Journal of Surgical Oncology 9:419-424 (1977)
The Glucagonoma Syndrome and Its Management .......................................................................................... .......................................................................................... ANNE KESSINGER, M.D., HENRY M. LEMON, M.D., and JOHN F. I;OLEY, M.D., Ph.D. The glucagonoma syndrome occurs in some but not all patients with a benign or malignant islet cell tumor and hyperglucagonemia. Manifestations may include anemia, diabetes mellitus, pruritic skin Iash, glossitis, stomatitis, weight loss, diarrhea, flexible fingernails, venous thromboses, low plasma amino acid levels, and coarse folds of the jejunum and ileum. Most patients are postmenopausal women, but men and women ages 40 to 65 have been affected. The course is variable depending upon lhe nature of the underlying tumor. Twenty-two cases of probable glucagonoma syndrome have been reported; twelve documented with glucagon levels. The hyperglucagonemia results from elevation of the proglucagon and true glucagon immunoreactive fractions of pancreatic glucagon. Management of the rash can be accomplished rarely with topical or systemic antibiotics or cortico*steroids.If the tumor is resectable, surgery reverses the syndrome. Patients with metastatic disease have responded to streptozotocin and DTIC.
.................................................................................. ..................................................................................
Key words: glucagonoma syndrome, islet cell carcinoma
INTRODUCTION The glucagonoma syndrome is an unusual disorder, presumably produced at least in part by the hypersecretion of pancreatic glucagon. There are 22 cases reported in the literature compatible with a diagnosis of glucagonoma syndrome : Averbach and Koehler, 1974; Becker et al., 1942; Case Records, 1975; Church and Crane, 1967; Danforth et al., 1976; Gossner and Korting, 1960; Kramer et al., 1976; Levin, 1968;Mallinson et al., 1974; McGavran et al., 1966;Valverde et al., 1976;'Weir et al., 1976. Twelve of these are documented with elevated plasma glucagon levels. The first probable case of glucagonoma syndrome was reported by Becker et al. (1942); they described the association of a peculiar skin rash, diabetes mellitus, and anemia with an islet cell carcinoma of the pancreas. Eighteen years later Gossner and Korting (1 960) reported a similar case and noted that extracts of the tumor produced From the University of Nebraska Medical Center, Section of Medical Oncology, Department of Internal Medicine, Omaha Address reprint requests to Anne Kessinger, M. D., Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NB 68105.
419
0 1977 Alan R. Liss, Inc., 150 Fifth Avenue, New York, NY 10011
420
Kessinger, Lemon, and Foley
hyperglycemia when injected into laboratory animals. McCavran et al. (1966) reported a third case and found that immunoassays of the tumor and the patient’s plasma revealed elevated glucagon levels. A series of individual cases were then reported in the dermatology literature and in 1974, Mallinson et al. recognized the similar presentations of 9 patients with islet cell tumors of the pancreas, and found elevated glucagon levels in the 4 patients that were further studied. They suggested the term “glucagonoma syndrome” could be applied t o their patients.
