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A Dose-Response Relationship to Radiotherapy for Cutaneous Lesions of Langerhans Cell Histiocytosis

A Dose-Response Relationship to Radiotherapy for Cutaneous Lesions of Langerhans Cell Histiocytosis Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 6680635, 6 pages https://doi.org/10.1155/2021/6680635 Case Report A Dose-Response Relationship to Radiotherapy for Cutaneous Lesions of Langerhans Cell Histiocytosis 1 2 3 1 Mark K. Farrugia, Carl Morrison, Francisco Hernandez-Ilizaliturri, and Saif Aljabab Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, USA Department of Pathology, Roswell Park Comprehensive Cancer Center, USA Department of Medicine-Lymphoma/Myeloma, Roswell Park Comprehensive Cancer Center, USA Correspondence should be addressed to Saif Aljabab; saif.aljabab@roswellpark.org Received 17 December 2020; Revised 9 March 2021; Accepted 13 March 2021; Published 25 March 2021 Academic Editor: Raffaele Palmirotta Copyright © 2021 Mark K. Farrugia 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. Langerhans cell histiocytosis (LCH) is a rare disease, afflicting approximately 4.6 and 1-2 per 1 million children and adults, respectively. While LCH can involve numerous organ systems such as the lung or bone, it is uncommon for the disease to be limited to the skin. Radiotherapy has an established role for osseous lesions. However, the efficacy and dose for nonosseous manifestations of the disease are not well described. In the current case report, we detail a 49-year-old adult male with skin- limited LCH requiring palliative radiotherapy (RT) to numerous sites for pain control. The patient was initially diagnosed and treated with single agent cytarabine for approximately 6 months. Despite treatment, he had little symptomatic response of his cutaneous lesions. We delivered a single dose of 8 Gray (Gy) to 3 separate skin lesions, including the bilateral groin, right popliteal region, and right axillary lesion, which resulted in pain reduction and partial response at four-month follow-up. Subsequently, we decided to treat the left axillary untreated lesion to a higher dose of 24 Gy in 12 fractions. At four-month follow-up, the left axilla RT resulted in complete clinical response and improved pain control compared to the right axilla. Following RT treatments, the patient was found to have a BRAF mutation, and vemurafenib was initiated. Further follow-up with positron emissions tomography demonstrated complete metabolic response in numerous disease areas, including both axillae. Based on this case report’s findings, a higher radiotherapy dose may be more effective for treating cutaneous LCH. 1. Introduction rarity of this illness, there is limited data regarding the radio- therapeutic regimens to employ for these patients, which often Langerhans cell histiocytosis (LCH) is a rare disease, afflicting describe a wide range of radiation doses avaiable [6–9]. In this approximately 4.6 and 1-2 per 1 million children and adults, case report, we describe an adult patient with a single system, respectively [1, 2]. LCH causes a granulomatous inflammatory multisite refractory cutaneous LCH who underwent multiple infiltrate which can damage any organ system; however, the courses of RT for different skin lesions, demonstrating a dose bone, skin, lungs, and pituitary are particularly susceptible. relationship between RT regimen and clinical response. In an international registry of adult LCH patients, 31.4% presented with single system disease where the most common 2. Case Report individually involved sites were the lung (51.1%), bone (38.3%), and skin (7%) [3]. Initial treatment typically includes The patient was a 49-year-old male with a history of chronic systemic therapy, and initial regimens can vary [4, 5] For hidradenitis involving the axillae and inguinal folds. He had a patients who do not respond to treatment, the clinical mani- past medical history of hypertension, type II diabetes melli- festations of LCH, especially in the skin and bones, can be tus, morbid obesity status post sleeve gastrectomy, and chro- quite morbid. In these instances, radiotherapy (RT) can be mophobe pituitary adenoma status post transsphenoidal useful for palliation of these symptoms. However, given the resection. The patient was a never smoker and denied any 2 Case Reports in Oncological Medicine using 3-dimensional conformal RT (3DCRT). Approxi- marijuana use. Prior to presentation, patient experienced ulcerative skin lesions within the axillae and inguinal folds mately 3 weeks following delivery of his RT, the patient was causing a nagging, throbbing pain with associated intermit- seen in follow-up. At that time, he described an improvement tent drainage over a period of 5 years. He was previously in pain and discharge of the treated skin lesions (Figure 3(a)). treated with adalimumab for a year and a half, as well as On exam, the right axilla had decreased in size with less doxycycline and prednisone 5 mg daily with no improvement ulceration, no mass was palpable in the right popliteal region, in