Unusual tumefactive spindle-cell lesions in the adrenal glands

Advances in Pathology Unusual Tumefactive Spindle-cell Lesions in the Adrenal Glands J. AIDAN CARNEY, MD, PHD, FRCPI In 1967, Reed and Patrick I drew attention to pec u l i a r microscopic, s p i n d l e - c e l l n o d u l e s t h a t w e r e closely associated with the capsule o f the a d r e n a l g l a n d in 11 p a t i e n t s ~ 1 0 w o m e n ( m e a n age, 70 years) and 1 m a n (age, 77 years). T h e lesions were c o n s i d e r e d to be the result o f failure o f m a t u r a t i o n o f a d r e n a l blastema into cortical cells, but their resemblance to o v a r i a n cortical s t r o m a was n o t e d . F o u r years later, W o n g a n d W a r n e r 2 i n t e r p r e t e d similar microscopic findings in eight w o m e n (six were postmenopausal) as being most consistent with metaplasia o f embryologically c o m p e t e n t m e s e n c h y m a l cells, especially those o f the a d r e n a l capsule, into ovarian theca; the process, it was thought, was possibly d u e to relatively u n o p p o s e d p i t u i t a r y activity. I n 1977, Fidler 3 a g r e e d with this interpretation and described microscopic, w e d g e - s h a p e d n o d u l e s r e s e m b l i n g ovarian s t r o m a o r theca in 14 w o m e n (13 were postmenopausal); the lesions often were muhicentric and bilateral. T h i s article describes macroscopic spindle-cell fibrotic masses in the a d r e n a l glands o f two patients. One, an 80-year-old man, had diffuse e n l a r g e m e n t o f b o t h a d r e n a l glands caused by the process; the other, a p o s t m e n o p a u s a l woman, had multiple small masses in o n e adrenal gland.

formed. There was no family history 9 adrenal disease, and the patient's three siblings and four children are well. Autopsy showed that the immediate cause of death was bronchopneumonia. However, the striking gross finding was e n l a r g e m e n t of both adrenal glands. Additional findings included moderate generalized arteriosclerosis and hyperplastic pulmonary hilar lymph nodes. The pituitary gland and the testes (one was undescended) were not examined. No explanation was found for the patient's general debility and wasting, and the death was attributed to an undetermined underlying disease process. Case 2. A 60-year-old women complained of gross hematuria. She had had four children and had reached the

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REPORT OF CASES

Case 1. An 80-year-old man had had numerous admissions to another hospital because of lymphadenopathy and vague illness for 2 years. Biopsy of cervical, inguinal, and supraclavicular lymph nodes had revealed only reactive hyperplasia. These diagnoses were confirmed at the Mayo Clinic. A clinical diagnosis was not made, and the patient was treated empirically for "lymphoma" with a course of cyclophosphamide in moderate doses; there was no improvement. During the last year of his life, he had progressive weight loss and general deterioration. On his final hospital admission, computed tamographic examination of the abdomen (performed as part of a search for occult malignancy) disclosed enlargement of both adrenal glands. Because of the patient's worsening condition, studies o f adrenal function and an adrenal biopsy were not perFrom the Section of Surgical Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Revision accepted for publication 26 November 1987. Address correspondence and reprint requests to Dr. Carney: Section of Surgical Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. 0046-8177/87 $0.00 + .25

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METRIC FIGURE t, Top, Outline of right adrenal gland is Indicated by dark color of residual cortex which is surrounded by thick whitish rind that also extends into the gland parenchyma. Boffom, Left adrenal gland ls enlarged by a solid, irregular, gray and white nodule. The thickened capsule of the gland is visible (arrows).

