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Departments of Medicine (R.E.L., S.L.W.) and Radiology (A.G.K.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Medicine (M.H.), Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033; and Emeritus Department of Medicine (R.E.P.), The New York Hospital–Cornell Medical Center, New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: . sw22{at}columbia.edu
Abstract
A 48-yr-old woman was evaluated 21 yr after receiving treatment for an ACTH-secreting metastatic pituitary carcinoma. She had been diagnosed with Cushing’s disease 35 yr earlier at the age of 14 yr and had undergone bilateral adrenalectomy. Six years later she developed Nelson’s syndrome, which was treated with resection of a pituitary adenoma followed by radiotherapy to the sella turcica. Eight years later she was found to have craniospinal metastases with three remote intracerebral lesions. Two of these lesions were surgically resected and stained positive for ACTH by immunofluorescence. She subsequently received whole-brain radiotherapy and is doing well 21 yr later with no lesions seen on magnetic resonance imaging and no evidence of recurrent metastatic disease. We present this case in detail along with a literature review of ACTH-secreting pituitary carcinoma.
A 48-YR-OLD woman with a history of an ACTH-producing pituitary carcinoma presented for follow-up endocrine evaluation. Cushing’s disease was diagnosed 34 yr earlier in 1966 when, at the age of 14, she first presented with weight gain and emotional instability. Plasma ACTH level was in the normal range. Skull radiographs were normal. A diagnosis of Cushing’s disease was made. Bilateral adrenalectomy was performed resulting in clinical remission, and she was begun on maintenance doses of hydrocortisone and fludrocortisone.
One year later the patient developed increased skin pigmentation. In October 1971 routine ophthalmologic examination revealed a central visual field defect in the right eye that progressed to impairment in the upper temporal quadrants in both eyes. She was referred to the New York Hospital–Cornell Medical Center for further evaluation. Pneumoencephalogram confirmed suprasellar extension of a pituitary tumor, pressing on the optic chiasm. Plasma ACTH levels were elevated.
In February 1972, frontal craniotomy with resection of a pituitary chromophobe adenoma was performed. This was followed by cyclotron radiotherapy to the sella turcica (total dose of 56 Gy) at Lawrence Laboratories (Berkeley, CA). Her visual fields returned to normal. Hypothyroidism developed postoperatively, and replacement therapy with T4 as well as conjugated estrogen and progestin was initiated.
Hyperpigmentation decreased markedly, and the patient was well until August 1979 when she developed dizzy spells, vertigo, and tinnitus. Initially Ménière’s disease was considered and she was treated medically, with some resolution of symptoms. In December 1979 the plasma ACTH level was 670 pmol/liter. In February 1980 she developed the acute onset of nausea and vomiting and was admitted to the hospital for evaluation and treatment with intravenous hydrocortisone. Computed tomography (CT) of the head revealed three contrast enhancing masses in the left frontal and temporal areas and upper pons (Fig. 1A
). The region of the sella and parasellar structures showed no definite abnormalities. Craniotomy with biopsy and partial excision of one lesion was performed. Pathology was positive for pituitary tissue; the cells stained positively for ACTH by immunofluorescence, establishing that the tumor was of pituitary origin. The cerebrospinal fluid ACTH level was 66 pmol/liter. After surgery she continued to experience occasional lightheadedness, vertigo, and tinnitus. One month later she developed progressive hearing loss in her right ear. She was readmitted and in April 1980 underwent a left frontal temporal craniotomy with partial excision of the metastatic tumors in the frontal area. Pathological examination revealed two subdural nodules, the largest measuring 1.0 x 1.0 x 1.5 cm in diameter, both being consistent with pituitary tissue. Postoperatively she developed a right peripheral cranial seventh nerve palsy and right facial pain and numbness. She was treated with whole-brain 60Co radiotherapy (total dose of 24 Gy). The facial weakness gradually improved, but the hearing in her right remained unchanged.
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). The two other enhancing lesions seen in 1980 were not seen. The ACTH level was 220 pmol/liter. The patient subsequently did well. She has had regular follow-up with ACTH levels and magnetic resonance imaging (MRI) studies of the head. In 1986 no intracranial masses were seen on MRI of the head.
