Cancer Biology & Therapy
ISSN: 1538-4047 (Print) 1555-8576 (Online) Journal homepage: http://www.tandfonline.com/loi/kcbt20
Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature Elisabetta Di Liso, Natale Pennelli, Gigliola Lodovichetti, Cristina Ghiotto, Angelo Paolo Dei Tos, PierFranco Conte & Laura Bonanno To cite this article: Elisabetta Di Liso, Natale Pennelli, Gigliola Lodovichetti, Cristina Ghiotto, Angelo Paolo Dei Tos, PierFranco Conte & Laura Bonanno (2015) Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature, Cancer Biology & Therapy, 16:8, 1128-1135, DOI: 10.1080/15384047.2015.1057359 To link to this article: http://dx.doi.org/10.1080/15384047.2015.1057359
Accepted author version posted online: 05 Jun 2015.
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BEDSIDE TO BENCH REPORT Cancer Biology & Therapy 16:8, 1128--1135; August 2015; © 2015 Taylor & Francis Group, LLC
Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature Elisabetta Di Liso1, Natale Pennelli2, Gigliola Lodovichetti2, Cristina Ghiotto1, Angelo Paolo Dei Tos3, PierFranco Conte1,4, and Laura Bonanno1,* 1
Medical Oncology 2; Istituto Oncologico Veneto IRCCS; Padova, Italy; 2Cytology and Pathology Laboratory; Padova, Italy; 3Department of Pathology; General Hospital; Treviso, Italy; 4Department of Surgery; Oncology and Gastroenterology; University of Padova; Padova, Italy
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Keywords: B-RAF, differential diagnosis, interdigitating dendritic cell sarcoma, Vemurafenib Abbreviations: WHO, world health organization; CD, cluster of differentiation; ECOG, eastern cooperative oncology group; PS, performance status; 18FDG- PET-CT, 18fluorodeoxyglucose-positron emission tomography-computed tomography; SUV, standardized uptake value; NSE, neuron specific enolase; CT, computed tomography; MRI, magnetic resonance imaging; ECG, electrocardiogram; CTCAE, common terminology criteria for adverse events; QTc, corrected QT interval; MHC, Major Histocompatibility Complex; HLA, human leukocyte antigen; EMA, ephitelial membrane antigen; ATP, adenosine triphosphate; Ig, immunoglobulin; TCR, t cell receptor; BCL2, B-cell lymphoma 2; IgH, heavy immunoglobulin; ALK, anaplastic lymphoma kinase; H3Ac, acetylated histone H3; TIM, T cell immunoglobulin mucin.
Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAF evaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAF mutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment.
Introduction Dendritic cell sarcoma is a rare and heterogeneous group of diseases, arising from different subtypes of dendritic cells. The World Health Organization classification (WHO) classifies dendritic cell sarcomas as histiocytic and dendritic-cell neoplasms.1 Dendritic cell neoplasms are classified according to the subtype of dendritic cell precursors and they include five groups of diseases: Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma and dendritic cell sarcoma not otherwise specified.2 Interdigitating cell sarcomas share morphological features both with lymphoma and sarcoma tumors. Accordingly, they
were previously classified as lymphomas, sarcomas or histiocytic neoplasms. Nowadays the histopathological diagnosis of interdigitating cell sarcoma is based on cytomorphology and immunohistochemistry.3 In particular, the diagnostic criteria include interdigitating cytoplasmatic processes, S100 positivity and lack of expression of cluster of differentiation (CD) 1a.4 Nevertheless, the differential diagnosis remains difficult and implies the exclusion of both non-neoplastic and neoplastic entities. Various treatment modalities have been used for the management of interdigitating dendritic cell sarcoma, including surgery, radiotherapy and chemotherapy. When the tumor is limited and surgically resectable, the mainstay of treatment is considered
*Correspondence to: Laura Bonanno; Email: [email protected] Submitted: 04/21/2015; Revised: 05/27/2015; Accepted: 05/27/2015 http://dx.doi.org/10.1080/15384047.2015.1057359
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Figure 1. Pre-surgical staging with total body 18 FDG- PET-CT showing a massive area of intense uptake in left axilla (SUV 13.5) without other localizations of disease.
surgery with adequate tumor-free margins, while no clear role for adjuvant therapy has been established yet. For non-resectable relapses and metastatic disease, chemotherapy is currently administered and some retrospective series have been published including different chemotherapy combinations commonly used for the treatment of lymphomas and sarcomas.5,6 B-RAF V600E mutation has been detected in several human tumors7 and it results in the activation of MAPkinase pathway independently of RAS activation. Vemurafenib, a small molecule inhibiting B-RAF, demonstrated efficacy in metastatic melanoma carrying V600E mutations.8 Some studies have recently reported B-RAF mutations in a subset of histiocytic tumors,9 particularly in histiocytic sarcoma and Langerhans cell histiocytosis.10 Here we report a case of metastatic interdigitating dendritic cell sarcoma carrying B-RAF V600E mutation and treated with Vemurafenib.
