We report the case of a corticomedullary mixed tumor of the adrenal gland in a 55-year-old woman with a left adrenal mass who presented with mild symptoms of Cushing syndrome and an elevated urinary cortisol level. The patient underwent a left adrenalectomy. A well-circumscribed 2.5-cm mass, composed of an admixture of adrenal cortical cells and pheochromocytes, and an incidental 0.7-cm myelolipoma were present in the resected left adrenal gland. The diagnosis of adrenal corticomedullary mixed tumor was confirmed by both immunohistochemistry and electron microscopy. To our knowledge, this is the eighth well-documented report of this rare tumor.

First described in 1969 by Mathison and Waterhouse,1 corticomedullary mixed tumors of the adrenal gland are defined histopathologically by the presence of a single tumor mass formed by an admixture of adrenal cortical and medullary cells.1,2 Because of the separate embryologic origin of the adrenal cortex and medulla, such tumors are rare, and only 7 well-documented cases have been reported.1–5 We report the case of a corticomedullary mixed tumor of the left adrenal gland with an incidental concurrent myelolipoma in a 55-year-old woman who presented with symptoms of Cushing syndrome and elevated urine cortisol levels.

Clinical Presentation

A 55-year-old woman originally presented with a lipoma in the soft tissue of the right flank. A magnetic resonance imaging scan performed at this time also showed a 1.8-cm mass in her left adrenal gland; the right adrenal gland was of normal size and unremarkable. After the removal of the right flank lipoma, a follow-up computed tomographic scan performed 6 months later showed that the left adrenal mass had enlarged to 2.8 cm and had the radiologic appearance of an adrenal adenoma. Clinically, the patient demonstrated mild symptoms of Cushing syndrome (truncal obesity) and hyperglycemia. A 24-hour urinary cortisol level drawn at this time was markedly elevated (2391.0 μg/24 h [6596.8 nmol/d]; normal range, 5.0–50.0 μg/24 h [13.8–138 nmol/d]). Her preoperative serum adrenocorticotropic hormone level was within the normal range (9 pg/mL [2.0 pmol/L]; normal range, 6–58 pg/mL [1.3–11.0 pmol/L]). A left adrenalectomy was performed. Postoperatively, the patient's urine cortisol levels returned to normal. The medical and family history of the patient was unremarkable.

Tissue was fixed in 10% phosphate-buffered neutral formaldehyde for 24 hours and embedded in paraffin. Routine hematoxylin-eosin–stained slides were prepared for histologic evaluation. Immunohistochemical staining of 5-μm paraffin sections was performed on the Dako Autostainer and Envision+ detection system (Dako Corporation, Carpinteria, Calif) for antibodies against calretinin (polyclonal, 1:25; Zymed, South San Francisco, Calif), inhibin-α subunit (clone R1, 1:60; Dako), melan A (clone A103, 1:25; Dako), chromogranin (polyclonal, 1:100; Zymed), synaptophysin (polyclonal, 1:75; Zymed), and pan-cytokeratin (clones 5D3 and LP34, 1:25; Novocastra Vector, Burlingame, Calif). In addition, immunohistochemical staining for adrenocorticotropic hormone (polyclonal, 1:250; Dako) was performed using a standard avidin-biotin complex (ABC kit, Vector Laboratories, Burlingame, Calif) with diaminobenzidine substrate (Dako).

Prior to immunohistochemistry, selected tissue sections were pretreated twice in an 1100-W microwave oven at 70% power for 4 minutes in 1× citrate buffer at pH 6.0 (Lab Vision Corporation, Fremont, Calif) for anticalretinin and in 1× target retrieval solution at pH 6.0 (Dako) for melan A. The tissue sections undergoing antigen retrieval for the inhibin-α subunit were processed in a Black and Decker steamer with a 1× target retrieval solution at pH 6.0 (Dako) for 40 minutes at 100°C. Sections for pan-cytokeratin immunostaining were treated with 0.01% trypsin solution for 15 minutes at 37°C. A double immunohistochemical stain was performed using antibodies to calretinin and chromogranin. The tissue section was incubated with the first primary antibody to calretinin, stained with the Dako Envision+ detection system, and developed with diaminobenzidine+ substrate (Dako). The same section was then incubated with the antibody to chromogranin using the Dako Envision+ detection system and developed with Blue Peroxidase Substrate (Vector Laboratories).

In addition, tissue from the tumor was fixed in 4% glutaraldehyde and submitted for electron microscopy.

Macroscopic Findings

The resected tumor was a single well-circumscribed ovoid mass measuring 2.5 × 2.4 × 2.0 cm confined within the normal adrenal gland. Cut surfaces of the tumor showed a heterogeneous yellow and tan appearance without areas of hemorrhage or necrosis (Figure 1).

Figure 1.

