Glucagonoma Maligno

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Glucagonomas are neuroendocrine tumours which

arise from -pancreatic cells and secrete glucagon andother peptides. The annual incidence is extremely low,

only approximately 1 in 20 million, (1) and only 262cases have been reported so far (2-5). Glucagonomas

are characterised by a slow growth rate even whenmalignant, and have been reported in patients aged 19

to 72 years (6). The incidence is the same in males andfemales, even though early reports suggested that they

predominantly occur in females (7). Approximately 60-80% of glucagonomas are malignant and at least 50%

of them are metastatic at the time of diagnosis and areconsequently associated with a poor prognosis. Metas-

tases occur primarily in the liver and in the peri-pan-creatic lymph nodes. Most glucagonomas are sporadic,

but they can be associated with mutations in MEN1 or

familial adenomatous polyposis (8).

Glucagonoma diagnosis is based on positive clinicalfeatures with biochemical findings of hyperglucago-

naemia and radiographic localisation of a pancreatic (orrarely extrapancreatic) tumour. Abdominal computed

tomography (CT) and scintigraphic scan after intra-venous administration of 111In-pentetreotide (Octre-

oscan

) are quite accurate and sensitive to detect andlocalize the tumour and to identify hepatic metastases

(9-12). Surgery is the first treatment of choice and canbe curative if the tumour is confined to the pancreas.

Cytoreductive surgery can also be used as palliativetreatment when the tumour is disseminated (13,14).

Systemic chemotherapy is generally only met withlimited success due to the unresponsiveness of this

tumour type (15). Somatostatin analogues are the first

J. Exp. Clin. Cancer Res., 25, 1, 2006 Case Report

135

Malignant Glucagonoma. New Options of Treatment

M. Appetecchia1, E. Ferretti1, M. Carducci2, F. Izzo3, L. Carpanese4, F. Marandino5, E. Terzoli3.

Endocrinology Unit1, Department of Medical Oncology3, Department of Radiology4 and Department of Pathology5; Regina Elena Cancer

Institute; Department of Dermatology2, San Gallicano Institute; Rome - Italy

Few cases of malignant glucagonomas have been described in the literature. In this paper we present a case of a77-year-old woman with necrolytic migratory erythema and high plasma glucagon and chromogranin A levelscaused by a neuroendocrine tumour. An abdominal CT scan suggested a pancreatic lesion and two liver metas-tases. The patient underwent pancreatic debulking and liver metastasectomy. Histological and immunohisto-chemical investigations revealed a well differentiated neuroendocrine tumour with vascular invasion and scat-tered immunopositivity for somatostatin receptors. The patient was treated with octreotide (20 mg i.m. every 28days) for three years without side effects. Three months after surgery symptoms of disease recurred accompanied

by hyperglucagonaemia and newly diagnosed liver lesions. The patient was treated with octreotide (30 mg i.m.every 28 days) and interferon- (6 MU s.c. 3 times per week) plus three cycles of hepatic chemoembolisation.Symptoms resolved after the first month of therapy, hormone levels decreased compared to untreated levels andmetastatic growth slowed as observed by radiographic evidence. The patient is now asymptomatic with persis-

tent hepatic disease and normal serum glucagon levels forty months after primary treatment. So far, only few im-munohistochemical studies are reported on malignant glucagonoma and combined treatment schedules. Wedemonstrated, for the first time, a scattered immunopositivity for somatostatin receptors in a malignantglucagonoma. For this reason, the somatostatin analogs therapy was instituted. A combined antiproliferative med-ical treatment and the hepatic chemoembolization have been able to control tumor growth and disease symptomsfor a long time after surgery.

Key Words: Glucagonoma, Immunohistochemistry, Somatostatin analogues, Octreotide, Interferon-,Chemoembolisation


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choice for symptomatic treatment. Long-acting somato-statin analogues result in disease stabilisation in 40% of

patients with metastatic gastroenteric endocrinetumours (16). Interferon- has been shown to haveantineoplastic activity in 50-80% of patients affected bycarcinoid tumours, due to its anti-proliferative effect ontumour cells (17-21). Chemoembolisation therapy for

metastatic neuroendocrine tumours has been demon-strated to reduce tumour bulk and circulating hormonelevels, and to palliate the symptoms of many patientswith liver-dominant metastases (22,23).