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Clinical Case Report A 59 year-old Caucasian male patient experienced a painless massive axillary lymphadenopathy, without any other symptoms of neoplastic disease. Eastern cooperative oncology group (ECOG) performance status (PS) was 0. His medical history was significant for mild arterial hypertension and his physiological anamnesis was significant for active smoking (30 pack/year). On physical examination, a fixed and hard mass of approximately 5 £ 6 cm was observed in left axilla. Ultrasound scan confirmed a solid mass of 6 cm indicated as suspicious for malignancy. Other investigations, including blood cell count, renal and liver function tests, did not show any abnormalities. Surgical biopsy was performed thus obtaining a diagnosis of nodular subcutaneous metastasis of giant cell cancer, probably of pulmonary origin. Total body 18fluorodeoxyglucose-positron emission tomographycomputed tomography (18 FDG- PET-CT) showed a large area
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Figure 2. Haematoxylin-eosin staining on surgical samples (A), immunohistochemistry results for S-100 (B) and CD68 (C).
of intense uptake in left axilla with standardized uptake value (SUV) of 13.5, while no other suspected localizations of disease were detected [1]. The lymph node mass was completely resected, with negative surgical margins. Microscopically, the tumor was characterized by spindle cell and pleomorphic cell proliferation. Immunohistochemistry was performed and it revealed strong positivity for S-100 protein, CD68 and CD45, focal positivity for neuron specific enolase (NSE) and desmin. No immunoreaction was found for any pankeratins, clusterin, CD34, MelanA and HMB45 (Fig. 2). On the basis of morphological and immunohistochemical findings, a definitive diagnosis of interdigitating dendritic cell sarcoma was made. No adjuvant treatment was performed. Nine months after surgery, the patient reported chest pain and total body CT (CT) scan with iodine contrast showed multiple pulmonary nodes and mediastinal lymph nodes. He was still in good clinical conditions, with an ECOG PS of 1. Total body18 FDG-PET-CT demonstrated pathologically increased metabolism in multiple areas: pulmonary nodules, mediastinal lymph nodes (SUV max 12.3), right gluteal muscle (SUV max 13.3) and diffuse bone involvement was also observed (Fig. 3). After multidisciplinary evaluation, palliative radiotherapy on the right gluteus and the right iliac bone (20 Gray/5Fractions) was performed. On the basis of the histology and of limited literature data, he underwent chemotherapy with epirubicin 60 mg/m2 (day 1) and ifosfamide 3000 mg/m2 (day 1), repeated every 3 weeks and with the use of prophylactic granulocytes colony stimulating factors. Total body CT performed after 3 cycles of chemotherapy showed stable disease, associated with the appearance of a single pontis focal area of 4 mm. Due to clinical stability and good tolerance to chemotherapy, another cycle of chemotherapy was administered and stereotactic radiation therapy was planned for brain metastasis. In the meantime, histological and immunoistochemical revision was performed in a second pathology center. The results confirmed the diagnosis of pleomorphic malignant neoplasm compatible with interdigitating dendritic cell sarcoma with possible differential diagnosis with amelanotic sarcomatoid melanoma. For this reason,
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dermatological evaluation was performed and ruled out the presence of any melanocytic atypia, while S-100 protein serum level was within normal range. The tumor sample was tested for the presence of exon 15 B-RAF mutations using authomized Sanger sequencing and a V600E mutation was detected. Three weeks later, the patient experienced dizziness, disorders of movement and cough. Total body CT with iodine contrast showed brain and systemic disease progression (Fig. 4). Brain magnetic resonance imaging (MRI) confirmed the progression of known pontis lesion and the onset of another frontal node of about 1 cm, surrounded by diffuse edema (Fig. 4). The patient underwent whole brain radiotherapy (30 Gray/10Fractions). Ten days after the conclusion of radiotherapy, due to molecular characterization and rapid systemic progression, we decided to treat him with specific B-RAF inhibitor Vemurafenib, 960 mg twice a day. When he started targeted therapy, he was symptomatic for cough, fatigue, bone pain and anorexia. Basal electrocardiogram (ECG) did not show any alterations. After one week, physical examination and biochemistry were performed. No significant laboratory abnormalities were found, whereas the patient reported initial symptoms improvement. Treatment-related toxicity was grade 1 oral mucositis, grade 2 skin toxicity, grade 1 diarrhea, according to common terminology criteria for adverse events (CTCAE) v4.0. After one month of treatment, he reported disappearance of cough and further subjective improvement of general conditions. Diarrhea worsened (6 stools per day) and biochemistry showed grade 4 hypokaliemia, associated with corrected QT interval (QTc) prolongation (550 msec). For this reason, Vemurafenib was temporarily discontinued and strict clinical and electrocardiographic monitoring was performed. Five days after the discontinuation of the drug, diarrhea improved to grade 2, while alternative potential causes of hypokaliemia were investigated and no endocrinological disorders emerged. Ten days after the discontinuation of the kinase inhibitor, the patients died of cerebral hemorrhage. Written informed consent was obtained from the wife of the patient for publication of this case report and any accompanying
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Figure 3. Total body 18 FDG- PET-CT performed at recurrence, demonstrating pathological hypermetabolism in pulmonary nodes and lymph nodes (SUV max 12.3), right gluteal muscle (SUV max 13.3) and diffuse bone involvement. Brain CT with iodine contrast was performed (not shown) and demonstrated no lesions.
images. A copy of the written consent is available for review by the Editor-in-Chief of the journal.
Discussion Dendritic cell tumors are extremely rare.11 They originate from dendritic cells, being a various group of immune accessory cells that process antigens into peptide fragments and bind proteins of Major Histocompatibility Complex (MHC); the complex is then recognized by antigen receptors on T-cell. Dendritic cell neoplasms have been classified by the International Lymphoma Study Group (1993) into 3 groups: interdigitating dendritic cell, follicular dendritic cell and Langerhans cell sarcomas. According to the mostly used WHO classification
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(2001), dendritic cell neoplasms are classified into 5 groups: Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma and dendritic cell sarcoma not otherwise specified.1 The pathogenesis of the group of diseases is not surely established: originally classified as belonging to stromal tumor, most recently dendritic cell tumors have been considered as haematopoietic malignant disorders.12 The study of immunophenotype increased difficulties in classification, due to the expression of both leukocyte antigen CD45 and human leukocyte antigen (HLA)-DR, markers of haematopoietic origin in tumor cell with morphological features of sarcoma.13,14 Even though clinical behavior and pathological prognostic classification share many common elements with sarcomas, the latest reviews have concluded for the haematopoietic origin.