The Syndrome The syndrome can include many signs and symptoms, but nearly every patient demonstrates a skin rash; normochromic normocytic anemia; weight loss; stomatitis; and diabetes mellitus. The rash, termed necrolytic migratory erythema (Wilkinson, 1971) can involve any area, but usually begins below the waist as small reddened macules which raise, coalesce, become bullous, rupture, and then heal, leaving areas of hyperpigmentation (Mallinson et al., 1974). The process takes 1-2 weeks t o complete and each stage of development can usually be found on a patient, as the rash progresses to involve more of the body or reappears in previously affected areas. Intense pruritis accompanies the skin lesions, and is the most distressing part of the syndrome for the patient. Many patients have painful stomatitis and glossitis which may be related pathologically t o the rash. Biopsy of established skin lesions shows nonspecific dermatitis, but the fresh lesions reveal necrolysis of the upper layers of the stratum Malpighii of the epidermis (Mallinson et al., 1974). The etiology of the rash is uncertain, but may be related t o the low plasma amino acid levels found in all patients with glucagonoma syndrome tested thus far (Case Records, 1975). The diabetes mellitus is usually mild, not associated with episodes of ketoacidosis, and may require insulin for management, but usually can be controlled with diet Mallinson et al., 1974). Presumably the diabetes is a result of glucagon excess. No satisfactory explanation has been found for the normochromic normocytic anemia of the syndrome. Bone marrow aspirates, bone marrow iron stores, serum iron, iron binding capacities, and iron metabolism studies are usually normal (Mallinson et al., 1974; Marless et al., 1970; Valverde et al., 1976); the few patients with low serum iron failed to respond to oral iron. Reversal of the syndrome with chemotherapy or surgery results in normalization of the hemoglobin (Mallinson et al., 1974; Valverde et al., 1976). Other manifestations seen in varying frequency include diarrhea, venous thromboses, flexible nails, and coarse folds of the jejunum and ileum. Infusions of pharmacologic amounts of glucagon in healthy fasting individuals produce a decrease in the concentrations of all amino acids studied (McCavran et al., 1966). The catabolic effect of glucagon may explain not only the low plasma amino acid levels in glucagonoma syndrome, but also the skin rash, stomatitis, anemia, flexible fingernails and weight loss (Case Records, 1975; Mallinson et al., 1974). Men and women from age 4 0 to 65 have been reported with the syndrome; most patients are women in the postmenopausal age group. The course is variable: one patient had symptoms that waxed and waned for 12 years prior to diagnosis (Mallinson et al., 1974), while another was dead 4 months after the syndrome appeared (Warin, 1974).
Glucagonoma Syndrome and Management
421
The Tumor An islet cell tumor, usually in the pancreas, has been found in each case; of those tumors studied more extensively, all have been alpha cell tumors showing glucagon-like activity. Each patient studied demonstrated elevated plasma glucagon immunoreactivity. The glucagonomas may be benign or malignant, accounting in part for the variable course of the syndrome. The liver is the most common site of metastatic involvement. Not all glucagon producing tumors are associated with the syndrome. In one instance, the tumor was found to be producing enteroglucagon, not pancreatic glucagon (Bloom, 1972; Gleeson et al., 1971). In other instances (Murray-Lyon et al., 1968; O’Neal et al., 1968), the tumors were producing glucagon plus other hormones, and the patients presented with symptoms related t o excess insulin, gastrin, ACTH and/or MSH. Although the glucagon immunoassays were performed at different laboratories, and levels may not be entirely comparable, it seems that in some cases, plasma glucagon levels in patients wit‘h glucagonomas but no syndrome approached those in patients with the syndrome (Stanley and Leichter, 1975). Thus there may be factors in addition t o glucagon hypersecretion that play a role in the pathogenesis of the glucagonoma syndrome. Recently we had occasion t o treat a patient with glucagonoma syndrome. TABLE I. Response of Glucagon and Insulin to Oral Glucose Tolerance Test in a Patient with Glucagonoma Syndrome Time
Glucose (mrimll
Fasting ?4hour 1 hour 2 hours 3 hours 4 hours 5 hours
164 221 194 137 108
77
41
Insulin (pUjml)
Glucagon (pcg/ml)
20 31 70 200 104 68 14
2,600 2,600 2,300 2,200 2,600 2,500 3,000
-