In May 2000 she presented to the Neuroendocrine Unit at Columbia Presbyterian Medical Center for follow-up. She noted a gradual weight gain of 10 pounds over the previous 5 yr. She felt that there was a general improvement in cutaneous hyperpigmentation. In addition to replacement hormonal therapy (hydrocortisone 20 mg in the morning, 10 mg at night; fludrocortisone 0.1 mg daily; T4 0.1 mg daily, and cyclic conjugated estrogen 0.625 mg and medroxyprogesterone acetate 10 mg), she was taking alendronate 10 mg daily for osteoporosis. On physical examination she was hyperpigmented. She did not appear Cushingoid. Blood pressure was 132/82 mm Hg and pulse 80 beats/min without positional changes. She weighed 149 pounds and measured 5 foot 4 in. Visual field examination was normal. She had mild right facial nerve palsy and decreased hearing in her right ear. There were faded striae over her hips. Plasma ACTH level (measured at 1200 h) was 101 pmol/liter. MRI revealed a small amount of residual pituitary tissue remaining in the sella. There was no evidence of a mass lesion or abnormal enhancement elsewhere (Fig. 2).
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We describe a unique patient who is doing well 21 yr after being diagnosed with an ACTH-secreting pituitary carcinoma and 35 yr after being diagnosed with Cushing’s disease. Pituitary carcinoma is extremely rare, representing less than 1% of all pituitary tumors (1, 2). Pituitary neoplasms are classified into three groups according to their biologic behavior: benign, invasive adenoma, and carcinoma. The majority of tumors are benign. Invasive adenomas comprise 5–35% of all tumors and can invade into the dura mater, cranial bone, or sphenoid sinus (3). The majority of these tumors do not lead to distant metastases. There are no unequivocal histopathologic characteristics of carcinoma; thus, the diagnosis of malignancy is reserved for pituitary neoplasms that have metastasized to remote areas of the central nervous system (CNS) or outside the CNS (3, 4, 5). Craniospinal metastases may arise via invasion into the subarachnoid space with subsequent tumor seeding along brain and spinal cord surfaces (6). Dissemination outside the cerebrospinal axis may occur via hematogenous or lymphatic spread. A 1998 review (2) reporting 95 cases of pituitary carcinoma found 68% of these to be hormone producing, with PRL (26%) and ACTH (25%) being the most common hormonal subtypes. Pituitary carcinomas producing GH are the next most common, with gonadotropin and TSH-producing carcinomas even more rarely reported. It is interesting that only 2–10% (7) of pituitary adenomas are ACTH secreting, yet in various reviews the percentage of pituitary carcinomas that secrete ACTH is much higher at 25–34% (1, 2, 8, 9). ACTH-secreting carcinomas also have the highest rate of systemic spread (67%) (1).
In addition to the case described above, 32 cases of ACTH-secreting pituitary carcinomas were found in the English-language literature (Table 1). The patients ranged in age from 13 to 69 yr at the time of presentation of Cushing’s disease with a mean age of 41 yr. There was a slight female preponderance with 61% of the 33 cases occurring in women. The time interval from presentation to diagnosis of carcinoma ranged from less than 1 month to 34 yr with an average latency period of 8 yr. As in our patient, almost half (15 of 33 cases, 45%) of the patients with ACTH-secreting pituitary carcinoma developed Nelson’s syndrome, which is a known complication that can occur in patients adrenalectomized for Cushing’s disease. Nelson’s syndrome occurs at an incidence of 8–38% (10, 11). Among patients with Nelson’s syndrome, the progression to carcinoma was slower with an average duration of 12.3 yr. Metastases outside the CNS occurred in 61% (20 of 33) of patients, with the liver the most common site of systemic spread (14 of 20, 70%). Other metastatic sites included bone, lung, and lymph nodes in descending order of frequency.
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The pathogenesis of pituitary carcinoma is unknown, and although the development from adenoma seems likely, little is known about the molecular basis of malignant transformation. In their series of 70 patients Thapar et al. (9) found a significant association between p53 expression and tumor behavior with an overexpression of the p53 tumor suppressor gene in all pituitary carcinomas, in a minority of invasive adenomas, but not in noninvasive adenomas. The pathophysiological significance of this remains unknown, and lack of p53 immunoreactivity does not rule out malignant progression (12). The possible involvement of the retinoblastoma (Rb) gene was suggested by the frequent occurrence of pituitary carcinomas in studies of mice with heterozygous deletions of the (Rb) gene and Rb(+/-) chimeras (13, 14). Hinton et al. (15) described an interesting patient with two adjacent but histologically discrete pituitary tumors, one a benign ACTH-positive adenoma and the other an ACTH-positive carcinoma that eventually metastasized. The adenoma expressed the Rb protein, but the carcinoma did not, suggesting that the loss of Rb expression may be important in the development of some pituitary carcinomas.
