Carcinomatous Polyarthritis

The term carcinomatous polyarthritis is used to describe the development of arthritis in association with malignancy, but it is distinct from arthritis associated with metastasis or direct tumor invasion. Table 122-2 lists common features of carcinomatous polyarthritis. It generally occurs in patients who are older; it has an explosive onset and often develops in close temporal correlation with discovery of the malignancy. Although it can have various presentations and may mimic the appearance of rheumatoid arthritis (RA)² or asymptomatic migratory polyarthritis,³ carcinomatous polyarthritis is more often a seronegative asymmetric disease with predominant involvement of the lower extremities and some sparing of the small joints of the hands. No evidence of direct tumor extension or metastasis has been found, and no specific histologic or radiographic appearance has been identified. Carcinomatous polyarthritis can occur in association with many types of malignancy, but has been reported in greatest frequency in association with breast, colon, lung, and ovarian cancers and with lymphoproliferative disorders.⁴ The underlying pathogenesis of this process has not been elucidated; however, the arthritic symptoms may be improved with successful treatment of the malignancy.⁵

Table 122-2 Features of Carcinomatous Polyarthritis

Vasculitis

Vasculitis in association with malignancy is uncommon and has a reported prevalence of only 8% among patients with malignancy.⁶ The association seems to be significantly higher with lymphoproliferative and myeloproliferative disorders than with solid tumors, and vasculitis commonly predates the identification of malignancy. The vasculitic process is most often small vessel and cutaneous and only rarely involves significant organs. Up to 5% of patients with cutaneous vasculitis have an underlying neoplasm.⁷ Treatment often requires the use of glucocorticoids and therapy directed against the underlying malignancy, although it seems that this is often ineffective. Table 122-1 shows malignancies associated with vasculitis. In the setting of malignancy, it is believed that persistent antigen stimulation from the tumor results in T cell activation or immune complex formation and deposition.

The development of small vessel vasculitis has been reported to antedate and postdate the development of lymphoproliferative and myeloproliferative diseases. One group looked retrospectively at 222 patients with vasculitis and identified 11 who had developed an associated malignancy.⁸ Of these 11 patients, 7 had hematologic neoplasia, and 4 had malignant solid tumors. Nine of the patients manifested cutaneous vasculitis, and the remaining 2 had vasculitic involvement in the bowel. In 4 patients, the development of vasculitis antedated the diagnosis of malignancy.⁸ Similar findings were reported by investigators, who found an underlying malignancy in 8 of 192 patients with cutaneous vasculitis. Most malignancies were hematologic (6 of 8) and predated (5 of 8) the diagnosis of cancer.⁹ In a retrospective analysis of 23 patients with cutaneous vasculitis and hematologic malignancies, the authors were able to attribute the presence of vasculitis to the malignancy itself in 61% of cases.¹⁰

Systemic vasculitis is much less commonly associated with underlying malignancy. Case reports and small series have found antineutrophil cytoplasmic antibody (ANCA)–negative and ANCA-positive vasculitis associated with hematologic malignancies.^11–13 Granulomatosis with polyangiitis (GPA) (formerly Wegener’s granulomatosis) has likewise been associated with the development of several types of malignancies, including lymphoproliferative disorders, bladder cancer, and renal cell carcinoma.^14,15 In some cases, the malignancy was diagnosed within months of the diagnosis of GPA,¹⁴ and in other reports, cancer developed many years after diagnosis and treatment of vasculitis,¹⁵ making it unclear whether the malignancies were a result of the vasculitis or possibly the treatment. A group from the Cleveland Clinic did a retrospective study to assess directly the temporal relationship between vasculitis and cancer.¹⁶ During an 18-year study period, the authors found only 12 cases of vasculitis and cancer diagnosed within the same 12-month period: Six patients had lymphoproliferative disorders, and 6 had solid tumors. In most cases, the vasculitis responded partially to immunosuppressive therapy, but investigators observed a more impressive improvement in vasculitis with definitive treatment for the underlying malignancy. A more recent study found 20 cases of malignancy among 200 patients with ANCA-positive vasculitis; 6 were diagnosed concurrently with a diagnosis of vasculitis, and 14 predated vasculitis by a median of 96 months.¹⁷ Only 4 of 20 malignancies in this series were lymphoproliferative; the remaining malignancies were solid organ tumors.