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Figure 4. After 5 cycles of chemotherapy, a total body CT demonstrated systemic progressive disease. In the figure lymph node, pulmonary and brain progression is depicted. The brain MR confirmed brain progression, with the enlargement of the known pontis lesion and the onset of a new frontal node of about 1 cm (not shown) surrounded by diffuse edema.
Consistently, interdigitating dendritic cells originate from haematopoietic precursor through three pathways: conversion of Langerhans cells during migration to the lymph node to capture antigens, differentiation of myeloid or lymphoid precursor cells.15 The interdigitating cells are primarily found in tissues where T cells predominate such as the paracortex in lymph nodes, tonsils and spleen,16 but also in non-lymphoid tissue where they capture antigens and then migrate to lymph nodes for presentation.17 In English literature, from 1978 to September 2014, only 100 cases of interdigitating cell sarcoma have been reported. In the described cases, patients were mainly Asiatic, the median age was 56.6 y and male: female ratio was 1.38:1.12 Solitary lymph node involvement was often reported at diagnosis, but one third of the cases occured in extranodal sites including nasopharynx, small intestine, testis, skin, tonsil, spleen, chest wall, bladder and breast.18 Patients were usually diagnosed with painless lymph node involvement, while systemic symptoms including fever, weight loss, fatigue or night sweats are rarely reported.19 Clinical behavior and prognosis are heterogeneous. A recent overview of published cases of dendritic cell sarcoma, including 55 cases of interdigitating cell sarcoma, has reported that the recurrence rate
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after surgical resection is 50% for tumors of at least 5 cm and 11.1% when the size is inferior to 5 cm. In this series described by De Pas and colleagues, the recurrence rate for localized disease treated with surgery was 40% and neither adjuvant chemotherapy nor post-surgical radiotherapy was able to significantly decrease the risk of relapse.2 In a more recent pooled-analysis, a local recurrence rate of 13% at 6 months and a distant metastasis rate of 39% at 9 months were reported.12 The median overall survival reported for advanced disease was 9 months2 and survival exceeding 5 years was overall very rare in not surgically treated patients.6 One of the main points of discussion concerning this rare disease is still differential diagnosis. According to the most recent pooled analysis, published last year, 11 out of 100 cases reviewed have had an erroneous pathological diagnosis.12 Differential diagnosis is based on clinical, cytomorphological, ultrastructural and immunohystochemical analyses. From the morphological point of view, interdigitating dendritic tumor cells are composed of fusiform spindle cells with indistinct cell border, abundant slightly eosinophilic cytoplasm, oval nuclei, finely dispersed chromatin and small nucleoli; occasionally multinucleated cells are found. The tumor architecture can be organized with a storiform, whorled or fascicular growth pattern.20 Cytologic atypia is variable ranging from moderate to severe, while marked pleomorphism is occasionaly reported. The mitotic figures are variable but usually few in number (less than 5 per 10 high-power fields).21 Tumors that could be morphologically indistinguishable from interdigitating cell sarcoma include inflammatory pseudotumor, follicular dendritic cell sarcoma, malignant Langerhans cell histiocytosis, anaplastic large-cell lymphoma, melanoma and sarcoma.1 As in the case we report, in consideration of S-100 positivity, melanoma should be always considered for differential diagnosis. Most melanomas show a nesting growth pattern and an epithelioid morphology associated with positivity for HMB45 and Melan-A. However, metastatic amelanocitic sarcomatoid melanoma represents a major diagnostic challenge. In contrast to Langerhans cells sarcoma, interdigitating tumor cells have not ultrastructural Birbeck granules,22 but they present complex interdigitating cytoplasmatic processes and lysosomes may be found.1 The immunophenotype of interdigitating cell sarcoma is characterized by strong immunoreaction with S-100 protein, while expression of CD1a, CD21 and CD35 is absent and CD68 is variable. The cells are also negative for cytokeratins, ephitelial membrane antigen (EMA), B-cell markers, T-cell markers, CD30, CD34 and myeloperoxidase.1 They are characterized by weak staining for esterase, alkaline phosphatase and ATPase.23 In contrast to lymphoma cells, Ig and t cell receptor (TCR) gene rearrangements are usually not detected, but t(14,18) translocation with B-cell lymphoma 2 (BCL2) rearrangement has been reported in a single case of dendritic cell sarcoma developed from follicular lymphoma6 and chromosome 12 trisomy with heavy immunoglobulin (IgH) rearrangement has been detected in a case developed from chronic lymphocytic leukemia.24 These previously published findings underline the complex and not
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fully understood relationship between haematopoietic malignancies and dendritic cell sarcoma. As far as molecular alterations typical of solid tumors are concerned, the presence of anaplastic lymphoma kinase (ALK) rearrangements have been investigated in the 2 published cases and no positive results have been reported.25,26 Even though p53 mutations have been detected more frequently in interdigitating cell sarcoma than other dendritic malignancies, the data are still overall controversial and the prognostic value of p53 mutations has not been established.27 A recent analysis has also reported higher frequency of acetylated histone H3 (H3Ac) expression in interdigitating dendritic cell and Langerhans cell sarcoma, when compared to Langerhans cell histiocytosis, being considered as the benign variant of the neoplasm.28 Finally, an American study published in 2010 has showed that histiocytic and dendritic cell neoplasms consistently express T cell immunoglobulin mucin 3 (TIM-3) and T cell immunoglobulin mucin 4 (TIM-4), which have been thus suggested as markers of these malignancies.29 Till now, no therapeutic approach has demonstrated consistent clinical efficacy. For localized disease, surgical resection is usually considered as the mainstay of treatment. There is no consensus on the role of adjuvant therapy. Although some indications of potential clinical benefit of adjuvant radiotherapy have been reported,30-32 the data on its role are still considered as controversial 2,5 and the latest pooled analysis published in 2013 has confirmed there is no statistically significant survival difference between patients treated with or without adjuvant radiotherapy.12 For advanced disease, chemotherapy has been usually administered, without precise guidelines available, due to the rarity of the disease and the absence of prospective clinical data. On the basis of published case and series reports, several schedules have been used including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), DHAP (dexamethasone, cisplatin, highdose cytarabine), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), ICE (ifosfamide, carboplatin, etoposide) and combination of cisplatin and epirubicin. Limited response, short duration of clinical benefit and a 2-year overall survival rate of about 30% have been reported.5,6,33 In 3 patients high-dose chemotherapy and autologous bone marrow transplantation have been tried without any benefit,34-36 whereas a case report has described one complete radiological response after a chemotherapy regimen for Hodgkin lymphoma (ABVD) in metastatic disease.37 Ultimately, the most used chemotherapy combinations contain alkylating agents and anthracyclines; in this context chemotherapy combinations indicated for sarcomas such as epirubicin and ifosfamide thus appear as a reasonable option. The study of prognostic molecular markers could help in individualizing systemic treatment even in the absence of prospective clinical trials, according to a modern view for rare diseases. On the basis of previously published series,2,12 prognostic markers should be studied separately in the different subtypes of dendritic cell sarcomas, thus making more and more difficult their identification and clinical validation.
