Adrenocortical Carcinoma Metastatic to the Orbit
George B. Bartley, M.D.,* R. Jean Campbell, M.D., ** Diva R. Salomão, M.D., ** Elizabeth A. Bradley, M.D.,* W. Richard Marsh, M.D.,¿ and Uldis Bite, M.D.§
Departments of Ophthalmology,* Laboratory Medicine and Pathology, ¡ and Neurologic Surgery# and the Division of Plastic Surgery,§ Mayo Clinic, Rochester, Minnesota, U.S.A.
Purpose: To describe the clinical course and histopathologic features of a patient with adrenocortical carcinoma metastatic to the orbit.
Methods: Case report and literature review.
Results: A 24-year-old man first came to medical attention because of symptoms referable to a 4.47-kg, nonfunctioning carcinoma of the left adrenal cortex. Several metastases ensued, including a large tumor to the right superior lateral bony orbit with extension to the brain, temporalis fossa, and orbit proper. The tumor was resected with the use of a combined neurosurgical, ophthalmic, and craniofacial approach. The pa- tient died of widespread metastatic disease 15 months after the orbital operation.
Conclusions: Metastasis to the orbit from adrenocortical carcinoma is rare. Surgi- cal resection is the treatment of choice, with adjunctive radiation therapy and chemotherapy in some cases. The prognosis is poor.
Adrenocortical carcinoma is a rare and lethal neo- plasm.1-7 Approximately one patient in three has metastases when the tumor is first detected, and metastatic disease develops in approximately 80% of patients. Spread to the orbit is rare. We report herein the clinical course of such an affected pa- tient.
CASE REPORT Clinical Course
In October 1995, a 24-year-old white male house painter was examined. He had a 5-month history of weakness in his legs, low back pain, and a sensation of abdominal pressure. No signs or symptoms of ex- cess steroid secretion were present. Computed to- mography of the abdomen evinced a 20-cm solid
mass in the left upper quadrant (Fig. 1), consistent with a tumor of the left adrenal gland. Although the left kidney was displaced, the renal vein did not ap- pear to be infiltrated by the tumor.
A left adrenalectomy was performed, and a 25.5 cm × 20 cm × 14 cm mass weighing 4,470 grams was excised. The histopathologic diagnosis was moderately differentiated (grade 3 of 4) adrenocor- tical carcinoma. Areas of necrosis and venous infil- tration were evident within the tumor. Flow cytome- try demonstrated DNA aneuploidy. A regional lymph node was negative for tumor spread. Re- placement steroids were given for 2 months, but chemotherapy was not considered necessary.
The patient did well until April 1996, when a metastasis to the left lung was diagnosed. A left upper lobe wedge resection was performed, and therapy with mitotane (1,1-dichlorodiphenyldi- chloroethane) was begun. Gonadal insufficiency de- veloped and was attributed to mitotane. Steroid re- placement was resumed.
Approximately 1 year later, the tumor metasta- sized to the third lumbar vertebra, resulting in radiculopathy and vertebral fracture. Radiotherapy (37.5 Gy) was administered. The third lumbar verte- bra was resected 5 months later, and a partial
Address correspondence to Dr. George B. Bartley, Depart- ment of Ophthalmology, Mayo Clinic, Rochester, MN 55905. Supported in part by a grant from Research to Prevent Blind- ness, Inc., New York, New York.
Presented in part by Dr. Campbell at the 1999 meeting of the Verhoeff-Zimmerman Society in Portland, Oregon, and by Dr. Bartley at the 2000 meeting of the Orbital Society in Paris, France.
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laminectomy of lumbar vertebrae 2 to 4 was per- formed. Metastatic adrenocortical carcinoma was present in the excised bone.
Concurrently, in October 1997, the patient had rapid onset of pain behind the right eye, diplopia, and edema and complete ptosis of the right upper eyelid. Best corrected visual acuity was 20/25 OD and 20/20 OS. Pupillary reactions, color vision, periorbital sensation, and ophthalmoscopy were normal, but ductions OD were mildly decreased in upgaze. A bone scan demonstrated increased uptake in the right bony orbit, consistent with a metastatic lesion. Radiotherapy (37.5 Gy) was administered; the diplopia, blepharoptosis, and eyelid edema im- proved promptly.