his chronic hidradenitis. Given the recalcitrant nature of and he had stable lesions in the left pannus. However, his left his chronic hidradenitis, he underwent a right axilla vault axilla was becoming more bothersome (Figure 3(b)) and it skin biopsy consistent with a diagnosis of LCH. He was sub- showed similar ulcerative lesions with associated discharge. sequently referred to medical oncology where he underwent Since the right axilla skin ulceration did not completely additional workup. resolve with 8 Gy, we decided to give a higher dose of 24 Gy Panel for pituitary function revealed lower than normal in 12 fractions using 3DCRT. During this period, molecular testosterone (89 ng/dL) and free testosterone (2.7 ng/dL); testing was performed which detected the presence of BRAF however, follicle stimulating hormone, luteinizing hormone, mutation and approximately 2 months post completion of thyroid stimulating hormone, thyroxine, cortisol, and adre- his second course of RT; he was started on vemurafenib. nocorticotropic hormone levels were within normal limits. The patient was seen in follow-up 4 months after completing Additional blood work demonstrated a mild anemia (hemo- his last fraction of RT with no evidence of disease in his left globin 12.3 g/dL) without significant derangements in white axilla (Figure 3(d)). By comparison, the right axilla had stable residual disease (Figure 3(c)). The patient continued to follow blood cell counts and lactate dehydrogenase levels. Bone marrow biopsy was negative for disease, magnetic resonance with medical oncology, and PET/CT obtained (7 months after imaging of the brain did not show any evidence of LCH RT, 5 months duration of vemurafenib) revealed complete associated lesions, and diagnostic computed tomography metabolic response of the axilla (Figures 4(a) and 4(b)) and sta- (CT) imaging of the chest did not demonstrate any pulmo- ble mixed response in the popliteal region (Figures 4(c) and 4(d)). To date, the patient continues to receive vemurafenib. nary involvement of LCH. Skull base to mid-thigh positron emission tomography with diagnostic computed tomogra- phy (PET/CT) revealed hypermetabolic adenopathy in the 3. Discussion bilateral iliofemoral, prepectoral, and right axillary regions with avidity observed in the skin folds of the arms and chest LCH is a rare disease, with the majority of patients presenting wall. Based on these findings, the patient was diagnosed with as children [10]. The role of radiotherapy in LCH has been skin-limited LCH. described as early as 1979, where Greenberger et al. detailed Three months after diagnosis, the patient was started on the management of LCH-involved bone utilizing radiation single agent, low-dose cytarabine 100 mg/m days 1-5 every doses ranging between 1 and 20 Gy with excellent local 28 days for 6 cycles. At the start of his second cycle of control [11]. Contemporary approaches using RT in LCH cytarabine, the patient complained of right leg swelling and over the past 20 years are summarized in Table 1. was found to have a right popliteal mass. US-guided biopsy The clinical presentation of LCH can be heterogeneous with some patients presenting with a single site of disease, while demonstrated LCH cells with oval nuclei showing features of nuclear grooves, occasional binucleation, and abundant cyto- others can have multisite of a single organ system or multisys- plasm without granules as well as strong diffuse cytoplasmic tem involvement. In the current case report, the patient staining for CD1a and variable weak to strong cytoplasmic presented with multisite, single organ disease. While he had a staining for S-100 (Figure 1). Prechemotherapy imaging did history of pituitary dysfunction, this appeared unrelated to not evaluate this region; therefore, it was unclear if it devel- his subsequent diagnosis of LCH. Skin-only LCH is less com- oped on treatment. The decision to continue therapy was mon than single-system bone disease but however has been made, and end of therapy PET/CT imaging demonstrated a described to occur in approximately 13% of patients [12]. mixed metabolic response to treatment with persistent avidity While Arico et al. reported the lung to be the commonly demonstrated in the previously described regions, including involved site in single-system disease, they only report man- the right popliteal (Figure 2). Clinically, the patient was still agement with systemic treatment and do not describe the experiencing irritation of bilateral axilla, groin/pannus, and percentage of patients who received RT. Other series focusing right knee. The patient was subsequently referred to radiation on patients managed with RT tend to have higher propor- oncology to discuss treatment options. tions of osseous disease [3]. Both the extent and site of During consultation, he endorsed continued irritation of disease have prognostic implications with regard to response the aforementioned skin folds, with the right popliteal, to RT and event-free survival. For example, Kriz et al. found groin/pannus, and right axilla as the most symptomatic. On 