TY - JOUR
AU - Arimura, Yoshihiro
AB - Abstract A 72-year-old woman presented 9 months ago with skin rash on her bilateral forearms, which was followed by intermittent high fever, and stiffness and swelling of her bilateral fingers. She was diagnosed with seronegative rheumatoid arthritis (RA). She had a past history of breast cancer and had undergone breast preservation surgery 13 years previously. During admission in our hospital, she developed high fever and leukocytosis with a relapsing skin rash, sore throat, polyarthralgia and increased levels of serum ALT/AST and ferritin, all of which fulfilled Yamaguchi’s criteria for adult-onset Still’s disease (AOSD). While we tried to exclude other diseases that may show AOSD-like manifestations, pancytopenia rapidly developed and bone marrow biopsy strongly suggested the diagnosis of macrophage activating syndrome (MAS). Accordingly, steroid pulse therapy was begun, followed by oral glucocorticoid therapy. Thereafter, all of her symptoms improved, but systemic rash, inflammatory signs and pancytopenia gradually progressed. The results of bone marrow pathology, which returned 2 weeks after the beginning of treatment, revealed hemophagocytosis with CK7-positive/CK20-negative atypical cells that suggested recurrence of breast cancer in the bone marrow, thus all of her AOSD-like symptoms were considered to be paraneoplastic manifestations of late-onset metastatic breast cancer. She was treated successfully with chemotherapy. When we see the patients showing AOSD-like symptoms with a history of malignancy, we should consider the possibility of paraneoplastic syndrome due to cancer recurrence. Adult-onset Still’s disease, Bone metastasis, Breast cancer, Macrophage activating syndrome, Paraneoplastic syndrome Introduction Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease that is characterized by a salmon pink skin rash, high-grade fever, arthritis, sore throat, lymphadenopathy, hepatosplenomegaly, and liver dysfunction. AOSD sometimes develops macrophage activating syndrome (MAS), which is a critical complication showing rapidly progressive pancytopenia [1]. Yamaguchi’s criteria have been used as a diagnostic standard, showing high sensitivity and specificity [2]. On the other hand, this criteria also emphasizes the importance of exception of other inflammatory disease. AOSD does not have disease-specific serological markers, such as anti-DNA antibody in systemic lupus erythematosus, therefore the exclusion of other systemic diseases is crucial for the diagnosis. In particular, malignant solid tumors such as hepatocellular cancer, septicemia, and other autoimmune diseases are sometimes diagnosed initially as AOSD. For the treatment of AOSD, high amounts of glucocorticoid (GC) and immunosuppressive agents have been used. These medications may have had some effects on pyrexia and arthralgia, even if these manifestations were caused by either malignancy or infectious disease, but these apparent improvements may lead to a delay in revealing true causes, and also there was a risk of adverse reactions such as infection, and bone marrow suppression. When making the diagnosis of AOSD, it is necessary to consider the possible presence of an associated malignancy. Case report A 72-year-old woman noticed a skin rash on her bilateral forearms and visited a local clinic 9 months ago (Figure 1). Intermittent high fever, stiffness and swelling of her bilateral fingers developed subsequently, thus she was diagnosed with seronegative rheumatoid arthritis. She was later referred to our hospital because of a persistent high fever that was not responsive to non-steroidal anti-inflammatory drugs (NSAIDs). She had a past history of breast cancer, when she curatively underwent breast preservation surgery with dissection of the regional axillary fossa lymph nodes 13 years previously, thereafter she was treated with hormone therapy during the following 5 years. Figure 1. Open in new tabDownload slide Clinical course, symptoms and therapies of this patient. mPSL: methyl prednisolone, PSL: prednisolone, CRP: C-reactive protein. Figure 1. Open in new tabDownload slide Clinical course, symptoms and therapies of this patient. mPSL: methyl prednisolone, PSL: prednisolone, CRP: C-reactive protein. At our outpatient clinic, she was treated unsuccessfully with salazosulfapyridine (SASP), and 1 month later, her systemic rash and high fever relapsed. SASP was discontinued because of suspected drug-induced exanthema. However, a skin rash spread over her upper and lower extremities, accompanied by a sore throat, high fever, and appetite loss, resulting in a 3-kg weight loss, and she was admitted to our hospital. Upon admission, her high fever initially improved. On admission, the patient’s height and body weight were 145.0 cm and 45.0 kg, respectively. The blood pressure was 122/62 mmHg, body temperature 36.6 °C, and the pulse 76 rpm. The consciousness level was clear. There were hepatosplenomegaly, lymph node swelling and skin eruption on bilateral upper and lower extremities. The laboratory findings revealed anemia with a hemoglobin level of 10.6 g/dl, a blood sedimentation ratio of 64 mm/hour, and a C-reactive protein level of 2.07 mg/dl. Rheumatoid factor, antinuclear antibody and anti-citrullinated protein antibody (anti-CCP antibody) were all negative, but matrix metalloproteinase-3 was slightly elevated (91.0 ng/dl). Serum ferritin and soluble interleukin-2 receptor (sIL-2R) levels were found to be 2633 ng/ml and 1980 U/ml, respectively. At Day 7, she presented with a high fever of 38.5 °C and leukocytosis (over 10,000/μl) accompanied by relapsing skin rash, sore throat, and polyarthralgia. Skin rash was small spotted erythema multiforme on the bilateral upper and lower extremities spreading over the abdomen. ALT and AST were elevated in association with an increase in serum ferritin levels to >10,000 ng/ml. We tried to find other diseases including infection, malignancy and other collagen disease. The results of frequent blood culture showed no pathogenic bacterium and fungi growth. Antistreptolysin, interferon-γ release assay (IGRA) for tuberculosis, anti-EB virus antibody, HIV antibody, and cytomegalovirus antigenemia were all negative. Imaging studies including enhanced computer tomography scan revealed no evidence of infectious diseases, and malignant tumor. We comprehensively measured tumor markers, but no significant increases were detected; CEA: 2.5 ng/ml, CA19-9: 2.9 U/ml, CA15-3: 9.3 U/ml, and CA125: 11.7 U/ml. Soluble IL-2 receptor (sIL-2R) showed a moderate increase (1430 U/ml), but no obvious lymph node swelling by imaging studies. Since she had a past history of breast cancer, we carefully searched for a possible local recurrence, without any suggestive findings. Although NSAIDs were administrated again, high fever, skin eruption, and liver damage persisted. During the course, hemoglobin and platelet levels began to decrease, raising concerns that macrophage activation syndrome (MAS) might occur. Therefore, a bone marrow biopsy was performed, and she was administered steroid pulse therapy with intravenous administration of 500 mg methylprednisolone for three consecutive days, followed by 40 mg/day of oral prednisolone. While treatment with GC has begun, imaging and laboratory tests searching for secondary causes such as infection and malignancy were intensively performed. A week after, all of her symptoms improved transiently, and her systemic rash and inflammatory markers of CRP and ferritin levels temporally showed a decrease to a normal range, but again increased to 1.8 mg/dl and 1000 mg/dl, respectively, after GC was tapered to 30 mg/day. Along with these data, the platelet count also showed a transient improvement to 35 × 104/μl, but decreased to 1.2 × 104/μl. The report of bone marrow biopsy, which returned two weeks after the beginning of GC treatment, revealed hemophagocytosis with abundant atypical cells showing a trabecular pattern (Figure 2). The atypical cells were found to be positively stained by CK7 but negative for CK20, which suggested late-onset metastatic breast