BACKGROUND
Paraneoplastic syndromes, arising from malignant diseases, manifest across various organ systems, notably the musculoskeletal system. These syndromes are indirect effects of a distant tumor, mediated by humoral mechanisms, distinct from direct tumor invasion or metastasis. Diagnosing paraneoplastic syndromes poses a challenge, especially when malignancy is not yet evident. Carcinomatous polyarthritis (CP) is one such paraneoplastic syndrome, linked to bronchogenic carcinoma and other solid tumors. CP mirrors other polyarthritides, often preceding cancer diagnosis, making timely recognition crucial for initiating appropriate treatment for the underlying neoplasm.
This article delves into a case of migratory asymmetric polyarthritis, eventually diagnosed as advanced stage lung carcinoma and attributed to carcinomatous polyarthritis. Our objective is to provide a comprehensive guide to the differential diagnosis of inflammatory polyarthritis, focusing on CP, and outlining the distinguishing features from more common polyarthritis causes. We will also explore the pathophysiology and management strategies for CP.
CASE PRESENTATION
A 43-year-old male presented with a six-month history of migratory inflammatory asymmetric polyarthritis. Despite multiple visits to his primary care physician and treatments with nonsteroidal anti-inflammatory drugs (NSAIDs) and a short course of low-dose prednisone, he experienced no relief. At presentation, his primary complaints were left ankle and wrist pain, although he reported prior discomfort in various joints, including the left shoulder, right foot, right shoulder and elbow, and right knee. He described evening pain that frequently disrupted his sleep and denied any long bone pain. Recent symptoms included sweats and fevers, but no weight changes. His medical history was significant for coronary artery disease and peripheral vascular disease, diagnosed during pre-operative assessment for back surgery, and a substantial 90-pack-year smoking history. He reported no recent sore throat, rash, diarrhea, or urethritis, and no history of tick exposure.
Physical examination revealed a temperature of 37.0°C, respiration rate of 18 breaths per minute, heart rate of 80 beats per minute, and blood pressure of 129/64 mmHg. He appeared pale, mildly short of breath, and in significant pain distress. The lateral metatarsal region of the left foot and left wrist showed swelling and erythema. Range of motion was severely limited due to pain, and no clubbing was observed. The remainder of the physical exam was unremarkable.
Laboratory findings included a white blood cell count of 13.6 k/cumm, hemoglobin of 10.4 g/dl, and platelets of 439 k/cumm. A metabolic panel showed hyponatremia (119 mmol/l). Other electrolytes and renal function were normal. Alkaline phosphatase was elevated at 431 IU/l, SGOT at 55 IU/l, and SGPT at 71 IU/l. Erythrocyte sedimentation rate (ESR) was 106 mm/h, and C-reactive protein (CRP) was 115 mg/l. C3 and C4 levels were elevated at 203 mg/dl and 47 mg/dl, respectively. Rheumatoid factor was 89 IU/ml, while antinuclear antibody and hepatitis serology were negative. X-rays of the left wrist and both ankles showed no joint space narrowing, erosions, or periosteal reaction. Long bones were not imaged. Joint aspiration of the right ankle revealed moderate neutrophils (6–30 per high-powered field) without crystals, and Gram stain and cultures were negative.
Initial treatment with prednisone 40 mg daily and naproxen 500 mg twice daily provided minimal symptom relief. A chest x-ray revealed a new left hilar mass. Subsequent computed tomography of the chest showed hilar and mediastinal lymphadenopathy, left chest wall metastasis, and peritoneal carcinomatosis. Lymph node biopsy confirmed small cell lung carcinoma. Further imaging revealed diffuse osseous metastasis. His joint pain was then attributed to carcinomatous polyarthritis. Following two cycles of cisplatinum plus etoposide chemotherapy, his arthritic symptoms completely resolved. However, his overall health declined, and he passed away weeks later.
Alt text: Chest X-ray revealing a left hilar mass, a key finding in the diagnosis of lung carcinoma in a patient presenting with migratory arthralgia.
