Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver case report and review of literature

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Zundler et al. BMC Cancer (2016) 16:130 DOI /s CASE REPORT Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver case report and review of
Zundler et al. BMC Cancer (2016) 16:130 DOI /s CASE REPORT Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver case report and review of literature Open Access Sebastian Zundler 1*, Ramona Erber 2, Abbas Agaimy 2, Arndt Hartmann 2, Franklin Kiesewetter 3, Deike Strobel 1, Markus F. Neurath 1 and Dane Wildner 1 Abstract Background: Pancreatic panniculitis is a rare condition, which has only been described in relation with pancreatic diseases up to now. It is characterized by necrotizing subcutaneous inflammation and is thought to be triggered by adipocyte necrosis due to systemic release of pancreatic enzymes with consecutive infiltration of neutrophils. We present the first case of a patient with pancreatic panniculitis caused by pancreatic-type primary acinar cell carcinoma (ACC) of the liver and without underlying pancreatic disease. Case presentation: A 73-year old Caucasian female patient was referred to our department with painful cutaneous nodules persisting for eight weeks and with marked lipasemia (~15000 U/l; normal range 60 U/l). Four weeks prior, several liver lesions had been detected. Empiric treatment with steroids did not show any effect. A biopsy of the skin nodules revealed pancreatic panniculitis, while abdominal imaging with ultrasound, computed tomography and magnetic resonance imaging detected no abnormal pancreatic findings. Ultrasound-guided biopsy of the liver lesions showed infiltrates of an ACC. The patient died soon thereafter. Autopsy failed to reveal any other primary for the ACC, so that a pancreatic-type ACC of the liver was diagnosed by exclusion. One hundred thirty cases of pancreatic panniculitis published within the last 20 years are reviewed. ACC of the pancreas is the most common underlying neoplastic condition. Patients with associated neoplasm are significantly older, take longer to be diagnosed and have higher lipase levels than patients with underlying pancreatitis. Extrapancreatic pancreatic-type ACC is very rare, but shows the same biological features as ACC of the pancreas. It is believed to develop from metaplastic or ectopic pancreatic tissue. Up to now, no pancreatic panniculitis in extrapancreatic ACC has been described. Conclusion: Pancreatic panniculitis should always be included in the differential diagnosis of lipolytic panniculitic lesions. It can be regarded as a facultative paraneoplastic phenomenon. When suspected, a thorough work-up for identification of the underlying disease is mandatory and extrapancreatic lesions (e.g. liver) should also be considered. While administration of octreotide or steroids can sometimes alleviate symptoms, immediate treatment of the associated condition is the only effective management option. Keywords: Pancreatic panniculitis, Acinar cell carcinoma, Pancreatitis, Paraneoplastic, Lipase, Liver * Correspondence: Equal contributors 1 Department of Medicine 1, University Hospital Erlangen, Ulmenweg 18, Erlangen, Germany Full list of author information is available at the end of the article 2016 Zundler et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated. Zundler et al. BMC Cancer (2016) 16:130 Page 2 of 14 Background Chiari was the first to describe the development of panniculitic lesions in patients with pancreatitis in 1883 [1]. Since then, several case reports and small case series have reported focal or generalized panniculitis in association with pancreatic diseases like acute or chronic pancreatitis, pancreatic carcinoma (ductal adenocarcinoma, acinar cell carcinoma, neuroendocrine carcinoma) or intraductal papillary mucinous neoplasm (IPMN) [2 6]. Up to 45 % of patients with pancreatic panniculitis show subcutaneous panniculitic nodules before the causal disease is recognized [2]. Therefore, these nodules can serve as an early and valuable clue to diagnosis of the underlying condition and trigger measurement of serum pancreatic enzymes, abdominal imaging or biopsy procedures. Histologic evaluation of the cutaneous lesions will typically reveal lobular neutrophilic necrotizing panniculitis intermingled with specific necrotic anucleate adipocytes called ghost cells [7]. The mechanism underlying the formation of panniculitic nodules in pancreatic panniculitis is poorly understood. However, it is commonly believed that systemically released pancreatic enzymes such as lipase and amylase cause distant lipolysis and fat necrosis with consecutive inflammatory reaction [8]. This is supported by the finding that the necrotic tissue stains positive for lipase [9]. However, serum levels of pancreatic enzymes do not correlate with clinical findings and similarly, in vitro