Malignant disease often needs to be considered in the initial evaluation of patients with synovitis. Cancer can affect the synovium directly, either as a primary tumor or as a metastasis. In addition, arthritis can also occur as a remote nonmetastatic effect of the tumor (paraneoplastic phenomenon). This article describes the various types of arthritis that can be seen in association with malignancy and the clinical approach to the diagnosis and management of cancer-related synovitis.
Arthritis can be a diagnostic challenge for clinicians because many local and systemic diseases can cause joint pain and effusion. An initial careful evaluation including a comprehensive history and physical examination is vital to establish possible differential diagnoses. The patient’s age, gender, and ascertainment of comorbidities, past medical and family history, and personal habits and lifestyle can provide invaluable diagnostic clues. In addition, laboratory tests on synovial fluid and imaging are often necessary to narrow down the list of possible causes. Malignant disease often needs to be considered in the initial evaluation of patients with synovitis. Cancer can affect the synovium directly, either as a primary tumor or as a metastasis. Arthritis can also occur as a remote nonmetastatic effect of the tumor (paraneoplastic phenomenon). In addition, patients with cancer receiving therapy are often immunosuppressed and therefore more susceptible to septic arthritis; they can also develop arthralgia, and sometimes synovitis, as a consequence of their treatment. This article describes the various types of arthritis that are seen in association with malignancy, and the clinical approach to the diagnosis and management of cancer-related synovitis. Box 1 provides a list of the most frequent diseases.
Synovial tumors
Primary benign tumors
Pigmented villonodular synovitis
Synovial chondromatosis
Hemangioma
Lipoma arborescens
Malignant tumors
Synovial chondrosarcoma
Malignant pigmented villonodular synovitis
Synovial sarcoma
Metastatic synovitis
Adenocarcinomas
Leukemia arthritis
Malignant lymphoma
Paraneoplastic syndromes involving the joint
Carcinoma polyarthritis
Remitting seronegative symmetric synovitis with pitting edema
Polymyalgia rheumatica
Lupuslike syndrome
Paraneoplastic adult Still disease
Relapsing polychondritis
Jaccoud arthropathy
Amyloid arthritis
Crystal-induced arthritis
Hypertrophic osteoarthropathy
Palmar fasciitis and polyarthritis
Panniculitis and arthritis
Multicentric reticulohistiocytosis
Arthritis associated with cancer therapy
Septic arthritis
Synovitis induced by cancer therapy
Arthralgia associated with cancer therapy
Primary synovial tumors
Synovial lining covers joints, bursa, and tendon sheaths, and tumors can originate from any of these structures, resulting in monoarthritis or oligoarthritis, localized bursitis, or single or multiple nodules. Primary synovial tumors are uncommon, and can be benign or malignant.
Primary Benign Synovial Tumors
Of 4000 arthrotomies of the knee performed at the Mayo Clinic during a 20-year period, only 95 cases were found to have benign tumors. Among those, pigmented villonodular synovitis (PVNS) and synovial chondromatosis were the predominant diagnoses.
PVNS
PVNS is a proliferative disorder of the synovial cells that leads to thickening and hypertrophy of the synovial membrane, in a villous architecture. The disorder is classified as intraarticular or extraarticular according to the location, and localized or diffuse according to the pattern of growth. Intraarticular lesions often affect the knee, and may be localized or diffuse within the joint. Localized synovitis presents as a well-defined nodule, and most frequently affects the infrapatellar fat pad of the knee. The diffuse form affects large weight-bearing joints, resulting in synovitis and sometimes a palpable mass, with serosanguinous or xanthocromic joint effusion. When the lesion originates in the tendon sheath, it is called giant cell tumor of tendon sheath. Localized lesions most commonly affect the tendons of the hand or wrist. There is a less common diffuse variant that can target tendons in the large joints of the lower extremities (diffuse giant cell tumor of tendon sheath). The diffuse variant is less well defined, with tumor projections into surrounding tissues.
PVNS was previously considered to be a reactive proliferative process; however, cytogenetic studies show clonal proliferation, consistent with a tumoral lesion. Structural genetic rearrangements of 1p11 to 13 are present in both forms of PVNS. In addition, trisomies of chromosomes 5 and 7 are found, more frequently in the diffuse form. These trisomies have also been detected in malignant PVNS.
