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INTRATHORACIC TUMORS ASSOCIATED WITH HYPOGLYCEMIA
INTRATHORACIC TUMORS ASSOCIATED
WITH
HYPOGLYCEMIA Herbert C. Maier, M.D.* New York, N.
and David Ban, M.D. (by
invitation),
Y.
I
N recent years an increasing number of extrapancreatic tumors associated with the development of hypoglycemia have been reported. A significant per centage of these neoplasms have been found within the thorax. A striking fea ture of these tumors is the occurrence of hypoglycemia when the growth has attained large size. The cerebral symptoms and signs associated with the low blood sugar level frequently mimic disease of the nervous system. Hence such patients may be considered, at first, to have a primary neurologic or psychiatric abnormality or, when roentgen studies have demonstrated the intrathoracic tumor, be misdiagnosed as having brain metastases secondary to the chest neo plasm. Recognition of this entity and surgical excision of the tumor results in dramatic relief of the hypoglycemic episodes. The fact that most of these eases have been recognized only within the last few years strongly suggests that their occurrence is actually not as rare as the available literature would seem to infer. The intrathoracic tumors that have been associated with the development of hypoglycemia have been predominantly pleural in location. Although the title of some of the case reports refer to lung or mediastinal tumors, the de scription of the operative or autopsy findings in these reports reveals that the growth lay predominantly within the pleural cavity. All of the neoplasms have been of large size at the time the hypoglycemia became manifest. In some in stances it is known that the tumor had been present for even many years before the blood sugar level became abnormally low. Then, in some cases, a rapid drop in blood sugar would occur with the onset of hypoglycemic episodes. In some instances, in a matter of a few weeks or months it would become increasingly difficult to keep the patient out of hypoglycemic coma by a high glucose intake. Finally, as in the case which we are reporting, the brain damage from an inade quate glucose supply to that organ may reach the stage where elevating the blood sugar to levels above normal by glucose infusion no longer brings the patient out of coma until the tumor is removed. From the Surgical Service, Lenox Hill Hospital, New York, N. T. Read at the Forty-second Annual Meeting of The American Association for Thoracic Surgery at St. Louis, Mo., April 16-18, 1962. •Address: 3 East 71st Street, New York 21, N. Y.
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These intrapleural tumors associated with hypoglycemia have usually been described by pathologists as consisting of spindle-shaped cells and apparently arc of mesodermal origin, but there has been no unanimity of opinion as to patho logic classification. The tumors are usually very vascular and this point should be borne in mind in theorizing on the mechanism of the production of the hypoglycemia. The ease with which the presence of hypoglycemia might be missed is indi cated by some of the case reports in the literature. On original examination of the patient, a blood sugar determination might be done and found to be within normal range. At this time no obvious hypoglycemic symptoms might be present. Then perhaps a few weeks later bizarre symptoms or behavior may lead to a diagnosis of a psychiatric condition and the patient is transferred to a mental hospital. Unless the association of improvement in symptoms with the ingestion of carbohydrate is noted, it may well be assumed that the abnormal behavior is unrelated to a tumor which has apparently not changed in size recently. Or the recent onset of neurologic manifestations may be attributed to the development of brain metastases and the patient is considered to be in curable. The situation with these extrapancreatic tumors associated with hypo glycemia is reminiscent of the early history of the recognition of islet cell tumors of the pancreas. A failure to appreciate the possibility that intrathoracic tumors may be related to the development of hypoglycemia has been evidenced by the fact that even in the last few years some of the patients with known intrathoracic tumors have had an abdominal exploration alone done as the intial operative procedure. In view of our current knowledge it would seem necessary to individualize the therapeutic approach. If there is a large intrathoracic tumor present which is of apparent pleural location, and no obvious evidence of a pancreatic tumor exists, it would seem best first to remove the intrathoracic tumor. If this is a spindle-cell tumor, the operation would be limited to the thorax. The post operative course would demonstrate whether the hypoglycemia had been cor rected. Our patient was unique in that she had both a large intrathoracic and an intra-abdominal mass. The clubbing of the fingers and the roentgen signs of pulmonary osteoarthropathy, however, suggested that the chest tumor might well be metabolically most important. Actually, the intra-abdominal tumor proved to be entirely unrelated to the patient's hypoglycemia in that it was found to be a huge parovarian cyst. CASE REPORT A 62-year-old white woman was sent to the Lenox Hill Hospital for the first time on Oct. 6, 1961 by Dr. George Serban. Two months before admission she had had the first of several episodes of aphasia, restlessness, weakness, and involuntary micturition occurring in the early morning. Following one of these she had been admitted to another hospital where a diagnosis of hypoglycemia was made. Blood sugar determinations ranged between 32 and 63 mg. per cent. Chest roentgenograms showed a mass in the right lung field. Operation was recommended and refused. The patient had been discharged feeling better.
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On the day of admission to Lenox Hill Hospital the patient was found unconscious in the early morning. At first she was thought to be merely in a deep sleep, but when she did not awaken after several hours her physician was called. Intravenous glucose was ad ministered with slight transitory improvement, but upon arrival a t the hospital that night she was comatose. The past history was significant in that the patient had had a vaginal hysterectomy for vaginal bleeding in 1948. A chest roentgenogram taken 10 years before had shown a tumor. This was confirmed on subsequent admissions to other hospitals. Thoraeotomy had been recommended on several occasions and always refused. Finally, hypertension and an ab dominal mass were discovered 21 months before admission to Lenox Hill Hospital.
