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Tocilizumab Controls Paraneoplastic Inflammatory Syndrome but Does Not Suppress Tumor Growth of Angiomatoid Fibrous Histiocytoma

Tocilizumab Controls Paraneoplastic Inflammatory Syndrome but Does Not Suppress Tumor Growth of... Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 5532258, 6 pages https://doi.org/10.1155/2021/5532258 Case Report Tocilizumab Controls Paraneoplastic Inflammatory Syndrome but Does Not Suppress Tumor Growth of Angiomatoid Fibrous Histiocytoma 1 1 2 1 1 Hideaki Sabe, Akitomo Inoue, Shigenori Nagata, Yoshinori Imura, Toru Wakamatsu, 1 1,3 Satoshi Takenaka, and Hironari Tamiya Department of Orthopedic Surgery, Osaka International Cancer Institute, Osaka 541-8567, Japan Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka 541-8567, Japan Department of Rehabilitation, Osaka International Cancer Institute, Osaka 541-8567, Japan Correspondence should be addressed to Hironari Tamiya; tamiya-hi@mc.pref.osaka.jp Received 17 January 2021; Revised 26 May 2021; Accepted 31 May 2021; Published 17 June 2021 Academic Editor: Ossama W. Tawfik Copyright © 2021 Hideaki Sabe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that rarely metastasizes but lacks effective systemic therapy once it propagates. In some reports, high interleukin-6 (IL-6) production promotes tumor growth by autocrine stimulation and tocilizumab, an IL-6 receptor antagonist, can control AFH growth. Here, we present a case report on a patient with local recurrence and distant lymph node metastasis of AFH treated with tocilizumab. As a result, the inhibition of the IL-6 signaling pathway controlled paraneoplastic inflammatory syndrome (PIS); however, the local recurrent tumor progressed. This case implied that IL-6 is not necessarily the cause of tumor growth in AFH. Therefore, physicians should bear in mind that watchful observation is needed whether tocilizumab can control tumor progression despite the amelioration of PIS associated with the attenuated effect of IL-6 on AFH. 1. Introduction surgery, chemotherapy, radiotherapy, and other medical agents, is warranted to control tumor progression in Angiomatoid fibrous histiocytoma (AFH) was initially advanced AFH. described as angiomatoid malignant fibrous histiocytoma Recently, the importance of interleukin-6 (IL-6) in AFH by Enzinger in the late 1970s [1]. AFH often presents in the has been highlighted. Some AFH tumors produce IL-6 con- subcutaneous region in the children and young adults’ tinuously [8, 9], promoting tumor growth by autocrine stim- extremities, with an approximate mean age of 30 years ulation. Tocilizumab, an IL-6 receptor antagonist, which (range: 2 months–71 years) [2]. The World Health Organiza- blocks IL-6 binding to the IL-6 receptor, can control tumor tion’s (WHO’s) classification categorized AFH as “intermedi- progression [10, 11]. Here, we present a recurrent AFH case ate tumors of uncertain differentiation [3].” Generally, AFH with nodal metastasis, which we attempted to control using is nonfatal. However, approximately 15% of patients with tocilizumab but failed to inhibit tumor progression. AFH develop local recurrence [4]. Therefore, it is often radi- cally resected with a wide margin [5]. Sometimes, unplanned 2. Case Presentation surgery is performed in subcutaneous tumors, including AFH, which may cause local recurrence or distant metastasis A 29-year-old female noticed a small subcutaneous nodule in [6, 7]. Few studies have reported on the effective treatment her right ankle region and underwent tumor resection in for metastatic or unresectable AFH. The occurrence of meta- 2015. One year later, she recognized a tumor recurrence at static and aggressive lesions is usually associated with a fetal the same region. She went to another hospital to undergo outcome. Therefore, a multidisciplinary approach, including tumor resection, with pathological diagnosis of pigmented 2 Case Reports in Oncological Medicine AFH growth (Figure 3(c)). Figure 4 shows the tumor sizes villonodular synovitis. After a while, she was referred to our hospital because of re-recurrence and came with an approx- and CRP levels according to the treatment course. imately 5 cm tumor with skin breakdown in the same region (Figure 1(a)). Magnetic resonance imaging (MRI) revealed a 3. Discussion tumor in the ankle region’s subcutaneous tissue presenting isointensity and high intensity in the inner cystic region on IL-6 was originally identified in the 1970s. Subsequently, it T1- and T2-weighted images, respectively (Figures 1(b) and was revealed that IL-6 plays a critical role in inflammatory 1(c)). Moreover, lymph node enlargement was detected in diseases (e.g., rheumatoid arthritis). An anti-IL-6 receptor the right inguinal and external