Our patient was treated with pituitary radiotherapy 8 yr before metastases were discovered. Radiation does increase the incidence of pituitary tumors in animals, but there is no evidence of this in humans (17). According to a recent review of brain tumors, even low doses of irradiation to the cranium can increase the incidence of meningiomas and glial tumors (16). In a study of 334 patients with pituitary adenoma treated with surgery and radiotherapy, five developed a second brain tumor after follow-up of 3760 person-years. However, no cases with malignant transformation of a pituitary adenoma were found (18). Radiation is unlikely to have a carcinogenic role based on the rarity of pituitary carcinomas, compared with the long history of the use of pituitary irradiation (19). A history of previous radiotherapy was reported in 22 of 33 (67%) of the reported cases of ACTH secreting pituitary carcinoma. Thirty-three percent of patients never received radiotherapy.
The role of surgery in facilitating tumor spread has also been questioned because of the necessary opening of subarachnoid spaces surrounding the pituitary during tumor excision (20). In case 6, spread to a cervical lymph node, an unusual site of metastases, occurred after the patient underwent biopsy via the nasal cavity. Surgical intervention is not a prerequisite for carcinoma as demonstrated by the six patients in Table 1 who never underwent cranial surgery.
Treatment
There is as yet no standard treatment for pituitary carcinoma, but most patients are treated with a combination of surgical resection and radiotherapy. In a series of 15 cases of pituitary carcinoma reported by Pernicone et al. (1), the patient with the longest survival underwent repeated resections of cerebellar metastases, leading the authors to speculate that such an approach of aggressive surgery may be appropriate for patients with metastatic deposits confined to the CNS. On the basis of their clinical finding, the same authors (1) concluded that radiation therapy had only a palliative effect. Despite this, one can hypothesize that ACTH-secreting pituitary carcinomas may be radiosensitive based on the results of a study of the long-term follow-up in patients with Cushing’s disease or Nelson’s syndrome in which 14 of 15 patients had decreased ACTH levels and clinical improvement after treatment with pituitary radiation (11). Cyproheptadine, octreotide, bromocriptine, and cabergoline have been reported to induce symptom improvement and plasma ACTH lowering or normalization in patients with Nelson’s syndrome (21, 22, 23, 24). In the above cases of ACTH-secreting carcinoma, however, neither hormonal therapy nor chemotherapy produced relief of symptoms, decreases in ACTH levels, or changes in the size of metastatic lesions. Mean overall survival from time of diagnosis of Cushing’s disease to death was 9.4 yr. Metastases outside the CNS were associated with a shorter survival than metastases confined to the craniospinal axes (6.6 yr, compared with 13.7 yr). Survival from diagnosis of pituitary carcinoma to death averaged 1.4 yr. The longest reported survival after carcinoma diagnosis was 21 yr, occurring in the patient described herein. In our patient, neither surgical resection nor medical therapy was able to eradicate her disease. Whole-brain radiation to the metastatic tumors was of significant benefit in treating and stabilizing her disease on the basis of the disappearance of the pons lesion and the lack of progression of disease over the subsequent 21 yr.
In summary, whereas pituitary adenomas represent almost 10% of all intracranial tumors (17), pituitary carcinomas are extremely rare. The pathogenesis of malignant transformation is not known. Though several cases in the literature describe patients surviving with metastases for more than 10 yr, the overall prognosis is poor. We describe a unique patient doing well 35 yr after being diagnosed with Cushing’s disease and 21 yr after the discovery of metastatic dural lesions. This case illustrates the potential benefit of aggressive management with both surgery and whole-brain radiotherapy in this disease.
Footnotes
Abbreviations: CNS, Central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; Rb, retinoblastoma.
Received December 26, 2001.
Accepted March 23, 2002.
References
This article has been cited by other articles:
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  W. Saeger, D. K Ludecke, M. Buchfelder, R. Fahlbusch, H.-J. Quabbe, and S. Petersenn Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry Eur. J. Endocrinol., February 1, 2007; 156(2): 203 - 216. [Abstract] [Full Text] [PDF]
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 G. A. Kaltsas, P. Nomikos, G. Kontogeorgos, M. Buchfelder, and A. B. Grossman Diagnosis and Management of Pituitary Carcinomas J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3089 - 3099. [Abstract] [Full Text] [PDF]
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