Malignant disease may be associated with a wide variety of musculoskeletal syndromes. Rarely the musculoskeletal system can be indirectly affected by paraneoplastic phenomena, such as carcinomatous polyarthritis (CP). The differential diagnosis for CP is broad and is often a diagnosis of exclusion. CP often presents similarly to other forms of inflammatory arthritis, and a detailed history and physical examination can often distinguish CP from other more common causes of polyarticular arthritis. However serological tests such as rheumatoid factor (RF) and anti-citrullinated peptide (anti-CCP) antibody positivity, while rare, can be misleading. Clinical awareness and suspicion are paramount in achieving an accurate diagnosis and early detection of an occult neoplasm is critical for prompt management and therapy. We report two cases presenting with this unique clinical phenotype associated with paraneoplastic polyarthropathy and review the literature.
Malignant disease may be associated with a wide variety of musculoskeletal syndromes [
Our first case involves 80-year-old female who presented with a three-day history of right-sided shoulder pain and associated fever. On further questioning the patient described asymmetric migratory joint pain over the preceding three-week period, affecting her left wrist, knees, and right shoulder. She had been taking nonsteroidal anti-inflammatory drugs (NSAIDs) without relief and was also receiving a two-week course of ciprofloxacin for a urinary tract infection. Physical examination revealed tenderness and painful restriction of motion of the right shoulder. There was also a right-sided knee effusion. The remainder of the physical examination was unremarkable.
Her medical history was significant for type 2 diabetes, ischaemic heart disease, and congestive heart failure. She was a lifelong nonsmoker and did not consume any alcohol. Review of systems was otherwise unremarkable.
Initial laboratory results revealed a white cell count of 11.9 × 109/L, hemoglobin 11.2 g/dL, and platelets 384 × 109/L. A metabolic panel was significant for mild hyponatremia (131 mmol/L) (normal levels 135–145 mmol/L) and a slightly raised urea (7.7 mmol/L) and creatinine (93
During her admission she developed nonspecific abdominal pain and tenderness in the right iliac fossa. A CT of abdomen was requested and reported no intra-abdominal pathology. However there was an incidental finding of a 3.3 cm multilobulated lesion in the inferior outer quadrant of the right breast (Figure
CT of abdomen. The red arrow illustrates a well circumscribed, multilobulated 3.3 cm lesion in the inferior outer quadrant of the right breast.
Encapsulated papillary carcinoma showing classical papillary architecture with surrounding fibrous capsule.
During that time her right shoulder pain spontaneously resolved. However she then developed new onset right wrist pain, swelling, and erythema. X-ray revealed moderate degenerative changes. Joint aspiration revealed markedly increased inflammatory cells but no crystals. Colchicine and NSAIDs were stopped and she was given IM methylprednisolone to which she responded well, and her CRP decreased to 70. She was seen in clinic one week later and had no appreciable synovitis on examination.
Six weeks later she underwent chemotherapy and radiotherapy for her breast cancer. She was seen again in clinic ten weeks later and she did not report any recurrence of her joint symptoms.
Our second patient, 71-year-old female, was referred by her general practitioner for evaluation of a six-month history of pain and swelling of her hands and feet. This was associated with early morning stiffness lasting greater than two hours daily. NSAIDs and a short course of prednisolone had failed to improve her symptoms.
Her past medical history was significant for ischaemic heart disease, hypertension, hyperlipidaemia, and peptic ulcer disease. She had a thirty-pack year history of smoking. Three of her four siblings had been treated for colorectal or breast neoplasms.
On examination she had thirteen tender and ten swollen joints including metacarpophalangeal (MCP), proximal interphalangeal (PIP), wrist, shoulder, ankle, and knee joints. Grade 2 clubbing was evident as was a multinodular goitre. Other than a raised CRP at 12 mg/L and serum calcium at 2.68 mmol/L, baseline laboratory investigations were normal. Rheumatoid factor and anti-CCP antibodies were both negative. Chest radiograph revealed a left upper lobe lesion, which was confirmed on CT. Subsequent biopsy identified a non-small cell adenocarcinoma. She underwent a lobectomy with a rapid resolution of her joint symptoms.
Migratory polyarthritis is a common presentation with a broad differential diagnosis [
CP is associated with a wide variety of solid tumours and haematologic malignancies, particularly cancers of the lung and ovaries (Table It must occur during the course of an identified malignant disease or precede clinical evidence of a malignancy. Symptoms cannot be the result of direct tumor invasion or compression. Symptoms improve with treatment of the underlining neoplasm.