37.7% of patients to have a single site of bone involvement, exam, he had ulcerative, violaceous lesion in the groin, 46.4% had multiple bony sites, and 15.9% of patients had pannus, and axilla. No mass could be palpated in the right organ involvement [7]. The radiographic control rate of all popliteal region. Due to multiple areas of involvement, we lesions using RT was 91.4%. When compared to a single site offered palliative RT, 8 Gy in 1 fraction to the most symptom- of disease, those with multiple bone lesions had worse overall atic lesions at that time which included the right popliteal survival while patients with organ involvement did substan- mass, the groin/pannus skin lesions, and right axilla skin tially worse than both groups. Furthermore, in an institu- lesion. Each of the three sites was treated in a single session tional review by Laird et al., it was found that 79% of Case Reports in Oncological Medicine 3 (a) (b) (c) (d) Figure 1: Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. (a) H&E of needle core biopsy at low power showing aggregates of Langerhans cells surrounded by small mature lymphocytes. (b) H&E of LCH cells with oval nuclei showing features of nuclear grooves, occasional binucleation, and abundant cytoplasm without granules. (c) IHC for CD1a showing strong diffuse cytoplasmic staining with membranous accentuation. (d) IHC for S-100 showing variable strong to weak cytoplasmic staining. (a) (b) (c) (d) Figure 2: PET/CT imaging prior to starting radiotherapy. Axial CT of patient axilla (arrows) (a) and corresponding PET image (b). Axial CT of patient’s right popliteal mass (arrow) (c) and corresponding PET image (d). 4 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 3: (a) Right axillary lesions 3 weeks after RT (8 Gy in 1 fraction). (b) Left axillary lesions prior to RT. Clinical response following RT for the right axilla (5-month posttreatment) (c) and left axilla (4-month posttreatment) (d). (a) (b) (c) (d) Figure 4: PET/CT imaging approximately 7 months after starting RT. Axial CT of patient axilla (arrows) (a) and corresponding PET image (b). Axial CT of patient’s right popliteal mass (arrow) (c) and corresponding PET image (d). patients have single-system disease with the bone as the most events were observed in bony lesions. In addition, those with common site involved [8]. In this study, complete symptom- nonbone lesions had significantly worse distant progression- atic response was observed in 89% of patients with bone free and overall survival. Similarly, Olschewski and Seegen- lesions at 1 year compared to 50% for nonosseous lesions schmiedt found those with bony lesions alone to achieve com- following RT. [8] Moreover, nonbone lesions were found to plete remission in 93% of cases with RT compared to 76% have a 3-year freedom from local failure of 63.2% where no complete remission in patients with multisystem disease [9]. Case Reports in Oncological Medicine 5 Table 1: Prior reports on the use of radiotherapy in Langerhans cell histiocytosis. Author Year Type n Median dose (Gy) Dose range (Gy) LC (%) Hristov et al. 2011 Case report 1 24 — 100 Kriz et al. 2013 Retrospective 80 15 3.0-50.4 77 Laird et al. 2018 Retrospective 39 11.4 7.5-50.4 87 Olschewski et al. 2006 Retrospective 98 24 2.0-40 77.5 Meyer et al. 2012 Case report 1 9 — 100 Kotecha et al. 2014 Retrospective 69 10 2.5-45 91.4 A wide spectrum of doses (2.0-50.4 Gy) has been used to References treat LCH-involved sites; however, the most common [1] A. Guyot-Goubin, J. Donadieu, M. Barkaoui, S. Bellec, median doses range between 10 and 24 Gy (Table 1). In the C. Thomas, and J. Clavel, “Descriptive epidemiology of child- current patient, an initial dose of 8 Gy in a single fraction hood Langerhans cell histiocytosis in France, 2000-2004,” was chosen, which is a frequently used regimen for palliation Pediatric Blood & Cancer, vol. 51, no. 1, pp. 71–75, 2008. and an accepted dose for palliative RT for hematologic malig- [2] I. Baumgartner, A. von Hochstetter, B. Baumert, U. Luetolf, nancies such as myeloma [13]. In contrast, 24 Gy in 12 frac- and F. Follath, “Langerhans'-cell histiocytosis in adults,” Med- tions was used for the second course of treatment, which is ical and Pediatric Oncology, vol. 28, no. 1, pp. 9–14, 1997. commonly used in non-Hodgkin’s lymphoma and myeloid- [3] M. Aricò, M. Girschikofsky, T. Généreau et al., “Langerhans derived cancers [14, 15]. In the current patient, 24 Gy was cell histiocytosis in adultsreport from the International Regis- associated with a superior clinical and symptomatic response try of the Histiocyte Society,” European Journal of Cancer, as compared to 8 Gy to the contralateral axilla. While a vol. 39, no. 16, pp. 2341–2348, 2003. previous study has shown excellent outcomes with low-dose [4] C. E. Allen, M. Merad, and K. L. McClain, “Langerhans-cell RT for LCH, others favor median doses > 12 Gy [6–9, 16, histiocytosis,” The New England Journal of Medicine, 17]. Given that these were soft tissue lesions which are inher- vol. 379, no. 9, pp. 856–868, 2018. ently less sensitive to RT, it is possible