MRI features of pancreatitis, panniculitis, polyarthritis and the fourth p: The “polka dot sign.” A case series and imaging review

Abstract

Pancreatitis, Panniculitis and Polyarthritis (PPP) syndrome is a poorly understood systemic illness that will initially present with pancreatitis followed by debilitating arthralgia and cutaneous manifestations. We present the largest descriptive case series known to date of 3 patients with 5 MRI’s diagnosed with PPP syndrome. In each case, a detailed review of the Magnetic Resonance Imaging (MRI) features of PPP syndrome are discussed with the introduction of a descriptive “polka dot sign.” Of the 5 joints evaluated, we found the predominant extra-pancreatic imaging features in PPP syndrome to be the extra-articular manifestations including panniculitis, bone marrow edema, enhancing osteitis and the “polka dot sign.” Mild to moderate inflammatory changes with joint effusion, synovitis and tenosynovitis may be present, although they will typically be a lesser feature. While the term “polyarthritis” still applies, we have found the name to be somewhat misleading as typical imaging features of inflammatory arthritis are not the predominant findings. On skin biopsy, the presence of “ghost cells” are diagnostic of this rare illness. Medical professionals should feel comfortable with the characteristic imaging manifestations of PPP syndrome in the context of pancreatitis.

Introduction

Pancreatitis, Panniculitis, and Polyarthritis (PPP) syndrome is a rare clinical triad incited by pancreatic enzyme dysfunction. The resultant pro-inflammatory state promotes adipocyte lipolysis and panniculitis with fat embolization leading to bone infarction and osteitis [[1], [2], [3], [4], [5], [6], [7], [8], [9]]. Concomitant polyarthralgia is believed to stem from the extension of inflammation into adjacent joints and bones.

Due to the varied clinical presentation, typically seen in critically ill patients, PPP syndrome is frequently underdiagnosed, with fewer than 70 cases reported worldwide [[10], [11]]. Among the reported cases, only a limited number include a detailed evaluation of the magnetic resonance imaging (MRI) features, which can serve as a valuable adjunct diagnostic tool to aid in early recognition and appropriate management [1,10,12].

Within the PPP triad, pancreatic insult, most commonly pancreatitis, remains the primary inciting process. Panniculitis may present clinically and on MRI, with biopsy showing characteristic “ghost cells” [13]. Polyarthritis, however, is less defined, encompassing both intra-articular and extra-articular features. This paper emphasizes that the predominant “arthritis” manifestations in PPP syndrome are extra-articular, including bone infarctions, osseous edema and osteitis. Intra-articular inflammatory changes such as effusion, synovitis and tenosynovitis are less prominent [[14], [15], [16]]. Thus, while the “polyarthritis” nomenclature still applies, it may be somewhat misleading, as typical findings for inflammatory arthritis are a lesser feature compared to the extra-articular manifestations; of which clinicians and radiologists should be aware. This case series also introduces a novel MRI descriptive feature termed the “polka dot sign,” characterized by diffuse punctate intramedullary T1 hypointense foci, which are distinct from the typical serpiginous T1/T2 hypointense signal changes seen with classic bone infarctions.

Case presentations

Case1

A 60-year-old male with alcoholism and chronic pancreatitis presented with epigastric pain, emesis, elevated WBC count of 11.7 u/L (N: 3.4-9.6) and elevated lipase of 4230 u/L (N: 13-60). Abdominal/pelvic CT demonstrated acute pancreatitis with a 1.4 cm pseudocyst communicating with the main pancreatic duct. Abdominal US also demonstrated acute calculous cholecystitis with extra-hepatic biliary dilatation. An ERCP revealed a biliary stricture resulting in sphincterotomy and common bile duct stent placement, followed by cholecystectomy and endoscopic ultrasound revealing a small peripancreatic fluid collection. Pulmonary, splenic and right popliteal vein thrombi were also found. The patient clinically improved and was discharged but returned 2 months later with bilateral ankle/foot pain for 2 days. Painless erythematous nodules on both of his lower extremities and raised hyperemia along the ulnar aspect of his right wrist raised suspicion for crystalline arthropathy (Fig. 1). Ankle MRI demonstrated multifocal bone marrow edema (BME), osteitis, “polka dot sign” and panniculitis (Fig. 2). Subsequent calf skin punch biopsy demonstrated lobular pannicular neutrophilic infiltration and fat necrosis with characteristic ghost cells, consistent with PPP syndrome. Treatment addressing the underlying cause of pancreatitis was recommended with subsequent stenting of a ventral pancreatic duct stricture and pseudocyst drainage. There was marked symptomatic improvement, and our patient was discharged shortly thereafter.

