BRIEF COMMUNICATION
OAT CELL CARCINOMA WITH HYPERCORTISOLEMIA PRESENTING TO A PSYCHIATRIC HOSPITAL AS A SUICIDE ATTEMPT
ARNOLD E. ANDERSEN, M.D.1 AND PAUL R. MCHUGH, M.D.2
This is the first reported case of an ectopic adrenocorticotrophic hor- mone (ACTH)-producing tumor which manifested itself initially to a psychiatric hospital as a suicide attempt. The patient, a 54-year-old fe- male, had a history of some typical depressive symptoms along with several atypical complaints, but had no classical features of Cushing’s disease. She suddenly attempted suicide and was referred to a psychiatric hospital where the diagnosis of Cushing’s syndrome was made. Her adrenals were removed and she improved, but later died of metastatic carcinoma of the lung. She is presented as an example of a depressive illness resulting from an endocrinopathy, with emphasis on the diagnostic and therapeutic problems of this class of depression. Suggestions are made for the workup of depressive disorders thought to be due to endocrine disease.
Psychological changes, especially depres- sion, occur frequently with Cushing’s dis- ease. Usually these changes occur along with, or after, obvious physical signs of the disease. Cushing’s syndrome due to ectopic adrenocorticotrophic hormone (ACTH) -se- creting tumors progresses rapidly, with few classical stigmata apparent, and with psy- chological symptoms sometimes appearing before the syndrome is recognized clinically. This paper reports a case of undiagnosed Cushing’s syndrome produced by an oat cell carcinoma of the lung presenting initially to a psychiatric hospital as a suicide attempt.
CASE PRESENTATION
The patient, a 54-year-old white female, was transferred to the New York Hospital-West- chester Division after making a suicide attempt.
1 Dr. Andersen was Assistant Resident in Psy- chiatry at the New York Hospital-Westchester Division. His current address is 10630 Kenilworth Ave., Bethesda, Md. 20014.
2 Dr. McHugh is Clinical Director of the New York Hospital-Westchester Division, and is As- sociate Professor of Psychiatry and Associate Pro- fessor of Neurology.
Approximately 3 months prior to admission, the patient complained of poor sleep, with early morning awakening. Her mood improved as the day progressed. She began to lose interest in sexual relations. Later she discontinued sports for the first time in 10 years because of fatigue and loss of interest. She spent more time in her room alone.
About 6 weeks prior to admission, she noted “puffiness” in her face, weight gain, and small whiskers around her mouth. Over the following weeks, she lost her appetite but did not lose weight. She complained of increased thirst and frequent urination. She rather suddenly got the idea that she had cancer of the lung and went to her local physician who assured her after a nor- mal physical exam and chest X-ray that she was healthy. Her mood continued mildly depressed, but she had no suicidal thoughts.
When the somatic complaints persisted, she was admitted to a general hospital. There, an elevated blood sugar and low serum potassium were discovered, and mild diabetes mellitus was diagnosed. Chest X-ray and urinalysis were nor- mal. Shortly before she was scheduled to leave the hospital, she suddenly took a dull luncheon
knife and stabbed herself multiple times in her arm, inflicting deep lacerations into tendons and muscles, and also stabbed herself in her throat and neck. She describes the experience as fol- lows: “All of a sudden something came over me. I was afraid I would start screaming … I hurt myself so I wouldn’t talk if I went beserk. That would be the best thing for my family.” She was immediately transferred to the New York Hos- pital-Westchester Division for psychiatric treat- ment.
The changes in this patient’s personality dur- ing the present illness are especially striking when one considers her social and psychological history. She was an energetic, active, cheerful woman, considered to be a “resource” person in the community, frequently sought out for lead- ership roles in civic and social affairs. Simultane- ously she successfully managed a large house- hold. She had no prior mental disturbances or psychiatric care, and was not given to introspec- tion, obsessionality, or anxiety. The dependabil- ity and constancy of her personality and life style help to explain the bewilderment of her family and friends when the symptoms of her illness appeared.
The patient smoked two packs of cigarettes per day. There was no history of cardiac, renal, hepatic, or endocrine disorders. Her mother had three episodes of a depressive illness, the last one associated with a suicide attempt, but was suc- cessfully treated with electroconvulsive therapy.