The patient had no additional ophthalmic signs or symptoms until May 1, 1998, when again right periorbital pain and diplopia developed. The right
upper eyelid ptosis and edema had recurred, ac- companied by moderate chemosis (Fig. 2). Best corrected visual acuity was 20/50 OD and 20/20 OS. Pupillary reactions, color vision, and perior- bital sensation were normal. Ductions OD were moderately limited in all positions of gaze. Axial right eye proptosis of 4 mm was measured, as was 8 mm of inferior displacement. The right optic disk was slightly swollen, and choroidal folds were present.
Computed tomography demonstrated an oste- olytic lesion consistent with metastatic adrenocorti- cal carcinoma in the right superior lateral bony orbit, with extension into the orbit, the cranial vault, and the temporal fossa, (Figs. 3 and 4). Prednisone (60 mg daily) was started, and within 4 days the or- bital soft tissue inflammation had abated consider- ably (Fig. 5). Because additional radiotherapy to the orbit was considered inadvisable, palliative surgical resection of the tumor was offered. The operation was performed on May 11, 1998, and consisted of a right frontal craniotomy, superior and lateral orbi- tectomy, eyelid-sparing vide supra exenteration, and reconstruction with split cranial bone grafts and a temporalis muscle flap. The patient recovered from the procedure uneventfully, with satisfactory restoration of the bony orbital framework, soft tis- sue volume, and conjunctival pouch (Fig. 6). He elected not to be fitted with an ocular prosthesis and preferred to wear an opaque right spectacle lens.
One month later, recurrent metastases were found in the patient’s lumbar spine, lung, and pelvis. Dox- orubicin was instituted with dexamethasone; mor- phine was given for pain relief. In June 1999, 13 months after resection of the orbital and intracranial
metastasis, an ophthalmic examination showed no evidence of recurrent tumor and normal function of the left eye. The patient’s overall status continued to deteriorate because of widespread metastatic dis- ease, and he died at home in August 1999.
Histopathology
Fig. 7 shows the resected orbital bone with the metastatic lesion. Histologic examination showed a neoplasm composed of cells with abundant eosinophilic granular cytoplasm in small clusters (Fig. 8). Mild anisonucleosis without significant nu- clear atypia was observed (Fig. 9). Mitoses and necrosis were not present.
Immunohistochemical studies showed positivity in the neoplastic cells for synaptophysin, neuron- specific enolase, inhibin, and p53. The cells were negative for cytokeratin and vimentin. Electron mi- croscopy showed cells with numerous cytoplasmic lysosomes (Fig. 10). The morphologic features
combined with immunophenotypic and ultrastruc- tural findings confirmed the diagnosis of metastatic adrenocortical carcinoma.
DISCUSSION
The prognosis for patients with adrenocortical carcinoma (ACC) is dismal. Fortunately, the tumor is rare: Its incidence is 1 to 2 per million persons per year, and it accounts for only 0.05% to 0.2% of all cancers. The mean age at diagnosis is 46 years, but ACC has been reported in patients of all ages. Women are affected slightly more often than men. Endocrine dysfunction (usually Cushing syndrome) is present in 50% to 80% of patients at the time of diagnosis. Usually only one adrenal gland is in- volved, but bilateral cases have been reported. Ap- proximately 30% to 40% of patients have metas-
METRIC |1
2
3
4
tases when the tumor is first detected, and recurrent or metastatic disease develops in nearly all pa- tients.1-7
ACC is usually larger than a benign adenoma. Its surface is soft, has a variegated pattern with a lobu- lar or nodular appearance, and often shows hemor- rhage and necrosis when cut. On histologic exami- nation of ACC, a variety of architectural patterns can be seen. A trabecular configuration is most com- mon, characterized by broad or slender columns of anastomosing cells separated by sinusoids of vary- ing width. An alveolar pattern may be seen, as may a myxoid pattern. Some tumors contain an admix- ture of architectural arrangements.
