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KEY FACTS
Canine Glucagonoma
West Chermside Veterinary Hospital Brisbane, Queensland, Australia
Natalie B. Langer, BVSc*
Iowa State University
Albert E. Jergens, DVM, MS Kris G. Miles, DVM, MS
ABSTRACT: Glucagonoma is a rare endocrine tumor of the alpha cells of the pancreatic islets.
Dogs with glucagonoma usually present with a characteristic dermatitis, primarily involving the footpads. Although the exact mechanisms for the skin lesions remain unknown, it is thought that hyperglucagonemia and other metabolic abnormalities contribute to their devel- opment. Although most canine patients with glucagonoma are diagnosed too late in the clini- cal course of disease for a cure to be achieved, it is possible to palliate signs with surgical and medical intervention.
T
he etiology of glucagonoma has not been elucidated, and no consistent risk factors have been identified for dogs or humans.1,2In humans, glucagonoma syndrome is characterized by hyperglucagonemia (from the glucagon-secreting tumor); skin rash (necrolytic migratory erythema [NME]);diabetes mellitus (DM); hypoaminoacidemia; and normocytic, normochromic anemia.3,4 The observation of NME in humans was once considered to be pathognomonic for glucagonoma syndrome. However, recent studies have shown that neither glucagonoma nor hyperglucagonemia are required for NME to occur in humans.5–7
Dogs have a skin condition corresponding to NME called superficial necrolytic dermatitis (SND), with 75 canine cases of SND reported in the veterinary litera- ture.8 However, only five of these cases were associated with hypergluca- gonemia.2,8Therefore, the diagnosis of SND does not confirm the presence of glucagonoma, although the two lesions may occur concurrently.
PATHOPHYSIOLOGY
Glucagonoma is an uncommon endocrine disease that is usually first recog- nized by the presence of dermatologic manifestations. However, these signs are not pathognomonic for glucagonoma.
Although the pathogenesis of SND and NME remains poorly understood, high serum levels of glucagon have been implicated as a factor in most human cases.3–7Data supporting this association include the observation that skin lesions can rapidly resolve following resection of glucagonoma or with the CE
56 Vol. 25, No. 1 January 2003
■ An inappropriately high level of serum glucagon and a demonstrable pancreatic mass help establish the diagnosis of glucagonoma.
■ Patients with elevated glucagon levels are often persistently hyperglycemic and may acquire diabetes mellitus.
■ Surgery is the treatment of choice for patients with glucagonoma.
*Ms. Langer was affiliated with Iowa State University at the time this article was written.
www.VetLearn.com administration of a potent glucagon inhibitor that pre-
vents the occurrence of abnormally high serum glucagon concentrations.5–7,9,10A variety of other meta- bolic abnormalities and nutritional deficiencies have also been implicated in the pathogenesis of SND.1,2,11 The various roles of glucagon, other hormones, and neuroendocrine peptides have not yet been elucidated.
Zinc deficiency, liver dysfunction, hypoalbuminemia, and essential fatty and amino acid deficiencies are also thought to play a role.1,2,9–11Furthermore, a thorough understanding of the pathogenesis of SND in glucagonoma has not been possible because of incon- sistencies among individual cases. In these instances, liver function and amino acid, zinc, and fatty acid concentrations were not measured in each human or canine case.1,2,11
Some patients with hyperglucagonemia may also develop concurrent DM.12,13 Because glucagon acts to promote gluconeogenesis and glycogenolysis, hyper- glycemia will occur if there is an excess of glucagon rela- tive to insulin.12,13 Hence, the onset of DM usually occurs when insulin production cannot match the excessive secretion of glucagon. This can be seen when glucagon concentration is very high and insulin produc- tion continues normally or when insulin production is impaired and glucagon concentrations are mildly ele- vated.1–4,12,13 Other patient factors contributing to DM may include preexisting insulin resistance.1,14
SIGNALMENT, CLINICAL HISTORY, AND PHYSICAL EXAMINATION
Glucagonomas are extremely rare, with approxi- mately 200 human cases reported worldwide in the past 60 years. Apart from the case reported here, only seven other cases of canine glucagonoma have been reported.12–17 No breed or sex predilection seems to exist. The presenting complaint in each case was char- acteristic dermatitis, primarily involving the foot- pads.8,12–15,17 Skin lesions occur particularly in areas of trauma, such as the distal limbs and footpads, muzzle, and mucocutaneous areas of the face.8,12–15,17 Skin lesions can also be noted on the elbows and hocks, on the pinnae, on the external genitalia, over the xiphister- num, and in the mouth.8,12–15,17Most lesions are crusted with subadjacent erosions or ulcers, but intact vesicular lesions can also occur.8,12,15
