Pancreatitis,panniculitis,polyarthritis syndrome as an initial manifestation of metastatic pancreatic cancer in a breast cancer patient: Importance of early recognition and multidisciplinary management: A case report

Abstract

Pancreatitis, panniculitis, and polyarthritis syndrome is a rare extrapancreatic triad associated with pancreatic disease and occasionally malignancy. We report a 51-year-old woman with prior hormone receptor-negative, human epidermal growth factor receptor 2-positive breast invasive ductal carcinoma (bilateral mastectomy, adjuvant trastuzumab/pertuzumab, radiation) who developed abrupt painful erythematous nodules of both legs and progressive polyarthralgia of the hands, knees, and ankles. Symptoms were initially treated as inflammatory rheumatic disease with systemic corticosteroids and disease-modifying therapy without benefit, leading to severe functional decline. Imaging later revealed a large hepatic mass; biopsy confirmed metastatic pancreatic acinar cell carcinoma, unifying the presentation as pancreatitis, panniculitis, and polyarthritis syndrome. Coordinated multidisciplinary care, oncology-directed chemotherapy, interventional pain management, and psychological support, improved pain control and mobility. This case adds to the limited pancreatitis, panniculitis, and polyarthritis literature and highlights that absent gastrointestinal symptoms can delay diagnosis; early recognition and collaborative management are essential in malignant pancreatitis, panniculitis, and polyarthritis presentations.

Introduction

Pancreatitis, panniculitis, and polyarthritis (PPP) syndrome is a rare triad of extrapancreatic manifestations associated with pancreatic disorders, including pancreatic malignancy. ¹ The clinical manifestations of PPP syndrome include two distinct features: erythematous cutaneous nodules most commonly affecting the lower extremities, and osteoarticular swelling with inflammatory reactions secondary to intraosseous necrosis.^1,2 Both manifestations are postulated to result from high circulating levels of pancreatic enzymes. ² Nevertheless, the precise pathophysiology of PPP syndrome remains elusive. ³ Since accompanying gastrointestinal symptoms such as abdominal pain, nausea, or emesis are often minimal, there is often a delay in diagnosis or misdiagnosis of PPP syndrome, leading to increased risks of morbidity and mortality.^1–3 This is especially critical for patients with complex medical comorbidities, including a prior history of extrapancreatic malignancy, as the combination of painful cutaneous nodules and polyarthralgia could be attributed to other disease processes, potentially leading to suboptimal therapies and adverse outcomes. ⁴

We present a case report of PPP syndrome in a patient with a germline breast cancer gene (BRCA) mutation, previous history of breast cancer, estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-positive (HER2+), who first presented with lobular panniculitis and polyarthritis symptoms attributed to rheumatologic origins, and was subsequently found to have metastatic pancreatic adenocarcinoma. This case aims to raise awareness of two important clinical aspects of PPP syndrome to improve patients’ quality of life: early recognition of this rare clinical triad in cancer patients to direct definitive treatments, and prompt involvement of a multidisciplinary team for a comprehensive approach to ameliorate patients’ symptoms.

Case presentation

Case history and examination

A 51-year-old Caucasian female with a history of hormone receptor-negative, HER2+ on immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), stage II, intraductal carcinoma of the left breast, presented with an acute onset of painful erythematous lesions on the bilateral lower extremities, as well as pain in her hands, knees, and ankles, 4 years after receiving definitive treatment for her breast cancer. The patient was found to have a germline BRCA mutation upon diagnosis of her breast cancer. Staging CT-scan at the time showed that the breast cancer was localized to her left breast only, with no metastatic disease. She underwent bilateral mastectomies, followed by standard adjuvant chemotherapy with trastuzumab/pertuzumab and radiation therapy for her breast malignancy. Subsequent surveillance imaging and routine follow-up evaluations confirmed that there was no evidence of disease. The patient’s physical examination during her initial presentation was notable for erythematous lesions on the lower extremities, along with edema in the hands, knees, and ankles.