Although its real incidence is unknown, PVNS is the most common benign tumor of the tendon sheaths and synovium. During a 17-year period, in a large epidemiologic study of PVNS in Memphis, Tennessee, the incidence of tenosynovitis was 9.2 cases per million per year, whereas joint synovitis alone occurred in 1.8 cases per million per year, with no bursitis reported during this period. The disease is more common in women, and the mean age of the patients is 40 years. A history of antecedent trauma is common, but its association with PVNS seems to be coincidental.
The tumor grows slowly so the clinical onset is generally insidious, with a gradually progressive course. The clinical presentation depends on the location of the disease. It can affect any joint, but the knee is most often involved, in up to 80% of cases. Patients are often asymptomatic or can have mild pain for several years. Swelling can occur, sometimes with mechanical symptoms such as locking and catching. Episodic joint effusions and hemarthrosis can occasionally occur and are associated with acute pain and limitation in the range of motion. In the diffuse form, the tumor can exceed the joint, and result in locally aggressive invasion that destroys the surrounding soft tissue and bone, with progressive functional limitation at later stages. In the hands, PVNS is often situated in the lateral zone of the digit, adjacent to the interphalangeal joint, arising between the flexor and extensor tendons. The lesion is usually fixed to deep structures but is not attached to the skin. There are reports of spinal involvement, most often in the posterior elements of the cervical spine, which can cause localized pain and radicular symptoms.
Radiographs may be normal or show nonspecific changes, depending on the duration of the lesion. Radiographic changes include joint effusion or increased soft tissue density, compatible with synovial hypertrophy. Erosions may be present in up to 50% of cases. Arthrography of the knee reveals localized or ill-defined filling defects, compatible with a mass or thickened synovium. Ultrasound may show joint effusion, synovial thickening, or a heterogeneous mass. Computed tomography (CT) scans can show a high-density soft tissue mass and bone lesions, but magnetic resonance imaging (MRI) is the modality of choice for diagnosis. It reveals the extent of thickening of the synovium with heterogeneous signal intensity caused by the combination of areas of low signal intensity (hemosiderin deposits and fibrous tissue) with areas of high signal intensity (fat content and congested synovium). Tumoral lesions show gadolinium enhancement. MRI is useful not only for the diagnosis but also in the preoperative planning and follow-up.
A biopsy guided by CT or ultrasound may be necessary when the MRI is nondiagnostic. The histology shows villous synovial proliferation, histiocytes, foam cells, and multinucleated giant cells. The findings are consistent among the different types of lesion, except for the margins, which are well defined in localized forms but extend to adjacent tissues in the diffuse variant. Mitotic figures may be prominent, but do not show atypia. The cells tend to be arranged in clusters, separated by matrix consisting of collagen and, occasionally, osteoid and bone. Iron pigment is always present. Giant cells express an osteoclast phenotype and release proteolytic enzymes such as metalloproteinase 2 and 9, which can explain the local destructive changes. Areas of infarctlike necrosis may be found, but they are not a prominent feature.
The treatment of PVNS is surgical. Localized disease PVNS can be successfully removed by simple excision, achieving complete relief of symptoms, with a low rate of local recurrence (<5%).
For diffuse PVNS, a complete synovectomy is required, which can be performed arthroscopically if the lesion is confined within the joint. In cases of extraarticular involvement, open synovectomy is indicated. Incomplete synovectomy is associated with an incidence of recurrence up to 50%. Recurrent lesions can also be a sign of malignant disease. There is evidence that low-dose postoperative radiotherapy may be beneficial in these cases. Arthroplasty plus extensive synovectomy is required to avoid recurrences and in advanced cases with severe secondary osteoarthritis.
Synovial chondromatosis
Synovial chondromatosis is a benign neoplasm of the synovial tissue, characterized by the presence of multiple metaplastic cartilaginous nodules under the surface of the synovial membrane in joints, tendons, or bursa. Osteochondromatosis, which is the ossification of these cartilaginous nodules, frequently occurs. This disorder is more common in men but its true incidence is unknown. The joints most frequently affected are the knees, hips, and elbows, but unusual sites, such as the temporomandibular joint, and soft tissues around the joints, have also been reported. No specific genetic abnormalities have been identified in association with this entity.
Clinically, pain and synovial effusion are the most common symptoms. Locking of the joint can also occur when the cartilaginous nodules detach and become free loose bodies within the joint. At an early stage of the disease, radiographs may be normal or only show indirect signs of swelling. Later, they can reveal typical multifocal, calcified, spherical loose bodies. Development of secondary osteoarthritis is frequent. Although CT is useful for imaging the calcifications, MRI is the preferred imaging for soft tissue assessment and it can detect chondromas at an earlier stage, when calcification has not occurred. T1-weighted images typically show multiple areas of signal void corresponding with incompletely calcified nodules. Complete cartilaginous nodules appear isointense to the muscle on T1-weighted images, whereas T2-weighted images show high signal enhancement corresponding with joint effusion and synovial proliferation.