DIFFERENTIAL DIAGNOSIS OF MIGRATORY POLYARTHRITIS
Migratory polyarthritis is a common presenting symptom in primary care settings. Its broad differential diagnosis encompasses infectious etiologies, crystal-induced arthropathy, rheumatoid arthritis (RA), vasculitic syndromes, connective tissue disorders, and spondyloarthritides. Less frequent causes include metastatic disease and paraneoplastic syndromes like carcinomatous polyarthritis. Patient history and physical examination often guide the etiology, but overlapping features can complicate diagnosis. We will review the differential diagnosis of inflammatory polyarthritis, emphasizing the distinction of CP.
Common Causes of Migratory Polyarthritis
Infectious Arthritis: Bacterial arthritis, Lyme disease, and viral arthritides are important considerations. Bacterial arthritis is typically characterized by fever, abrupt onset, monoarthritis, purulent joint aspirate, and risk factors like IV drug use or immunosuppression. Lyme disease, while potentially presenting as asymmetric polyarthritis, can be ruled out with negative serology, lack of tick exposure, and absence of systemic symptoms. Viral arthritis, often associated with parvovirus B19 or hepatitis viruses, usually presents with a more acute and self-limiting course than CP.
Crystal-Induced Arthropathy: Gout and pseudogout are readily distinguished by joint aspiration and crystal analysis. The absence of crystals in the presented case effectively excludes these conditions.
Rheumatoid Arthritis (RA): RA is a prevalent inflammatory polyarthritis, but differentiating it from CP can be challenging, especially in older adults. RA typically presents with symmetric polyarthritis, often involving small joints of hands and feet, morning stiffness, and radiographic erosions over time. While CP can mimic RA, certain clinical features and investigations aid in differentiation, which we will discuss further.
Spondyloarthritides: Reactive arthritis and enteropathic arthritis are seronegative spondyloarthropathies considered in the differential. Reactive arthritis often follows urethritis or diarrhea caused by specific infections and may involve axial symptoms, mucocutaneous lesions, and uveitis. Enteropathic arthritis is associated with inflammatory bowel disease. The patient’s history, sterile joint aspirate, and lack of response to NSAIDs make infectious and seronegative arthropathies less likely in this case.
Less Common Causes: Paraneoplastic Syndromes and Carcinomatous Polyarthritis
Hypertrophic Osteoarthropathy (HOA): HOA, another paraneoplastic syndrome, involves oligoarthritis, digital clubbing, and periostitis of long bones. It commonly affects large joints symmetrically and is associated with bone tenderness. The absence of clubbing, long bone tenderness, and periosteal reaction on x-rays in our patient argues against HOA.
Vasculitic Syndromes and Connective Tissue Diseases: Conditions like systemic lupus erythematosus (SLE), rheumatic fever, scleroderma, and mixed connective tissue disease can present with polyarthritis. However, these typically involve systemic manifestations such as neurologic, mucocutaneous, renal, or gastrointestinal symptoms, along with specific autoantibodies. The absence of systemic involvement and negative ANA in our patient reduces the likelihood of these conditions. Rheumatic fever, characterized by migratory arthritis, is preceded by pharyngitis and accompanied by carditis and erythema marginatum, which were absent in this case.
CARCINOMATOUS POLYARTHRITIS: A DETAILED EXPLORATION
Carcinomatous polyarthritis (CP) is a paraneoplastic syndrome associated with various solid tumors, including lung, gastric, colon, breast, ovarian, laryngeal, and pancreatic cancers (Table 1). Its exact prevalence is unknown but considered rare. CP typically manifests around the age of cancer onset, with reported cases ranging from 43 to 76 years, median age 61, and no apparent gender predilection. Crucially, CP can precede cancer diagnosis by 1 to 20 months, often manifesting within 3 months of joint symptoms.