Pig. 1.—Roengenogram of chest demonstrates large mass in right hemithorax. On admission to the hospital she was observed to be an obese white woman in coma. The blood pressure was 130/90 mm. Hg, pulse 108, respirations 34, and temperature 101° F . The fingers were clubbed. There was some stiffness of the neck. The eyes deviated to the left. There was an extensor plantar response on the left and the musculature of the left side was hypotonic. The chest tumor was not appreciated on the admission physical examination. Abdominal examination revealed a large rounded tumor just below the umbilicus. Laboratory Findings.—The blood count was normal except for mild anemia. TJrinalysis was unremarkable. Fasting blood sugar levels of 49, 49 and 46 mg. per cent were found. Serum electrolytes were normal except for a mild hypopotassemia (2.6 mEq. per liter). Liver function tests showed only a moderate elevation of the alkaline phosphatase and slight prolongation of the prothrombin time. Blood calcium and phosphorus were normal. The cerebrospinal fluid was normal except that on one determination a sugar of 20 mg. per cent was found. Chest roentgenograms showed a large, lobulated mass occupying the middle two thirds of the right lung field without calcification, mediastinal displacement, atelectasis, or pleural
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fluid (Fig. 1 ) . A plain film of the abdomen showed a well-circumscribed oval density in the mid-abdomen. Considerable periostitis was noted in the upper femora and subsequent films of the long bones showed periosteal new bone formation compatible with a diagnosis of pulmonary osteoarthropathy. Skull x-ray studies were normal. Pneumoencephalograms showed only enlargement of the subarachnoid spaces suggestive of cerebral atrophy. Electro encephalogram showed a diffuse slow wave abnormality without evidence of a focal lesion. The electrocardiogram was normal. Course in the Hospital.—On admission to the hospital an intravenous infusion of 5 per cent glucose in water was started. The patient improved somewhat but remained stuporous and aphasie. Diagnostic studies 'were initially directed toward establishing the presence or absence of disease of the central nervous system. I t soon became evident, however, that the patient did not have either a primary or metastatic intracranial neoplasm and that in all probability the process was not primarily neurologic. I t was believed that the patient had hypoglycemia on the basis of an extrapancreatic neoplasm. The fact that she had two tumors, one in the chest and one in the abdomen, made it difficult to decide whether either or both were responsible for the hypoglycemia. Since she did not improve significantly on continuous infusion of glucose, even though the blood sugar was maintained between 63 and 169 mg. per cent, it was considered that operation should not be delayed longer and that both tumors should be removed at the same operation. Accordingly, one week after admission to the hospital the patient was operated upon with the plan to do a thoracotomy first. Priority was determined by two considerations: (1) that the thoracic tumor was more likely to be responsible for the hypoglycemia than the abdominal one, since the latter did not seem to be either an islet cell tumor or a retroperitoneal sarcoma, and (2) that removal of a large chest tumor, even if not the cause of hypo glycemia, would render laparotomy safer by virtue of the attendant improvement in pul monary function. On Oct. 14, 1961, she was operated upon while still virtually comatose. The chest was opened through a standard posterolateral thoracotomy incision. A large tumor was found in the posterior portion of the right pleural cavity extending almost from the diaphragm to the apex of the chest. I t was lobulated, dark red, and very vascular. I t was attached to the parietal pleura in several places and also had a broad area of attachment to the right upper lobe, but approximately 90 per cent of its surface was free in the pleural space. Its main blood supply came from the chest wall and particularly from one of the intercostal vessels. The lung was normal as were the mediastinal structures. The tumor was removed intact. The lung expanded normally and the chest was closed. The patient was then turned on her back and a laparotomy was performed through a right lower, paramedian incision. A large parovarian cyst was found arising from the right adnexa. I t was simply excised. The abdomen was explored. The pancreas felt normal and no other abnormality was found. The entire procedure was well tolerated. The postoperative course was satisfactory. Glucose infusions were given during opera tion and the following day. On the second postoperative day a nasogastric tube was in serted and tube feedings were begun. She was unresponsive initially but gradually improved and by the fourth postoperative day seemed to be awake but unaware of her surroundings and unable to communicate. On the fifth day she began to answer questions in French, her first language, and during the succeeding days became increasingly more alert. By the seventeenth day she was able to eat well enough to forego tube feedings. Ambulation was begun and convalescence continued. Blood sugars were 165, 131, 125, and 103 mg. per cent on the first, second, fourth, and twenty-sixth postoperative days, respectively, and a glucose tolerance test on the forty-fourth postoperative day was normal. The patient was discharged from the hospital 52 days after operation in good condition. The neurologic signs had regressed completely. I t is noteworthy that she had poor memory and mentation and it is probable t h a t she had some permanent neurologic damage. Six months following operation she was doing well. There has been no recurrence of hypo glycemia or of the tumor thus far.
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Pathologic Examination.—The thoracic tumor was an encapsulated, lobulated mass that weighed 860 grams. There were many dilated blood vessels on the surface. On section the tumor was rather soft. The cut surface was pale, mottled gray-pink and gray-yellow. Microscopic Examination.—The tumor was extremely cellular. The cells were fairly uniform in size, closely packed, and supported by a scanty fibrillar stroma which contained thin-walled, congested blood vessels. The cells were oval and sometimes elongated. The cytoplasm was scanty and the nuclei were round or oval, exhibiting a prominent chromatin network. A number of elongated endothelial-lined spaces were noted in the tumor which in areas showed considerable hemorrhagic extravasation (Fig. 2).
Figr. 2.—Photomicrograph of pleural tumor. The abdominal mass had the gross and microscopic features of a parovarian cyst. A specimen of the chest tumor was sent to the Department of Surgical Pathology at the Columbia-Presbyterian Medical Center for tissue culture and histologic study. I t was the opinion of Dr. Ozzello and associates that the cultural features of this tumor were unusual and had been seen only once before by them, in an explant of a mesothelioma. Special studies did not reveal beta cell granules in either the histologic sections or the cul tured tissue. The histology and behavior in vitro pointed to an epithelial-like tumor with an irregular and scanty amount of reticulum and no architectural differentiation. Hemangiopericytoma or other tumor of vascular origin was felt to be excluded. The tumor was there fore reported as a " f mesothelioma associated with hypoglycemia.''