At the mental status examination, the patient appeared sad, but was cooperative and alert.
Mood: Q. “How are your spirits?” A. “I’ve been feeling so guilty.” She showed no retarda- tion of speech or motion. Occasionally her an- swers were sarcastic or ironic in tone and con- tent.
Speech: There was no circumstantiality, biz- zareness, or vagueness.
Delusions: She maintained she was guilty of an indiscretion so bad she would have to kill herself to keep her family from being shamed.
Hallucinations: None.
Cognitive Functions: She was oriented to time, place, and person. She could remember three objects for 5 minutes, remember the presi- dents backwards, and do serial sevens quickly. Her insight was poor. She had no explanation for her behavior except that she suddenly felt she was going crazy and would talk about her delusion, unless she could kill herself first.
On physical examination, the patient was thin, tanned, dehydrated, and appeared physi- cally ill. She had small telangiectasias on her face, and light whiskering around her mouth. She had no moon facies, striae, or truncal obe- sity. There were large, deep lacerations on her left arm, and ecchymoses on both arms. Several knife wounds on her neck were visible. Pertinent physical findings included blood pressure, 120/ 80, and pulse, 72 and regular. There was no thyroid enlargement. The lungs were clear, and the heart normal. The abdomen was normal, with no masses palpable. Neurological examina- tion was normal except for general muscular weakness, and slow relaxation of deep tendon reflexes.
Laboratory Studies: Urinalysis: specific grav- ity, 1.005, acid pH, negative sugar, negative ace- tone. Normal sediment. Complete blood count: hemoglobin, 13.0 g per cent; hematocrit, 36 per cent; white blood-cell count, 14,150 with a differ- ential of 7 lymphocytes, 2 monos, 83 polymorpho- nuclear leukocytes, 8 bands. Calcium, 9.0 mg per cent; chlorides, 83 mEq/liter; CO2 content, 38 mmol/liter; sodium, 139 mEq/liter; potas- sium, 2.1 mEq/liter; blood urea nitrogen, 17 mg per cent; fasting blood sugar, 140 mg per cent; serum glutamic oxalopyruvic transaminase, 55 units (normal 20-40 units) ; lactic dehydrogen- ase, 710 units (normal 150-350). 7 a.m. plasma cortisol, 127.4 ug per cent; 7 p.m. plasma corti- sol, 133.9 ug per cent. Urinary collection, 24- hour, (2,710 cc) showed 17-keto steroids of 117 mg and 17-hydroxy steroids of 128 mg. Urinary sodium, 6.0 mEq/liter; urinary potassium, 59 mEq/liter. Stools were positive for blood. Serum thyroxin, 0.4 µg/100 ml. Ts uptake, 55 per cent. Protein-bound iodine, 1.9 ug/100 ml. Chest films, skull films, and pituitary fossa tomograms were normal. Visual fields were normal. The car- diogram was consistent with hypokalemia, but otherwise normal.
HOSPITAL COURSE
The patient was put on constant observation. She adapted well to a therapeutic community setting and socialized with other patients. She continued to maintain her guilt feelings. With 100 mEq of potassium daily her serum potas- sium rose to 3.4. Cushing’s syndrome was the diagnosis made from history, examination, and laboratory data. Shortly before she was to be
electively transferred to the Peter Bent Brigham Hospital, Boston, for definitive treatment of her endocrine disorder, she became obtunded over the course of 12 hours, with profound apathy, and disorientation. In Boston, she responded quickly to parenteral thyroid medications and additional potassium. The high plasma cortisols and other metabolic abnormalities were con- firmed. Emergency intravenous pyelogram and tomograms were normal. Renal arteriograms were normal. Chest X-ray was normal. Because no primary tumor site could be found, the pa- tient underwent a bilateral adrenalectomy for relief of her symptoms. Each adrenal weighed over 22 gm, and both showed severe cortical hyperplasia. In addition, there was at least one grossly visible, and several microscopically visi- ble foci of malignant cells in the adrenals, which histologically were similar to an oat cell carci- noma of the lung.
