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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 . 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 . 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 at the distal ends of It was first reported in 1916 that a rheumatic disease long . 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). 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 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 and polymyositis appear eight to 12 months before the development of Scleroderma-like syndrome tumor disease.[2] It differs from (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 -like syndromes tend to be normal. If a patient with such symptoms Recurrent polychondritis also has disproportional pain, severe , Multicentric reticulohistiocytosis Oncogenic hepatosplenomegaly, lymphadenomegaly, inadequate 20 Turk J Rheumatol inflammation.[11] Deeply localized 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 . 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 , 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 , 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 involving tumor antigens (iii) direct effusions are non-inflammatory and contain amyloid vascular damage caused by the hairy cells in hairy deposits.[8,13] The diagnosis can be confirmed by bone cell leukemia. Autoantibodies, such as rheumatoid marrow examination, serum and urine electrophoresis, factor, the antineutrophil cytoplasmic antibody, and or a biopsy of the synovium. Carpal tunnel syndrome, antinuclear antibodies, are negative in patients with [15,16] subcutaneous amyloid deposition, macroglossia, paraneoplastic vasculitis. cardiomyopathy, and nephropathy are other clinical Raynaud’s syndrome manifestations. The disease responds to the treatment Raynoud’s syndrome may occur in association with for multiple myeloma and symptomatic treatment of gastrointestinal, lung, ovarian, and renal carcinoma arthritis with NSAIDs. or with lymphoproliferative diseases. The symptoms Secondary gout are generally asymmetric with digital gangrene. Hyperuricemia and gout are mainly associated with Underlying malignancy should be considered in severe hematological malignancies (leukemia, polycythemia Raynoud cases, especially in individuals 50 years of vera, lymphomas, etc.), but they may also develop as age or older. Cryoglobulinemia, vasospasm due to a result of the rapid lysis of cells after chemotherapy. immune complexes, hypercoagulopathy, and vasculitis [6,8] The severity of gout changes with the severity of are suggested as possible causes of the pathogenesis. the underlying malignancy, liver involvement, and Paraneoplastic erythromelalgia presence of hypercalcemia. Hyperuricemia can be prevented by adequate hydration and allopurinol Erythromelalgia is characterized by burning pain, treatment before chemotherapy.[3] erythema, and a feeling of heat on the feet or hands without evidence of arterial occlusion. Symptoms are VASCULITIDES increased by exercise and exposure to heat. About 20% of secondary erythromelalgia cases occur in patients Paraneoplastic vasculitides with myeloproliferative diseases, such as polycythemia Cutaneous leukocytoclastic vasculitis (LV) is rubra vera and essential thrombocythemia. Symptoms the most frequently encountered paraneoplastic may begin months or years before the principal disease. vasculitis,[14] with palpable purpura, urticaria, and Therefore, blood count tests should be performed maculopapular eruptions being observed, Sometimes regularly in these patients. Daily 325-650 mg aspirin it is also accompanied by arthritis. Skin lesions may intake is recommended. Erythromelalgia can be treated be seen before, at the time of, or after the diagnosis of by the management of the underlying malignancy.[17,18] Paraneoplastic Rheumatic Disorders 21

