Pancreatitis, panniculitis and polyarthritis (PPP) syndrome

Abstract

A young male presented with intermittent high-grade fever, asymmetric polyarthritis and erythematous, tender nodules over left shin for 2 months duration. He had a history of alcohol dependence with multiple episodes of acute pancreatitis. With polyarthritis progressing relentlessly, unresponsive to non-steroidal anti-inflammatory drugs and steroids, a provisional diagnosis of sarcoidosis was considered. Indeed, he was treated with azathioprine and rituximab with no effect. Biopsy of the skin nodule revealed subcutaneous fat necrosis, foam cells, deposition of eosinophilic amorphous material and calcification. Synovial fluid aspiration from the arthritic knee obtained purulent but surprisingly culture-negative material, rich in triglycerides. Abdominal CT confirmed chronic pancreatitis. Final diagnosis of pancreatitis, panniculitis and polyarthritis (PPP) syndrome was made. He underwent surgical pancreatic ductal drainage leading to complete remission of symptoms. PPP syndrome triad occurs due to leakage of pancreatic enzymes into systemic circulation and subsequent fat necrosis. Surgical drainage of pancreatic duct is often curative.

Background

PPP syndrome is typically a triad of pancreatitis, panniculitis and polyarthritis. The basic pathology is the leakage of pancreatic enzymes into the systemic circulation leading to fat necrosis in the subcutaneous tissue, bones and joints. The diagnosis usually evades the presenting clinician, most often a physician or orthopaedician, resulting in multitude of expensive investigations and ineffective therapies. The clinical masquerades include disparate types of vasculitis, arthritis or sarcoidosis. The pancreatic ductal leakage occurs due to either pancreatitis or pancreatic malignancies with a mortality rate of 25% or 75%, respectively. Once accurately diagnosed, surgical management of pancreatic ductal drainage in chronic pancreatitis and surgical resection for pancreatic malignancy can be curative. Here, we present a case of PPP syndrome due to chronic pancreatitis successfully treated surgically.

Case presentation

A young man in his early 30s, manual labourer by profession, presented with intermittent high-grade fever, chills and rigours and abdominal discomfort of 10 days duration. He additionally had complaints of joint pains and swelling involving both knee joints, left wrist and left elbow for the preceding 2 months. He reported associated painful nodules over right shin for a duration of 1 month prior to the day of presentation. Historical enquiry revealed habituation to alcohol consumption. At the time of presentation, he had undergone extensive investigations for his symptoms from local hospital inclusive of contrast-enhanced CT of chest and abdomen. Indeed, he had already been treated with azathioprine and rituximab on suspicion of sarcoidosis, with no symptomatic relief. He additionally was admitted for abdominal pain, approximately 6 months earlier, apparently for acute pancreatitis. Furthermore, he had undergone bilateral D/J stenting for bilateral renal calculi.

On examination, he was normotensive with a blood pressure of 135/87 mm Hg, heart rate of 92 beats per minute. Pallor was present. Patient was febrile with tenderness over right ankle as well as bilateral knee and elbow joints. His both knee joints had effusion. Right shin had a single erythematous tender nodule around 3 cm in diameter, within subcutaneous plane (figure 1).

Figure 1.

Tender nodule over right shin due to panniculitis.

Left calf was swollen and tender. Abdominal examination revealed minimal epigastric tenderness. Rest of systemic and chest examination was unremarkable.

Investigations

At the time of admission, patient had elevated total leucocyte counts (14 300/mL) and C reactive protein (20 mg/L), yet normal procalcitonin (0.27 µg/L). Liver function tests, serum electrolytes and renal function test were within normal limits. Rheumatoid factor (negative), antinuclear antibody (negative) and IgE (156 UI/mL) performed in view of joint pain and swelling were normal. Serum amylase (1450 U/L) and serum lipase (296 U/L) were elevated, prompting a clinical diagnosis of acute pancreatitis. Serum angiotensin-converting enzyme (ACE) was 15.70 U/L, which further ruled out granulomatous pathology. A contrast-enhanced multiphase abdominal CT was repeated, which demonstrated calcification of uncinate process of pancreas with minimal interstitial oedema and multiple bilateral renal calculus along with few enlarged mesenteric lymph nodes. Doppler of lower limbs ruled out deep venous thrombosis but revealed bilateral bakers cyst (left>right) along with a 17×2×3 cm collection in intermuscular plane, extending from left popliteal fossa to the middle third of the leg. MRI of both knees revealed synovial thickening with enhancement and significant effusion—suspicious of synovitis due to abnormal marrow signals and absent cortical collection (figure 2A and B). Furthermore, joint space fluid aspiration was done, which showed visibly purulent fluid but on cytology, only inflammatory cells without atypia were seen. Blood cultures and synovial fluid/effusion cultures were negative for gram-positive, gram-negative and acid-fast bacilli. Wet mount of synovial fluid aspirate showed lipid crystals (figure 3), and skin biopsy from erythematous lesion over the right shin revealed enzymatic fat necrosis (figure 4).

