Journal of Neuro-Oncology, 2:59 66 (1984) © 1984 Martinus Nljhoff Publishers, Boston. Printed in the Netherlands.

Metastatic small cell carcinoma of the lung presenting as pituitary apoplexy and Cushing's syndrome

Vijay Chandra] Larry W. McDonald 2 & Robert J. Anderson 3 University of lllinois, Chicago, Illinois, USA 1Department of Neurology; 2Neuropathology Laboratory, Department of Neurosurgery; 3Section of Endocrinology, Department of Medicine, V.A. West Side Medical Center and College of Medicine

Keywords: metastases to pituitary, apoplexy, Cushing's syndrome

Summary

We describe a woman with metastatic small cell carcinoma of the lung who presented with pituitary apoplexy and hyperprolactinemia. Within seventeen months she developed florid Cushing's syndrome with anasarca, hyperpigmentation, hypertension with marked hypercortisolemia (not suppressible with 8 mg dexamethasone), elevated serum ACTH, hypokalemic metabolic alkalosis, and multiple hepatic metastases. This picture suggested the presence of ectopic ACTH syndrome. She died 26 months after the episode of pituitary apoplexy. Primary small cell carcinoma of the lung was diagnosed post-mortem. Metastases were present in the left lung, regional lymph nodes, heart, liver, bone marrow, sphenoid bone, anterior pituitary and pituitary capsule. Posterior pituitary was normal. There was no evidence of pituitary hyperplasia, of adenoma or of primary pituitary carcinoma. The results suggest the presence of a primary ACTH-producing small cell carcinoma of the lung that metastasized to the parasellar sphenoid bone and then extended to the anterior pituitary and dura to mimic a primary intrasellar cause of pituitary apoplexy and Cushing's syndrome. The case demonstrates how difficult it may be to diagnose the etiology of Cushing's syndrome and it emphasizes a unique variation in the presentation of small cell carcinoma of the lung.

Introduction

Pituitary tumors are usually primary benign tumors. Less commonly they may be primary ma- lignant tumors or metastatic from other organs. Clinicians often try to differentiate between prim- ary and secondary tumors based on initial presenta- tion. Anterior pituitary hormone overproduction or insufficiency and visual loss in any combination without evidence of malignancy elsewhere suggest pituitary adenoma (1). Diabetes insipidus or ex- tra-ocular nerve dysfunction with evidence of ma- lignancy at another site suggest a metastatic lesion (1). Metastases are more common in the posterior pituitary than in the anterior pituitary (1, 2). The most common primary tumor site in women with secondary metastasis to the pituitary is the breast

(3, 4). However, small cell carcinoma of the lung with a metastasis adjacent to the posterior pituitary and erosion of posterior clinoid processes can also occur (5).

Attempts to differentiate primary pituitary tu- mors from lesions metastatic to the pituitary can be difficult, especially when the metastatic tumor itself may produce hormones. Ectopic production of ACTH in lung carcinoma is well documented (5, 6). Small cell carcinoma is the most common histolog- ic type of lung tumor to produce clinically apparent Cushing's syndrome (7). However, 72% of patients with different types of lung carcinoma have elevat- ed plasma ACTH concentrations without clinical evidence of the ectopic ACTH syndrome (6, 8). Only 2.8% of patients with small cell carcinoma of the lung in one study developed clinical Cushing's

Address for reprints; Larry W. McDonald, MD, Department of Neurosurgery, 912 South Wood Street, Chicago 1L 60612, USA

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syndrome (9). This may be due, in part, to the rapid progression of the neoplastic process in some pa- tients, to unrestrained effects of severe hypercorti- solemia in others, or to production of a large mo- lecular weight form of ACTH, probably proACTH, that has little or no activity in a radioreceptor assay or in bioassay systems (8).

We present a patient with small cell carcinoma of the lung that violated several of the generalizations made above. The initial metastatic lesion was re- stricted to the sphenoid bone, diaphragm sella and anterior pituitary and masqueraded as a rapidly expanding pituitary tumor leading to visual failure. At the time of initial presentation, there was no evidence of neoplasm elsewhere or of Cushing's syndrome. The patient lived for 26 months after the pituitary apoplexy and developed florid Cushing's syndrome consistent with ectopic ACTH produc- tion and widespread metastatic disease. Primary small cell carcinoma of the lung was diagnosed post-mortem.

