Autoimmune Syndromes in Cancer

Chapter 42

Autoimmune Syndromes in Cancer Dr Lior Seluk1, Dr Shaye Kivity1,2,3 1Department

of Medicine A, Ramat-Gan, Israel; 2Sackler School of Medicine, Ramat Aviv, Israel; 3The Zabludowicz Center for Autoimmune Diseases, Ramat-Gan, Israel

MUSCULOSKELETAL-ASSOCIATED PARANEOPLASTIC SYNDROMES Paraneoplastic Arthritis Arthritis can precede and lead to the detection of cancer. A large cohort (n = 65) of patients with paraneoplastic arthritis demonstrated a male predominance and initial presentation mainly with acute asymmetric arthritis [1,2].

Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) This syndrome is characterized by distal swelling of the hands and feet and occurs mainly in the elderly. RS3PE patients respond very well to corticosteroids and have an excellent prognosis. Several small studies have demonstrated up to 30% of associated malignancy, especially those with a poor response to corticosteroids [2].

Dermatomyositis Associated With Malignancy Dermatomyositis is associated with an underlying neoplastic disease in about 20% of all cases [2,3]. However, when clinical features overlap with other collagen vascular diseases (e.g., interstitial lung involvement, Raynaud’s phenomenon) and the presence of various autoantibodies (AAbs) suggestive for connective tissue disease (antisynthetase, anti-Ro52, or systemic sclerosis–associated antibodies), tumor risk is not increased [2]. Up to 83% of dermatomyositis patients with malignancy have anti–NXP-2 and anti–TIF-1γ (anti-p155) antibodies [4].

Hypertrophic (Pulmonary) Osteoarthropathy Hypertrophic osteoarthropathy (HOA) is characterized by clubbing of the distal phalanges of the fingers and/or toes with periostitis causing bone and joint pain and often synovitis. HOA can occur in relation to malignancies, mainly intrathoracic ones (1% of primary lung cancer) but not solely. It is suspected that platelet-derived growth factor or vascular endothelial growth factor produced by the tumor cells contributes to the pathogenesis of HOA [2].

HEMATOLOGICAL PARANEOPLASTIC SYNDROMES Autoimmune Hemolytic Anemia This syndrome is among the most prevalent paraneoplastic phenomena known. It is characterized by accelerated destruction of erythrocytes by circulating AAbs [5]. In a series of 175 patients with autoimmune hemolytic anemia (AIHA), up to 14% can be associated with malignancy in the background. Paraneoplastic-AIHA is mainly linked to hematological malignancies such as lymphomas and leukemia [6]; however, association with solid tumors such as bladder and ovarian cancer were described [7–9]. Most patients with paraneoplastic AIHA due to solid tumors suffer from advanced metastatic disease, yet respond to surgical resection [7,10]. In paraneoplastic AIHA, the AAbs are mainly of the “warm” type; however, “cold” AAbs have also been reported as well as mixed type [7,8].

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Autoimmune Thrombocytopenia The main cause of thrombocytopenia in cancer patients is bone marrow aplasia due to cytotoxic chemotherapy or radiation. Less common causes are bone marrow infiltration by the tumor, drug-induced immune thrombocytopenia, or disseminated intravascular coagulation. A rare syndrome similar to idiopathic thrombocytopenic purpura (ITP) has been reported in patients with malignancies as well. It is the clinical course of 1%–5% of patients with chronic lymphocytic leukemia [6]. It is rare cause of thrombocytopenia in solid tumors: in a review of 68 cases of paraneoplastic thrombocytopenia, the most common tumor was lung (15 of 68 patients) and breast cancer (15 of 68 patients), followed by renal cell, ovarian and gastrointestinal cancers, and very rare in prostate cancer [11]. The syndrome occurred either before (with a median of 5 years), concurrent with, or after the diagnosis of the cancer. Patients respond to corticosteroids and splenectomy, as in treatment for primary ITP. In several cases the presence of antiplatelet AAbs has been detected.

Autoimmune Neutropenia This is an extremely rare condition reported in patients with hematological malignancies [6]. A single case of paraneoplastic neutropenia and malignant melanoma was reported [12]. Before diagnosis is made, other secondary causes should be excluded such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren syndrome, celiac disease, hyperthyroidism (Graves disease), Crohn disease, and other (auto) immune diseases as well as prior rituximab treatment [6].