In 1985, Caldwell and McCallum published the key features of cancer polyarthritis and suggested distinguishing features to aid in narrowing the differential [
Malignancies associated with carcinomatous polyarthritis. Four cases, highlighted in bold, have shown anti-CCP positivity. Rheumatoid factor (RF), anti-citrullinated protein antibody (anti-CCP), positive (+), negative (−), not included (NI), Non-Small Cell Lung Cancer (NSCLC), Squamous Cell Cancer (SCC), Small Cell Lung Cancer (SCLC), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphoid Leukemia (CLL).
Case report and reference | Type of malignancy | RF | Anti-CCP |
---|---|---|---|
|
|
|
|
Present case | NSCLC |
|
|
Zupancic et al. [ |
SCC lung | + | NI |
Stummvoll et al. [ |
Adenocarcinoma colon |
|
NI |
Stummvoll et al. [ |
SCC Lung |
|
NI |
|
|
|
|
Nadal et al. [ |
Prostate cancer | NI |
|
Bradley and Pinals [ |
Spindle cell cancer | + | NI |
Pines et al. [ |
Breast |
|
NI |
Pines et al. [ |
Unknown primary |
|
NI |
Pines et al. [ |
SCLC |
|
NI |
Acosta Madiedo et al. [ |
NSCLC |
|
NI |
Chuan et al. [ |
Tubular adenocarcinoma stomach |
|
NI |
Eggelmeijer and Macfarlane [ |
Supraglottic SCC |
|
NI |
Bennett et al. [ |
Ovarian adenocarcinoma | + | NI |
Simon and Ford [ |
Adenocarcinoma colon |
|
NI |
Mok and Kwan [ |
Unknown primary | + | NI |
|
|
|
|
|
|
|
|
Sheehy et al. [ |
NSCLC (adenocarcinoma) | + | NI |
Bivalacqua et al. [ |
NSCLC (adenocarcinoma) | NI | NI |
Docquier et al. [ |
Uterine adenocarcinoma |
|
NI |
Haroon and Phelan [ |
Pancreatic cancer |
|
NI |
Ardalan and Shoja [ |
Multiple myeloma |
|
NI |
Leslie [ |
Cervical cancer | NI | NI |
Baijens and Manni [ |
cT4N2cM0 hypopharynx carcinoma | NI | NI |
Martorell et al. [ |
Serocystadenocarcinoma ovary |
|
NI |
Martorell et al. [ |
Serocystadenocarcinoma ovary | + | NI |
Martorell et al. [ |
Ovarian carcinoma |
|
NI |
Martorell et al. [ |
Serocystadenocarcinoma ovary |
|
NI |
Medsger et al. [ |
Ovarian adenocarcinoma | NI | NI |
Medsger et al. [ |
Ovarian adenocarcinoma | NI | NI |
Medsger et al. [ |
Ovarian adenocarcinoma | NI | NI |
Medsger et al. [ |
Ovarian adenocarcinoma | NI | NI |
Medsger et al. [ |
Ovarian adenocarcinoma | NI | NI |
Medsger et al. [ |
Ovarian adenocarcinoma | NI | NI |
Baron [ |
SCLC |
|
NI |
Baer and Phillips [ |
Pancreatic adenocarcinoma | NI | NI |
Taggart et al. [ |
Adenocarcinoma Fallopian tube |
|
NI |
Taggart et al. [ |
Ovarian adenocarcinoma | NI | NI |
Michaels and Sorber [ |
Pancreatic adenocarcinoma |
|
NI |
Shiel et al. [ |
SCLC | NI | NI |
Shiel et al. [ |
Ovarian adenocarcinoma | NI | NI |
Pfinsgraff et al. [ |
CML |
|
NI |
Pfinsgraff et al. [ |
Pancreatic adenocarcinoma, parathyroid adenoma | NI | NI |
Pfinsgraff et al. [ |
Squamous cell carcinoma unknown primary |
|
NI |
Pfinsgraff et al. [ |
Adenocarcinoma unknown primary | NI | NI |
Pfinsgraff et al. [ |
Hodgkin disease | NI | NI |
Valverde-Garcia et al. [ |
Breast cancer | NI | NI |
Cammilleri et al. [ |
Follicular B cell lymphoma |
|
NI |
Willemse et al. [ |
Adenocarcinoma of the coelomic epithelium |
|
NI |
Van den Bergh et al. [ |
Adenocarcinoma of prostate prolactinoma |
|
NI |
Mathieu et al. [ |
CLL | NI | NI |
Vinker et al. [ |
Ovarian adenocarcinoma | NI | NI |
Saxman and Seitz [ |
Breast carcinoma |
|
NI |
Grados et al. [ |
Transitional cell carcinoma of the renal pelvis |
|
NI |
Grados et al. [ |
Adenocarcinoma of the uterus |
|
NI |
Enomoto et al. [ |
Early-stage gastric carcinoma | + | NI |
Denschlag et al. [ |
Fallopian tube carcinoma |
|
NI |
Giannakopoulos et al. [ |
Ovarian adenocarcinoma |
|
NI |
Yogarajah et al. [ |
Ovarian adenocarcinoma | NI | NI |
Bolibar et al. [ |
Ovarian adenocarcinoma |
|
NI |
Preda et al. [ |
Ovarian adenocarcinoma | NI | NI |
