The association between malignancy and rheumatic diseases is complex and intriguing. A two-way relationship exists in that a malignancy can arise in the setting of preexisting rheumatic disease or as a result of its treatment and certain treatments for cancer manifest rheumatic syndromes. Paraneoplastic syndromes are the expression of an underlying cancer, frequently occult, and can be caused by a wide variety of remote tumor effects unrelated to the mechanical impact of the tumor mass or distant metastases. They result from substances released from tumor cells like hormones, peptides, antibodies, or from immunologic and other host reactions to the tumor. Rheumatic syndromes can be important clues to occult neoplasia [1,2]. The pathogenesis of paraneoplastic rheumatologic diseases is complex and not fully understood in the majority of instances. In the absence of a defined pathogenic link between the malignancy and the rheumatic syndrome, the association between these diseases has been based on a suggestive temporal concurrence and a parallel clinical course. The treatment of malignancy-associated rheumatic diseases is frequently challenging; poor response to therapies used in nonparaneoplastic rheumatic conditions is commonly observed and improvement or complete response may be achieved with successful treatment of the underlying malignancy. Although paraneoplastic rheumatic syndromes are rare, clinicians should be aware that they can be the first sign of an occult malignancy and that early recognition is critical for early cancer diagnosis and treatment.
PARANEOPLASTIC JOINT DISEASE
Paraneoplastic joint disease can have variable presentations.
A migratory or additive nonerosive, nondeforming, asymmetric polyarthritis of explosive onset, involving more commonly large joints and sparing the wrists and hands, accompanied by constitutional symptoms and elevated markers of inflammation has been described in older patients in association with an underlying malignancy [3,4]. A paraneoplastic polyarthritis affecting the small joints has also been described . These characteristics are not specific and may overlap with features of late-onset rheumatoid arthritis, remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and polymyalgia rheumatica among others . Paraneoplastic polyarthritis has been described in association with solid tumors as well as hematologic malignancies. Laboratory findings are also not specific, especially in this elderly population with underlying malignancy: rheumatoid factor was detected in six of 13 patients in one series . Anticyclic citrullinated peptides (CCP) measurement can be useful in this setting , although cases of anti-CCP-positive paraneoplastic polyarthritis have also been reported [8,9].
REMITTING SERONEGATIVE SYMMETRICAL SYNOVITIS WITH PITTING EDEMA
Data suggesting a higher prevalence of underlying malignancy in patients with RS3PE come from retrospective and prospective studies that suggest that the malignancy rate in association with RS3PE may be as high as 54% , including solid tumors, most frequently prostate cancer, and hematologic malignancies. The clinical presentation is usually a polyarthritis of sudden onset with pitting edema of the hands, in patients above the age of 50 years, more commonly in men. Rheumatoid factor is typically negative and erosions are absent. In contrast to RS3PE without malignancy, paraneoplastic RS3PE presents with more prominent constitutional symptoms and tends to respond poorly to glucocorticoids. A high serum level of matrix metalloproteinase 3 was found to be characteristic of paraneoplastic RS3PE in one study [11▪].
Polymyalgia rheumatica (PMR) is a relatively common disease of the elderly characterized by pain and stiffness in the shoulders, hip girdle, and neck. Markers of inflammation are typically elevated. About half of patients also develop peripheral synovitis. Paraneoplastic PMR has been described most commonly in association with myelodysplatic syndromes . An association rather than a cause-effect relationship is suggested in these cases, as PMR symptoms abated with treatment of the underlying malignancy. Atypical PMR has been described in patients with metastatic cancers: these patients had an earlier onset of symptoms, asymmetric presentation, sedimentation rate less than 40 or more than 100 mm/h, poor or delayed response to low dose glucocorticoids and long-lasting symptoms .
Primary or AL (immunoglobulin light chain) amyloidosis is a plasma cell disorder characterized by the overproduction and tissue deposition of monoclonal Ig light chains or fragments. Amyloid deposits in AL amyloidosis can involve the synovium, leading to rheumatic symptoms [13,14]. Amyloid arthropathy may occur in 0.1–6% of patients with multiple myeloma, with an onset either coincident with or subsequent to the diagnosis of myeloma. It affects commonly the shoulders, knees, wrists, and metacarpophalangeal and proximal interphalangeal joints. Patients can have subcutaneous nodules similar to rheumatoid nodules. Submandibular gland involvement, macroglossia, carpal tunnel syndrome are common accompanying manifestations. Congo red staining of synovial spun sediment can show amyloid deposits from synovial fragments.
POLYARTHRITIS WITH PANNICULITIS
Lobular panniculitis with extensive fat necrosis on skin biopsy along with arthritis and/or bone necrosis have been described in association with pancreatic disease including pancreatitis  (i.e. pancreatitis, panniculitis, and polyarthritis or PPP syndrome) and pancreatic tumors [16,17]. The ankles, knees, wrists, and metacarpophalangeal joints are most commonly affected. Characteristic radiographic findings include loss of joint space, osteolytic lesions, pathologic fractures, and progression to osteonecrosis. Joint disease does not respond well to nonsteroidal antiinflammatories and glucocorticoids . No other proven beneficial treatment has been described.