Other common historical complaints included weight loss, polydipsia, and polyuria.2,13–15The signifi- cant weight loss that occurs in these patients may be due to the catabolic effects of glucagon on fat and pro- tein metabolism.1 Glucagon-induced protein catabo- lism may also explain the normochromic, normocytic anemia and hypoaminoacidemia that are often seen.1
DIAGNOSIS
For patients presenting with skin lesions consistent with SND, a basic patient workup, including a com- plete blood cell count (CBC), serum biochemistry pro- file, and urinalysis, should be conducted. These tests are useful in screening for underlying diseases that may cause the dermatologic signs. Major diagnostic differ- entials for the skin lesions, apart from hepatocutaneous syndrome and glucagonoma, include pemphigus foli- aceus, systemic lupus erythematosus, generic dog food dermatosis, and zinc-responsive dermatosis.8,14No cells are usually seen on cytology of the vesicular fluid in cases of SND, although inflammatory cells do occur in the other aforementioned differentials.8 Hence, cytol- ogy of skin exudate and skin scrapings should also be conducted. Some patients with SND have coexisting bacterial or fungal (yeast or dermatophyte) dermatitis.8
Common laboratory findings in canine glucagonoma include mild nonregenerative anemia and elevated liver enzymes (i.e., alanine aminotransferase [ALT], alkaline phosphatase [ALP]).1,2,13 Other abnormalities found in some dogs were hypoalbuminemia, decreased blood urea nitrogen, and persistent hyperglycemia; however, only two of the seven previously reported canine cases included a diagnosis of concurrent DM.12–14 Results of liver function tests (bile acid assays or ammonium tol- erance test) conducted in five of the eight cases were normal.12–17The observations of increased liver enzymes and normal liver function tests are strong indicators that further diagnostic tests to rule out glucagonoma should be pursued.
Skin biopsies are required to confirm SND, and histopathology was consistent with SND in all eight reported cases. Skin biopsies from early lesions show diffuse parakeratotic hyperkeratosis with high-level confluent vacuolation of keratinocytes, which results in a band of upper-level epidermal edema.8,16–18 Dermal changes are usually minimal but can include superficial edema and perivascular accumulation of lymphocytes and plasma cells.8,13Chronic lesions rarely show epider- mal edema and have marked parakeratotic hyperkerato- sis, epidermal hyperplasia, and surface crusting.8,18 Chronic lesions may also have a superficial to lichenoid inflammatory infiltrate.8Submission of multiple punch biopsy tissue specimens from the edges of early lesions is most helpful for a histopathologic diagnosis of SND.8,13,18
Diagnostic imaging of the abdomen and thorax may show evidence of local or metastatic disease. Although glucagonomas in humans rarely spread to the lungs, thoracic radiographs may demonstrate the presence of metastasis.2,11,19Abdominal radiography and ultrasonog- raphy are useful to screen for hepatic disease and pan-
. Summary of Reported Canine Glucagonoma Cases (1990–2002) Glucagon SkinDiabetesLevelAmino Presence of entLesions?Mellitus?(pg/ml)Acid LevelsImagingMetastasisImmunohistochemistrySurgeryOutcome rier, 11 y, MYesYesNANAUltrasonographyNA+ GlucagonYesDied 3 days after surgery12 (mass in right+ Somatostatin pancreatic limb)+ Insulin or retriever,YesYesNANAUltrasonographyNA+ GlucagonYesEuthanized 3 days after (WNL)+ Somatostatinsurgery12 + Insulin reed, 5 y, FSYesNo526NAUltrasonographyYes+ GlucagonNoEuthanized 6 wk after (small liver)– Somatostatinpresentation17 – Insulin 8 y, MNYesNo83013 of 18UltrasonographyYes+ GlucagonYesEuthanized 5 days after decreased(hyperechoic area in– Somatostatinsurgery16 the liver)– Insulin d poodle,YesNo39720 of 24UltrasonographyYes+ GlucagonYesEuthanized 9 mo after Ndecreased(WNL)+ Somatostatinsurgery14 r spaniel,YesNo700NAUltrasonographyYes+ GlucagonNoEuthanized 2 wk after (WNL)– Somatostatinpresentation15 + Insulin mountainYesNo3754 of 5UltrasonographyYes+ GlucagonNoEuthanized 4 wk after , FSdecreased(multiple liver+ Somatostatinpresentation13 nodules) or retriever,YesNo820NAUltrasonographyYes+ GlucagonYesAlive 4 mo after surgery (multiple liver– Insulin lesions) CT (mass in left pancreatic limb) sitive; –= negative; F= female; FS= female spayed; M= male; MN= male neutered; NA= not available; WNL= within normal limits.