the additional dose [5] H. Gadner, M. Minkov, N. Grois et al., “Therapy prolongation and/or fractionation was particularly helpful in this setting. improves outcome in multisystem Langerhans cell histiocyto- In addition to the comparative effects of RT dose, the sis,” Blood, vol. 121, no. 25, pp. 5006–5014, 2013. patient demonstrated a compelling and durable response to [6] B. Hristov, A. C. Hristov, S. H. Lin, R. J. Arceci, and M. D. the small molecule inhibitor vemurafenib. Previously, BRAF Wharam Jr., “Chemotherapy-refractory cutaneous Langer- mutations were found to be present in 57% percent of hans cell histiocytosis treated with radiotherapy,” Practical achieved specimens, and as such, BRAF inhibition has been Radiation Oncology, vol. 1, no. 3, pp. 204–207, 2011. explored as a potential therapeutic option in LCH [18] In a [7] J. Kriz, H. T. Eich, F. Bruns et al., “Radiotherapy in langerhans phase 1/2 trial of LCH and Erdheim-Chester disease patients, cell histiocytosis - a rare indication in a rare disease,” Radia- vemurafenib elicited a 41% response by Response Evaluation tion Oncology, vol. 8, no. 1, p. 233, 2013. Criteria in Solid Tumors (RECIST) [19]. Furthermore, a [8] J. Laird, J. Ma, K. Chau et al., “Outcome after radiation therapy number of case reports have demonstrated efficacy of BRAF for Langerhans cell histiocytosis is dependent on site of inhibition in pediatric LCH [4]. Despite these findings and involvement,” International Journal of Radiation Oncology � the high incidence of BRAF mutations in LCH, BRAF inhibi- Biology � Physics, vol. 100, no. 3, pp. 670–678, 2018. tion remains a subject of investigation in these patients. [9] T. Olschewski and M. H. Seegenschmiedt, “Radiotherapy for While these findings are restricted to a single patient with bony manifestations of Langerhans cell histiocytosis. Review short interval follow-up, the following case report suggests a and proposal for an international registry,” Strahlentherapie dose response relationship regarding RT for the LCH- und Onkologie, vol. 182, no. 2, pp. 72–79, 2006. involved skin in an adult patient, supporting the use of higher [10] M. Su, Y. J. Gao, C. Pan, J. Chen, and J. Y. Tang, “Outcome of doses such as 24 Gy in this relatively resistant subsite of disease. children with Langerhans cell histiocytosis and single-system involvement: a retrospective study at a single center in Shang- hai, China,” China. Pediatr Hematol Oncol., vol. 35, no. 7-8, pp. 385–392, 2018. Data Availability [11] J. S. Greenberger, J. R. Cassady, N. Jaffe, G. Vawter, and A. C. The data used to support the findings of this study are Crocker, “Radiation therapy in patients with histiocytosis: included within the article. management of diabetes insipidus and bone lesions,” Interna- tional Journal of Radiation Oncology � Biology � Physics, vol. 5, no. 10, pp. 1749–1755, 1979. Conflicts of Interest [12] B. Willis, A. Ablin, V. Weinberg, S. Zoger, W. M. Wara, and K. K. Matthay, “Disease course and late sequelae of Langer- hans' cell histiocytosis: 25-year experience at the University The authors declare no relevant conflicts of interest. 6 Case Reports in Oncological Medicine of California, San Francisco,” San Francisco. J Clin Oncol., vol. 14, no. 7, pp. 2073–2082, 1996. [13] R. W. Tsang, B. A. Campbell, J. S. Goda et al., “Radiation ther- apy for solitary plasmacytoma and multiple myeloma: guide- lines from the international lymphoma radiation oncology group,” International Journal of Radiation Oncology � Biology � Physics, vol. 101, no. 4, pp. 794–808, 2018. [14] R. L. Bakst, B. S. Dabaja, L. K. Specht, and J. Yahalom, “Use of radiation in extramedullary leukemia/chloroma: guidelines from the international lymphoma radiation oncology group,” International Journal of Radiation Oncology � Biology � Phys- ics, vol. 102, no. 2, pp. 314–319, 2018. [15] T. Illidge, L. Specht, J. Yahalom et al., “Modern radiation ther- apy for nodal non-Hodgkin lymphoma–target definition and dose guidelines from the International Lymphoma Radiation Oncology Group,” International Journal of Radiation Oncol- ogy � Biology � Physics, vol. 89, no. 1, pp. 49–58, 2014. [16] R. Kotecha, R. Venkatramani, R. F. Jubran, A. Arkader, A. J. Olch, and K. Wong, “Clinical outcomes of radiation therapy in the management of Langerhans cell histiocytosis,” Ameri- can Journal of Clinical Oncology, vol. 37, no. 6, pp. 592–596, [17] A. Meyer, M. Stark, J. H. Karstens, H. Christiansen, and F. Bruns, “Langerhans cell histiocytosis of the cranial base: is low-dose radiotherapy effective?,” Case Reports in Oncological Medicine, vol. 2012, Article ID 789640, 3 pages, 2012. [18] G. Badalian-Very, J. A. Vergilio, B. A. Degar et al., “Recurrent BRAF mutations in Langerhans cell histiocytosis,” Blood, vol. 116, no. 11, pp. 1919–1923, 2010. [19] D. M. Hyman, I. Puzanov, V. Subbiah et al., “Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations,” The New England Journal of Medicine, vol. 373, no. 8, pp. 726– 736, 2015. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Oncological Medicine Hindawi Publishing Corporation