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The existence of molecular or pathological prognostic factors is currently controversial. The only confirmed prognostic factors for interdigitating dendritic cell sarcomas are clinical: tumors involving the abdomen or measuring more than 5 cm in diameter have been described as more aggressive.2 On the other hand, histopathologic features such as mitotic count, presence of necrosis, nuclear pleomorphism have been studied as potential prognostic factors in little retrospective series but neither of them demonstrated to be related to outcome.6,18 Some studies have reported that high proliferation index Ki-67 is correlated to poor survival.18,20,38 In addition, p53 positivity could be associated with poor survival,6,18 although the role of p53 mutations still remains controversial. The B-RAF gene encodes for a serine-threonine kinase belonging to the MAP-kinase signaling pathway. RAS activation induces RAF phosphorylation, which, in turn, activates MEK and ERK. Activated ERK translocates to the nucleus where it acts phosphorylating transcription factors with stimulating effects on cell survival and proliferation. In melanoma, B-RAF is mutated in 40–60% of cases and about 40 different mutations have been detected. The most frequent mutation, found in about 90% of cases, causes the substitution of valine with glutamic acid at codon 600. Functionally, the mutation implies constitutive activation of ERK. B-RAF V600E mutation has been found in specific forms of histiocytosis: Langerhans cell histiocytosis (57% of studied cases) 39 and Erdheim-Chester disease (54%).40 Also B-RAF V600K was detected in one case of Langerhans cell histiocytosis.40 After the first findings, a potential role for B-RAF mutation in the pathogenesis of histiocytic and dendritic cell tumors has been studied and 129 cases of histiocytic, dendritic cell sarcomas and other related lesions were reviewed from the archives of 10 hospitals in Korea and analyzed for the presence of B-RAF mutations. According to this study, histiocytic sarcoma exhibites the highest positivity rate (5/8; 62.5%), followed by Langerhans cell tumor (7/28; 25%) and follicular dendritic cell sarcoma (5/27, 18.5%). Other dendritic cell sarcomas did not harbor B-RAF mutations but only one case of interdigitating cell sarcoma was included in the retrospective analysis. In this series of patients, B-RAF mutations’ carriers did not show any specific clinico-pathological features.10 More recently, one B-RAF V600E mutation was detected in a case of interdigitating dendritic cell sarcoma, characterized by aggressive clinical behavior and lack of responsiveness to chemotherapy.41 As far as hematological malignancies are concerned, B-RAF mutations have been found in the majority of hairy cell leukemia, but not in other B-cell malignancies. In this disease a potential pathogenetic role has been suggested and some experiences of targeted treatment have been published.42-44 Vemurafenib is a kinase inhibitor of B-RAF approved for the treatment of patients with metastatic melanoma carrying B-RAF V600 mutations. After the discovery of B-RAF genetic alterations in histiocytosis and dendritic cell sarcomas, little experiences of specific targeted therapy have been published. Haroche et al. have recently reported 3 cases of patients with systemic histiocytosis, carrying B-RAF V600E mutation and treated with
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Vemurafenib. All the 3 patients experienced clinical improvement within some days after the beginning of the treatment and radiological responses associated with reduced FDG –uptake through PET-CT have been recorded.45 No data on the activity of Vemurafenib or other B-RAF inhibitors in dendritic cell sarcoma have been published until now. To the best of our knowledge, here we report the first case of interdigitating dendritic cell sarcoma carrying B-RAF V600E mutation and treated with specific targeted therapy. Pathological diagnosis criteria, clinical presentation, time and pattern of relapse are consistent with previously published series. After chemotherapy, following brain and systemic progression, the patient has been treated with Vemurafenib according to molecular characterization. Treatment with Vemurafenib obtained clear clinical response, but radiological response could not be evaluated due to fatal brain hemorrhage, probably related to rapid tumor shrinkage. Toxicity experienced by our patient is consistent with published literature data about B-RAF inhibition. Grade 4 toxicity with associated ECG abnormalities forced us to discontinue the drug even in the presence of evident clinical benefit and we were not able to assess the effect of the interruption on the course of the disease. References 1. Jaffe HS, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press 2001; International Agency for Research on Cancer, Lyon, France. 