Pancreatic Panniculitis

Etiology

Pancreatic panniculitis is more commonly seen in middle-aged men with a history of chronic alcoholism and who also suffer from acute or chronic pancreatitis.[2][3][6] While pancreatic acinar cell carcinoma is about 1% of all primary pancreatic cancers, it is the most common malignancy associated with pancreatic panniculitis.[4] Sixteen percent of acinar cell carcinoma patients have symptoms of pancreatic panniculitis.[4] 

Pancreatic acinar cell carcinoma can also be associated with pancreatic, panniculitis, and polyarthritis (PPP) syndrome.[7] Pancreatic panniculitis could be the first manifestation of other pancreatic malignancies, including ductal adenocarcinoma, intraductal mucinous cancer, and neuroendocrine tumors.[4] 

Pancreatic pseudocysts, posttraumatic pancreatitis, pancreas divisum, and hemophagocytic syndrome have also been reported with this panniculitis.[8] Post-ERCP pancreatitis can also present with pancreatic panniculitis.[9][10] 

Idiopathic pancreatic panniculitis has also been reported, where no pancreatic disease was found after appropriate investigation. The skin biopsies in these cases confirmed histopathological features consistent with pancreatic panniculitis.[11]

Epidemiology

Approximately 2% to 3% of all patients presenting with disorders of the pancreas present with pancreatic panniculitis. This condition is 4 times more common in men than women.[1][2] The average age of these patients is usually around 60, and patients with alcohol use disorder have a higher incidence of this disease.[1][2] Patients with pancreatic panniculitis and malignancy are often older.[4]

A recent meta-analysis of global trends of acute pancreatitis found that, overall, pancreatitis is increasing, especially alcohol-associated pancreatitis, due to the increased alcohol consumption in developing nations and Asian countries. Areas of the United States might be experiencing stabilizing plateaus of pancreatitis numbers, indicating incidence peaks.[12] 

As acute pancreatitis increases worldwide, pancreatic panniculitis may be observed in more cases. However, this is difficult to determine as these studies regarding acute pancreatitis do not include accompanying numbers for pancreatic panniculitis. While systematic retrospective reviews of case studies reporting pancreatic panniculitis have been done, it is difficult to determine its presentation's exact incidence and prevalence, mainly when various etiologies exist for this panniculitis.[4]

Pathophysiology

The exact pathophysiology explaining the skin manifestations of pancreatic panniculitis is not completely understood but is thought to be related to the release of pancreatic enzymes.[2][3][4] Trypsin is theorized to increase microcirculatory and lymphatic channel permeability allowing lipase and amylase to enter the body's peripheral circulation. Elevated amounts of lipase and amylase can cause fat necrosis and lipolysis outside the abdomen, with a concurrent inflammatory response.[3][4] Another theory proposes that pancreatic enzyme degradation is impaired, causing an increase in serum lipase. Additionally, lipase levels have been detected within biopsy after particular intracellular staining, and monoclonal antibodies targeting lipase were used.[13] Similarly, this lipolysis may occur within the synovium causing joint pain in PPP syndrome, with joint aspiration demonstrating a highly viscous fluid with elevated lipid content.[5]

The role of specific cytokines, such as adipokines, immune complexes, and vascular damage that allows for immune complex deposition are also proposed mechanisms for this disease's pathophysiology.[5] These mechanisms may occur concurrently or separately and are still under investigation. There have been reports in the literature of patients with normal levels of pancreatic enzymes still present with pancreatic panniculitis, with biopsy findings confirming the diagnosis.[14] Alternative explanations for this presentation include the involvement of transient lipase and amylase elevations or decreased ability to clear these enzymes in certain disease states or when taking certain medications, such as end-stage kidney disease or the usage of immunomodulators.[11]

Histopathology

Histologically, the skin biopsies of pancreatic panniculitis have distinct features. There are descriptions of 2 types of pancreatic panniculitis histologically, septal panniculitis and lobular panniculitis.[3] Septal panniculitis can be observed in the early stages due to pancreatic enzymatic transition from blood to fat lobules, disrupting the endothelial septa with a concurrent demonstration of adipocyte necrosis.[14] 

