Adult onset still's disease as a paraneoplastic syndrome: a case report and review of the literature.
A 69-year-old man with a 2 month history of fever was admitted to our hospital on June 2012. He had been followed with a diagnosis of chronic renal failure (CRF) due to polycystic kidney disease for 7 years and received hemodialysis. In a routine follow-up, a renal mass had been detected, and a left nephrectomy was performed approximately 3 months before admission to our hospital. The diagnosis of sarcomatoid RCC was made by pathological evaluation. Nearly one week after the operation, symptoms including fever, sweating, and chill appeared. Initially, these symptoms were intermittent but became continuous almost after the first month. He had been hospitalized at another hospital and administered various antibiotics with several diagnoses, such as respiratory and urinary tract infections, with no response. He was discharged from that hospital upon his own request and transferred to ours. At admission, he had remittent fever reaching up to 39.8[degrees] C, fatigue, and lethargy. In the physical examination, conjunctival pallor, hepatomegaly, splenomegaly, and axillary lymph node enlargement was found along with fever. He had evanescent skin rash in all extremities. Besides, his metacarpophalengeal, proximal interphalengeal and wrist joints were swollen and tender bilaterally. In his complete blood count, leukocytosis with left shift (31,500/[mm.sup.3], with 86% neutrophils), anemia (hemoglobin: 8.0 gr/dL), and thrombocytosis (457,000/[mm.sup.3]) were detected. Evaluation of blood biochemistry was consistent with CRF; the creatine and blood urea nitrogen levels were 4.75 mg/dL and 75 mg/dL, respectively. Except for hypoalbuminemia, other biochemical tests were within normal limits, including liver function tests. Acute phase reactants including erythrocyte sedimentation rate and C-reactive protein were elevated (140 mm/h and 424.2 mg/dL, respectively). Given the fever, leukocytosis, and the history of surgical intervention, ultrasonography was performed to exclude intra-abdominal abscess formation, which revealed multiple cysts in the liver and right kidney, and hepatomegaly and splenomegaly (long axes were 172 and 144 mm, respectively). The blood, sputum, pharynx swab, and urine cultures were obtained; empirical antibiotic treatment was started with meropenem (500 mg/d) and teicoplanin (400 mg/72 hours). Because of the lethargy and confusion, computed tomography of the brain and lumbar puncture were performed and found normal. All cultures were negative, and the symptoms did not respond to this treatment. Etiologic investigations for anemia disclosed markedly elevated serum ferritin levels (4,815 ng/ml, normal range 22 to 322 ng/ml). Meantime, his repeated cultures were found negative, and anti-fungal treatment was begun, while without any response. Positron emission tomography was performed, which showed an increased activity in the right renal region and intestines that were considered as due to primer or metastatic lesions of the primary tumor. Because his fever was unresponsive to antibiotics, hyperferritinemia and splenomegaly, AOSD, and hemophagocytic lymphohistiocytosis were considered in the differential diagnosis. Autoantibodies, rheumatoid factor, and other immunologic markers, including MPO-ANCA and PR3-ANCA, were negative. Fibrinogen, triglyceride levels, hepatic function tests were normal, and no cytopenia was detected except for anemia. Bone marrow aspiration, biopsy, and a culture were obtained. The culture was negative, and there was no malignant infiltration or hemophagocytosis. Therefore, the diagnosis of hemophagocytic lymphohistiocytosis was less likely. The patient was fulfilling the criteria for AOSD as suggested by Yamaguchi (fever, leukocytosis, lymphadenopathy, splenomegaly, and serologic tests were negative). (16) Actually, these criteria necessitate the exclusion of malignancy. However, since the symptoms and laboratory findings were highly suggestive of AOSD, the patient was diagnosed as paraneoplastic syndrome with AOSD-like features, and a moderate dose of corticosteroid (30 mg/day, methyl prednisolone) was administered. His fever, arthralgia, skin rash, and fatigue resolved immediately, and acute phase reactants decreased. He was discharged after the planning of chemotherapy with interferon.