Fig. 1.

Case 1: Medical photographs of the right ankle and bilateral feet (A) depicting scattered erythematous nodules throughout both lower extremities (white arrows).

Fig. 2.

Case 1: MRI, Sagittal T1 of right ankle (A) depicting innumerable T1 hypointense foci throughout the calcaneus and cuboid consistent with a “polka dot” sign (black circles). Case 1: Sagittal post gadolinium fat saturated Spoiled Gradient Echo (Post Gd FS SPGR) of the right ankle (B). Enhancing osteitis throughout the posterior calcaneus and cuboid (white circles).

Imaging review- case 1

Ankle MRI: (Fig. 2 A and B)

There was moderate calcaneocuboid BME, with mild to moderate enhancing osteitis on a background of diffuse T1 hypointensities consistent with the “polka dot sign” (Fig. 2 A and B). There was no serpiginous morphology of bone infarcts. Erosions, synovitis, tenosynovitis and effusions were absent. Panniculitis, with enhancing soft tissue signal changes were present about Kager’s fat pad and the lateral malleolus. No significant osteoarthritis was present.

Forefoot MRI: (Figs. 3 A, B, C, and D)

Fig. 3.

Case 1: MRI, Coronal T1 of the right forefoot (A) depicting innumerable T1 hypointense foci throughout the 5th metatarsal consistent with the “polka dot” sign (white oval). Case 1: MRI, Coronal T2 FS of the right forefoot (B,C). White arrows depict scattered intraosseous edema throughout the 5th metatarsal (B), 1st metatarsal and proximal 1st phalanx (C). Open arrow depicts a small 1st MTP joint effusion (C). Case 1: MRI, Coronal Post Gd FS SPGR of the right forefoot (D) with black ovals highlighting enhancing osteitis throughout the 1st metatarsal and proximal first phalanx. Curved arrow depicts moderate enhancing synovitis of the 1st MTP joint (D).

There was advanced BME and enhancing osteitis with diffuse “polka dot sign” in the bones of the 1st and 5th rays, (Figs. 3 A, B, C, and D). There was mild-moderate intraosseous edema of the 1st metatarsal head and entire 1st proximal phalanx with moderate enhancing osteitis (Figs. 3 C and D). Serpiginous bone infarcts and erosions were absent. There was mild enhancing tenosynovitis of the 1st and 5th ray flexor tendons. There was moderate enhancing synovitis at the 1st and 5th metatarsophalangeal (MTP) joints with a trace 1st MTP joint effusion (Figs. 3 C and D). Mild 1st MTP and advanced 5th toe edematous enhancing soft tissue panniculitis was present. Throughout the forefoot, only mild osteoarthritis was present at the 1st MTP joint.

Case 2

A 46y/o male with seronegative rheumatoid arthritis (RA), alcoholism and recurrent pancreatitis presented with abdominal and right ankle pain. Labs demonstrated elevated amylase of 2083 u/L (N: 30-110) and lipase of 4772 u/L (N: 13-60). Abdominal CT and MRCP demonstrated acute on chronic pancreatitis, left hepatic lobe abscess, splenic and portal vein thrombosis. MRI of the right ankle depicted panniculitis, “polka dot sign” and serpiginous bone infarcts in a background of BME and osteitis. His arthralgia was initially attributed to his RA although the imaging findings were atypical for classic inflammatory arthritis. He was receiving longstanding steroid therapy for treatment of RA. The patient clinically improved and was discharged shortly after, but later returned with multiple painful nodules on his upper and lower extremities (Fig. 4), and bilateral knee joint effusions. He underwent knee joint aspiration which was negative for infection. Biopsy of right ankle and hip skin nodules revealed lobular panniculitis with fat necrosis and neutrophilic infiltrates. A diagnosis of PPP syndrome was then made. He completed a 6-week course of antibiotics for hepatic abscess and was placed on anticoagulation for portal vein thrombosis, but was lost to follow up.

Fig. 4.

Case 2: Medical photographs of the right ankle (A) and bilateral legs and (B) depicting scattered erythematous nodules throughout both lower extremities (white arrows).

Imaging review- Case 2

Ankle MRI: (Fig. 5 A, B and C; Fig. 6 A, B, C and D)

Fig. 5.