Postoperatively, she did well for the first week, and was noted to have a pleasant and friendly mood, and increased strength. One week postoperative repeat chest X-rays showed for the first time a paratracheal tumor and a right pleural effusion. Scalone node biopsy revealed a metastatic anaplastic oat cell carcinoma. Her pleural effusion and lung infiltrate rapidly ex- panded. She became comatose and died 3 weeks postoperative. Postmortem examination showed a malignant mass, 8 by 4 cm, in the right upper lobe, with involvement of mediastinal lymph nodes, liver, and spleen. Microscopically, the tumor was termed a poorly differentiated small cell carcinoma of the lung.
DISCUSSION
This patient was a diagnostic problem because she presented many of the typical features of a depressive disorder, but also had several significant features that were unlike those usually found. Quite character- istic of depression were the disturbance in sleep pattern, and the onset of a diurnal mood variation, with low spirits in the morning. She lost interest in marital rela- tions. Later she withdrew from social and athletic activities, and began to have so- matic complaints not associated with changes on physical or radiological exami- nation. Finally she presented to a psychiat-
ric hospital with a serious suicide attempt growing out of feelings of self-blame, worthlessness, and delusional guilt. Consist- ent with her diagnosis of depression was the family history of an affective disorder.
Among the atypical features were the fol- lowing. She had specific physical signs and complaints not associated with depression: pedal edema, slight whiskering around the mouth of recent onset, and polydypsia. Contrary to the usual pattern of severe de- pression, she gained rather than lost weight. In her general medical hospital workup, the abnormal glucose tolerance test and hypo- kalemia were early clues to an underlying disease. Finally, the telangiectasias, ecchy- moses, whiskering, slow reflexes, and gener- ally ill appearance on initial examination in this hospital suggested a possible endocrine disorder. There were, however, none of the classical signs of Cushing’s disease: no truncal obesity, striae, moon facies, or hy- pertension.
The impression of Cushing’s syndrome made from history and physical examina- tion was confirmed by laboratory studies. The high persistent plasma cortisols, low po- tassium, and elevated sugar being the most helpful values. The extraordinarily high cor- tisols found in this patient and in other pa- tients with ectopic ACTH-secreting tumors should not be confused with the mildly hy- percortisol states found in most depressed patients. Gibbons and McHugh (3) reported that the severity of depression in nonendo- crine patients is statistically correlated in a linear fashion with elevated plasma corti- sols. Their most severely depressed patients had an average plasma cortisol of 23 ug per cent, but lacked both the physical signs of Cushing’s disease, and the severe metabolic abnormalities of adrenal carcinoma or ec- topic ACTH-secreting tumors. Signifi- cantly, their cortisol levels returned to nor- mal when their depression improved, and no underlying endocrinopathy was found. The true pathological basis of this patient’s dis- ease was established by the clinical appear-
ance of cancer, and its histological observa- tion by biopsy and later postmortem.
Numerous studies have noted the fre- quent association of psychological changes with diseases that produce cortical hyperse- cretion. Four years before Cushing grouped the now familiar symptoms of Cushing’s disease into a recognizable syndrome, W. Hurst Brown (1) described “A Case of Plu- riglandular Syndrome: ‘Diabetes of Bearded Women.‘” His patient had diabe- tes, facial hirsutism, hypertension, and mental changes. She was found at autopsy to have an oat cell carcinoma. Leyton, Turnbull, and Bratton (4) first implied a relationship between a neoplasm and the “pluriglandular disturbance” which we would now call Cushing’s syndrome. Thorne (8) first suggested that a bronchogenic car- cinoma may itself exert a corticotrophic ef- fect.
About the time of Thorne’s paper, more detailed studies of psychological changes in patients with Cushing’s syndrome began to appear. Starr (7) reviewed 53 proven cases of Cushing’s syndrome and found personal- ity changes in 60 per cent, regardless of the pathological etiology of the syndrome. Se- vere depression was the most common men- tal disturbance, occurring in 25 per cent; “frank psychosis” occurred in 15 per cent, unusual nervousness or irritability in 15 per cent, mental dullness, anxiety, or insomnia in 10 per cent. Euphoria was rare, in con- trast to its frequent occurrence in patients receiving exogenous steroids. Ten per cent of his series attempted suicide, an incidence 1000 times that of the general population.