experiments suggest that this explanation is not sufficient [10]. In addition to the cutaneous manifestation, arthritis is often found in patients with pancreatic panniculitis, clinically referred to as pancreatitis panniculitis polyarthritis (PPP) syndrome. It is thought that pancreatic enzymes are also able to trigger necrosis and inflammation in the synovium [11]. Furthermore, there are reports about panniculitis in the bone marrow, at submucosal sites or within the thoracic or peritoneal cavity [2, 11, 12]. Acinar cell carcinoma (ACC) is a rare pancreatic malignancy, representing about 1 % of all primary pancreatic neoplasms [13]. ACC is the most common malignancy found in patients with pancreatic panniculitis [14] and symptoms of pancreatic panniculitis can be found in up to 16 % of ACC patients [4]. On very rare occasions, pancreatic-type ACC can also arise as a primary neoplasm at extrapancreatic locations, such as liver, stomach, jejunum and colon [15 18]. In such cases, extrapancreatic ACC is believed to originate from either ectopic, metaplastic of transdifferentiated pancreatic tissue and shares biologic features with primary pancreatic ACC [15]. Here, we report the first case of pancreatic panniculitis in association with a primary pancreatic-type ACC of the liver without underlying pancreatic disease. Moreover, we present a review of case reports and case series of pancreatic panniculitis from the last 20 years, summarizing important knowledge and data about this disease entity. Case presentation A 73-year-old Caucasian female patient was referred to our department for further work-up of painful cutaneous lesions (Fig. 1) and several masses within her liver. Eight weeks prior, she had observed an erythematous nodule on her right chest. Subsequently, similar cutaneous lesions had developed on her arms and legs, and later also on her buttocks and back. She did not report any abdominal complaints. Outpatient treatment with topical and systemic steroids based on a suspicion of erythema nodosum (EN) did not yield substantial effect. Four weeks prior, several liver lesions had been detected by ultrasound and were interpreted as metastases of a previously treated breast cancer. Additional imaging with computed tomography (CT) and magnetic resonance imaging (MRI) had been carried out (Fig. 2) and confirmed the liver lesions. As the nodules on her skin continued to spread and became increasingly painful, she was presented to the Department of Dermatology in our clinic. There, another attempt of steroids and an intensified local therapy resulted in no improvement of her clinical condition. Due to raising inflammatory parameters a work-up for possible infectious causes and an antibiotic therapy with piperacillin/tazobactam, and later with meropenem were initiated. A colonoscopy revealed two small polyps, which were completely removed. Pancreatic enzymes were markedly elevated. A punch biopsy of one of the skin lesions was obtained showing a lobular necrotizing panniculitis with ghost cells compatible with pancreatic panniculitis (Fig. 3). CT, MRI and repeated ultrasound examinations (Fig. 4) did not reveal any pathological findings in the pancreas. In contrast enhanced CT multiple sharply-bounded liver lesions were visualized in both liver lobes. Compared Fig. 1 Several panniculitic lesions on the right leg of the patient, one of them ( ) shortly after having spontaneously drained brownish-oily fluid Zundler et al. BMC Cancer (2016) 16:130 Page 3 of 14 Fig. 2 Imaging of the liver lesions ( ) with ultrasound (a) and CT (b) with the CT obtained during outpatient care, the lesions had progressed in size and measured from 1 cm to 6 cm. The perfusion pattern was non-hypervascular and the density was hypointense, partly comparable with the density of water. No necrotic areas were described within the lesions. Because of a progressive worsening of her clinical condition and increasing laboratory markers of inflammation, the patient was referred to our Department of Internal Medicine. She complained about intensive pain all over her skin and required increasing dose rates of opioid analgetics. She did not report any weight loss, night sweats, fever, nausea or vomiting, abdominal pain or problems with food intake. Her past medical history was remarkable for invasive ductal breast cancer diagnosed in 1982 with local recurrences in 1990 and Moreover, a superficial spreading malignant melanoma had been treated in 2011 and a coronary artery disease with percutaneous coronary intervention in 2008 was reported. Family history was significant for malignant melanomas in all siblings and her mother. Continuous Fig. 3 Biopsy from a skin lesion showing lobular neutrophilic, necrotizing panniculitis and so called ghost cells ( ) medication included acetyl salicylic acid, lercanidipine, metoprolol, enalapril and pravastatin with no recent change. No allergic condition was