Vasculitis associated with underlying malignancy is often poorly responsive to conventional therapy directed against the vasculitis. In one series of 13 patients with cutaneous vasculitis and lymphoproliferative or myeloproliferative disorder, symptoms of vasculitis were poorly responsive to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, antihistamines, and antiserotonin agents. Although investigators described lessening of the severity of vasculitis after chemotherapy directed against the malignancy, they generally found chemotherapy to be ineffective. Of 13 patients identified, 10 died as a direct result of the malignancy.¹⁸ Similarly, Hutson and Hoffman¹⁶ found general concurrence between improvement in vasculitic syndrome and definitive treatment for the associated underlying malignancy. More recently, a study of cutaneous small vessel vasculitis associated with solid tumors (most commonly lung, breast, and prostate) found a significant response to immunosuppressive therapy directed against the vasculitis, although concurrent treatments for the underlying malignancy were undertaken.¹⁹

Cryoglobulinema

Cryoglobulins are immunoglobulins that precipitate at reduced temperature. Cryoglobulinemia can be characterized by hyperviscosity symptoms or by vasculitis. Patients often have fatigue, arthralgia or arthritis, cutaneous vasculitis or purpura, neuropathy, digital ischemia, and visceral organ involvement (renal or pulmonary). Three types of cryoglobulins have been identified:

Panniculitis

The fasciitis-panniculitis syndrome, which includes eosinophilic fasciitis, is characterized by swelling and induration of the skin that extends into deeper subcutaneous tissues and is associated with fibrosis and chronic inflammation. Patients may develop arthritis and subcutaneous nodules similar to those seen in erythema nodosum. The arthropathy seems to be secondary to periarticular fat necrosis, can be monoarticular or polyarticular,²⁷ and may mimic RA or juvenile RA.²⁸ Blood and tissue eosinophilia is commonly, but not always, present.²⁹ This syndrome can be idiopathic and have a benign course, or it can be secondary to a variety of infectious, vascular, or traumatic events. In a few patients, the fasciitis-panniculitis syndrome is associated with an underlying malignancy. Hematologic malignancies are most often associated with this syndrome and are usually diagnosed concurrently or within the first year.^30,31 Pancreatic cancer and pancreatitis also can be associated with this syndrome.^27,28 Patients with cancer-associated fasciitis-panniculitis syndrome are predominantly female and are generally refractory to prednisone.²⁹

Palmar Fasciitis

Palmar fasciitis with arthritis is a syndrome characterized by progressive bilateral contractures of the digits, fibrosis of the palmar fascia, and inflammatory polyarthritis.^32,33 The metacarpophalangeal and proximal interphalangeal joints are most commonly affected; other affected joints include the elbows, wrists, knees, ankles, and feet. Indurated reticulate palmar erythema can also be seen as part of the palmar fasciitis spectrum.³⁴ Palmar fasciitis is almost uniformly associated with the presence of an underlying malignancy, most often ovarian, breast, gastric, and pancreatic tumors.^33,35,36 Although initially thought to be an atypical variant of reflex sympathetic dystrophy, the severity of manifestations, bilateral presentation, and strong association with occult malignancy suggest that, in these cases, palmar fasciitis is a distinct entity that behaves as a paraneoplastic syndrome. Glucocorticoids, chemotherapy, or both do not seem to result in improvement, although fasciitis occasionally regresses with treatment of the underlying malignancy.³²

Reflex Sympathetic Dystrophy

Reflex sympathetic dystrophy and a variant, shoulder-hand syndrome, are characterized by regional pain, swelling, vasomotor instability, and focal osteoporosis in a given limb; this condition is thought to be caused by sympathetic dysfunction. Absence of associated antecedent factors, such as stroke, myocardial infarction, or trauma, and failure to respond to conventional therapy warrant a search for an underlying malignancy. A variety of malignancies have been associated with the development of reflex sympathetic dystrophy or its variants.^37,38 Pancoast tumor of the lung apices and other malignancies that infiltrate the stellate ganglion or brachial plexus have been described in patients with reflex sympathetic dystrophy.^39–41 Therapy directed against the underlying malignancy may lead to some amelioration of symptoms associated with reflex sympathetic dystrophy.