Renal cell carcinoma (RCC) originates from the renal cortex and constitutes approximately 80% of primary renal neoplasms. Signs and symptoms of the disease can vary. The classic triad is flank pain, hematuria, and a palpable abdominal mass, although it is not common. On the other hand, many patients with RCC present with or subsequently develop paraneoplastic syndromes including anemia, fever, hypercalcemia, erythrocytosis, thrombocytosis, and AA amyloidosis. (17)
The association between rheumatic diseases and malignancy is somewhat complicated. Numerous rheumatic diseases can accompany, predate, or succeed to an underlying malignancy. It has been suggested that rheumatic disorders associated with malignancy can be classified as; 1. musculoskeletal disorders due to direct involvement of bones, joints, or muscles; 2. paraneoplastic syndromes; 3. altered immune system causing both the musculoskeletal and the neoplastic diseases; and 4. adverse reactions to anticancer therapy. (18) In the meantime, several rheumatic diseases, such as rheumatoid arthritis, Sjogren's syndrome, dermatomyositis, appear to predispose the development of malignancy, especially lymphopoetic and hematopoetic malignancies. On the other hand, some of them occur in a paraneoplastic fashion. Paraneoplastic rheumatic disorders can be defined as "signs and symptoms, which occurred in the course of malignant disease and induced by hormones, peptides, antibodies or other mediators rather than primary tumor or metastases." There is a wide range of paraneoplastic rheumatic disorders reported in the literature including myopathies, vasculitis, polymyalgia rheumatica, polyarthritis, and lupus-like syndromes. However, malignancy associated AOSD is somewhat rare and little is known about it.
AOSD is a rare systemic inflammatory disease and characterized by spiking fever, evanescent salmon-pink maculopapular rash, arthritis, and leukocytosis with left-shift. Other common clinical findings consist of sore throat, abnormal liver function tests, lymphadenopathy, and splenomegaly. (19) Hyperferritinemia is an important laboratory test that supports the diagnosis of AOSD in an appropriate clinical setting. Nevertheless, the diagnosis of this entity depends on the exclusion of malignant, infectious, and other rheumatic disorders. Exclusion of malignancy is of special concern, and all malignant diseases especially lymphomas, solid cancers, and myeloproliferative disorders should be taken into account. There have been several cases in literature reporting patients presented with AOSD-like symptoms in association with neoplastic diseases.
We have reported a patient with RCC presented with signs and symptoms highly suggestive of AOSD. There is an ongoing debate about the co-occurrence of AOSD and solid cancers; it is controversial whether it is a paraneoplastic syndrome or just a coincidence. Indeed, it is not easy to distinguish them. One can speculate that if the corticosteroid treatment could resolve the symptoms, the possibility of coincidence is more reasonable. However, it is not always the case in AOSD, considering the patients necessitating agents other than corticosteroids, such as anti-TNFs, interleukin-1 and 6 blockers, to resolve their symptoms. On the contrary, given the fact that paraneoplastic syndromes occur due to the effects of certain mediators, these mediators might also be involved in the development of paraneoplastic AOSD. Therefore, having a good response to corticosteroids in such a scenario would not be an unexpected situation.