Acidophilic, lipid-depleted cells predominate in most ACC, but some tumors are composed of an abundance of lipid-laden cells. The cytoplasm may contain coarse granules that resemble lipofuscin as well as round-to-oval, periodic acid Schiff (PAS)- positive, eosinophilic, hyaline globules that appear
similar to those seen in pheochromocytoma. The delicate stroma contain many thin-walled blood vessels. Nuclear pleomorphism and atypia may be striking in some tumors. Because such features also may be present in tumors that are clinically benign, interpretation of needle biopsy specimens may be challenging.8 Mitotic figures, typical and atypical, are common. Some ACC are markedly anaplastic with hyperchromasia, giant cells, and abundant mi- totic activity. In other tumors, the histologic features are similar to an adenoma, with tumor invasion into or beyond its capsule or into blood vessels as the only evidence of malignancy. In view of the vari- ability of the microscopic presentation, it is not sur- prising that ultrastructural findings similarly are myriad.9,10
Immunohistochemical analyses suggest that ACC may originate from neuroendocrine foci.10,11
At present, there is no pathognomonic immunohis- tochemical profile for ACC. Typically, the tumor is positive for neuron-specific enolase and synap- tophysin (a neuroendocrine marker) and negative for cytokeratin.10-14 Immunoreactivity to the het- eroglycoprotein inhibin in adrenocortical tumors has been shown to correlate with clinical and lab- oratory evidence of cortisol or androgen produc- tion and serves as a useful differentiating feature from renal cell carcinoma (clear cell type).15,16 The patient described herein, however, had a hor- monally nonfunctioning tumor despite positive in- hibin staining. No correlation has been established
between Ki-67, proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGF-r), insulin-like growth factor (IGF), and p53 positivity and survival in patients with ACC.17 A recent study showed that abnormalities of p53 expression may occur as a late event, associated with tumor progression but without prognostic significance.18
Patients with ACC are at risk both from the tumor itself and from the endocrinologic consequences of excess hormone production. Surgical resection is the mainstay of treatment, even in patients with ex- tensive metastatic disease.2 Mitotane (1,1-dichloro- diphenyldichloroethane), an analogue of a common pesticide, promotes atrophy of adrenal tissue and thus has been used as a chemotherapeutic agent. Unfortunately, mitotane does not improve survival, although it does ameliorate hormonal hypersecre- tion in functioning tumors. Cisplatin, adriamycin, doxorubicin, and VP16 also have been used but with
generally disappointing results. Radiation therapy is reserved for the treatment of metastatic foci.3,4,6
Median survival in most series ranges from 14 to 23 months, with 20% to 36% of patients alive at 5 years. A recent study identified three independent prognostic risk factors in resectable tumors: size, the presence of hemorrhage within the tumor, and the number of mitoses.5 Patients whose primary tu- mors were larger than 12 cm had a 5-year survival rate of 22%, compared with a 53% survival rate in patients with smaller lesions. The survival statistics were identical (22% versus 53%) if areas of hemor- rhage within the tumor were identified. A mitotic count of 6 or more per 10 high-power fields was as- sociated with a 5-year survival rate of 13%, whereas the survival rate was 51% if fewer than 6 mitoses were present. Patients with none of these risk fac- tors had a 5-year survival rate of 83%. The rate de- creased to 42% with 1 factor, 33% with 2 factors, and 0% with all 3 risk factors.
ACC typically spreads through the adrenal veins, inferior vena cava, and regional lymphatics to the lungs, liver, and paraaortic lymph nodes. Metastasis to the orbit is rare. Burch,19 in 1932, reported a 33- year-old man with bilateral adrenocortical carcino- mas in whom a metastasis to the right orbit was con- firmed at autopsy. Additionally, he described three probable cases and one possible case in a review of published reports. Henderson et al.20 included one case, a 77-year-old woman, in his extensive survey of 1,376 orbital tumors from the Mayo Clinic. Like Burch’s case, the patient studied by Henderson and colleagues also had bilateral adrenocortical carcino- mas with metastasis to the right orbit. Luton and coworkers2 listed 1 patient with metastasis to the orbit among a series of 105 patients with ACC, but details of the case were not provided.
In summary, adrenocortical carcinoma is a rare tumor of probable neuroendocrine origin that infre- quently spreads to the orbit. Surgical resection is the treatment of choice, although radiation therapy and chemotherapy may be considered as adjuncts. Long-term survival rates are poor.
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