Figure 2.

(A) MRI knee lateral view: synovial thickening, minimal joint effusion, marrow abnormality all suggest inflammation. (B) MRI knee anteroposterior view.

Figure 3.

Synovial fluid aspirate showing lipid crystals composed of cholesterol and triglycerides, appreciated as microspherules, which polarised with a Maltese cross appearance (200× magnification).

Figure 4.

(A) Skin biopsy from right shin shows changes in subcutaneous fat. The lobules show fat necrosis in the form of enlarged ghost-like fat cells, eosinophilic amorphous material within the fat spaces and calcification seen as basophilic deposition (100×). (B) Skin biopsy from right shin shows changes in subcutaneous fat. The lobules show fat necrosis in the form of enlarged ghost-like fat cells, eosinophilic amorphous material within the fat spaces and calcification seen as basophilic depositio (400×).

Differential diagnosis

Infective aetiology was the initial provisional diagnosis in view of elevated inflammatory markers and polyarthritis. However, persistent symptoms despite antibiotic administration and negative cultures ruled out infection. Erythema nodosum and polyarthritis suggested the possibility of autoimmune disease. However, in our patient, ANA and rheumatoid factor were normal. Moreover, there was a lack of response to steroids. Sarcoidosis was next considered. Although a normal CT chest, normal ACE levels and absence of uveitis excluded sarcoidosis, a therapeutic trial with rituximab and azathioprine was given from a local hospital on strong clinical suspicion. Lipid-rich synovial fluid aspirate from the knee joint was the first clue to the presence of enzymatic necrosis. Histopathology from right leg skin lesion showing panniculitis confirmed lipase overactivity. The presence of biochemical and radiological pancreatitis completed the diagnosis of PPP syndrome.

Treatment

Once clinical suspicion of PPP syndrome was made, we re-evaluated the patient with CT abdomen to assess the pancreas, which showed diffuse parenchymal calcification in the uncinate process, along with mild atrophy of head and uncinate process (figure 5). Pancreatic duct appeared mildly dilated measuring 2.4 mm. Body and tail of pancreas were normal. There were no intraductal

Figure 5.

CT showing pancreatic uncinate process calcification.

calculi or strictures. Suspicious segmental thrombosis of posterior division of right portal vein was noted (figure 6). Patient subsequently underwent pancreatic drainage and head coring (Frey’s procedure). Intraoperatively, a firm pancreas was felt, with calcifications in the uncinate process and head of pancreas. A pseudocyst in the uncinate process fistulising into a small tributary of portal vein was visualised. The suspected pseudocyst was densely stuck to superior mesenteric vein (SMV) in the SMV-uncinate groove. After excision of pseudocyst and ligation of the fistula, intraoperative serum amylase and lipase dropped from 686 U/L and 774U/L to 431 U/L and 375 U/L, respectively. Patient was managed with adequate supportive care, and he was discharged after 13 days.

Figure 6.

CT showing partial thrombosis of junction of splenic and superior mesentric vein.

Outcome and follow-up

Patient was followed up on outpatient basis. He had complaints of persistent joint swelling and tolerable pain for a period of 3 months postoperatively. No new skin lesions were recorded. Inflammatory markers gradually reduced to an optimal level and patient improved symptomatically over the next 4 months. During review at 4 months following surgery, the patient reported resumption of work as a manual labourer.

Asymptomatic incisional hernia was discovered 1 year following surgery for which patient has sought no further management.

Discussion

Pancreatic panniculitis seen in 2–3% of patients with pancreatitis was first described by Chiari in 1883.¹ In 1908, Berner described the much rarer triad of pancreatitis, panniculitis (subcutaneous tissue inflammation) and polyarthritis often referred to as ‘PPP syndrome’. English articles published between September 2009 and January 2019 were reviewed using the key words ‘pancreatitis’, ‘panniculitis’ and ‘arthritis’. So far, 32 cases have been published in the English literature.²