REVIEW OF REPORTED CASES
We have analyzed the cases in the literature and a total of 45 cases of nonpancreatic tumor associated with hypoglycemia, excluding hepatic and adrenal neoplasms, have been studied. In 15 instances (including our case), the tumor was within the chest.1"13 Only 3 of these intrathoracic neoplasms were reported prior to 1958. An analysis of the findings in the patients with chest tumors follows. There were 9 females and 6 males in the intrathoracic group. The patients ranged in age from 42 to 82 years, with the greatest incidence in the sixth
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decade of life. Nine patients presented manifestations of hypoglycemia. The symptoms were of all grades of severity, ranging from weakness and sweating, through abnormal behavior, mental confusion, and aphasia, to convulsions and coma. The symptoms frequently appeared at night or in the early morning and were relieved by eating. Occasionally patients were admitted initially to neuropsychiatric services and transferred to medical or surgical services after the hypoglycemic basis of the neurologic symptoms was discovered. Six pa tients presented symptoms attributable to their tumors, such as cough, dyspnea, chest pain, anorexia, and weight loss. These patients later developed symptoms of hypoglycemia. Nine patients had episodes of convulsions and coma. The duration of the hypoglycemic symptoms was generally short; one year or less in all patients and usually less than 6 months, even though the tumors in all instances were very large. In most cases physical signs of an intrathoracic mass were demonstrable. Clubbing of the fingers was recorded in 3 patients. Thyroid enlargement was observed in 2 patients and a thyroid nodule in 2 others. Gynecomastia was seen in one case. Many determinations of the blood sugar were made and, with a few ex ceptions, values under 50 mg. per cent were obtained. The lowest value re ported was 10 mg. per cent. Preoperative glucose tolerance tests were done in 4 patients. In 3 patients the fasting levels were low with low or normal peaks and low end points. In the fourth patient a normal fasting level with a high normal sustained peak and a normal end point were found. Tests for thyroid, hepatic, and adrenal dysfunction were within normal limits. In all patients a mass was seen on roentgenograms of the chest. In 5 cases chest films showed the tumor one to 12 years prior to the onset of hypoglycemia. In one patient a tumor of the diaphragm had been removed 7 years before the onset of hypoglycemia when a huge local recurrence, demonstrable radiographically, was present. In several instances the infrapulmonary location and con tour of the tumor led to confusion between a high diaphragm and a neoplasm. The radiographic findings of hypertrophic pulmonary osteoarthropathy were demonstrated in only 2 cases. Attempts were made to control hypoglycemic symptoms by dietary means and supplementary oral or parenteral glucose with limited success. Five pa tients underwent initial exploratory laparotomy. Partial pancreatectomy was done in 4 patients and biopsy of the pancreas in one; all without benefit. Three of these patients then underwent thoracotomy with removal of their tumors. The fourth patient never was in good enough condition to tolerate thoracotomy and died with persistent hypoglycemia and heart failure. The fifth patient was subjected to a second laparotomy and died in the immediate postoperative period. Nine patients were subjected to primary thoracotomy. The tumor was removed in 7 and was considered to be inoperable in 2. One patient had neither laparotomy nor thoracotomy. His pulmonary reserve was regarded as too pre carious to permit thoracotomy, although it was believed that the chest tumor
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was responsible for hypoglycemia. He had only an aspiration biopsy and the subsequent course is unknown. Successful removal of the intrathoracic tumor alleviated the hypoglycemia in 9 patients. Recurrence of the tumor with hypoglycemia and death occurred in one patient after 3 years. Eight patients are apparently well, but the periods of follow-up are comparatively short: less than one year in 6 patients and less than 3 years in the other 2 cases. Postoperative glucose tolerance tests showed reversion toward the normal pattern. The tumors were all very large. The weights were recorded in 12 patients and ranged from 860 to 3,500 grams. Twelve neoplasms were considered to be pleural tumors arising from diaphragm, mediastinum or chest wall, while 3 were thought to have arisen from lung, although it is quite likely that in these pa tients the lung was secondarily involved. The histologic diagnoses made were fibrosarcoma in 4 cases, spindle-cell sarcoma in 3, mesothelioma in 3, fibroma and neurofibroma in 2 patients each, and neurofibrosarcoma in 1 case. Five patients came to autopsy and in all of these the pancreas was normal. In 2 patients, colloid goiters were described and in one of these there was pitui tary and adrenal hyperplasia as well. In the other 3 patients, however, the thyroid, pituitary, and adrenal glands were considered to be normal. In four instances, bio-assay of the tumor tissue for insulin-like activity was carried out. The results were positive in one, equivocal in one, and negative in 2. In 2 patients, plasma insulin activity was determined and found to be within normal limits. Several theories have been proposed to explain the hypoglycemia seen in these patients. The most reasonable hypotheses are that the tumor either elaborates a substance with insulin-like activity, or it avidly utilizes and stores carbohydrate at the expense of the rest of the body. Some evidence favors the secretory theory and yet the presence of an insulin-like substance has not been consistently demonstrated, although in one patient not only was insulin activity demonstrable in the tumor, but excessive plasma insulin activity was found preoperatively that disappeared after the tumor was removed. In those pa tients in whom both bio-assays of insulin activity and detailed studies of carbo hydrate metabolism were performed, and in whom the assays were negative, it was thought that a defect in the utilization and storage of glucose and amino acids in the tumor itself was responsible. Other unproved theories implicate hypothetical substances capable of stimulating the islands of Langerhans to produce insulin or of interfering with the insulinase systems, or that there may be abnormal amino acids with hypoglycemia-inducing properties. Defects in hepatic, adrenal, and pituitary function have not been demonstrated. SUMMARY