CASE REPORT A 56-year-old white female was noted t o have an abnormal glucose tolerance test in 1970. Her condition was managed with diet. In February 1974, an epigastric left upper quadrant mass appeared. She complained of weak fingernails and dryness of her legs. Hemoglobin was 11.1 gm%.Liver scan was abnormal, and calcifications in the lungs, liver, and spleen secondary t o histoplasmosis were found on x rays. At laparotomy, the liver was large and mottled with numerous greyish white deposits up t o 2.5 cm in diameter. Large fleshy nodes in the retroperitoneal area and a large, firm movable mass at the splenic hilum were noted. All other abdominal and pelvic organs were normal, including the pancreas. Liver and lymph node biopsies were reviewed by Dr. M. B. Dougherty, Rochester, Minnesota, and diagnosed as containing metastatic islet cell carcinoma. Plasma cortisol, serotonin, and urine amylase levels were normal. In April 1974, she was referred to the University of Nebraska Medical Center complaining of epigastric pain, a 10-pound weight loss in 2 months, and diarrhea of 1 year’s
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duration which became more severe following surgery. Physical examination revealed a smooth red tongue and red oral mucosa. The liver extended 13 cm below the xiphoid process, and a left upper quadrant mass separate from the liver was noted - presumably the tumor found in the splenic hilum at surgery. Hemoglobin was 8.6 gm%.Urine 5-HIAA, serum iron, and iron binding capacity were normal. Liver scan showed definite progression of metastases when compared t o the pre-surgery scan. Streptozotocin 1.35 gm i.v. was given weekly for 4 weeks every other month. The liver scan in June 1974 showed no progression, suggesting arrest of the disease by streptozotocin. Subjectively, her pain lessened, she gained 2 kg, was more active, and developed a ravenous appetite. In July 1974, a rash appeared over her right hip; small erythematous macules progressed to papular and then bullous lesions that coalesced and healed, leaving hyperpigmentation. Intense pruritis accompanied the rash which proceeded to involve the abdomen, perineum, extremities and back. Treatment with topical and systemic antibiotics produced brief temporary relief. Biopsy revealed nonspecific dermatitis. Watery diarrhea and glossitis persisted. In September 1974, plasma glucagon analysis performed by Dr. R. Unger, Dallas, Texas, was 3,000 pcg/ml (normal 40-120 pcg/ml) and plasma amino acid level was 94.3 pM/ 100 ml (control 228 -+ 26 yM/100 ml). The rash spared only the head and shoulders, the tongue was red and smooth, the oral mucosa was cherry red, and the liver was nonpalpable. The left upper quadrant mass was no longer palpable. The liver scan showed a decrease in the diameter of 2 of 3 visible metastases by 1 cm. Hemoglobin was 10.8 gm%.A %hour glucose tolerance test with insulin and glucagon levels was done (Table I). In spite of the apparent improvement of the liver metastases and the disappearance of the left upper quadrant mass, the patient was now nearly incapacitated by the pruritic rash, diarrhea, and painful mouth. Chemotherapy was therefore changed to Dimethyl triazeno imidazole carboxamide (DTIC) 250 mg/M* i.v. daily for 5 days every 4 weeks. An immediate improvement in the rash followed, along with a gradual disappearance of the diarrhea and normalization of the hemoglobin. Three months later plasma glucagon was 1,200 pcg/ml, and the plasma amino acid level was 107.4 yM/100 ml. After one year of DTIC therapy, the frequency of the 5-day course was reduced to every 8 weeks. Plasma glucagon in December 1975 was 360 pcg/ml. Liver scan in July 1976 was unchanged from the September 1974 scan, the abdominal examination was normal, the tongue and oral mucosa were normal, and there was no trace of the rash.
DISCUSSION Because the patient described here was initially thought to have a metastatic nonfunctioning islet cell carcinoma, therapy was initiated with streptozotocin. Although she did seem to have a favorable response to the drug (improved activity, decreased size of liver metastases, disappearance of palpable abdominal mass), she developed the glucagonoma rash while tumor growth was apparently controlled. It is only possible to speculate why this happened. In animal studies, streptozotocin has been found effective in destroying only the beta cells of the pancreatic islets (Lazarus and Shapiro, 1972). This patient’s tumor may have consisted initially of relatively few glucagon-producing cells, the bulk of the tumor being made up of non-functioning islet cells. Streptozotocin has been reported effective in the treatment of malignant glucagonomas (Case Records, 1975; Danforth et al., 1976), but if in this case the drug were effective in destroying the non-functioning
Glucagonoma Syndrome and Management
423