iliac regions (Figures 1(d) antibody, tocilizumab, blocks IL-6 receptor signaling cascade and 1(e)). In our institute, histological review revealed via IL-6 binding to the IL-6 receptor and is commonly used AFH. A proliferation of uniform spindle-shaped histiocytoid for chronic and acute inflammatory diseases [12]. As previ- cells with blunt nuclear atypia and scattered mitoses, accom- ously shown, IL-6 is highly expressed in cancers and a poten- panying pseudoangiomatous spaces and a pericapsular lym- tial promising target but with no approved drugs for cancer phoplasmacytic rim, was seen with immunohistochemical therapy so far [13]. negativity for S-100 protein, smooth muscle actin (SMA), AFH is a rare soft tissue tumor, having low-grade malig- CD31, and STAT6 (Figures 2(a)–2(e)). Moreover, a chimeric nancy, usually occurring in children and young adults’ transcript EWSR1 exon 7/ATF1 exon 5 was detected using extremities [5]. Morphologically, it is a multinodular prolif- reverse transcription polymerase chain reaction (primers: eration of bland spindle to ovoid eosinophilic cells, some- ′ ′ times lining pseudoangiomatous spaces and covered with a EWSR1, forward 5 -TCCTACAGCCAAGCTCCAAGTC-3 ′ ′ thick fibrous pseudocapsule, featuring a pericapsular cuff of ; ATF1, reverse 5 -GCCTGGACTTGCCAACTGTAAG-3 ). prominent lymphoplasmacytic infiltrates. Immunohisto- On the first visit to our hospital, the patient’s blood test chemically, the most relevant finding is the expression of des- showed C-reactive protein (CRP), hemoglobin (Hb), and min in approximately 40% of cases, suggesting myogenic IL-6 of 9.84 mg/dl, 9.2 g/dl, and 51.5 pg/ml, respectively, indi- differentiation [14]. There are three types of characteristic cating PIS with elevated inflammatory response and mild translocation as a causative gene in AFH: t(2;22)(q33;q12) anemia associated with chronic inflammation (Table 1). EWSR1-CREB1, t(12;22)(q13;q12) EWSR1-ATF1, and The treatment plan was determined by conducting an open t(12;16)(q13;p11) FUS-ATF1 [8]. Translocations are the ini- biopsy of the right inguinal lymph node swelling, resulting in tial or early steps in tumor formation, resulting in gene the diagnosis of lymph node metastasis of AFH (Figure 2(f fusions. It frequently leads to the formation of novel, )). Three months after the first visit, the tumor had been grow- tumor-specific chimeric transcription factors, which can ing rapidly with severe PIS deterioration (Table 1). Therefore, cause gene expression dysregulation [15]. The EWSR1 pro- we performed an additional extensive resection of the recur- tein, a member of the TET family, is characterized by a rent tumor with flap reconstruction. The inflammatory COOH-terminal RNA-binding domain, acting as an adapter response quickly regressed to normal levels following surgery. between transcription and RNA processing. The CREB pro- At 3 and 6 months postoperation, the pelvis lymph node tein is a transcription factor regulating cell proliferation, dif- metastasis remained in a stable size and the CRP level ferentiation, and survival [10]. The EWSR1-CREB1 fusion increased, respectively. Eight months postoperatively, MRI gene, being the most frequent, is constitutively active to pro- showed a local recurrence (Figure 3(a)). Because the CRP level mote CREB1 target gene transcription, including IL-6. The increased along with tumor growth, prednisolone (30 mg/day) IL-6 promoter region includes the binding sites of nuclear was initiated to reduce the inflammatory response. However, factor-kappa B, CREB, CCAAT/enhancer binding protein, CRP remained positive and the tumor size continues to grow. and activator protein 1. Whether the EWSR1-ATF1 tran- Hence, we increased the prednisolone dose to 40 mg/day and script detected in this tumor can activate the IL-6 gene simi- considered administering tocilizumab. larly is unknown. According to a study, an excessive After knowing the risks and benefits, the patient con- production of IL-6 is detected in AFH with the EWSR1- sented to off-label therapy using tocilizumab, an IL-6 recep- ATF1 fusion gene, similar to this case [9]. IL-6 triggers tor antagonist. She received the subcutaneous injection STAT3 activation related to cell growth, antiapoptosis, and fortnightly at 162 mg/body. After the treatment started, labo- inflammatory reactions and acts as an autocrine growth fac- ratory parameters normalized within a few weeks, with tor in a malignant tumor, such as renal cell or prostate cancer improved PIS symptoms. Specifically, the CRP level, which [16, 17]. Similarly, IL-6 may also play pivotal roles in both was 1.62 mg/dl before the treatment, lowered to less than PIS and AFH tumor growth [10]. Thus, patients with AFH 0.01 mg/dl in a month and was kept normal. The prescribed