In literature, there are 15 cases with AOSD-like disorder associated with malignancies including breast carcinoma, lung carcinoma, thyroid papillary carcinoma, esophageal carcinoma, and some hematologic malignancies (1-15) (Table 1). Some of them precede or occur at the same time with the diagnoses of malignancies, whereas others manifest afterward. Commonly encountered clinical (fever, sore throat, arthralgia, arthritis, and rash) and laboratory (leukocytosis, increased acute phase reactants, and hyperferritinemia) features of malignancy associated AOSD were similar to primary AOSD. All of the cases responded to high-dose corticosteroids or chemotherapy regimens consisting of corticosteroids. In these published cases, almost all of the patients' AOSD-like symptoms occurred simultaneously with the underlying neoplasm or its relapse. The cases reporting neoplasms that occurred after the diagnosis of AOSD seem to be somewhat confusing. For example, Nakagawa and coworkers reported a case with chronic myelogenous leukemia that occurred 2 years after AOSD diagnosis. It is not clear, as the investigators suggested, whether it was a coincidence or a complication of cyclosporine A and cyclophosphamide treatment. (8) Furthermore, the case reported by Bosch-Barrera and colleagues was also complicated. (11) It was stated that the patient had developed fever, arthralgia, and rash, and laboratory examination revealed elevated Creactive protein, pancytopenia, and hyperferritinemia during the chemotherapy. Although this patient had seemed to fulfill the Yamaguchi criteria, the diagnosis of hemophagocytic lymphohistiocytosis could not be excluded since the investigators have reported that the patient had pancytopenia. Kato and associates presented a similar patient with NK/T-cell lymphoma, firstly diagnosed as AOSD, and later hemophagocytic lymphohistiocytosis. (20)
On the other hand, other cases with AOSD and malignancies suggest the overlook of an occult neoplasm. Despite the initial comprehensive investigation, some malignancies could not be detected. These cases emphasize one to consider the possibility of an underlying neoplasm, not only at initial evaluation, but also during the follow-up.
In conclusion, since most of the reported cases were concurred with primary neoplasm or relapse, and resolved after the treatment targeted to the underlying malignancies, AOSD seems to be a paraneoplastic syndrome. To control the symptoms, corticosteroids seem to be effective in patients with known underlying malignancies until the efficacy of anti-tumor therapy becomes evident. Furthermore, when a patient with a previous diagnosis of malignancy developed fever and hyperferritinemia, hemophagocytic lymphohistio cytosis should be considered in the differential diagnosis. Most importantly, the diagnosis of AOSD, as well as its differential diagnosis, should be made more cautiously, and it seems crucial to follow these patients more closely particularly within the first 2 years of presentation.
None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony.
(1.) von Lilienfeld-Toal M, Merkelbach-Bruse S, Dumoulin FL. An unusual presentation of a common disease. Ann Rheum Dis. 2004 Jul;63(7):887-8.
(2.) Drenth JP, de Kleijn EH, de Mulder PH, van der Meer JW. Metastatic breast cancer presenting as fever, rash, and arthritis. Cancer. 1995 Apr 1;75(7):1608-11.
(3.) Neishi J, Tsukada Y, Maehara T, et al. Adult Still's disease as a paraneoplastic manifestation of breast cancer. Scand J Rheumatol. 2000;29(5):328-30.
(4.) Rogues AM, Vidal E, Boudinet F, et al. Breast cancer with systemic manifestations mimicking Still's disease. J Rheumatol. 1993 Oct;20(10):1786-7.
(5.) Komano Y, Kubota T, Wakabayashi S, et al. A case of paraneoplastic syndrome mimicking adult-onset Still's disease. Mod Rheumatol. 2004;14(5):410-3.
(6.) Wong P, Tam LS. Lymphoma in a patient with adult onset Still's disease refractory to immunosuppressants. Hong Kong Bull Rheum Dis. 2009;9:58-60.
(7.) Sono H, Matsuo K, Miyazato H, et al. A case of adult-onset Still's disease complicated by non-Hodgkin's lymphoma. Lupus. 2000;9(6):468-70.
(8.) Nakagawa Y, Furusyo N, Taniai H, et al. Chronic myelogenous leukemia that occurred two years after the diagnosis of adult Still's disease. Intern Med. 2005 Sep;44(9):994-7.
(9.) Geurts DE, van der Velden WJ, Hebeda KM, Raemaekers JM. Richter's syndrome developing in a patient with adult onset Still's disease. Ann Hematol. 2009 Jan;88(1):81-4.
(10.) Wu N, Li Q, Gu CX, et al. Paraneoplastic syndrome mimicking adult-onset Still's disease caused by advanced lung cancer: a case report. BMC Cancer. 2011 Nov 16;11:487.
(11.) Bosch-Barrera J, Montero A, Lopez-Picazo JM, et al. Adult onset Still's disease after first cycle of pemetrexed and gemcitabine for non-small cell lung cancer. Lung Cancer. 2009 Apr;64(1):124-6.