SKIN AND MUSCLE DISEASES result of a decreased acetylcholine release at the presynaptic neuromuscular junction and cholinergic Dermatomyositis, polymyositis (DM, PM) autonomic endings. Underlying malignancy may be The relationship between malignancies and myositis diagnosed approximately one to two years after the has not yet been clearly identified. Increased initiation of muscle strength loss.[8] There are no cancer incidence among patients with DM is well pathophysiological or clinical differences between known.[19] Additionally, DM and PM can be associated primary LES and paraneoplastic LES. It is believed with various malignancies, such as lung, ovarian, that autoantibodies against the cellular membrane of breast, and nasopharyngeal carcinoma along with small-cell lung carcinoma block the neural testis tumors, lymphoma, leukemia, and malign channels by cross-reaction.[26,27] melanoma.[20] More severe skin lesions are seen Palmar fasciitis-polyarthritis syndrome in patients with paraneoplastic DM, and they do not respond to conventional immunosuppressive Palmar fasciitis-polyarthritis syndrome is mainly treatment.[3,19] Cancer associated with myositis is related to ovarian carcinoma. However, it may also generally described in older people, with the risk being be associated with endometrial, gastric, and prostate higher in females.[3,21] cancers along with leukemia and Hodgkin’s disease. Scleroderma-like syndrome The clinical manifestation consists of a thickening of the palmar fascia and symmetrical arthritis Scleroderma like-skin changes can be observed which commonly affects the knees, ankles, elbows, concomitantly with gastric, breast, and lung and wrists. In severe cases, clinical presentation tumors as well as with metastatic melanoma and resembles Dupuytren’s contracture. The arthritis [22] osteoclastic myeloma. POEMS syndrome is is resistant to treatment with corticosteroids and defined as osteoclastic myeloma associated with NSAIDs. A cure can be achieved by treatment of , endocrinopathy, monoclonal the primary tumor. The prognosis is poor if palmar protein and scleroderma-like skin lesions. Anti- fasciitis-polyarthritis syndrome is associated with topoisomerase I antibody levels are higher in metastatic diseases.[28,29] oncological patients who have scleroderma-like skin changes.[3] However, the skin lesions do not improve Panniculitis-polyarthritis syndrome with the treatment of the underlying malignancy. This syndrome is characterized by inflammation Therefore, this situation is considered to be a kind [23] of the subcutaneous adipose tissue and usually of metastasis rather than a paraneoplastic event. is associated with pancreatic malignancies. Paraneoplastic erythema nodosum Arthropathy, subcutaneous sensitive nodules, synovitis, polyserositis, and bone lesions can be Paraneoplatic erythema nodosum (EN) is a type observed. The skin lesions appear as tender, red of panniculitis that is observed idiopathically or secondarily to drugs, infections, and rheumatic subcutaneous nodules. The possibility of pancreatic diseases. However, if it persists longer than six cancer should be considered in older patients who weeks, malignancy-associated EN should be present with tender subcutaneous nodules and [10,30] considered. Paraneoplastic EN occurs most unexplained arthritis. commonly in patients with Hodgkin’s lymphoma, Paraneoplastic eosinophilic fasciitis non-Hodgkin’s lymphoma, and leukemia. Cases of hepatocellular carcinoma have also been reported. Paraneoplastic eosinofilic fasiitis is an uncommon The lesions regress after treatment of the underlying connective tissue disease characterized by diffuse malignancy.[24,25] fasiitis, eosinophilia, unexplained symmetrical pain, and woody induration of the skin at the hands and/ Lambert-Eaton syndrome (LES) or feet. The disease usually is observed in patients Lambert-Eaton syndrome occurs most with lymphoproliferative diseases. The skin of the frequently in patients with small-cell carcinoma affected extremity is thick and tight. Contractures may of the lungs, which affects about 16% of develop due to skin sclerosis. The absence of Raynoud’s patients.[26,27] It is characterized by severe , syndrome and unresponsiveness to corticosteroid in the proximal muscles, especially at treatment distinguishes eosinofilic fasiitis from the lower extremities, and hyporeflexia and is the scleroderma.[31,32] 22 Turk J Rheumatol