Gross photograph of a corticomedullary mixed tumor. The tumor is well circumscribed with a heterogeneous tan and yellow cut surface. A normal adrenal gland is evident at the bottom. Figure 2. Myelolipoma composed of normal-appearing hematopoietic cells and adipocytes with adjacent normal adrenocortical tissue visible at the bottom (hematoxylin-eosin, original magnification ×100). Figure 3. Electron micrographs of a corticomedullary mixed tumor. A, The cell on the upper left has numerous cytoplasmic granules consistent with adrenal medullary origin, while the cell on the lower right has numerous cytoplasmic lipid droplets consistent with adrenal cortical origin (original magnification ×3000). B, Higher magnification of cytoplasmic dense-core granules characteristic of adrenal medullary cells (original magnification ×45 000).

Figure 1.

Gross photograph of a corticomedullary mixed tumor. The tumor is well circumscribed with a heterogeneous tan and yellow cut surface. A normal adrenal gland is evident at the bottom. Figure 2. Myelolipoma composed of normal-appearing hematopoietic cells and adipocytes with adjacent normal adrenocortical tissue visible at the bottom (hematoxylin-eosin, original magnification ×100). Figure 3. Electron micrographs of a corticomedullary mixed tumor. A, The cell on the upper left has numerous cytoplasmic granules consistent with adrenal medullary origin, while the cell on the lower right has numerous cytoplasmic lipid droplets consistent with adrenal cortical origin (original magnification ×3000). B, Higher magnification of cytoplasmic dense-core granules characteristic of adrenal medullary cells (original magnification ×45 000).

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Light Microscopic Findings

Under light microscopy, the tumor was well encapsulated and composed of polygonal cells with a clear cytoplasmic membrane arranged in sheets, nests, and cords with a rich vascular network. Upon further careful histologic evaluation, 2 different cell populations were identified, one containing abundant clear vacuolated cytoplasm and small round nuclei with inconspicuous nuclei consistent with an adrenal cortical origin and the other containing granular amphophilic-to-basophilic cytoplasm, variably sized nuclei with clumped chromatin, and distinct nucleoli consistent with a medullary origin (Figure 4, A and B). No mitotic activity or necrosis was present. The adjacent adrenal tissue was notable for the presence of a separate 0.7-cm yellow nodule but was otherwise unremarkable. Microscopically, this nodule was composed of normal-appearing trilineage hematopoietic tissue and adipocytes, which are characteristic of myelolipoma (Figure 2).

Figure 4.

Corticomedullary mixed tumor. A, The tumor is composed of polygonal cells with a clear cytoplasmic membrane arranged in sheets, nests, and cords (hematoxylin-eosin, original magnification ×100). B, Cells of adrenal cortical origin contain clear vacuolated cytoplasm with small dark nuclei, while cells of adrenal medullary origin contain granular basophilic cytoplasm with variably sized nuclei (hematoxylin-eosin, original magnification ×400). C and D, Double immunohistochemical staining for calretinin (diaminobenzidene substrate [Vector Laboratories], brown chromogen) and chromogranin (Blue Peroxidase [Vector Laboratories], blue chromogen) confirms the presence of calretinin-positive adrenocortical cells (brown) and chromogranin-positive pheochromocytes (blue) (diaminobenzidene substrate and Blue Peroxidase, original magnifications ×100 [C] and ×400 [D])

Figure 4.

Corticomedullary mixed tumor. A, The tumor is composed of polygonal cells with a clear cytoplasmic membrane arranged in sheets, nests, and cords (hematoxylin-eosin, original magnification ×100). B, Cells of adrenal cortical origin contain clear vacuolated cytoplasm with small dark nuclei, while cells of adrenal medullary origin contain granular basophilic cytoplasm with variably sized nuclei (hematoxylin-eosin, original magnification ×400). C and D, Double immunohistochemical staining for calretinin (diaminobenzidene substrate [Vector Laboratories], brown chromogen) and chromogranin (Blue Peroxidase [Vector Laboratories], blue chromogen) confirms the presence of calretinin-positive adrenocortical cells (brown) and chromogranin-positive pheochromocytes (blue) (diaminobenzidene substrate and Blue Peroxidase, original magnifications ×100 [C] and ×400 [D])

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Immunohistochemical Findings

The presence of 2 distinct populations of cells within the main tumor was confirmed by immunohistochemical analysis. The cells morphologically consistent with adrenocortical cells were negative for chromogranin and synaptophysin but positive for the adrenocortical markers inhibin-α, melan A, and calretinin. Conversely, the cells morphologically consistent with pheochromocytes were negative for these adrenocortical markers but were positive for chromogranin and synaptophysin. Double immunostaining for chromogranin and calretinin showed the 2 distinctively different cells intermixed within the tumor (Figure 4, C and D). All tumor cells were negative for adrenocorticotropic hormone and pan-cytokeratin.

Electron Microscopic Findings

Electron microscopy performed on the paraffin-fixed tissue confirmed the presence of 2 distinct populations of cells in the tumor: one consistent with adrenocortical cells that contained moderate amounts of lipid droplets, mitochondria with tubulovesicular cristae, and lysosomes in the cytoplasm and the other consistent with medullary cells that contained numerous dense-core granules in the cytoplasm, some of which appeared to be only partially filled by the electron-dense secretory product (Figure 3).