Case report

A 58 year-old black female with a 2-year history of gradual loss of vision and rapid deterioration in the previous two months was admitted to the Uni- versity of Illinois Hospital in August, 1979. She had smoked one pack of cigarettes per day for 20 years. Her blood pressure was 140/80 and she was moder- ately obese. Visual acuity in the left eye was 20/400. Vision in the right eye was restricted to detection of hand movement f rom two feet away. Galactorrhea was not present. Baseline serum hormone levels were: prolactin, 69.5 ng/ml (normal 4-24); total thyroxine (T4) , 4.0/.tg/dl (normal 5-12); and TSH, 0.9 # I U / m l (normal 0.9-7.3). Serum electrolytes, glucose and creatinine were normal. Skull x-rays and sella tomograms (Fig. 1) revealed an enlarged sella with erosion of the floor and of the dorsum sella. CT scan with infusion studies showed an en- larged pituitary fossa but no cerebral metastases (Fig. 2).

Fig, 1. Tomogram of sella turcica showing an enlarged sella and erosion of the floor and dorsum of the sella.

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Fig. 2. CT scan of the head (August, 1979) showing an enlarged pituitary fossa but no cerebral metastases.

Clinical course

Four days after admission, she suddenly became blind and had an emergency frontal craniotomy. The optic nerves were decompressed by piecemeal resection of hemorrhagic suprasellar tumor adja- cent to and inferior to the chiasm. The pathologic diagnosis was pituitary adenoma (most likely pro- lactinoma) with pleomorphic nuclei. However, the specimen was extensively infiltrated with flesh hemorrhage. Her vision improved to the point that she could count fingers with both eyes. A morning serum cortisol level two weeks post-operatively was 38.6 ~tg/dl (normal 7-22). She received a 5 000 rad course of radiation therapy to the pituitary over 8 weeks. Five months post-operatively her blood pressure was 164/92, serum electrolytes, glucose, cortisol, TSH, and growth hormone were normal. Baseline serum prolactin was 42 ng/mS. Pituitary reserve of cortisol, growth hormone, and TSH were normal in response to combined "insulin hypo- glycemia and T R H (protirelin) stimulation. A blunted response of the slightly elevated prolactin level was consistent with persistence of a prolacti- noma. She did well until February of 1981, when she was hospitalized to evaluate generalized edema and hyperpigmentation. Her blood pressure was 200/120. She had typical physical features of Cush-

ing's syndrome accompanied by hepatomegaly and anasarca. Serum potassium was 3.0 mEq/1 (normal 3.5-5.3) and carbon dioxide was 34 mmol/1 (nor- mal 24-32). Serum sodium, chloride, glucose and creatinine were normal. Liver function tests were: SGOT, 40 IU (normal 8-27); SGPT, 105 IU (nor- mal 8-34); alkaline phosphatase, 363 IU (normal 2-520). Serum hormone values were: cortisol, 82 #g/dl; ACTH, 152 p g / m l ( n o r m a l 2 0 100); T4, 4.1 tsg/dl; TSH, 1.7 ~IU/ml ; and gastrin, 76.6 pg /ml (normal <100). Baseline 24 hour urine free cortisol was 4567 #g (normal 20-90) and 17-hydroxycorti- costeroid was 44 mg (normal 4-12). Urine steroid values and serum ACTH and cortisol values did not decrease after a standard high dose (8 mg) dexa- methasone suppression test. Chest x-ray showed bilateral pleural effusions and an indistinct peri- pheral right lower lobe lesion. Lung tomograms and pleural fluid were negative and a pleural biopsy was unsuccessful. The liver contained multiple fil- ling defects on liver-spleen scan, and a CT scan of the abdomen revealed a mass in the area of the head of the pancreas. Bone marrow biopsy and aspirate were negative. Percutaneous liver biopsy tissue and tissue obtained at peritoneoscopy showed metastat- ic epithelial tumor. Immunoperoxidase stains for A C T H and argentaffin stains were negative. Tissue for electron microscopy studies was not adequate to

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Fig. 3. CT scan of pituitary fossa region (September, 1981 ) showing a lesion involving the bone of the pituitary fossa and extending into the sphenoid sinus.

