Panniculitis in a patient with pancreatic acinar cell carcinoma

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1 Panniculitis in a patient with pancreatic acinar cell carcinoma M. Peetermans, N. Struyf, E. Kruithof, V. Duwel, D. Verhoeven, W. Demey We describe the case of a 75 year old woman who was diagnosed with pancreatic acinar cell carcinoma after she presented with subcutaneous nodules on the lower legs compatible with panniculitis. This case illustrates the need for a thorough search for internal disease in case of panniculitis to diagnose potentially life-threatening illness in an early stage. (Belg J Med Oncol 2012;6: ) Case presentation A 75 year old female presented with painless subcutaneous nodules on her lower limbs. They came in crops and some showed erythema of the overlying skin. There were no other complaints. Her medical history was uneventful, except for arterial hypertension which was well-controlled with a calcium antagonist and an ACE inhibitor. There was no history of cigarette smoking or alcohol abuse. On physical examination, we saw a healthyappearing, afebrile woman. On both lower limbs, firm subcutaneous nodules were noticed. The largest had a dia-meter of two centimetres. They were slightly tender to palpation. There were no signs of arthritis. A punch biopsy of a nodule showed a picture of panniculitis with a sparse lymphohistiocytic inflammatory infiltrate which invaded the fat lobule (Figure 1). Fungal and Ziehl-Neelsen staining were negative. There was no evidence of vasculitis. The laboratory results revealed a normal full blood count, no signs of inflammation or eosinophilia. Renal function, liver tests and amylase were normal; lipase was 8394 U/L. The protein electrophoresis revealed no abnormalities. Anti-CCP antibodies, rheuma factor and ANCA were negative, C3 and C4 were normal. There was an elevated antinuclear antibody (1/320), a normal angiotensine converting enzyme titre; hepatitis B and C serology were negative. CA 19.9 and chromogranin were normal, CA 15.3 was elevated to 186 U/L, and CEA was elevated to 21.1 ng/ml. Urine sediment showed neither haematuria nor leukocyturia nor proteinuria. A chest radiograph and mammography were normal. Abdominal ultrasound showed a thin walled cystic structure in the left upper quadrant. A CT scan of the abdomen (Figure 2) confirmed the presence of a cystic structure of 7.6 cm diameter next to the pancreatic tail. The cyst was septated and had an irregular wall. There were neither enlarged local adenopathies nor arguments for liver metastases. A chest CT showed no signs of lung metastases. Endoscopic ultrasound with needle aspiration cytology revealed that the cyst contained fluid with an inflammatory cytology (leukocyte count 350/µL with 94% neutrophils; many histiocytes, no malignant cells). Needle aspiration specimens of the adjacent Authors: M. Peetermans MD, Resident in Internal Medicine, AZ KLINA Hospital, Brasschaat, Belgium; N. Struyf MD, Department of Gastroenterology, AZ KLINA Hospital, Brasschaat, Belgium; E. Kruithof MD PhD, Department of Rheumatology, AZ KLINA Hospital, Brasschaat, Belgium; V. Duwel MD, Department of Pathology, AZ KLINA Hospital, Brasschaat, Belgium; D. Verhoeven MD, Department of Medical Oncology, AZ KLINA Hospital, Brasschaat, Belgium; W. Demey MD, Department of Medical Oncology, AZ KLINA Hospital, Brasschaat, Belgium. Please send all correspondence to: W. Demey MD, Department of Medical Oncology, AZ KLINA Hospital, Augustijnslei 100, B-2930, Brasschaat, Belgium, tel.: +32 (0) , wim.demey@klina.be. Conflict of interest: the authors have nothing to disclose and indicate no potential conflicts of interest. Key words: acinar cell carcinoma, panniculitis, paraneoplastic. 124