www.VetLearn.com creatic lesions. Abdominal ultrasonography was con-
ducted in all eight cases of canine glucagonoma, but a pancreatic mass was visible in only one case.12–17How- ever, four dogs had ultrasonographically visible liver abnormalities, including multiple hypoechogenic foci throughout the liver.12–17This abnormal appearance of the liver has sometimes been described as a “honey- comb” pattern, but it is not pathognomonic for the presence of glucagonoma.1,8,13
In humans, primary pancreatic tumor and metastatic disease are localized primarily by computed tomogra- phy (CT).1,11 Unfortunately, although locating the tumor before surgical intervention is extremely valu- able, it is not always possible. In humans, increased sensitivity and specificity in imaging pancreatic neu- roendocrine tumors has recently been achieved through the use of endoscopic ultrasonography and may one day become valuable in evaluating canine pancreatic lesions.20 Sites of glucagonoma metastasis have also been detected in humans using indium-111–labeled octreotide scintigraphy.21 The use of radiolabeled octreotide to facilitate the diagnosis of pancreatic insulinoma has been successful in 10 dogs but has not yet been used in any reported canine glucagonoma cases. Precisely determining the tumor extent is also very important because therapeutic interventions are influenced by the presence or absence of metastasis.1,11 The case reported here is the first documented case involving CT of glucagonoma in a dog.
Serum glucagon levels were measured in six of the eight canine cases and found to be elevated in each case13 (Table 1). The occurrence of elevated serum glucagon concentrations in the absence of hypoglycemia is strongly suggestive of the existence of an endocrino- logically active alpha-cell tumor.2,13,22 However, other conditions, including DM, have been associated with high glucagon concentrations; hence, definitive diagno- sis is made only by histopathologic documentation of a pancreatic tumor immunoreactive for glucagon.13,22
TREATMENT
Complete surgical resection of the glucagon-secret- ing tumor is the treatment of choice. Curative surgery can be attempted if metastasis is not identified before surgery.1,11,23 Careful exploration of the abdomen should be conducted, and biopsies of suspicious areas within the liver and regional lymph nodes should be obtained.24In dogs, metastasis is common. Five of the seven previously reported cases had confirmed metasta- tic lesions involving the liver (three dogs), regional lymph nodes (one dog), or both liver and regional lymph nodes (one dog).13 Even when metastasis has occurred, surgery may still be helpful for palliating
signs. In humans, tumor debulking may decrease the intensity of skin lesions in some instances.11Liver trans- plantation and complete pancreatectomy have been performed in a few human patients with variable suc- cess, but unfortunately this is not yet feasible in dogs.23
Some degree of success in treating human glucagonoma has been achieved with the use of chemotherapeutic agents, including dacarbazine alone and streptozotocin combined with 5-fluorouracil.11 Currently, octreotide is the chemotherapeutic drug of choice.8,11 Octreotide is an analog of somatostatin and has been found to decrease the concentration of several polypeptide hormones, including insulin, glucagon, gastrin, secretin, and motilin.9,19,22 In humans, it was found to help control hormone secretion and reduce tumor growth.11The drug can be parenterally adminis- tered only in a short-acting preparation (Sandostatin, Novartis, SC two to four times daily) or as a long-act- ing slow-release preparation (Sandostatin LAR, typi- cally administered once every 4 weeks).11 Appropriate dosages for the use of somatostatin analogues have not yet been established in dogs. Additionally, the high cost of Sandostatin precludes its routine use in most canine patients. Hepatic arterial chemoembolization of metas- tases has also been attempted in a few human cases.1,11 This method of treatment attempts to induce selective necrosis of hepatic metastases.11
Dietary supplementation with essential fatty acids, zinc, and certain amino acids may also help resolve the dermatologic signs in both humans and dogs.1,8,11,13One formula (developed at the University of California) used a combination of high-quality protein (one egg yolk per 4.5 kg of body weight), a zinc supplement (zinc sulfate, 10 mg/kg/day), and a fatty acid supplement.8 Amino acid supplementation may also be beneficial, especially if it is formulated to meet the specific deficiencies iden- tified on the patient’s amino acid profile.8
PROGNOSIS
Unfortunately, most canine patients with glucagonoma have been diagnosed too late in the clini- cal course of disease for a cure to be possible. However, successful short-term palliation of signs may be achieved with early surgical and medical intervention.