Investigations and treatment

Initial outpatient evaluation by her primary care provider suggested a rheumatological origin of her symptoms, specifically erythema nodosum secondary to inflammatory arthritis. Patient was referred to a rheumatologist and treated with corticosteroids, colchicine, folic acid, and methotrexate. Although the prednisone course provided modest improvement in reducing her joint swelling, the patient’s polyarthralgia persisted. After conferring with several dermatologists and rheumatologists for additional opinions, the collective consensus was that her bilateral lower-extremity lesions unequivocally exemplified the classic clinical phenotype of erythema nodosum. Invasive diagnostic procedures, including biopsies, were deemed unnecessary by the specialists for initial therapeutic recommendations, particularly given the patient’s pronounced reluctance to pursue any invasive testing or treatment modalities at that juncture. The patient was placed on several more courses of systemic steroid tapers and high-dose nonsteroidal anti-inflammatory drug (NSAID) therapy with varying degrees of short-term benefit to her symptoms. Her pain continued to worsen 3 months after initial presentation, leading to significant impairment of mobility and requiring evaluation in the emergency department (ED) for treatment of severe polyarthralgia.

During her emergent evaluation, the patient’s erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were significantly elevated at 97 mm/h and 17.5 mg/dL, indicating non-specific inflammation, but suggestive of a flare of her underlying rheumatologic diagnosis. At this juncture, the patient also disclosed an insidious onset and progressive exacerbation of abdominal pain over the preceding month, which she attributed to gastrointestinal effects from recent prolonged NSAID therapy alongside multiple courses of high-dose corticosteroids. Given these new symptoms, a CT abdomen/pelvis with contrast was performed in the ED to rule out acute abdominal processes. A large 12.5 cm right hepatic lobe mass and pancreatic tail lesion were incidentally found, suspicious for malignancy (Figure 1). Biopsy of the hepatic mass, along with biomarkers, indicated a pancreatic primary tumor, less likely metastatic disease from her prior breast cancer or primary hepatocellular carcinoma. Given the patient’s history of HER2-positive breast carcinoma, markers for breast differentiation and biomarkers were performed. GATA3, which is usually positive in breast carcinoma, was negative, and Her2 was also negative in the tumor from the liver, arguing against a metastasis from the patient’s prior breast primary. Heptatocellular markers were negative, and PAX8 was negative, arguing against a Müllerian primary. Trypsin was positive, raising the possibility of a pancreatic acinar carcinoma, which was later confirmed after the specimen was sent to pathology from her distal pancreatectomy. At this point, given the patient’s new metastatic cancer diagnosis, clinical priorities shifted from focusing on the rheumatologic condition to initiating urgent oncologic treatment.

Figure 1.

MR cholangiopancreatogram with and without contrast. A large 12.5 cm heterogeneous mass in the right hepatic lobe of pancreatic origin (yellow arrow) and a 3.3 cm mass in the pancreatic tail (red arrow): (a) axial view and (b) coronal view.

The patient’s lower extremity pain continued to be severe with further functional impairments, including a progressive decrease in mobility. Rheumatology was consulted and performed a right knee arthrocentesis, which showed an inflammatory effusion without any crystals. Cultures evaluating for infectious etiologies were all negative. Disease-modifying antirheumatic drugs and biologic therapy were considered, but ultimately deferred due to the potential negative impact these medications would have on the patient’s new metastatic cancer diagnosis and urgent need to initiate systemic cancer therapy. Advanced imaging evaluations were recommended to further delineate the etiology of her polyarthralgia; however, the diagnostic process was significantly impeded by the patient’s severe discomfort and inability to tolerate the requisite positioning for these modalities. Nevertheless, an MRI study of the patient’s left knee revealed no acute fractures but significant bone marrow lesions in the femur and tibia, along with rim-enhancing loculated fluid collections within the lateral and posterior compartment musculatures (Figure 2). Dermatology was consulted to re-evaluate the persistent painful erythematous cutaneous nodules. The team again concurred with the prior diagnosis of erythema nodosum. ESR and CRP continued to be elevated at this time, 87 mm/h and 8.4 mg/dL, respectively. While non-specific, these are typically elevated in erythema nodosum, especially during the acute phase of the inflammatory response. Unfortunately, both these markers may also be elevated in PPP syndrome, and do not correlate with the underlying etiology. Biopsy of the nodules was offered to the patient, but due to the psychological stressors of receiving a new cancer diagnosis, the patient declined biopsy and any further procedures. The oncology team suggested that inflammatory arthritis was likely secondary to high lipase secretion from paraneoplastic causes and felt that her symptoms would improve with targeted cancer-directed therapy.

Figure 2.