Certain large intrathoracic neoplasms, chiefly intrapleural in location, may be associated with a hypoglycemia which may first become manifest long after the chest tumor developed. The onset of the hypoglycemic symptoms may be
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rather abrupt and of such bizarre character that a psychiatric or cerebrovascular condition may be erroneously diagnosed, or brain metastases suspected. Dra matic correction of the hypoglycemic state follows surgical excision of the tumor and a ease herewith reported demonstrates that a satisfactory recovery may still occur in spite of some brain damage from prolonged cerebral hypoxia secondary to an inadequate supply of glucose to the brain. Further experience is necessary to permit a better pathologic classification of these neoplasms which, when found in the chest, seem to be chiefly mesodermal tumors composed of spindle-shaped cells. Moreover, the mechanism of the production of the hypoglycemia remains to be clarified. REFERENCES 1. Doege, K. W.: Fibrosarcoma of the Mediastinum, Ann. Surg. 92: 955, 1930. 2. Arkless, H. A.: Coincidence of Rhabdomyofibroma of the Diaphragm, Idiopathic Hypoglycemia, and Retroperitoneal Sarcoma, M. Bull. V. A. 19: 225, 1942. 3. Skillern, P . G., McCormack, L. J., Hewlett, J . S., and Crile, G., J r . : Hyperinsulinism Due to Islet Cell Tumors Simulating Sarcoma, Diabetes 3: 133, 1954. 4. Zollner, S., and Winkelbauer, A.: Intrathorakaler Tumor mit Spontanhypoglykamie, Klin. Med. 13: 289, 1958. 5. August, J . T., and Hiatt, H. H . : Severe Hypoglycemia Secondary to a Nonpancreatic Fibrosarcoma With Insulin Activity, New England J . Med. 258: 17, 1958. 6. Mahkota, S.: Spontane hipoglikemije pri obseznih tumorjih pljuc, Zdrav. Vestn. 27: 326, 1958. 7. Andreew, D., Goranow, I., and Krastinow, G.: Hypoglykamie bei einem Intrathorakel Gelagerten Fibrom, Endokrinologie 38: 167, 1959. 8. Rossman, E. M.: Mediastinal Neurofibrosarcoma Causing Hypoglycemia, Arch. Int. Med. 104: 640, 1959. 9. Miller, D. R., Bolinger, R. E., Janigan, D., Crockett, J . E., and Friesen, S. R.: Hypo glycemia Due to Non Pancreatic Mesodermal Tumors, Ann. Surg. 150: 684, 1959. 10. Kuijjer, P. J . : A Tumor of the Lung With Disturbances in the Sugar Metabolism, Arch. chir. neerl. 13: 81, 1961. 11. Paulson, G. S., Feehan, J. J., and Westaby, R. S.: Severe Hypoglycemia Due to Mesothelioma Arising in Pleural Cavity, South Dakota J . Med. & Pharm. 14: 5, 1961. 12. Dolder, D. G.: Spontane hypoglykemie bij een patient met een groot longgezwel, Nederl. tijdschr. geneesk. 105: 2030, 1961. 13. Schmidt, H. W., and Schurholz, K.: Hypoglykamische Anfalle durch intrathorakalen Tumor, Deutsch. Med. Wchnschr. 86: 2231, 1961. DISCUSSION DR. HOWARD A. F R A N K , Boston, Mass.—I think this is a fascinating group of tumors, and we must be grateful to Dr. Maier for gathering them for us in this way. Their histologic appearance so little suggests active secretion, and one wonders what nature has in mind placing hormonal activity in so inert-looking a mass of connective tissue. Seeing this title in the program, I thought Dr. Maier might like to have a follow-up added to his series. This was the case of an 82-year-old woman whom we saw in 1956. She entered the hospital in coma, and was thought to have had a cerebral vascular accident; she had very advanced vascular disease. A house officer noticed that her coma lightened each time she received an infusion con taining glucose. A measurement of her blood sugar between transfusions was 28 to 30 mg. per cent. Her chest film showed a large mass in the lower left lung field. I t had been seen one year earlier in a chest film taken during a hospitalization for heart disease. Carbohydrate metabolism had been normal at that time. In view of available reports of tumors of this sort associated with insulin-like activity, we did a thoraco-abdominal exploration and found
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this to be a large solid tumor with a very vascular attachment to the lower lobe of the lung. Its origin seemed to be the central tendon of the diaphragm. We resected the central portion of the diaphragm with the tumor and the loft lower lobe. The pancreas was normal. Im mediately after operation she behaved as though her own insulin secretion was temporarily insufficient. Within the next few days there was a return to normal carbohydrate metabolism which remained normal in the following 3 % years. Assays of the tumor by the rat diaphragm method showed insulin-like activity totaling three or more times the insulin content of a normal pancreas. She died after 3 % years, of a true cerebrovascular accident. At postmortem examina tion, she had a 0.5 cm. nodule of recurrent tumor in the diaphragm, but no recurrence of carbohydrate disturbance. Drs. Castleman and Freiman have re-examined the original and final specimens of this tumor, and now classify it as a fibrous mesothelioma. DR. W I L L I A M M. L E E S , Lincolnwood, 111.—I arise to add a little to Dr. Maier's discussion, in that one of the patients he reported on was operated upon by me. The one patient we operated upon had a 1,400 gram tumor. She had a 40 mg. blood sugar. She had clonic and tonic convulsions. We had to continue an intravenous glucose infusion preoperatively and immediately postoperatively. She did quite well after the opera tion, and returns to see me each year to tell me she is fine. DR. MAIER (Closing).—I wish to thank Dr. Frank and Dr. Lees for their discussions. On the basis of the knowledge derived from the retroperitoneal or intra-abdominal tumors, which number over 30 in the literature, it is evident that we must wait a longer time before we decide on the rate of recurrence of these tumors, because a considerable number of those that have occurred in the retroperitoneal area have shown evidence of local recur rence, sometimes massive, even after 5, 10, or more years. The various theories that have been advanced to explain the hypoglycemia are of great interest, and a very brief reference to them is made in the published paper.