may experience systemic symptoms (e.g., pyrexia, anemia, prednisolone, which was tapered by 10 mg every 2 weeks in and malaise) due to tumor cytokine production, similar to the first 2 months, was eventually discontinued in 3 months. this case [18]. Several reasons exist for choosing the afore- Images showed that both the ankle tumor and external iliac mentioned treatment for this case in our hospital. At the time lymph node metastasis retained their size 2 months following of referral to our hospital by the previous doctor, the patient the start of tocilizumab treatment (Figure 3(b)). However, had an AFH local recurrence and an external iliac lymph the tumor enlarged up to 51 mm 4 months after the first eval- node metastasis following resection surgery. Since the tumor uation despite adequate PIS control using tocilizumab. It was self-destructing, a local surgical intervention was indicates that tocilizumab had no suppressive effect on required. Moreover, the tumor produced IL-6, caused Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) Figure 1: Local recurrence and lymph node metastasis at the initial visit. (a) Visual appearance of the ankle region during the patient’s first visit to our hospital. (b) Axial image of the ankle region acquired using T1-weighted MRI. (c) Axial image of the ankle region acquired using T2-weighted MRI. (d) Axial image focused on the inguinal iliac lymph node acquired using positron emission tomography (PET). (e) Axial image focused on the external iliac lymph node acquired using PET. inflammatory syndrome, and may be getting bigger, due to the normalized IL-6 production, owing to primary lesion IL-6 autocrine stimulation. Considering the patient’s general resection. Second, radical metastasis treatment is difficult. condition, we determined that causative primary tumor We feared that lymphadenectomy would cause lymphedema, removal was necessary. For the lymph node metastasis, we which could affect the patient’s ability to perform daily living determined that careful follow-up without resection is neces- activity. Therefore, we decided to perform only additional sary. First, we hoped that the size will get smaller because of wide resection of the primary tumor. Postoperatively, the 4 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) Figure 2: Photomicrographs of the angiomatoid fibrous histiocytoma. (a) Local recurrence featuring solid nodules of epithelioid to spindle cells arranged in a syncytial pattern with peripheral blood cells (hematoxylin and eosin (HE) stain, ×200). Tumor cells negative for (b) S-100 protein, (c) smooth muscle actin, (d) CD31, and (e) STAT6 (immunohistochemical stains, ×200). (f) Excisional biopsy revealing inguinal node metastasis of the tumor (HE, ×20). CRP levels and IL-6 improved to normal ranges rapidly. The may be difficult. According to a study, chemotherapy (e.g., ifosfamide and doxorubicin) can effectively reduce the tumor lymph metastasis remained at a stable size. Then, the patient had a tumor recurrence. However, we believe that the afore- size of local recurrence or lymph node metastases postopera- mentioned treatment route was reasonable since we were tively [19]. Conversely, some studies have reported that che- able to treat the skin’s self-destructive area, prevent lymph- motherapy is ineffective [5]. Until recently, there is little edema, and temporally improve PIS symptoms. evidence for the efficacy of other treatment modalities on AFH’s standard treatment is surgical resection [18]. Even AFH, except for surgery. However, Villiger et al. have so, for patients with distant metastasis or frequent local reported that tocilizumab may be effective to control AFH recurrence, similar to this case, radical whole tumor resection growth [11]. As described above, IL-6 is produced Case Reports in Oncological Medicine 5 Table 1: The transition of laboratory parameters (e.g., C-reactive protein (CRP), hemoglobin (Hb), albumin (Alb), and interleukin-6 (IL-6)) and the size of the tumor and lymph node in our hospital during the first visit. First visit Before surgery After surgery Recurrence Before tocilizumab After tocilizumab CRP (mg/dl) 9.8 18 0.05 2.21 1.89 0.25 Hb (g/dl) 9.2 7.5 12.1 11.3 11.4 10.4 Alb (mg/dl) 3.5 2.3 4 4.2 4.1 3.9 IL-6 (pg/dl) 51.5 N/A 0.935 N/A 12.4 N/A Tumor size (mm) 49 55 0 19 23 51 Lymph node size (mm) 19 22 21 27 27 27 Before surgery: the primary tumor; after surgery: tumor recurrence; N/A: not applicable. (a) (b) (c) Figure 3: Tumor progression of the local recurrent tumor during tocilizumab treatment. (a) Axial image of the recurrence tumor in the ankle region acquired using T2-weighted MRI at the time of recurrence. (b) Axial image of the recurrence tumor in the ankle region acquired using T2-weighted MRI 2 months after starting on tocilizumab treatment. (c) Axial image of the recurrence tumor in the ankle region acquired using T2-weighted MRI 4 months after the first evaluation. The tumor is indicated by the arrows in red. CRP Tumor size continuously in AFH, which may promote tumor growth by (mg/dl) (mm) autocrine stimulation [10]. Hence, using tocilizumab to block 3.5 60 the effects of IL-6 may control AFH growth [11, 20]. Based on these reports, we obtained the patient’s consent to try this off-label therapy after explaining its risks and benefits. Toci- 2.5 lizumab was able to suppress tumor growth temporally. However, this effect did not last—eventually, the tumor 30 progressed. 