Lobular fat necrosis is predominant with adjacent neutrophilic infiltration.[5] There is often focal calcification and adipocytes without nuclei, often referred to as "ghost cells" or "ghost adipocytes," which are characteristic of this condition.[14][15] 

A digital bone biopsy from a pediatric case of PPP syndrome demonstrated the destruction of bone structure with fatty tissue saponification and the absence of inflammatory cells, indicating the relationship between fatty acids and increased cytokine production leading to joint inflammation.[16]

History and Physical

Patients commonly present with pancreatic panniculitis in their seventh decade of life, but they can be older if the etiology is pancreatic malignancy. The disease usually involves the eruption of tender nodules on the lower extremities. These lesions can also be present on the thighs, hips, buttocks, breasts, upper extremities, scalp, and around various joints.[3] This panniculitis may precede typical signs of pancreatitis or pancreatic neoplasm. More persistent nodules accompanied by dark, central ulcerations with drainage of brown, oily secretions can also occur. This constellation of findings is often associated with an underlying pancreatic malignancy.[5] 

Skin lesions may not always be painful. However, increasingly difficult-to-control pain from panniculitis can be an initial presentation for patients seeking care and further evaluation.

A migratory polyarthritis may also occur alongside panniculitis, which should raise suspicion for PPP syndrome. In addition to polyarthritis, intramedullary fat necrosis and polyserositis can occur in patients with PPP syndrome.[5] In the case of PPP syndrome, approximately one-third of patients completely lack or only present with very mild abdominal symptoms, with skin and joint complaints being more predominant.[4] 

Clinicians should obtain a complete patient history, especially for alcohol use, prior procedures or surgery, history of malignancy in the patient or family, and trauma.

Evaluation

Evaluation of pancreatic panniculitis should begin with a thorough physical exam, but investigation of underlying causes can become difficult if this is not suspected initially. The tender, firm and erythematous nodules can be seen before signs of pancreatic disease, so an investigation of etiologies must be performed considering the patient's history and risk factors for malignancy. 

Necessary labs include complete blood and cell counts, lipase, amylase, transaminases, bilirubin, and inflammatory markers. Lipase is significantly more elevated in patients with pancreatic malignancy than in those with pancreatitis. Lipase values greater than 4414 U/I were found to have a higher sensitivity and specificity for a malignant etiology for pancreatic panniculitis.[4] 

CT abdomen/pelvis with contrast is best to evaluate for pancreatic inflammation, mass, or metastatic disease. This may be a necessary initial step in assessing an abdominal source for panniculitis.

Previous case reports investigating pancreatic malignancies have obtained tumor markers such as CA 19–9. However, it is important to note that in pancreatic acinar cell carcinoma, mixed acinar-ductal, and mixed acinar-neuroendocrine subtypes, elevations in CA 19-9 are not usually seen. Younger patients may have elevated alpha-feto protein.[17]

A biopsy is required for the diagnosis and has pathognomonic findings of anucleated adipocytes, lobular fat necrosis, and leukocyte infiltration to surrounding necrotic adipocytes. The biopsy provides a definitive diagnosis of pancreatic panniculitis.[15]

While not part of a routine investigation, there have been unique features of pancreatic panniculitis of the lower extremities on MRI.[18] Since this disease process is dominated by fat necrosis, minimal or no intrinsic contrast enhancement is demonstrated on MRI. Still, peripheral enhancement is seen from granulation or underlying fibrous tissue in these areas corresponding to localized inflammation in the subcutaneous layer.