ADRENALTUMEFACTIVESPINDLE-CELLLESIONS(Carney]

A FIGURE 2. A, Portion of gland has been expanded and replaced by fibrous mass that abuts cortex and medulla. Portions of the capsule are markedly thickened [arrows]. Irregular wavy fibrous bands extend from the capsule into the retroperitoneal fat. (x 7.) B, More or less parallel coarse fibrous bands emanate from adrenal capsule (right] and coalesce to form "capsule" The nodular appearance of the fibrosis is evident. [ x 40.)

menopause at age 50 years. Because of perimenopausal symptoms, she had been treated with conjugated estrogens and later with medroxyprogesterone. Excretory urographic and abdominal sonographic examinations disclosed a tumor in the left kidney. Chest roentgenograms revealed two masses in the right lung compatible with metastatic carcinoma. The patient was normotensive and had no clinical signs of adrenal hyperfunctiou or other endocrine abnormality. A radical left nephrectomy (which included adrenalectomy) was performed. The kidney contained a renal cell carcinoma that had invaded perinephric fat, the renal pelvis, and the renal vein. The findings in tile adrenal gland are described below. At 1 year after surgery, the patient is receiving chemotherapy for the metastatic pulmonary disease. PATHOLOGIC FINDINGS Case 1. T h e adrenal glands were normal in shape, weighed 23 and 32 g, respectively, and felt hard. On the cut surface, the b r o w n and focally yellow c o r t e x was intermittently i n t e r r u p t e d by whitish tissue that extended into the medullary portion o f the gland, in places forming multinodular masses up to 1.3 • 1.2 • 1 cm. It also penetrated into the periadrenal fat, forming a whitish rind

around the gland that blended peripherally with the yellowish retroperitoneal fat (fig. 1). Microscopically, the adrenal glands were similar. Almost all of the capsule was massively thickened; focally, however, its thickness was normal. Emanating from the capsule at right angles or in an arborizing fashion, a series of thick, hypocellular, fibrous bands radiated into the periadrenal fat for a limited distance and then terminated, or they swept laterally, joining together to form a pseudocapsule (fig. 2). Commonly, the fibrous tissue was arranged in a nodular fashion. T h e areas between tile fibrous bands were occupied by three types of tissue: 1) small amounts of residual native adipose tissue, 2) large markedly hypocellular zones of loose myxomatous tissue featuring d i s p e r s e d collagen fibers a n d n a r r o w collagen bundles, and 3) zones of variable cellularity (fig. 3A). In the third type, the cellularity was greatest at the "advancing" peripheral edge, where the cells were polygonal and spindle, were large, and had homogeneous, acidophilic cytoplasm occasionally featuring an aggregated yellowish pigment reminiscent of lipofuscin (figs. 3B and C). The nuclei were vesicular and sometimes had a prominent eosinophilic nucleolus; 981

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FIGURE 3. A, Partial replacement of pertadrenal adipose tissue by dense, hyalinized, fibrous tissue [top center] and by hypocellular tissue [lower left]. B, Moderately cellular tissue composed of cells with spindle and polygonal nuclei and acidophilic cytoplasm. Several of the vesicular nuclei have a fine groove [arrows] and a small nucleolus. Cellularity is increased by mast cells with round pyknotic nuclei. C, Cellular infiltrate replacing periadrenal adipose tissue. The cells feature copious amounts of granular, eosinophilia cytoplasm and vesicular nuclei with distinct, sometimes prominent, eosinophilic nucteoli. A sprinkling of inflammatory cells is present (lower right]. [A, x l00, B and C, x 400.]

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ADRENAL TUMEFACT1VESPINDLE-CELLLESIONS [Carney]