Pathologic changes include cartilaginous metaplasia of the intimal layer in a solid matrix without myxoid change. Calcification between chondrocytes is common.
Treatment consists of the surgical removal of loose bodies by arthroscopy or synovectomy. Recurrence can occur in approximately 30% of cases. Secondary osteoarthritis is frequent, but malignant transformation is extremely rare.
Synovial hemangioma
Synovial hemangioma is a rare benign vascular tumor of the synovium. The knee is most commonly affected, followed by the shoulder and the ankle. It typically occurs in adolescents who report a history of pain in the affected joint and can develop recurrent atraumatic hemartrosis. Radiographs are normal or show nonspecific features. MRI is the preferred imaging modality for diagnosis, although angiography also accurately shows vascular lesions. Histologically, there is proliferation of vessels, capillary or cavernous, in the synovium. Preoperative embolization can be useful. Treatment involves the complete surgical removal of the involved area.
Lipoma arborescens
Lipoma arborescens is a benign lipomatous proliferation involving the synovium. This condition is rare, and occurs most frequently in men in the fourth and fifth decades of life. The knee is most commonly affected. Symptoms include joint effusion and locking. MRI reveals characteristic villous synovial masses with enhanced fat intensity signal. Histologically, the lesion consists of typical mature fatty tissue in the subsynovium. Treatment consists of the complete removal of involved synovium. Recurrence is rare.
Primary Malignant Synovial Tumors
Synovial chondrosarcoma
This malignant neoplasia of the hyaline cartilage can originate from existing synovial chondromatosis or develop de novo. It is extremely rare, with only a few cases reported. There is a female predominance, and the age at onset ranges between 30 and 70 years.
Clinical presentation resembles the characteristics of the benign variant, but the progression is faster. MRI shows findings similar to those of synovial chondromatosis; however, the mass is larger and the bone is usually compromised. The biopsy shows cartilaginous nodules, but chondrocytes have a sheetlike arrangement and the matrix shows marked myxoid changes. Cellular atypia is moderate, with spindle cells surrounding the nodules; the adjacent bone may be infiltrated.
If complete removal is successful, recurrence is rare. However, this is often difficult to achieve, and the overall prognosis is poor, with a mortality of up to 50%.
Malignant PVNS
Malignant PVNS (MPVNS) is extremely rare and it can be difficult to differentiate from benign aggressive PVNS. It is unclear whether this malignancy arises de novo or in areas of benign PVNS. Some investigators reserve this diagnosis for lesions in which a typical-appearing benign PVNS coexists with frankly malignant areas, or when the original lesion is typical of a benign variant and the recurrence seems to be malignant. Swelling and pain of the affected joint are the main symptoms.
Biopsy reveals nodules that invade surrounding soft tissues, with diffuse, compact sheets and fascicles of oval and round cells with large hyperchromatic nuclei and more prominent nucleoli than are found in typical cases of PVNS. Atypical mitosis is seen, as well as diffuse necrotic areas.
Wide excision is essential to avoid recurrences, and amputation is required in some cases. These patients require long-term follow-up for local recurrence or metastatic disease even years after the initial presentation. Prognosis is not well documented; a case series reported by Bertoni and colleagues showed a mortality of 50% associated with pulmonary metastases.
Synovial sarcoma
Synovial sarcoma includes a spectrum of uncommon mesenchymal neoplasms that histologically resemble synovium, but there is not sufficient evidence that it truly arises from, or differentiates into, synovium. In general, the tumor develops primarily from soft tissues in periarticular regions of the extremities, usually the legs, and then invades the joint. Primary synovial sarcoma originating from articular synovium is extremely rare.
Synovial sarcoma accounts for 6% of all soft tissue sarcomas, with an incidence of 2.75 per 100,000 per year. It affects young adults 15 to 40 years of age, most commonly men. The most common manifestation is a painless mass, which occurred in half of the patients in one study. Less frequently, pain can be the initial complaint (15%). The presence of constitutional symptoms is rare (2%).
Radiographic findings show a round or oval radiopacity, usually located in close proximity to a large joint. About 20% of cases present a periosteal reaction or involvement of the underlying bone. The most characteristic radiologic finding is the presence of multiple spotty calcifications, found in 15% to 20% of patients. CT does not provide additional specific findings and MRI is useful for determining the extent of the lesion.