In this report we describe a case of metastaticglucagonoma in which the immunopositivity forsomatostatin receptors was clearly demonstrated. The

patient was successfully treated with surgery followedby combination therapy with somatostatin analoguesand interferon-, and chemoembolisation of livermetastases.

Case Report

A 77-year-old woman presented with a desquamat-ing pruritic rash in May 2001. She reported approxi-mately 10 kg of weight loss in the past few months.Physical examination was suggestive of necrolyticmigratory erythema and biochemical tests revealedhigh blood glucose levels. An abdominal CT scanrevealed a pancreatic lesion and two liver metastases(Fig.1A). Two chest, abdomen and pelvis single photonemission CT (SPECT) scans acquired at 24 and 48 hrs

and a whole-body scintigraphy scan using 111In-octreotide (111 MBq) showed abnormal uptake in asection of the pancreatic tail and in two small areas inthe right lobe of the liver.

Endocrine work-up confirmed the suspected diagno-sis of glucagonoma syndrome with high serum levels ofglucagon (566 pg/mL), chromogranin A (460 U/L) andneuron specific enolase (59 ng/mL) at diagnosis.

In July 2001, the patient underwent tumour debulk-ing and liver metastasectomy. The cut section of the

pancreatic tail revealed two solid encapsulated lesions.The gall bladder was also removed because of a non

specific nodular lesion. Histological examinationrevealed a well-differentiated neuroendocrine tumourof the pancreas with vascular invasion. The hepaticlesions showed the same features. Chronic cholecystitiswith adenomyomatosis was found in the gall bladder.

The histological sections were prepared forimmunohistochemistry as follows. Tumour pancreaticand liver samples were routinely fixed in formalin andembedded in paraffin. Serial 3 m sections were cut

and mounted on protein-coated glass slides. The sec-tions were immunostained with antibodies againstglucagon (rabbit polyclonal; Dako), cytokeratin(MNF116; Dako), synaptophysin (SYN38; Dako),chromogranin A (DAK-A3; Dako), neuron specific

enolase (rabbit polyclonal; Dako), somatostatin recep-tor subtypes 2 (SSTR2) and 5 (SSTR5) (rabbit poly-clonal kindly provided by Professor A. Spada from theUniversity of Milan, Italy), using the streptavidin-

biotin-peroxidase complex technique.Glucagon and cytokeratin were detected in the cyto-

plasm. Synaptophysin and neuron specific enolaseshowed a more diffuse cytoplasmic distribution, andchromogranin A was not detected. Scattered distribu-

M. Appetecchia et al.

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Fig. 1 - CT scan of glucagonoma lesion at diagnosis (A)demostrating the pancreatic localization, and the CT scan

images after three years of disease showing the livers

metastasis (B).


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tion of SSTR2 and SSTR5 expression was observed.The immunostaining for glucagon (a), cytokeratin

(b), synaptophysin (c) and neuron specific enolase (d)are reported in Fig.2.

After surgery, it was decided to treat the patient witha slow-release somatostatin analogue octreotide (San-dostatin LAR; Novartis), 20 mg intramuscularlyevery 28 days. After the first injection, circulatingglucagon levels fell to 160 pg/mL, and after the third

injection to 84 pg/mL. Three months later the patientnoticed itchy cutaneous lesions in the legs and a 10kgweight loss. An abdominal CT scan revealed twohypoechogenic lesions in the right liver lobe (VII andVIII segment 2), one hyperechogenic nodule on thesame side, one hyperechogenic nodule in the left lobe,and microcalcifications in the VI segment. High bloodglucose levels (130 mg/dL) were also reported. Serumglucagon levels were also raised at 142 pg/mL. Circu-

lating chromogranin A and neuron specific enolasewere also high. Alanine phosphatase was 319 U/L andcarcinoembryonic agent was in the normal range (< 4.6ng/mL). Octreotide was then given at a dose of 30 mgevery 28 days. Interferon- was introduced at the doseof 6 MU subcutaneously 3 times per week. On treat-ment, a rapid improvement in neoplastic symptoms wasobserved. Serum glucagon levels decreased to 120

pg/mL. Four months later the patient again noticed

cutaneous lesions in the legs and biochemical analysisrevealed high circulating levels of glucagon, neuronspecific enolase and chromogranin A. Stable hepaticlesions were found on the abdominal CT scan.Octreotide was initiated at a dose of 30 mg every 21days.