WITH
HYPOGLYCEMIA Herbert C. Maier, M.D.* New York, N.
and David Ban, M.D. (by
invitation),
Y.
I
N recent years an increasing number of extrapancreatic tumors associated with the development of hypoglycemia have been reported. A significant per centage of these neoplasms have been found within the thorax. A striking fea ture of these tumors is the occurrence of hypoglycemia when the growth has attained large size. The cerebral symptoms and signs associated with the low blood sugar level frequently mimic disease of the nervous system. Hence such patients may be considered, at first, to have a primary neurologic or psychiatric abnormality or, when roentgen studies have demonstrated the intrathoracic tumor, be misdiagnosed as having brain metastases secondary to the chest neo plasm. Recognition of this entity and surgical excision of the tumor results in dramatic relief of the hypoglycemic episodes. The fact that most of these eases have been recognized only within the last few years strongly suggests that their occurrence is actually not as rare as the available literature would seem to infer. The intrathoracic tumors that have been associated with the development of hypoglycemia have been predominantly pleural in location. Although the title of some of the case reports refer to lung or mediastinal tumors, the de scription of the operative or autopsy findings in these reports reveals that the growth lay predominantly within the pleural cavity. All of the neoplasms have been of large size at the time the hypoglycemia became manifest. In some in stances it is known that the tumor had been present for even many years before the blood sugar level became abnormally low. Then, in some cases, a rapid drop in blood sugar would occur with the onset of hypoglycemic episodes. In some instances, in a matter of a few weeks or months it would become increasingly difficult to keep the patient out of hypoglycemic coma by a high glucose intake. Finally, as in the case which we are reporting, the brain damage from an inade quate glucose supply to that organ may reach the stage where elevating the blood sugar to levels above normal by glucose infusion no longer brings the patient out of coma until the tumor is removed. From the Surgical Service, Lenox Hill Hospital, New York, N. T. Read at the Forty-second Annual Meeting of The American Association for Thoracic Surgery at St. Louis, Mo., April 16-18, 1962. •Address: 3 East 71st Street, New York 21, N. Y.
321
MAIER AND BARE
322
J. Thoracic and Cardiovas. Surg.
These intrapleural tumors associated with hypoglycemia have usually been described by pathologists as consisting of spindle-shaped cells and apparently arc of mesodermal origin, but there has been no unanimity of opinion as to patho logic classification. The tumors are usually very vascular and this point should be borne in mind in theorizing on the mechanism of the production of the hypoglycemia. The ease with which the presence of hypoglycemia might be missed is indi cated by some of the case reports in the literature. On original examination of the patient, a blood sugar determination might be done and found to be within normal range. At this time no obvious hypoglycemic symptoms might be present. Then perhaps a few weeks later bizarre symptoms or behavior may lead to a diagnosis of a psychiatric condition and the patient is transferred to a mental hospital. Unless the association of improvement in symptoms with the ingestion of carbohydrate is noted, it may well be assumed that the abnormal behavior is unrelated to a tumor which has apparently not changed in size recently. Or the recent onset of neurologic manifestations may be attributed to the development of brain metastases and the patient is considered to be in curable. The situation with these extrapancreatic tumors associated with hypo glycemia is reminiscent of the early history of the recognition of islet cell tumors of the pancreas. A failure to appreciate the possibility that intrathoracic tumors may be related to the development of hypoglycemia has been evidenced by the fact that even in the last few years some of the patients with known intrathoracic tumors have had an abdominal exploration alone done as the intial operative procedure. In view of our current knowledge it would seem necessary to individualize the therapeutic approach. If there is a large intrathoracic tumor present which is of apparent pleural location, and no obvious evidence of a pancreatic tumor exists, it would seem best first to remove the intrathoracic tumor. If this is a spindle-cell tumor, the operation would be limited to the thorax. The post operative course would demonstrate whether the hypoglycemia had been cor rected. Our patient was unique in that she had both a large intrathoracic and an intra-abdominal mass. The clubbing of the fingers and the roentgen signs of pulmonary osteoarthropathy, however, suggested that the chest tumor might well be metabolically most important. Actually, the intra-abdominal tumor proved to be entirely unrelated to the patient's hypoglycemia in that it was found to be a huge parovarian cyst. CASE REPORT A 62-year-old white woman was sent to the Lenox Hill Hospital for the first time on Oct. 6, 1961 by Dr. George Serban. Two months before admission she had had the first of several episodes of aphasia, restlessness, weakness, and involuntary micturition occurring in the early morning. Following one of these she had been admitted to another hospital where a diagnosis of hypoglycemia was made. Blood sugar determinations ranged between 32 and 63 mg. per cent. Chest roentgenograms showed a mass in the right lung field. Operation was recommended and refused. The patient had been discharged feeling better.
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On the day of admission to Lenox Hill Hospital the patient was found unconscious in the early morning. At first she was thought to be merely in a deep sleep, but when she did not awaken after several hours her physician was called. Intravenous glucose was ad ministered with slight transitory improvement, but upon arrival a t the hospital that night she was comatose. The past history was significant in that the patient had had a vaginal hysterectomy for vaginal bleeding in 1948. A chest roentgenogram taken 10 years before had shown a tumor. This was confirmed on subsequent admissions to other hospitals. Thoraeotomy had been recommended on several occasions and always refused. Finally, hypertension and an ab dominal mass were discovered 21 months before admission to Lenox Hill Hospital.