Erythromelalgia

Erythromelalgia is an enigmatic condition characterized by attacks of severe burning, erythema, and warmth of the extremities with symptoms predominantly involving the feet.^42,43 Symptoms are often exacerbated when the extremities are placed in a dependent position, during ambulation, or during exposure to increased temperatures. Partial relief can be obtained through elevation or cooling of the extremity. This disorder can occur idiopathically (60%) or secondary to another disease (40%).^42,44 Myeloproliferative disorders, including polycythemia vera and essential thrombocytosis, are common primary causes and have been found to precede the diagnosis of erythromelalgia by several years.^7,43,45 The underlying pathophysiology of this disease is unknown; however, it is often associated with thrombocythemia. In the largest published retrospective cohort, 168 patients at the Mayo Clinic were identified with this diagnosis between 1970 and 1994.⁴⁶ The authors found that after a mean follow-up of 8.7 years, 31.9% of patients reported worsening of disease, 26.6% reported no change, 30.9% reported improvement, and 10.6% reported complete resolution of symptoms. Kaplan-Meier survival curves revealed a significant decrease in survival compared with controls. A history of myeloproliferative disease was found in 15 of 168 patients. The exact cause of the symptoms is unclear, but microvascular arteriovenous shunting has been hypothesized.⁴⁷ In cases of secondary erythromelalgia, platelet breakdown products and platelet microthrombi may underlie disease pathogenesis.⁷ The most effective therapy seems to be the use of daily aspirin, leading to significant relief of symptoms, which is believed to be related to inhibition of cyclooxygenase-1. A host of other therapies have been tried with varying success.⁴⁸ Because of the association with myeloproliferative diseases, routine monitoring with complete blood counts is prudent.

Polymyalgia Rheumatica

Polymyalgia rheumatica is a disorder affecting older adults that manifests with discomfort and stiffness in the shoulder and hip girdle, fatigue, anemia of chronic disease, and elevated erythrocyte sedimentation rate (ESR). Classically, this condition responds to moderate doses of prednisone within 48 hours. A variety of other conditions can have presentations that mimic polymyalgia rheumatica, including other rheumatic disorders, systemic infections, and malignancy.⁴⁹ Although the association between polymyalgia rheumatica and malignancy has been controversial, atypical features of polymyalgia rheumatica may suggest the presence of occult malignancy, including age younger than 50 years, limited or asymmetric involvement of typical sites, ESR less than 40 mm/hr or greater than 100 mm/hr, severe anemia, proteinuria, and poor or delayed response to 20 mg daily of prednisone. Kidney, lung, and colon cancer and multiple myeloma are most often found in patients presenting with atypical polymyalgia rheumatica.^50–52 One study of patients undergoing evaluation for possible polymyalgia rheumatica found 10% to have a diagnosis of malignant neoplasms.⁵³ In contrast, several prospective studies have shown that patients who present with classic polymyalgia rheumatica or temporal arteritis do not seem to have an increased risk of developing malignancy over age-matched controls.^54–58