Two types of histology have been recognized. The classic biphasic type consists of epithelial cells lining glandular spaces that secrete chondroitin sulfate and hyaluronic acid, surrounded by fibroblastlike spindle cells that also secrete mucinous material. The monophasic variety is found in 39% of all cases, and only contains spindle cells arranged in cords, sheets, or nests.
Almost all patients present specific genetic translocations [t(X;18)(p11.2;q11.2)] that are rarely associated with other types of sarcomas. The translocation involves the fusion of the SYT gene on chromosome 18 with either the SSX1 or SSX2 gene on the X chromosome. Most tumors with SYT-SSX2 are monophasic, whereas almost all biphasic tumors have the SYT-SSX1 fusion.
In general, the tumor grows slowly, with a well-defined appearance, giving a misleading impression of a benign process that can delay the diagnosis for years. Metastatic lesions develop in about 50% of cases, most commonly to the lung, bone, and regional lymph nodes. Factors associated with poor prognosis include large tumor size, invasion of bone and neurovascular structures, metastases at the time of diagnosis, high-grade histology, and insufficient surgical resection. Treatment requires wide local resection or amputation. Recent evidence shows favorable oncologic and functional outcomes with wide excision surgery along with plastic surgery reconstruction to facilitate limb salvage. Surgery is often followed by radiation or chemotherapy. A recent study suggested that synovial sarcomas are more responsive to doxorubicin and ifosfamide treatment than other soft tissue sarcomas.
Local recurrence after adequate treatment is about 40%. Patients with synovial sarcoma should be followed for more than 10 years because of the high risk of developing late metastases with high mortality. Reported 5-year survival rates for synovial sarcoma range from 36% to 76%, and only 20% to 63% live for more than 10 years. Synovial sarcomas have immunohistochemical overexpression of the epidermal growth factor receptor (EGFR), and new targeted treatment options have emerged recently, using EGFR antagonists.
Metastatic synovitis
Solid Tumors
Arthritis caused by metastatic synovitis is a rare manifestation of solid tumors. Typically, there is a monoarthritis of a large joint, the knee being most frequently involved (>50%), commonly with a metastasis in the adjacent bone. There are many reported cases in the literature, most of them usually associated with adenocarcinoma, especially bronchogenic carcinoma and, less frequently, colon, renal cell, laryngeal, and breast carcinoma. Synovial fluid in malignant joint disease is usually sanguineous and noninflammatory. Cytologic examination of the synovial fluid can detect atypical cells (45%–63%), avoiding the need for biopsy of the synovium. Radiographs can be normal or show a lesion in the adjacent bone when it is compromised, which can also show increased uptake in technetium-99 bone scans. It is important to consider a synovial metastasis in patients with a history of previous malignancy presenting with unexplained monoarthritis, especially of a large joint. Generally, prognosis is poor, with average survival of less than 5 months. In addition to treatment of the underlying malignancy, palliative treatment with chemotherapy or radiation therapy in the affected joint usually provides relief of symptoms.
Leukemic Arthritis
Leukemic arthritis needs to be suspected in patients with leukemia who develop unexplained joint pain and swelling. The overall prevalence of leukemic arthritis in patients with leukemia is estimated to be 4% in adults and 14% in children. It is more frequent in acute than in chronic leukemia, and it can occur at any time in the course of the disease. Several mechanisms have been described, including direct infiltration of leukemic cells into the synovium, synovial reaction to periosteal or capsular infiltration, and hemorrhage caused by thrombocytopenia. Immune complex disease has also been proposed as a cause of arthritis in these patients. Overall, the predominant mechanism seems to be synovial infiltration. The arthritis is most commonly asymmetric and oligoarticular, and the joint most frequently affected is the knee. Typically, the patient complains of severe pain, out of proportion to the degree of the joint effusion, and often accompanied by systemic fever. Analysis of the synovial fluid is not always helpful, because blast cells are not commonly found in the synovial fluid. Blinded synovial biopsies may miss a focus of leukemic cells. Immunofluorescence, immunocytologic analyses, and flow cytometry are techniques that allow an increased diagnostic yield. Symptomatic treatment is disappointing. Leukemic arthritis improves with successful treatment of the underlying disease; refractory cases can be treated with radiation therapy.
Malignant Lymphomas
Lymphoma infiltration of the joints is extremely rare. In a series of more than 37,000 cases of lymphoma during a 6-year period, Krüger and colleagues reported only 20 cases (0.05%) of secondary infiltration of the joint. Large joints were more affected and low-grade lymphomas were more prevalent. Survival time was variable, ranging between 11 and 27 months, depending on the grade of malignancy and tumoral extension.