2. De Pas T, Spitaleri G, Pruneri G, Curigliano G, Noberasco C, Luini A, Andreoni B, Testori A, de Braud F. Dendritic cell sarcoma: an analytic overview of the literature and presentation of original five cases. Crit Rev Oncol/Hematol 2008; 65:1-7; PMID:17658269; http://dx.doi.org/10.1016/j. critrevonc.2007.06.003 3. Jayaram G, Mun KS, Elsayed EM, Sangkar JV. Interdigitating dendritic reticulum cell sarcoma: cytologic, histologic and immunocytochemical features. Diagn Cytopathol 2005; 33:43-8; PMID:15945093; http:// dx.doi.org/10.1002/dc.20275 4. Weiss LM, Beckstead JH, Warnke RA, Wood GS. Leu6-expressing cells in lymph nodes: dendritic cells phenotypically similar to interdigitating cells. Hum Pathol 1986; 17:179-84; PMID:3081423; http://dx.doi.org/ 10.1016/S0046-8177(86)80291-X 5. Kairouz S, Hashash J, Kabbara W, McHayleh W, Tabbara IA. Dendritic cell neoplasms: an overview. Am J Hematol 2007; 82:924-8; PMID:17636477; http://dx. doi.org/10.1002/ajh.20857 6. Gaertner EM, Tsokos M, Derringer GA, Neuhauser TS, Arciero C, Andriko JA. Interdigitating dendritic cell sarcoma. A report of four cases and review of the literature. Am J Clin Pathol 2001; 115:589-97; PMID:11293908; http://dx.doi.org/10.1309/M95G7DQ2-TLQL-7Q11 7. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417:949-54; PMID:12068308; http://dx.doi.org/10.1038/nature00766 8. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New Engl J
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With the above-mentioned limitations, our reported experience represents a proof-of-concept of a new approach to rare disease in oncology and hematology. The treatment of rare malignant disease is frequently based on single-center experiences and little retrospective series reports. Therapeutic approach often refers to evidence obtained for more frequent tumors with similar histological or clinical features. The wide diffusion of genetic characterization could completely change the perspective on rare disease by tailoring treatment more on molecular targets than on histological and clinical definition. Even in the absence of histological certain diagnosis, molecular target identification could lead the treatment choice and extend to rare diseases the outcome improvement associated with targeted therapy. In conclusion, the reported case represents the first published experience of B-RAF targeted therapy in malignant dendritic cell sarcoma. Molecular characterization could open new perspectives of treatment in dendritic cell sarcomas and overall in very rare disease, warranting further study on this approach and specifically designed clinical trials. Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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lymphocytic lymphoma to interdigitating dendritic cell sarcoma: evidence for transdifferentiation of the lymphoma clone. Am J Clin Pathol 2009; 132:928-39; PMID:19926586; http://dx.doi.org/10.1309/ AJCPWQ0I0DGXBMHO Nayer H, Murphy KM, Hawkins AL, Long PP, Gillison M, Borowitz M, Griffin CA. Clonal cytogenetic abnormalities and BCL2 rearrangement in interdigitating dendritic cell sarcoma. Leukemia Lymphoma 2006; 47:2651-4; PMID:17169812; http://dx.doi.org/ 10.1080/10428190600879896 Galli F, Petraitiene V, Muthu SK, James S, Koppana VR, Arya A. Challenges in the differential diagnosis of interdigitating dendritic cell sarcoma of intraparotid lymph node vs. metastatic malignant melanoma with unknown primary site. Int J Surg Pathol 2015; 23:24852; PMID:25722315 Amir G, Weintraub M. Association of cell cycle-related gene products and NF-kappaB with clinical parameters in Langerhans cell histiocytosis. Pediat Blood Cancer 2008; 50:304-7; PMID:17455317; http://dx.doi.org/ 10.1002/pbc.21198 Orii T, Takeda H, Kawata S, Maeda K, Yamakawa M. Differential immunophenotypic analysis of dendritic cell tumours. J Clin Pathol 2010; 63:497-503; PMID:20439325; http://dx.doi.org/10.1136/ jcp.2009.067819 Dorfman DM, Hornick JL, Shahsafaei A, Freeman GJ. The phosphatidylserine receptors, T cell immunoglobulin mucin proteins 3 and 4, are markers of histiocytic sarcoma and other histiocytic and dendritic cell neoplasms. Hum Pathol 2010; 41:1486-94; PMID:20656318; http://dx.doi.org/10.1016/j. humpath.2010.04.005 Chan JK, Fletcher CD, Nayler SJ, Cooper K. Follicular dendritic cell sarcoma. Clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized. Cancer 1997; 79:294-313; PMID:9010103; http://dx.doi.org/10.1002/(SICI)1097-0142(19970115) 79:2%3c294::AID-CNCR13%3e3.0.CO;2-W Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM. Development of follicular dendritic cell sarcoma
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in hyaline-vascular Castleman’s disease of the nasopharynx: tracing its evolution by sequential biopsies. Histopathology 2001; 38:510-8; PMID:11422494; http:// dx.doi.org/10.1046/j.1365-2559.2001.01134.x Galati LT, Barnes EL, Myers EN. Dendritic cell sarcoma of the thyroid. Head Neck 1999; 21:273-5; PMID:10208672; http://dx.doi.org/10.1002/(SICI) 1097-0347(199905)21:3%3c273::AID-HED14%3e3. 