show neurosecre tory granules. The high levels of serum and urine cor t isol , the

modera t e e levat ion of serum A C T H , the hypoka - lemic metabol ic alkalosis , hyper tens ion, per iphera l

edema, and progress ive hype rp igme n ta t i on sup- po r t ed the presence of the ec topic A C T H syn- drome. The indolent course in a cushingoid pat ient and the a b d o m i n a l CT scan suggested a pancrea t ic source of A C T H . Smal l cell c a rc inoma or carc inoid t u m o r of the lung, and p r imary p i tu i ta ry ca rc inoma were considered to be less likely possibili t ies. She received two cycles of s t rep tozoc in and 5- f luorour- acil for p robab le non-be ta islet cell c a r c inoma of the pancreas . The hypercor t i so lemia was t reated with a combina t i on of me ty rapone (1 to 2 g in s /day in d ivided doses) and aminog lu te th imide (250 mg three t i m e s / d a y ) with main tenance doses of cort i - sone acetate. Three months la ter she was admi t t ed for a third cycle of chemothe rapy . A mode ra t e de- crease in serum t r ansaminase levels suggested she might be improving . Whi le she remained on metyr- apone and aminog lu te th imide , the serum cort isol was 21.0 # g / d l and the serum A C T H was 461 pg /ml . Liver enzyme levels were no rma l in mid- June, 1981.

Fig. 4. Photo-micrograph showing bronchial cartilage on right and small cell tumor on left part of field. H & E stain, × 60.

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Fig. 5A. Frontal section of anterior lobe and stalk of pituitary. Hemorrhage and tumor are seen more darkly staining in the base of pituitary and outside the capsule (c) of the pituitary. Mallory-Heidenhain stain X 8. Fig. 5B. Higher magnification of small cell tumor outside of pituitary capsule shown in Fig. 5A. H & E stain, X 640.

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She became progressively dehydrated and le- thargic, and required hospitalization in early Sep- tember 1981. Her skin was more deeply pigmented and her face contained multiple acneiform lesions. Blood pressure was 126/80. Serum chemistry and hormones were: creatinine, 1.7 rag/dl; albumin, 2.7 gin/dl; SGOT, 81 IU; SGPT, 24 IU; alkaline phos- phatase, 559 IU; cortisol, 27.4 /~g/dl; ACTH, 251 pg/ml. Lumbar puncture and blood cultures were unremarkable. CT scan of the head showed a lesion involving the bone of the pituitary fossa and ex- tending into the sphenoid sinus (Fig. 3). Glucocor- ticoids were given and the metyrapone and amino- glutethimide were stopped. She became hypoten- sire, hypoglycemic and thrombocytopenic with a gram-negative septicemia, and died 43 days after admission.

At autopsy the right lung contained a primary endobronchial small cell carcinoma (Fig. 4). Wi- despread metastases were found in the left lung, regional lymph nodes, heart, liver, bone marrow, and pancreatic lymphatics. Bilateral adrenal corti- cal hemorrhage was present in glands that weighed 12 grams each. The brain showed a slight right parietal lobe subarachnoid hemorrhage. There was a plaque of tumor 2 cm in diameter and 1 cm thick on the inner side of the right parietal dura. There was a hemorrhagic softening in the right frontal lobe which showed fungal hyphae on microscopic examination. Inflammatory reaction was slight. Post-mortem blood cultures were positive for E. coli. The posterior pituitary was normal. Tumor tissue was found involving the anterior pituitary and the pituitary capsule (Fig. 5A & B) but the overall structure of the stalk and the pituitary was preserved. There was no evidence of a distinct pitui- tary adenoma, pituitary hyperplasia or of primary pituitary carcinoma. There was no pathological ev- idence of extensive radiation effect. Since the pitui- tary capsule is continuous with the periosteum of the sella, the tumor must also have involved the parasellar osseous tissue as shown in the CT scan in Fig. 3. The lesions in the pituitary, dura and lung were histologically similar. Review of the pituitary specimen obtained in August 1979, revealed that the histological features were similar to the speci- men obtained at autopsy; but because of extensive hemorrhage in the surgical specimen, a different diagnosis was made in 1979.

