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Adult onset still's disease as a paraneoplastic syndrome: a case report and review of the literature.

Adult onset Still's disease (AOSD) is a systemic inflammatory disease with unknown etiology resembling the systemic form of juvenile rheumatoid arthritis. In addition to the high spiking fever, it is characterized by evanescent salmon pink rash, sore throat, liver dysfunction, lymphadenopathy, hepatosplenomegaly, arthritis, and leukocytosis. Since it has no pathognomonic clinical or laboratory signs, its diagnosis is one of exclusion. Along with the infections, malignancies consist of major concern in differential diagnosis. Although the diagnosis of AOSD necessitate to exclude neoplasm, there are case reports suggesting the presence of AOSD or an AOSD-like syndrome in the course of various malignant diseases including leukemia, lymphoma, breast cancer, esophageal cancer, lung cancer, and thyroid cancer. (1-15) On the other hand, it is controversial whether this phenomenon is a coincidental process or a paraneoplastic condition. Here we are presenting a patient with sarcomatoid renal cell carcinoma (RCC) who also displays symptoms and signs consistent with AOSD, and to our knowledge, this is the first case reporting this co-occurrence.


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.

Disclosure Statement

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;
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,
                                macular rash,
                                sore throat
Breast cancer (2)   F     49    intermittent
Breast cancer (3)   F     45    Polyarthralgia,

Breast cancer (4)   F     52    fever, joint
                                pleuritis, and
Breast cancer (5)   F     49    Fever, rash,
                                sore throat

Lymphoma (6)        M     49    Fever, sore
                                pleuritic chest

Lymphoma (7)        M     50    fever,

Chronic             M     25    Fever, sore
myelogenous                     throat, rash
leukemia (8)

Richter's           F     53    intermittent
syndrome (9)                    fevers, rigors,
                                night sweats,
                                weight loss,
                                arthralgia, rash.
Lung cancer (10)    M     56    sore
                                throat, fever,
Lung cancer (11)    M     62    Fever,

Lung Cancer (12)    NA    NA    NA
Papillary           F     32    high spiking
thyroid                         fevers, sore
cancer (13)                     throat, and
Papillary           M     68    Fever,
thyroid                         arthralgia,
cancer (14)                     myalgia, sore
                                throat, macular
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
                    (concurred with
Breast cancer (3)   7 years after
                    (concurred with
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

Lymphoma (7)        12 months before

Chronic             2 years before
myelogenous         neoplasm
leukemia (8)

Richter's           7 months before
syndrome (9)        neoplasm

Lung cancer (10)    1 month after

Lung cancer (11)    5 months after

Lung Cancer (12)    NA
Papillary           At the same time
cancer (13)

Papillary           At the same time
cancer (14)

Esophageal          9 months before
cancer (15)         neoplasm

Diagnosis           Treatment

Breast cancer (1)   Aspirin
                    lumpectomy and
                    lymph node dissection

Breast cancer (2)   NSAIDs
                    5-fluorouracil, methotrexate
                    and prednisone
Breast cancer (3)   prednisolone

Breast cancer (4)   Steroids

Breast cancer (5)   Steroid
                    5-fluorouracil, tamoxifen)
Lymphoma (6)        NSAIDs
                    DMARDs (Metotrexate
                    leflunomide, sulphasalazine,
                    cyclosporine A)
                    vincristine, Adriamycin,
Lymphoma (7)        Prednisone

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,
                    pemetrexed, gemcitabine)
Lung Cancer (12)    NA
Papillary           Corticosteroids
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

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

Lymphoma (6)        No response NSAIDs and
                    Responded to Corticosteroids but
                    required high doses
                    Complete remission after

Lymphoma (7)        Responded to high dose
                    of steroids; remission with
                    maintenance treatment
                    consisting low dose steroid and

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
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

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
Geographic Code:1USA
Date:Apr 1, 2013
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