Malignancy and Rheumatic Disorders - The Association Between Them

Introduction

Malignancy is a complex disease that gives rise to various symptoms and shows association with various diseases. One such association is with rheumatoid arthritis. Some rheumatoid disorders show a tendency of paraneoplastic syndrome (a condition with underlying cancer). Few other rheumatoid disorders have a risk of developing cancer. The treatment for rheumatoid arthritis can lead to cancer as they have immunosuppression. Malignancy metastasis to the musculoskeletal system and cancer treatment also exhibit rheumatic symptoms. In certain conditions, cancer exhibits rheumatoid arthritis-like symptoms. The exact etiology and mechanism remain unclear. A hypothesis suggests an antibody immune response to a similar antigen of tumor cells and rheumatoid arthritis.

What Are Rheumatoid Arthritis-Associated Malignancies?

The classification is mainly of three types

1. Rheumatoid paraneoplastic syndromes.

2. Inflammatory myopathies.

3. Malignancy caused by immunomodulators.

What are Rheumatoid Paraneoplastic Syndromes?

Paraneoplastic conditions are not caused due to cancer. However, they can be caused due to cancer-derived mediators or proteins like antigens, hormones, peptides, etc. The syndromes often predate cancer occurrence and are a sign of underlying cancer. The condition resolves with cancer treatment. The disorders associated with the paraneoplastic syndrome are:

• Hypertrophic Osteoarthropathy: In this condition, there is an abnormal proliferation of skin and skeletal tissue at the distal part of the extremities. The symptoms include clubbing of fingers and toes and arthritis. They are further classified into primary and secondary. In addition, an association with lung cancer is seen.

• Carcinoma Polyarthritis: This occurs alongside breast, colon, and lung cancer. The etiology is unknown. This condition is predominant in the elderly. The serology test is negative. Asymmetrical arthritis of the lower extremities is seen. Symptoms appear six to eight months before the tumor disease.

• Vasculitis: A rare condition, the paraneoplastic response is due to immune complex formation. Cutaneous leukocytoclastic vasculitis is commonly associated with malignancy. Vascular injury by antibodies to endothelial cells causes this condition. Therefore, the response to treatment could be better.

• Palmar Fasciitis: Characteristic features include bilateral contracture of digits and fibrosis of palmar fascia. The condition is associated with ovarian cancer. Poor response to treatment is seen if the condition develops after tumor metastasis.

• Reflex Sympathetic Dystrophy Syndrome: It is characterized by regional pain, swelling, vasomotor instability, and focal osteoporosis in the limb. In addition, it is associated with Pancoast tumors of the lungs, colon, and ovaries.

• Erythromelalgia: Acute onset of severe burning, erythema, and warmth of the extremities, predominantly in feet. The symptoms predate myeloproliferative disorders. Therefore, patients should undergo repeated blood workups due to a higher risk of malignancy.

• Polymyalgia Rheumatica: Discomfort, shoulder and hip girdle stiffness, fatigue, anemia, and increased erythrocyte sedimentation rate are seen in older adults.

• Amyloidosis: In patients, insoluble proteinaceous material is deposited in the extracellular matrix of various organs. Associated with multiple myeloma.

• Raynaud’s Syndrome: It is common in older patients. Digital necrosis is seen. Associated with lymphoma and adenocarcinoma.

• Multicentric Reticulohistiocytosis: A rare lung, stomach, breast, and colon carcinoma disorder. Symptoms include subcutaneous nodules and erosive polyarthritis.

• Panniculitis: The condition mimics erythema nodosum and is associated with lymphoma and leukemia. Malignancy should be considered if the condition persists for more than six weeks.

• Lupus-Like Syndrome: It is a rare condition associated with ovarian cancer and hairy cell leukemia. Symptoms include pleural effusion and pneumonitis.

• Scleroderma-Like Syndrome: It is associated with adenocarcinoma and carcinoid tumors. In osteosclerotic myeloma, cancer is seen as a paraneoplastic condition. Skin lesions do not improve with cancer treatment, which is considered metastasis.