Nine months later, circulating glucagon, neuron spe-cific enolase and chromogranin A levels were raisedagain and radiographic scan revealed growing liver

Malignant Glucagonoma

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Fig. 2 - Distribution of glucagon (a), cytokeratin (b), synaptophysin (c) and neuron specific enolase (d) detected by immunohistochem-

istry of glucagonoma tissue.


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metastases. Octreotide therapy was changed to 30 mgevery 15 days and interferon- was continued with thesame schedule. Chemoembolisation of the liver lesionswas started in order to help provide disease control. The

patient underwent three cycles of hepatic arterychemoembolisation from March 2003 to June 2004. Foreach cycle, after an overnight fast, a catheter was insert-

ed into the hepatic artery and 50 mg superselectiveachiloblastin with 10 mL lipidol ultrafluid 900-1200 mgspheres was administered.

The patient continued the combination therapy at thesame dose above described up to the present time. Shefeels good with a clear improvement in quality of lifeand without any evidence of disease progression.Serum glucagon levels were stable during the follow-up

period.Stable hepatic lesions were found on the abdominal

CT scan as shown in Fig.1B.

Discussion

Immunohistochemical studies and single or com-bined treatment schedules have only been described ina few cases of malignant glucagonomas thus far (24).Several reports have described the expression of thefive specific somatostatin receptors subtypes (SSTRs)in normal and neoplastic neuroendocrine tissue (25).However, data on protein expression of SSTRs are noteasily available due to the lack of specific antibodiesthat can be used for immunolocalisation. We had access

to polyclonal antibodies specifically targeted againstSSTR5 and SSTR2 and were therefore able to localisethese two receptors in our histological sections. Weshowed, for the first time, a scattered distribution for

both receptor subtypes in the membrane and in thecytoplasm of glucagonoma cells. This result was of par-ticular clinical interest as the somatostatin receptors

bind not only the native peptide but exogenous somato-statin analogues, a class of drugs commonly used forthe treatment of neuroendocrine tumours. The somato-statin analogues are considered the medical treatmentof choice for the symptoms of glucagonoma

(5,15,16,26-28), although their effects on tumourgrowth are still matter of debate (15,16,26,29,30).

Chemotherapy has been used extensively in the pastfor the management of neuroendocrine tumours and themost commonly used drug is streptozotocin in mono-or combined chemotherapy with doxorubicin or 5-fluo-rouracil without effects (24).

Neuroendocrine tumors are not chemosensitive, thisprobably is due to their low rate of mitosis. Moreover,

these tumours show high expression of the multidrugresistance gene and high levels of the antiapoptoticgene Bcl-2, which both contribute to the resistance tochemotherapeutic agents (24).

Currently, chemotherapy may be beneficial forselected poorly differentiated cases, while therapy withsomatostatin analogues and/or with interferon- may

control the clinical symptoms when present and mayalso affect tumor growth (19,31-33).

Because of the only modest success of current ther-apeutic schedules, and since we obtained goodimmunopositivity for SSTRs, we decided to treat our

patient with combination therapy consisting of thesomatostatin analogue octreotide and interferon-. Thistreatment resulted in good disease control for more thana year.

Radical resection of hepatic metastases, dependingon their number and location, is recommended whenthey are present, as the patient survival rate will

improve (2,34-36). Hepatic artery embolisation, orchemoembolisation, has also been used and is associat-ed with good control of glucagonoma symptoms in the

presence of disseminated liver disease, but without anyproven survival advantage (15,22,23,30,37). In our casewe decided to carry out chemoembolisation more thenone year after primary surgical resection due to the radi-ological evidence of new hepatic lesions.

The patient had a complete resolution of skin rash,normalisation of plasma glucagon, chromogranin Aandneuron specific enolase levels, and metastatic diseasestabilisation. The patient's quality of life significantly

improved, and she is still alive 40 months after debulk-ing surgery.

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Received: May 26, 2005

Accepted in revised form: October 25, 2005

M. Appetecchia, MD

Endocrinology Unit, Regina Elena Cancer Institute,

Via Elio Chianesi, 53 - 00144 Rome, Italy

Tel./Fax: +39 06 52666026

E-mail: [email protected]

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Glucagonoma Maligno