Metastatic synovitis
Solid Tumors
Arthritis caused by metastatic synovitis is a rare manifestation of solid tumors. Typically, there is a monoarthritis of a large joint, the knee being most frequently involved (>50%), commonly with a metastasis in the adjacent bone. There are many reported cases in the literature, most of them usually associated with adenocarcinoma, especially bronchogenic carcinoma and, less frequently, colon, renal cell, laryngeal, and breast carcinoma. Synovial fluid in malignant joint disease is usually sanguineous and noninflammatory. Cytologic examination of the synovial fluid can detect atypical cells (45%–63%), avoiding the need for biopsy of the synovium. Radiographs can be normal or show a lesion in the adjacent bone when it is compromised, which can also show increased uptake in technetium-99 bone scans. It is important to consider a synovial metastasis in patients with a history of previous malignancy presenting with unexplained monoarthritis, especially of a large joint. Generally, prognosis is poor, with average survival of less than 5 months. In addition to treatment of the underlying malignancy, palliative treatment with chemotherapy or radiation therapy in the affected joint usually provides relief of symptoms.
Leukemic Arthritis
Leukemic arthritis needs to be suspected in patients with leukemia who develop unexplained joint pain and swelling. The overall prevalence of leukemic arthritis in patients with leukemia is estimated to be 4% in adults and 14% in children. It is more frequent in acute than in chronic leukemia, and it can occur at any time in the course of the disease. Several mechanisms have been described, including direct infiltration of leukemic cells into the synovium, synovial reaction to periosteal or capsular infiltration, and hemorrhage caused by thrombocytopenia. Immune complex disease has also been proposed as a cause of arthritis in these patients. Overall, the predominant mechanism seems to be synovial infiltration. The arthritis is most commonly asymmetric and oligoarticular, and the joint most frequently affected is the knee. Typically, the patient complains of severe pain, out of proportion to the degree of the joint effusion, and often accompanied by systemic fever. Analysis of the synovial fluid is not always helpful, because blast cells are not commonly found in the synovial fluid. Blinded synovial biopsies may miss a focus of leukemic cells. Immunofluorescence, immunocytologic analyses, and flow cytometry are techniques that allow an increased diagnostic yield. Symptomatic treatment is disappointing. Leukemic arthritis improves with successful treatment of the underlying disease; refractory cases can be treated with radiation therapy.
Malignant Lymphomas
Lymphoma infiltration of the joints is extremely rare. In a series of more than 37,000 cases of lymphoma during a 6-year period, Krüger and colleagues reported only 20 cases (0.05%) of secondary infiltration of the joint. Large joints were more affected and low-grade lymphomas were more prevalent. Survival time was variable, ranging between 11 and 27 months, depending on the grade of malignancy and tumoral extension.
Paraneoplastic synovitis
Paraneoplastic syndromes are a group of heterogeneous disorders associated with malignant diseases but that are not directly caused by the physical effects of the primary tumor or its metastases. The syndromes may be caused by (1) tumor production of substances that directly or indirectly cause distant symptoms; (2) depletion of normal substances, leading to paraneoplastic manifestation; or (3) host response to the tumor that results in the syndrome. The paraneoplastic syndrome may precede, coexist with, or develop after the cancer is diagnosed. It usually follows a parallel course with the tumor, generally improves, and even remits with the treatment of the underlying disease, and relapses with recurrences.
A patient with a malignant disease can present various rheumatic manifestations such as arthralgia, arthritis, myositis, vasculitis, panniculitis, or fasciitis. It is necessary to determine whether these manifestations are related to the malignancy, or whether they represent a primary rheumatic disease or adverse events associated with drug therapies. Clinicians should be aware of a paraneoplastic syndrome as the first sign of an occult malignancy, and its recognition may be critical for early tumor detection. This article reviews those rheumatic paraneoplastic syndromes that can present with synovitis.
Many paraneoplastic syndromes causing synovitis have been described in the literature. All of them are rare and epidemiologic evidence is scarce. The literature mostly consists of case reports and series that are insufficient to establish true prevalence or incidence rates.