Case 2: MRI, Sagittal T1 of the right ankle (A) depicting scattered T1 hypointense foci throughout the calcaneus consistent with the “polka dot” sign (white circle). Sagittal T2FS MRI of the ankle (B) showing moderate calcaneal bone marrow edema (white circle) with superimposed serpiginous morphology of bone infarcts (white arrows). Sagittal Post Gd FS SPGR (C) demonstrating enhancing osteitis through the calcaneus (white circle).

Fig. 6.

Case 2: MRI, Axial T1 of the distal tibia at the ankle (A) depicting serpiginous morphology of typical bone infarcts (white arrows). Axial T1 (B) and Post Gd FS SPGR (C) of the hindfoot with scattered T1 hypointensities throughout the calcaneus consistent with the “polka dot sign” (white oval-B) on a background of enhancing osteitis (black oval-C) and superimposed serpiginous morphology of bone infarcts (white arrows-B). Black arrowhead (C) depicts peroneus longus enhancing tenosynovitis. Curved black arrow (C) demonstrates enhancing panniculitis. MRI, Coronal Post Gd FS SPGR of the right ankle (D) depicts enhancing osteitis in the lateral and medial malleoli (open arrow).

There was mild to moderate calcaneal BME with moderate enhancing osteitis on a background of the “polka dot sign” (Fig. 5 A, B, C; Fig. 6 B and C). There was moderate BME and enhancing osteitis in the lateral malleolus, and to a lesser extent, the distal tibia and medial malleolus (Fig. 6 D). Serpiginous bone infarcts were primarily seen in the calcaneus (Fig. 5 B, Fig. 6 A and B), but also in the lateral malleolus, medial malleolus and distal tibia (Fig. 6 A and B). Erosive changes were absent. There was panniculitis with advanced enhancing soft tissue signal changes and mild enhancing peroneus longus tenosynovitis (Fig. 6C). A moderate tibiotalar joint effusion with moderate enhancing synovitis was present.

Case 3

A 32y/o male with quadriplegia and renal transplantation on chronic immunosuppression presented with abdominal pain and sepsis from a wound infection after recent cholecystectomy and ventral hernia repair. Pertinent labs included elevated WBC count of 26 u/L (N: 3.4-9.6), elevated lipase of 9100 u/L (N: 13-60), increased ESR of 95 mm/h (N: 2-12) and CRP of 163.1 mg/L (n < 8). PT was prolonged to 21.4 sec (N: 9.4-12.5). CT abdomen/pelvis demonstrated an anterior abdominal wall peri-incisional abscess, portal vein thrombus and gallstone associated pancreatitis. The patient also endorsed bilateral lower extremity pain and joint swelling for 1 week, with a new 1 cm nodular right calf lesion. He also had pain and swelling in his left elbow, with negative infectious or crystalline aspirate. Subsequent elbow and knee MRI’s demonstrated panniculitis, BME, osteitis, “polka dot sign” and serpiginous bone infarcts. Small knee and moderate elbow joint effusions with mild synovitis were also noted. Aspiration of a small knee joint effusion demonstrated cloudy fluid, negative for infection. Calf and hip skin biopsies revealed lobular panniculitis, lending to a diagnosis of PPP syndrome. This patient unfortunately clinically declined and passed away shortly thereafter.

Imaging review- Case 3

Elbow MRI: (Fig. 7 A and B)

Fig. 7.

Case 3: MRI, Sagittal T1 of the elbow (A) shows subtle T1 hypointensities throughout the distal humerus consistent with a “polka dot” sign (white circle). MRI, sagittal T2 FS of the elbow (B) depicts distal humeral bone marrow edema (black circle).

There was moderate distal humeral BME, mild enhancing osteitis and mild “polka dot sign" (Fig. 7 A and B). There was mild-moderate distal humeral and olecranon marrow edema. A small serpiginous infarct was present in the trochlea. Erosions and tenosynovitis were absent. There was a moderate elbow joint effusion with mild enhancing synovitis. Mild enhancing panniculitis about the elbow was present.

Knee MRI: (Fig. 8 A and B)

Fig. 8.

Case 3: MRI, Sagittal T1 of the knee (A) depicts scattered T1 hypointensities throughout the proximal tibia consistent with the “polka dot” sign (white circle). MRI, Sagittal Post Gd FS SPGR (B) demonstrates prominent enhancing osteitis throughout the proximal tibia (black circle) and small knee joint effusion with mild enhancing synovitis (white curved arrow).