PALMAR FASCIITIS AND POLYARTHRITIS SYNDROME
This syndrome has been most commonly described in association with ovarian cancer; however, many other malignancies have also been reported [18,19]. Patients present with firm, painful nodules with thickening and erythema of the palmar fascia, hand pain and stiffness, digital swelling with flexion contractures with or without involvement of other joints like the shoulders and knees. There is no known effective treatment although some improvement may be seen with treatment of the underlying malignancy.
MULTICENTRIC RETICULOHISTIOCYTOSIS (MRH)
MRH, a non-Langerhans cell proliferative histiocytosis, is a rare systemic disorder of unknown cause characterized clinically by papules and nodules associated with rapidly destructive polyarthritis that can progress to arthritis mutilans. MRH is associated with an underlying malignancy in 25% of cases [20,21] and tends to be relatively resistant to glucocorticoids and disease modifying antirheumatic drugs.
PARANEOPLASTIC BONE DISEASE
Paraneoplastic bone disease includes hypertrophic osteoarthropathy, tumor-induced osteomalacia, and hypercalcemia of malignancy.
Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of the skin and osseous tissue in the distal parts of the extremities. Clinical presentation includes digital clubbing, periostosis of tubular bones, and characteristically non-inflammatory synovial effusions, which are most prominent in the large joints. In its secondary form, HOA is usually associated with lung cancer and other intra-thoracic diseases including infections, cystic fibrosis, right-to-left cardiac shunts, and other malignancies. Bone scintigraphy showed paraneoplastic HOA findings in 0.7% of the lung cancer patients especially males, smokers, and with advanced disease . Symptoms and bone scintigraphy findings improved in half of the patients with treatment of their lung cancer. Bisphosphonates can be effective in relieving bone and joint pain in refractory HOA. Zolendronic acid may be more efficacious than pamidronate in this setting .
Tumor-induced osteomalacia (TIO), also called oncogenic hypophosphatemic osteomalacia, is a rare paraneoplastic form of renal phosphate wasting disease resulting in severe hypophosphatemia, a defect in vitamin D metabolism with inappropriately low plasma calcitriol concentrations and osteomalacia. It can occur as an acquired disorder classically in association with benign mesenchymal tumors, although it has been described with other types of tumors . Most cases of TIO result from increased levels of fibroblast growth factor-23 (FGF-23) and/or the frizzled-4 protein produced by the tumor . One challenging aspect of TIO is localizing the tumor that can arise from bone or soft tissue at any location. Starting with functional imaging with F-18 fluorodeoxyglucose positron emission tomography, with computed tomography (FDG-PET/CT) or 111-Indium octreotide scintigraphy, followed by anatomical imaging is recommended . In a recent study from China [26▪], technetium-99m octreotide scintigraphy successfully located tumors in 95% (37/39) of patients with TIO. Systemic venous sampling of FGF-23 may help tumor localization . The treatment of choice is complete surgical resection of the tumor when possible and treatment with phosphate and calcitriol supplementation when the tumor cannot be localized and excised.
HYPERCALCEMIA OF MALIGNANCY
Humoral hypercalcemia of malignancy resulting from ectopic secretion of parathyroid hormone-related peptide (PTHrp) accounts for 80% of cases of hypercalcemia in malignancy. PTHrp results in increased bone resorption, decreased renal phosphorous reabsorption and increased distal renal tubular calcium retention . Osteolytic metastases locally releasing cytokines and tumor production of 1,25-dihydroxyvitamin D are other causes of hypercalcemia in malignancy.