In contrast to composite tumors of the medulla, tumors involving both the adrenal cortex and medulla are rare. Wieneke et al2 have proposed that the term corticomedullary mixed tumor refer to a single tumor mass composed of an admixed population of adrenal cortical and medullary cells. This term excludes cases of simultaneously occurring adrenal cortical adenomas and pheochromocytomas as well as cases of adenocorticotropic hormone–producing pheochromocytomas with associated adrenal cortical hyperplasia. On the basis of histologic, immunohistochemical, and ultrastructural findings, the current case fulfills the definition of a corticomedullary mixed tumor of the adrenal gland and thus, to our knowledge, represents the eighth case reported in the medical literature.

Including the patient described in this report, adrenal corticomedullary mixed tumors have been described in 7 women and 1 man ranging in age from 32 to 61 years (mean age, 50 years).1–5 Like the majority of previously described patients, the patient of this report presented with symptoms and signs of cortisol excess (eg, mild Cushing syndrome, hyperglycemia, and high urine cortisol level), and these symptoms and signs resolved after the removal of her adrenal tumor. Like the previously reported cases, there was no histologic or clinical evidence of malignancy in the current case. The pathogenesis of corticomedullary mixed tumors of the adrenal gland remains unclear. Given the rarity of these tumors and the separate embryologic origin of the adrenal cortex and medulla, it might represent a “collision tumor,” as previously suggested.2 

To our knowledge, the presence of a concomitant myelolipoma within the adjacent, otherwise unremarkable adrenal tissue has not previously been reported in adrenal corticomedullary mixed tumors. Although most cases represent incidental findings in asymptomatic patients, adrenal myelolipomas arising in patients with Cushing syndrome and other endocrine abnormalities have been reported.6–10 Given the poorly understood pathogenesis of myelolipomas, it is unclear in this case whether this finding is merely incidental or whether it is somehow related to the presence of the nearby hormonally active corticomedullary mixed tumor.

In summary, adrenal corticomedullary mixed tumors are very rare benign tumors of the adrenal gland. They typically occur in adult female patients with clinical presentations of cortisol excess that usually resolve after a simple adrenalectomy. We report the eighth case of this rare tumor and, to our knowledge, the first case with a simultaneously occurring myelolipoma in the same adrenal gland.

Mathison
,
D. A.
and
C. A.
Waterhouse
.
Cushing's syndrome with hypertensive crisis and mixed adrenal cortical adenoma-pheochromocytoma (corticomedullary adenoma).
Am J Med
1969
.
47
:
635
641
.
Wieneke
,
J. A.
,
L. D. R.
Thompson
, and
C. S.
Heffess
.
Corticomedullary mixed tumor of the adrenal gland.
Ann Diagn Pathol
2001
.
5
:
304
308
.
Akai
,
H.
,
K.
Sanoyama
, and
K.
Namai
.
et al
.
A case of adrenal mixed tumor of pheochromocytoma and adrenocortical adenoma presenting diabetes mellitus and hypertension.
Nippon Naibunpi Gakkai Zasshi
1993
.
69
:
659
669
.
Michal
,
M.
and
F.
Havlicek
.
Corticomedullary tumors of the adrenal glands.
Pathol Res Pract
1996
.
192
:
1082
1089
.
Ohta
,
T. I.
,
T.
Motoyama
, and
T.
Imai
.
et al
.
Cortico-medullary mixed tumor (pheochromocytoma and cortical adenoma) of the adrenal gland.
J Urol Pathol
1995
.
3
:
157
164
.
Boronat
,
M.
,
A.
Moreno
,
y
Ramon
, and
S.
Cajal
.
et al
.
Subclinical Cushing's syndrome due to adrenal myelolipoma.
Arch Pathol Lab Med
1997
.
121
:
735
737
.
Kanj
,
H. A.
,
J.
Noronha
, and
A. F.
D'Aguillo
.
et al
.
Bilateral adrenal myelolipomas with Cushing's syndrome.
JAMA
1988
.
259
:
3034
3036
.
Vyberg
,
M.
and
L.
Sestoft
.
Combined adrenal myelolipoma and adenoma associated with Cushing's syndrome.
Am J Clin Pathol
1986
.
86
:
541
545
.
Yildiz
,
L.
,
I.
Akpolat
, and
K.
Erzurumlu
.
et al
.
Giant adrenal myelolipoma: case report and review of the literature.
Pathol Int
2000
.
50
:
502
504
.
Yoshioka
,
M.
,
K.
Fujimori
, and
M.
Wakasugi
.
et al
.
Cushing's disease associated with adrenal myelolipoma, adrenal calcification, and thyroid cancer.
Endocr J
1994
.
41
:
461
466
.

Author notes

Corresponding author: Albert Y. Chu, MD, MHS, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 6 Founders Pavilion, 3400 Spruce St, Philadelphia, PA 19104 ([email protected])