The long-term prognosis of glucagonomas in dogs and humans remains poor.1,2,8,11
CASE REPORT
A 6-year-old male castrated Labrador retriever pre- sented to the local veterinary practitioner with multiple skin lesions, lethargy, and weight loss. Physical exami- nation revealed severe generalized muscle atrophy, pal- pable hepatomegaly, and multiple crusting skin lesions.
The cutaneous lesions involved the distal aspect of all four legs but were worse on the footpads (Figure 1).
Initial laboratory testing comprising a CBC and serum biochemical profile revealed mild nonregenerative ane- mia, hyperglycemia, and elevated ALT and ALP. The dog showed no response to prednisone (0.5 mg/kg/day for 2 weeks). On reexamination, skin biopsies were obtained. Histopathology demonstrated diffuse paraker- atotic hyperkeratosis with upper-level epidermal edema.
These morphologic lesions were interpreted as being most consistent with a diagnosis of SND (Figure 2).
The dog was referred to the Iowa State University Vet- erinary Teaching Hospital for further diagnostic evalua- tion. The dog’s owners noted that the skin condition had worsened since the initial visit to the local veterinarian.
The limb lesions were more extensive, and the ventral abdomen also showed involvement. A new CBC showed mild, mature neutrophilia with mild, normocytic, nor- mochromic, nonregenerative anemia. A biochemistry panel revealed elevated ALP of 461 IU/L (range: 20 to 115) and elevated ALT of 468 IU/L (range: 24 to 105).
Blood glucose was normal. Urinalysis revealed no abnor- malities. Thoracic radiographs were within normal lim- its. Abdominal radiographs demonstrated marked gener- alized hepatomegaly. Three separate lesion patterns disrupted the normal hepatic architecture on abdominal ultrasonography. Two large hyperechoic liver masses (6- cm diameter) were seen in separate lobes (Figure 3).
Many smaller hyperechoic masses with hypoechoic rims were scattered throughout the liver parenchyma as well.
Numerous small hypoechogenic nodules were also observed. The presence of gas-filled small intestinal loops precluded visualization of the pancreas.
Because of the common association between SND and liver dysfunction, bile acid tests were conducted to
evaluate liver function. Both preprandial and postpran- dial levels were within normal limits, indicating normal hepatobiliary function. Blood was submitted for serum glucagon concentration; however, amino acid levels Figure 1—Skin lesions on the distal limbs included hyper-
keratosis and crusting lesions.
Figure 2—Histopathology of skin biopsy showing marked diffuse parakeratotic hyperkeratosis and upper-level epider- mal edema.
Figure 3—Transverse view of a predominantly hyperechoic mass in the left medial lobe of the liver (A). Sagittal view of the left lateral lobe of the liver demonstrates smaller “target- like” complex lesions (B).
A
B
www.VetLearn.com were not measured. This patient’s glucagon concentra-
tion was 820 pmol/L. This was considered elevated, although clearly defined reference ranges for canine serum glucagon concentrations have not been firmly established. However, values less than 200 pmol/L are generally considered normal.13–17
One month later, CT of the abdomen with emphasis on pancreatic architecture was performed. A mass lesion in the left limb of the pancreas was identified (Figure 4).
CT also confirmed the presence of two large masses and many multifocal lesions throughout the liver.
