Turk J Rheumatol 2012;27(1):18-23 doi: 10.5606/tjr.2012.002 Invited Review Paraneoplastic Rheumatic Disorders Paraneoplastik Romatizmal Hastalıklar Ömer Faruk ŞENDUR Department of Physical Medicine and Rehabilitation, Medical Faculty of Adnan Menderes University, Aydın, Turkey Paraneoplastic rheumatic disorders are defined as Altta yatan malign bir hastalık nedeniyle ortaya rheumatic symptoms resulting from an underlying çıkan, tümör veya metastaz ile direkt ilişkisi olmayan malignant disease, which is not directly related to a romatizmal semptomlar paraneoplastik romatizmal tumor or metastasis. The clinical course of the disease hastalıklar olarak tanımlanır. Hastalığın klinik is generally in parallel with the underlying malignancy. seyri, genellikle altta yatan malignensi ile paralellik Such kind of rheumatic symptoms are unresponsive gösterir. Bu tip romatizmal semptomlar konvansiyonel to conventional treatments, while mostly improve with tedavilere yanıt vermezken, çoğunlukla altta yatan successful treatment of the underlying malignancy. malignensinin başarılı tedavisi ile düzelir. Bu tip Early diagnosis of malignancies may be possible with olgularda hekimin paraneoplastik romatizmal suspicion of paraneoplastic rheumatic disorders by hastalıklardan şüphelenmesi malignensinin erken tanı physicians in such cases. almasını sağlayabilir. Key words: Malignancies; paraneoplastic syndromes; rheumatic Anahtar sözcükler: Maligniteler; paraneoplastik sendromlar; diseases. romatizmal hastalıklar. The term “paraneoplastic syndromes” refers to of rheumatic diseases (v) rheumatic diseases which symptoms caused by a malignancy but which are not developed as complications from malignancy directly related to the tumor mass nor its metastasis. treatments. These kinds of symptoms are present in approximately This review focuses on paraneoplastic rheumatic 10% of all cancer cases at the time of diagnosis. disorders (RDs). This involves the non-metastatic Approximately 50% of cancer patients experience distant effects of tumors on the musculoskeletal paraneoplastic symptoms at least once during their system. The main distinguishing feature between disease. Although the majority of these are endocrine paraneoplastic RD and tumors associated with RDs in nature, hematological, rheumatic, and neurological is that the rheumatic symptoms in the former are symptoms are also seen.[1] decreased or abolished by excision or radical treatment The concomitant presence of malignancies with of the tumor. The majority of paraneoplastic RDs rheumatic diseases may appear in various forms: precede the onset of the malignancy by months or even (i) metastasis to musculoskeletal system (ii) non- years. Although some types of paraneoplastic RDs are metastatic paraneoplastic rheumatic diseases (iii) very rarely reported in the literature, we believe that malignancies secondary to a rheumatic disease (iv) this number should be higher. Unfortunately, a lack malignancies which developed as complications due of knowledge about this condition causes delays in to immunosuppressive drugs used for the treatment diagnosis and loss of very precious time. Received: February 22, 2012 Accepted: February 28, 2012 Correspondence: Ömer Faruk Şendur, M.D. Adnan Menderes Üniversitesi Tıp Fakültesi Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 09100 Aydın, Turkey. Tel: +90 256 - 444 12 56 e-mail: [email protected] ©2012 Turkish League Against Rheumatism. All rights reserved. Paraneoplastic Rheumatic Disorders 19 PATHOGENESIS response to steroids, or disease-modifying drugs, then further investigation regarding malignancies should be Decreasing paraneoplastic RD symptoms in line with performed. Symptoms in carcinomatous polyarthritis the primary tumor treatment can provide an idea do not respond to conventional anti-rheumatic about the pathogenesis. There are three proposed treatment. A successful cure is obtained by treating the hypotheses:[2] underlying malignancy. a) Paraneoplastic RD and malignancy are Hypertrophic osteoarthropathy (HOA) independently triggered by the same initiative factor (bacteria, virus, radiation, etc.) Hypertrophic osteoarthropathy is mostly associated with lung adenocarcinoma. The prevalance b) Paraneoplastic RD is caused by toxins produced varies between 6% and 12%.[9,10] It may also occur in by the tumor cells, which trigger inflammation. patients with lung metastases of other malignancies, c) Paraneoplastic RD is mediated by hypersensitivity pleural mesothelioma, or intrathoracic lymphoma. reaction, which develops against intracellular antigens The symptoms emerge months before the underlying [11] secreted by apoptotic cancer cells. The presence of malignancy. Although the exact etiology is autoantibodies against nuclear proteins and double- unknown, humoral, vascular, immunologic, and vagal neural reflex mechanisms are implicated in the stranded deoxyribonucleic acid (ds-DNA) in the serum [10,12] of people with paraneoplastic RD is used as evidence pathogenesis. for this suggestion.