A Dose-Response Relationship to Radiotherapy for Cutaneous Lesions of Langerhans Cell Histiocytosis

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Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 6680635, 6 pages https://doi.org/10.1155/2021/6680635 Case Report A Dose-Response Relationship to Radiotherapy for Cutaneous Lesions of Langerhans Cell Histiocytosis 1 2 3 1 Mark K. Farrugia, Carl Morrison, Francisco Hernandez-Ilizaliturri, and Saif Aljabab Department of Radiation Medicine, Roswell Park Comprehensive Cancer Center, USA Department of Pathology, Roswell Park Comprehensive Cancer Center, USA Department of Medicine-Lymphoma/Myeloma, Roswell Park Comprehensive Cancer Center, USA Correspondence should be addressed to Saif Aljabab; saif.aljabab@roswellpark.org Received 17 December 2020; Revised 9 March 2021; Accepted 13 March 2021; Published 25 March 2021 Academic Editor: Raffaele Palmirotta Copyright © 2021 Mark K. Farrugia 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. Langerhans cell histiocytosis (LCH) is a rare disease, afflicting approximately 4.6 and 1-2 per 1 million children and adults, respectively. While LCH can involve numerous organ systems such as the lung or bone, it is uncommon for the disease to be limited to the skin. Radiotherapy has an established role for osseous lesions. However, the efficacy and dose for nonosseous manifestations of the disease are not well described. In the current case report, we detail a 49-year-old adult male with skin- limited LCH requiring palliative radiotherapy (RT) to numerous sites for pain control. The patient was initially diagnosed and treated with single agent cytarabine for approximately 6 months. Despite treatment, he had little symptomatic response of his cutaneous lesions. We delivered a single dose of 8 Gray (Gy) to 3 separate skin lesions, including the bilateral groin, right popliteal region, and right axillary lesion, which resulted in pain reduction and partial response at four-month follow-up. Subsequently, we decided to treat the left axillary untreated lesion to a higher dose of 24 Gy in 12 fractions. At four-month follow-up, the left axilla RT resulted in complete clinical response and improved pain control compared to the right axilla. Following RT treatments, the patient was found to have a BRAF mutation, and vemurafenib was initiated. Further follow-up with positron emissions tomography demonstrated complete metabolic response in numerous disease areas, including both axillae. Based on this case report’s findings, a higher radiotherapy dose may be more effective for treating cutaneous LCH. 1. Introduction rarity of this illness, there is limited data regarding the radio- therapeutic regimens to employ for these patients, which often Langerhans cell histiocytosis (LCH) is a rare disease, afflicting describe a wide range of radiation doses avaiable [6–9]. In this approximately 4.6 and 1-2 per 1 million children and adults, case report, we describe an adult patient with a single system, respectively [1, 2]. LCH causes a granulomatous inflammatory multisite refractory cutaneous LCH who underwent multiple infiltrate which can damage any organ system; however, the courses of RT for different skin lesions, demonstrating a dose bone, skin, lungs, and pituitary are particularly susceptible. relationship between RT regimen and clinical response. In an international registry of adult LCH patients, 31.4% presented with single system disease where the most common 2. Case Report individually involved sites were the lung (51.1%), bone (38.3%), and skin (7%) [3]. Initial treatment typically includes The patient was a 49-year-old male with a history of chronic systemic therapy, and initial regimens can vary [4, 5] For hidradenitis involving the axillae and inguinal folds. He had a patients who do not respond to treatment, the clinical mani- past medical history of hypertension, type II diabetes melli- festations of LCH, especially in the skin and bones, can be tus, morbid obesity status post sleeve gastrectomy, and chro- quite morbid. In these instances, radiotherapy (RT) can be mophobe pituitary adenoma status post transsphenoidal useful for palliation of these symptoms. However, given the resection. The patient was a never smoker and denied any 2 Case Reports in Oncological Medicine using 3-dimensional conformal RT (3DCRT). Approxi- marijuana use. Prior to presentation, patient experienced ulcerative skin lesions within the axillae and inguinal folds mately 3 weeks following delivery of his RT, the patient was causing a nagging, throbbing pain with associated intermit- seen in follow-up. At that time, he described an improvement tent drainage over a period of 5 years. He was previously in pain and discharge of the treated skin lesions (Figure 3(a)). treated with adalimumab for a year and a half, as well as On exam, the right axilla had decreased in size with less doxycycline and prednisone 5 mg daily with no improvement ulceration, no mass was palpable in the right popliteal region, in his chronic hidradenitis. Given the recalcitrant nature of and he had stable lesions