Discussion

The initial clinical presentation of our patient was consistent with hemorrhage into a pituitary adenoma and pituitary apoplexy. Her rapidly dete- riorating vision, enlarged and eroded sella, hyper- prolactinemia, and the necrotic tumor removed at surgery were all compatible with the diagnosis. The occurrence of Cushing's syndrome, widespread metastases and a protracted clinical course made the accurate diagnosis of her disease less obvious. In retrospect, at the time of her first presentation with pituitary apoplexy in August 1979, the pitui- tary lesion was probably an extension of tumor from the parasellar osseous metastases. The proba- ble sequence of events was a primary small cell carcinoma in the lung which metastasized to the parasellar sphenoid bone, eroded the bone and then spread to the anterior pituitary and to the suprasel- lar regions and, later, into the sphenoid sinus. The posterior pituitary was not involved. Metastatic lesions in the parasellar sphenoid bone are well- known (10) and rarely 'intrasellar adenoma and juxtasellar metastasis may co-exist' (1). These sec- ondary deposits are usually a part of widespread metastatic disease to the bone (10). Teers and col- leagues reviewed 88 cases of metastatic carcinoma to the pituitary and found that there were no cases in which the gland was involved by extension from an adjacent osseous metastasis (2). One the other hand, Hagestrand studied the frequency of metas- tasis to the pituitary from various primary sites. He states that in about half the cases, metastasis 'might have been set up by spread from secondary growths in an adjacent part of the skeleton' (3). No further details were given. Thus, wide discrepancy exists between the two studies.

Metastatic tumor may reach the region of the pituitary by any of several routes. Hematogenous spread to the gland parenchyma or rarely the dia- phragm sella may occur. This is usually a part of widespread metastatic disease, though initial pre- sentation of anaplastic bronchial carcinoma as a pituitary mass has been reported (1). Hematoge- nous spread is more comon to the posterior pitui- tary which receives a direct arterial supply (1, 2). The anterior lobe is probably involved by extension from the posterior lobe. Metastasis to the anterior lobe could also occur secondary to involvement of the thalamic-hypothalmic area because the by-

pophyseal portal plexus probably 'filters' malig- nant cells in the systemic circulation (2). Metastatic tumor in the parasellar area may also extend to the anterior pituitary. It must be pointed out that con- ventional skull x-rays may miss lesions in the par a- sellar area (10). Even tomograms have similar drawbacks. However, with the advent of high reso- lution CT scanning, this diagnosis should become easier. In our case, parasellar bone metastases were identified by CT scan in 1981 but not in 1979, perhaps because of improved resolution of the new CT scanning machine. Most of the articles review- ing large numbers of patients were done before the CT era and this may explain why this route of spread has not been more frequently reported. Needless to say, it is crucial to ascertain if the lesion is primary or secondary as this will profoundly affect treatment and prognosis.

Evaluation of the tumors that produce a clinical- ly apparent Cushing's syndrome (most commonly bronchogenic carcinoma, thymoma, non-beta islet cell carcinoma, and bronchial carcinoid) shows that small cell carcinoma is responsible for about half of the cases (9). However, the number of patients with small cell carcinoma of the lung who develop ob- vious Cushing's syndrome is probably less than 5% (9, l 1). Marked hypercortisolemia, elevated serum ACTH, metabolic alkalosis, hyperpigmentation and edema are often characteristic aspects 0fectop- ic ACTH production in the presence or absence of classical cushingoid features. Our patient is unusual in that she developed prominent physical aspects of Cushing's syndrome in addition to the hypokalemie metabolic alkalosis. The diagnosis of ectopic ACTH production by the small cell carcinoma is firm on clinical grounds, and would have been enhanced by the demonstration of neurosecretory granules and ACTH in the tumor. The lack of immunoperoxi- dase stainable ACTH in the tumor does not exclude ectopic ACTH production, and may be the result of an altered carcinoma ACTH molecule (7). Several studies depict a bleak outlook for patients with small cell carcinoma of the lung. Those with inop- erable disease frequently survived less than three months after diagnosis, and none lived longer than ten months (7, 9, 12). Our patient's prolonged course (26 months) after eraniotomy is also unusual but not unknown. Two patients with Cushing's syndrome and oat cell carcinoma survived three and seven years respectively, after bilateral adrenal-

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ectomy (13). The behavior of the tumors in our patient and in the latter two patients were more similar to a bronchial carcinoid or to a non-beta islet cell pancreatic tumor with ectopic ACTH pro- duction and an indolent course (I 1, •4). Yet, in our case the lesion was typical for primary small cell carcinoma of the lung (Fig. 4). The pancreas had similar carcinoma cells in the lymphatics that sug- gested metastatic disease.

This case supports the hypothesis that the ante- rior pituitary gland may be involved by tumor me- tastases via extension from the adjacent parasellar sphenoid bone. The case also demonstrates how difficult it can be to diagnose the etiology of Cush- ing's syndrome (15) and it emphasizes a unique variation in the presentation of small cell carcino- ma of the lung.

Acknowledgments

We thank the physicians in the Departments of Neurosurgery, Internal Medicine and Section of Oncology who contributed to the patient's care and Dr. Glenn Dobben for interpreting the radiological tests.

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