1.5 The role of IL-6 in AFH is unclear. However, this case report suggests that IL-6 is not necessarily critical for the AFH growth and controlling tumor growth with tocilizumab only is difficult. Following tocilizumab administration, the 0.5 CRP level rapidly became normal and PIS symptoms, such 0 0 as anemia or malaise, improved. In conclusion, tocilizumab 0 0.5 24 10 (months) can control PIS caused by inhibiting the effects of IL-6, although it does not always suppress tumor growth. In addi- Prednisolone tion, moderate doses of prednisolone could suppress PIS. Tocilizumab Considering the side effects of a moderate-dose steroid, toci- lizumab was more suitable in suppressing PIS. CRP According to other studies, tocilizumab treatment for Tumor size patients with AFH associated with EWSR1-ATF1 transloca- Figure 4: Scheme of the treatment indicating the tumor sizes and tions did not suppress tumor progression [9]. A difference CRP levels. The time of tumor recurrence was regarded as time zero. in tocilizumab’s tumor suppression between EWSR1-ATF1 and EWSR1-CREB1 translocations possibly exists. Further 6 Case Reports in Oncological Medicine investigation is warranted to clarify the difference in these [10] M. Akiyama, M. Yamaoka, Y. Mikami-Terao et al., “Paraneo- plastic syndrome of angiomatoid fibrous histiocytoma may be fusion genes. caused by EWSR1-CREB1 fusion-induced excessive interleukin-6 production,” Journal of Pediatric Hematolo- Data Availability gy/Oncology, vol. 37, no. 7, pp. 554–559, 2015. [11] P. M. Villiger, S. Cottier, M. Jonczy, V. H. Koelzer, P. Roux- There are no available data. Lombard, and S. Adler, “A simple Baker’s cyst? Tocilizumab remits paraneoplastic signs and controls growth of IL-6- Consent producing angiomatoid malignant fibrous histiocytoma,” Rheumatology, vol. 53, no. 7, pp. 1350–1352, 2014. The patient provided consent to participate and for the pub- [12] S. Kang, M. Narazaki, H. Metwally, and T. Kishimoto, “Histor- lication of this case report. ical overview of the interleukin-6 family cytokine,” Journal of Experimental Medicine, vol. 217, no. 5, pp. 1–10, 2020. Conflicts of Interest [13] N. Kumari, B. S. Dwarakanath, A. Das, and A. N. Bhatt, “Role of interleukin-6 in cancer progression and therapeutic resis- The authors declare no potential conflicts of interest with tance,” Tumor Biology, vol. 37, no. 9, pp. 11553–11572, 2016. respect to the research, authorship, and publication of this [14] S. Rossi, K. Szuhai, M. Ijszenga et al., “EWSR1-CREB1 and article. EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocy- toma,” Clinical Cancer Research, vol. 13, no. 24, pp. 7322– Authors’ Contributions 7328, 2007. [15] K. Thway and C. Fisher, “Angiomatoid fibrous histiocytoma: All authors reviewed and approved the final manuscript. the current status of pathology and genetics,” Archives of Pathology & Laboratory Medicine, vol. 139, no. 5, pp. 674– Acknowledgments 682, 2015. [16] L. Alberti, M. C. Thomachot, T. Bachelot, C. Menetrier-Caux, The paper was supported by JSPS KAKENHI (grant numbers I. Puisieux, and J. Y. Blay, “IL-6 as an intracrine growth factor 18K16639 and 21K16670). for renal carcinoma cell lines,” International Journal of Cancer, vol. 111, no. 5, pp. 653–661, 2004. References [17] W. Xiao, D. R. Hodge, L. Wang, X. Yang, X. Zhang, and W. L. Farrar, “Co-operative functions between nuclear factors NFκB [1] F. M. Enzinger, “Angiomatoid malignant fibrous histiocytoma. and CCAT/enhancer-binding protein-β (C/EBP-β) regulate A distinct fibrohistiocytic tumor of children and young adults the IL-6 promoter in autocrine human prostate cancer cells,” simulating a vascular neoplasm,” Cancer, vol. 44, no. 6, The Prostate, vol. 61, no. 4, pp. 354–370, 2004. pp. 2147–2157, 1979. [18] A. Bauer, B. Jackson, E. Marner, and D. Gilbertson-Dahdal, [2] K. Thway, “Angiomatoid fibrous histiocytoma: a review with recent genetic findings,” Archives of Pathology and Laboratory “Angiomatoid fibrous Histiocytoma: a case report and review of the literature,” Journal of Radiology Case Reports, vol. 6, Medicine, vol. 132, no. 2, pp. 273–277, 