A case report of pancreatic panniculitis due to acute pancreatitis with intraductal papillary mucinous neoplasm

Background Pancreatic panniculitis is a rare skin manifestation in pancreatic disease patients that most frequently develops on the lower legs. We report the unique case of a 68-year-old man who suffered from pancreatic panniculitis on his trunk associated with acute pancreatitis due to an intraductal papillary mucinous neoplasm. Case presentation A 68-year-old man complained of a 2-day history of a tender subcutaneous nodule on his trunk. Laboratory tests and abdominal contrast computed tomography were consistent with acute pancreatitis due to an intraductal papillary mucinous neoplasm. A skin biopsy of the nodule histologically displayed lobular panniculitis with characteristic “ghost cells”, which indicated pancreatic panniculitis. Conclusions In order to avoid a missed or delayed diagnosis, clinicians should bear in mind that pancreatic panniculitis can be the first manifestation of pancreatic disease when encountering subcutaneous nodules on the trunk.


Background
Pancreatic panniculitis is a rare skin manifestation associated with pancreatic disorders that presents in approximately 3% of patients with acute or chronic pancreatic disease [1]. The disorder most commonly develops on the lower legs as ill-defined erythematous subcutaneous nodules. Such nodules are detected in up to 45% of patients with pancreatic panniculitis before recognition of the original pancreatic disease [1]. Accordingly, the chief complaint of the patient is sometimes erythematous nodule detection before abdominal symptoms. Clinicians therefore have the risk of overlooking the underlying pancreatic disease. We herein report the rare case of a 68-year-old man who had pancreatic panniculitis on his trunk associated with acute pancreatitis due to an intraductal papillary mucinous neoplasm (IPMN).

Case presentation
A 68-year-old male patient was referred to our hospital by his primary care physician for further evaluation of a painful subcutaneous nodule on his upper middle abdomen, which was suspected to be abdominal cellulitis. Five days before admission, he had suffered from epigastralgia, nausea, and anorexia. Four days before admission, his epigastralgia had improved. Two days prior to admission, he noticed an erythematous nodule on his abdomen. His chief complaint on admission to our hospital was the painful nodule on his abdomen. He had been under medical treatment with aspirin, atorvastatin, colestimide, nicorandil, and famotidine for past medical histories of coronary artery bypass grafting (CABG), appendectomy, and dyslipidemia. He had no allergies. He had smoked 1 pack per day for 33 years before quitting 15 years earlier. He habitually drank 20 g of ethanol per day, with no history of heavy drinking. On examination, his temperature was 38.8°C, blood pressure was 144/74 mmHg, and pulse was 98/min with regular rhythms. A painful and tender erythematous nodule was palpable on his epigastrium at the lower edge of a postoperative scar from CABG. The nodule was 2.5 cm in diameter and surrounded by pale erythema (Fig. 1a). Laboratory tests revealed a white blood cell count elevation of 15,650/μL along with a C-reactive protein (CRP) abnormality of 24.4 mg/dL, with no amylase or lipase elevation (Table 1). Abdominal contrast computed tomography (CT) confirmed grade 1 acute pancreatitis (Fig. 2a) and a 20 mm multifocal cystic mass at the pancreatic body along with an 8 mm dilation of the main pancreatic duct, which were compatible with a diagnosis of IPMN (Fig. 2b). Thereafter, he commenced intravenous fluid infusion and antibiotic therapy. On hospital day 3, he became afebrile and showed improvements in inflammatory clinical parameters. A punched biopsy of the skin lesion on hospital day 4 revealed lobular panniculitis without vasculitis findings. Histological analysis uncovered focal necrosis of adipocytes and "ghost-like" cells with calcification surrounded by neutrophil-rich inflammatory infiltration, which indicated pancreatic panniculitis (Fig. 3). Intravenous fluid infusion and antibiotic therapy were continued until discharge on hospital day 12 for nodule pain disappearance along with CRP normalization. The erythematous