Raynaud’s Phenomenon and Digital Necrosis

The development of digital necrosis or profound Raynaud’s phenomenon may suggest the presence of infection, inflammatory disease, or an underlying malignancy. In patients older than 50 years, the development of Raynaud’s phenomenon, particularly in an asymmetric fashion or in association with digital necrosis, should raise the possibility that this is a paraneoplastic process. These features often antedate the diagnosis of the malignancy by an average of 7 to 9 months.^59,60 A variety of solid tumors and lymphoproliferative disorders have been associated with this syndrome.^59–65 Certainly, the presence of digital necrosis in patients with dermatomyositis is highly suggestive of the presence of an underlying malignancy. Mechanisms proposed include cryoglobulinemia, immune complex–induced vasospasm, hypercoagulability, marantic endocarditis with emboli, and necrotizing vasculitis.⁶⁵ Therapy with interferon-α also has been reported in association with the development of Raynaud’s phenomenon and digital necrosis.^66–68

Remitting Seronegative Symmetric Synovitis with Pitting Edema

Remitting seronegative symmetric synovitis with pitting edema (RS₃PE) is an uncommon disorder primarily affecting the metacarpophalangeal joints and the wrists. Although the underlying cause and pathogenesis of this illness are unclear, lymphoma, myelodysplastic syndromes, and several solid tumors, mostly adenocarcinoma, all have been reported in association with it.^69–73 One retrospective study from a single center in the United States found that 3 of 14 patients with RS₃PE developed cancer.⁷⁴ Characteristics that suggest possible underlying malignancy include the presence of systemic features, such as fever or weight loss, and a poor response to glucocorticoids.^71,72

Multicentric Reticulohistiocytosis

Multicentric reticulohistiocytosis is a rare condition characterized by the presence of cutaneous papules often associated with a destructive arthritis of the interphalangeal joints of the hands. The papules are flesh-colored to brown-yellow and are classically present in the periungual region and on the dorsal hands and face. Arthritis mutilans may develop in 50% of cases. The characteristic histologic appearance of tissue infiltration with histiocytes and multinucleated giant cells can be found in affected skin, joints, and occasionally internal organs.⁷⁵ Multicentric reticulohistiocytosis has been reported in association with hyperlipidemia, malignancies, and autoimmune diseases. Malignancy has been associated in 25% to 31% of cases, although most literature consists of individual case reports.^76,77 The most frequently seen malignancies include carcinoma of the lung, stomach, breast, cervix, colon, and ovary.⁷⁵

Lupus-like Syndromes

Lupus-like syndromes are rarely associated with underlying malignancy. Isolated case reports have described lupus-like syndromes with ovarian carcinoma^78,79 and hairy cell leukemia⁸⁰; subacute cutaneous lupus was reported in a patient with breast carcinoma.⁸¹ Studies on the presence of antinuclear antibodies (ANAs) in patients with cancer have yielded mixed results. Two studies were unable to find a significantly increased prevalence of ANAs in patients with solid tumor or lymphoma compared with healthy controls.^82,83 In contrast, one smaller study found an increased prevalence in patients with non-Hodgkin’s lymphoma compared with controls (21% vs. 0),⁸⁴ and another study found a prevalence of ANAs of 27.7% in 274 patients with various malignancies compared with 6.45% of 140 healthy controls.⁸⁵ No predictive features seem to suggest occult malignancy in patients presenting with lupus-like syndromes or positive ANAs.

Antiphospholipid Antibodies

Antiphospholipid antibodies and their association with thromboses have been described as a primary syndrome and a secondary phenomenon in autoimmune diseases, primarily SLE. More recently, antiphospholipid antibodies have been associated with a variety of malignancies. Correlations between antiphospholipid antibodies in cancer patients and thromboembolic events have been less clear, however.

Several studies have shown the presence of antiphospholipid antibodies in patients with solid tumors and lymphoproliferative disorders at a higher frequency than the 1% to 5% seen in the general population.^86,87 An early study of 216 consecutive patients with cancer found 22% positive for anticardiolipin antibodies compared with 3.4% in controls. This study found a two-fold increase in the development of thromboembolism in patients with positive antibodies compared with patients with negative serologies; it also indicated that most thromboembolic events occurred in patients with higher antibody titers.⁸⁸ Other studies have confirmed the association between malignancy and antiphospholipid antibodies (12.5% to 68%), but have been unable to show a correlation with thromboembolic events.^{84,86,89–93} A correlation between antibody titer and disease activity has been shown in some studies,^81,83 and decreased survival in others.^93,94 A review of the literature concluded that antiphospholipid antibodies resolve in one-third of cancer patients after treatment for the underlying malignancy.⁹⁵

