Paraneoplastic Musculoskeletal Syndromes and Hypertrophic Osteoarthropathy
Alan T. Kaell
INTRODUCTION
If a close temporal relation exists between the discovery of a malignancy and the onset of a rheumatic syndrome, an association is often presumed. In many cases, the association may be coincidental. In other cases, the response of the rheumatic syndrome to successful management of the malignancy suggests an inter-relation of the two problems. Similarly, the recurrence of a rheumatic syndrome that heralds or follows the relapse of a malignancy is an even stronger indication of a pathogenetic linkage.
The clinical and temporal relation between various rheumatic syndromes and malignant neoplasms takes any one of several forms.
Rheumatic syndrome as a manifestation of an established or occult malignancy.
Malignancy occurring in the setting of an established rheumatic syndrome.
Malignancy as a complication of antirheumatic therapy.
Rheumatic syndrome as a complication of antineoplastic therapy.
ETIOPATHOGENESIS
The pathogenesis of a rheumatic syndrome in a patient with cancer may be known.
Cancer may primarily involve joints, bones, muscles, blood vessels, or nerves and thereby mimic rheumatic disease. Examples of this include neuroblastoma and leukemia in children.
Alternatively, cancer may invade adjacent tissues or secondarily metastasize to such tissues. This is seen in both solid neoplasms and hematologic malignancies.
Hyperuricemia from high cellular turnover (e.g., leukemia) may manifest as gout.
The pathogenesis of a rheumatic syndrome in a patient with cancer is often unknown and remains speculative.
Systemic manifestations of cancer can occur without tissue invasion by the tumor itself. Such remote effects, or paraneoplastic phenomena, may present as rheumatic syndromes. A cytokine or immune-mediated pathogenesis is likely. Dermatomyositis (DM) in patients with ovarian carcinoma is an example of this phenomenon.
In hypertrophic osteoarthropathy (HOA) (pulmonary), the pathogenesis remains speculative. Humoral factors such as platelet-derived growth factors, cellular, neural, and vascular mechanisms have been suggested.
The pathogenesis of increased lymphoma in certain patients with rheumatic disease is unknown but may reflect underlying immune dysregulation, abnormalities in apoptosis, genetic predispositions, or a risk associated with certain therapies.
The pathogenesis of increased malignancy associated with certain therapies is unknown but may reflect alterations in immune surveillance. The determination of the reasons for excess cases of cancer is confounded by the lack of ideal control groups, an unknown denominator of patients with the illness, and the necessity to utilize historical databases.
An increased incidence of large B-cell non-Hodgkin’s lymphoma (NHL), noted with untreated classic rheumatoid arthritis (RA) and Sjögren’s syndrome, is perhaps related to abnormalities in apoptosis.
Lymphoma and certain solid neoplasms are associated with some immunosuppressive therapies, presumably reflecting alterations in tumor surveillance or apoptosis. Patients with RA and on treatment with methotrexate also develop non-Hodgkin’s lymphomas that contain Epstein-Barr virus (EBV), the latter likely acting as a cofactor along with the medication given.
Finally, some therapies for cancer may be associated with rheumatic syndromes. The pathogenesis remains speculative.
PREVALENCEI. RHEUMATIC SYNDROME AS A MANIFESTATION OF AN ESTABLISHED OR OCCULT MALIGNANCY
The incidence of malignancy presenting as a rheumatic disease is unclear, but likely ranges between 1% and 10% of all malignancies. The incidence is likely to be higher for HOA and DM. Unclassified rheumatic disorders in hospitalized patients may be associated with an underlying occult neoplasm in up to 24% of cases during a 2-year period. The frequency may be higher in men and patients older than 50 years. The malignancy is usually discovered on routine physical examination.
HOA (Table 57-1)—the incidence of HOA is highest among patients with lung cancer.
DM—may herald underlying malignancy of any type. Overall, malignancy occurs in 5% to 20% of individuals with myositis. DM has a stronger association with cancer than does polymyositis and inclusion body myositis. The association is most apparent in men older than 40 years. Myositis may precede the discovery of a malignancy by several months to a few years. Among the many types of malignancies that present with myositis, lung, breast, and ovarian carcinomas are the most common.
Polyarticular, pauciarticular, or monarticular arthritis as a presenting manifestation of malignancy is less than 1% for solid neoplasms, but is more likely in hematologic neoplasia. An age-appropriate cancer assessment needs to be done in all patients presenting with arthritis.
II. MALIGNANCY OCCURING IN THE SETTING OF AN ESTABLISHED RHEUMATIC SYNDROME
The observed number of cases of any particular type of cancer in patients with a rheumatic disease is likely to exceed the expected number of cases of cancer seen in sex- and age-matched general population. If therapy appears to be associated with an observed increase in malignancy, then the expected number of cases of cancer should be determined from a disease- and age-matched, untreated population. Unfortunately, such data are sparse.