Pig. 1.—Roengenogram of chest demonstrates large mass in right hemithorax. On admission to the hospital she was observed to be an obese white woman in coma. The blood pressure was 130/90 mm. Hg, pulse 108, respirations 34, and temperature 101° F . The fingers were clubbed. There was some stiffness of the neck. The eyes deviated to the left. There was an extensor plantar response on the left and the musculature of the left side was hypotonic. The chest tumor was not appreciated on the admission physical examination. Abdominal examination revealed a large rounded tumor just below the umbilicus. Laboratory Findings.—The blood count was normal except for mild anemia. TJrinalysis was unremarkable. Fasting blood sugar levels of 49, 49 and 46 mg. per cent were found. Serum electrolytes were normal except for a mild hypopotassemia (2.6 mEq. per liter). Liver function tests showed only a moderate elevation of the alkaline phosphatase and slight prolongation of the prothrombin time. Blood calcium and phosphorus were normal. The cerebrospinal fluid was normal except that on one determination a sugar of 20 mg. per cent was found. Chest roentgenograms showed a large, lobulated mass occupying the middle two thirds of the right lung field without calcification, mediastinal displacement, atelectasis, or pleural
324
MAIEK AND BABB
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Cardiovas. Surg.
fluid (Fig. 1 ) . A plain film of the abdomen showed a well-circumscribed oval density in the mid-abdomen. Considerable periostitis was noted in the upper femora and subsequent films of the long bones showed periosteal new bone formation compatible with a diagnosis of pulmonary osteoarthropathy. Skull x-ray studies were normal. Pneumoencephalograms showed only enlargement of the subarachnoid spaces suggestive of cerebral atrophy. Electro encephalogram showed a diffuse slow wave abnormality without evidence of a focal lesion. The electrocardiogram was normal. Course in the Hospital.—On admission to the hospital an intravenous infusion of 5 per cent glucose in water was started. The patient improved somewhat but remained stuporous and aphasie. Diagnostic studies 'were initially directed toward establishing the presence or absence of disease of the central nervous system. I t soon became evident, however, that the patient did not have either a primary or metastatic intracranial neoplasm and that in all probability the process was not primarily neurologic. I t was believed that the patient had hypoglycemia on the basis of an extrapancreatic neoplasm. The fact that she had two tumors, one in the chest and one in the abdomen, made it difficult to decide whether either or both were responsible for the hypoglycemia. Since she did not improve significantly on continuous infusion of glucose, even though the blood sugar was maintained between 63 and 169 mg. per cent, it was considered that operation should not be delayed longer and that both tumors should be removed at the same operation. Accordingly, one week after admission to the hospital the patient was operated upon with the plan to do a thoracotomy first. Priority was determined by two considerations: (1) that the thoracic tumor was more likely to be responsible for the hypoglycemia than the abdominal one, since the latter did not seem to be either an islet cell tumor or a retroperitoneal sarcoma, and (2) that removal of a large chest tumor, even if not the cause of hypo glycemia, would render laparotomy safer by virtue of the attendant improvement in pul monary function. On Oct. 14, 1961, she was operated upon while still virtually comatose. The chest was opened through a standard posterolateral thoracotomy incision. A large tumor was found in the posterior portion of the right pleural cavity extending almost from the diaphragm to the apex of the chest. I t was lobulated, dark red, and very vascular. I t was attached to the parietal pleura in several places and also had a broad area of attachment to the right upper lobe, but approximately 90 per cent of its surface was free in the pleural space. Its main blood supply came from the chest wall and particularly from one of the intercostal vessels. The lung was normal as were the mediastinal structures. The tumor was removed intact. The lung expanded normally and the chest was closed. The patient was then turned on her back and a laparotomy was performed through a right lower, paramedian incision. A large parovarian cyst was found arising from the right adnexa. I t was simply excised. The abdomen was explored. The pancreas felt normal and no other abnormality was found. The entire procedure was well tolerated. The postoperative course was satisfactory. Glucose infusions were given during opera tion and the following day. On the second postoperative day a nasogastric tube was in serted and tube feedings were begun. She was unresponsive initially but gradually improved and by the fourth postoperative day seemed to be awake but unaware of her surroundings and unable to communicate. On the fifth day she began to answer questions in French, her first language, and during the succeeding days became increasingly more alert. By the seventeenth day she was able to eat well enough to forego tube feedings. Ambulation was begun and convalescence continued. Blood sugars were 165, 131, 125, and 103 mg. per cent on the first, second, fourth, and twenty-sixth postoperative days, respectively, and a glucose tolerance test on the forty-fourth postoperative day was normal. The patient was discharged from the hospital 52 days after operation in good condition. The neurologic signs had regressed completely. I t is noteworthy that she had poor memory and mentation and it is probable t h a t she had some permanent neurologic damage. Six months following operation she was doing well. There has been no recurrence of hypo glycemia or of the tumor thus far.
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Pathologic Examination.—The thoracic tumor was an encapsulated, lobulated mass that weighed 860 grams. There were many dilated blood vessels on the surface. On section the tumor was rather soft. The cut surface was pale, mottled gray-pink and gray-yellow. Microscopic Examination.—The tumor was extremely cellular. The cells were fairly uniform in size, closely packed, and supported by a scanty fibrillar stroma which contained thin-walled, congested blood vessels. The cells were oval and sometimes elongated. The cytoplasm was scanty and the nuclei were round or oval, exhibiting a prominent chromatin network. A number of elongated endothelial-lined spaces were noted in the tumor which in areas showed considerable hemorrhagic extravasation (Fig. 2).
Figr. 2.—Photomicrograph of pleural tumor. The abdominal mass had the gross and microscopic features of a parovarian cyst. A specimen of the chest tumor was sent to the Department of Surgical Pathology at the Columbia-Presbyterian Medical Center for tissue culture and histologic study. I t was the opinion of Dr. Ozzello and associates that the cultural features of this tumor were unusual and had been seen only once before by them, in an explant of a mesothelioma. Special studies did not reveal beta cell granules in either the histologic sections or the cul tured tissue. The histology and behavior in vitro pointed to an epithelial-like tumor with an irregular and scanty amount of reticulum and no architectural differentiation. Hemangiopericytoma or other tumor of vascular origin was felt to be excluded. The tumor was there fore reported as a " f mesothelioma associated with hypoglycemia.''