0.CO;2-Q Fonseca R, Yamakawa M, Nakamura S, van Heerde P, Miettinen M, Shek TW, Myhre Jensen O, Rousselet MC, Tefferi A. Follicular dendritic cell sarcoma and interdigitating reticulum cell sarcoma: a review. Am J Hematol 1998; 59:161-7; PMID:9766802; http://dx. doi.org/10.1002/(SICI)1096-8652(199810)59:2%3c 161::AID-AJH10%3e3.0.CO;2-C Weiss LM, Berry GJ, Dorfman RF, Banks P, Kaiserling E, Curtis J, Rosai J, Warnke RA. Spindle cell neoplasms of lymph nodes of probable reticulum cell lineage. True reticulum cell sarcoma? Am J Surg Path 1990; 14:405-14; PMID:2158241; http://dx.doi.org/ 10.1097/00000478-199005000-00001 Rousselet MC, Francois S, Croue A, Maigre M, SaintAndre JP, Ifrah N. A lymph node interdigitating reticulum cell sarcoma. Arch Pathol Lab Med 1994; 118:183-8; PMID:8311662 Salisbury JR, Ramsay AD, Isaacson PG. Histiocytic lymphoma: a report of a case with an unusual phenotype. J Pathol 1985; 146:99-106; PMID:3891942; http://dx.doi.org/10.1002/path.1711460204 Olnes MJ, Nicol T, Duncan M, Bohlman M, Erlich R. Interdigitating dendritic cell sarcoma: a rare malignancy responsive to ABVD chemotherapy. Leukemia Lymphoma 2002; 43:817-21; PMID:12153170; http://dx.doi.org/10.1080/10428190290016944 Kawachi K, Nakatani Y, Inayama Y, Kawano N, Toda N, Misugi K. Interdigitating dendritic cell sarcoma of the spleen: report of a case with a review of the literature. Am J Surg Pathol 2002; 26:530-7; PMID:11914634; http://dx.doi.org/10.1097/ 00000478-200204000-00018
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39. Satoh T, Smith A, Sarde A, Lu HC, Mian S, Trouillet C, Mufti G, Emile JF, Fraternali F, Donadieu J, et al. B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PloS One 2012; 7:e33891; PMID:22506009; http://dx.doi. org/10.1371/journal.pone.0033891 40. Sahm F, Capper D, Preusser M, Meyer J, Stenzinger A, Lasitschka F, Berghoff AS, Habel A, Schneider M, Kulozik A, et al. BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 2012; 120:e28-34; PMID:22859608; http://dx.doi.org/10.1182/blood2012-06-429597 41. O’Malley DP, Agrawal R, Grimm KE, Hummel J, Glazyrin A, Dim DC, Madhusudhana S, Weiss LM. Evidence of BRAF V600E in indeterminate cell tumor and interdigitating dendritic cell sarcoma. Ann Diag Pathol 2015; 19:113-6; PMID:25787243; http://dx.doi.org/ 10.1016/j.anndiagpath.2015.02.008 42. Ahmadzadeh A, Shahrabi S, Jaseb K, Norozi F, Shahjahani M, Vosoughi T, Hajizamani S, Saki N. BRAF mutation in hairy cell leukemia. Oncol Rev 2014; 8:253; PMID:25992240; http://dx.doi.org/10.4081/ oncol.2014.253 43. Vergote V, Dierickx D, Janssens A, Verhoef G, Tousseyn T, Vandenberghe P, Wolter P, Delforge M. Rapid and complete hematological response of refractory hairy cell leukemia to the BRAF inhibitor dabrafenib. Ann Hematol 2014; 93:2087-9; PMID:24863690; http://dx.doi.org/10.1007/s00277-014-2104-2 44. Bailleux C, Robert G, Ginet C, Re D, Thyss A, Sudaka I, Peyrottes I, Hofman P, Auberger P, Peyrade F. Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib. Oncoscience 2015; 2:44-9; PMID:25815361 45. Haroche J, Charlotte F, Arnaud L, von Deimling A, Helias-Rodzewicz Z, Hervier B, Cohen-Aubart F, Launay D, Lesot A, Mokhtari K, et al. High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 2012; 120:2700-3; PMID:22879539; http://dx. doi.org/10.1182/blood-2012-05-430140
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ISSN: 1538-4047 (Print) 1555-8576 (Online) Journal homepage: http://www.tandfonline.com/loi/kcbt20
Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature Elisabetta Di Liso, Natale Pennelli, Gigliola Lodovichetti, Cristina Ghiotto, Angelo Paolo Dei Tos, PierFranco Conte & Laura Bonanno To cite this article: Elisabetta Di Liso, Natale Pennelli, Gigliola Lodovichetti, Cristina Ghiotto, Angelo Paolo Dei Tos, PierFranco Conte & Laura Bonanno (2015) Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature, Cancer Biology & Therapy, 16:8, 1128-1135, DOI: 10.1080/15384047.2015.1057359 To link to this article: http://dx.doi.org/10.1080/15384047.2015.1057359
Accepted author version posted online: 05 Jun 2015.
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Date: 05 November 2015, At: 18:56
BEDSIDE TO BENCH REPORT Cancer Biology & Therapy 16:8, 1128--1135; August 2015; © 2015 Taylor & Francis Group, LLC
Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature Elisabetta Di Liso1, Natale Pennelli2, Gigliola Lodovichetti2, Cristina Ghiotto1, Angelo Paolo Dei Tos3, PierFranco Conte1,4, and Laura Bonanno1,* 1
Medical Oncology 2; Istituto Oncologico Veneto IRCCS; Padova, Italy; 2Cytology and Pathology Laboratory; Padova, Italy; 3Department of Pathology; General Hospital; Treviso, Italy; 4Department of Surgery; Oncology and Gastroenterology; University of Padova; Padova, Italy
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Keywords: B-RAF, differential diagnosis, interdigitating dendritic cell sarcoma, Vemurafenib Abbreviations: WHO, world health organization; CD, cluster of differentiation; ECOG, eastern cooperative oncology group; PS, performance status; 18FDG- PET-CT, 18fluorodeoxyglucose-positron emission tomography-computed tomography; SUV, standardized uptake value; NSE, neuron specific enolase; CT, computed tomography; MRI, magnetic resonance imaging; ECG, electrocardiogram; CTCAE, common terminology criteria for adverse events; QTc, corrected QT interval; MHC, Major Histocompatibility Complex; HLA, human leukocyte antigen; EMA, ephitelial membrane antigen; ATP, adenosine triphosphate; Ig, immunoglobulin; TCR, t cell receptor; BCL2, B-cell lymphoma 2; IgH, heavy immunoglobulin; ALK, anaplastic lymphoma kinase; H3Ac, acetylated histone H3; TIM, T cell immunoglobulin mucin.
Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAF evaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAF mutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment.
Introduction Dendritic cell sarcoma is a rare and heterogeneous group of diseases, arising from different subtypes of dendritic cells. The World Health Organization classification (WHO) classifies dendritic cell sarcomas as histiocytic and dendritic-cell neoplasms.1 Dendritic cell neoplasms are classified according to the subtype of dendritic cell precursors and they include five groups of diseases: Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma and dendritic cell sarcoma not otherwise specified.2 Interdigitating cell sarcomas share morphological features both with lymphoma and sarcoma tumors. Accordingly, they
were previously classified as lymphomas, sarcomas or histiocytic neoplasms. Nowadays the histopathological diagnosis of interdigitating cell sarcoma is based on cytomorphology and immunohistochemistry.3 In particular, the diagnostic criteria include interdigitating cytoplasmatic processes, S100 positivity and lack of expression of cluster of differentiation (CD) 1a.4 Nevertheless, the differential diagnosis remains difficult and implies the exclusion of both non-neoplastic and neoplastic entities. Various treatment modalities have been used for the management of interdigitating dendritic cell sarcoma, including surgery, radiotherapy and chemotherapy. When the tumor is limited and surgically resectable, the mainstay of treatment is considered
*Correspondence to: Laura Bonanno; Email: [email protected] Submitted: 04/21/2015; Revised: 05/27/2015; Accepted: 05/27/2015 http://dx.doi.org/10.1080/15384047.2015.1057359
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Figure 1. Pre-surgical staging with total body 18 FDG- PET-CT showing a massive area of intense uptake in left axilla (SUV 13.5) without other localizations of disease.
surgery with adequate tumor-free margins, while no clear role for adjuvant therapy has been established yet. For non-resectable relapses and metastatic disease, chemotherapy is currently administered and some retrospective series have been published including different chemotherapy combinations commonly used for the treatment of lymphomas and sarcomas.5,6 B-RAF V600E mutation has been detected in several human tumors7 and it results in the activation of MAPkinase pathway independently of RAS activation. Vemurafenib, a small molecule inhibiting B-RAF, demonstrated efficacy in metastatic melanoma carrying V600E mutations.8 Some studies have recently reported B-RAF mutations in a subset of histiocytic tumors,9 particularly in histiocytic sarcoma and Langerhans cell histiocytosis.10 Here we report a case of metastatic interdigitating dendritic cell sarcoma carrying B-RAF V600E mutation and treated with Vemurafenib.
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Clinical Case Report A 59 year-old Caucasian male patient experienced a painless massive axillary lymphadenopathy, without any other symptoms of neoplastic disease. Eastern cooperative oncology group (ECOG) performance status (PS) was 0. His medical history was significant for mild arterial hypertension and his physiological anamnesis was significant for active smoking (30 pack/year). On physical examination, a fixed and hard mass of approximately 5 £ 6 cm was observed in left axilla. Ultrasound scan confirmed a solid mass of 6 cm indicated as suspicious for malignancy. Other investigations, including blood cell count, renal and liver function tests, did not show any abnormalities. Surgical biopsy was performed thus obtaining a diagnosis of nodular subcutaneous metastasis of giant cell cancer, probably of pulmonary origin. Total body 18fluorodeoxyglucose-positron emission tomographycomputed tomography (18 FDG- PET-CT) showed a large area
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Figure 2. Haematoxylin-eosin staining on surgical samples (A), immunohistochemistry results for S-100 (B) and CD68 (C).
of intense uptake in left axilla with standardized uptake value (SUV) of 13.5, while no other suspected localizations of disease were detected [1]. The lymph node mass was completely resected, with negative surgical margins. Microscopically, the tumor was characterized by spindle cell and pleomorphic cell proliferation. Immunohistochemistry was performed and it revealed strong positivity for S-100 protein, CD68 and CD45, focal positivity for neuron specific enolase (NSE) and desmin. No immunoreaction was found for any pankeratins, clusterin, CD34, MelanA and HMB45 (Fig. 2). On the basis of morphological and immunohistochemical findings, a definitive diagnosis of interdigitating dendritic cell sarcoma was made. No adjuvant treatment was performed. Nine months after surgery, the patient reported chest pain and total body CT (CT) scan with iodine contrast showed multiple pulmonary nodes and mediastinal lymph nodes. He was still in good clinical conditions, with an ECOG PS of 1. Total body18 FDG-PET-CT demonstrated pathologically increased metabolism in multiple areas: pulmonary nodules, mediastinal lymph nodes (SUV max 12.3), right gluteal muscle (SUV max 13.3) and diffuse bone involvement was also observed (Fig. 3). After multidisciplinary evaluation, palliative radiotherapy on the right gluteus and the right iliac bone (20 Gray/5Fractions) was performed. On the basis of the histology and of limited literature data, he underwent chemotherapy with epirubicin 60 mg/m2 (day 1) and ifosfamide 3000 mg/m2 (day 1), repeated every 3 weeks and with the use of prophylactic granulocytes colony stimulating factors. Total body CT performed after 3 cycles of chemotherapy showed stable disease, associated with the appearance of a single pontis focal area of 4 mm. Due to clinical stability and good tolerance to chemotherapy, another cycle of chemotherapy was administered and stereotactic radiation therapy was planned for brain metastasis. In the meantime, histological and immunoistochemical revision was performed in a second pathology center. The results confirmed the diagnosis of pleomorphic malignant neoplasm compatible with interdigitating dendritic cell sarcoma with possible differential diagnosis with amelanotic sarcomatoid melanoma. For this reason,