Studies of the prevalence of antiphospholipid antibodies in unselected patient populations have shown an association with underlying malignancy. A prospective study in France found that 7% of 1014 consecutive patients admitted to a medical ward had antiphospholipid antibodies.⁹⁶ In antibody-positive patients, cancer was the most frequently associated disease. A more recent study in patients presenting with a first ischemic stroke found a significantly higher rate of development of cancer within 12 months in patients who had anticardiolipin antibodies (19% vs. 5%).⁹⁷

Osteomalacia

Osteomalacia is the softening of bones often associated with failure of adequate calcification secondary to renal dysfunction or to lack of vitamin D. Osteomalacia has been associated with benign and malignant solid tissue and mesenchymal tumors.⁹⁸ Tumors causing oncogenic osteomalacia have been shown to overproduce fibroblast growth factor 23 (FGF-23), and elevated serum levels of FGF-23 can be detected in patients with this paraneoplastic condition.^99,100 Octreotide scintigraphy may be a useful tool for identifying occult tumors.¹⁰¹ With removal of the tumor, there often seems to be resolution of the osteomalacia and normalization of serum FGF-23 levels.¹⁰⁰

Sarcoidosis

Noncaseating granulomata can occur in numerous settings and are not pathognomonic for sarcoidosis. Granulomata resembling those of sarcoidosis may be found in lymph nodes that drain sites of malignancy. These tumor-related tissue reactions resulting in granuloma formation have been described with many types of malignant lesions, including solid tumors and lymphomas.^102,103 The clinical and radiographic presentation of sarcoidosis and cancer can be virtually indistinguishable, making it important to pursue aggressive evaluation in a patient with sarcoidosis.^104,105

The risk of malignancy developing in patients with an established diagnosis of sarcoidosis is controversial. Some studies have shown an increased risk of developing lung cancer and lymphoma,^106–108 whereas others have shown no increased risk of cancer over the general population.^104,109,110

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is a rare disorder with angiodestructive and lymphoproliferative features involving the lung and, less often, the skin and central nervous system. Although lymphocytic infiltration of vessels is a hallmark of the disease, lymphomatoid granulomatosis now seems to fall within the spectrum of lymphoproliferative disorders.¹¹¹ Despite the predominance of T cells within inflammatory infiltrates, studies have suggested that an Epstein-Barr virus (EBV)-associated B cell proliferation may underlie the pathogenesis of the disease.^112,113 Prognosis is generally poor, with a median survival from diagnosis of 14 months,¹¹⁴ although more recent reports suggest some response to rituximab therapy.^115,116 Frank lymphomas evolve in 25% of cases.¹¹⁷

Sjögren’s Syndrome

Sjögren’s syndrome, an autoimmune exocrinopathy, is characterized by a benign lymphocytic infiltrate of salivary and lacrimal glands that leads to the development of sicca syndrome (keratoconjunctivitis and xerostomia).¹⁴⁷ The development of lymphoproliferative disorders in the setting of Sjögren’s syndrome is perhaps the prototypic example of chronic autoimmune disease with increased risk of malignancy. In 1964, investigators first reported the development of four cases of lymphoproliferative disorders in a cohort of 58 patients with Sjögren’s syndrome.¹⁴⁸ In 1978, 7 of 136 patients with sicca syndrome were identified as having developed non-Hodgkin’s lymphoma. Compared with the expected incidence of cancer among women of the same age range, a 44-fold increased risk of developing non-Hodgkin’s lymphoma was noted.¹⁴⁹ These findings have been reproduced numerous times in other cohorts. Lymphoproliferative disorders complicate approximately 4% to 10% of cases of primary Sjögren’s syndrome.^150–157 The relative risk for development of lymphoproliferative disorders in patients with primary Sjögren’s syndrome ranges from 6 to 44,^{149,158–163} and a meta-analysis of cohort studies has found a pooled SIR of 18.8.¹⁶⁰ Most lymphoproliferative disorders were non-Hodgkin’s lymphoma, specifically mucosa-associated lymphoid tissue (MALT) lymphoma, other marginal-zone lymphomas, and diffuse large B cell lymphoma.^155,156 Waldenström’s macroglobulinemia, chronic lymphocytic leukemia, and multiple myeloma were more rarely reported.^{149,153,154,159}