2 lobulated soft structure of 5 cm diameter in the pancreatic tail showed numerous malignant cells compatible with adenocarcinoma. The pancreatic tumour did not invade vascular structures. A resection of the pancreatic tail, combined for technical reasons with splenectomy and partial gastrectomy was carried out following explorative laparoscopy which revealed no ascites, peritoneal or liver laesions. Macroscopic examination of the resection specimen showed a large tumoural mass (6.5x4cm) with an adjacent cystic structure. Histopathological examination revealed a tumoural mass composed of lobules with a mostly trabecular growth pattern, interspersed between fibrous septa. Tumour cells had a fine granular eosinophilic cytoplasm, large nuclei and prominent nucleoli; they formed glandular acini (Figure 3). The collagenous wall without epithelial lining of the adjacent cyst was also invaded by tumour. The postoperative history was uneventful, panniculitis disappeared. After three months, the patient developed secondary diabetes which is well-controlled. Figure 1. Punch biopsy of a subcutaneous laesion on the lower leg (haematoxylin-eosin, 20x). Differential diagnosis of panniculitis Confronted with subcutaneous nodules, the clinician faces a broad differential diagnosis including soft tissue tumours (e.g. lipoma, neurofibroma), cysts, tophi, metastatic calcifications and panniculitis. The clinical presentation of panniculitis is uniform, as mostly tender and often erythematous subcutaneous nodules. It is divided, on a histopathological basis, into predominantly septal and predominantly lobular panniculitis (Table 1). 1-4 Other histopathological features of interest are the presence or absence of vasculitis, the type of inflammatory infiltrate and the presence or absence and type of fat necrosis. 1 However, an accurate etiological diagnosis is seldom possible based on histopathology alone. Panniculitis is a dynamic process, biopsy specimens are often inadequate (too small or superficial) and atypical presentations exist. 1-4 Relapsing febrile nodular panniculitis or Weber-Christian disease is a form of panniculitis seen in young women with recurrent fever, arthralgia and myalgia and no signs of internal disease. According to some authors this is not a separate disease entity, but a mixed group of panniculitides of different aetiology. 1 Figure 2. Abdominal CT scan and endoscopic ultrasound. Cystic structure (arrow) and adjacent tumoural mass (star) of the pancreas. Figure 3. Pathological examination of the pancreas resection specimen (haematoxyllin-eosin, 20x). The acinar, trabecular and solid growth pattern is clearly visible

3 Table 1. Classification of panniculitides. 1-4 Lobar Without vasculitis - lipodermatosclerosis (venous insufficiency) - subcutaneous Sweet syndrome - subcutaneous sarcoidosis - lupus erythematosus profundus - cytophagic histiocytic panniculitis/ Tc cell panniculitic lymphoma - metabolic panniculitis (pancreatic and alpha-1 antitrypsin deficiency) - infectious panniculitis: S.aureus, atypical mycobacteria, fungi etc - factitia, trauma, irradiation, steroid, calciphylaxis etc With vasculitis - erythema induratum (Bazin) - erythema nodosum leprosum Septal - erythema nodosum - rheumatoid nodules - necrobiotic xanthogranuloma - morphea/scleroderma* - necrobiosis lipoidica* - subcutaneous granuloma annulare* - acrodermatitis chronica atrophicans* - cutaneous polyarteritis nodosa - superficial thrombophlebitis * Frequent dermal involvement. Most panniculitides are an expression of internal disease and require a thorough history and clinical examination, supplemented with carefully chosen technical investigations. Our suggested approach can be found in Table 2. In the presented case, the elevated lipase pointed to the diagnosis of pancreatic panniculitis. This was first described in 1883 by Chiari. 5 It is a form of metabolic panniculitis which is associated with a spectrum of pancreatic diseases, ranging from acute and chronic pancreatitis, over anatomical variations of the pancreas to pancreatic malignancy. 4,6 Pancreatic panniculitis occurs in 2-3% of all patients with pancreatic diseases; about 100 cases have been reported so far. 4,6,7 The typical clinical presentation shows multiple erythematous to red-brown subcutaneous nodules on the lower legs, with a softer centre. 4,6 These laesions may ulcerate with an oily discharge or leave atrophic scars. The skin laesions frequently precede the diagnosis of pancreatic disease and therefore are important to recognise. 6,7 Skin laesions resolve with treatment of the underlying pancreatic disease. In malignant cases, a more prolonged course is seen. 4,7,8 Pathologic examination reveals focal coagulative fat necrosis with liquefaction and saponification. Virtually pathognomic is the presence of intensely and granular basophilic adipocytes, encircled by thick shadowy walls due to dystrophic calcification (ghost cells). 1,6-8 At the periphery, there is a mixed inflammatory infiltrate composed of neutrophils, histiocytes and lymphocytes. 4,6 It is hypothesised that pancreatic enzymes of damaged acini enter the bloodstream. Trypsin may increase the permeability of blood vessels and allow lipase to enter the subcutaneous fat tissue. Pancreatic lipase has been identified in areas of fat necrosis using immunohistochemical techniques. 4,6,7,9,10 There is also typically articular involvement (54-88% of cases), mostly of the knee, ankle, wrist or metacarpophalangeal joint. 6,7,11 The arthritis is secondary to periarticular fat necrosis, and about half of the cases show a chronic evolution. 6,11 The combination of panniculitis, polyarthritis and pancreatitis is referred to as the PPP syndrome. 11 The triad of panniculitis, polyarthritis and eosinophilia in the presence of a pancreatic neoplasm is called Schmid s triad and is associated with a poor prognosis. 6,7,12 Infrequently, pancreatic panniculitis is also associated with medullar fat necrosis of bone, pulmonary 126

