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Reversal of a neurologic paraneoplastic syndrome with octreotide (sandostatin) in a patient with glucagonoma
Reversal of a Neurologic Paraneoplastic Syndrome with Octreotide (Sandostatin) in a Patient with Glucagonoma ALEXHOLMES,M.B.B.s., CHRISTINEKILPATRICK,M.D., JOSEPHPROIETTO,M.B.B.s., Ph.D., MICHAELD. GREEN,M.B.B.s., Victoria, Australia
A 69-year-old woman with classic glucagonoma syndrome had associated progressive neurologic disease manifest as dementia, ataxia, optic atrophy, and lower limb weakness. Visual evoked responses (VERs) were absent biiterally. After an attempt at resection was unsuccessfuJ therapy was started with somatostatin analogue (Sandostatin, SMS 201495). Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness. Subsequent VERa revealed bilateral delayed responses.
From the Departments of Medical Oncology (AH, MDG), Neurology (CK), and Endocrinology (JP), The Royal Melbourne Hospital, and the Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Requests for reprints should be addressed to Michael D. Green, M.B.B.S., Department of Medical Oncology, c/o Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia. Manuscript submitted June 15, 1990, and accepted in revised form November 19. 1990.
434
October 1991 The American Journal of Medicine
CASE REPORT History A previously healthy 69-year-old woman was diagnosed as having diabetes mellitus in 1979. This was well controlled with diet alone until 1987, when therapy with gliblenclamide was started. At that time, angular stomatitis was noted. In the ensuing months, the patient developed a migratory ulcerating rash on the lower limbs in addition to gradual weight loss, visual deterioration, slowed mentation, gait disturbance, and urinary incontinence. In January 1988, a computed tomographic (CT) scan of the abdomen revealed a 5-cm pancreatic mass with a single lesion in the left hepatic lobe. This was believed to be due to a pancreatic cancer with metastasis. Her diabetes progressively worsened over this time, and insulin therapy was started in May 1988. Over the next 12 months, there was persistent diarrhea and fecal incontinence, progressive dementia, ataxia, and leg weakness that rendered the patient bedridden, and extensive progression of the rash, especially around the perineum. In April 1989, a calf vein thrombosis was diagnosed and treated with anticoagulant. In August 1989, the patient was hospitalized for re-evaluation. Examination revealed extensive necrolytic migratory erythema (NME) with onycholysis and stomatitis. Neurologic examination revealed a global decrease in cognitive function, with particular involvement of short-term memory and abstract thinking and an abnormally labile affect. There was gross truncal and limb ataxia, and lower limb examination revealed flaccid profound weakness in all muscle groups with hyperreflexia and bilateral extensor plantar responses. The patient had great difficulty in writing, as evidenced by her signature (Figure l), and was unable to read any form of printed matter. Visual acuity was reduced bilaterally to 6/60, and funduscopy revealed bilateral optic atrophy. Laboratory Studies Laboratory examination of blood samples revealed the following values: serum glucagon 4,400 pg/mL (normal: 20 to 150 pg/mL), albumin 28 g/L, alkaline phosphatase 101 IU/L (normal: less than 90 III/L), and y-glutamyltransferase 121 IU/L (nor-
Volume 91
NEUROLOGIC
1989
Figure 1. tures
over
Sample a 3-year
of patient’s period.