Michael and Gibbons (6) quote a similar figure of greater than 50 per cent psychiat- ric disturbances. They note that “a fairly common feature of the mental changes in Cushing’s syndrome is the occurrence of acute, brief episodes of grossly disturbed behavior.” (p. 267, emphasis added). The severity of the psychological and physical changes are not related, but in general, the more rapid the development of the syn-
drome, the more severe the psychological symptoms. Most obvious psychological symptoms appear when the disease is suffi- ciently advanced to be recognizable.
Recent more neurophysiologically ori- ented studies have begun to suggest means by which hypercortisol states affect brain function. For example, Curzon (2) articu- lates the idea that adrenal cortical control of pyrrolase activity, a key enzyme in tryp- tophan and therefore 5-hydroxytryptamine metabolism, may explain the close associa- tion between changes in cortisols and psy- chological states. Other workers have noted an association between hypercortisol states and burst activity on the electroencephalo- gram.
There are three types of noniatrogenic hypercortisol states. First there is Cushing’s disease, a hypersecretion of the adrenal cor- tex resulting from excess pituitary ACTH, often associated with a small pituitary ade- noma. Cushing’s disease usually presents with classical moon facies, striae, hyperten- sion, and changes in body habitus, but with mild metabolic abnormalities. Second, there is the hypercortisol state associated with adrenal adenomas and carcinomas. The car- cinomas are often abrupt in onset, with in- sufficient time to develop all the typical signs of Cushing’s disease. Third is the hy- percortisol state caused by nonendocrine tumors secreting ACTH that were first carefully documented in the early 1960’s (5). These ectopic ACTH-secreting tumors produce a syndrome that is often explosive in onset, with severe changes in electrolyte balance, especially hypokalemic alkalosis, difficult to control diabetes, very high plasma cortisols, and skin pigmentation; few have typical external features of Cush- ing’s disease.
Our patient is a dramatic example of a depressive disturbance appearing with sui- cidal intensity in a patient with Cushing’s syndrome caused by an ectopic ACTH-pro- ducing tumor. She had few of the external signs of Cushing’s disease. She was easily
mistaken for an example of manic-depres- sive disorder, depressed type, but for a few atypical features. These proved of crucial importance in diagnosis. This is believed to be the first reported case of an undiagnosed oat cell carcinoma presenting initially to a psychiatric hospital as a severe depression with a suicide attempt.
She demonstrated that patients with de- pression from Cushing’s syndrome can and do commit suicide, regardless of the patho- logical etiology. The tendency to sudden brief episodes of disturbed behavior, the ab- sence of some typical depressive symptoms, the presence of somatic signs, and the rapid progression of the somatic signs and symp- toms help make the differentiation from manic-depressive disorder. These patients should be watched closely with all suicide precautions until their mental state is nor- mal, which may be some time after defini- tive therapy for hypercortisolemia has been undertaken and plasma steroid values have returned to normal.
Where an endocrine disorder is suspected as the underlying basis of a depressive dis- order, the following studies will be useful for initial assessment: complete blood count, urinalysis, electrolytes, glucose toler- ance test, morning and evening plasma cor- tisols, 24-hour urine collection for 17-hy- droxy and 17-keto steroids, circulating thy- roxine (T4), T3 uptake, and serum calcium. These tests should point to Cushing’s syn- drome or disease, thyroid disorders, and hy- perparathyroidism, the most common endo- crinopathies associated with psychological changes, if they are present in the patient. If a hypercortisol state is found, standard tests to determine the specific pathological etiology should be done.
Although many of the nonendocrine tu-
mors elaborating ACTH are malignant, as in this case, some are amenable to complete surgical extirpation, and should be vigor- ously sought. In patients having nonopera- ble primary tumors, treatment is still advis- able to relieve the patient during the re- maining lifespan of the burden of a severe psychological illness and the debilitating ef- fects of the hypercortisol state. If the source of the tumor is not obvious, a bilateral ad- renalectomy will relieve the symptoms. Also, metabolic inhibitors of cortisol pro- duction may be tried. Depressive states as- sociated with Cushing’s syndrome will not respond well to conventional antidepres- sants or to electroconvulsive therapy. Therefore lack of clinical response to con- ventional treatment in depressed patients should also raise the question of an under- lying endocrinopathy.
REFERENCES
1. Brown, W. H. A case of pluriglandular syn- drome: “Diabetes of bearded women.” Lancet, 2: 1022-1023, 1928.
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