Causes Of Cancers In

It is possible that various tumors, and particularly solid cancers, occur simply by chance in patients with SLE with no causal relationship between the development of malignancy and SLE. However, the data of all studies indicate that NHL occurs more commonly in SLE patients compared with the general population.

Possible causes for the increased risk of NHL among patients with SLE include the use of cytotoxic agents, a common etiologic agent, similar genetic susceptibility and immunoregulatory disturbances of B and T cells in patients with SLE that predisposes to malignancy. These possible mechanisms will be detailed below.

6.1. Cytotoxic and Immunosuppressive Agents

Cyclophosphamide is used in a large proportion of SLE patients with diffuse proliferative glomerulonephritis, in patients with severe CNS involvement and in refractory cases of SLE. Methotrexate and aza-thioprine are commonly given to patients with SLE and their main role is steroid sparing agents.

It has been suggested that the use of those agents may be associated with the development of malignancies. Cyclophosphamide therapy has been reported to be associated with bladder cancer, NHL, acute and chronic leukemia.

In a previous study [54], 6% of organ transplant recipient developed malignancies within the first few years after transplantation and immunosuppressive therapy. The most common cancers were, lymphoma and skin and cervix carcinoma. Out of the 20 SLE patients and NHL included in 4 SLE cohorts [12, 13, 15, 16], only 3 received cyclophosphamide before the diagnosis of NHL. Most of the reported case of ANLL in patients with SLE, occurred in patients who received immunosuppressive agents, including cyclophosphamide and azathioprine.

To determine whether, or not, the risk of cancer in SLE is associated with cyclophosphamide therapy, Pettersson et al. [13], selected 3 controls for each patients with SLE and cancer. The controls were matched by age and the year of onset of SLE. The odd ratio related to cyclophosphamide therapy was 0.6 (CI, 0.6-3.5), suggesting that the development of malignancy in patients with SLE is not associated with cytostatic therapy. Similarly, none of the 6 Canadian

SLE patients who developed lymphoproliferative cancers were treated with cyclophosphamide before the diagnosis of the malignancy [12]. In a 5-year follow-up study [50] of SLE patient treated with intravenous cyclophosphamide, none of the patients developed malignancies.

Azathioprine is widely used in the treatment of SLE. Few cases have suggested that treatment with azathioprine may be followed by the development of acute leukemia or NHL [55]. However, in a large cohort of patients with RA treated with azathioprine and other disease modifying drugs, the risk for the development of NHL among patients treated with azathioprine was not statistically different from the that of RA patients who did not received the drug [56],

Cytotoxic therapy may induce malignant transformation by several mechanisms including direct oncogenic effect and severe immunosuppression that prevent the destruction of mutant malignant cells or elimination of oncogenic viruses.

Taken together, the data indicate that treatment with cytostatic agents may trigger the development of cancers only in the minority of SLE patients who developed malignancies, and obviously the development of NHL and other neoplasms in patients with SLE is related to other possible causes.

Treatment of neoplastic diseases immunomodulat-ing agents may result in a state of autoimmunity. SLE and other autoimmune diseases may develop following therapy with interferon [57, 58], Several case of patients with myeloproliferative disorders including chronic myelogenous leukemia (CML) and essential thrombocytosis (ET) developed SLE following treatment with a- and y-interferons [57, 58], Twenty percent of 137 patients with CGL or ET developed rheumatic symptoms [58] after interferon therapy. During interferon therapy, 18 (72%) of 25 patients with CGL had ANA positivity. Of these, 15 reported symptoms related to rheumatic diseases and 3 patients fulfilled the classification criteria for SLE.

In another study, 19% of 135 patients with malignant carcinoid, developed autoimmune diseases including autoimmune thyroid disease, SLE, pernicious anemia and vasculitis [59], The data indicate that interferon therapy may trigger the development of autoimmunity and should not be used in patients with clinical and laboratory features suggesting autoimmune diseases.

6.2. Common Etiologic Agent

Environmental agents have been associated with the pathogenesis of SLE. Of these, ultraviolet B (UVB) light, infectious agents and exposure to certain drugs and hormones [1], Flare of the skin disease may occur in more than 70% of patients with SLE after exposure to UVB [60], It has been suggested that UVB may make the DNA to be more immunogenic and to mobilize Ro and La antigens to the surface of keratinocytes. This leads to the binding of anti-Ro and anti-La to those cells, activating of cytotoxic T cells [61] and induction of damage to the keratinocytes.

UVB is the strongest risk factor for basal cell and SCC of the skin. Patients with SLE were found to develop SCC of the skin into chronic disceid lesions, suggesting that UVB is a common etiologic agent for discoid lupus and skin cancer in the same patient [51, 52],

Patients with SLE have an increased risk of infections. Sepsis and other bacterial and viral infections are the most common cause of death among patients with SLE [14, 62], Furthermore, SLE patients, and particularly those on prolonged immunosuppressive therapy, are at increased risk of chronic or recurrent viral infections. Recently, several cases of chronic hepatitis C were reported in patients with SLE [63, 64], Patients with chronic infection with hepatitis C are also at increased risk of developing hepatic malignancies and lymphoproliferative disorders [65], suggesting that chronic infection with HCV may trigger the development of cancer in patients with SLE.