VASCULITIS ASSOCIATED WITH MALIGNANCY Vasculitis may be rarely associated with malignancy. The most prevalent histopathology type is cutaneous leukocytoclastic vasculitis. Hematologic malignancies are identified as a cause in more than half of the cases, with myelodysplasia and nonHodgkin lymphoma being the most frequent diagnoses. Among solid tumors, lung, breast, and urogenital cancers are the most common causes of paraneoplastic vasculitis [2]. Instances of vasculitis have been reported to occur both before and after onset of malignancy. Greer et al. reported 13 patients with malignancy-related vasculitis, which were poorly responsive to therapy, and chemotherapy directed at the underlying malignancy was also generally ineffective [13].

NEUROLOGICAL PARANEOPLASTIC SYNDROMES The paraneoplastic neurological syndromes (PNSs) are a heterogeneous group that may affect any part of the central and peripheral nervous system, the neuromuscular junction, or the muscles. These syndromes are rare and vary with the neurologic syndrome and tumor type. The main presentations are encephalomyelitis (pathological involvement of all parts of the central nervous system and peripheral nervous system), limbic encephalitis (pathological involvement in the amygdale and hippocampus), subacute cerebellar degeneration (pathological involvement in Purkinje cells), opsoclonus-myoclonus, subacute sensory neuronopathy (pathological involvement in the dorsal root ganglia), and Lambert–Eaton myasthenic syndrome [14,15]. There has been an attempt to divide the PNS into two groups, according to the location of the antigen that the antibodies target [16–18]. In the first group, antibodies are directed against intracellular neuronal proteins and can be detected in the serum and CSF. These antibodies have a strong association with underlying tumor (Table 42.1) and are

TABLE 42.1  “Well-Characterized” Paraneoplastic Antibodies, Associated Tumors, and Neurological Presentations Antibody

Neurological Presentation

Tumor

Anti-HU (ANNA1)

Encephalomyelitis, sensory neuronopathy, chronic gastrointestinal pseudo-obstruction, paraneoplastic cerebellar degeneration (PCD), limbic encephalitis

Small cell lung cancer (SCLC)

Anti-Yo (PCA1)

Cerebellar degeneration

Ovary, breast

Anti-RI (ANNA2)

Brainstem encephalitis

SCLC, breast

Antiamphiphysin

Stiff person syndrome

SCLC, breast

Anti-MA2 (Ta)

With limbic/diencephalic encephalitis, brainstem encephalitis/PCD

Testis, lung

Anti-CV2 (CRMP5)

encephalomyelitis, chorea, sensory neuronopathy, sensorimotor neuropathy, chronic gastrointestinal pseudo-obstruction, paraneoplastic cerebellar degeneration, limbic encephalitis

SCLC, thymoma

Autoimmune Syndromes in Cancer Chapter | 42  469

TABLE 42.2  Autoimmune Encephalitis Antibodies, Associated Tumors, and Neurological Presentations Antibody

Neurological Presentation

Tumor

Anti-VKGC (Anti LGI-1; Anti-CASPR2)

Limbic encephalitis, Morvan’s syndrome Creutzfeldt–Jakob disease-like syndrome

SCLC, Thymoma

NMDA receptor

Encephalitis with initial psychiatric features followed by catatonia, dystonia, aphasia, and hypoventilation

Ovarian teratoma

AMPA receptor

Limbic encephalitis Atypical psychosis

SCLC, breast, thymoma

GABA B receptor

Limbic encephalitis

SCLC

VGCC

Lambert–Eaton myasthenic syndrome (LEMS), paraneoplastic cerebellar d­egeneration (PCD)