known. On examination she was in poor general condition (ECOG performance status 4), tachycardic (102 bpm), slightly tachypnoeic (22/min) and normotensive (128/ 78 mmhg). Her temperature was 36.9 C. Subcutaneous erythematous and painful nodules of 2 5 cm size were noticed throughout her integument. Some of them were spontaneously draining a brownish oily fluid. Moreover, more than 200 melanocytic nevi were observed on her skin. Examination of the head, especially focusing on the salivary glands was unremarkable. There was no pain on abdominal palpation, the liver was palpable 2 cm under the right costal arch and bowel sounds were normal. There was a positive tap sign on both patellae. Laboratory results of interest were: leukocyte count 21.5 * 10^3/μl (ref * 10^3/μl), hemoglobin 10.0 g/dl (ref g/dl), ASAT 52 U/l (ref. 35U/l), GGT 235 U/l (ref. 40 U/l), AP 186 U/l (ref U/l), lipase U/l (ref. 60 U/l) and CRP 237 mg/l (ref. 5 mg/l). Alpha-Amylase, uric acid, ACE, CEA, CA19-9 and AFP were within normal range. Serology for Yersinia enterocolitica and pseudotuberculosis was negative, as well as testing for Mycobacterium tuberculosis and atypical mycobacteria. Rheumatologic testing including ANAs and ANCAs was unremarkable. Screening for possible infectious foci did not reveal any other source explaining the elevated CRP. Therefore, it was attributed to the skin lesions, which displayed clinical signs of inflammation and were partly draining pus in the further course. However, as microbiological evaluation was not able to prove any causative organism and inflammation markers were not substantially declining despite escalation of antibiotic treatment with additional vancomycin, skin lesions were classified as sterile. Leukocytosis was explained by concomitant steroid therapy. Ultrasound displayed several liver lesions in both lobes with a maximum size of 53 mm. The pancreas was Zundler et al. BMC Cancer (2016) 16:130 Page 4 of 14 exacerbation of pain, increasing tachycardia and hypotension. Therefore, no tumor-specific treatment could be initiated. The patient died ten days after admission to our ward. Pathological and autopsy findings Histopathological analysis of the core biopsy obtained from the liver mass revealed a cellular epithelial neoplasm composed of monomorphic polygonal or rounded cells arranged in compact acinar and trabecular structures (Fig. 5a, b). Immunohistochemical study revealed strong expression of pancytokeratin (KL-1) with variable expression of CK7 and diffuse strong cytoplasmic expression of trypsin (Fig. 5c), but lipase and amylase were negative. All other markers in the differential diagnosis were negative (CK5, CK20, HepPar-1, Synaptophysin, Chromogranin A, NSE, CD56, TTF1, ER, PR, protein S100, GATA3 and PAX8). These findings including in particular the strong and specific expression of trypsin confirmed the diagnosis of pancreatic-type ACC in the liver. Autopsy confirmed several liver masses measuring up to six centimeters in size. There was no evidence of a salivary gland tumor or a primary pancreatic tumor. Additionally, review of the slides from the patient s previous breast cancer confirmed a breast cancer of no special type and excluded the possibility of acinar-like differentiation. Thus, the previous breast cancer was also unrelated to the patient's ACC. Cause of her death was attributed to multiorgan failure due to severe systemic inflammatory response syndrome. Final diagnosis was pancreatic panniculitis due to primary pancreatic-type acinar cell carcinoma of the liver. Taking into account the conspicuous accumulation of malignancies in our patient and her family, genetic analysis for familial atypical multiple mole-melanoma (FAMMM) syndrome was recommended to her relatives. Fig. 4 Abdominal imaging showing no evidence of pancreatic pathology. a CT. b MRI. c ultrasound homogeneous and free of focal lesions. The pancreatic duct was not dilated and no avascular areas could be detected upon administration of ultrasound contrast agent. Ultrasound-guided puncture of one of the liver masses was performed leading to the histopathological diagnosis of a pancreatic-type ACC. Unfortunately, the condition of the patient had severely deteriorated in the meantime with further Review of literature In addition to the presented case, 130 reports on pancreatic panniculitis were identified in the English literature between January 1994 and November 2014 by using the search terms pancreatic panniculitis, subcutaneous fat necrosis AND pancreas and lipase hypersecretion syndrome in PubMed and by checking results for appropriate cross-references. Including the above case, all 131 cases (Table 1) were analyzed in respect to available data on age and gender of the patients, the underlying condition, additional symptoms, the sequence of the appearance of panniculitis and the diagnosis of the underlying disease, laboratory values and the