cells, and less effective in suppressing the glucagon-producing (alpha ?) cells, allowing them to proliferate, then the tumor could regress in size but have a larger proportion of glucagon-producing cells, allowing the syndrome to fully develop. In spite of apparent control of tumor bulk by streptozotocin, the patient was incapacitated by the rash, glossitis, and diarrhea, so the chemotherapy was changed. DTIC was selected because it is effective in the treatment of malignant melanoma, a neoplasm whose embryologic cellular origin is, like the islet cell, the neural crest. The patient’s response to this drug was dramatic: her symptomatology disappeared, the metastases noted on liver scan failed to increase in size or number, the plasma amino acid level increased, and the plasma glucagon level fell. The absence of a pancreatic tumor at laparotomy is a curious finding in this case. Possibly the origin could be at another site, since the islet cell is of M U D origin, and APUD cells are distributed throughout the body (Pearse, 1974). The primary tumor may have been in the pancreas but too small for the surgeon to detect, or the mass at the splenic hilum may have been an accessory pancreas containing the primary tumor. A pancreatic scan revealed a faint increase in uptake of tracer activity separate from the pancreas, but no conclusions could be drawn from this finding. The patient is feeling well and is reluctant to undergo studies requiring hospitalization at this time. Glucagon The plasma glucagon immunoreactivity of this patient was further investigated by Valverde et al. (1974). The total hyperglucagonemia observed was a result of elevation of 2 of the 4 known pancreatic glucagon immunoreactive fractions, true glucagon and proglucagon. This pattern has subsequently been found in 3 more patients with glucagonoma syndrome (Weir et al., 1976), and a fourth patient demonstrated an elevation of proglucagon alone (Case Records, 1975). After treatment with DTIC, our patient’s glucagon level fell secondary to a decrease in proglucagon and true glucagon immunoreactive fractions. Treatment Control of the glucagonoma rash has not been especially successful on a long term basis for most patients using topical and systemic antibiotics or steroid preparations, but the occasional patient will have a worthwhile remission (Mallinson et al., 1974). Diiodohydroxyquin and azathioprine have also been effective for control of the rash in a few cases (Mallinson et al., 1974). Control of the underlying tumor should produce the most effective results. However, somatostatin has recently been found to have an inhibitory effect on alpha cell function (Leblanc, 1975) and may be an effective agent in controlling the devastating clinical effects, assuming the pathogenesis of the syndrome depends on excess glucagon production. The best prognosis exists for patients with benign glucagonomas that are surgically resectable, resulting in a disappearance of the syndrome. One patient apparently has been cured of the syndrome by surgical removal of a malignant non-metastatic islet cell carcinoma (Mallinson et d., 1974). Two patients with hepatic metastases and glucagonoma syndrome have demonstrated a remission by virtue of a decrease in plasma glucagon levels and symptoms after treatment with streptozotocin (Case Records, 1975; Danforth et al., 1974), and the patient reported here achieved a clinical and chemical remission with DTIC.
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ACKNOWLEDGMENTS The authors gratefully acknowledge Dr. Joseph Stitcher, Lincoln, Nebraska, for his referral and contributions to the management of the patient. We are indebted t o the National Cancer Institute, Bethesda, Maryland, for the initial supply of DTIC. We thank Ms. Carla Gaul for her secretarial assistance.
REFERENCES Averback, R. C., and Koehler, P. R. (1974). The many faces of islet cell tumors. Am. J. Roentgen. 119: 133. Becker, S. W., Kahn, D., and Rothman, S. (1974). Cutaneous manifestations of internal malignant tumors. Arch. Derm. Syph. 45:1069. Bloom, S. R. (1975). An enteroglucagon tumor. Gut 13:520. Case Records of the Massachusetts General Hospital (Case 20-1975). N. Eng. J. Med. 292: 1117. Church, R. E. and Crane, W. A. J. (1967). A cutaneous syndrome associated with islet cell carcinoma of the pancreas. Br. J. Derni. 79:284. Danforth, D. N., Triche, T., Doppman, J. L. e t al. (1976). Elevated plasma proglucagon-like component with a glucagon-secreting tumor. Effect of streptozotocin. N. Eng. J. Med. 295:242. Gleeson, M. H., Bloom, S. R., Polak, J. M. et al. (1971). Endocrine tunior in kidney affecting small bowel structure, motility and absorptive function. Gut 12:773. Gossner, W. and Korting, G. W. (1960). Metastasierendes Inselzell Karzinom vom A-Zell typ bei einem Fall von Peniphigus foliaceus mit Diabetes renalis. Dtsch. med. Wschr. 