SCLC

termed “well characterized” paraneoplastic or onconeuronal antibodies. The pathogenic mechanism is believed to be mediated by cytotoxic T-cells, and the antibodies are thought to be markers in most cases. The second group (Table 42.2) of antibodies is directed against neuronal cell surface or synaptic proteins, including receptors and is detected in the serum and CSF as well [19,20]. Antibodies in this group are mainly associated with autoimmune encephalitis; however, overlap syndromes affecting CNS/peripheral nervous system also occur. The autoimmune encephalitis PNS may affect children [21,22] and are less associated with cancer than the “well characterized” PNS [20]. Studies suggest these antibodies have a direct pathogenic effect on the target antigens and a correlation between antibody titers and neurological outcome has been documented. PNS may occur years before or after a detectable cancer and may occur with or without detectable antibodies. Serum antibodies may occur without neurological symptoms or NPS. Thus, diagnosis is mostly done by clinical suspicion and exclusion of secondary causes such as metastases, stroke, metabolic and nutritional deficits, infections, coagulopathy, and chemo/biological/radiotherapy side effects. Treatment is targeted both to remove the antigen source by treating the cancer, and suppression of the immune-mediated response (by plasma exchange, intravenous immunoglobulins, glucocorticoids, cyclophosphamide, and rituximab) [23,24].

AUTOANTIBODIES IN MALIGNANT DISEASES AAbs are investigated for use as biomarkers of cancer screening, prognostic markers for disease staging, monitoring the efficacy of therapeutic response, and the identification of potential targets for personalized immunotherapy [25–28]. In some cases, an increase in serum levels of AAbs has been shown to precede the development of disease symptoms by several months to years and correlate with cancer incidence [25,28–30]. These AAbs are presented in early stages of carcinogenesis due to cancer immunosurveillance, the process by which the immune system recognizes and destroys invading pathogens as well as host cells that have become cancerous. These antigens are denoted collectively as tumor associated antigens (TAAs). The persistence and stability of antibodies against TAAs in the serum of cancer patients is an advantage over other potential markers, including the TAAs themselves, which are released by tumors but rapidly degraded [26]. Yet the general estimate even for the best TAAs is that they may evoke humoral response in only 5%–10% of cancer patients. One example of the potential of serologic AAbs to diagnose early-stage cancer is the discovery of the extracellular protein kinase A autoantibody as a universal cancer biomarker. This antibody was found to be elevated in a wide range of cancers of various stages [25]. Another example is the most investigated AAb anti-p53; these antibodies have been detected in the sera of workers exposed to vinyl chloride who developed angiosarcoma of the liver and in the sera of heavy smokers and uranium workers who developed lung cancer [27]. It has been reported that in patients with esophageal carcinoma, in which up to 60% of patients were detected with anti-p53, its levels had a potential of evaluating the response to the treatment and prognosis. However, the detection frequency at the time of diagnosis of other cancers has been reported in as little as 7%. To date, no single AAb biomarker has been used as a cancer biomarker due to the low sensitivity and specificity of single markers.

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Antinuclear Antibodies In several studies an increased titer of IgG and IgM antinuclear antibody (ANA) has been reported with a speckled pattern observed occasionally. In vitro, the AAbs react with both normal and malignant tissues [31]. In one series ANA was found in 19% of 342 patients with various cancers (vs. 1% in controls). The cancer most reported to correlate with positive ANA is breast cancer [32–34], in which positive ANA is also associated with a worse prognosis. There are also reports of positive ANA in patients with lung, gastrointestinal, uterus, hepatocellular carcinomas, and malignant melanomas and leukemia [35–37]. In contrast, several authors have not found increased levels of ANA in patients with lung carcinoma and chronic lymphatic leukemia. These discrepancies may be due to different techniques employed. It is noteworthy that anti-dsDNA and anti-Sm antibodies have been rarely associated with malignancy, whereas anti-ssDNA and antihistone antibodies have been described in patients with leukemias and other solid tumors [38,39].

Rheumatoid Factor The association of rheumatoid factor (RF) and cancer has been reported to vary from 11% to 85%, perhaps due to different malignancies as well as different measuring techniques or positivity thresholds [36,40]. Higher RF frequency was also shown in association with a larger tumor burden. In a cohort of 295,837 participants RF was associated with a greater risk of cancer mortality; however, this association was not considerably different after hsCRP levels had also been adjusted for [41].

Antismooth Muscle Antibody IgG and IgM antismooth muscle antibodies (ASMAs) were detected in the sera of patients with melanoma, breast, ovarian, lung, and cervical carcinoma. However, the association of ASMA with malignancy is controversial and most major studies are from the 1970s [33,34,42,43]. The presence of ASMA may be due to exposure of an actomyosin-like antigen on the membrane of the tumor cells [44].

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