Treatment / Management

The primary treatment of pancreatic panniculitis is to address the underlying cause.[13] For example, as IV fluids and early enteral feeding in acute pancreatitis are associated with lower infection and mortality rates, this also aids in the resolution of the panniculitis within a few days.[19] (B3)

In cases where pancreatic neoplasms are associated with pancreatic panniculitis, the tumor is often advanced by the time the cutaneous lesions appear. Nevertheless, early treatment may be beneficial. In pancreatic acinar cell carcinoma treated with a chemotherapy regimen of folinic acid, fluorouracil, irinotecan, and oxaliplatin, pancreatic panniculitis was resolved after multiple cycles.[17][20] (B3)

While the subcutaneous nodules can resolve by treating pancreatic disease, hyperpigmented, atrophic scarring can remain.[14] Using NSAIDs, steroids, and immunosuppressive agents solely for panniculitis is not an effective management strategy, but if inflammation and nodules are painful, appropriate analgesia should be administered.[5][10](B3)

Differential Diagnosis

The differential diagnosis for pancreatic panniculitis includes other forms of panniculitis, and, additionally, it is essential to distinguish it from other skin finds associated with pancreatic diseases.[10] 

Panniculitides are a group of medical conditions that are characterized by inflammation of the subcutaneous fat. In some cases, panniculitides can be associated with lower extremity ulcers. Two other specific forms of panniculitis that are known to cause lower extremity ulcers are erythema induratum (also known as nodular vasculitis) and panniculitis caused by alpha-1-antitrypsin deficiency.

Erythema induratum is a type of panniculitis typically seen in middle-aged women. Erythema induratum presents as tender nodules that develop on the lower legs and may ulcerate. An immune reaction to bacteria, such as Mycobacterium tuberculosis or other mycobacteria, causes the condition. Panniculitis caused by alpha-1-antitrypsin deficiency is a rare genetic disorder in which there is a deficiency in the alpha-1-antitrypsin protein, leading to a buildup of abnormal protein in the liver and lungs. This can also cause panniculitis, which presents as painful nodules on the lower legs that may ulcerate.[21]

Erythema nodosum is the most common form of panniculitis and may be similar to pancreatic panniculitis in appearance but will not be associated with pancreatitis and is rarely associated with pancreatic malignancy. Erythema nodosum will not ulcerate nor secrete a viscous fluid. Necrolytic migratory erythema, a manifestation usually associated with neuroendocrine tumors such as glucagonoma, can also include central foci with crusting or necrosis. However, they are more so plaques instead of nodules.[2] 

Skin biopsy can differentiate pancreatic panniculitis from the conditions mentioned above. Still, it is also important to note the presence of pancreatic disease when diagnosing pancreatic panniculitis versus other similarly presenting skin manifestations.

Other conditions to keep on the differential list include migratory thrombophlebitis, cutaneous abscesses, lupus panniculitis Weber-Christian disease, or arthropod bites.[10][15]

Prognosis

The prognosis is dependent on the etiology of pancreatic panniculitis. For example, pancreatic acinar cell carcinoma is the most common pancreatic malignancy linked to pancreatic panniculitis despite its rarity and carries a very poor prognosis.[17][22] In the United States, about one-fifth of patients develop severe acute pancreatitis, with a 20% mortality rate.[19]

Complications

Complications from pancreatitis and malignancy occur when the etiology of pancreatic panniculitis is not properly investigated, as pancreatic panniculitis can precede any common signs of pancreatitis or pancreatic neoplasm.[4] Infection, pancreatic necrosis, fistula formation, pancreatic insufficiency/failure, cyst and pseudocyst formation, metastatic disease, and increased mortality are all associated complications.[19][23]

Rarely lipase hypersecretion syndrome (LHS), a paraneoplastic syndrome associated with pancreatic acinar cell carcinoma, can reduce survival to less than one year.[23] Lipase hypersecretion syndrome is a condition that can arise in patients with pancreatic acinar cell carcinoma, which often spreads to the liver. The development of pancreatic panniculitis, joint inflammation, and increased eosinophils characterizes LHS. It can often present with pancreatic panniculitis as one of its first signs, and many patients have metastatic disease to the liver.[23]

In one published case of PPP presenting with panniculitis and rapidly declining renal function, osteonecrosis of multiple joints, kidney basement membrane necrosis with the glomerular crescent formation, and fat necrosis with calcifications were found in gastric submucosa and bone marrow on autopsy after in-hospital death.[6]