There was moderate proximal tibial BME, moderate enhancing osteitis and mild “polka dot sign” (Fig. 8 A and B). Mild intraosseous BME with enhancing osteitis was present in the distal femur, proximal tibia and patellar apex (Fig. 8 B). Small serpiginous bone infarcts were present within the proximal tibia, distal femur and patellar apex. There were no erosions, or tenosynovitis. A moderate knee joint effusion with mild enhancing synovitis was present (Fig. 8 B). Mild enhancing panniculitis was present about the knee.

Imaging summary

The imaged regions included the ankle and forefoot in patient 1, the ankle in patient 2, and the elbow and knee in patient 3. Moderate to advanced bone marrow edema, enhancing osteitis and the “polka dot sign” were the predominant imaging features in all patients. Typical serpiginous bone infarcts were present in 3/5 (60%) MRI’s. Mild tenosynovial fluid was present in 1/5 (20%) MRI’s. No patient had moderate to advanced lobular tenosynovial fluid. Mild enhancing tenosynovitis was present in 2/5 (40%) MRIs. Synovitis was present in 4/5 (80%) joints, being moderate in 2/5 (40%) MRIs and mild in 2/5 (40%). Joint effusions were present in 4/5 (80%) MRIs with moderate sized effusions in 3/5 (60%) and a small effusion in 1/5 (20%). Erosions and inflammatory enthesitis were absent in all patients. Minimal signs of osteoarthritis were present in 1/5 (20%) MRI’s, located at the 1st MTP joint, a typical site of osteoarthritis. All patients had multifocal osseous involvement with polyarthralgia.

Panniculitis was a universal finding, manifested as enhancing soft tissue changes around the affected appendicular osseous structures, with 2/5 (40%) being advanced, 2/5 (40%) being moderate and 1/5 (20%) being mild. No truncal lesions were identified.

Another ubiquitous imaging finding was venous thrombus, with portal thrombus seen in all patients and splenic thrombus identified in 2/3 (66%) patients. Pulmonary emboli and DVT were identified in 1/3 (33%) patients. Pseudocysts (2/3, 66%) and abscess (1/3, 33%) were also present in this cohort.

Discussion

PPP syndrome remains a debilitating triad with a mortality rate of up to 24% which may go under-diagnosed unless key clinical and imaging features are promptly recognized [1,10,11,17,18]. In line with this cohort, PPP is most commonly observed in middle-aged males, typically peaking in the fifth decade of life [1,10,11]. Chronic pancreatitis is the most frequent inciting process, though other pancreatic insults, including malignancy, ischemia, trauma, and pancreatic fistulas have been reported [11].

The pathophysiology of PPP is thought to result from pancreatic enzymatic leakage (including amylase, lipase, trypsin and phospholipase A) into the systemic circulation [[7], [8], [9], [10], [11]]. This leads to adipocyte lipolysis, fat embolization to the skin and joints, and subsequent ischemia and inflammation. Pancreatic enzyme levels correlate with extra-pancreatic manifestations, as seen in our cohort, where all patients had pancreatic enzyme levels 5-10 times above normal [2,12]. An interesting universal finding in this cohort was venous thrombosis, with all patients showing portal thrombosis, and a majority having splenic thrombus. It is conceivable that large vessel thrombosis predisposes to aberrant pancreatic enzyme circulation, leading to the extra-pancreatic manifestations. However, thrombosis may be the sequelae of a pro-inflammatory state from underlying pancreatic dysfunction. In either case, the presence of thrombus may serve as a useful diagnostic adjunct.

This case series introduces a novel MRI descriptive feature seen in all patients termed the “polka dot sign,” characterized by diffuse punctate intramedullary T1 hypointense foci (Figs. 2A, 3A, 5A, 6B, 7A and 8A). Although similar features are seen in hematologic conditions like myeloma, leukemia or hemoglobinopathies (eg, sickle cell), the authors posit that the imaging appearance in PPP results from evolving liquefactive necrosis in the bone marrow, serving as a valuable imaging clue for early recognition [19,20]. The bone marrow changes in PPP are important to recognize to avoid unnecessary work up for osteomyelitis.

Panniculitis, joint, and osseous symptoms are usually seen in the small and medium sized appendicular skeleton, predominantly in the lower extremities, although the upper extremities may also be involved. Panniculitis presents as painful, or nonpainful erythematous nodules that may spread if untreated [2,21]. MRI will commonly reveal T2 intermediate to hyperintense, enhancing soft tissue changes. Skin punch biopsy reveals neutrophilic infiltrate surrounding necrotic adipocytes with absent nuclei, termed “ghost cells,” which are diagnostic of pancreatic panniculitis [22,23].