tile spindle-shaped ones often had a fine groove or fold (fig. 3B). Mitotic figures were rare. Spindle and polygonal cells stained positively for S-100 protein; a Bodian stain did not show any axons. Mast cells were numerous. In some transverse sections of the glands, the fibrous proliferation was wholly outside the gland, the cortex being virtually uninvolved. Occasionally, the process was delimited by a fibrous band mimicking a capsule that ran parallel to the adrenal capsule. Fibrous bands also extended into the gland, became confluent, and f o r m e d large, solid, hyalinized fibrous zones that replaced much of the gland, cortex, and medulla. Occasionally, zones of polygonal cells with eosinophilic cytoplasm and vesicular nuclei, resembling small steroid-type cells, were encountered. Sudan black B staining showed light cytoplasmic positivity. T h e substantial zones of residual cortex and foci of cortical cells enmeshed in the fibrous proliferation had a stimulated appearance. Case 2. T h e adrenal gland weighed 15 g. Two yellow nodules measuring 2.5 x 2 • 2 cm and 1.5 cm in diameter, respectively, were evident on the cut surface. T h e y were set in a background of a diffusely thickened, yellow cortex. These findings are typical of diffuse and nodular adrenocortical hyperplasia, a diagnosis that was confirmed microscopically. There were also three white, unencapsulated nodules, 6, 4, and 3 mm in diamater, in a medullary position (fig. 4). Microscopically, these nodules were composed of 1) collagen arranged in solid masses, nodules, and wide bands and 2) spindle and polygonal cells. The collagen f r e q u e n t l y f o r m e d deeply eosinophilic plaques and nodules within which were laminated calcospherites (fig. 5A). T h e cells were primarily Ioc a t e d at the p e r i p h e r y o f the fibrous nodules. Spindle cells were aggregated into short or long packets and featured pointed spindle nuclei, some twisted and others indented or otherwise irregular in outline (fig. 5B). These cells did not stain with antibody to S-100 protein. T h e nuclei were Vesicular with a generally open chromatin appearance and punctuated by finely speckled chromatin, and they exhibited a very narrow longitudinal or transverse fold. Nucleoli were small, and there was often an intranuclear vacuole. T h e polygonal cells were organized into clusters arranged concentrically with interdigitation of cell borders. Cytoplasm was homogeneous and lightly eosinophilic. Collagen fibers and small collagen bundles, deeply eosinophilic, developed among the cells o f the clusters (fig. 5C). Also, in some clusters there was condensation of tile cells so that their nuclei, usually separated by moderate amounts of cytoplasm, became closely related, mimicking a syncytial appearance. Mitotic figures were not seen. Besides these grossly visible masses, there were multiple microscopic foci typical of ovarian thecal metaplasia. These zones, broadly or tenuously attached to the adrenal capsule, protruded among the columns of cortical cells as wedges or broad fingerlike formations or plaques (fig. 6). T r a p p e d clusters 983

FIGURE 4. Diffuse and nodular cortical hyperplasia characterized by diffuse thickening of the cortex and two nodules, one bright and one dark yellow. Also, multiple white nodules are in the medulla [arrows]. One [double arrows] is indistinct, merges with the adrenal cortex, and is 6 mm in diameter.

of cortical cells were frequently seen in the lesions which were composed of hyalinized fibrous tissue mostly arranged in vague nodules and broad, hyaline, deeply eosinophilic bundles and aggregates of closely packed, small spindle cells reminiscent of ovarian cortical stromal cells. In one instance, the fibrotic process extended across the entire width o f an ala from one aspect of the capsule to that directly opposite; in several areas the process penetrated vertically into the cortex, sweeping laterally as the central veins were approached and seeming to blend with the venous muscle coat. DISCUSSION

In both cases, unusual a d r e n a l tumefactive spindle-cell lesions were seen. Tile findings in case 1 suggest a specific pathology: the adrenal involvement was symmetric and bilateral (a pattern suggestive of a n o n r a n d o m event), diffuse (raising the possibility of a generalized disorder of some adrenal tissue), and distributed outside and inside the adrenal capsule. It seems unlikely that these f e a t u r e s o c c u r r e d by chance; they probably represent a specific disorder or part o f one. T h e relationship o f the pathologic findings in case 1 to those in case 2 is not known. In the latter case, the pathologic process did not affect the periadrenal tissues, and the condition of the remaining adrenal gland is unknown.

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FIGURE 5. A, Medullary nodule composed of hyalinized fibrous plaques (lower left and upper right) and vaguely outlined clusters of spindle cells separated by fibrous bands of varying thickness. Inset. Laminated calcospherite. B, Adrenocortical cells separated by bands and clusters of spindle cells, often in concentric arrangement. Many nuclei are round, oval, and spindle, or they are vesicular with a small nucleolus; others are shrunken and pyknotic. C, Broad collagen bundles are present in nodules of oval cells. (A, x 250; inset, B, and C, x 400.)