MRI of the left knee with and without contrast. Extensive bone marrow replacing lesions (yellow arrow) in the femur and tibia, large complex joint effusion, and extensive, rim-enhancing loculated fluid collections (red arrow) within the lateral and posterior compartment musculature: (a) sagittal view T2 FS, (b) sagittal view T1 PD, (c) coronal view T2 FS post contrast, and (d) axial view T2 FS.

A consultation with the pain management team was placed given the patient’s persistent severe pain and its impact on her mobility. During the evaluation, the patient rated her pain as 9/10 at its worst and 3/10 at its best on a numeric rating scale (NRS). The pain was primarily localized to her ankles and knees, non-radiating, and described as a constant, sharp, throbbing sensation that was aggravated by ambulation and any physical activities.

Her mobility and activities of daily living were significantly limited due to pain, necessitating the use of a walker for balance. Due to the initial concerns of her gastrointestinal symptoms being attributed to prolonged systemic NSAID and steroid use, the patient adamantly declined any medications from those classes. A multimodal regimen was recommended by the consulting team of pain specialists, including opioid therapy, acetaminophen, muscle relaxants, and neuropathic medications, which the patient tried but stated to be unhelpful.

During her hospitalization, inpatient chemotherapy was started with folinic acid, fluorouracil, and oxaliplatin. After initiation of chemotherapy, patient’s serum lipase levels were noted to decrease significantly from 1256 to 470 U/L. Amylase levels were consistently within the normal limits, ranging 40–60 U/L, as it can often occur in PPP syndrome, with systemic hyperlipasemia as the key diagnostic finding. Her pain had also finally started to improve, when it was previously minimally responsive to aggressive medical management. Given the coinciding pattern of improvement, the oncology team concluded that PPP was the likely cause of her severe polyarthralgia. Upon hospital discharge, the patient’s pain had improved moderately, and she was able to ambulate short distances with a walker.

One month after hospital discharge, the patient underwent an elective laparoscopic distal pancreatectomy and splenectomy. Although the exposure was noted to be difficult due to the enlarged left lobe of the liver and enlarged spleen, the surgical team was successful in dissecting off any adhesions from the targeted area on the distal pancreas and spleen. The specimens were sent to pathology, confirming the diagnosis of acinar cell carcinoma with clear surgical margins. Postoperatively, her serum lipase levels further decreased from 328 to a normal level of 14 U/L, and the edema in her lower extremities improved.

Patient was also referred to a gynecologist as part of her follow-up for the germline BRCA mutation. For the management of ovarian cancer risk, risk-reducing surgery was offered. After much deliberation, the patient ultimately underwent bilateral salpingo-ophorectomy 1 year later.

Outcome and follow-up

Postoperatively, the patient was referred to an outpatient pain specialist to evaluate persistent chronic pain in her bilateral lower extremities. The patient reported that while the pain had improved with recent cancer-targeted treatment, it had never completely resolved. At the time of hospital discharge after her surgery, the patient was instructed to take a combination of acetaminophen, pregabalin, duloxetine, methocarbamol, extended-release oxycodone, and hydromorphone as needed for breakthrough pain. However, she had self-discontinued most of her multimodal regimen and was only taking hydromorphone by the time she established care with the outpatient pain specialist. She endorsed progressive polyarthralgia predominantly affecting her lower extremities. Her chronic daily pain was rated on average 6–7/10 on NRS. Physical exam was notable for an antalgic gait, requiring a cane for assistance, but a walker was no longer needed. There was no longer any evidence of lower extremity cutaneous nodules, but significant pain was elicited in her bilateral ankles and knee joints with range of motion exercises and weight-bearing tasks (Supplemental Material).

The pain specialist discussed the patient’s non-compliance with her multimodal pain regimen prescribed upon discharge, which the patient attributed to the high pill burden, inefficacy of treatments recommended, compounded by psychosocial stressors related to her diagnosis of metastatic cancer and multiple comorbidities.

Further imaging studies were facilitated to evaluate the patient’s predominant and persistent symptoms in the bilateral lower extremities. Updated MRI studies of the right (Figure 3) and left knee (Figure 4) revealed improvement of loculated intramuscular fluid and edema but persistent intramedullary osteonecrosis affecting the femur, with progression of extensive osteonecrosis of the tibia compared to the prior study. MRI studies of the right (Figure 5) and left ankle (Figure 6) also revealed significant medullary osteonecrosis with subchondral fractures affecting the tibial plafond bilaterally.