PPP syndrome is now established to be the outcome of direct secretion of pancreatic enzymes into the bloodstream causing systemic fat necrosis especially in subcutaneous fat, tissue, bones and joints.³ The level of serum lipase does not correspond with the severity of pancreatitis but corresponds to the extent of extra-pancreatic fat tissue necrosis. Patients who develop pancreatic panniculitis usually present with tender, oedematous, erythematous to brown, subcutaneous nodules on the lower legs with the tendency for spontaneous ulceration. Lesions tend to exude a viscous, yellow-brown, oily substance that represents liquefactive necrosis of enzymatic fat in subcutaneous tissue.^{4 5} These nodules show resolution when the inflammatory episode of the pancreas regresses. It is also noted that subcutaneous nodules in patients with pancreatic carcinoma tend to be more chronic with frequent recurrences, ulceration and involvement of cutaneous areas beyond the lower extremities. In rare instances, pancreatic panniculitis is associated with necrosis of the abdominal fat, bone marrow fat, pleural effusions, mesenteric thrombosis and leukemoid reaction.⁶ One case report described a patient with pancreatic panniculitis secondary to pancreatic carcinoma developing a wood-like induration of the fingers as a consequence of an associated fasciitis.⁶

Pancreatic panniculitis typically demonstrates features of lobular panniculitis with intense necrosis of adipocytes. These necrotic adipocytes with no nuclei and finely granular and basophilic material in the cytoplasm due to calcification are known as ‘ghost adipocytes’. This liquefactive necrosis of adipocytes may manifest as spontaneous discharge of oily brown material, often mistaken as ‘pus’. From a pathological stand point, immunohistochemical demonstration with anti-lipase monoclonal antibodies within the necrotic adipocytes confirms the presence of pancreatic lipase in subcutaneous plane.⁷

In patients with PPP syndrome, arthritis can occur due to either periarticular fat necrosis or direct extension from the subcutaneous fat necrosis to the adjacent joint space. Most joint involvement is polyarticular, involving mainly the foot, ankle, hand or wrist joints. On aspiration, the involved joint fluid often shows viscous and creamy to yellowish material on gross appearance, mimicking pus.⁸ However, culture negativity and microscopy demonstrating positively birefringent lipid crystals of fat globules will confirm absence of pus. Furthermore, biochemical fluid analysis for lipids will show high cholesterol and triglyceride and reaffirm the diagnosis.⁸

An early diagnosis of PPP syndrome is difficult when joint involvement or panniculitis dominates with few symptoms of pancreatitis or vice versa. Joint involvement usually follows its own course, without any response to treatment with non-steroidal anti-inflammatory drugs, steroid or immunosuppressants. Due to its multifarious presentation, delay occurs in diagnosis and treatment of the underlying pancreatitis, thus leading to significant mortality.⁵ In addition, osteoarticular involvement as explained can cause permanent disability, leading to significant morbidity.⁸ The syndrome can precede, coincide or succeed the pancreatic symptoms. PPP syndrome can present at any age, but usually occurs in middle-aged men with significant history of alcohol abuse.^5–8 Main aetiological factors include—acute or chronic pancreatitis, pancreatic carcinoma, neuroendocrine carcinoma, insulinoma, abdominal trauma or pancreatic duct stenosis.^{4 5} Some authors have noted the presence of a pseudocyst, while others described a fistula between the pseudocyst and the SMV.^3–5 These fistulas are tiny and difficult to visualise in preoperative imaging. The presence of mesenteric vein thrombosis, plausibly an aftermath of profound inflammation, has frequently been associated with the diagnosis. This finding in a patient with suspected PPP syndrome should probably lead to surgical exploration, irrespective of presence or absence of symptoms of pancreatitis. It is important to emphasise that in most cases, the abdominal symptoms were mild or absent, despite high levels of lipase. Treatment of PPP syndrome is primarily directed to the underlying pancreatic disease. In spite of the varied features of presentation, if diagnosed early, patients can experience complete resolution of the symptoms when the pancreatic anomaly is surgically corrected.⁵

Learning points.

• Pancreatitis, panniculitis and polyarthritis (PPP) syndrome is a rare triad presenting with pancreatitis, panniculitis and polyarthritis.

• Patients often approach a physician (due to fever, tender skin nodules) or a surgeon (due to abdominal pain) or an orthopaedician (due to joint pains) and evades diagnosis.

• Lobular panniculitis, showing coagulative necrosis of the adipocytes, leading to typical ghost adipocytes, is a clue to diagnosis.

• Diagnosis can be clinched by lipid-rich synovial fluid, hyperamylasaemia and abdominal cross-sectional imaging demonstrating pancreatic pathology, either chronic pancreatitis or pancreatic malignancy, that caused the enzymatic leak into systemic circulation.

• Surgical drainage of pancreatic duct in chronic pancreatitis or resection in case of pancreatic malignancies can be curative.

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