85:434. Kramer, S., Machina, T., and Marcus, R. (1976). Metabolic studies in the malignant glucagonoma syndrome. Diabetes (Suppl. 1) 25:370, (Abst. #200). Lazarus, S. S. and Shapiro, S. H. (1972). Serial morphologic changes in rabbit pancreatic islet cells after streptozotocin. Lab. Invest. 27: 174. Leblanc, H. (1975). Inhibitory action of somatostatin on pancreatic alpha and beta cell function. J. C h i . Endocrin. & Metab. 40:568. Levin, M. E. (1968). Endocrine syndromes associated with pancreatic islet cell tumors. Med. Clins. N. Amer. 52:295. Mallinson, C. N., Bloom, S. R., Warin, A. P. e t al. (1974). A glucagonoma syndrome. Lancet 2 : l . Marless, E. B., Aoki, T. T., Unger, R. H. e t al. (1970). Glucagon levels and metabolic effects in fasting man. J. Clin. Invest. 49:2256. McGavran, M. H., Unger, R. H., Recant, L. et al. (1966). A glucagon-secreting alpha cell carcinoma of the pancreas. New Eng. J. Med. 274:1408. Murray-Lyon, I. M., Eddleston, A. L. W. F., Williams, R. e t al. (1968). Treatment of multiple islet cell tumor with streptozotocin. Lancet 2:895. ONeal, L. W., Kipnis, D. M., Luse, S. A. e t al. (1968). Secretion of various endocrine substances by ACTH-secreting tumors - gastrin, serotonin, parathormone, vasopressin, glucagon. Cancer 21: 1219. Pearse, A. G. E. (1974). The APUD cell concept and its implications in pathology. Pathol. Ann. 9:27. Stanley, R. J. and Leichter, S. (1975). Pancreatic glucagonoma: a clinical-angiographic correlation. Case report. Missouri Med. 72:134. Valverde, I., Lemon. H. M., Kessinger, A. et al. (1976). Distribution of plasma glucagon immunoreactivity in a patient with suspected glucagonoma. J. Clin. Endo. & Metab. 42:804. Warin, A. P. (1974). Necrolytic migratory erythema with glucagon-secreting tumor of the pancreas. Proc. R. SOC.Med. 67:1008. Weir, G. C., Horton, E. S., Aoki, T. T. et al. (1976). Increased circulating large glucagon imniunoreactivity in the glucagonoma syndrome. Diabetes (Suppl. 1) 25:326, (Abst. #23). Wilkinson, D. S. (1971). Necrolytic migratory erythema with pancreatic carcinoma. Proc. R. SOC.Med. 64: 1197.
The Glucagonoma Syndrome and Its Management .......................................................................................... .......................................................................................... ANNE KESSINGER, M.D., HENRY M. LEMON, M.D., and JOHN F. I;OLEY, M.D., Ph.D. The glucagonoma syndrome occurs in some but not all patients with a benign or malignant islet cell tumor and hyperglucagonemia. Manifestations may include anemia, diabetes mellitus, pruritic skin Iash, glossitis, stomatitis, weight loss, diarrhea, flexible fingernails, venous thromboses, low plasma amino acid levels, and coarse folds of the jejunum and ileum. Most patients are postmenopausal women, but men and women ages 40 to 65 have been affected. The course is variable depending upon lhe nature of the underlying tumor. Twenty-two cases of probable glucagonoma syndrome have been reported; twelve documented with glucagon levels. The hyperglucagonemia results from elevation of the proglucagon and true glucagon immunoreactive fractions of pancreatic glucagon. Management of the rash can be accomplished rarely with topical or systemic antibiotics or cortico*steroids.If the tumor is resectable, surgery reverses the syndrome. Patients with metastatic disease have responded to streptozotocin and DTIC.
.................................................................................. ..................................................................................
Key words: glucagonoma syndrome, islet cell carcinoma
INTRODUCTION The glucagonoma syndrome is an unusual disorder, presumably produced at least in part by the hypersecretion of pancreatic glucagon. There are 22 cases reported in the literature compatible with a diagnosis of glucagonoma syndrome : Averbach and Koehler, 1974; Becker et al., 1942; Case Records, 1975; Church and Crane, 1967; Danforth et al., 1976; Gossner and Korting, 1960; Kramer et al., 1976; Levin, 1968;Mallinson et al., 1974; McGavran et al., 1966;Valverde et al., 1976;'Weir et al., 1976. Twelve of these are documented with elevated plasma glucagon levels. The first probable case of glucagonoma syndrome was reported by Becker et al. (1942); they described the association of a peculiar skin rash, diabetes mellitus, and anemia with an islet cell carcinoma of the pancreas. Eighteen years later Gossner and Korting (1 960) reported a similar case and noted that extracts of the tumor produced From the University of Nebraska Medical Center, Section of Medical Oncology, Department of Internal Medicine, Omaha Address reprint requests to Anne Kessinger, M. D., Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NB 68105.
