Adrenogenital syndrome

The patient is a 19-year-old white man with a medical history significant for a salt-wasting form of congenital adrenal hyperplasia that was diagnosed at birth. He underwent puberty in third grade and had advanced bone age. At the age of 16 years, he was noted to have testicles of 25 cm3. Routine examination at the age of 19 years revealed bilateral testicular masses (left, 9 x 5.5 cm; right, 9 x 5 cm). The patient denied any pain, and medications at this time included fludrocortisone acetate and cortisone acetate. Ultrasound of the testicles revealed an infiltrative process bilaterally. Serum (3-human chorionic gonadotropin and a-fetoprotein levels were within normal limits. The patient was assumed to have a malignant neoplasm and underwent a left orchiectomy.

The specimen included a 197-g, 10.5 x 6 X 5.5-cm testicle. The cut surface was firm and brown, with a scant amount of scattered white fibrous tissue. A 1-cm remnant of normal-appearing testicular tissue was present (Figure 1 ). Microscopically, the lesion was composed of sheets of cells with a moderate amount of cytoplasm with small vacuoles. The nuclei were round, varied in size, and contained nucleoli. A few cells had a light brown intracytoplasmic pigment, presumably lipofuscin. There were a few foci of intracytoplasmic, slightly grainy, red staining material. There were no crystals of Reinke or mitoses identified. There was a variable amount of fibrovascular stroma present, and the lesion was confined within the capsule of the testicle (Figures 2 and 3).

Electron microscopy of this lesion revealed abundant irregular mitochondria, some with a typical lamellar form of cristae. There were foa of lysosomes that contained lipid droplets and abundant, well-developed smooth endoplasmic reticulum (Figure 4).

Immunohistochemical studies showed a focally positive reaction to antitestosterone and a positive reaction to anticortisol. The tumor was negative for S100 protein.

What is your diagnosis?

Pathologic Diagnosis: Testicular Tumor of the Adrenogenital Syndrome

More than 40 cases of benign testicular tumors that occurred in patients with previous diagnoses of the adrenogenital syndrome have been reported in the literature.14 These tumors continue to be a diagnostic challenge because of their histologic similarity to the Leydig cell tumor, a potentially malignant neoplasm.

Testicular tumors of the adrenogenital syndrome (TTAGS) are grossly well-demarcated, unencapsulated, brown to green tumors with lobules separated by thick fibroseptae. They have pushing borders and obliterate most of the testicular parenchyma. Histologically, they are composed of sheets, nests, and cords of large polygonal cells with eosinophilic cytoplasm. They contain lipochromic pigment and, to date, have not been shown to have crystals of Reinke. Most nuclei are small and round with central nucleoli. Bizarre nuclei are also seen, and rare mitoses have been reported.1

Useful criteria to differentiate TTAGS from Leydig cell tumors include clinical history of the adrenogenital syndrome bilaterality and decrease in size of tumors after corticosteroid therapy. TTAGS have a dark brown-green macroscopic appearance, whereas Leydig cell tumors have a yellow-tan macroscopic appearance. Lipochromic pigment is found in greater amounts in the TTAGS, and seminiferous tubules with atrophy sclerosis are present in the surrounding parenchyma. Seminiferous tubules are usually replaced by tumor in the Leydig cell tumor. Crystals of Reinke are found in 25% to 40% of Leydig cell tumors and have never been reported in TTAGS.2

Electron microscopy of Leydig cell tumors reveals intracytoplasmic organelles and inclusions of steroid-secreting cells, such as vesicular smooth endoplasmic reticulum, whorls of smooth endoplasmic reticulum membranes occasionally surrounding lipid droplets, pleomorphic mitochondria with tubulovesicular or lamellar cristae, and prominent primary and secondary lysosomes, including lipofuscin, lipid droplets, and occasional crystals of Reinke. The only indicators of malignancy may be pleomorphic nuclei and large, multiple nucleoli.5