PARANEOPLASTIC
( 3 months
of
treatment
SYNDROME
IN GLUCAGONOMA
/ HOLMES
ET AL
)
signa-
mal: less than 50 IU/L). Generalized hypoaminoacidemia was present. Fasting serum insulin and Cpeptide levels were 120mU/L (normal: less than 15 mu/L) and 2.6 nmol/L (normal: 0.2 to 0.69 nmol/L), respectively. Serum bilirubin, serum electrolytes, gastrin, parathyroid hormone, calcitonin, vasoactive intestinal peptide, amylase, cholesterol, calcium, creatine kinase, hemoglobin, platelet and differential white cell counts, clotting profile, Bi2, and folate were all normal. Results of serologic testing for Treponema pallidurn, human immunodeficiency virus, and human T-cell leukemia virus type I were negative. The cerebrospinal fluid was acellular with a normal protein concentration and no oligoclonal bands. A CT scan of the abdomen showed a spherical 5-cm mass in the body of the pancreas, with proximal and distal pancreatic duct calcification and splenic vein dilation. A magnetic resonance imaging (MRI) scan of the abdomen demonstrated two superficial 2-cm liver metastases. A CT scan of the brain revealed mild cortical and cerebellar atrophy and ventricular dilation. An MRI scan of the brain detected multiple white-matter lesions of up to 1.5 cm in size on Tz-weighted images, especially in the periventricular regions. In addition, significant brainstem atrophy was found. Results of a total myelogram were normal. Visual evoked responses (VERs) to pattern reversal stimulus using checks were absent. Histopathologic examination of a skin biopsy of the rash was consistent with NME. Progress and Management A laparotomy was performed in September 1989. The tumor was found to be adherent to superior mesenteric vasculature, and debulking was excluded because of high tissue vascularity. An excision biopsy of the hepatic lesions was performed. Microscopic examination of biopsy specimens demonstrated solid sheets of cuboidal cells with uniform nuclei and sparse amphophilic cytoplasm strongly staining for glucagon. The development of NME
within and adjacent to the laparotomy scar was noted 48 hours after surgery. Somatostatin analogue (SMS 201-995) in a dose of 50 pg subcutaneously twice daily was started 7 days after laparotomy. Over the next 3 months, all of the patient’s symptoms markedly improved. At follow-up in December 1989, the rash, angular stomatitis, and diarrhea had resolved, and the patient had gained 10 kg. She was reading and walking with the assistance of a walker; in addition, her handwriting had dramatically improved (Figure 1). Neurologic examination revealed normal visual acuity and fields but persistent optic atrophy. Lower limb power was improved, although there was residual pyramidal weakness with flaccidity, hyperreflexia, and extensor plantar responses. Mental status examination revealed normal cognitive function and affect. The plasma glucagon level was 167 pg/L. MRI scan of the brain showed persistence of the white-matter lesions. An abdominal CT scan found no change in tumor size. VERs demonstrated latencies to PI00 of 128 and 115 ms and amplitudes of 4 PV and 3.5 PV in the left and right eyes, respectively, indicating improvement in optic nerve conduction.
COMMENTS The glucagonoma syndrome has been well described. Its most common features are NME, angular stomatitis, onycholysis, mild diabetes, diarrhea, monochromic monocytic anemia, hypoaminoacidemia, and recurrent venous thrombosis associated with a tumor of the (Y islet cells of the pancreas. Hypocholesterolemia, gastrointestinal disturbance, and neuropsychiatric symptoms have also been reported [1,2]. Khandekar et al [2] described a patient with classic features of glucagonoma with a syndrome of progressive dementia, optic atrophy, ataxia, nystagmus, generalized hyperreflexia, and lower limb weakness and spasticity. Results of a CT scan of the head were normal, and glucagon was found in the cerebrospinal fluid. The patient was treated with
October
1991
The American
Journal
of Medicine
Volume
91
435
NEUROLOGIC PARANEOPLASTIC SYNDROME IN GLUCAGONOMA / HOLMES ET AL
streptozotocin and &fluorouracil, resulting in a neoplastic encephalomyelitis. The case further sugmarked improvement in symptoms and signs as gests that, as an underlying process, a circulating well as a return of normal cognitive function. The factor exists that may have an important pathogensimilarity between that case and the one now re- ic role in this and other paraneoplastic neurologic ported strongly supports the existence of a specific syndromes. neurologic paraneoplastic syndrome associated with glucagonomas. Furthermore, isolated central ACKNOWLEDGMENT scotoma has been described as an early phenomeWe would like to acknowledge Professor Brian Tress and Miss Lucy Negro for her non in the glucagonoma syndrome [2,3]. This has secretarial assistance. been thought to be due to retrobulbar neuritis [3], and may represent an alternative manifestation of the same pathologic process. REFERENCES The therapeutic options for glucagonoma are sur1. Stacpoole PW. The glucagonoma syndrome: clinical features, diagnosis and gical resection [4], chemotherapy [4,5], somatostatreatment. Endocr Rev 1981; 3: 347-61. tin analogue [6,7], interferon [8], and tumor emboli2. Khandekar JD, Oyer D, Miller H. Vick NA. Neurological involvement in glucagonoma syndrome. Cancer 1979; 441 2014-6. zation [8,9]. As in the case presented, some reports ER. van der LoosTUM. van der Eerden AHAM. Retrobulbar neurihave described resolution of the rash in response to tis3. Lambrecht as the first sign of the glucagonoma syndrome. Int Opthalmoll987; 11: 13-5. somatostatin analogue [7,10], although this is not 4. Prim FtA, Badrinath K. Banerji M, Sparagana M, Dorsch TR. Lawrence AM. invariably associated with a decrease in plasma glu- Operative and chemotherapeutic management of malignant glucagon produccagon [ll]. Other investigators have described no ing tumours. Surgery 1981; 713-9. 