticotropin, Cortisone and Hydrocortisone in General Surgery. S. CLIN. NORTH AMERICA 34: 1201 (Oct.) 1954. Geschickter, G. F.: Tumors of the Suprarenal Gland. Arch. Path. 15: 775, 1933. Graham, J. R.: Pheochromocytoma and Hypertension. An Analysis of 207 Cases. Internat. Abst. Surg., Surg., Gynec. & Obst. 92: 105, 1951. Grimson, K. J., Emlet, J. R. and Hamblen, E. C.: Diagnosis and Management of Tumors of the Adrenal Gland. Ann. Surg. 134: 463, 1951. Kenyon, A. T.: Adrenal Cortical Tumors, Physiologic Considerations. Surgery 16: 194,1944. Kepler, E. J. and Mason, H. L.: Relation of Urinary Steroids to the Diagnosis of Adrenal Cortical Tumors and Adrenal Cortical Hyperplasia. Quantitative and Isolation Studies. J. Clin. Endocrino!. 7: 543, 1947. Mason, H. L. and Engstrom, W. W.: The 17-Ketosteroids, Their Origin, Determination and Significance. Physiolo. Rev. 30: 321, 1950. Priestley, J. T.: Lesions of the Adrenal Gland. S. CLIN. NORTH AMERICA 32: 1053 (Aug.) 1952. Priestley, J. T., Sprague, R. C., Walters, W. and Salassa, R. N.: Subtotal Adrenalectomy for Cushing's Syndrome. Ann. Surg. 134: 464, 1951. Richards, V. and Hatch, F. N.: Surgical Experiences with Pheochromocytoma. Ann. Surg. 134: 40, 1951. Scott, W. W. and Hudson, P. B.: Surgery of the Adrenal Glands. Springfield, Ill., Charles C Thomas, 1954. Sprague, R. G., Kivale, W. F. and Priestley, J. T.: Management of Certain Hyperfunctioning Lesions of the Adrenal Cortex and Medulla. J.A.M.A. 151: 629,1953. Tashima, I. S.: Surgical Treatment of Lesions and Diseases of the Adrenal Glands. Surg. Staff Bull., Veterans Administration Hospital, Des Moines, Iowa, Vol. 9, No.2, June, 1955. Wintersteiner, C.: The Adrenogenital Syndrome. J.A.M.A. 116: 2679, 1941. Veterans Administration Center Des Moines 10, Iowa