Figure 3.

MRI of the right knee with and without contrast. Osteonecrosis of the entire visualized femur (yellow arrow), with normal muscle bulk and no significant effusion or loculated fluid: (a) sagittal view, IR, (b) coronal view, T2 FS, (c) axial view, T2 FS, and (d) axial view, T1 FS.

Figure 4.

MRI of the left knee with and without contrast. Demonstrates osteonecrosis involving the entire visualized tibia and a reduced focus of osteonecrosis in the femur (yellow arrow), with normal muscle bulk, significantly reduced effusion, and peri-muscular loculated fluid collections: (a) sagittal view, IR, (b) coronal view, T2 FS, (c) axial view, T2 FS, and (d) axial view, T1 FS.

Figure 5.

MRI of the right ankle with and without contrast. Demonstrates medullary bone osteonecrosis involving the entire visualized tibia, distal fibula, and talus (yellow arrow). Early degenerative/arthritic changes affect the tibiotalar and talonavicular articulations, with chondral loss and early subchondral cystic changes: (a) sagittal view, STIR, (b) sagittal view, T1, (c) coronal view, PD FS, and (d) axial view, T2.

Figure 6.

MRI of the left ankle with and without contrast. Demonstrates medullary bone osteonecrosis involving the entire visualized tibia (yellow arrow): (a) sagittal view, STIR, (b) sagittal view, T1, (c) coronal view, PD FS, and (d) axial view, T2.

While the cause of her avascular necrosis is unknown, the patient was treated with multiple courses of high-dose corticosteroids early on in her presentation. She denied any trauma throughout her disease course. The cumulative effects of corticosteroid therapy may have contributed to the development of this complication, leading to chronic pain in her bilateral lower extremities despite the resolution of the initial cutaneous nodules.^4,5 Several targeted interventions were discussed as the patient was non-compliant with her medication regimen and expressed reluctance to modify her behavior. Interventional options, including targeted joint viscosupplementation, genicular nerve thermal radiofrequency ablation, and peripheral nerve stimulation, were presented to the patient to consider, but the patient elected to defer all.

Given the occurrence of multiple significant medical events in a short span of time, including receiving a new metastatic cancer diagnosis and undergoing all its associated treatments, the patient developed a high degree of anxiety around medical appointments. A multidisciplinary team approach was implemented expeditiously in the outpatient setting, including involvement of Integrative Oncology, which offered psychosocial support for the patient and her family on an ongoing basis to mitigate the impact of recent stressors on the patient’s quality of life.

Discussion

There is a lack of robust clinical literature on systematic studies of PPP syndrome, with fewer than a hundred clinical reports documented worldwide.^5,6 Despite the rarity of PPP syndrome, it has a high mortality rate of more than 20%. While this patient survived, her quality of life has been negatively affected due to impaired functional capacity, limited mobility, and other sequelae from the chronic pain she has experienced. She is monitored closely by her oncology team and continues treatment with olaparib for her pancreatic cancer. It is important to be cognizant that PPP syndrome can manifest in acute and chronic pancreatic disorders, including malignancy, trauma, and ischemic abdominal pathologies.^2,6 Its pathophysiology remains to be clearly delineated, but available clinical data point to fat tissue necrosis in visceral organs, bones, and subcutaneous tissues mediated by drastic elevation of pancreatic enzyme levels, including lipase (primarily), amylase, phosphorylases, and trypsin, which mediate proinflammatory reactions in other body structures.^2,5,6 Lipase is typically markedly elevated and is the key diagnostic finding. Amylase may also be elevated, although lipase is generally more specific. These enzymes reach the circulation due to underlying pancreatic disease (acute or chronic pancreatitis, pancreatic carcinoma, or acinar cell carcinoma) and cause peripheral lipolytic activity leading to fat necrosis in subcutaneous tissues and joints. This condition can affect patients of all age groups, but it has a propensity to affect middle-aged males, especially those with a recorded history of alcohol abuse.^1,6