419
0 1977 Alan R. Liss, Inc., 150 Fifth Avenue, New York, NY 10011
420
Kessinger, Lemon, and Foley
hyperglycemia when injected into laboratory animals. McCavran et al. (1966) reported a third case and found that immunoassays of the tumor and the patient’s plasma revealed elevated glucagon levels. A series of individual cases were then reported in the dermatology literature and in 1974, Mallinson et al. recognized the similar presentations of 9 patients with islet cell tumors of the pancreas, and found elevated glucagon levels in the 4 patients that were further studied. They suggested the term “glucagonoma syndrome” could be applied t o their patients.
The Syndrome The syndrome can include many signs and symptoms, but nearly every patient demonstrates a skin rash; normochromic normocytic anemia; weight loss; stomatitis; and diabetes mellitus. The rash, termed necrolytic migratory erythema (Wilkinson, 1971) can involve any area, but usually begins below the waist as small reddened macules which raise, coalesce, become bullous, rupture, and then heal, leaving areas of hyperpigmentation (Mallinson et al., 1974). The process takes 1-2 weeks t o complete and each stage of development can usually be found on a patient, as the rash progresses to involve more of the body or reappears in previously affected areas. Intense pruritis accompanies the skin lesions, and is the most distressing part of the syndrome for the patient. Many patients have painful stomatitis and glossitis which may be related pathologically t o the rash. Biopsy of established skin lesions shows nonspecific dermatitis, but the fresh lesions reveal necrolysis of the upper layers of the stratum Malpighii of the epidermis (Mallinson et al., 1974). The etiology of the rash is uncertain, but may be related t o the low plasma amino acid levels found in all patients with glucagonoma syndrome tested thus far (Case Records, 1975). The diabetes mellitus is usually mild, not associated with episodes of ketoacidosis, and may require insulin for management, but usually can be controlled with diet Mallinson et al., 1974). Presumably the diabetes is a result of glucagon excess. No satisfactory explanation has been found for the normochromic normocytic anemia of the syndrome. Bone marrow aspirates, bone marrow iron stores, serum iron, iron binding capacities, and iron metabolism studies are usually normal (Mallinson et al., 1974; Marless et al., 1970; Valverde et al., 1976); the few patients with low serum iron failed to respond to oral iron. Reversal of the syndrome with chemotherapy or surgery results in normalization of the hemoglobin (Mallinson et al., 1974; Valverde et al., 1976). Other manifestations seen in varying frequency include diarrhea, venous thromboses, flexible nails, and coarse folds of the jejunum and ileum. Infusions of pharmacologic amounts of glucagon in healthy fasting individuals produce a decrease in the concentrations of all amino acids studied (McCavran et al., 1966). The catabolic effect of glucagon may explain not only the low plasma amino acid levels in glucagonoma syndrome, but also the skin rash, stomatitis, anemia, flexible fingernails and weight loss (Case Records, 1975; Mallinson et al., 1974). Men and women from age 4 0 to 65 have been reported with the syndrome; most patients are women in the postmenopausal age group. The course is variable: one patient had symptoms that waxed and waned for 12 years prior to diagnosis (Mallinson et al., 1974), while another was dead 4 months after the syndrome appeared (Warin, 1974).