2008. no. 11, pp. 8–15, 2012. [3] WHO Classification of Tumours Editorial Board, “Soft tissue and bone tumours: WHO classification of tumors 5th edition,” [19] S. Ogden, S. Harave, J. McPartland et al., “Angiomatoid fibrous IARC Press, 2020. histiocytoma: a case of local recurrence and metastases to loco- regional lymph nodes that responded to chemotherapy,” Pedi- [4] C. D. M. Fletcher, “The evolving classification of soft tissue atric Blood & Cancer, vol. 64, no. 6, article e26376, 2017. tumours - an update based on the new 2013 WHO classifica- tion,” Histopathology, vol. 64, no. 1, pp. 2–11, 2014. [20] S. L. Potter, N. M. Quintanilla, D. K. Johnston, B. Naik- [5] K. Saito, E. Kobayashi, A. Yoshida et al., “Angiomatoid fibrous Mathuria, and R. Venkatramani, “Therapeutic response of histiocytoma: a series of seven cases including genetically con- metastatic angiomatoid fibrous histiocytoma carrying EWSR1-CREB1 fusion to the interleukin-6 receptor antibody firmed aggressive cases and a literature review,” BMC Muscu- loskeletal Disorders, vol. 18, no. 1, p. 31, 2017. tocilizumab,” Pediatric Blood & Cancer, vol. 65, no. 10, article e27291, 2018. [6] K. Kikuta, R. Nakayama, S. Yamaguchi et al., “Wide-spread ignorance on the treatment of subcutaneous malignant tumors; a questionnaire-based study,” Japanese Journal of Clinical Oncology, vol. 48, no. 2, pp. 130–134, 2018. [7] K. Hashimoto, S. Nishimura, R. Kakinoki, and M. Akagi, “Treatment of angiomatoid fibrous histiocytoma after unplanned excision: a case report,” BMC Research Notes, vol. 11, no. 1, p. 628, 2018. [8] K. Thway and C. Fisher, “Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions,” The American Journal of Surgical Pathology, vol. 36, no. 7, pp. e1–e11, 2012. [9] L. Eberst, P. A. Cassier, M. Brahmi, F. Tirode, and J.-Y. Blay, “Tocilizumab for the treatment of paraneoplastic inflamma- tory syndrome associated with angiomatoid fibrous histiocy- toma,” ESMO Open, vol. 5, no. 3, article e000756, 2020. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

Tocilizumab Controls Paraneoplastic Inflammatory Syndrome but Does Not Suppress Tumor Growth of Angiomatoid Fibrous Histiocytoma

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Copyright © 2021 Hideaki Sabe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 5532258, 6 pages https://doi.org/10.1155/2021/5532258 Case Report Tocilizumab Controls Paraneoplastic Inflammatory Syndrome but Does Not Suppress Tumor Growth of Angiomatoid Fibrous Histiocytoma 1 1 2 1 1 Hideaki Sabe, Akitomo Inoue, Shigenori Nagata, Yoshinori Imura, Toru Wakamatsu, 1 1,3 Satoshi Takenaka, and Hironari Tamiya Department of Orthopedic Surgery, Osaka International Cancer Institute, Osaka 541-8567, Japan Department of Diagnostic Pathology and Cytology, Osaka International Cancer Institute, Osaka 541-8567, Japan Department of Rehabilitation, Osaka International Cancer Institute, Osaka 541-8567, Japan Correspondence should be addressed to Hironari Tamiya; tamiya-hi@mc.pref.osaka.jp Received 17 January 2021; Revised 26 May 2021; Accepted 31 May 2021; Published 17 June 2021 Academic Editor: Ossama W. Tawfik Copyright © 2021 Hideaki Sabe et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that rarely metastasizes but lacks effective systemic therapy once it propagates. In some reports, high interleukin-6 (IL-6) production promotes tumor growth by autocrine stimulation and tocilizumab, an IL-6 receptor antagonist, can control AFH growth. Here, we present a case report on a patient with local recurrence and distant lymph node metastasis of AFH treated with tocilizumab. As a result, the inhibition of the IL-6 signaling pathway controlled paraneoplastic inflammatory syndrome (PIS); however, the local recurrent tumor progressed. This case implied that IL-6 is not necessarily the cause of tumor growth in AFH. Therefore, physicians should bear in mind that watchful observation is needed whether tocilizumab can control tumor progression despite the amelioration of PIS associated with the attenuated effect of IL-6 on AFH. 1. Introduction surgery, chemotherapy, radiotherapy, and other medical agents, is warranted to control tumor progression in Angiomatoid fibrous histiocytoma (AFH) was initially advanced AFH. described as angiomatoid malignant fibrous histiocytoma Recently, the importance of interleukin-6 (IL-6) in AFH by Enzinger in the late 1970s [1]. AFH often presents in the has been highlighted. Some AFH tumors produce IL-6 con- subcutaneous region in the children and young adults’ tinuously [8, 9], promoting tumor growth by autocrine stim- extremities, with an approximate mean age of 30 years ulation. Tocilizumab, an IL-6 receptor antagonist, which (range: 2 months–71 years) [2]. The World Health Organiza- blocks IL-6 binding to the