Given that pancreatic disorders most often present with gastrointestinal symptoms, the initial absence of these symptoms often leads to PPP syndrome being overlooked when patients present for workup with a focus on painful cutaneous panniculitis and polyarthritis.^1–5 The extrapancreatic manifestations of polyarthralgia and cutaneous lesions have many differential diagnoses, including those of infectious or rheumatological origin, leading to diagnostic challenges, especially when clinicians have no prior knowledge or experience in directing treatment for this rare condition.^3,7 Painful erythematous cutaneous panniculitis, occurring in 2%–3% of patients with pancreatic disorders, often precedes any gastrointestinal symptoms. ³ These cutaneous nodules are typically located on the extremities and are often misdiagnosed as erythema nodosum due to similar physical features.^5,6,8,9 However, treatment recommendations for the two pathologies vary considerably, with lobular panniculitis being poorly responsive to typical erythema nodosum therapies, including NSAIDs and systemic corticosteroids. To complicate the clinical picture further, there have been reports of lobular panniculitis in the setting of normal lipase levels. ³ Biopsy of skin lesions is indicated to identify histological features, including fat necrosis and “ghost” adipocytes that have lost their nuclei to the necrotic process, distinct in lobular panniculitis. ³

As the patient refused biopsy, it is unknown whether the erythematous cutaneous nodules on her lower extremities were from lobular panniculitis. In general, polyarthritis has a lower incidence compared to lobular panniculitis. Its manifestation is more commonly symmetrical and oligoarticular in nature, predominantly affecting the feet, ankles, and knees, but can also involve distal articular surfaces such as the wrists and hands.^2,3,6–9 The presentation of polyarthralgia with swelling could be misleading, redirecting clinicians to suspect inflammatory or infectious pathologies of de novo origin. Moreover, given that intraosseous necrosis can appear as lytic lesions on X-ray studies, these lesions may be suspected to be secondary to bony metastases, potentially leading to additional antineoplastic therapies. ⁷ Some reports have demonstrated that high levels of lipase were found in synovial fluids of patients affected by panniculitis and polyarthritis, along with evidence supporting that both adipocyte and pancreatic lipase are responsible for mediating this necrosis process.^10-12 It has been reported that more than 50% of patients who recovered from PPP syndrome suffered no permanent osteoarticular or cutaneous injuries, even though intraosseous necrosis can lead to substantial bony damage.^13,14 Furthermore, PPP syndrome generally carries a poor prognosis, with no consensus on a treatment algorithm except targeting the underlying primary pancreatic disorder. ¹⁴ Notably, the efficacy of palliative therapies directed at mitigating osteoarticular inflammation and pain is significantly diminished when underlying pancreatic etiologies are not treated definitively.^3,7-9

Additionally, anxiety and depression are common but frequently underrecognized psychological disorders associated with significant medical events, especially with metastatic cancer diagnosis. ¹⁵ Cancer-related pain therapies have evolved from a focus on symptom palliation to an integrative approach to encompass multidisciplinary strategies to improve patient outcomes and promote therapy adherence. ¹⁶

Conclusion

Misdiagnosis of PPP syndrome may occur throughout a patient’s clinical course, especially in a patient with complex pathology, including aggressive primary pancreatic malignancy. Despite the limited research available, it is important to emphasize early recognition of this rare clinical triad to minimize the impact of osseous complications leading to irreversible articular damage and to avoid delays in definitive therapy and pain palliation. Chronic pain generators in cancer patients, such as degenerative arthritis, secondary myofascial symptoms, and physical impairment, pose additional challenges for clinicians in accurately diagnosing and prescribing definitive therapy for PPP syndrome. Recognizing this rare but debilitating condition is crucial, as it can significantly impact patients’ daily activities and functional capacity both physically and psychologically. Therefore, it is imperative for medical teams to be cognizant of these challenges and promptly engage a multidisciplinary team. This group of relevant specialists, including experienced oncological pain specialists and psychological support, is essential to enhance compliance with prescribed therapies, reduce morbidity and mortality risks, and optimize outcomes with a multimodal cancer pain management regimen.

Supplemental Material

sj-docx-1-sco-10.1177_2050313X261438390 – Supplemental material for Pancreatitis, panniculitis, polyarthritis syndrome as an initial manifestation of metastatic pancreatic cancer in a breast cancer patient: Importance of early recognition and multidisciplinary management: A case report

Supplemental material, sj-docx-1-sco-10.1177_2050313X261438390 for Pancreatitis, panniculitis, polyarthritis syndrome as an initial manifestation of metastatic pancreatic cancer in a breast cancer patient: Importance of early recognition and multidisciplinary management: A case report by Sandra Sacks and Bi Mo in SAGE Open Medical Case Reports