Glucagonoma Syndrome and Management
421
The Tumor An islet cell tumor, usually in the pancreas, has been found in each case; of those tumors studied more extensively, all have been alpha cell tumors showing glucagon-like activity. Each patient studied demonstrated elevated plasma glucagon immunoreactivity. The glucagonomas may be benign or malignant, accounting in part for the variable course of the syndrome. The liver is the most common site of metastatic involvement. Not all glucagon producing tumors are associated with the syndrome. In one instance, the tumor was found to be producing enteroglucagon, not pancreatic glucagon (Bloom, 1972; Gleeson et al., 1971). In other instances (Murray-Lyon et al., 1968; O’Neal et al., 1968), the tumors were producing glucagon plus other hormones, and the patients presented with symptoms related t o excess insulin, gastrin, ACTH and/or MSH. Although the glucagon immunoassays were performed at different laboratories, and levels may not be entirely comparable, it seems that in some cases, plasma glucagon levels in patients wit‘h glucagonomas but no syndrome approached those in patients with the syndrome (Stanley and Leichter, 1975). Thus there may be factors in addition t o glucagon hypersecretion that play a role in the pathogenesis of the glucagonoma syndrome. Recently we had occasion t o treat a patient with glucagonoma syndrome. TABLE I. Response of Glucagon and Insulin to Oral Glucose Tolerance Test in a Patient with Glucagonoma Syndrome Time
Glucose (mrimll
Fasting ?4hour 1 hour 2 hours 3 hours 4 hours 5 hours
164 221 194 137 108
77
41
Insulin (pUjml)
Glucagon (pcg/ml)
20 31 70 200 104 68 14
2,600 2,600 2,300 2,200 2,600 2,500 3,000
-
CASE REPORT A 56-year-old white female was noted t o have an abnormal glucose tolerance test in 1970. Her condition was managed with diet. In February 1974, an epigastric left upper quadrant mass appeared. She complained of weak fingernails and dryness of her legs. Hemoglobin was 11.1 gm%.Liver scan was abnormal, and calcifications in the lungs, liver, and spleen secondary t o histoplasmosis were found on x rays. At laparotomy, the liver was large and mottled with numerous greyish white deposits up t o 2.5 cm in diameter. Large fleshy nodes in the retroperitoneal area and a large, firm movable mass at the splenic hilum were noted. All other abdominal and pelvic organs were normal, including the pancreas. Liver and lymph node biopsies were reviewed by Dr. M. B. Dougherty, Rochester, Minnesota, and diagnosed as containing metastatic islet cell carcinoma. Plasma cortisol, serotonin, and urine amylase levels were normal. In April 1974, she was referred to the University of Nebraska Medical Center complaining of epigastric pain, a 10-pound weight loss in 2 months, and diarrhea of 1 year’s
422
Kessinger, Lemon, and Foley
duration which became more severe following surgery. Physical examination revealed a smooth red tongue and red oral mucosa. The liver extended 13 cm below the xiphoid process, and a left upper quadrant mass separate from the liver was noted - presumably the tumor found in the splenic hilum at surgery. Hemoglobin was 8.6 gm%.Urine 5-HIAA, serum iron, and iron binding capacity were normal. Liver scan showed definite progression of metastases when compared t o the pre-surgery scan. Streptozotocin 1.35 gm i.v. was given weekly for 4 weeks every other month. The liver scan in June 1974 showed no progression, suggesting arrest of the disease by streptozotocin. Subjectively, her pain lessened, she gained 2 kg, was more active, and developed a ravenous appetite. In July 1974, a rash appeared over her right hip; small erythematous macules progressed to papular and then bullous lesions that coalesced and healed, leaving hyperpigmentation. Intense pruritis accompanied the rash which proceeded to involve the abdomen, perineum, extremities and back. Treatment with topical and systemic antibiotics produced brief temporary relief. Biopsy revealed nonspecific dermatitis. Watery diarrhea and glossitis persisted. In September 1974, plasma glucagon analysis performed by Dr. R. Unger, Dallas, Texas, was 3,000 pcg/ml (normal 40-120 pcg/ml) and plasma amino acid level was 94.3 pM/ 100 ml (control 228 -+ 26 yM/100 ml). The rash spared only the head and shoulders, the tongue was red and smooth, the oral mucosa was cherry red, and the liver was nonpalpable. The left upper quadrant mass was no longer palpable. The liver scan showed a decrease in the diameter of 2 of 3 visible metastases by 1 cm. Hemoglobin was 10.8 gm%.A %hour glucose tolerance test with insulin and glucagon levels was done (Table I). In spite of the apparent improvement of the liver metastases and the disappearance of the left upper quadrant mass, the patient was now nearly incapacitated by the pruritic rash, diarrhea, and painful mouth. Chemotherapy was therefore changed to Dimethyl triazeno imidazole carboxamide (DTIC) 250 mg/M* i.v. daily for 5 days every 4 weeks. An immediate improvement in the rash followed, along with a gradual disappearance of the diarrhea and normalization of the hemoglobin. Three months later plasma glucagon was 1,200 pcg/ml, and the plasma amino acid level was 107.4 yM/100 ml. After one year of DTIC therapy, the frequency of the 5-day course was reduced to every 8 weeks. Plasma glucagon in December 1975 was 360 pcg/ml. Liver scan in July 1976 was unchanged from the September 1974 scan, the abdominal examination was normal, the tongue and oral mucosa were normal, and there was no trace of the rash.