Carcinoma Polyarthritis
This syndrome occurs in older patients with cancer and is characterized by abrupt onset of asymmetric arthritis, which can be oligoarticular or polyarticular, and with a migratory or additive pattern. It most often involves the large joints of the lower extremities, sparing the joints of the hands. Generally, the synovitis is not associated with erosions, deformities, or rheumatoid nodules, and previous family history of rheumatoid arthritis and rheumatoid factor are negative. However, symmetric arthritis, resembling rheumatoid arthritis, has been reported. In a series of 13 patients, rheumatoid factor was detected in 46%. This finding could be explained by the underlying malignancy and older age of patients, which can be associated with positive rheumatoid factor. The use of the anticyclic citrullinated peptide (anti-CCP) could be useful in these cases because the test seems to be negative in cancer-related arthritis.
The synovial fluid can be mildly inflammatory and the biopsy shows nonspecific synovitis. The differential diagnosis for carcinoma polyarthritis is broad and it is often a diagnosis of exclusion. Because it occurs in patients with advanced age, one of the most important differential disorders is late-onset rheumatoid arthritis, which can be difficult to exclude because carcinoma polyarthritis can appear before the diagnosis of cancer.
Carcinoma polyarthritis occurs in association with solid tumors such as breast, colon, lung, gastric, and ovarian cancer, as well as lymphoproliferative disorders. The pathogenesis of the disorder has not been clearly elucidated. Possible mechanisms include the deposit of immune complexes in the synovium, and cross reactivity between tumor antigens and the synovium. The arthritis usually responds to nonsteroidal antiinflammatory drugs (NSAIDs) and steroids. Its course can follow the underlying disease, with remissions depending on the response of the tumor to cancer therapy.
Remitting Seronegative Symmetric Synovitis with Pitting Edema
The syndrome of remitting seronegative symmetric synovitis with pitting edema (RS3PE) may be the initial manifestation of an idiopathic rheumatic disease in elderly patients or may present as a paraneoplastic condition. It is characterized by the sudden onset of symmetric arthritis involving predominantly the wrists, carpal joints, small hand joints, and the flexor sheaths, accompanied by marked dorsal swelling of the hands with pitting edema (boxing-glove hand). Pitting edema over the feet and pretibial areas is also observed in some patients. Typically, acute-phase reactants are increased, rheumatoid factor is persistently seronegative, and the edema is sensitive to small doses of steroids.
Paraneoplastic RS3PE is associated with several solid and hematologic malignancies. Prostatic, colonic, gastric, ovarian, and endometrial adenocarcinomas are the most commonly associated solid tumors. RS3PE has also been reported in patients with chronic lymphocytic leukemia, lymphoma, and myelodysplastic syndrome. The pathogenic mechanism is unknown but it has been postulated that the underlying neoplasia induces an immunogenic T cell inflammatory response. The presence of systemic signs and symptoms such as fever, anorexia, and weight loss, and poor response to low doses of steroids (10 mg/d), suggest paraneoplastic RS3PE.
Polymyalgia Rheumatica
Polymyalgia rheumatica is an inflammatory rheumatic condition in elderly patients, characterized by aching and morning stiffness in the truncal and proximal muscle groups of the shoulder, hip girdle, and neck area. In addition, it can be associated with an asymmetric and nonerosive synovitis, which usually affects knees, wrists, and metacarpophalangeal joints. Its association with malignancy is controversial, as are the recommendations for potential investigation of coexistent malignancy. Naschitz summarized atypical features of polymyalgia rheumatica that could suggest underlying occult cancer: age less than 50 years, asymmetric involvement, erythrocyte sedimentation rate less than 40 or higher than 100 mm/h, poor response to low doses of steroids, and long-lasting symptoms. Hematologic malignancies have been more frequently associated with this disorder, although solid tumors have also been reported recently.
Lupuslike Syndrome
This syndrome resembles systemic lupus erythematosus, and is characterized by nondeforming arthritis, serositis and Raynaud phenomenon. Antinuclear antibody is positive in 70% and anti–double-stranded deoxyribonucleic acid (DNA) in 50% of the cases. It has been associated with breast, lung and ovarian cancer, leukemia, and lymphoma. Treatment consists of NSAIDs and steroids.
Paraneoplastic Adult Still Disease
Adult Still disease is manifested by polyarthralgias/arthritis, spiking fever, and evanescent macular erythematous eruption. The association between this condition and cancer is uncommon and uncertain, and only a few cases have been reported in the literature.
Relapsing Polychondritis
Relapsing polychondritis is a rare disorder, diagnosed if at least 3 of the following signs are present: bilateral chondritis of the external ears, inflammatory polyarthritis, ocular inflammation, nasal chondritis, vestibular/auditory malfunction, and respiratory tract chondritis. A few cases have been described in association with malignancies, but causality remains uncertain. Symptomatic treatment consists of NSAIDs or steroids.