Discussion and conclusions
Pancreatic panniculitis is a rare skin manifestation associated with pancreatic disease. In the clinical setting, panniculitis is noticed as erythematous, ill-defined, and/or redbrown nodules [2] that generally affect the lower limbs and buttocks, rarely the trunk and upper extremities [3]. Only 9 cases have been described of pancreatic panniculitis on the trunk [3][4][5][6][7][8][9][10][11]. We encountered a unique case of subcutaneous nodules on the abdomen with latent IPMN. Skin biopsy revealed the typical histological findings of pancreatic panniculitis of lobular neutrophilic necrotizing panniculitis intermingled with specific necrotic anucleate adipocytes, called "ghost cells" [12].
The mechanism of pancreatic panniculitis onset remains unknown. It is hypothesized that systemically released pancreatic enzymes such as amylase and lipase can cause lipolysis and fat necrosis [13,14], resulting in pancreatic panniculitis as a specific clinical phenotype. However, several cases of pancreatic panniculitis with normal serum pancreatic enzymes have been reported [15,16], as in the present case. One possible reason for our patient was that his pancreatic amylase had already peaked due to pancreatitis improvement since such pancreatitis symptoms as epigastralgia had improved 4 days before admission. Therefore, it is clinically important to consider pancreatic panniculitis in patients with subcutaneous nodules even in the absence of abdominal symptoms for underlying pancreatic disorders, regardless of pancreatic enzyme status. This may avoid a missed or significantly delayed diagnosis of primary pancreatic disease.
The main pancreatic diseases related to pancreatic panniculitis have been reported as acute or chronic pancreatitis, pancreatic carcinoma (ductal adenocarcinoma, acinar  Chronic pancreatitis with pseudocyst [48] cell carcinoma, or neuroendocrine carcinoma), and IPMN.
In the present case, the underlying pancreatic disease was acute pancreatitis due to IPMN. Zundler et al. reviewed that subcutaneous lesions were noted prior to the diagnosis of pancreatic disease in 48.9% of reported cases [3]. In terms of clinical course, the period between subcutaneous lesion appearance and the detection of abdominal disorders could be several months for pancreatic panniculitis [17]. Table 2 summarizes the literature on pancreatic panniculitis displaying subcutaneous nodules as a chief complaint before diagnosing pancreatic disease. We searched the English-written literature between 1994 and 2019 using the parameters "pancreatic panniculitis" and "subcutaneous fat necrosis AND pancreas" in PubMed to identify 56 reported cases. The site of the nodules was predominantly the leg, with some cases on the trunk or arm. It should be noted that the period between subcutaneous lesion appearance and detection of the pancreatic disease was up to 48 weeks, and the underlying pancreatic disorder was a pancreatic neoplasm in nearly half of patients. Of all reported cases summarized in Table 2, only 2 were described as latent IPMN presenting as pancreatic panniculitis [22,41]. Pancreatic panniculitis could therefore serve as the impetus for an intensive search for pancreatic neoplasms in order to prevent a potentially long delay in diagnosis [17,60].
In conclusion, clinicians should bear in mind that pancreatic panniculitis can be the chief complaint of pancreatic disease when encountering subcutaneous nodules on the trunk to prevent a missed or delayed diagnosis.

Acknowledgements
We greatly appreciated Drs. Keiko Shibata, Soichiro Shibata, Koujiro Tokutake, Toru Fujisawa, Hiromitsu Mori, and Yoshiaki Matsuda for their helping to see the patients as one team. We thank Trevor Ralph for his English editorial assistance.
Authors' contributions YY and SJ, conception and design of the research, and writing the paper; YY, TI, MM, SW, management of the case, making the clinical diagnosis and collection of all data; TI, MM, and SW, data interpretation; SJ and TU, revision of the manuscript. All authors have read and approved the final manuscript.

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Availability of data and materials N/A Ethics approval and consent to participate Ethics approval by committee was not required for this case report.

Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Competing interests
The authors declare that they have no conflicts of interest.