IL-6 receptor, can control tumor tion’s (WHO’s) classification categorized AFH as “intermedi- progression [10, 11]. Here, we present a recurrent AFH case ate tumors of uncertain differentiation [3].” Generally, AFH with nodal metastasis, which we attempted to control using is nonfatal. However, approximately 15% of patients with tocilizumab but failed to inhibit tumor progression. AFH develop local recurrence [4]. Therefore, it is often radi- cally resected with a wide margin [5]. Sometimes, unplanned 2. Case Presentation surgery is performed in subcutaneous tumors, including AFH, which may cause local recurrence or distant metastasis A 29-year-old female noticed a small subcutaneous nodule in [6, 7]. Few studies have reported on the effective treatment her right ankle region and underwent tumor resection in for metastatic or unresectable AFH. The occurrence of meta- 2015. One year later, she recognized a tumor recurrence at static and aggressive lesions is usually associated with a fetal the same region. She went to another hospital to undergo outcome. Therefore, a multidisciplinary approach, including tumor resection, with pathological diagnosis of pigmented 2 Case Reports in Oncological Medicine AFH growth (Figure 3(c)). Figure 4 shows the tumor sizes villonodular synovitis. After a while, she was referred to our hospital because of re-recurrence and came with an approx- and CRP levels according to the treatment course. imately 5 cm tumor with skin breakdown in the same region (Figure 1(a)). Magnetic resonance imaging (MRI) revealed a 3. Discussion tumor in the ankle region’s subcutaneous tissue presenting isointensity and high intensity in the inner cystic region on IL-6 was originally identified in the 1970s. Subsequently, it T1- and T2-weighted images, respectively (Figures 1(b) and was revealed that IL-6 plays a critical role in inflammatory 1(c)). Moreover, lymph node enlargement was detected in diseases (e.g., rheumatoid arthritis). An anti-IL-6 receptor the right inguinal and external iliac regions (Figures 1(d) antibody, tocilizumab, blocks IL-6 receptor signaling cascade and 1(e)). In our institute, histological review revealed via IL-6 binding to the IL-6 receptor and is commonly used AFH. A proliferation of uniform spindle-shaped histiocytoid for chronic and acute inflammatory diseases [12]. As previ- cells with blunt nuclear atypia and scattered mitoses, accom- ously shown, IL-6 is highly expressed in cancers and a poten- panying pseudoangiomatous spaces and a pericapsular lym- tial promising target but with no approved drugs for cancer phoplasmacytic rim, was seen with immunohistochemical therapy so far [13]. negativity for S-100 protein, smooth muscle actin (SMA), AFH is a rare soft tissue tumor, having low-grade malig- CD31, and STAT6 (Figures 2(a)–2(e)). Moreover, a chimeric nancy, usually occurring in children and young adults’ transcript EWSR1 exon 7/ATF1 exon 5 was detected using extremities [5]. Morphologically, it is a multinodular prolif- reverse transcription polymerase chain reaction (primers: eration of bland spindle to ovoid eosinophilic cells, some- ′ ′ times lining pseudoangiomatous spaces and covered with a EWSR1, forward 5 -TCCTACAGCCAAGCTCCAAGTC-3 ′ ′ thick fibrous pseudocapsule, featuring a pericapsular cuff of ; ATF1, reverse 5 -GCCTGGACTTGCCAACTGTAAG-3 ). prominent lymphoplasmacytic infiltrates. Immunohisto- On the first visit to our hospital, the patient’s blood test chemically, the most relevant finding is the expression of des- showed C-reactive protein (CRP), hemoglobin (Hb), and min in approximately 40% of cases, suggesting myogenic IL-6 of 9.84 mg/dl, 9.2 g/dl, and 51.5 pg/ml, respectively, indi- differentiation [14]. There are three types of characteristic cating PIS with elevated inflammatory response and mild translocation as a causative gene in AFH: t(2;22)(q33;q12) anemia associated with chronic inflammation (Table 1). EWSR1-CREB1, t(12;22)(q13;q12) EWSR1-ATF1, and The treatment plan was determined by conducting an open t(12;16)(q13;p11) FUS-ATF1 [8]. Translocations are the ini- biopsy of the right inguinal lymph node swelling, resulting in tial or early steps in tumor formation, resulting in gene the diagnosis of lymph node metastasis of AFH (Figure 2(f fusions. It frequently leads to the formation of novel, )). Three months after the first visit, the tumor had been grow- tumor-specific chimeric transcription factors, which can ing rapidly with severe PIS deterioration (Table 1). Therefore, cause gene expression dysregulation [15]. The EWSR1 pro- we performed an additional extensive resection of the recur- tein, a member of the TET family, is characterized by a rent tumor with flap reconstruction. The inflammatory COOH-terminal RNA-binding domain, acting as an adapter