REVIEW OF REPORTED CASES
We have analyzed the cases in the literature and a total of 45 cases of nonpancreatic tumor associated with hypoglycemia, excluding hepatic and adrenal neoplasms, have been studied. In 15 instances (including our case), the tumor was within the chest.1"13 Only 3 of these intrathoracic neoplasms were reported prior to 1958. An analysis of the findings in the patients with chest tumors follows. There were 9 females and 6 males in the intrathoracic group. The patients ranged in age from 42 to 82 years, with the greatest incidence in the sixth
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decade of life. Nine patients presented manifestations of hypoglycemia. The symptoms were of all grades of severity, ranging from weakness and sweating, through abnormal behavior, mental confusion, and aphasia, to convulsions and coma. The symptoms frequently appeared at night or in the early morning and were relieved by eating. Occasionally patients were admitted initially to neuropsychiatric services and transferred to medical or surgical services after the hypoglycemic basis of the neurologic symptoms was discovered. Six pa tients presented symptoms attributable to their tumors, such as cough, dyspnea, chest pain, anorexia, and weight loss. These patients later developed symptoms of hypoglycemia. Nine patients had episodes of convulsions and coma. The duration of the hypoglycemic symptoms was generally short; one year or less in all patients and usually less than 6 months, even though the tumors in all instances were very large. In most cases physical signs of an intrathoracic mass were demonstrable. Clubbing of the fingers was recorded in 3 patients. Thyroid enlargement was observed in 2 patients and a thyroid nodule in 2 others. Gynecomastia was seen in one case. Many determinations of the blood sugar were made and, with a few ex ceptions, values under 50 mg. per cent were obtained. The lowest value re ported was 10 mg. per cent. Preoperative glucose tolerance tests were done in 4 patients. In 3 patients the fasting levels were low with low or normal peaks and low end points. In the fourth patient a normal fasting level with a high normal sustained peak and a normal end point were found. Tests for thyroid, hepatic, and adrenal dysfunction were within normal limits. In all patients a mass was seen on roentgenograms of the chest. In 5 cases chest films showed the tumor one to 12 years prior to the onset of hypoglycemia. In one patient a tumor of the diaphragm had been removed 7 years before the onset of hypoglycemia when a huge local recurrence, demonstrable radiographically, was present. In several instances the infrapulmonary location and con tour of the tumor led to confusion between a high diaphragm and a neoplasm. The radiographic findings of hypertrophic pulmonary osteoarthropathy were demonstrated in only 2 cases. Attempts were made to control hypoglycemic symptoms by dietary means and supplementary oral or parenteral glucose with limited success. Five pa tients underwent initial exploratory laparotomy. Partial pancreatectomy was done in 4 patients and biopsy of the pancreas in one; all without benefit. Three of these patients then underwent thoracotomy with removal of their tumors. The fourth patient never was in good enough condition to tolerate thoracotomy and died with persistent hypoglycemia and heart failure. The fifth patient was subjected to a second laparotomy and died in the immediate postoperative period. Nine patients were subjected to primary thoracotomy. The tumor was removed in 7 and was considered to be inoperable in 2. One patient had neither laparotomy nor thoracotomy. His pulmonary reserve was regarded as too pre carious to permit thoracotomy, although it was believed that the chest tumor
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was responsible for hypoglycemia. He had only an aspiration biopsy and the subsequent course is unknown. Successful removal of the intrathoracic tumor alleviated the hypoglycemia in 9 patients. Recurrence of the tumor with hypoglycemia and death occurred in one patient after 3 years. Eight patients are apparently well, but the periods of follow-up are comparatively short: less than one year in 6 patients and less than 3 years in the other 2 cases. Postoperative glucose tolerance tests showed reversion toward the normal pattern. The tumors were all very large. The weights were recorded in 12 patients and ranged from 860 to 3,500 grams. Twelve neoplasms were considered to be pleural tumors arising from diaphragm, mediastinum or chest wall, while 3 were thought to have arisen from lung, although it is quite likely that in these pa tients the lung was secondarily involved. The histologic diagnoses made were fibrosarcoma in 4 cases, spindle-cell sarcoma in 3, mesothelioma in 3, fibroma and neurofibroma in 2 patients each, and neurofibrosarcoma in 1 case. Five patients came to autopsy and in all of these the pancreas was normal. In 2 patients, colloid goiters were described and in one of these there was pitui tary and adrenal hyperplasia as well. In the other 3 patients, however, the thyroid, pituitary, and adrenal glands were considered to be normal. In four instances, bio-assay of the tumor tissue for insulin-like activity was carried out. The results were positive in one, equivocal in one, and negative in 2. In 2 patients, plasma insulin activity was determined and found to be within normal limits. Several theories have been proposed to explain the hypoglycemia seen in these patients. The most reasonable hypotheses are that the tumor either elaborates a substance with insulin-like activity, or it avidly utilizes and stores carbohydrate at the expense of the rest of the body. Some evidence favors the secretory theory and yet the presence of an insulin-like substance has not been consistently demonstrated, although in one patient not only was insulin activity demonstrable in the tumor, but excessive plasma insulin activity was found preoperatively that disappeared after the tumor was removed. In those pa tients in whom both bio-assays of insulin activity and detailed studies of carbo hydrate metabolism were performed, and in whom the assays were negative, it was thought that a defect in the utilization and storage of glucose and amino acids in the tumor itself was responsible. Other unproved theories implicate hypothetical substances capable of stimulating the islands of Langerhans to produce insulin or of interfering with the insulinase systems, or that there may be abnormal amino acids with hypoglycemia-inducing properties. Defects in hepatic, adrenal, and pituitary function have not been demonstrated. SUMMARY