Adrenocortical hyperplasia and adrenocortical neoplasms have pleomorphic mitochondria with tubulovesicular and lamelliform cristae and occasional inclusions. The smooth endoplasmic reticulum is well developed, and there is evidence of lipid rich and depleted cells. There may be occasional rudimentary cell junctions and thin basement membranes.5

In general, steroid-secreting lesions contain numerous lipid droplets and a well-developed smooth endoplasmic reticulum. Primary and pleomorphic secondary lysosomes and mitochondria with tubulovesicular cristae are also found.5 Therefore, it is doubtful that electron microscopy is a useful study for diagnosing or characterizing TTAGS.

The cell of origin of TTAGS has been debated. Adrenal cortical rest cells, Leydig cells, and hilar pluripotential cells have been suggested as potential cells of origin. The finding of focally positive immunohistochemical reactivity with antitestosterone, as well as location of the lesion, may suggest a Leydig cell origin. Adrenocortical rest cells have also been proposed, with evidence of 11-(3-hydroxylase activity and cortisol production in TTAGS. Adrenal rests are usually found in the hilar region and not intraparenchymally. Therefore, it is possible that TTAGS arise from an initially small nonpalpable mass, possibly in the hilar region at an early age, before detection. However, zones of the adrenal cortex are lacking in TTAGS.1,4

The importance of distinguishing TTAGS from Leydig cell tumors on fine needle biopsy specimens rests in the fact that metastases have never been reported in TTAGS and orchiectomy may be unnecessary with this diagnosis. Tumor regression with corticosteroid therapy is possible, although noncompliance and side effects of these drugs and eventual nonresponsiveness of some tumors may necessitate eventual orchiectomies.1,2

In summary, it is important to distinguish TTAGS from Leydig cell tumors, since metastases of TTAGS have never been reported and conservative treatment of this lesion may be possible. Because of the bilaterality, TTAGS most likely represents interstitial hyperplasia. Although the evidence of the cell of origin remains inconclusive, the most likely explanation is the Leydig cell under hormonal influence. This lesion has been shown to respond to elevated levels of adrenocorticotropic hormone and to regress with cortisone. The cells have been shown to produce cortisol and show a positive immunohistochemical staining pattern to antitestosterone and anticortisol. Electron microscopy of TTAGS shows a nonspecific pattern consistent with a steroid-secreting lesion. The best diagnostic criteria to distinguish TTAGS from Leydig cell tumors continues to be clinical history, biochemical behavior, and histologic features.

References

1. Rutgers JL, Young RH, Scully RE. The testicular "tumor" of the adrenogenital syndrome. Am / Surg Pathol. 1988;12:503-513.

2. Knudsen JL, Savage A, Mobb GE. The testicular 'tumour' of adrenogenital syndrome: a persistent diagnostic pitfall, Histopathology 1991;19:468-470.

3. Keely EJ, Matwijiw I, Thliveris JA, Faiman C. Congenital adrenal hyperplasia with testicular tumors, aggression, and gonadal failure. Urology. 1993;41:346349.

4. Combes-Moukhovsky ME, Kottler ML, Valensi P, Boudou P, Sibony M, Attali JR. Gonadal and adrenal catheterization during adrenal suppression and gonadal stimulation in a patient with bilateral testicular tumors and congenital adrenal hyperplasia. J Clin Endocrine! Metab. 1994;79:1390-1394.

5. Erlandson RA. Diagnostic Transmission Electron Microscopy of Tumors. New York, NY: Raven Press; 1994.

Janine Mangini, MD; Peter R. Olson, MD

Accepted for publication August 16, 1999.

From the Department of Pathology, Allegheny General Hospital, Pittsburgh, Pa.

Presented by Janine Mangini, MD, at the Pennsylvania Association of Pathologists' Annual Meeting, Hershey, Pa, May 3, 1997, as part of a residents' forum.

Reprints not available from the author.

Copyright College of American Pathologists May 2000
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