response quickly regressed to normal levels following surgery. between transcription and RNA processing. The CREB pro- At 3 and 6 months postoperation, the pelvis lymph node tein is a transcription factor regulating cell proliferation, dif- metastasis remained in a stable size and the CRP level ferentiation, and survival [10]. The EWSR1-CREB1 fusion increased, respectively. Eight months postoperatively, MRI gene, being the most frequent, is constitutively active to pro- showed a local recurrence (Figure 3(a)). Because the CRP level mote CREB1 target gene transcription, including IL-6. The increased along with tumor growth, prednisolone (30 mg/day) IL-6 promoter region includes the binding sites of nuclear was initiated to reduce the inflammatory response. However, factor-kappa B, CREB, CCAAT/enhancer binding protein, CRP remained positive and the tumor size continues to grow. and activator protein 1. Whether the EWSR1-ATF1 tran- Hence, we increased the prednisolone dose to 40 mg/day and script detected in this tumor can activate the IL-6 gene simi- considered administering tocilizumab. larly is unknown. According to a study, an excessive After knowing the risks and benefits, the patient con- production of IL-6 is detected in AFH with the EWSR1- sented to off-label therapy using tocilizumab, an IL-6 recep- ATF1 fusion gene, similar to this case [9]. IL-6 triggers tor antagonist. She received the subcutaneous injection STAT3 activation related to cell growth, antiapoptosis, and fortnightly at 162 mg/body. After the treatment started, labo- inflammatory reactions and acts as an autocrine growth fac- ratory parameters normalized within a few weeks, with tor in a malignant tumor, such as renal cell or prostate cancer improved PIS symptoms. Specifically, the CRP level, which [16, 17]. Similarly, IL-6 may also play pivotal roles in both was 1.62 mg/dl before the treatment, lowered to less than PIS and AFH tumor growth [10]. Thus, patients with AFH 0.01 mg/dl in a month and was kept normal. The prescribed may experience systemic symptoms (e.g., pyrexia, anemia, prednisolone, which was tapered by 10 mg every 2 weeks in and malaise) due to tumor cytokine production, similar to the first 2 months, was eventually discontinued in 3 months. this case [18]. Several reasons exist for choosing the afore- Images showed that both the ankle tumor and external iliac mentioned treatment for this case in our hospital. At the time lymph node metastasis retained their size 2 months following of referral to our hospital by the previous doctor, the patient the start of tocilizumab treatment (Figure 3(b)). However, had an AFH local recurrence and an external iliac lymph the tumor enlarged up to 51 mm 4 months after the first eval- node metastasis following resection surgery. Since the tumor uation despite adequate PIS control using tocilizumab. It was self-destructing, a local surgical intervention was indicates that tocilizumab had no suppressive effect on required. Moreover, the tumor produced IL-6, caused Case Reports in Oncological Medicine 3 (a) (b) (c) (d) (e) Figure 1: Local recurrence and lymph node metastasis at the initial visit. (a) Visual appearance of the ankle region during the patient’s first visit to our hospital. (b) Axial image of the ankle region acquired using T1-weighted MRI. (c) Axial image of the ankle region acquired using T2-weighted MRI. (d) Axial image focused on the inguinal iliac lymph node acquired using positron emission tomography (PET). (e) Axial image focused on the external iliac lymph node acquired using PET. inflammatory syndrome, and may be getting bigger, due to the normalized IL-6 production, owing to primary lesion IL-6 autocrine stimulation. Considering the patient’s general resection. Second, radical metastasis treatment is difficult. condition, we determined that causative primary tumor We feared that lymphadenectomy would cause lymphedema, removal was necessary. For the lymph node metastasis, we which could affect the patient’s ability to perform daily living determined that careful follow-up without resection is neces- activity. Therefore, we decided to perform only additional sary. First, we hoped that the size will get smaller because of wide resection of the primary tumor. Postoperatively, the 4 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) Figure 2: Photomicrographs of the angiomatoid fibrous histiocytoma. (a) Local recurrence featuring solid nodules of epithelioid to spindle cells arranged in a syncytial pattern with peripheral blood cells (hematoxylin and eosin (HE) stain, ×200). Tumor cells negative for (b) S-100 protein, (c) smooth muscle actin, (d) CD31, and (e) STAT6 (immunohistochemical stains, ×200). (f) Excisional biopsy revealing inguinal node metastasis of the tumor (HE, ×20). CRP