cancer. In addition, the tumor markers of breast cancer, NCC-ST-439, and BCA225, were turned out after the onset of MAS. NCC-ST-439 showed slight increase (19 U/ml) and BCA 225 was in normal range (≤30 U/ml). We speculated that the AOSD-like symptoms could be a presentation of paraneoplastic syndrome caused by breast cancer recurrence, although it had been in remission for 13 years. The patient was moved to another hospital to undergo chemotherapy for breast cancer with bone marrow metastasis. After six sessions of chemotherapy, she remained in remission even though the dosages of GC were reduced. Later, her serum IL-18 and IL-6 levels were found to be markedly elevated to >5000 pg/ml (normal, <200 pg/ml) and 12.8 pg/ml (normal, <4.0 pg/ml), respectively. After 6 months remission, her IL-18 levels decreased to 383 pg/ml, and IL-6 also decreased to 2.3 pg/ml. Figure 2. Open in new tabDownload slide Bone marrow specimen acquired from the iliac bone. (a) Hematoxylin & eosin staining (HE) of bone marrow specimen from the iliac bone shows strand-formation of poorly differentiated adenocarcinoma cells among normal myeloid cells (200×). (b) Adenocarcinoma cells stained with HE shown under high power (400×). (c) CK7 staining of the bone marrow specimen. (d) CK20 staining of the bone marrow specimen. Figure 2. Open in new tabDownload slide Bone marrow specimen acquired from the iliac bone. (a) Hematoxylin & eosin staining (HE) of bone marrow specimen from the iliac bone shows strand-formation of poorly differentiated adenocarcinoma cells among normal myeloid cells (200×). (b) Adenocarcinoma cells stained with HE shown under high power (400×). (c) CK7 staining of the bone marrow specimen. (d) CK20 staining of the bone marrow specimen. Discussion Here, we reported a case of late-onset metastatic breast cancer that initially presented with AOSD-like symptoms. We concluded that the symptoms similar to AOSD might be paraneoplastic syndrome caused by the recurrence of breast cancer that had been in remission for 13 years. It is well known that cancer is revealed by variable cancer-related symptoms. The clinical features of AOSD as a paraneoplastic syndrome are not well known, but may include the resistance to NSAIDs or GC therapy [3–9], and also the late onset usually in the elderly patients with ages over 40 years like this patient. Although our case fulfilled the Yamaguchi’s criteria, the criteria requires the exclusion of other disease conditions such as malignancy and infections. Notably, it has been reported that among various malignancies showing AOSD-like symptoms, the prevalence of solid cancer and hematological malignancy was 61 and 39%, respectively, and in various solid cancers [3–7], Liozon et al. [8] reported that breast cancer was the most frequent (26%), followed by lung cancer (10%), thyroid cancer (10%), esophageal cancer (10%), and renal cell carcinoma (10%) [8]. These malignancies may not be found until months or years later, especially in recurrence breast cancer [5,9]. In our case, the patient develop to MAS on the way of diagnosing process, thereby we reluctantly began the GC therapy. Even if the symptoms fulfilled the criteria for AOSD, we should be careful about the diagnosis by itself as the exclusion of other disease is essential. We emphasize that the criteria is a necessary, but not a sufficient condition. Moreover, our case developed MAS during admission. According to a cohort study of 169 the Japanese patients revealed that the prevalence of MAS was slightly higher in the patients with AOSD-like symptoms as paraneoplastic syndrome than the patient with idiopathic AOSD [10]. When the patient showed the AOSD-like symptoms, cancer cells were detected only in bone marrow biopsy without any findings of local relapses. Breast cancer is known to metastasize often, with the rate in >20% of the cases at the time of an initial diagnosis. Meanwhile, it is also reported that breast cancer sometimes shows late-onset metastasis [11]. This suggests that breast cancer may easily spread to other organs at its initial