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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; firstname.lastname@example.org 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 . 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) . 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 .” 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 . Therefore, it is often radi- cally resected with a wide margin . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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 . Conversely, some studies have reported that che- able to treat the skin’s self-destructive area, prevent lymph- motherapy is ineﬀective . 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 . 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 . 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 . 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 . 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Published: Jun 17, 2021
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