UNCLASSIFIED SYNDROMES proximal muscles can be observed. The possibility of an underlying tumor should be considered in adult Paraneoplastic reflex sympathetic dystrophy (RSD) osteomalacia of unknown etiology. In the majority Paraneoplastic RSD is associated with metastatic of cases, tumor excision is adequate for treatment. tumors of the lungs, colon, ovaries, and prostate as If total resection of the tumor is not possible, then well as chronic myeloid leukemia. Typical RSD signs phosphate and active D supplements should like diffuse burning pain, allodynia, swelling, and be given.[9,39,40] [33,34] decreased extremity function are encountered. In conclusion, paraneoplastic RDs refers to Symptoms may precede the diagnosis of the underlying symptoms caused by a malignancy but which have malignancy. The pathogenesis is unknown. no direct relationship to the tumor mass or its Paraneoplastic lupus-like syndromes metastasis. Certain rheumatic symptoms may be predictive signs of an undiagnosed malignancy. Lupus-like syndromes may be predictive signs Furthermore, diagnosis of paraneoplastic rheumatic for breast and ovarian cancers along with hairy cell disease can provide early diagnosis of underlying leukemia. Clinical manifestation may consist of malignancies. polyserositis, pneumonitis, Raynaud’s syndrome with digital necrosis, non-erosive inflammatory arthritis, Acknowledgment and . Leucopenia and ANA We would like to thank Elif Aydın, M.D. for her (antinuclear antibody) positivity can be seen, but contribution to the reviews. ANA positivity without rheumatic symptoms is not predictive of occult malignancy.[2,3,6] Declaration of conflicting interests Recurrent polychondritis The authors declared no conflicts of interest with respect to the authorship and/or publication of this Recurrent polychondritis is observed in 30% of article. patients with chronic inflammatory diseases and may occasionally be a paraneoplastic syndrome. It is Funding characterized by inflammatory attacks of The authors received no financial support for the tissues at the nose, , trachea-bronchial, and joints. research and/or authorship of this article. Associations with myelodysplastic syndromes and non-Hodgkin’s lymphoma have been reported.[35,36] REFERENCES Multicentric reticulohistiocytosis 1. Nathanson L, Hall TC. Introduction: paraneoplastic Multicentric reticulohistiocytosis is a rare systemic syndromes. Semin Oncol 1997;24:265-8. 2. Racanelli V, Prete M, Minoia C, Favoino E, Perosa disease presenting with subcutaneous nodular lesions F. Rheumatic disorders as paraneoplastic syndromes. and symmetrical, erosive polyarthritis. Multicentric Autoimmun Rev 2008;7:352-8. reticulohistiocytosis is associated with malignancy in 3. Szekanecz Z, Szekanecz E, Bakó G, Shoenfeld Y. about 28% of reported cases. Histiocytic giant cells Malignancies in autoimmune rheumatic diseases - a mini- are observed in the histological examination of the review. Gerontology 2011;57:3-10. skin. The arthritis generally involves the proximal 4. Stertz G. Polymyositis. Berl Klin Wochenshr 1916;53:489. and distal phalangeal joints of the hands. This feature 5. Mok CC, Kwan YK. Rheumatoid-like polyarthritis as helps to differentiate it from RA. The arthritis is self- a presenting feature of metastatic carcinoma: a case limiting; however, disability may develop as a result presentation and review of the literature. Clin Rheumatol of deformities. Symptoms can be improved when the 2003;22:353-4. underlying malignancy is treated.[37,38] 6. András C, Csiki Z, Ponyi A, Illés A, Dankó K. Paraneoplastic rheumatic syndromes. Rheumatol Int 2006;26:376-82. 7. Farhey Y, Luggen M. Seropositive, symmetric Oncogenic osteomalacia is associated with benign polyarthritis in a patient with poorly differentiated lung tumors which originate in the mesenchymal cells. carcinoma: carcinomatous polyarthritis, hypertrophic There is , hyperphosphaturia, and osteoarthropathy, or rheumatoid arthritis? Arthritis Care decreased concentrations of 1.25 dihydroxyvitamin Res 1998;11:146-9. D3 concentrations in the plasma. Diffuse bone 8. Fam AG. Paraneoplastic rheumatic syndromes. Baillieres pain, spontaneous fractures, and weakness in the Best Pract Res Clin Rheumatol 2000;14:515-33. Paraneoplastic Rheumatic Disorders 23

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