A tentative diagnosis of a glucagon-secreting pancre- atic tumor was made, and the owners agreed to an exploratory laparotomy on their dog. The goals of sur- gery were to confirm the diagnosis, resect the primary pancreatic mass, and obtain multiple liver biopsies for histopathologic evaluation. Although spread of glucagonoma to the liver is common and hepatic lesions had been visualized on abdominal ultrasonogra- phy and CT, metastasis could not be confirmed with- out histopathology.
At the time of surgery, the pancreatic mass (Figure 5) was easily visualized in the left pancreatic limb. Addi- tionally, multiple well-demarcated, off-white, firm cir- cular masses (ranging from 0.1 to 1 cm in diameter) were found on the serosal surface and within the parenchyma of the liver (Figure 6). Partial pancreatec- tomy to remove the left limb of the pancreas was per- formed in addition to liver biopsy.
Although a common complication of pancreatic sur- gery is pancreatitis, the dog had an uneventful recovery from surgery. Neither abdominal pain nor vomiting was noted postoperatively, and glucose levels remained within the normal range. Water and food were with- held for 24 hours following surgery and then gradually reintroduced. Empiric therapy included treatment with S-adenosylmethionine (Denosyl SD4, Nutramax). S- adenosylmethionine has been shown to increase levels of hepatic glutathione, an important antioxidant.25 Hence, Denosyl SD4 is recommended for managing hepatic diseases to help maintain and protect liver func- tion.25The dog was discharged 3 days after surgery.
Initial histopathology of the pancreatic mass was consistent with an endocrine neoplasm of the pancre- atic islets (Figure 7). Similar cells were also found among hepatocytes on microscopic examination of the liver biopsy specimens. Immunohistochemistry of the tumor cells (in both liver and pancreas) were positive for glucagon but negative for insulin. Additional immunohistochemical stains with specificity for Figure 5—Gross appearance of the pancreatic mass.
Figure 6—Intraoperative view of the liver.
Figure 4—Transverse CT of the cranial abdomen with intra- venous contrast. A mass is present in the left limb of the pan- creas. Nonenhancing liver lesions are also observed. (RK = right kidney)
somatostatin, amyloid polypeptide, and pancreatic polypeptide were unavailable; thus they were not con- ducted in this patient. A final diagnosis of pancreatic glucagonoma with hepatic metastases was made.
The dog was returned for reevaluation and suture removal 10 days after discharge. The owners reported that the dog had been doing well at home except for an intermittent selective appetite. The skin lesions had mildly improved, and no further weight loss was noted.
Both ALT and ALP levels remained elevated but were lower than previously observed. ALP was now 415 IU/L, and ALT was 150 IU/L. Plasma glucagon levels were also reassessed at this visit and were still very high at 800 pmol/L, indicating the presence of functional liver metastases. The dog’s owners declined further pal- liative treatment with chemotherapy. Four months after this recheck, the owners were contacted by telephone and the dog was still doing well clinically.
ACKNOWLEDGMENTS
The authors thank Ron Myers, DVM, DACVP (Department of Veteri- nary Pathology, Iowa State University); Jim Noxon, DVM, DACVIM (Department of Veterinary Clinical Sciences, Iowa State University);
Vicki Wilke, DVM (Department of Veterinary Clinical Sciences, Iowa State University); David Mason, BVetMed (Department of Veterinary Clinical Sciences, Iowa State University); Robert King, DVM, DACVIM (Department of Veterinary Clinical Sciences, Iowa State University);
Charlie Brockus, DVM, DACVIM (Department of Veterinary Clinical Pathology, Iowa State University); and Jim Fosse (Biomedical Communi- cations, Iowa State University).
REFERENCES
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3. Wermers RA, Fatourechi V, Kvols LK: Clinical spectrum of hyperglucagonemia associated with malignant neuroendocrine tumors. Mayo Clin Proc 71:1030–1038, 1996.
4. Wermers RA, Fatourechi V, Wynne AG, et al: The glucagonoma syndrome: Clinical and pathological features in 21 patients.
Medicine (Baltimore) 75:53–63, 1996.
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6. Sinclair SA, Reynolds NJ: Necrolytic migratory erythema and zinc deficiency. Br J Dermatol 136:783–785, 1997.