[3] The classical disease triad for HOA is the combination of oligo or polyarthritis, clubbing in the CLASSIFICATION toes and fingers, and periostitis at the distal ends of It was first reported in 1916 that a rheumatic disease long bones. Rapid progression is seen with this disease, could herald a malignancy.[4] Many paraneoplastic RDs which is related to malignancy. Sometimes a burning have been defined since that time (Table 1). pain accompanies the clubbing of fingers. Arthritis is mostly seen in the metacarpophalangeal joints, knees, ARTHRITIS ankles, elbows, wrists, and proximal interphalangeal joints. They are usually symmetrical and painful. Carcinomatous Polyarthritis (Rheumatoid However, synovial fluid analysis shows no sign of Arthritis-Like) Carcinomatous polyarthritis is a seronegative inflammatory arthritis and may be the first sign of Table 1. Classification of paraneoplastic syndromes an existent malignancy. Although the pathogenesis Arthritis of synovitis is not clearly known, possible pathogenic Carcinomatous polyarthritis factors include immune mechanisms such as hormones, Hypertrophic osteoarthropathy cytokines, peptides, antibodies and cytotoxic Amyloid arthritis lymphocytes.[5] Secondary gout Vasculitides Carcinomatous polyarthritis has been associated Paraneoplastic vasculitis with breast, lung, colon, ovarian, gastric, and Raynaud’s syndrome and digital gangrene oropharynx cancer as well as esophageal tumors and Erythromelalgia [2,6,7] Skin and muscle diseases lymphoproliferative diseases. Usually the symptoms Dermatomyositis and polymyositis appear eight to 12 months before the development of Scleroderma-like syndrome tumor disease.[2] It differs from rheumatoid arthritis Erythema nodosum (RA) due to the initiation at advanced age, acute Lambert-Eaton syndrome onset, predominantly asymmetrical lower extremity Palmar fasciitis involvement, and sparing of wrist and hand joints. Panniculitis Eosinophilic fasciitis Also, unlike RA, the absence of erosions, deformities, Unclassified syndromes rheumatoid factor, rheumatoid nodules, and family Reflex sympathetic dystrophy history is observed.[8] Furthermore, joint radiographs Lupus-like syndromes tend to be normal. If a patient with such symptoms Recurrent polychondritis also has disproportional pain, severe weight loss, Multicentric reticulohistiocytosis Oncogenic osteomalacia hepatosplenomegaly, lymphadenomegaly, inadequate 20 Turk J Rheumatol inflammation.[11] Deeply localized bone pain is present malignancies. Cutaneous LV may be associated with due to periostitis. The pain is especially prominent at myeloproliferative and lymphoproliferative diseases the distal part of the lower extremities and typically along with myelodysplastic syndrome. Lesions are increases during movement and decreases when the legs similar to those observed in patients without underlying are elevated. These patients may have skin thickening malignancies. However, older age, the absence of any at the forehead and neck as well as gynecomastia.[10] infection, or the presence of an autoimmune disease, which can explain the vasculitis, chronic relapses, and There is no specific laboratory sign. The unresponsiveness to conventional treatments, should sedimentation rate is usually high. Alkaline suggest an underlying malignancy. phosphatase levels may be higher in cases with periostitis. Symmetrical periostitis may be observed in Polyarthritis nodosa is the second most frequent direct radiographies of the long bones. Scintigraphic type of paraneoplastic vasculitis.[14] It is mostly abnormalities may precede the radiographic findings. associated with hairy cell leukemia. The clinical Although pain is relieved by nonsteroidal anti- manifestation consists of fever, cutaneous vasculitis, inflammatory drugs (NSAIDs), a cure is only possible myalgia, arthritis, acute abdomen due to mesenteric by treating the underlying neoplasm. vasculitis, and foot drop due to mononeuritis multiplex. Amyloid arthritis Although the etiology of paraneoplastic vasculitis Amyloid arthritis is generally described in patients is not yet clearly known, suggested mechanisms are: with multiple myeloma. The arthritis is characterized (i) vascular damage caused by cross-reactions between by monoclonal light chains (AL amyloid) accumulation antibodies against tumor cells and the vascular at synovium. Typically it involves the shoulders, knees endothelium (ii) vascular inflammation caused by and wrists bilaterally and is relatively painless. Sinovial immune complexes