in the left pannus. However, his left his chronic hidradenitis, he underwent a right axilla vault axilla was becoming more bothersome (Figure 3(b)) and it skin biopsy consistent with a diagnosis of LCH. He was sub- showed similar ulcerative lesions with associated discharge. sequently referred to medical oncology where he underwent Since the right axilla skin ulceration did not completely additional workup. resolve with 8 Gy, we decided to give a higher dose of 24 Gy Panel for pituitary function revealed lower than normal in 12 fractions using 3DCRT. During this period, molecular testosterone (89 ng/dL) and free testosterone (2.7 ng/dL); testing was performed which detected the presence of BRAF however, follicle stimulating hormone, luteinizing hormone, mutation and approximately 2 months post completion of thyroid stimulating hormone, thyroxine, cortisol, and adre- his second course of RT; he was started on vemurafenib. nocorticotropic hormone levels were within normal limits. The patient was seen in follow-up 4 months after completing Additional blood work demonstrated a mild anemia (hemo- his last fraction of RT with no evidence of disease in his left globin 12.3 g/dL) without significant derangements in white axilla (Figure 3(d)). By comparison, the right axilla had stable residual disease (Figure 3(c)). The patient continued to follow blood cell counts and lactate dehydrogenase levels. Bone marrow biopsy was negative for disease, magnetic resonance with medical oncology, and PET/CT obtained (7 months after imaging of the brain did not show any evidence of LCH RT, 5 months duration of vemurafenib) revealed complete associated lesions, and diagnostic computed tomography metabolic response of the axilla (Figures 4(a) and 4(b)) and sta- (CT) imaging of the chest did not demonstrate any pulmo- ble mixed response in the popliteal region (Figures 4(c) and 4(d)). To date, the patient continues to receive vemurafenib. nary involvement of LCH. Skull base to mid-thigh positron emission tomography with diagnostic computed tomogra- phy (PET/CT) revealed hypermetabolic adenopathy in the 3. Discussion bilateral iliofemoral, prepectoral, and right axillary regions with avidity observed in the skin folds of the arms and chest LCH is a rare disease, with the majority of patients presenting wall. Based on these findings, the patient was diagnosed with as children [10]. The role of radiotherapy in LCH has been skin-limited LCH. described as early as 1979, where Greenberger et al. detailed Three months after diagnosis, the patient was started on the management of LCH-involved bone utilizing radiation single agent, low-dose cytarabine 100 mg/m days 1-5 every doses ranging between 1 and 20 Gy with excellent local 28 days for 6 cycles. At the start of his second cycle of control [11]. Contemporary approaches using RT in LCH cytarabine, the patient complained of right leg swelling and over the past 20 years are summarized in Table 1. was found to have a right popliteal mass. US-guided biopsy The clinical presentation of LCH can be heterogeneous with some patients presenting with a single site of disease, while demonstrated LCH cells with oval nuclei showing features of nuclear grooves, occasional binucleation, and abundant cyto- others can have multisite of a single organ system or multisys- plasm without granules as well as strong diffuse cytoplasmic tem involvement. In the current case report, the patient staining for CD1a and variable weak to strong cytoplasmic presented with multisite, single organ disease. While he had a staining for S-100 (Figure 1). Prechemotherapy imaging did history of pituitary dysfunction, this appeared unrelated to not evaluate this region; therefore, it was unclear if it devel- his subsequent diagnosis of LCH. Skin-only LCH is less com- oped on treatment. The decision to continue therapy was mon than single-system bone disease but however has been made, and end of therapy PET/CT imaging demonstrated a described to occur in approximately 13% of patients [12]. mixed metabolic response to treatment with persistent avidity While Arico et al. reported the lung to be the commonly demonstrated in the previously described regions, including involved site in single-system disease, they only report man- the right popliteal (Figure 2). Clinically, the patient was still agement with systemic treatment and do not describe the experiencing irritation of bilateral axilla, groin/pannus, and percentage of patients who received RT. Other series focusing right knee. The patient was subsequently referred to radiation on patients managed with RT tend to have higher propor- oncology to discuss treatment options. tions of osseous disease [3]. Both the extent and site of During consultation, he endorsed continued irritation of disease have prognostic implications with regard to response the aforementioned skin folds, with the right popliteal, to RT and event-free survival. For example, Kriz et al. found groin/pannus, and right axilla as the most symptomatic. On 37.7% of patients to have a single site of bone involvement, exam, he had ulcerative, violaceous