Malignant Transformation In Autoimmune Diseases

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Malignant tumors specifically lymphoid malignancies are diagnosed with increasing frequency in various autoimmune diseases. The cancer may appear during the diagnosis of the autoimmune disease or many years later. This association has important clinical and therapeutic implications. First, it may imply that in certain autoimmune diseases screening tests for malignancies should be performed routinely. Moreover, it has to be determined if the treatment given to these autoimmune diseases contributed to the malignant transformation or whether the malignancies appear independent of the treatment.

8.1. Rheumatoid Arthritis [64-72]

Many workers have reported an association between rheumatoid arthritis (RA) and malignancies. Two cohort analyses of cancer morbidity have shown an excess of risk of cancer at all sites in patients with rheumatoid arthritis. Special emphasis has been given to the simultaneous occurrence of lymphoprolifera-tive neoplasms and rheumatoid arthritis. In the study reported by Isomaki et al. [64] the relative risk for lymphoma in RA patients was 2.7 compared with the general population. A wide range of types of lym-phoproliferative neoplasms has been reported in RA including Hodgkin's disease, various non-Hodgkin's lymphomas, and myelomas. The mean interval between the two diseases was 13 years [66-67], Some workers have attributed the development of lymphomas in patients with RA to the treatment. In one large series including 643 patients with RA treated with immunosuppressive drugs a 13-fold increase in the incidence of lymphomas was found. However, in the study reported by Isomaki et al. [64] the 2.7-fold excess of lymphomas was determined in the absence of immunosuppressive drugs. Therefore it can be con-

eluded that patients with RA have two to three times greater risk for lymphoproliferative malignancies in the absence of immunosuppressive therapy, and this risk is further increased after such treatment.

8.2. Systemic Lupus Erythematosus (SLE)

There are many anecdotal reports of SLE patients who developed malignancies, including both epithelial tumors and lymphoproliferative neoplasms. However, only a few studies which included large series of patients have demonstrated such an association, and some of these studies were too small or not well controlled. The view that SLE is associated with lymphomas stems from animal models of SLE, namely, NZB/NZW F1 and MRL/lpr mice, that spontaneously develop malignant lymphomas [77], and from case reports of patients with SLE who developed lymphomas. In summary, although there is no definite evidence for an association between SLE and lymphoma, lupus patients with enlarged lymph nodes should be reviewed regularly and biopsies should be performed if a malignancy is suspected.

The association between SS and lymphoma was first described in 1963; this association was established following the report by Kassan et al. [83] that 7 out of 136 SS patients developed lymphomas, 44 times the frequency expected in the general population. The high prevalence of lymphomas in patients with SS could not be due to irradiation or chemotherapy, as patients who did not receive such treatment showed and increased risk of lymphoma. In a recent study in which 100 SS patients were followed for 34 months, 3 cases of lymphoma were detected [84], The time interval between the development of SS and the diagnosis of lymphoma may be as long as 20 years. The lymphomas can be of B- or T-cell origin. Some workers have suggested that reactivation of Epstein-Barr virus (EB V) in SS patients may cause development of lymphomas. Indeed, EBV DNA was detected in increase amounts in the tumor tissue of an SS patient that developed Hodg-kin's disease [86]. This finding if confirmed by other studies is of major importance as early aniviral treatment may prevent the development of lymphomas in

SS patients. Another interesting finding was reported by Pisa et al. [89] who studied 7 SS patients who developed lymphomas. In 5 of these patients translocations of the protooncogene bcl-2 t(14:18) were found.

8.4. Dermatomyositis and Polymyositis [90-99]

The well known association between dermatomyositis internal malignancies has been substantiated by many studies [31], The incidence of cancer in patients with dermatomyositis has been reported to be 7—24% [90, 93]. One of the major difficulties in estimating the incidence of malignancy in dermatomyositis and polymyositis arises from the lack of common criteria for diagnosing these diseases. In 1975, Bohan and Peter [95] defined criteria for the diagnosis of dermatomyositis and polymyositis. These criteria include progressive symmetrical proximal weakness, muscle biopsy consistent with myositis, elevated muscle enzymes, abnormal electromyogram and cutaneous signs of dermatomyositis. In a recent large series of 392 patients with dermatomyositis and 396 patients with polymyositis which were diagnosed using these criteria the incidence of cancer was 15 and 9%, respectively [31], The tumors associated with dermatomyositis and polymyositis are epithelial malignancies mainly of the colon, breast, lung, pancreas and ovary [31], However, rare cases of hepatoma, melanoma, and lymphoma have been reported. The strong association between dermatomyositis/polymyositis and cancer has lead some investigators to recommend a thorough search for occult malignancy in any patient with dermatomyositis/polymyositis [99].

8.5. Scleroderma [100-107]

The association between scleroderma and lung cancer was first reported in 1953 [100], and since then has been substantiated by other studies. Although some workers did not find increased incidence of lung cancer in patients with scleroderma, two recent controlled studies have demonstrated increased risk for lung cancer in scleroderma. The incidence of lung cancer in scleroderma in these studies was 0.9-5% [101-104]. The most prevalent histologic type of lung cancer associated with scleroderma is bronchoalveolar carcinoma. It should be noted that lung cancer occurs in patients with scleroderma after long-standing pulmonary fibrosis, but is not associated with cigarette smoking or immunosuppressive therapy [105, 106]. Breast carcinoma has also been associated with systemic sclerosis [105-107]. Increased incidence of malignant tumors has also been reported in mixed connective tissue disease. The relative risk for developing cancer in patients with mixed connective tissue disease was 12.9 [107].

8.6. Autoimmune Thyroid Diseases

Several studies have found an increased risk of thyroid lymphoma in patients with thyroiditis. In a large controlled study, including 829 patients with chronic lymphocytic thyroiditis and 829 age- and sex-matched patients with colloid goiter, patients with thyroiditis had an increased risk of myeloproliferative and lymphoproliferative neoplasms. Acute leukemia has also been reported to be associated with autoimmune thyroid diseases [109-112],

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