Patients with RA do not appear to have an overall increased risk of cancer, and the risk of gastrointestinal neoplasms may be decreased compared to the general population.
Patients with RA do have a higher relative risk of Hodgkin’s disease, NHL, and leukemia compared to the general population. This increased risk of NHL correlates with the severity and duration of RA and is independent of drug therapy. The copresence of Sjögren’s syndrome raises this risk. The risk ranges from two- to 25.8-fold for patients with the most severe RA, and this risk is thought to increase by 2.6 times for every 10 years of increase in age. The mean time between the onset of RA and NHL ranges from 11 to 17 years.
DM is associated with all types of cancer. Incidence varies widely, depending upon the series studied.
Patients with hepatitis C and its rheumatic complications have a higher risk of NHL.
Patients with systemic lupus erythematosus (SLE) exposed to cyclophosphamide are at increased risk for leukemia and bladder cancer.
Clubbing or HOA may signal underlying neoplasia (see Table 57-1).
Progressive systemic sclerosis can be associated with bronchoalveolar cell carcinoma.
Patients with Wegener’s granulomatosis exposed to cyclophosphamide are at increased risk for leukemia and bladder cancer.
III. Malignancy as a complication of antirheumatic therapy
may be associated with an increased risk of malignancy or NHL. The true incidence of these associations is difficult to ascertain and range between 0.1% and 3%. In some cases, the underlying disease may predispose to the malignancy (e.g., RA, Sjögren’s syndrome, and hepatitis C). In other
cases, the risk of malignancy is more directly related to drug exposure (e.g., cyclophosphamide) and may correlate with the dose and duration of exposure as well as postexposure duration. There are inherent statistical and epidemiologic problems in defining the actual cancer risk in diseases in which we are unaware of the number of patients with the disease; the screening of all patients with cancer is incomplete; the confirmation of the diagnosis is not certain; and the monitoring systems are poor.
cases, the risk of malignancy is more directly related to drug exposure (e.g., cyclophosphamide) and may correlate with the dose and duration of exposure as well as postexposure duration. There are inherent statistical and epidemiologic problems in defining the actual cancer risk in diseases in which we are unaware of the number of patients with the disease; the screening of all patients with cancer is incomplete; the confirmation of the diagnosis is not certain; and the monitoring systems are poor.
Table 57-1 Conditions Associated with Hypertrophic Osteoarthropathy | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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Azathioprine (Imuran)—NHL.
Methotrexate—NHL, in particular, EBV-associated.
Cyclophosphamide (Cytoxan)—bladder carcinoma/leukemia.
Anti-tumor necrosis factor-α(anti-TNF-α) biologics. The use of biologics to date is not associated with an increased incidence of observed solid malignancies over that expected in the general population or patients with RA. NHL incidence is elevated in patients with RA treated with TNF-α antagonists, but this has been attributed to
the known higher incidence associated with RA itself. Because the experience with these drugs is only for 6 years, longer observation is needed.
Anti-interleukin (IL-1) anakinra (Kineret)—no clear and convincing evidence of excess malignancies.
Leflunomide (Arava)—no clear and convincing evidence of excess malignancies exists.
IV. RHEUMATIC SYNDROME AS A COMPLICATION OF ANTINEOPLASTIC THERAPY
(See section Clinical manifestations.) The incidence of rheumatic syndromes related to antineoplastic therapies is variable and ranges from 1% to 25% depending upon the agent and the syndrome. The interferon agents and neutrophil growth factors such as granulocyte–colony-stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF have the highest incidence of nonspecific myalgias and arthralgias.
CLINICAL MANIFESTATIONSThe clinical and temporal relation between various rheumatic syndromes and malignant neoplasms can take any one of several forms.
I. RHEUMATIC SYNDROME AS A MANIFESTATION OF AN ESTABLISHED OR OCCULT MALIGNANCY
Primary bone and joint neoplasms. Primary bone tumors such as chondrosarcoma, giant cell tumor, and osteogenic sarcoma may present as monarticular pain. They can either directly invade the joint capsule and synovium or induce a synovial reaction by involving juxta-articular bone.
Tenosynovial sarcomas are rare and usually present as a painless soft-tissue mass near a joint of the lower extremity. Extension directly into the joint is uncommon.