Certain large intrathoracic neoplasms, chiefly intrapleural in location, may be associated with a hypoglycemia which may first become manifest long after the chest tumor developed. The onset of the hypoglycemic symptoms may be
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rather abrupt and of such bizarre character that a psychiatric or cerebrovascular condition may be erroneously diagnosed, or brain metastases suspected. Dra matic correction of the hypoglycemic state follows surgical excision of the tumor and a ease herewith reported demonstrates that a satisfactory recovery may still occur in spite of some brain damage from prolonged cerebral hypoxia secondary to an inadequate supply of glucose to the brain. Further experience is necessary to permit a better pathologic classification of these neoplasms which, when found in the chest, seem to be chiefly mesodermal tumors composed of spindle-shaped cells. Moreover, the mechanism of the production of the hypoglycemia remains to be clarified. REFERENCES 1. Doege, K. W.: Fibrosarcoma of the Mediastinum, Ann. Surg. 92: 955, 1930. 2. Arkless, H. A.: Coincidence of Rhabdomyofibroma of the Diaphragm, Idiopathic Hypoglycemia, and Retroperitoneal Sarcoma, M. Bull. V. A. 19: 225, 1942. 3. Skillern, P . G., McCormack, L. J., Hewlett, J . S., and Crile, G., J r . : Hyperinsulinism Due to Islet Cell Tumors Simulating Sarcoma, Diabetes 3: 133, 1954. 4. Zollner, S., and Winkelbauer, A.: Intrathorakaler Tumor mit Spontanhypoglykamie, Klin. Med. 13: 289, 1958. 5. August, J . T., and Hiatt, H. H . : Severe Hypoglycemia Secondary to a Nonpancreatic Fibrosarcoma With Insulin Activity, New England J . Med. 258: 17, 1958. 6. Mahkota, S.: Spontane hipoglikemije pri obseznih tumorjih pljuc, Zdrav. Vestn. 27: 326, 1958. 7. Andreew, D., Goranow, I., and Krastinow, G.: Hypoglykamie bei einem Intrathorakel Gelagerten Fibrom, Endokrinologie 38: 167, 1959. 8. Rossman, E. M.: Mediastinal Neurofibrosarcoma Causing Hypoglycemia, Arch. Int. Med. 104: 640, 1959. 9. Miller, D. R., Bolinger, R. E., Janigan, D., Crockett, J . E., and Friesen, S. R.: Hypo glycemia Due to Non Pancreatic Mesodermal Tumors, Ann. Surg. 150: 684, 1959. 10. Kuijjer, P. J . : A Tumor of the Lung With Disturbances in the Sugar Metabolism, Arch. chir. neerl. 13: 81, 1961. 11. Paulson, G. S., Feehan, J. J., and Westaby, R. S.: Severe Hypoglycemia Due to Mesothelioma Arising in Pleural Cavity, South Dakota J . Med. & Pharm. 14: 5, 1961. 12. Dolder, D. G.: Spontane hypoglykemie bij een patient met een groot longgezwel, Nederl. tijdschr. geneesk. 105: 2030, 1961. 13. Schmidt, H. W., and Schurholz, K.: Hypoglykamische Anfalle durch intrathorakalen Tumor, Deutsch. Med. Wchnschr. 86: 2231, 1961. DISCUSSION DR. HOWARD A. F R A N K , Boston, Mass.—I think this is a fascinating group of tumors, and we must be grateful to Dr. Maier for gathering them for us in this way. Their histologic appearance so little suggests active secretion, and one wonders what nature has in mind placing hormonal activity in so inert-looking a mass of connective tissue. Seeing this title in the program, I thought Dr. Maier might like to have a follow-up added to his series. This was the case of an 82-year-old woman whom we saw in 1956. She entered the hospital in coma, and was thought to have had a cerebral vascular accident; she had very advanced vascular disease. A house officer noticed that her coma lightened each time she received an infusion con taining glucose. A measurement of her blood sugar between transfusions was 28 to 30 mg. per cent. Her chest film showed a large mass in the lower left lung field. I t had been seen one year earlier in a chest film taken during a hospitalization for heart disease. Carbohydrate metabolism had been normal at that time. In view of available reports of tumors of this sort associated with insulin-like activity, we did a thoraco-abdominal exploration and found
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this to be a large solid tumor with a very vascular attachment to the lower lobe of the lung. Its origin seemed to be the central tendon of the diaphragm. We resected the central portion of the diaphragm with the tumor and the loft lower lobe. The pancreas was normal. Im mediately after operation she behaved as though her own insulin secretion was temporarily insufficient. Within the next few days there was a return to normal carbohydrate metabolism which remained normal in the following 3 % years. Assays of the tumor by the rat diaphragm method showed insulin-like activity totaling three or more times the insulin content of a normal pancreas. She died after 3 % years, of a true cerebrovascular accident. At postmortem examina tion, she had a 0.5 cm. nodule of recurrent tumor in the diaphragm, but no recurrence of carbohydrate disturbance. Drs. Castleman and Freiman have re-examined the original and final specimens of this tumor, and now classify it as a fibrous mesothelioma. DR. W I L L I A M M. L E E S , Lincolnwood, 111.—I arise to add a little to Dr. Maier's discussion, in that one of the patients he reported on was operated upon by me. The one patient we operated upon had a 1,400 gram tumor. She had a 40 mg. blood sugar. She had clonic and tonic convulsions. We had to continue an intravenous glucose infusion preoperatively and immediately postoperatively. She did quite well after the opera tion, and returns to see me each year to tell me she is fine. DR. MAIER (Closing).—I wish to thank Dr. Frank and Dr. Lees for their discussions. On the basis of the knowledge derived from the retroperitoneal or intra-abdominal tumors, which number over 30 in the literature, it is evident that we must wait a longer time before we decide on the rate of recurrence of these tumors, because a considerable number of those that have occurred in the retroperitoneal area have shown evidence of local recur rence, sometimes massive, even after 5, 10, or more years. The various theories that have been advanced to explain the hypoglycemia are of great interest, and a very brief reference to them is made in the published paper.