Case Reports

Panniculitis, Pancreatitis, and Polyarthritis: A Rare Clinical Syndrome

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Comment

A triad of pancreatic panniculitis, pancreatitis, and polyarthritis characterizes a rare entity known as PPP syndrome. Pancreatic panniculitis is a rare form of subcutaneous lobular fat necrosis associated with various underlying pancreatic disorders. Approximately 0.3% to 3.0% of patients with an underlying pancreatic disorder are affected with pancreatic panniculitis.9 Pancreatic panniculitis has been found in roughly 2% to 3% of patients with acute or chronic pancreatitis and pancreatic carcinoma, most commonly the acinar cell type.10 Narváez et al8 reported that nearly two-thirds of patients diagnosed with PPP syndrome have minimal to absent abdominal symptoms that often lead to misdiagnosis and affect the overall prognosis of patients with pancreatic disease. Any delay in the diagnosis of PPP syndrome leads to a worse prognosis, with a mortality rate reported to be approximately 24%.8 Potts et al5 provided a review of 27 patients with pancreatic panniculitis in which all 8 patients with pancreatic carcinoma and 42% (8/19) of patients with pancreatitis died.

Pancreatic panniculitis in the setting of PPP syndrome commonly presents with erythematous to brown, exquisitely tender, edematous, subcutaneous nodules on the lower legs. Lesions can range in size from several millimeters to 5 cm. The subcutaneous nodules may spontaneously ulcerate and exude oily viscous material from the liquefactive necrosis of adipocytes. In approximately 40% of patients, skin lesions are the presenting feature.11 Lesions typically resolve only after the pancreatic inflammation regresses, leaving behind atrophic hyperpigmented scars.3 Other presenting symptoms may include joint pain, pitting edema, and subcutaneous nodules, which can precede the diagnosis by up to 9 months.

The exact pathogenesis of PPP syndrome remains unclear. The most widely recognized hypothesis suggests that pancreatic enzymes (eg, trypsin, amylase, lipase, phospholipase A) released from the damaged pancreas are transported through the bloodstream to distant visceral and soft tissue sites, leading to lipolysis and inflammation to the surrounding subcutis and bone marrow.3 Ferrari et al12 reported this effect as a product of the accumulation of high levels of free fatty acids within the joint space by the action of lipolytic pancreatic enzymes on adipose cell membranes, resulting in acute arthritis.

Histopathologic findings of pancreatic panniculitis vary based on the acuity of the disease. Acute lesions typically demonstrate lobular and septal panniculitis. Szymanski and Bluefarb13 described the pathognomonic histologic findings of focal liquefactive necrosis and anucleate necrotic adipocytes surrounded by a shadowy and thickened cell membrane signifying the characteristic ghost cells. Fine basophilic material also may be seen intermixed with the necrotic adipocytes, representing saponified calcium. A brisk inflammatory infiltrate involving lymphocytes, macrophages, and neutrophils tends to surround the areas of necrotic adipocytes. Chronic lesions often demonstrate a paucity of fat necrosis and ghost cells and more granulomatous infiltrate. Langerhans giant cells, macrophages, and lymphocytes predominate in the subcutaneous fat.

Laboratory findings associated with pancreatic panniculitis may include elevated serum amylase, lipase, and/or trypsin levels. Not all the enzymes have to be elevated simultaneously. On occasion, one enzyme may be within reference range while the others are elevated. Rarely, patients may have an elevated lipase level with no signs of underlying pancreatic disease, which demonstrates that panniculitis does not correlate with the enzyme levels. In all cases of suspected pancreatic panniculitis, a complete laboratory workup is recommended including lipase, amylase, and trypsin serum levels. Eosinophilia may be a prominent finding in patients with pancreatic panniculitis and tends to occur in association with an underlying pancreatic carcinoma. Patients with pancreatic panniculitis associated with pancreatic carcinoma tend to have more severe, diffuse, and persistent subcutaneous nodules that often are refractory to treatment with frequent recurrence. A rare constellation of findings known as Schmid triad is comprised of panniculitis, polyarthritis, and eosinophilia and typically portends a poor prognosis secondary to an underlying pancreatic tumor.14 Cutaneous nodules may predate the diagnosis of pancreatic carcinoma by several months, thus signifying the need for a high index of suspicion in patients with lower leg subcutaneous nodules.

Joint disease most commonly involves the ankles, knees, wrists, and MCP joints.5,6,11 It has been suggested that arthritic symptoms are from periarticular fat necrosis or a direct extension from the necrotic subcutaneous tissue to the adjacent joint space.15 Dahl et al3 reported the composition of joint effusion fluid in 3 patients with PPP syndrome. The aspirate in all 3 patients contained viscous yellow material similar to the necrotic adipose tissue seen draining from subcutaneous nodules. Joint aspirate analysis demonstrated increased concentration of free fatty acids in the joint fluid consistent with severe lipolysis.3

The PPP syndrome acronym may be misleading to physicians, as arthritis is not always polyarticular. Dahl et al3 reported that monoarticular or oligoarticular arthritic symptoms were present in 56% of patients studied. In rare cases, the arthritic symptoms antedated the diagnosis of clinically asymptomatic pancreatic disease. Arthritis can be either symmetric or asymmetric and infrequently follows a chronic course, leading to radiographic lytic lesions and symptoms that often are unresponsive to conventional therapy.16

Treatment of PPP syndrome is largely supportive, with a focus on correcting the underlying pancreatic disease. It is imperative to identify any complicating factors contributing to high levels of circulating pancreatic enzymes. Pseudocysts must be addressed if discovered in these patients, as they often perpetuate the substantial release of pancreatic enzymes into the serum, leading to characteristic subcutaneous fat necrosis and arthritis. Sepsis also is a concern, likely secondary to bacterial colonization of the ulcerated subcutaneous nodules and compromised skin barrier. Nonsteroidal anti-inflammatory drugs and corticosteroids have been used for symptomatic relief but usually are ineffective and have not been shown to reduce the duration of the disease.12,16 Octreotide has been utilized and may potentially reduce pancreatic enzyme secretion leading to improvement in cutaneous and musculoskeletal lesions.17 Plasmapheresis has been used as an adjuvant treatment in patients with persistent hyperamylasemia and hyperlipasemia, but reports are anecdotal. Often reserved for severe disease, cholecystectomy, pancreatic duct removal, and pancreaticoduodenectomy have demonstrated success in the management of chronic pancreatitis and panniculitis. Dahl et al3 reported 2 cases in which cholecystectomy was performed with complete resolution of the skin and pancreatic disease. Our patient was initially treated symptomatically with NSAIDs and corticosteroids but there was no clinical response. The patient eventually underwent a pancreaticoduodenectomy 9 months after the onset of symptoms with complete resolution of joint pain and swelling, greater than 50% resolution of his lower leg subcutaneous nodules, and remarkable reduction in amylase and lipase levels on 1-month follow-up.

Conclusion

Panniculitis, pancreatitis, and polyarthritis syndrome is a rare diagnosis characterized by a triad of pancreatic panniculitis, pancreatitis, and polyarthritis. Adjuvant therapies for PPP syndrome, such as NSAIDs, corticosteroids, plasmapheresis, and octreotide, have been used with equivocal results, but definitive treatment requires correction of the primary pancreatic disorder. More importantly, many pancreatic diseases can cause pancreatic panniculitis, but extensive, refractory, or ulcerated cases could be an early indicator of an occult pancreatic malignancy and should prompt early evaluation with a multidisciplinary approach. This approach should incorporate management from dermatology, internal medicine, rheumatology, gastroenterology, surgery, and primary care.

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