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Adrenal Lymphocytic Infiltration and Adrenocortical Tumors in a Patient with 21-Hydroxylase Deficiency

N Engl J Med 1999; 340:1121-1122April 8, 1999

Article

To the Editor:

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency results in deficient production of cortisol and aldosterone, chronic stimulation of the adrenal cortex by corticotropin, and overproduction of androgens. Cortisol-replacement therapy often fails to normalize corticotropin and androgen secretion, and high doses may be needed.1 Adrenocortical tumors, including cancers, are rare in patients with 21-hydroxylase deficiency but have been reported in patients with large adrenal glands and presumably inadequate cortisol therapy.2

A 16-year-old girl with 21-hydroxylase deficiency was evaluated for hirsutism and primary amenorrhea. She had a muscular habitus, hyperpigmentation, and a low voice. Physical examination revealed a beard, cystic acne, and Tanner stage 2 breast development. While taking 25 mg of hydrocortisone and 0.5 mg of fludrocortisone daily, she had high serum corticotropin, 17-hydroxyprogesterone, and testosterone concentrations and high levels of plasma renin activity.

Because of persistent, severe symptoms, autonomy of adrenocortical steroidogenesis, and marked adrenal enlargement suggestive of tumor formation despite appropriate adjustments in therapy, informed consent was obtained for bilateral adrenalectomy, and the operation was performed without complications. Both adrenal glands weighed 52 g and had a nodular hyperplastic structure. Histologic and immunohistochemical analyses revealed massive lymphocytic infiltration with formation of lymphoid follicles (Figure 1AFigure 1Histologic Sections of the Adrenal Cortex of a Patient with Severe Congenital Adrenal Hyperplasia. and Figure 1B) and diffuse sheets of adrenal cells with compact cytoplasm, an increased mitotic rate, atypical mitotic figures, and a high nuclear grade suggestive of adrenal carcinoma (Figure 1C). There was no staining for major-histocompatibility-complex class II molecules, which is present in adrenal adenomas but not in carcinomas.3 Subsequently, while receiving 20 mg of hydrocortisone and 0.5 mg of fludrocortisone daily, the patient had regular menses, an increase in breast size, resolution of acne, improvement of hirsutism and mood, and a decrease in muscle strength and salt wasting. Two years after surgery, there was no evidence of recurrence.

A major cause of our patient's adrenal findings was prolonged corticotropin stimulation. The lymphocytic infiltration of her adrenal glands may be a secondary finding; however, a local lymphocyte–adrenal-cell interaction might have contributed to her hyperandrogenism and adrenocortical growth and histologic signs of carcinoma. Cytokines produced by leukocytes increase adrenal steroid production independently of corticotropin.4 Moreover, the growth of tumor cells may be potentiated by lymphocytes and cytokines, and aberrant expression of a cytokine receptor has been implicated in the formation of an adrenal adenoma.5

Bilateral adrenalectomy was a successful treatment for this patient and should be considered in patients with congenital adrenal hyperplasia with difficult-to-control hyperandrogenism and large nodular adrenal glands.

Deborah P. Merke, M.D.
Stefan R. Bornstein, M.D.
Demetrios Braddock, M.D., Ph.D.
George P. Chrousos, M.D.
National Institutes of Health, Bethesda, MD 20892

5 References

1. 1

   Merke DP, Cutler GB Jr. New approaches to the treatment of congenital adrenal hyperplasia. JAMA 1997;277:1073-1076
   CrossRef | Web of Science | Medline

2. 2

   Bauman A, Bauman CG. Virilizing adrenocortical carcinoma: development in a patient with salt-losing congenital adrenal hyperplasia. JAMA 1982;248:3140-3141
   CrossRef | Web of Science | Medline

3. 3

   Marx C, Wolkersdorfer GW, Brown JW, Scherbaum WA, Bornstein SR. MHC class II expression -- a new tool to assess dignity in adrenocortical tumours. J Clin Endocrinol Metab 1996;81:4488-4491
   CrossRef | Web of Science | Medline

4. 4

   Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995;332:1351-1362
   Full Text | Web of Science | Medline

5. 5

   Willenberg HS, Stratakis CA, Marx C, Ehrhart-Bornstein M, Chrousos GP, Bornstein SR. Aberrant interleukin-1 receptors in a cortisol-secreting adrenal adenoma causing Cushing's syndrome. N Engl J Med 1998;339:27-31
   Full Text | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Deborah P. Merke, Gordon B. Cutler. (2001) NEW IDEAS FOR MEDICAL TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA. Endocrinology & Metabolism Clinics of North America 30:1, 121-135
   CrossRef

2. 2

   Deborah Merke, Mahmoud Kabbani. (2001) Congenital Adrenal Hyperplasia. Paediatric Drugs 3:8, 599-611
   CrossRef

3. 3

   Merke, Deborah P., Chrousos, George P., Eisenhofer, Graeme, Weise, Martina, Keil, Margaret F., Rogol, Alan D., Van Wyk, Judson J., Bornstein, Stefan R., . (2000) Adrenomedullary Dysplasia and Hypofunction in Patients with Classic 21-Hydroxylase Deficiency. New England Journal of Medicine 343:19, 1362-1368
   Full Text

4. 4

   Stefan R. Bornstein. (2000) Cytokines and the adrenal cortex: basic research and clinical implications. Current Opinion in Endocrinology & Diabetes 7:3, 128-137
   CrossRef