5. Kvols LK, Buck M. Chemotherapy of metastatic carcinoid and islet cell turesponse [12]. A reduction in tumor size is usually mors. Am J Med 1987; 82: 77-83. not noted, although occasional reports have sug- 6. Elsborg L, Glenthoj A. Effect of somatostatin in necrolytic migratory erythema of glucagonoma. Acta Med Stand 1985; 218: 245-9. gested otherwise [13]. 7. Altimari AF, Bhoopalam N, D’Dorsio T. Lange CL, Sandberg L, Prinz RA. Use of The importance of this case is in the suggestion a somatostatin analogue (SMS 201-995) in the glucagonoma syndrome. Surthat a circulating factor is associated with the develgery 1986; 100: 989-96. opment of the neurologic syndrome. This is unlikely 8. Sheehan-Dare RA, Simmons AU, Cotterill JA. Janke PG. Hepatic tumours with hyperglucagonemia. Response to treatment with human lymphoblastoid interto be glucagon, given the rarity of the syndrome even in patients with very high glucagon levels. The feron. Cancer 1988; 62: 912-O. 8. Allinson PH. Therapeutic embolization. Br J Hosp Med 1979; 20: 707-15. resolution of symptoms with somatostatin ana- 10. Boden G, Ryan IG, Eisenschmid BL. Shelmet JJ, Owen OE. Treatment of logue, without a change in tumor size, suggests that inoperable glucagonoma with long acting somatostatin analogue SMS 201-995. the analogue is either inhibiting the production or N Engl J Med 1986; 314: 1686-9. 11. Santangelo WC, Unger RH, Orci L. eta/. Somatostatin analog-induced remisblocking the action of this factor. sion of necrolytic migratory erythema without changes in plasma glucagon This is the second case reported of a well-defined concentration. Pancreas 1986; 1: 464-9. neurologic paraneoplastic syndrome associated 12. Wood SM. Kraenzlin ME, Adrian TE, Bloom SR. Treatment of patients with with glucagonoma and the first report of its success- pancreatic endocrine tumours using a new long-acting somatostatin analogue: and peptide responses. Gut 1985; 26: 438-44. ful treatment with somatostatin analogue. The symptomatic 13. Kvols LK, Buck M, Moertal CG, et al. Treatment of metastatic islet cell pathologic nature of this syndrome is unclear, al- carcinoma with somatostatin analogue (SMS 201-995). Ann Intern Med 1987; 107: 162-8. though it has some features consistent with para-
436
October 1991 The American Journal of Medicine
Volume 91
A 69-year-old woman with classic glucagonoma syndrome had associated progressive neurologic disease manifest as dementia, ataxia, optic atrophy, and lower limb weakness. Visual evoked responses (VERs) were absent biiterally. After an attempt at resection was unsuccessfuJ therapy was started with somatostatin analogue (Sandostatin, SMS 201495). Over the ensuing 3 months, there was a decrease in the plasma glucagon level, resolution of the rash, weight gain, reversal of the dementia, and an improvement in coordination and limb weakness. Subsequent VERa revealed bilateral delayed responses.
From the Departments of Medical Oncology (AH, MDG), Neurology (CK), and Endocrinology (JP), The Royal Melbourne Hospital, and the Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Requests for reprints should be addressed to Michael D. Green, M.B.B.S., Department of Medical Oncology, c/o Post Office, The Royal Melbourne Hospital, Victoria 3050, Australia. Manuscript submitted June 15, 1990, and accepted in revised form November 19. 1990.
434
October 1991 The American Journal of Medicine
CASE REPORT History A previously healthy 69-year-old woman was diagnosed as having diabetes mellitus in 1979. This was well controlled with diet alone until 1987, when therapy with gliblenclamide was started. At that time, angular stomatitis was noted. In the ensuing months, the patient developed a migratory ulcerating rash on the lower limbs in addition to gradual weight loss, visual deterioration, slowed mentation, gait disturbance, and urinary incontinence. In January 1988, a computed tomographic (CT) scan of the abdomen revealed a 5-cm pancreatic mass with a single lesion in the left hepatic lobe. This was believed to be due to a pancreatic cancer with metastasis. Her diabetes progressively worsened over this time, and insulin therapy was started in May 1988. Over the next 12 months, there was persistent diarrhea and fecal incontinence, progressive dementia, ataxia, and leg weakness that rendered the patient bedridden, and extensive progression of the rash, especially around the perineum. In April 1989, a calf vein thrombosis was diagnosed and treated with anticoagulant. In August 1989, the patient was hospitalized for re-evaluation. Examination revealed extensive necrolytic migratory erythema (NME) with onycholysis and stomatitis. Neurologic examination revealed a global decrease in cognitive function, with particular involvement of short-term memory and abstract thinking and an abnormally labile affect. There was gross truncal and limb ataxia, and lower limb examination revealed flaccid profound weakness in all muscle groups with hyperreflexia and bilateral extensor plantar responses. The patient had great difficulty in writing, as evidenced by her signature (Figure l), and was unable to read any form of printed matter. Visual acuity was reduced bilaterally to 6/60, and funduscopy revealed bilateral optic atrophy. Laboratory Studies Laboratory examination of blood samples revealed the following values: serum glucagon 4,400 pg/mL (normal: 20 to 150 pg/mL), albumin 28 g/L, alkaline phosphatase 101 IU/L (normal: less than 90 III/L), and y-glutamyltransferase 121 IU/L (nor-
Volume 91
NEUROLOGIC
1989
Figure 1. tures
over
Sample a 3-year
of patient’s period.