• Lambert-Eaton Syndrome (LES): Lambert-Eaton syndrome occurs mostly in patients with small-cell carcinoma of the lungs. Characteristics include fatigue and weakness in extremities.

What Are Inflammatory Myopathies?

Malignancy develops years after diagnosis of rheumatic disease. It can be due to chronic stimulation of rheumatic disease that leads to cancer. The cause can also be genetic, viral, or lifestyle related. Examples include

• Sjogren’s Syndrome: Benign lymphocytic infiltration of salivary and lacrimal glands. Chronic B cell stimulation, EBV (epstein-barr virus), or chromosomal translocation causes malignancy such as lymphoma. In addition, chronic B cell stimulation decreased apoptosis of B cells and reduced natural killer cell activity leading to lymphoma formation.

• Systemic Lupus Erythematosus: Gynecological malignancy and lymphoma may be seen.

• Systemic Sclerosis: Occurs in old age in organs with inflammation and fibrosis, such as the breast and lungs. Associated with lymphoma.

• Vasculitis: Wegner’s granulomatosis is associated with the development of malignancies, including bladder cancer and renal cell cancer.

• Spondyloarthritis: Studies indicate malignancy risk.

• Paget’s Disease: Sudden onset and worsening pain indicate malignancies like osteosarcoma.

• Dermatomyositis and Polymyositis: Dermatomyositis exhibits increased cancer risk. Malignancy is seen mostly among elderly females. The common malignancies include lung, ovarian, and breast.

What Is Malignancy Caused by Immunomodulators?

Medications used in rheumatoid arthritis alter immune function. Therefore, increasing the duration of treatment with medications increases cancer risk.

• Cyclophosphamide: With increased dosage and duration risk of bladder cancer and skin cancer is enhanced.

• Methotrexate: There is an increased risk of lymphomas. In addition, increase the risk of lymphoproliferative disorder due to EBV (epstein-barr virus) infections.

• Azathioprine: An immunosuppressive drug that increases the risk of lymphoproliferative disorder.

• Cyclosporine: A disease-modifying anti-rheumatic drug that increases malignancy risk and lymphoproliferation in patients with organ transplantation.

• Infliximab: An anti-tumor necrosis factor (TNF) increases the risk of hematologic malignancy.

What Are the Malignancies Exhibiting Rheumatic Symptoms?

Solid tumors and hematological malignancies exhibit rheumatic symptoms. When a patient with cancer presents with arthritis, myalgia, or fasciitis, it is important to diagnose whether the rheumatic symptoms are the result of cancer, have developed independently as rheumatic disease, or are due to drugs used in the treatment of the disease. Patients with a history of malignancy who are undergoing treatment for rheumatoid arthritis have to be screened for any underlying malignancy. Rheumatic symptoms may be the first sign of cancer. The rheumatic conditions with malignancy origin are unresponsive to rheumatoid arthritis treatment. These symptoms may resolve with cancer treatment.

What Are the Diagnostic Tests?

The malignancy risk of rheumatoid arthritis among the elderly, familial history of malignancy, smokers, and chronic patients with long treatment is higher. For malignancy detection, positron emission tomography(PET) or computed tomography (CT) must be done. A yearly examination for rheumatoid patients of high-risk groups is suggested.

How Are They Treated?

Most rheumatic diseases associated with malignancies are refractory to treatment with steroids and disease-modifying anti-inflammatory drugs. In a few cases, treatment with drugs for rheumatic diseases can exacerbate malignancies. However, treatment of malignancies or chemotherapy can lead to resolution of symptoms. In hypertrophic osteoarthropathy, treatment of lung cancer can resolve clinical symptoms of rheumatology. In carcinomatous polyarthritis and palmar fasciitis removing underlying tumors can improve symptoms.

Conclusion

It is important to recognize the relationship between malignancy and rheumatoid diseases to diagnose and treat them appropriately. Since the presentation of symptoms is similar between the two diseases, the physician must be vigilant to catch the disease early. In addition, we must establish studies to identify disease development mechanisms to understand the condition better.