lesion in the groin, 46.4% had multiple bony sites, and 15.9% of patients had pannus, and axilla. No mass could be palpated in the right organ involvement [7]. The radiographic control rate of all popliteal region. Due to multiple areas of involvement, we lesions using RT was 91.4%. When compared to a single site offered palliative RT, 8 Gy in 1 fraction to the most symptom- of disease, those with multiple bone lesions had worse overall atic lesions at that time which included the right popliteal survival while patients with organ involvement did substan- mass, the groin/pannus skin lesions, and right axilla skin tially worse than both groups. Furthermore, in an institu- lesion. Each of the three sites was treated in a single session tional review by Laird et al., it was found that 79% of Case Reports in Oncological Medicine 3 (a) (b) (c) (d) Figure 1: Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. (a) H&E of needle core biopsy at low power showing aggregates of Langerhans cells surrounded by small mature lymphocytes. (b) H&E of LCH cells with oval nuclei showing features of nuclear grooves, occasional binucleation, and abundant cytoplasm without granules. (c) IHC for CD1a showing strong diffuse cytoplasmic staining with membranous accentuation. (d) IHC for S-100 showing variable strong to weak cytoplasmic staining. (a) (b) (c) (d) Figure 2: PET/CT imaging prior to starting radiotherapy. Axial CT of patient axilla (arrows) (a) and corresponding PET image (b). Axial CT of patient’s right popliteal mass (arrow) (c) and corresponding PET image (d). 4 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 3: (a) Right axillary lesions 3 weeks after RT (8 Gy in 1 fraction). (b) Left axillary lesions prior to RT. Clinical response following RT for the right axilla (5-month posttreatment) (c) and left axilla (4-month posttreatment) (d). (a) (b) (c) (d) Figure 4: PET/CT imaging approximately 7 months after starting RT. Axial CT of patient axilla (arrows) (a) and corresponding PET image (b). Axial CT of patient’s right popliteal mass (arrow) (c) and corresponding PET image (d). patients have single-system disease with the bone as the most events were observed in bony lesions. In addition, those with common site involved [8]. In this study, complete symptom- nonbone lesions had significantly worse distant progression- atic response was observed in 89% of patients with bone free and overall survival. Similarly, Olschewski and Seegen- lesions at 1 year compared to 50% for nonosseous lesions schmiedt found those with bony lesions alone to achieve com- following RT. [8] Moreover, nonbone lesions were found to plete remission in 93% of cases with RT compared to 76% have a 3-year freedom from local failure of 63.2% where no complete remission in patients with multisystem disease [9]. Case Reports in Oncological Medicine 5 Table 1: Prior reports on the use of radiotherapy in Langerhans cell histiocytosis. Author Year Type n Median dose (Gy) Dose range (Gy) LC (%) Hristov et al. 2011 Case report 1 24 — 100 Kriz et al. 2013 Retrospective 80 15 3.0-50.4 77 Laird et al. 2018 Retrospective 39 11.4 7.5-50.4 87 Olschewski et al. 2006 Retrospective 98 24 2.0-40 77.5 Meyer et al. 2012 Case report 1 9 — 100 Kotecha et al. 2014 Retrospective 69 10 2.5-45 91.4 A wide spectrum of doses (2.0-50.4 Gy) has been used to References treat LCH-involved sites; however, the most common [1] A. Guyot-Goubin, J. Donadieu, M. Barkaoui, S. Bellec, median doses range between 10 and 24 Gy (Table 1). In the C. Thomas, and J. Clavel, “Descriptive epidemiology of child- current patient, an initial dose of 8 Gy in a single fraction hood Langerhans cell histiocytosis in France, 2000-2004,” was chosen, which is a frequently used regimen for palliation Pediatric Blood & Cancer, vol. 51, no. 1, pp. 71–75, 2008. and an accepted dose for palliative RT for hematologic malig- [2] I. Baumgartner, A. von Hochstetter, B. Baumert, U. Luetolf, nancies such as myeloma [13]. In contrast, 24 Gy in 12 frac- and F. Follath, “Langerhans'-cell histiocytosis in adults,” Med- tions was used for the second course of treatment, which is ical and Pediatric Oncology, vol. 28, no. 1, pp. 9–14, 1997. commonly used in non-Hodgkin’s lymphoma and myeloid- [3] M. Aricò, M. Girschikofsky, T. Généreau et al., “Langerhans derived cancers [14, 15]. In the current patient, 24 Gy was cell histiocytosis in adultsreport from the International Regis- associated with a superior clinical and symptomatic response try of the Histiocyte Society,” European Journal of Cancer, as compared to 8 Gy to the contralateral axilla. While a vol. 39, no. 16, pp. 2341–2348, 2003. previous study has shown excellent outcomes with low-dose [4] C. E. Allen, M. Merad, and K. L. McClain, “Langerhans-cell RT for LCH, others favor median doses > 12 Gy [6–9, 16, histiocytosis,” The New England Journal of Medicine, 17]. Given that these were soft tissue lesions which are inher- vol. 379, no. 9, pp. 856–868, 2018. ently less sensitive to RT, it is possible the additional dose [5] H. Gadner, M. Minkov, N. Grois et al., “Therapy prolongation