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ADRENALTUMEFACT1VESPINDLE-CELLLESIONS[Carney)

FIGURE 6, Afibrous nodule protrudes from the adrenal capsule into the cortex, replacing cortical cells. It is composed peripherally of two hyalinized plaques [arrows) and centrally of vaguely outlined nodules of spindle cells. (xl00.] 9

T h e n a t u r e o f these spindle-cell lesions is unknown. Positive i m m u n o s t a i n i n g f o r S-100 protein was o b t a i n e d in o n e case, s u g g e s t i n g a possible schwannian origin, but a Bodian stain was negative. T h e r e was n o staining f o r S-100 p r o t e i n in case 2. T h e idea that these lesions might r e p r e s e n t a tumefactive m a n i f e s t a t i o n o f so-called o v a r i a n thecal metaplasia is a p p e a l i n g but must be a p p r o a c h e d with caution. In the first place, the basis f o r the entity "ovarian thecal metaplasia" is the m o r p h o l o g i c similarity, by r o u t i n e microscopy, o f certain cellular and hypocellular, fibrotic spindle-cell lesions in association with the a d r e n a l capsule a n d o v a r i a n cortical stroma. Such an association can hardly be r e g a r d e d as p r o o f that the two tissues are identical. Furtherm o r e , t h e a d r e n a l lesions have b e e n o b s e r v e d in men, albeit very rarely. O n the o t h e r h a n d , t h e r e is p r e c e d e n t for believing that certain a d r e n a l tissue(s) can u n d e r g o metaplasia into gonadal cells, such as the Leydig, g r a n u l o s a , a n d theca cell types. 4-7 Also, bilateral o o p h o r e c t o m y at birth in certain strains o f mice c a u s e d u n d i f f e r e n t i a t e d cells in the a d r e n a l capsule to be t r a n s f o r m e d morphologically and functionally into a tissue resembling ovarian stroma. 8 T h u s far, a d r e n a l ovarian thecal metaplasia and the tumefactive spindle-cell adrenal lesions described in this article have not caused symptoms or signs that can be a t t r i b u t e d to the abnormalities. Could the undiagnosed fatal illness in o u r case 1 have b e e n related to the bilateral a d r e n a l a b n o r m a l i t y ? T h e r e is n o

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r e a s o n to believe s o - - a t least o n the basis o f the k n o w n functional characteristics o f ovarian fibromas and thecomas. 9 F u t u r e e x p e r i e n c e with similar cases may p r o v i d e the answer.

Acknowledgments. The author thanks William J. Beckfield, MD, Eau Claire, Wisconsin, who contributed case 1. REFERENCES 1. Reed RJ, Patrick JT: Nodular hyperplasia of the adrenal cortical blastema. Bull Tulane Univ Med Faculty 26:151, 1967 2. Wong T-W, Warner NE: Ovarian thecal metaplasia in the adrenal gland. Arch Pathol 92:319, 1971 3. Fidler WJ: Ovarian thecal metaplasia in adrenal glands. Am .1 Clin Pathol 67:318, 1977 4. Scully RE, Cohen RB: Ganglioneuroma of adrenal medulla containing cells morphologically identical to hilus cells (extraparenchymal Leydig cells). Cancer 14:421, 1961 5. Orselli RC, Bassler TJ: Theca granulosa cell tumor arising in adrenal. Cancer 31:474, 1973 6. Horvath E, Chalvardjian A, Kovacs K, et al: Leydig-likecellsin the adrenals of a woman with ectopic ACTH syndrome. HUM PATHOL11:284, 1980 7. Aguirre P, Scully RE: Testosterone-secreting adrenal ganglioneuroma containing Leydig ceils. Am J Surg Pathol 7:699, 1983 8. Fekete E, Woolley G, Little CC: Histological changes following ovariectomy in mice: I. dba high tumor strain. J Exp Med 74:1, 1941 9. Scully RE: Tumors of the ovary and maldeveloped gonads. In Atlas of Tumor Pathology, 2nd series, fascicle 16. Washington, DC, Armed Forces Institute of Pathology, 1979, p 177

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