Krishna et al. [ |
Breast cancer |
|
NI |
Qureshi and Saavedra [ |
Ovarian adenocarcinoma |
|
NI |
Clarke et al. [ |
Transitional cell carcinoma of the bladder |
|
NI |
Nahar and Al-Rajhi [ |
Ovarian adenocarcinoma |
|
NI |
Sandhya and Danda [ |
Breast carcinoma | NI | NI |
Mcgivern and Mcaleese [ |
NSCLC | NI | NI |
Salmon et al. [ |
Ovarian adenocarcinoma |
|
NI |
Salmon et al. [ |
Ovarian adenocarcinoma |
|
NI |
Salmon et al. [ |
Uterine cancer | NI | NI |
Shetty et al. [ |
Neuroendocrine tumour of adrenal gland |
|
NI |
(i) Close temporal relationship (12 months) between onset of arthritis and malignancy (ii) Late age at onset (iii) Asymmetric joint involvement (iv) Explosive onset (v) Predominance of lower extremity involvement with sparing of wrists and small joints of hands (vi) Absence of Rheumatoid Factor (RF) (vii) Absence of rheumatoid nodules (viii) No family history of rheumatic disease (ix) Non-specific histopathologic appearance of synovial lining (x) Absence of characterisitic radiologic lesions
CP however remains a diagnosis of exclusion and must be distinguished from other more common causes of polyarthritis. Infectious causes due to bacteria or Lyme disease may be associated with fever, acute symptom onset, and monoarthritis. A thorough clinical history is useful in detecting seronegative spondyloarthropathies. Reactive arthritis is usually preceded by an infection such as campylobacter-induced diarrhea, while enteric arthritis may be seen in patients with a history of inflammatory bowel disease. Finally the crystal arthropathies can be easily distinguished by joint aspiration and visualisation of crystals under the microscope.
Distinguishing CP from a late onset form of RA, however, is challenging. Previous studies have shown that the incidence of both increases with age. Both may present over the course of weeks to months with similar signs and symptoms, namely, soft tissue swelling, limited range of motion of affected joints, and morning stiffness [
Several case reports included in Box
Our first case had a positive rheumatoid factor, which can be partially explained by the underlying malignancy, which is associated with a positive rheumatoid factor in 10–20 percent of patients [
An additional means to differentiate these two disorders was postulated by measuring anti-cyclic citrullinated peptide (anti CCP) antibodies. Anti-CCP has a similar sensitivity to RF (50–75%) with a higher specificity (90–95%) [
One prevailing theme however is resolution of rheumatic symptoms after treatment of the underlying malignancy [
To date, the pathogenesis of this disorder remains unclear. Bradley and Pinals suggested that circulating immune complexes (CIC), which have been observed in over 60 percent of some types of cancers, may play a pivotal role [
Carcinomatous polyarthritis is a rare disorder associated with a wide variety of malignancies. The differential diagnosis for CP is broad and is often a diagnosis of exclusion. Several of the classical features initially proposed to distinguish CP may be unreliable, and positive serological tests such as rheumatoid factor and anti-CCP antibody positivity can be misleading. A comprehensive history and physical examination is paramount in distinguishing CP from other more common causes of polyarticular arthritis, with careful attention to social and family history to detect any possible risk factors for cancer. Clinical awareness and suspicion remain the most important factors in achieving an accurate diagnosis. Early diagnosis of an occult neoplasm is critical for prompt management and therapy and can ultimately be lifesaving.
The authors declare that there is no conflict of interests regarding the publication of this paper.