Generally, the development of lymphoma is a late manifestation of Sjögren’s syndrome, often seen after 6.5 years of disease.^151,152,164 Clinical and laboratory features seem to be associated with or predictive of development of lymphoproliferative disorders, including palpable purpura,^{148,153,154,163} cutaneous ulcerations,¹⁵⁰ cryoglobulinemia,^154,155 low serum complement levels,_,^153–155165 monoclonal gammopathies,^166,167 cytopenias,^148,155,163 splenomegaly,^148,155 and adenopathy.¹⁵⁰ Progression to high-grade lymphoma portends a poor prognosis.* In contrast, the incidence of other malignancies or all-cause mortality was not increased in patients with Sjögren’s syndrome compared with the general population.^{159,163,164,168} It is believed that chronic B cell stimulation may lead to the malignant transformation of clonal lines characteristic of Sjögren’s syndrome.¹⁴⁷ The presence of a viral trigger accounting for malignant transformation is one possible theory. EBV, among other viruses, has been implicated, but studies have failed to find EBV or other viral particles in lymphoma specimens associated with Sjögren’s syndrome.¹⁶⁹

Other reports have described the presence of chromosomal translocations with increased frequency in patients with Sjögren’s syndrome who have developed lymphoma. One group of investigators identified the presence of translocations of the proto-oncogene bcl-2¹⁷⁰ in 5 of 7 patients with Sjögren’s syndrome and lymphoma by the use of polymerase chain reaction. Such translocations were found in peripheral blood or bone marrow in 5% of unselected patients with Sjögren’s syndrome without evidence of lymphoma in another study.¹⁷¹ Conversely, no evidence of bcl-2 translocations was present in 50 salivary gland biopsy specimens of patients with Sjögren’s syndrome without evidence of lymphoma.¹⁷² Analysis of biopsy specimens taken before the development of lymphoma from the 7 patients previously mentioned revealed no evidence of bcl-2 translocation. Translocation seemed to correlate with the development of lymphoma in at least a subset of patients with Sjögren’s syndrome, and the use of polymerase chain reaction technology may allow early detection of malignant transformation.^171–173

Rheumatoid Arthritis

Data from numerous studies since the 1970s are persuasive that RA is associated with a twofold to threefold increased risk for the development of lymphoproliferative disorders, the magnitude of which has remained constant despite dramatic changes in therapy. Many factors, including chronic inflammation and immune dysregulation, in addition to potential oncogenic properties of immunosuppressive therapies for the treatment of RA, must be considered when the risk of development of hematologic malignancies is evaluated. It is often difficult to separate the effects of medication use from the underlying severity of inflammation that makes medication use necessary or indicated, a concept termed confounding by indication.¹⁷⁴ This association has been highlighted further by widespread use of tumor necrosis factor (TNF) inhibitors for patients with refractory disease and the potential for these medications to interfere with innate immune tumor surveillance.