7. Blackford S, Wright S, Roberts DI: Necrolytic migratory ery- thema without glucagonoma: The role of essential fatty acids. Br J Dermatol 125:460–462, 1991.
8. Scott DW, Miller WH, Griffin CE: Muller and Kirk’s Small Ani- mal Dermatology, ed 6. Philadelphia, WB Saunders, 2001, pp 868–873.
9. Sohier JM: Rapid improvement of skin lesions in glucagonomas with intravenous somatostatin infusion. Lancet 1:40, 1980.
10. Byrne KP: Metabolic epidermal necrosis-hepatocutaneous syn- drome. Vet Clin North Am Small Anim Pract 29(6):1337–1355, 1999.
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12. Gross TL, O’Brien TD, Davies AP, et al: Glucagon-producing pancreatic endocrine tumors in dogs with superficial necrolytic dermatitis. JAVMA 197:1619–1622, 1990.
13. Allenspach K, Arnold P, Glaus T, et al: Glucagon-producing neuroendocrine tumor associated with hypoaminoacidemia and skin lesions. J Small Anim Pract 41:402–406, 2000.
14. Torres S, Johnson K, McKeever P, et al: Superficial necrolytic dermatitis and a pancreatic endocrine tumor in a dog. J Small Anim Pract 38:246–250, 1997.
15. Torres S, Caywood DD, O’Brien TD, et al: Resolution of super- ficial necrolytic dermatitis following excision of a glucagon- secreting pancreatic neoplasm in a dog. JAAHA 33:313–319, 1997.
16. Bond R, McNeil PE, Evans H, et al: Metabolic epidermal necro- sis in two dogs with different underlying diseases. Vet Rec 136:466–471, 1995.
17. Miller WH, Anderson WI, McCann J: Necrolytic migratory erythema in a dog with a glucagon-secreting endocrine tumor.
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Figure 7—Histologic appearance of the pancreatic endocrine tumor. Note how the neoplastic tissue infiltrates the normal pancreatic islet architecture.
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1. Glucagonomas are tumors of the a. pancreatic delta cells.
b. pancreatic beta cells.
c. zona fasciculata of the adrenal cortex.
d. pancreatic alpha cells.
2. Why do some patients with glucagonoma develop concurrent DM?
a. They are consuming a high-carbohydrate diet.
b. Neoplastic pancreatic alpha cells invade the insulin- producing pancreatic beta cells.
c. Prolonged hyperglycemia causes down-regulation of insulin receptors.
d. Insulin secretion cannot match excessive glucagon secretion.
3. Factors involved in the pathogenesis of SND include a. low zinc, glucagon, and essential fatty acid levels.
b. low zinc, high glucagon, and low essential amino acid levels.
c. high zinc, high glucagon, and low albumin levels.
d. high glucagon, low albumin, and high essential amino acid levels.
4. The most common clinical sign in patients with glucagonoma is
a. syncopal episodes.
ARTICLE #4 CE TEST
CE
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b. polydipsia.
c. dermatitis mainly involving the footpads.
d. bradycardia.
5. Skin biopsies to confirm SND should be taken from the a. dorsal surface of the paws.
b. edges of early lesions.
c. ventral abdomen, ears, and neck.
d. axillary and inguinal regions.
6. Diagnosis of canine glucagonoma is confirmed by a. elevated glucagon concentration in the absence of
hypoglycemia.
b. histopathology of a pancreatic tumor immunoreac- tive for glucagon.
c. elevated glucagon concentration and abnormal liver function.
d. both a and b
7. A common postoperative complication of pancreatic surgery is
a. pancreatitis.
b. diabetes insipidus.
c. septic peritonitis.
d. ventricular premature contractions.
8. Metastasis of glucagonoma to the liver is confirmed by a. pancreatic histopathology.
b. an increased postprandial bile acid result.
c. liver histopathology.
d. ultrasonographically visible multifocal liver nod- ules.
9. The chemotherapeutic drug of choice for gluca- gonoma is
a. streptozotocin.
b. octreotide.
c. melphalan.
d. dacarbazine.
10. Diagnostic differentials for SND skin lesions include a. zinc deficiency and systemic lupus erythematosus.
b. pemphigus foliaceous and biotin deficiency.
c. zinc deficiency and acral lick dermatitis.
d. bacterial folliculitis and diskoid lupus erythematosus.