phase, but may enter the “resting-phase” or “cell cycle arrest” because of its susceptibility to the anti-neoplastic agents administered, and may finally relapse after the cessation of the treatment. Although the mechanism by which AOSD-like syndrome develops in cancer patients remains unclear, some reports suggest that pro-inflammatory cytokines that are produced in cancer cells or systemic reactions may play important roles [3,5,12]. As mentioned above, there is a difference in the prevalence of AOSD-like manifestation by the types of cancer, and breast cancer is most frequently observed among solid cancers. Gunel et al. [13,14] reported that the levels of interleukin-18 (IL-18), a pro-inflammatory cytokine, were increased in patients with breast cancer exhibiting AOSD-like symptoms, causing polyarthritis, high fever, leukocytosis, and an increase in the serum C-reactive protein and IL-17 levels [13,14]. Furthermore, IL-18 is sometimes known to stimulate macrophages excessively, which may lead to MAS [1]. In our case, no systemic symptoms were seen when the primary breast cancer was found, similar to the one reported by Fontanella et al. [15]. There are some reports on the mechanisms by which IL-18 are overproduced in metastatic cancer; an offensive process by breast cancer itself, and a defensive reaction against cancer by host immune-competent cells such as macrophages [15]. According to the former hypothesis, breast cancer may undergo transformation during metastasis, enabling the cells to survive in other organs and transform to produce pro-inflammatory cytokines [16]. Therefore, a relapse of metastatic cancer may express the various symptoms that are unlikely to show in the original lesion. Some reports described an increase in serum IL-18 levels in the patient with metastatic cancer, as compared with those of the patients without metastasis [13]. On the contrary, a host defense mechanism suggests that IL-18 may activate natural killer cells, which may eliminate malignant cells from the organs. Immune cells such as macrophages also secrete IL-6, thus the elevated levels of IL-18 and IL-6 may cause systemic symptoms similar to idiopathic AOSD [17]. Also, a remarkable increase in serum ferritin levels, which is characteristic feature of AOSD, ensues due to stimulation of hepcidin production by the cytokines [18]. Thus, it is speculated that both metastatic breast cancer and AOSD may develop along a common pathway through overproduction of pro-inflammatory cytokines. Indeed, the IL-18 and IL-6 levels in the sera of the present patient decreased after the remission of the disease by chemotherapy. In conclusion, when making the diagnosis of AOSD, it is important to exclude other diseases presenting with AOSD-like syndrome, in particular, the paraneoplastic syndrome complicated by malignancy such as late-onset metastatic breast cancer. Acknowledgements We would like to give special thanks to Dr. Hidemitsu Yasuda, Medical Director, Department of Breast Surgery, Center Hospital of the National Center for Global Health and Medicine, who treated the metastatic breast cancer. We also wish to acknowledge Prof. Hiroshi Kanma, Dr. Makoto Mochizuki, Dr. Hiroaki Shimoyamada and Dr. Aya Isomura, Department of Pathology, Kyorin University School of Medicine, for the pathological diagnosis. Conflict of interest None. References Jamilloux Y , Gerfaud-Valentin M, Martinon F, Belot A, Henry T, Seve P Pathogenesis of adult-onset Still's disease: new insights from the juvenile counterpart . Immunol Res . 2015 ; 61 ( 1–2 ): 53 – 62 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Yamaguchi M , Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. . Preliminary criteria for classification of adult Still's disease . J Rheumatol . 1992 ; 19 ( 3 ): 424 – 30 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Komano Y , Kubota T, Wakabayashi S, Ochi S, Nonomura Y, Hagiyama H, et al. . A case of paraneoplastic syndrome mimicking adult-onset Still's disease . Mod Rheumatol . 