4 Table 2. Suggested investigations in panniculitis extensive clinical history and examination histopathology including stain for fungi and acid-fast bacilli; bacterial culture* full blood count, renal function, electrolytes including calcium, liver and pancreatic enzymes, protein electrophoresis, complement, antinuclear factor (flow cytometry when indicated; throat swab and/or Mantoux test when indicated) urine sediment chest radiograph abdominal ultrasound (abdominal CT scan when indicated) (fundoscopic examination when indicated) * A deep (wedge) biopsy of the most recent laesion is required infiltrates and mesenteric thrombosis. 4,7 Neoplastic laesions associated with pancreatic panniculitis are mostly of the acinar cell type. 9 Acinar cell carcinoma presents (ACC) 1-2% of pancreatic neoplasms, although acinar cells occupy more than 80% of normal pancreatic tissue It affects patients at a younger mean age than ductal cell adenocarcinoma. 14 CEA and CA 19.9 are typically low. 13 These tumours have a mean survival of 19 months, more than one third of cases present with metastatic or locally advanced disease. 6,13,14 Lymph node metastasis and invasion into the surrounding tissue seem less likely to occur in ACC than in ductal adenocarcinoma. 13 Prognosis is thus intermediate between ductal adenocarcinoma and (neuro)-endocrine tumours of the pancreas. Up to 10% of ACCs are associated with panniculitis, which is also referred to as the lipase hypersecretion syndrome. 14,15 In this case, the constellation of a normal amylase and highly elevated lipase is common (as was seen in our patient). 9 The few reports of association of neuro-endocrine tumours with pancreatic panniculitis might be due to mixed histologies and difficult differential diagnosis. 9 On an abdominal CT scan, ACC typically presents as an exophytic oval or round, well-marginated and often lobulated mass. If the laesion is large, it may show cystic areas or central necrosis. 16 On pathological examination, ACC shows an architectural pattern of cells forming glandular acini, intermixed with trabecular and solid patterns. These acinar cells remind of the growth pattern and secretary products of normal pancreatic acini, often producing digestive enzymes such as trypsin, chymotrypsin and lipase. 14 They have large nuclei, prominent nucleoli, and apically located, diastase-resistant, periodic acid-schiff positive zymogen granules. 9,14 Conclusion We present the case of a 75 years old patient with panniculitis as first presentation of acinar pancreatic cancer. After surgery with curative intent the panniculitis resolved. There is a known association between panniculitis and acinar pancreatic cancer wich typically has a better prognosis than classic pancreatic cancer. Key messages for clinical practice Pancreatic cancer associated with panniculitis is typically of the acinar type. Prognosis of acinar pancreatic cancer is much better than prognosis of ductal adenocarcinoma of the pancreas

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