(12.) Kim HJ, Kwok SK, Shin JH, Cho CS. A Case of Bronchioloalveolar Carcinoma Presenting Adult-onset Still's Disease-like Manifestations due to Paraneoplastic Syndrome. J Korean Rheum Assoc. 2008 Mar;15(1):70-5.
(13.) Ahn JK, Oh JM, Lee J, et al. Adult onset Still's disease diagnosed concomitantly with occult papillary thyroid cancer: paraneoplastic manifestation or coincidence? Clin Rheumatol. 2010 Feb;29(2):221-4.
(14.) Inoue R, Kato T, Kim F, et al. A case of adult-onset Still's disease (AOSD)-like manifestations abruptly developing during confirmation of a diagnosis of metastatic papillary thyroid carcinoma. Mod Rheumatol. 2012 Sep;22(5):796-800.
(15.) Shibuya Y, Matuo K, Kawada T, et al. Adult onset Still's disease associated esophageal cancer: a case report. Ryumachi. 2003 Jun;43(3):577-82.
(16.) Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still's disease. J Rheumatol. 1992 Mar;19(3):424-30.
(17.) Gold PJ, Fefer A, Thompson JA. Paraneoplastic manifestations of renal cell carcinoma. Semin Urol Oncol. 1996 Nov;14(4):216-22.
(18.) Naschitz JE, Rosner I. Musculoskeletal syndromes associated with malignancy (excluding hypertrophic osteoarthropathy). Curr Opin Rheumatol. 2008 Jan;20(1):100-5.
(19.) Fautrel B. Adult-onset Still's disease. Best Pract Res Clin Rheumatol. 2008 Oct;22(5):773-92.
(20.) Kato T, Tanabe J, Kanemoto M, et al. A case of extranodal NK/T-cell lymphoma, nasal type mimicking typical manifestations of adult-onset Still's disease (AOSD) with hemophagocytic syndrome: diagnostic consideration between malignant lymphoma without lymphadenopathy and AOSD. Mod Rheumatol. 2009;19(6):675-80. Epub 2009 Jul 17.
Sedat Yilmaz, M.D., Muhammet Cinar, M.D., Ismail Simsek, M.D., Hakan Erdem, M.D., Can Polat Eyigun, M.D., and Salih Pay, M.D., are in the Division of Rheumatology, Gulhane School of Medicine, Ankara, Turkey. Ahmet Karakas,, M.D., and Omer Coskun, M.D., are in the Department of Infectious Diseases and Clinical Microbiology, Gulhane School of Medicine, Ankara, Turkey.
Correspondence: Sedat Yilmaz, M.D., Gulhane School of Medicine, Division of Rheumatology, 06018 Etlik-Ankara, Turkey; email@example.com.
Table 1 The Cases of Malignancy Associated Adult Onset Still's Disease in Literature Diagnosis Sex Age Clinical features Breast cancer (1) F 52 spiking fevers, transient macular rash, myalgia, arthralgia, sore throat Breast cancer (2) F 49 intermittent fever, polyarthralgias, rash Breast cancer (3) F 45 Polyarthralgia, fever Breast cancer (4) F 52 fever, joint inflammation, pleuritis, and pericarditis Breast cancer (5) F 49 Fever, rash, sore throat Lymphoma (6) M 49 Fever, sore throat, pleuritic chest discomfort, polyarthritis Lymphoma (7) M 50 fever, arthritis, myalgias. Chronic M 25 Fever, sore myelogenous throat, rash leukemia (8) Richter's F 53 intermittent syndrome (9) fevers, rigors, night sweats, anorexia, weight loss, myalgia, arthralgia, rash. Lung cancer (10) M 56 sore throat, fever, arthralgia Lung cancer (11) M 62 Fever, arthralgia, rash Lung Cancer (12) NA NA NA Papillary F 32 high spiking thyroid fevers, sore cancer (13) throat, and polyarthralgia Papillary M 68 Fever, thyroid arthralgia, cancer (14) myalgia, sore throat, macular eruption Esophageal M 77 fever, arthritis cancer (15) and rash Diagnosis Diagnosis Time Breast cancer (1) At the same time Breast cancer (2) 15 months after neoplasm (concurred with relapse) Breast cancer (3) 7 years after neoplasm (concurred with