and/or fractionation was particularly helpful in this setting. improves outcome in multisystem Langerhans cell histiocyto- In addition to the comparative effects of RT dose, the sis,” Blood, vol. 121, no. 25, pp. 5006–5014, 2013. patient demonstrated a compelling and durable response to [6] B. Hristov, A. C. Hristov, S. H. Lin, R. J. Arceci, and M. D. the small molecule inhibitor vemurafenib. Previously, BRAF Wharam Jr., “Chemotherapy-refractory cutaneous Langer- mutations were found to be present in 57% percent of hans cell histiocytosis treated with radiotherapy,” Practical achieved specimens, and as such, BRAF inhibition has been Radiation Oncology, vol. 1, no. 3, pp. 204–207, 2011. explored as a potential therapeutic option in LCH [18] In a [7] J. Kriz, H. T. Eich, F. Bruns et al., “Radiotherapy in langerhans phase 1/2 trial of LCH and Erdheim-Chester disease patients, cell histiocytosis - a rare indication in a rare disease,” Radia- vemurafenib elicited a 41% response by Response Evaluation tion Oncology, vol. 8, no. 1, p. 233, 2013. Criteria in Solid Tumors (RECIST) [19]. Furthermore, a [8] J. Laird, J. Ma, K. Chau et al., “Outcome after radiation therapy number of case reports have demonstrated efficacy of BRAF for Langerhans cell histiocytosis is dependent on site of inhibition in pediatric LCH [4]. Despite these findings and involvement,” International Journal of Radiation Oncology � the high incidence of BRAF mutations in LCH, BRAF inhibi- Biology � Physics, vol. 100, no. 3, pp. 670–678, 2018. tion remains a subject of investigation in these patients. [9] T. Olschewski and M. H. Seegenschmiedt, “Radiotherapy for While these findings are restricted to a single patient with bony manifestations of Langerhans cell histiocytosis. Review short interval follow-up, the following case report suggests a and proposal for an international registry,” Strahlentherapie dose response relationship regarding RT for the LCH- und Onkologie, vol. 182, no. 2, pp. 72–79, 2006. involved skin in an adult patient, supporting the use of higher [10] M. Su, Y. J. Gao, C. Pan, J. Chen, and J. Y. Tang, “Outcome of doses such as 24 Gy in this relatively resistant subsite of disease. children with Langerhans cell histiocytosis and single-system involvement: a retrospective study at a single center in Shang- hai, China,” China. Pediatr Hematol Oncol., vol. 35, no. 7-8, pp. 385–392, 2018. Data Availability [11] J. S. Greenberger, J. R. Cassady, N. Jaffe, G. Vawter, and A. C. The data used to support the findings of this study are Crocker, “Radiation therapy in patients with histiocytosis: included within the article. management of diabetes insipidus and bone lesions,” Interna- tional Journal of Radiation Oncology � Biology � Physics, vol. 5, no. 10, pp. 1749–1755, 1979. Conflicts of Interest [12] B. Willis, A. Ablin, V. Weinberg, S. Zoger, W. M. Wara, and K. K. Matthay, “Disease course and late sequelae of Langer- hans' cell histiocytosis: 25-year experience at the University The authors declare no relevant conflicts of interest. 6 Case Reports in Oncological Medicine of California, San Francisco,” San Francisco. J Clin Oncol., vol. 14, no. 7, pp. 2073–2082, 1996. [13] R. W. Tsang, B. A. Campbell, J. S. Goda et al., “Radiation ther- apy for solitary plasmacytoma and multiple myeloma: guide- lines from the international lymphoma radiation oncology group,” International Journal of Radiation Oncology � Biology � Physics, vol. 101, no. 4, pp. 794–808, 2018. [14] R. L. Bakst, B. S. Dabaja, L. K. Specht, and J. Yahalom, “Use of radiation in extramedullary leukemia/chloroma: guidelines from the international lymphoma radiation oncology group,” International Journal of Radiation Oncology � Biology � Phys- ics, vol. 102, no. 2, pp. 314–319, 2018. [15] T. Illidge, L. Specht, J. Yahalom et al., “Modern radiation ther- apy for nodal non-Hodgkin lymphoma–target definition and dose guidelines from the International Lymphoma Radiation Oncology Group,” International Journal of Radiation Oncol- ogy � Biology � Physics, vol. 89, no. 1, pp. 49–58, 2014. [16] R. Kotecha, R. Venkatramani, R. F. Jubran, A. Arkader, A. J. Olch, and K. Wong, “Clinical outcomes of radiation therapy in the management of Langerhans cell histiocytosis,” Ameri- can Journal of Clinical Oncology, vol. 37, no. 6, pp. 592–596, [17] A. Meyer, M. Stark, J. H. Karstens, H. Christiansen, and F. Bruns, “Langerhans cell histiocytosis of the cranial base: is low-dose radiotherapy effective?,” Case Reports in Oncological Medicine, vol. 2012, Article ID 789640, 3 pages, 2012. [18] G. Badalian-Very, J. A. Vergilio, B. A. Degar et al., “Recurrent BRAF mutations in Langerhans cell histiocytosis,” Blood, vol. 116, no. 11, pp. 1919–1923, 2010. [19] D. M. Hyman, I. Puzanov, V. Subbiah et al., “Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations,” The New England Journal of Medicine, vol. 373, no. 8, pp. 726– 736, 2015.

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Case Reports in Oncological MedicineHindawi Publishing Corporation

Published: Mar 25, 2021

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