Table 1. Clinical Features of Carcinomatous Polyarthritis
| Case report and (reference) | Type of neoplasm | Age/sex | Symmetric (S) vs. asymmetric (A) | Timing* (weeks) | Small joint involvement |
|---|---|---|---|---|---|
| Present case | Small cell carcinoma of lung | 43 years/M | A | 24 | + |
| Stummvoll et al. 4 | Adenocarcinoma of colon | 49 years/M | S | 6 | + |
| Eggelmeijer et al. 9 | Supraglottic squamous cell carcinoma | 50 years/M† | S | 44/52 | +/+ |
| Bennett et al. 10 | Adenocarcinoma of ovary | 59 years/F | S | 12 | + |
| Madiedo JM et al. 7 | Non-small cell carcinoma | 59 years/F | S | 28 | + |
| Pines et al. 5 | Breast cancer | 60 years/F | S | 14 | + |
| Pines et al. 5 | Unknown primary | 62 years/F | S | 12 | + |
| Pines et al. 5 | Oat cell carcinoma | 68 years/M | S | 6 | + |
| Chuan et al. 8 | Tubular adenocarcinoma of stomach | 68 years/M | S | 80 | + |
| Bradley et al. 3 | Spindle cell carcinoma | 69 years/M | S | 6 | + |
| Stummvoll et al. 4 | Small Cell carcinoma of lung | 70 years/M | S | 4 | + |
| Simon and Ford 11 | Adenocarcinoma Of colon | 76 years/F | S | 16 | + |
F = female, M = male, + Positive, – negative, Time period between arthritis symptoms and diagnosis of neoplasm, †This patient presented with carcinoma polyarthritis twice*
Alt text: Table summarizing clinical features of carcinomatous polyarthritis across multiple case reports, highlighting the diversity in associated neoplasms and arthritis characteristics.
Differentiating CP from Rheumatoid Arthritis
Distinguishing CP from RA can be particularly challenging, as both can present with polyarthritis. While classic RA onset is between 30-55 years, incidence increases with age, overlapping with CP presentation. Both conditions can develop over weeks to months, featuring soft tissue swelling, limited joint motion, and morning stiffness. Elevated ESR and CRP, indicative of inflammation, and anemia are also common in both.
Historically, CP was described as having a late-age onset, acute presentation, asymmetric joint involvement, predilection for lower extremities, sparing wrists and hands, benign radiographs, and absent rheumatoid factor. However, recent reviews, including the presented case series, reveal these features are not consistently observed. Symmetric joint involvement, including wrists and hands, is frequently seen in CP. Furthermore, rheumatoid factor can be present in CP, potentially due to the malignancy itself, which is associated with positive rheumatoid factor in 10-20% of patients. However, the observed positive rate in CP cases often exceeds this expected percentage, suggesting other contributing factors. ANA can also be positive in some CP cases. Synovial fluid analysis typically shows non-specific inflammatory changes, and radiographs are generally unremarkable except for age-related changes.
Table 2. Differential Diagnosis of Migratory Polyarthritis
| Palindromic rheumatoid arthritis |
|---|
| Crystal induced arthropathy |
| Reactive arthritis |
| Autoimmune disease (e.g., SLE, rheumatic fever) |
| Infectious polyarthritis (e.g., Lyme disease, chlamydia) |
Alt text: Table outlining the differential diagnosis of migratory polyarthritis, encompassing various rheumatologic and infectious conditions to consider alongside carcinomatous polyarthritis.