Jaccoud Arthropathy
Jaccoud arthropathy is a rapidly developing, nonerosive, deforming arthropathy, most commonly affecting the hands. On physical examination, no true joint effusion or tenderness is found, and there is no synovitis. It has been reported as the initial manifestation of lung carcinoma, but its causal relationship with cancer at large remains unclear.
Amyloid Arthritis
Amyloid arthropathy occurs in patients with multiple myeloma and results from the deposition of monoclonal light chains in the synovium. In a series of 43 patients with multiple myeloma, only 2 had amyloid arthritis. This synovitis can resemble rheumatoid arthritis with symmetric involvement of the upper extremities involving shoulders, wrists, and the small joints of the hands. The typical shoulder-pad sign is a visible enlargement of the anterior shoulder that results from swelling of the glenohumeral joint and amyloid deposition in periarticular soft tissues. Arthrocentesis reveals a noninflammatory synovial fluid and the sediment contains amyloid bodies that are synovial villi with amyloid deposits. Under polarized light microscopy using Congo Red staining, the amyloid deposits in the synovium and in the sediment appear apple-green birefringent. The presence of other clinical manifestations, including peripheral neuropathy, carpal tunnel syndrome, macroglossia, cardiomyopathy, and nephropathy, should alert the clinician to this potential diagnosis.
Therapy primarily consists of treating the underlying myeloma, and symptomatic treatment with analgesic or NSAIDs. The prognosis is poor.
Crystal-Induced Arthritis
Although gout and pseudogout are not always included in the classification of paraneoplastic arthritis, they can be considered as such because they can be caused by a substance, uric acid, produced through tumor lysis and resulting in remote effects such as gouty arthritis or, in severe cases, tumor lysis syndrome. The diagnosis is confirmed by the presence of crystals and inflammatory exudate in the synovial fluid. Secondary gout can occur with malignancies in which hyperuricemia is frequent through (1) increased urate production, as seen in myeloproliferative and lymphoproliferative disorders, and in solid tumors with the use of cytotoxic chemotherapy ; and (2) decreased renal clearance induced by drugs such as cyclosporine and tacrolimus. Although hyperuricemia is frequent in patients who have cancer, it is unclear how often these patients develop gouty arthritis. In a series of 63 patients with myeloproliferative disorders and gout, the development of arthritis was associated with the duration of the hematologic illness. In comparison with primary gout, patients with tumor-related gouty arthritis tend to be older, have no family history of gout, and have a higher prevalence of nephrolithiasis and tophi. Typical podagra is not common, with knees, elbows, and ankles being the most frequently affected joints. Generally, this arthritis is less responsive to routine therapy than primary gout. Preventive measures include aggressive intravenous hydration and the administration of hypouricemic agents, such as allopurinol, febuxostat, or rasburicase.
Pseudogout is caused by intraarticular deposition of calcium pyrophosphate dehydrate (CPPD) crystals. It most often occurs as monoarthritis or oligoarthritis. Plain radiographs show stippled calcifications of articular and meniscal cartilage (chondrocalcinosis) predominantly in knees, wrists, hips, and the pubic symphysis. Pseudogout can occur in patients who have cancer who develop severe and persistent hypercalcemia. This hypercalcemia can be caused by the ectopic secretion of different substances (PTH-related protein, 1,25-(OH) 2 D 3 , or cytokines) by the tumor. Hypercalcemia is most commonly observed in patients with lung, breast, and hematologic cancer. The increased serum calcium may predispose to CPPD crystallization in the joint. Joint aspiration combined with steroid injection is often sufficient for acute CPPD arthritis. In recurrent cases, oral NSAIDs and/or low-dose colchicine may relieve the symptoms. Low-dose corticosteroids, methotrexate, and hydroxychloroquine have been used in patients with primary chronic disease unresponsive to other therapies.
Hypertrophic Osteoarthropathy
Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of the skin and osseous tissue at the distal parts of the extremities. Prominent clinical features of HOA include digital clubbing and periostitis of tubular bones. Mild accompanying synovitis can also occur, most commonly in the knees, ankles, wrists, and metacarpophalangeal joints. The synovial fluid is a noninflammatory liquid, however the histology shows mild synovitis with vascular dilatation and sparse lymphocytic infiltration.
Plain radiographs reveal periosteal thickening that can involve only a few bones or all tubular bones, with normal joints. Acro-osteolysis may be found in severe and long-standing cases. Isotopic bone scans can show a pericortical, linear concentration of the radionuclide along the shafts of affected bones and allow detection in early stages, even before the development of symptoms.