In 1978, an SIR of 2.7 for lymphoma was reported in a group of 46,101 Finnish RA patients compared with the general population.¹⁷⁵ A similarly increased risk of 2.4 for lymphoma was seen later in a group of 20,699 Danish patients,¹⁷⁶ and an SIR of 1.9 to 2 was reported in a large cohort of 76,527 Swedish patients.^177,178 In the United States, an increased risk of 1.9 was found in a cohort of 18,527 patients,¹⁷⁹ and an SIR of 2.2 was noted in a separate cohort of 8458 patients 65 years old and older.¹⁸⁰ In the United Kingdom, an SIR of 2 to 2.4 for lymphoma was observed in an inception cohort of 2015 patients with inflammatory arthritis compared with the general population,¹⁸¹ and an SIR of 2.04 to 2.39 was seen for non-Hodgkin’s lymphoma in a cohort of 26,623 RA patients in Scotland.¹⁸² A meta-analysis of nine cohort studies of RA patients found a pooled SIR of 3.9 for lymphoma using a random effects model.¹⁶¹ Canadian investigators found an increased risk of leukemia (SIR, 2.47) among RA patients, but were unable to confirm elevated rates of lymphomas compared with the general population.¹⁸³ Data from case-control studies of patients with non-Hodgkin’s lymphoma have shown similar results: Odds ratios of 1.3 to 1.5 were found for underlying RA.^160,162 These associations have been recently confirmed in other populations, including patients from Japan,¹⁸⁴ Taiwan,¹⁸⁵ California,¹⁸⁶ and Spain.¹⁸⁷ In general, lymphomas in patients with RA seem to be predominately diffuse large B cell type and recently have been shown to favor nongerminal center subtypes.¹⁸⁸

Most studies have suggested that the risk for development of lymphoma is related to the degree of inflammation. The Swedish group identified high inflammatory activity (defined by ESR, swollen and tender joint counts, and the physician’s global assessment of disease activity) as a significant risk factor, with an odds ratio of 25.8 compared with low disease activity.¹⁸⁹ No association between any specific drug and the development of lymphoma was identified; however, the cohort examined was treated between 1965 and 1983, and few of these patients were apparently treated with immunosuppressive drugs, making the lack of association less certain. In a follow-up case-control study of 378 lymphomas in a Swedish group of RA patients published more recently, a 71-fold increased risk of lymphoma was reported in patients with high cumulative disease activity compared with low disease activity.¹⁹⁰ Immunosuppressive therapy did not seem to modify risk for lymphoma in this study. Patients did not have increased rates of lymphoma development before disease onset.¹⁹¹ Patients with Felty’s syndrome (a variant of RA associated with neutropenia and splenomegaly) were found in a Veterans Affairs study of 906 men to have a twofold increase in total cancer incidence, but a 12-fold increase in risk of non-Hodgkin’s lymphoma.¹⁹²

Systemic Lupus Erythematosus

The risks of developing malignancy in association with SLE have been difficult to estimate in the past. Small series and cohort studies have noted that patients with SLE might be at increased risk for malignancy, including non-Hodgkin’s lymphoma, sarcoma, and breast carcinoma.^205–209 Other small series have not found differences,²¹⁰ however, or have found infrequent associations²¹¹ in number or type of malignancy between patients with lupus and the general population.²¹⁰ Conflicting results also are seen in case-control studies of larger groups of patients, with some cohorts showing an increased overall risk of malignancy,^212–214 although others have failed to do so.^215–218 Some studies that did not find increased risk of overall malignancies in patients with SLE have shown increased risk of lymphoproliferative disorders, however.^{160,162,216–218} Confounding factors complicating interpretation of these studies include possible incomplete ascertainment of malignancies, inclusion of nonrepresentative cohorts of patients with SLE, and selection of inappropriate control populations.²¹⁹

To determine more adequately whether individuals with SLE are at increased risk, studies of large multinational cohorts, systematic reviews, and meta-analyses of pooled data are necessary. The SIR of individual studies has ranged from 1.1 to 2.6.²²⁰ A meta-analysis of six of the clinical cohort studies found a slightly increased risk of overall malignancies in cohorts of patients with SLE, with an SIR of 1.58.²²¹ This analysis showed an increased risk of lymphoma in these cohorts, with an SIR of 3.57 for non-Hodgkin’s lymphoma and 2.35 for Hodgkin’s disease. A separately performed meta-analysis of the incidence of lymphoma in patients with SLE found an SIR of 7.4.¹⁶¹ Individual hospital discharge database studies have shown a consistently higher risk of non-Hodgkin’s lymphoma (SIR, 3.72 to 6.7), but these studies examined only hospitalized patients with SLE.²⁰⁰ Pooled analysis showed a slightly elevated risk for the development of breast cancer, with an SIR of 1.53, but they did not find an increased risk of lung or colorectal cancer in these patients.²²¹ The same confounding factors influencing individual studies are a factor in interpreting these pooled data.