PARANEOPLASTIC
( 3 months
of
treatment
SYNDROME
IN GLUCAGONOMA
/ HOLMES
ET AL
)
signa-
mal: less than 50 IU/L). Generalized hypoaminoacidemia was present. Fasting serum insulin and Cpeptide levels were 120mU/L (normal: less than 15 mu/L) and 2.6 nmol/L (normal: 0.2 to 0.69 nmol/L), respectively. Serum bilirubin, serum electrolytes, gastrin, parathyroid hormone, calcitonin, vasoactive intestinal peptide, amylase, cholesterol, calcium, creatine kinase, hemoglobin, platelet and differential white cell counts, clotting profile, Bi2, and folate were all normal. Results of serologic testing for Treponema pallidurn, human immunodeficiency virus, and human T-cell leukemia virus type I were negative. The cerebrospinal fluid was acellular with a normal protein concentration and no oligoclonal bands. A CT scan of the abdomen showed a spherical 5-cm mass in the body of the pancreas, with proximal and distal pancreatic duct calcification and splenic vein dilation. A magnetic resonance imaging (MRI) scan of the abdomen demonstrated two superficial 2-cm liver metastases. A CT scan of the brain revealed mild cortical and cerebellar atrophy and ventricular dilation. An MRI scan of the brain detected multiple white-matter lesions of up to 1.5 cm in size on Tz-weighted images, especially in the periventricular regions. In addition, significant brainstem atrophy was found. Results of a total myelogram were normal. Visual evoked responses (VERs) to pattern reversal stimulus using checks were absent. Histopathologic examination of a skin biopsy of the rash was consistent with NME. Progress and Management A laparotomy was performed in September 1989. The tumor was found to be adherent to superior mesenteric vasculature, and debulking was excluded because of high tissue vascularity. An excision biopsy of the hepatic lesions was performed. Microscopic examination of biopsy specimens demonstrated solid sheets of cuboidal cells with uniform nuclei and sparse amphophilic cytoplasm strongly staining for glucagon. The development of NME
within and adjacent to the laparotomy scar was noted 48 hours after surgery. Somatostatin analogue (SMS 201-995) in a dose of 50 pg subcutaneously twice daily was started 7 days after laparotomy. Over the next 3 months, all of the patient’s symptoms markedly improved. At follow-up in December 1989, the rash, angular stomatitis, and diarrhea had resolved, and the patient had gained 10 kg. She was reading and walking with the assistance of a walker; in addition, her handwriting had dramatically improved (Figure 1). Neurologic examination revealed normal visual acuity and fields but persistent optic atrophy. Lower limb power was improved, although there was residual pyramidal weakness with flaccidity, hyperreflexia, and extensor plantar responses. Mental status examination revealed normal cognitive function and affect. The plasma glucagon level was 167 pg/L. MRI scan of the brain showed persistence of the white-matter lesions. An abdominal CT scan found no change in tumor size. VERs demonstrated latencies to PI00 of 128 and 115 ms and amplitudes of 4 PV and 3.5 PV in the left and right eyes, respectively, indicating improvement in optic nerve conduction.