levels and IL-6 improved to normal ranges rapidly. The may be difficult. According to a study, chemotherapy (e.g., ifosfamide and doxorubicin) can effectively reduce the tumor lymph metastasis remained at a stable size. Then, the patient had a tumor recurrence. However, we believe that the afore- size of local recurrence or lymph node metastases postopera- mentioned treatment route was reasonable since we were tively [19]. Conversely, some studies have reported that che- able to treat the skin’s self-destructive area, prevent lymph- motherapy is ineffective [5]. Until recently, there is little edema, and temporally improve PIS symptoms. evidence for the efficacy of other treatment modalities on AFH’s standard treatment is surgical resection [18]. Even AFH, except for surgery. However, Villiger et al. have so, for patients with distant metastasis or frequent local reported that tocilizumab may be effective to control AFH recurrence, similar to this case, radical whole tumor resection growth [11]. As described above, IL-6 is produced Case Reports in Oncological Medicine 5 Table 1: The transition of laboratory parameters (e.g., C-reactive protein (CRP), hemoglobin (Hb), albumin (Alb), and interleukin-6 (IL-6)) and the size of the tumor and lymph node in our hospital during the first visit. First visit Before surgery After surgery Recurrence Before tocilizumab After tocilizumab CRP (mg/dl) 9.8 18 0.05 2.21 1.89 0.25 Hb (g/dl) 9.2 7.5 12.1 11.3 11.4 10.4 Alb (mg/dl) 3.5 2.3 4 4.2 4.1 3.9 IL-6 (pg/dl) 51.5 N/A 0.935 N/A 12.4 N/A Tumor size (mm) 49 55 0 19 23 51 Lymph node size (mm) 19 22 21 27 27 27 Before surgery: the primary tumor; after surgery: tumor recurrence; N/A: not applicable. (a) (b) (c) Figure 3: Tumor progression of the local recurrent tumor during tocilizumab treatment. (a) Axial image of the recurrence tumor in the ankle region acquired using T2-weighted MRI at the time of recurrence. (b) Axial image of the recurrence tumor in the ankle region acquired using T2-weighted MRI 2 months after starting on tocilizumab treatment. (c) Axial image of the recurrence tumor in the ankle region acquired using T2-weighted MRI 4 months after the first evaluation. The tumor is indicated by the arrows in red. CRP Tumor size continuously in AFH, which may promote tumor growth by (mg/dl) (mm) autocrine stimulation [10]. Hence, using tocilizumab to block 3.5 60 the effects of IL-6 may control AFH growth [11, 20]. Based on these reports, we obtained the patient’s consent to try this off-label therapy after explaining its risks and benefits. Toci- 2.5 lizumab was able to suppress tumor growth temporally. However, this effect did not last—eventually, the tumor 30 progressed. 1.5 The role of IL-6 in AFH is unclear. However, this case report suggests that IL-6 is not necessarily critical for the AFH growth and controlling tumor growth with tocilizumab only is difficult. Following tocilizumab administration, the 0.5 CRP level rapidly became normal and PIS symptoms, such 0 0 as anemia or malaise, improved. In conclusion, tocilizumab 0 0.5 24 10 (months) can control PIS caused by inhibiting the effects of IL-6, although it does not always suppress tumor growth. In addi- Prednisolone tion, moderate doses of prednisolone could suppress PIS. Tocilizumab Considering the side effects of a moderate-dose steroid, toci- lizumab was more suitable in suppressing PIS. CRP According to other studies, tocilizumab treatment for Tumor size patients with AFH associated with EWSR1-ATF1 transloca- Figure 4: Scheme of the treatment indicating the tumor sizes and tions did not suppress tumor progression [9]. A difference CRP levels. The time of tumor recurrence was regarded as time zero. in tocilizumab’s tumor suppression between EWSR1-ATF1 and EWSR1-CREB1 translocations possibly exists. Further 6 Case Reports in Oncological Medicine investigation is warranted to clarify the difference in these [10] M. Akiyama, M. Yamaoka, Y. Mikami-Terao et al., “Paraneo- plastic syndrome of angiomatoid fibrous histiocytoma may be fusion genes. caused by EWSR1-CREB1 fusion-induced excessive interleukin-6 production,” Journal of Pediatric Hematolo- Data Availability gy/Oncology, vol. 37, no. 7, pp. 554–559, 2015. [11] P. M. Villiger, S. Cottier, M. Jonczy, V. H. Koelzer, P. Roux- There are no available data. Lombard, and S. Adler, “A simple Baker’s cyst? Tocilizumab remits paraneoplastic signs and controls growth of IL-6- Consent producing angiomatoid malignant fibrous histiocytoma,” Rheumatology, vol. 53, no. 7, pp. 1350–1352, 2014. The patient provided consent to participate and for the pub- [12] S. 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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Jun 17, 2021

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