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Glucagonoma-Associated Neuropsychiatric and Affective Symptoms: Diagnostic Dilemmas Raised by Paraneoplastic Phenomena

TO THE EDITOR: We describe a patient with at least a 7-year history of symptoms attributed to bipolar affective disorder (BPAD) or systemic lupus erythematosus (SLE), for whom an in-hospital work-up included a biopsy-confirmed glucagon-secreting neuroendocrine tumor (NET). Such tumors may present with signs and symptoms of BPAD or SLE—for which treatment is given but is unsuccessful—and may be present for years before a definitive diagnosis is made. This case illustrates the importance of the need to accurately diagnose neuropsychiatric symptoms and, if they are refractory to generally-accepted treatment approaches, to consider other, less-common conditions as the cause of the clinical syndrome.

Glucagonoma syndrome, first reported by Becker in 1942, is a rare paraneoplastic condition associated with tumors of the pancreas.¹ The syndrome comprises hyperglycemia, a cutaneous rash, called necrolytic migratory erythema, anorexia, venous thrombosis, and neuropsychiatric disturbances, most often depression and/or psychosis. Glucagonomas are slow-growing, malignant neuroendocrine tumors, with the majority located in the distal pancreas. Most glucagonomas are well-circumscribed, solid, and highly vascularized.² It is common for them to be discovered well after metastasis, with the history revealing elements of the disorder to have been present years before the diagnosis was made.³ In many cases, their existence is unveiled because of the peculiar syndrome they produce, after other investigations into multifarious, seemingly disparate symptoms yield little else.

We report a case of a 47-year-old woman with a history of both systemic lupus erythematosus (SLE) and bipolar affective disorder (BPAD), whose symptoms likely resulted from a biopsy-confirmed pancreatic neuroendocrine tumor, with glucagonoma syndrome that mimicked both conditions.

Case Report

"Ms. A," a 47-year-old woman, presented to the hospital with several months of abdominal pain, weight loss, anorexia, and an intermittent skin rash. She had an existing diagnosis of SLE, apparently in remission. She reported a remote history of an erythematous, scaling rash on her face and groin, an ulcerative eruption of her mucous membranes, a history of spontaneous late-term abortions, and a remote kidney injury. After radiologic and histologic examinations confirmed a neuroendocrine tumor with glucagon secretion, she was treated with distal pancreatectomy and splenectomy, and was started on octreotide.

The Psychiatric Consultation Service was asked to evaluate and treat her BPAD. On examination, she was tearful and withdrawn, with decreased energy and concentration, excessive guilt, poor appetite, and poor sleep. She denied suicidal ideation or psychotic symptoms. She described discrete periods of expansive mood and depression, but denied other symptoms of BPAD such as flight of ideas, pressured speech, racing thoughts, distractibility, or excessive involvement in pleasurable activities.

This case is of interest because the patient had carried a diagnosis of seronegative SLE and BPAD for several years without benefit from targeted therapy for either condition. Given that NETs may be present for several years before there is a diagnosis,³ we surmise that it took many years for her NET to produce symptoms severe enough to require hospitalization, comprehensive work-up, and definitive treatment. Before this admission, her more manageable symptoms never "pointed" toward a specific diagnosis and, instead, were misattributed to the conditions mimicked by this paraneoplastic syndrome—SLE or BPAD. After tumor excision, the patient’s condition rapidly improved.

Discussion

Among the most intriguing aspects of the glucagonoma syndrome are the accompanying psychiatric disturbances. Although the pathophysiology remains nebulous, hormone dysregulation has been suggested as the chief cause of the associated psychiatric symptoms.⁴ One hypothesis suggests that the mood disturbances associated with pancreatic endocrine tumors may occur as a consequence of disruption of the hormonal milieu, and that anxiety symptoms may be related to dysregulation of GABAergic function and acid–base imbalance.⁵ To date, the fundamental link between glucagon excess and psychiatric disorders remains unclear. Further complicating the clinical picture, many different hormones may be secreted from the same neuroendocrine tumor.⁶ For example, insulinomas are NETs that secrete insulin, the opposing hormone to glucagon, and these also may result in psychiatric symptoms caused by rapidly changing blood-glucose concentrations.

The skin rash seen in glucagonoma syndrome, necrolytic migratory erythema, begins on a foundation of annular erythema, and progresses gradually to superficial blisters that resolve within 1 to 2 weeks, usually leaving an area of hyperpigmentation.⁷ Although they are predominantly located on the groin and the lower extremities, there are numerous reports of their presence in other areas of the body, especially those subject to frequent mechanical stress, such as the perioral area. Oftentimes, multiple biopsies are necessary before the diagnosis is confirmed.⁷ More pertinent to this case, this condition may be confused with the eruptive rash of SLE.

This patient presents a complicated picture, with an ill-defined history of longstanding psychiatric symptoms, skin rashes, negative lupus serologies, recurrent venous thromboses, weight loss, and abdominal pain. In this tenuous account, there is only one certain diagnosis, that of an NET. The syndrome that has traditionally been described with glucagonomas, therefore, offers perhaps the only reasonable explanation for this patient’s symptoms.

This case reinforces the common knowledge that general-medical conditions may remain semi-quiescent and unrecognized for years because of their misattribution. Paraneoplastic phenomena represent an even greater diagnostic dilemma to the physician if they simultaneously mimic several different medical conditions.

REFERENCES

1. Becker SW, Kahn D, Rothman S: Cutaneous manifestations of internal malignant tumors. Arch Dermatol Syphilol 1942; 45:1069–1080
2. Wermers RA, Fatourechi V, Wynne AG, et al: The glucagonoma syndrome: clinical and pathologic features in 21 patients. Medicine 1996; 75:53–63[CrossRef][Medline]
3. Dourakis SP, Alexopoulou A, Georgousi KK, et al: Glucagonoma syndrome: survival 21 years with concurrent liver metastases. Am J Med Sci 2007; 334:225–227[CrossRef][Medline]
4. Aoki A, Tsukada T, Yasuda H, et al: Multiple endocrine neoplasia type 1 presented with manic-depressive disorder: a case report with an identified MEN1 gene mutation. Jpn J Clin Oncol 1997; 27:419–422[Abstract/Free Full Text]
5. Green AI Austin CP: Psychopathology of pancreatic cancer. a psychobiologic probe. Psychosomatics 1993; 34:208–221[Medline]
6. Jabbour SA, Davidovici BB, Wolf R: Rare syndromes. Clin Dermatol 2006; 24:299–316[CrossRef][Medline]
7. Kovacs RK, Korom I, Dobozy A, et al: Necrolytic migratory erythema. J Cutan Pathol 2006; 33:242–245[CrossRef][Medline]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Articles by McGevna, L. Articles by Rabinowitz, T. PubMed Citation Articles by McGevna, L. Articles by Rabinowitz, T. Syndromes Secondary to General Medical Disorders

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