COMMENTS The glucagonoma syndrome has been well described. Its most common features are NME, angular stomatitis, onycholysis, mild diabetes, diarrhea, monochromic monocytic anemia, hypoaminoacidemia, and recurrent venous thrombosis associated with a tumor of the (Y islet cells of the pancreas. Hypocholesterolemia, gastrointestinal disturbance, and neuropsychiatric symptoms have also been reported [1,2]. Khandekar et al [2] described a patient with classic features of glucagonoma with a syndrome of progressive dementia, optic atrophy, ataxia, nystagmus, generalized hyperreflexia, and lower limb weakness and spasticity. Results of a CT scan of the head were normal, and glucagon was found in the cerebrospinal fluid. The patient was treated with
October
1991
The American
Journal
of Medicine
Volume
91
435
NEUROLOGIC PARANEOPLASTIC SYNDROME IN GLUCAGONOMA / HOLMES ET AL
streptozotocin and &fluorouracil, resulting in a neoplastic encephalomyelitis. The case further sugmarked improvement in symptoms and signs as gests that, as an underlying process, a circulating well as a return of normal cognitive function. The factor exists that may have an important pathogensimilarity between that case and the one now re- ic role in this and other paraneoplastic neurologic ported strongly supports the existence of a specific syndromes. neurologic paraneoplastic syndrome associated with glucagonomas. Furthermore, isolated central ACKNOWLEDGMENT scotoma has been described as an early phenomeWe would like to acknowledge Professor Brian Tress and Miss Lucy Negro for her non in the glucagonoma syndrome [2,3]. This has secretarial assistance. been thought to be due to retrobulbar neuritis [3], and may represent an alternative manifestation of the same pathologic process. REFERENCES The therapeutic options for glucagonoma are sur1. Stacpoole PW. The glucagonoma syndrome: clinical features, diagnosis and gical resection [4], chemotherapy [4,5], somatostatreatment. Endocr Rev 1981; 3: 347-61. tin analogue [6,7], interferon [8], and tumor emboli2. Khandekar JD, Oyer D, Miller H. Vick NA. Neurological involvement in glucagonoma syndrome. Cancer 1979; 441 2014-6. zation [8,9]. As in the case presented, some reports ER. van der LoosTUM. van der Eerden AHAM. Retrobulbar neurihave described resolution of the rash in response to tis3. Lambrecht as the first sign of the glucagonoma syndrome. Int Opthalmoll987; 11: 13-5. somatostatin analogue [7,10], although this is not 4. Prim FtA, Badrinath K. Banerji M, Sparagana M, Dorsch TR. Lawrence AM. invariably associated with a decrease in plasma glu- Operative and chemotherapeutic management of malignant glucagon produccagon [ll]. Other investigators have described no ing tumours. Surgery 1981; 713-9. 5. Kvols LK, Buck M. Chemotherapy of metastatic carcinoid and islet cell turesponse [12]. A reduction in tumor size is usually mors. Am J Med 1987; 82: 77-83. not noted, although occasional reports have sug- 6. Elsborg L, Glenthoj A. Effect of somatostatin in necrolytic migratory erythema of glucagonoma. Acta Med Stand 1985; 218: 245-9. gested otherwise [13]. 7. Altimari AF, Bhoopalam N, D’Dorsio T. Lange CL, Sandberg L, Prinz RA. Use of The importance of this case is in the suggestion a somatostatin analogue (SMS 201-995) in the glucagonoma syndrome. Surthat a circulating factor is associated with the develgery 1986; 100: 989-96. opment of the neurologic syndrome. This is unlikely 8. Sheehan-Dare RA, Simmons AU, Cotterill JA. Janke PG. Hepatic tumours with hyperglucagonemia. Response to treatment with human lymphoblastoid interto be glucagon, given the rarity of the syndrome even in patients with very high glucagon levels. The feron. Cancer 1988; 62: 912-O. 8. Allinson PH. Therapeutic embolization. Br J Hosp Med 1979; 20: 707-15. resolution of symptoms with somatostatin ana- 10. Boden G, Ryan IG, Eisenschmid BL. Shelmet JJ, Owen OE. Treatment of logue, without a change in tumor size, suggests that inoperable glucagonoma with long acting somatostatin analogue SMS 201-995. the analogue is either inhibiting the production or N Engl J Med 1986; 314: 1686-9. 11. Santangelo WC, Unger RH, Orci L. eta/. Somatostatin analog-induced remisblocking the action of this factor. sion of necrolytic migratory erythema without changes in plasma glucagon This is the second case reported of a well-defined concentration. Pancreas 1986; 1: 464-9. neurologic paraneoplastic syndrome associated 12. Wood SM. Kraenzlin ME, Adrian TE, Bloom SR. Treatment of patients with with glucagonoma and the first report of its success- pancreatic endocrine tumours using a new long-acting somatostatin analogue: and peptide responses. Gut 1985; 26: 438-44. ful treatment with somatostatin analogue. The symptomatic 13. Kvols LK, Buck M, Moertal CG, et al. Treatment of metastatic islet cell pathologic nature of this syndrome is unclear, al- carcinoma with somatostatin analogue (SMS 201-995). Ann Intern Med 1987; 107: 162-8. though it has some features consistent with para-
436
October 1991 The American Journal of Medicine
Volume 91