Lymphoproliferative disorders
Leukemia. Leukemic cells may directly infiltrate articular tissues. Polyarthritis occurs more often with hematologic malignancies than with solid neoplasms. In childhood, the metaphyseal portion of bones is occupied by red marrow. Acute lymphocytic leukemia can present as a migratory or symmetric polyarthritis by infiltrating the periosteum, joint capsule, or metaphysis. It may even mimic rheumatic fever or juvenile idiopathic arthritis (JIA). The ankle or knee is usually involved. Characteristically, the joint pain is quite severe, awakens children at night, and is disproportionate to any physical findings. The erythrocyte sedimentation rate (ESR) may be normal. Articular manifestations may develop before the appearance of leukemic cells in the peripheral blood. An elevated serum lactate dehydrogenase or mild leukopenia may help distinguish children with malignant neoplasms who present with musculoskeletal complaints from those who ultimately have JIA. In some cases, immunocytologic analysis can identify leukemic cells in synovial fluid.
Vasculitis seen in patients with leukemia is usually limited to cutaneous involvement. Recurrent leukemic infiltrations into muscles may mimic localized, tender swelling of polyarteritis. Hairy-cell leukemia has been associated with polyarteritis nodosa. Rheumatic manifestations can precede or follow the clinical onset of leukemic symptoms and diagnosis. Pathogenesis involves either leukemic infiltration or immune-driven inflammation.
Lymphoma. Monarticular or polyarticular symptoms may be related to lymphomatous involvement of juxta-articular bone. Both Hodgkin’s and NHL may present with musculoskeletal symptoms. This is attributed to either induction of a synovial reaction by adjacent osseous lymphoma or direct invasion of the joint capsule or synovium. In patients with T-cell lymphomas, a chronic polyarthritis may also develop.
Vasculitis associated with lymphoma is usually limited to cutaneous involvement, presumably on an immune basis. In rare patients with intravascular lymphoma, multiorgan involvement may mimic vasculitis and symmetric polyarthritis.
Angioimmunoblastic lymphadenopathy can be associated with rash, polyarthritis, polyclonal hypergammaglobulinemia, and Coombs’-positive hemolytic anemia. This condition may mimic SLE.
Myelodysplastic disorders have also been associated with a variety of musculoskeletal symptoms and signs, including polyarthritis, lupuslike conditions, polychondritis, vasculitis, and erythromelalgia.
Gout, secondary to rapid cell turnover or tumor lysis, is seen mainly in patients with leukemias and lymphomas. Institution of allopurinol helps prevent this complication. The dosage of azathioprine and 6-mercaptopurine must be reduced by 75% or avoided if the patient receives concomitant allopurinol therapy.
Paraproteinemias
Amyloid arthropathy is attributed to deposition of amyloid light chain protein and is associated with dysproteinemias, such as multiple myeloma. It occurs in up to 5% of patients with myeloma and is more common in men and those with γ light chains. This arthropathy can mimic RA and is associated with carpal tunnel syndrome, shoulder pad sign, and nodules. Erosions are rarely noted. Additional clinical clues that warrant consideration of amyloidosis are hepatosplenomegaly, congestive heart failure, macroglossia, pinch purpura, raccoon eyes, and nephrosis. Biopsy sites to establish a tissue diagnosis include abdominal fat, rectum, synovium, and bone marrow.
POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) can mimic a systemic, multiorgan rheumatic disorder. The skin changes are similar to those of scleroderma. Raynaud’s phenomenon, digital ischemic necrosis, and vasculitis may occur in patients with dysproteinemias. Tendon xanthomas, typically seen in familial hypercholesterolemia, have been reported with near-normal lipid levels in patients with dysproteinemias such as multiple myeloma and monoclonal gammopathy of unknown significance (MGUS).
Metastatic carcinomatous arthritis associated with solid neoplasms. Metastatic deposits of solid neoplasms in bone, synovium, or periarticular tissue can masquerade as monarthritis or polyarthritis. This is a rare occurrence.
In children, neuroblastoma should be considered as a cause of metastatic carcinomatous arthritis. In most instances, the primary neoplasm is evident. If the tumor is occult, tomography, bone scan, or biopsy becomes necessary for accurate diagnosis. In general, therapy is directed toward the underlying neoplasm.
HOA
The clinical presentation is one of periostitis and chronic periosteal reaction. Periostitis occurs predominantly at the distal ends of the long bones. The term periostosis may more accurately describe these radiologic changes without necessarily implying an inflammatory mechanism. If early periostitis is not evident on plain radiographs, bone scan is useful in demonstrating its presence. Patients present with symmetric painful tenderness and swelling near the wrist and ankle regions. The discomfort is typically exacerbated by dependency of the limb, and relieved by its elevation. Periostitis without clubbing does not constitute HOA. Periostitis alone can occur in hypervitaminosis A and retinoic acid toxicity, thyroid acropachy, hyperphosphatemia, and sarcoidosis.Related posts:
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