DISCUSSION Because the patient described here was initially thought to have a metastatic nonfunctioning islet cell carcinoma, therapy was initiated with streptozotocin. Although she did seem to have a favorable response to the drug (improved activity, decreased size of liver metastases, disappearance of palpable abdominal mass), she developed the glucagonoma rash while tumor growth was apparently controlled. It is only possible to speculate why this happened. In animal studies, streptozotocin has been found effective in destroying only the beta cells of the pancreatic islets (Lazarus and Shapiro, 1972). This patient’s tumor may have consisted initially of relatively few glucagon-producing cells, the bulk of the tumor being made up of non-functioning islet cells. Streptozotocin has been reported effective in the treatment of malignant glucagonomas (Case Records, 1975; Danforth et al., 1976), but if in this case the drug were effective in destroying the non-functioning
Glucagonoma Syndrome and Management
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cells, and less effective in suppressing the glucagon-producing (alpha ?) cells, allowing them to proliferate, then the tumor could regress in size but have a larger proportion of glucagon-producing cells, allowing the syndrome to fully develop. In spite of apparent control of tumor bulk by streptozotocin, the patient was incapacitated by the rash, glossitis, and diarrhea, so the chemotherapy was changed. DTIC was selected because it is effective in the treatment of malignant melanoma, a neoplasm whose embryologic cellular origin is, like the islet cell, the neural crest. The patient’s response to this drug was dramatic: her symptomatology disappeared, the metastases noted on liver scan failed to increase in size or number, the plasma amino acid level increased, and the plasma glucagon level fell. The absence of a pancreatic tumor at laparotomy is a curious finding in this case. Possibly the origin could be at another site, since the islet cell is of M U D origin, and APUD cells are distributed throughout the body (Pearse, 1974). The primary tumor may have been in the pancreas but too small for the surgeon to detect, or the mass at the splenic hilum may have been an accessory pancreas containing the primary tumor. A pancreatic scan revealed a faint increase in uptake of tracer activity separate from the pancreas, but no conclusions could be drawn from this finding. The patient is feeling well and is reluctant to undergo studies requiring hospitalization at this time. Glucagon The plasma glucagon immunoreactivity of this patient was further investigated by Valverde et al. (1974). The total hyperglucagonemia observed was a result of elevation of 2 of the 4 known pancreatic glucagon immunoreactive fractions, true glucagon and proglucagon. This pattern has subsequently been found in 3 more patients with glucagonoma syndrome (Weir et al., 1976), and a fourth patient demonstrated an elevation of proglucagon alone (Case Records, 1975). After treatment with DTIC, our patient’s glucagon level fell secondary to a decrease in proglucagon and true glucagon immunoreactive fractions. Treatment Control of the glucagonoma rash has not been especially successful on a long term basis for most patients using topical and systemic antibiotics or steroid preparations, but the occasional patient will have a worthwhile remission (Mallinson et al., 1974). Diiodohydroxyquin and azathioprine have also been effective for control of the rash in a few cases (Mallinson et al., 1974). Control of the underlying tumor should produce the most effective results. However, somatostatin has recently been found to have an inhibitory effect on alpha cell function (Leblanc, 1975) and may be an effective agent in controlling the devastating clinical effects, assuming the pathogenesis of the syndrome depends on excess glucagon production. The best prognosis exists for patients with benign glucagonomas that are surgically resectable, resulting in a disappearance of the syndrome. One patient apparently has been cured of the syndrome by surgical removal of a malignant non-metastatic islet cell carcinoma (Mallinson et d., 1974). Two patients with hepatic metastases and glucagonoma syndrome have demonstrated a remission by virtue of a decrease in plasma glucagon levels and symptoms after treatment with streptozotocin (Case Records, 1975; Danforth et al., 1974), and the patient reported here achieved a clinical and chemical remission with DTIC.
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ACKNOWLEDGMENTS The authors gratefully acknowledge Dr. Joseph Stitcher, Lincoln, Nebraska, for his referral and contributions to the management of the patient. We are indebted t o the National Cancer Institute, Bethesda, Maryland, for the initial supply of DTIC. We thank Ms. Carla Gaul for her secretarial assistance.
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