HOA is most often associated with non–small cell lung cancer (squamous cell or adenocarcinoma). Other rarely associated tumors include nasopharyngeal cancer, mesothelioma, renal cell carcinoma, esophageal cancer, gastric tumor, pancreatic cancer, breast phyllodes tumor, melanoma, thymic cancer, and Hodgkin lymphoma.
The pathogenesis remains unknown and several theories have been proposed. Initially, neural involvement was thought to play a role, given the good response to vagotomy and atropine. More recently, it has been observed that platelet-derived growth factors (PDGF) are increased in HOA, and some investigators have proposed that the release of PDGF-like factors by neoplasia can cause this disorder.
If the primary cause can be treated, the symptoms of HOA are most likely to improve or resolve. Symptomatic treatment includes analgesics, NSAIDs, or low-dose steroids, if needed. Unilateral thoracic vagotomy has been used in the past for severe cases in patients with lung cancer. Bisphosphonates and somatostatin analogues such as octreotide have also been proposed as therapy.
Palmar Fasciitis and Polyarthritis
Palmar fasciitis is a disabling paraneoplastic condition characterized by a severe symmetric thickening of the palmar fascia affecting the flexor retinaculum and the flexor tendons of the hands, resulting in claw hands. Articular involvement of the upper extremities can occur, and, in the shoulders, it can result in severe adhesive capsulitis. The course of the disease is severe and rapidly progressive.
This fibrosing disorder was initially described in patients with ovarian carcinoma. More recently, it has also been associated with breast, lung, pancreatic, stomach, prostate, and uterine cancer. Clinical differential diagnoses include Dupuytren, scleroderma, eosinophilic fasciitis, reflex sympathetic dystrophy, and diabetic cheiroarthropathy.
Treatment is disappointing. The symptoms rarely respond to analgesics, NSAIDs, steroids, physical therapy, or ganglion blockade. In general, successful tumoral excision is followed by an improvement of the symptoms, or at least by the arrest of the progression.
Panniculitis and Arthritis
Paraneoplastic panniculitis results from subcutaneous fat necrosis with the subsequent development of multiple erythematous and painful nodules, often in the lower extremities. The nodules may ulcerate and secrete an oily substance. When they develop adjacent to a joint, a reactive synovitis can occur. Skin biopsy shows steatonecrosis, and ghost-like cells characterized by a thick wall with no nucleus are pathognomonic of this condition.
This entity is associated with pancreatitis and pancreatic cancer, and should be suspected in patients who present with weight loss and jaundice. However, it usually occurs late in the course of the disease and may not be helpful for an early diagnosis of pancreatic cancer. 115 It has been postulated that the lipase and amylase that are increased in the serum of these patients increase the permeability of the microcirculation, inducing fat necrosis. Treatment is challenging because panniculitis is often resistant to treatment with steroids.
Multicentric Reticulohistiocytosis
Multicentric reticulohistiocytosis is a systemic disease of unknown cause, characterized by a reactive proliferation of histiocytes in nodules in the skin, mucosa, subcutaneous tissue, synovium, and bone. This disorder is very rare, and a review of 96 case reports published in the last 34 years describes an association with cancer in up to 31%. Articular involvement is the initial manifestation in 40% of the patients, associated with skin lesions in 29%. The arthritis most often affects the wrists, metacarpophalangeal joints, and distal interphalangeal joints, although any joint can be involved. Typically, the arthritis is destructive with radiographic marginal erosions. The clinical course can be relapsing and remitting, and can be severe with progression to arthritis mutilans.
Skin lesions show reddish, brown, pink, or gray papules or nodules that typically affect hands, face, trunk, legs, and mucosa. These lesions can cluster around the nail, resulting in an appearance of a string of coral beads, which is pathognomonic. In addition, xanthelasmas and vermicular lesions bordering the nostrils are found. Skin biopsy shows histiocytic multinucleated giant cells with eosinophilic, finely granulated, and ground-glass cytoplasm, which are hallmarks of the disease.
Treatment consists of analgesics, NSAIDs, and steroids as needed. Successful treatment has been reported using alkylating agents, methotrexate, and, more recently, with tumor necrosis factor inhibitors. This paraneoplastic disorder can persist despite treatment of the concomitant malignancy. Nevertheless, it usually remits spontaneously after a few years.
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Neoplasm Mimics of Rheumatologic Presentations: Sialadenitis, Ocular Masquerade Syndromes, Retroperitoneal Fibrosis, and Regional Pain Syndromes
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