relapse) Breast cancer (4) At the same time Breast cancer (5) At the same time Lymphoma (6) Symptoms were at the same time, but diagnosis of AOSD was made 1 year before. Lymphoma (7) 12 months before neoplasm Chronic 2 years before myelogenous neoplasm leukemia (8) Richter's 7 months before syndrome (9) neoplasm Lung cancer (10) 1 month after neoplasm Lung cancer (11) 5 months after neoplasm Lung Cancer (12) NA Papillary At the same time thyroid cancer (13) Papillary At the same time thyroid cancer (14) Esophageal 9 months before cancer (15) neoplasm Diagnosis Treatment Breast cancer (1) Aspirin lumpectomy and lymph node dissection Breast cancer (2) NSAIDs cyclophosphamide, 5-fluorouracil, methotrexate and prednisone Breast cancer (3) prednisolone Breast cancer (4) Steroids Surgery Breast cancer (5) Steroid Chemotherapy-1 (Adriamycin, cyclophosphamide) Mastectomy Chemotherapy-2 (cyclophosphamide, 5-fluorouracil, tamoxifen) Lymphoma (6) NSAIDs Corticosteroids DMARDs (Metotrexate leflunomide, sulphasalazine, cyclosporine A) Chemotherapy (cyclophosphamide, vincristine, Adriamycin, prednisolone) Lymphoma (7) Prednisone Cyclophosphamide Chronic prednisolone myelogenous cyclosporine A leukemia (8) Cyclophosphamide Richter's cyclophosphamide, syndrome (9) doxorubicin, vincristine, and prednisone (CHOP) and rituximab Lung cancer (10) Nimesulide Lung cancer (11) Chemotherapy (Carboplatin, paclitaxel, erlotinib, pemetrexed, gemcitabine) prednisolone Lung Cancer (12) NA Papillary Corticosteroids thyroid cancer (13) Papillary Steroid thyroid total thyroidectomy, foll 131I cancer (14) thyroid ablation treatment Esophageal Steroids cancer (15) Diagnosis Course of AOSD Breast cancer (1) Responded to aspirin After surgery, complete remission despite cessation of aspirin. Breast cancer (2) No response NSAIDs Complete remission with chemotherapy Breast cancer (3) Responded to moderate doses, could not be tapered < 10 mg/day. Breast cancer (4) Not respond to steroids Complete remission after surgery Breast cancer (5) Responded to steroids Complete remission with chemotherapy Lymphoma (6) No response NSAIDs and DMARDs Responded to Corticosteroids but required high doses Complete remission after chemotherapy. Lymphoma (7) Responded to high dose of steroids; remission with maintenance treatment consisting low dose steroid and Cyclophosphamide. Chronic Responded to pulse steroid and myelogenous cyclophosphamide; leukemia (8) remission continued with maintenance treatment consisting low dose steroid and cyclosporine A Richter's Complete remission syndrome (9) Lung cancer (10) Responded to nimesulide. Chemotherapy was continued. No relapse. Lung cancer (11) Occurred during chemotherapy regimen, responded to steroid Lung Cancer (12) NA Papillary No response to moderate dose. thyroid Complete remission after high cancer (13) dose. Papillary Responded to steroids thyroid No recurrence after surgery and cancer (14) radionuclide treatment Esophageal Responded to high dose of cancer (15) steroids; could not be tapered < 15 mg/day. NA, not available; M, male; F, female. References are respectively arranged from 1 to 15.
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|Author:||Yilmaz, Sedat; Karakas, Ahmet; Cinar, Muhammet; Coskun, Omer; Simsek, Ismail; Erdem, Hakan; Eyigun,|
|Publication:||Bulletin of the NYU Hospital for Joint Diseases|
|Article Type:||Clinical report|
|Date:||Apr 1, 2013|
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