Table 3. Laboratory and Radiographic Features of CP
| Case report and (reference) | Rheumatoid factor | ANA | ESR (mm/h) | CRP (mg/dl) | Synovial fluid | X-ray |
|---|---|---|---|---|---|---|
| Present case | + | – | 106 | 11.5 | SI | N |
| Stummvoll et al. 4 | – | – | 35 | 2.9 | NP | STS |
| Eggelmeijer et al. 9 | -/- | -/- | 30/53 | NP | NP | MDC/MDC |
| Bennett et al. 10 | + | + | 36/132 | 4+ | NS | MDC |
| Madiedo et al. 7 | – | – | 110 | NP | N | N |
| Pines et al. 5 | – | – | NP | NP | NP | NP |
| Pines et al. 5 | + | + | 95 | NP | NP | NP |
| Pines et al. 5 | + | – | N | NP | NP | NP |
| Chuan et al. 8 | + | – | 103 | NP | NP | N |
| Bradley et al. 3 | – | + | 107 | NP | SI | STS |
| Stummvoll et al. 4 | – | + | 53 | 4.6 | NP | STS |
| Simon and Ford 11 | + | – | 97 | 3.0 | SI | NE |
+ Positive, – negative, STS = soft tissue swelling, SI = sterile inflammation, N = normal, MDC = minimal degenerative changes, NE = joint space narrowing and erosions, NS = nonspecific, NP = not performed
Alt text: Table summarizing laboratory and radiographic features of carcinomatous polyarthritis from various case reports, highlighting variability and non-specificity of findings.
Diagnostic Approach to CP
CP remains a diagnosis of exclusion. Clinicians must systematically rule out other more common causes of polyarthritis. Given the overlapping features with RA, particularly in older patients, a high index of suspicion is crucial in patients presenting with new-onset migratory arthritis, especially at a later age, or with risk factors for malignancy. While historically proposed differentiating features are unreliable, considering the clinical context, lack of response to typical arthritis treatments (NSAIDs, prednisone), and presence of systemic symptoms like unexplained weight loss, fatigue, or new respiratory symptoms should raise suspicion for CP. In such cases, age-appropriate cancer screening and further investigations are warranted. Anti-cyclic citrullinated peptide antibodies (anti-CCP), useful in RA diagnosis, have not been reported in CP and may aid in differentiation, although further research is needed.
Pathophysiology of CP
The pathogenesis of CP is not fully understood. Circulating immune complexes (CIC) have been implicated, observed in over 60% of some cancers, and may deposit in synovium, triggering sterile inflammation. Elevated levels of platelet-activating factor have also been found to correlate with tumor presence and symptom resolution, potentially linking CIC to platelet activation. However, studies have failed to consistently demonstrate immune complexes in CP synovium, suggesting other mechanisms are involved. Alternative hypotheses include cross-reaction between tumor antigens and synovium, disruption of ‘antiarthritic’ barriers by tumor or immune response, and autoimmune phenomena involving tumor-draining lymph node lymphocytes. Currently, no single mechanism is definitively substantiated.
Management of CP
The cornerstone of CP management is treating the underlying malignancy. In reported cases, including the presented case, successful tumor resection or chemotherapy often leads to resolution of arthritic symptoms. Recurrence of arthritis may herald tumor recurrence, emphasizing the importance of ongoing monitoring. While chemotherapy agents can treat refractory RA, the lack of prior migratory arthritis episodes, failure to respond to NSAIDs and prednisone, and concurrent cancer diagnosis strongly support CP in our patient.
CONCLUSION
Carcinomatous polyarthritis is a rare but clinically significant paraneoplastic syndrome that presents a diagnostic challenge due to its mimicry of more common polyarthritides, particularly rheumatoid arthritis. A high index of suspicion is essential in patients with new-onset migratory arthritis, especially in older individuals or those with cancer risk factors. While historical differentiating features are not always reliable, clinical context, treatment response, and systemic signs are crucial for diagnosis. CP is a diagnosis of exclusion, requiring thorough investigation to rule out other causes of polyarthritis and prompt consideration of underlying malignancy. Treatment focuses on the underlying cancer, with successful cancer therapy typically resolving the arthritic manifestations. Reappearance of arthritic symptoms should prompt evaluation for tumor recurrence. In cases of migratory arthralgia, especially with atypical features or in at-risk individuals, carcinomatous polyarthritis should be considered in the differential diagnosis, necessitating a comprehensive diagnostic approach to ensure timely cancer detection and management.
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