outcome. The stated percentages refer to the respective number of cases including data on the analyzed parameter. Statistical analysis was Zundler et al. BMC Cancer (2016) 16:130 Page 5 of 14 Fig. 5 Histomorphology and immunohistochemistry of the liver tumor (from core biopsy). a core biopsy of the liver showing liver tissue adjacent to the acinar cell carcinoma, haematoxylin/eosin staining, 10-fold magnification. b compact acinar structures and trabeculae seen at higher magnification, haematoxylin/eosin staining, 40-fold magnification. c The tumor cells stained strongly for trypsin, 40-fold magnification performed with IBM SPSS Statistics (IBM, Armonk, NY, USA) using Student s T-test or Fisher s exact test where applicable. p 0.05 was considered significant. Graphs were generated with SigmaPlot (Systat, San Jose, CA, USA). Overall, 65 cases (49.6 %) were due to acute or chronic pancreatitis and 60 cases (45.8 %) had an underlying neoplastic condition. In six cases (4.6 %) other reasons were present, e.g. pancreas transplant rejection or pancreaticovascular fistula (Table 2). Patients with pancreatic panniculitis had a mean age of 54.8 years. Yet, patients with neoplastic causes were significantly older than individuals with pancreatitis (Fig. 6a) % of the patients were male with no difference in sex distribution between underlying pancreatitis and malignancy. In 48.9 %, cutaneous lesions were noted prior to the diagnosis of the underlying disease. The mean duration from appearance of the first lesion to diagnosis was 85 days +/ 110 days (range: days; median 42 days). This period was significantly longer when pancreatic panniculitis was due to a neoplasm than when a pancreatitis was present (Fig. 6b). Moreover, the portion of patients developing panniculitis before the diagnosis of the underlying condition was by trend higher in patients with neoplastic disease (66.7 %) than in patients with pancreatitis (48.3 %; p = 0.06). A PPP syndrome with additional signs of arthritis was present in 49 cases (37.4 %). One hundred twelve case reports (85.5 %) contained information on the serum levels of at least one pancreatic enzyme. In all but two of these reports (1.8 %) either amylase or lipase were elevated in one of these two cases only amylase had been measured. The mean level of lipase was U/l +/ U/l (range U/l, median U/l). Again, patients with pancreatitis and neoplastic conditions differed markedly with tumor patients having significantly higher lipase levels (Fig. 6c). ROC analysis identified a lipase level of 4414 U/l as best cut-off value with higher values having a sensitivity of 73.0 % and a specificity of 82.1 % for the diagnosis of a neoplastic cause (AUC = 0.785, 95 % CI 0.68 to 0.89). Only limited data was available concerning survival and follow-up. 12 patients with pancreatitis (21.4 %) died from complications. For underlying malignancy, followup data was available for 29 patients. A Kaplan-Meier plot of survival was computed, yielding a median survival of 4.75 months after appearance of the first skin lesion (Fig. 6d). Discussion Panniculitis is a clinical finding, which can be caused by various etiologic factors including infectious, immunologic and neoplastic conditions [19 21]. In our case, numerous causes could be excluded, while others were very unlikely: No infectious organism could be detected directly or indirectly. Continuous medication was unchanged and unsuspicious for causing erythema nodosum. Imaging had not yielded any evidence Zundler et al. BMC Cancer (2016) 16:130 Page 6 of 14 Table 1 Overview of pancreatic panniculitides described in English literature between January 1994 and November 2014 Patient Ref. Age Sex Underlying condition Outcome of skin lesions/follow-up 1 our pat. 73 f ACC of the liver death ten weeks after first skin lesion 2 [53] 55 m metastatic pancreatic NEC n.r. 3 [54] 38 m acute pancreatitis resolution 4 [7] 63 m acute pancreatitis resolution 5 [55] 81 f hemosuccus pancreaticus death 19 weeks after first skin lesion 6 [56] 26 f acute pancreatitis resolution 7 [57] 27 f acute pancreatitis resolution 8 [58] 34 m chronic pancreatitis n.r. 9 [59] 63 f acute pancreatitis resolution 10 [60] 83 m pancreatic ACC resolution of skin lesions after surgery, death 34 months after first skin lesion 11 [60] 75 m Acute pancreatitis resolution 12 [60] 60 m Large pancreatic neoplasm n.r. 13 [61] 68 f metastatic pancreatic ACC death six months after first skin lesion 14 [62] 61 f acute pancreatitis resolution 15 [63] 63 f acute pancreatitis resolution 16 [64] 49 m acute pancreatitis resolution 17 [47] 69 m hepatic metastasis of previous-ly resected resolution after metastasectomy, follow-up n.r. pancreatic ACC 18 [65] 71 f chronic pancreatitis with pseudocyst n.r. 19 [66] 66 f serous cystadenoma of the pancreas n.r. 20 [67] 39 m chronic pancreatitis death six weeks after firs
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