A more recent series of studies analyzing nearly 9500 lupus patients (≈77,000 patient-years of observation) in a multinational cohort study has helped to define better potential associations with malignancy.^222,223 The authors found a slightly increased risk of malignancies overall (SIR, 1.15) with higher risks for the development of hematologic malignancies (SIR, 2.75), particularly non-Hodgkin’s lymphoma (SIR, 3.64).²²² Forty-two cases of non-Hodgkin’s lymphoma were identified, most of which were of aggressive histologic subtypes.²²⁴ The incidence of lymphoma in this study was evident early in the course of SLE, rather than after many years of chronic disease activity or use of multiple immnosuppressive medications.^223,225 The elevated risk of non-Hodgkin’s lymphoma in this cohort seemed to be independent of race or ethnicity, although white patients seemed to have higher rates of malignancy in general compared with patients of other ethnicities.²²⁶ In a case-control study within the multisite international SLE cohort, age, disease-related damage, and smoking were found to be associated with increased risk of malignancy; use of immunosuppressant medications (particularly lagged 5 years) may contribute to increased risk of hematologic malignancy.²²⁷

Although the exact cause of the association is unknown, several theories have arisen to explain the possible connection between SLE and malignancy, especially B cell lymphoma. Some authors have postulated that certain immunologic defects may predispose patients to SLE and B cell lymphoma, including apoptosis dysfunction, chronic antigenic stimulation, and overexpression of bcl-2 oncogene.^220,228 Viruses, EBV in particular, also have been postulated as part of the development of SLE and lymphoma.^220,228 Studies have not conclusively validated any of these theories to date, however.

The relative prevalence of cervical cancer in SLE patients is difficult to estimate because national cancer registries often do not record malignancies in situ. Cervical cancer remains an important issue for women with SLE, and an increased risk may come about for different reasons, including (1) reduced clearance of human papillomavirus (HPV), the causal agent in most cases of cervical cancer; (2) increased risks of cervical cancer associated with immunosuppressive medications; and (3) reduced rates of routine Pap smears and other screening procedures in a population of patients with chronic illnesses. In the large multinational study performed more recently, the SIR for invasive cervical cancer was found to be elevated at 1.26, albeit with confidence intervals that cross the null.²²² Other studies have confirmed increased risks of abnormal Pap smears and cervical dysplasia in women with SLE.^229,230 Different studies have implicated increased prevalence of HPV infection and other sexually transmitted diseases,^230–233 and immunosuppression^232–235 may partly explain this association. As with mammography, women with SLE seem less likely to undergo routine Pap testing than women in the general population.^236,237

Several studies have identified a link between SLE and the development of lung cancer.²²⁵ Indeed, the largest multinational cohort of SLE subjects found an increased incidence of lung cancer compared with the general population (SIR, 1.37; 95% CI, 1.05 to 1.76).²²² Further analyses of the cases of lung cancer in this cohort revealed a variety of tumor types, including adenocarcinoma, bronchoalveolar carcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, and carcinoid tumor.²³⁸ Most cases (71%) occurred in smokers, 25% of cases were in men, and few (20%) had previous exposure to immunosuppressive agents.²³⁸ To date, no particular demographic or clinical features have been found to explain this apparently increased risk.

Overall, the presence of SLE seems to carry a small increased risk for the development of cancer, particularly lymphoproliferative disorders such as non-Hodgkin’s lymphoma, lung cancer, and cervical cancer. The underlying causes of these associations are unknown, but they do not seem to be exclusively related to the use of immunosuppressive or cytotoxic agents.* Data suggest that lupus patients may be less likely to receive recommended cancer screening.