2004 ; 14 ( 5 ): 410 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat von Lilienfeld-Toal M , Merkelbach-Bruse S, Dumoulin FL An unusual presentation of a common disease . Ann Rheum Dis . 2004 ; 63 ( 7 ): 887 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Drenth JP , de Kleijn EH, de Mulder PH, van der Meer JW Metastatic breast cancer presenting as fever, rash, and arthritis . Cancer . 1995 ; 75 ( 7 ): 1608 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Neishi J , Tsukada Y, Maehara T, Ueki K, Maezawa A, Nojima Y Adult Still's disease as a paraneoplastic manifestation of breast cancer . Scand J Rheumatol . 2000 ; 29 ( 5 ): 328 – 30 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Rogues AM , Vidal E, Boudinet F, Loustaud V, Arnaud M, Liozon F Breast cancer with systemic manifestations mimicking Still's disease . J Rheumatol . 1993 ; 20 ( 10 ): 1786 – 7 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Liozon E , Ly KH, Vidal-Cathala E, Fauchais AL [Adult-onset Still's disease as a manifestation of malignancy: report of a patient with melanoma and literature review] . Rev Med Interne . 2014 ; 35 ( 1 ): 60 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Sun NZ , Brezinski EA, Berliner J, Haemel A, Connolly MK, Gensler L, et al. . Updates in adult-onset Still disease: atypical cutaneous manifestations and associations with delayed malignancy . J Am Acad Dermatol . 2015 ; 73 ( 2 ): 294 – 303 . Google Scholar Crossref Search ADS PubMed WorldCat Asanuma YF , Mimura T, Tsuboi H, Noma H, Miyoshi F, Yamamoto K, Sumida T Nationwide epidemiological survey of 169 patients with adult Still's disease in Japan . Mod Rheumatol . 2015 ; 25 ( 3 ): 393 – 400 . Google Scholar Crossref Search ADS PubMed WorldCat Siegel R , Naishadham D, Jemal A Cancer statistics for Hispanics/Latinos, 2012 . CA Cancer J Clin . 2012 ; 62 ( 5 ): 283 – 98 . Google Scholar Crossref Search ADS PubMed WorldCat Diakowska D , Markocka-Maczka K, Grabowski K, Lewandowski A Serum interleukin-12 and interleukin-18 levels in patients with oesophageal squamous cell carcinoma . Exp Oncol . 2006 ; 28 ( 4 ): 319 – 22 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Gunel N , Coskun U, Sancak B, Gunel U, Hasdemir O, Bozkurt S Clinical importance of serum interleukin-18 and nitric oxide activities in breast carcinoma patients . Cancer . 2002 ; 95 ( 3 ): 663 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Gunel N , Coskun U, Sancak B, Hasdemir O, Sare M, Bayram O, et al. . Prognostic value of serum IL-18 and nitric oxide activity in breast cancer patients at operable stage . Am J Clin Oncol . 2003 ; 26 ( 4 ): 416 – 21 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Fontanella C , Fanotto V, Rihawi K, Aprile G, and Puglisi F Skeletal metastases from breast cancer: pathogenesis of bone tropism and treatment strategy . Clin Exp Metastasis . 2015 ; 32 ( 8 ): 819 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat Ono M , Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, et al. . Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells . Sci Signal . 2014 ; 7 ( 332 ): ra63 . Google Scholar Crossref Search ADS PubMed WorldCat Ahn JK , Oh JM, Lee J, Kim SW, Cha HS, Koh EM Adult onset Still's disease diagnosed concomitantly with occult papillary thyroid cancer: paraneoplastic manifestation or coincidence? Clin Rheumatol . 2010 ; 29 ( 2 ): 221 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Moore C Jr, Ormseth M, Fuchs H Causes and significance of markedly elevated serum ferritin levels in an academic medical center . J Clin Rheumatol . 2013 ; 19 ( 6 ): 324 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat © 2016 Japan College of Rheumatology This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Adult-onset Still’s disease-like manifestation accompanied by the cancer recurrence after long-term resting state
JO - Modern Rheumatology
DO - 10.1080/14397595.2016.1259547
DA - 2019-07-04
UR - https://www.deepdyve.com/lp/oxford-university-press/adult-onset-still-s-disease-like-manifestation-accompanied-by-the-c80ytc16HP
SP - 704
EP - 707
VL - 29
IS - 4
DP - DeepDyve
ER -