The association between cancer and inflammatory myopathies has been extensively reported in dermatomyositis, polymyositis, and to a much lesser extent with inclusion body myositis (IBM), amyopathic dermatomyositis, and necrotizing myopathy. Population-based studies estimated the standardized incidence ratios (SIRs) for malignancy compared with the general population at 3.8–7.7 for dermatomyositis and 1.7–2.0 for polymyositis . In Western countries, common malignancies associated with dermatomyositis include ovarian, lung, pancreatic, gastric, and colorectal cancers . Among Asians, dermatomyositis is seen strongly associated with nasopharyngeal carcinoma . Polymyositis has strongest association with non-Hodgkin lymphoma, as well as lung and bladder cancers. Adenocarcinoma was the most common tumor type associated with dermatomyositis and polymyositis accounting for 70% of malignancies . In recent studies, there was a trend toward an increased SIR in dermatomyositis but no increased risk of malignancy in polymyositis or IBM [32▪] or necrotizing myopathy [33▪]. Cancer is most commonly recognized within 2 years of the diagnosis of dermatomyositis or polymyositis. Risk factors for underlying malignancy in myositis include older age of onset, resistance to treatment, severe cutaneous involvement with ulcerations, leukocytoclastic vasculitis (LCV), severe muscle disease with dysphagia and respiratory failure, and low C4 level. Features in association with myositis that are thought to be possibly protective include Raynaud's phenomenon, interstitial lung disease, arthritis, fever, positive antinuclear antibodies (ANA), antibodies to extractable nuclear antigens and antisynthetase antibodies [29,32▪]. CAM has been associated with an autoantibody against a 155 kDa protein or antip155 with this antibody being detected with higher frequency in malignancy subgroups compared with patients with idiopathic dermatomyositis [34,35]. The exact role of testing for this antibody for cancer screening in patients with myositis is not well established and commercial testing is not yet available. In a recent study [36▪] from Japan, three of eight adults with inflammatory myositis who were positive for anti-NXP2 (anti-MJ) antibody, a major myositis-specific autoantibody in juvenile dermatomyositis, had malignancy found within 3 years. Available data suggest that tumors and injured and regenerating muscle possess potential antigenic similarities. The nascent tumor may be an antigen source in myositis that may be critical in disease initiation; an immune response directed against the nascent tumor also targets injured and regenerating muscle which expresses these ‘autoantigens’, thus perpetuating the inflammatory response . Screening for underlying malignancy in patients with new diagnosis of inflammatory myositis is mandatory, as we know that this carries a poorer prognosis. There is no consensus on how extensive such screening work-up should be. A careful history, complete physical exam, appropriate laboratory tests and age-appropriate cancer screening are indicated in all patients. Any abnormalities detected that may signal the presence of an occult cancer should be further investigated. Additional testing should be guided by patient's age, sex, type of myositis, ethnicity, environmental exposures, and CAM risk factors. These tests may be repeated as appropriate at follow-up as the risk of malignancy persists up to 5 years after the initial diagnosis.
The association between cancer and vasculitis is uncommon and difficult to establish as many reports lack the temporal relationship necessary to draw valid conclusions regarding the association. Overall, paraneoplastic vasculitides are estimated to represent about 2–5% of all vasculitides [38,39]. In an 18.5-year study , only 12 patients were diagnosed with both cancer and vasculitis within a 12-month period. Fain et al. reported 60 patients with vasculitides associated with malignancies over a 10-year study. Of note, this study included 14 patients in whom the interval between the diagnoses of vasculitis and cancer exceeded 12 months. Hematologic malignancies accounted for 50 and 63% of cancers in these two studies respectively. Carcinomas of the urinary tract accounted for 40% of solid tumors associated with paraneoplastic vasculitides in another study . LCV was the most common vasculitis reported in these three series: 58, 45 and 60% of patients. LCV is known to have a higher association with hematologic malignancies. Recently, Podjasek et al.[41▪] reported 17 patients with LCV in association with solid organ malignancies diagnosed over a 13-year period; a quarter of these had lung carcinoma. In contrast to prior reports, about half of these patients had remission of their vasculitis with immunosuppressive treatment alone. The only cancer-specific association with a given vasculitis is that of hairy cell leukemia and polyarteritis nodosa , a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, also described in a variety of other malignancies. Granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis), microscopic polyangiitis and allergic granulomatosis and angiitis (Churg Strauss syndrome) have rarely been described as paraneoplastic manifestations. Only one patient was diagnosed with GPA in association with a malignancy (renal cell carcinoma) over a 18.5 year retrospective study . Henoch Schonlein purpura (HSP), an immune-mediated systemic vasculitis associated with immunoglobulin A deposition, is most common in children. It has rarely been described in association with malignancy in adults, more commonly with solid tumors . Patients’ characteristics in reported cases included male sex, older age, and kidney involvement . Out of 53 patients with HSP above the age of 41 years in one study , 23 patients were reported to have underlying malignant tumors. Disease onset and course in nine of these patients suggested a strong association with cancer.
OTHER PARANEOPLASTIC RHEUMATIC SYNDROMES
A paraneoplastic lupus-like syndrome presenting with serositis, Raynaud's phenomenon and positive ANA has been rarely described in patients with malignancies , although the relation is still uncertain. Two cases of subacute cutaneous lupus in association with metastatic adenocacinoma were recently reported . A close temporal relationship between cancer diagnosis and the clinical onset of systemic sclerosis (SSc) has been described in a variety of cancers . One study  showed that scleroderma patients with RNA polymerase III autoantibodies and cancer have a close interval between cancer diagnosis and the onset of SSc symptoms with a unique nucleolar pattern of RNA polymerase III expression in their cancers. Twenty-two out of 200 patients with relapsing polychondritis had an associated myelodysplastic syndrome in one study . Cases of relapsing polychondritis-associated with lymphoma have also been reported .
A wide range of autoimmune phenomenon can occur in the setting of malignancies but the pathogenesis has not been elucidated in most instances. Therefore, this association has been based on plausible temporal concurrence, clinical course, and response to cancer therapy. Clinicians should be aware that paraneoplastic rheumatologic syndromes can be the first sign of an occult malignancy or its recurrence. Early recognition is critical for early cancer diagnosis and treatment. An underlying malignancy should be suspected in patients with rheumatologic diseases that do not respond as expected to therapy. Effective treatment of cancer is likely to lead to improvement in the paraneoplastic disease.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 150).
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