Kojima et al. [66] performed clinicopathological and immunohistochemical analyses on 5 patients with B-cell lymphoma and rheumatic diseases. (2 patients with SLE, 2 with dermatomyositis and 1 with scleroderma). In 3 of the 4 cases examined, Epstein-Barr virus (EBV) encoded small RNAs were seen in a small to large number of the lymphoma cells. The data indicate that, similar to the general population, infection with EBV in SLE patients may be associated with the development of NHL.

Thirty percent of sera of patients with SLE were found to react with retroviral gag protein p24 [67]. Similarly, 24% of sera of patients with SLE were found to bind type C retroviral particles [67]. Ito et al. [68] reported that a patient with lupus nephritis developed adult T-cell leukemia associated with human T-cell leukemia virus (HTLV) type 1.

Human papillomavirus (HPV) has been associated with the development of premalignant and malignant tumors of the vagina and cervix [69], Cohen et al. [70] described an SLE patient with cutaneous lesions who was treated with azathioprine and developed multiple lesions of SCC of the skin. HPV type 11 DNA and the oncogenes neu and ras were identified in the tissue of the SCC, suggesting a role for HPV in the development of SCC of the skin in SLE.

In summary, patients with SLE are at increased risk of infection with various viruses. In selected cases the viral infection may trigger the development of cancer.

Hormonal factors are implicated in the pathogenesis of SLE [1], Alterations in the metabolism of estrogen SLE have been associated with the pathogenesis of SLE and gynecological cancers. States of increased levels of estrogen such as ovulation induction, pregnancy and estrogen replacement therapy have been reported to be associated with the development of SLE [1].

The role of estrogen in the pathogenesis of SLE is unclear. In one study, 17-/i-estradiol was found to induce up to a 5-fold increase of 52 and 60 kDa SS/A Ro expression in human keratinocytes [71]. This induction of Ro and La antigens may trigger the generation of anti-Ro and anti-La autoantibodies, or it may facilitate the binding of anti-Ro and anti-La antibodies to keratinocytes.

In women with endometrial carcinoma, it has been reported that exposure to unopposed estrogen from either endogenous or exogenous sources is a risk factor for the development of the carcinoma.

6.3. Genetic Susceptibility

Several genes are associated with an increased risk for the development of SLE and, therefore, they are classified as susceptibility genes. SLE is strongly associated with specific haplotypes of the HLA system. HLA DR3, DR2, B8, C4A, DQw2 and others are associated with an elevated relative risk for the development of SLE. The disease is also associated with single gene deletion as in C2 and C4 deficiency. Other genetic constellations related to the development of SLE include genes encoding the constant region of the immunoglobulin heavy chain molecules (Gm allotypes) [1].

The malignant transformation of normal cells is associated with genetic abnormalities. The possibilities of malignant transformation include the overactiva-tion of genes (proto-oncogenes) that promotes cell division, and the malfunction of genes that normally suppress growth and abnormalities in genes that repair DNA. The abnormalities of these genes usually occur as a result of point mutation, amplification or translucation.

Since SLE is associated with abnormal growth of cells of the immune system, several researches have studies the expression of various oncogenes in patients with SLE.

In vitro studies [72] have indicated that activation and proliferation of the B cells, from normal people and SLE patients with IgM antibodies, resulted in expression of c-myc proto-oncogene RNA. Boumpas et al. [72] found that in vitro activation of T and B cells from patients with SLE had significantly increased expression of c-myc, c-myb and c-raf RNA compared with normal cells. Similarly, peripheral blood mononuclear cells (PBMC) from SLE patients expressed significantly more c-myc RNA than did healthy controls [74-75]. In another study [76], the c-myc and c-myb expression was directly related to disease activity.

B and T cells from SLE patients were also found to express the bcl-2 oncogene which is associated with prolonged survival of lymphocytes and protection from apoptosis. This oncogene is highly associated with human follicular lymphoma [77]. The expression of the bcl-2 in the lymphocytes of patients with SLE was not related to the degree of disease activity.

Unlike malignancy, the activation of oncogenes is not associated with mutations, translocation, deletion or amplification [78]. Therefore, no malignant transformation in the majority of patients with autoimmune diseases. However, in selected cases the prolonged activation of oncogenes, and particularly bcl-2, may result in genetic abnormality associated with malignant transformation and lymphoproliferative disease.

6.4. Immunological Abnormalities

SLE is associated with hyperactivation of B and T cells, secretion of large amount of autoantibodies and activation of cytokines network [1, 79]. All of those abnormalities in the immune system may be associated with tissue damage and malignant transformation.

The characteristics of lymphocytes of lymphoma cells from patients with SLE were reported only in a few studies. Munzert et al. [17] described a patient with SLE who developed B-cell type NHL and M expansion of CD5+ B cells in his blood. CD5+ B cells are the equivalent of Lyb-1 B cells in mice which are associated with autoimmunity and lymphoma [80], In humans, CD5+ B cells are associated with CLL, a disease characterized by a high rate of autoimmune features including autoimmune hemolytic anemia and thrombocytopenia. A link between CD5+ cell and RA was reported, however, their role in SLE is unclear [80-81],

In animals, spontaneous SLE-like disease and lymphomas develop in various strains of mice including NZW, NZWxNZB and B/W mice [82-84], In all of these mice, a marked proliferation of Ly-1 B cells was observed [79].

Taken together, CD5+ and Ly-1 B cells expansion may occur in some patients and mice with SLE that may be associated with lymphoproliferative disorders.

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