While most patients will present with symptomatic pancreatitis, polyarthralgia may be the presenting symptom in 1/4 of patients, although it is often overlooked [11]. The commonly affected joints include the ankles, knees, wrists and MCP joints; with less frequent involvement of the elbows, PIP and DIP joints [1,10,11]. Joint involvement may prompt extensive rheumatologic workups, as physical exam findings can mimic septic, inflammatory or crystalline arthritis [1,[24], [25], [26], [27]]. The singular patient in our cohort with history of seronegative inflammatory arthritis was not found to have clinically active disease during their PPP course. Synovial fluid analysis often reveals increased lipid content with liquefied lipid crystals and histopathology showing necrotic fat and connective tissue [1]. Furthermore, joint pathologic studies have demonstrated low levels of lymphocyte and macrophage infiltration, as opposed to increased infiltrates typically seen in inflammatory arthritis [28]. This is concordant with a mild to moderate inflammatory response seen at the level of the joint in the current cohort.

MRI findings in this cohort emphasize the dominance of extra-articular manifestations which is important to recognize as the typical imaging morphology of inflammatory arthritis will not be all encompassing [[14], [15], [16]]. MRI demonstrated only mild to moderate synovitis, small to moderate sized joint effusions and mild, if any, tenosynovitis. More pronounced were the extra-articular manifestations consisting of moderate to advanced BME, enhancing osteitis and the “polka dot sign” which were present in all patients. Noteworthy, peri-articular bone marrow edema and osteitis were rarely centered at the joint space - a finding usually seen in septic or inflammatory arthritis - but rather occurred as diffuse intramedullary changes secondary to bone infarcts and presumed fat emboli extending away from the joint space. Classic serpiginous bone infarctions were completely absent in 2 MRIs suggesting that the absence of this feature does not exclude a PPP diagnosis.

Erosive changes were universally absent in our cohort, with no described marginal erosions in previous literature. In addition, intra-articular pre-erosive changes, such as inflammatory cysts or marginal BME/osteitis, were not present [25,26]. We believe that true inflammatory erosions are unlikely to occur in PPP as the inflammatory process is primarily concentrated in the joint fluid rather than the synovio-entheseal complex, and therefore not robust enough to incite secondary joint erosions, or have inflammatory enthesitis with periostitis [19,20,29]. While destructive bone changes, including moth-eaten, permeative or lytic appearances have been reported, these were not centered at the joint space and were believed to arise from bone infarctions and subsequent osseous destruction [[14], [15], [16],30]. However, some studies do suggest that prolonged intra-articular exposure to pancreatic enzymes may predispose to infections, contributing to osteo-necrotic changes in a small subset of patients [24].

Ultimately, while the “pancreatitis” and “panniculitis” components within PPP are relatively straightforward on cross-sectional imaging, the “polyarthralgia” aspect has been less well detailed in the literature. The current cohort highlights that the “polyarthralgia” in PPP syndrome is largely manifested as infarction, multifocal moderate to advanced edema and osteitis; with a smaller inflammatory component at the joint space, manifested as mild to moderate effusion and synovitis. Treatment of PPP involves addressing the underlying pancreatic dysfunction and providing supportive care. In some instances, NSAID and steroid therapy have been used for short term symptomatic arthritis relief, but consensus management dictates correcting the underlying cause of pancreatitis to prevent recurrence [1,2]. A multidisciplinary team approach remains essential for diagnosis and management of this rare entity.

Conclusion

PPP syndrome is characterized by complex, multifocal imaging findings, and its management necessitates a multidisciplinary approach. The presence of arthralgias in a patient with pancreatitis often leads to an extensive work-up for infectious, inflammatory or crystalline arthritis, and osteomyelitis. However, MRI is an invaluable tool that can highlight the dominant extra-articular features of PPP, including panniculitis, bone marrow edema, enhancing osteitis and the “polka dot sign”. Serpiginous morphology of bone infarcts may or may not be present. In addition, seemingly milder inflammatory changes at the joint with effusion and synovitis may also be seen, although will typically be a lesser feature in comparison to the extra-articular manifestations. Radiologists and clinicians should be familiar with the characteristic imaging features of PPP, and consider the diagnosis when arthralgias and soft tissue swelling are present in the setting of pancreatitis.

Patient consent

Written informed consent was obtained from all 3 patients for publication of the details of their medical cases and any accompanying images. Efforts have been made to ensure anonymity. The manuscript does not contain clinical studies or patient data.