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dermatological evaluation was performed and ruled out the presence of any melanocytic atypia, while S-100 protein serum level was within normal range. The tumor sample was tested for the presence of exon 15 B-RAF mutations using authomized Sanger sequencing and a V600E mutation was detected. Three weeks later, the patient experienced dizziness, disorders of movement and cough. Total body CT with iodine contrast showed brain and systemic disease progression (Fig. 4). Brain magnetic resonance imaging (MRI) confirmed the progression of known pontis lesion and the onset of another frontal node of about 1 cm, surrounded by diffuse edema (Fig. 4). The patient underwent whole brain radiotherapy (30 Gray/10Fractions). Ten days after the conclusion of radiotherapy, due to molecular characterization and rapid systemic progression, we decided to treat him with specific B-RAF inhibitor Vemurafenib, 960 mg twice a day. When he started targeted therapy, he was symptomatic for cough, fatigue, bone pain and anorexia. Basal electrocardiogram (ECG) did not show any alterations. After one week, physical examination and biochemistry were performed. No significant laboratory abnormalities were found, whereas the patient reported initial symptoms improvement. Treatment-related toxicity was grade 1 oral mucositis, grade 2 skin toxicity, grade 1 diarrhea, according to common terminology criteria for adverse events (CTCAE) v4.0. After one month of treatment, he reported disappearance of cough and further subjective improvement of general conditions. Diarrhea worsened (6 stools per day) and biochemistry showed grade 4 hypokaliemia, associated with corrected QT interval (QTc) prolongation (550 msec). For this reason, Vemurafenib was temporarily discontinued and strict clinical and electrocardiographic monitoring was performed. Five days after the discontinuation of the drug, diarrhea improved to grade 2, while alternative potential causes of hypokaliemia were investigated and no endocrinological disorders emerged. Ten days after the discontinuation of the kinase inhibitor, the patients died of cerebral hemorrhage. Written informed consent was obtained from the wife of the patient for publication of this case report and any accompanying
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Figure 3. Total body 18 FDG- PET-CT performed at recurrence, demonstrating pathological hypermetabolism in pulmonary nodes and lymph nodes (SUV max 12.3), right gluteal muscle (SUV max 13.3) and diffuse bone involvement. Brain CT with iodine contrast was performed (not shown) and demonstrated no lesions.
images. A copy of the written consent is available for review by the Editor-in-Chief of the journal.
Discussion Dendritic cell tumors are extremely rare.11 They originate from dendritic cells, being a various group of immune accessory cells that process antigens into peptide fragments and bind proteins of Major Histocompatibility Complex (MHC); the complex is then recognized by antigen receptors on T-cell. Dendritic cell neoplasms have been classified by the International Lymphoma Study Group (1993) into 3 groups: interdigitating dendritic cell, follicular dendritic cell and Langerhans cell sarcomas. According to the mostly used WHO classification
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(2001), dendritic cell neoplasms are classified into 5 groups: Langerhans cell histiocytosis, Langerhans cell sarcoma, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma and dendritic cell sarcoma not otherwise specified.1 The pathogenesis of the group of diseases is not surely established: originally classified as belonging to stromal tumor, most recently dendritic cell tumors have been considered as haematopoietic malignant disorders.12 The study of immunophenotype increased difficulties in classification, due to the expression of both leukocyte antigen CD45 and human leukocyte antigen (HLA)-DR, markers of haematopoietic origin in tumor cell with morphological features of sarcoma.13,14 Even though clinical behavior and pathological prognostic classification share many common elements with sarcomas, the latest reviews have concluded for the haematopoietic origin.
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Figure 4. After 5 cycles of chemotherapy, a total body CT demonstrated systemic progressive disease. In the figure lymph node, pulmonary and brain progression is depicted. The brain MR confirmed brain progression, with the enlargement of the known pontis lesion and the onset of a new frontal node of about 1 cm (not shown) surrounded by diffuse edema.
Consistently, interdigitating dendritic cells originate from haematopoietic precursor through three pathways: conversion of Langerhans cells during migration to the lymph node to capture antigens, differentiation of myeloid or lymphoid precursor cells.15 The interdigitating cells are primarily found in tissues where T cells predominate such as the paracortex in lymph nodes, tonsils and spleen,16 but also in non-lymphoid tissue where they capture antigens and then migrate to lymph nodes for presentation.17 In English literature, from 1978 to September 2014, only 100 cases of interdigitating cell sarcoma have been reported. In the described cases, patients were mainly Asiatic, the median age was 56.6 y and male: female ratio was 1.38:1.12 Solitary lymph node involvement was often reported at diagnosis, but one third of the cases occured in extranodal sites including nasopharynx, small intestine, testis, skin, tonsil, spleen, chest wall, bladder and breast.18 Patients were usually diagnosed with painless lymph node involvement, while systemic symptoms including fever, weight loss, fatigue or night sweats are rarely reported.19 Clinical behavior and prognosis are heterogeneous. A recent overview of published cases of dendritic cell sarcoma, including 55 cases of interdigitating cell sarcoma, has reported that the recurrence rate
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after surgical resection is 50% for tumors of at least 5 cm and 11.1% when the size is inferior to 5 cm. In this series described by De Pas and colleagues, the recurrence rate for localized disease treated with surgery was 40% and neither adjuvant chemotherapy nor post-surgical radiotherapy was able to significantly decrease the risk of relapse.2 In a more recent pooled-analysis, a local recurrence rate of 13% at 6 months and a distant metastasis rate of 39% at 9 months were reported.12 The median overall survival reported for advanced disease was 9 months2 and survival exceeding 5 years was overall very rare in not surgically treated patients.6 One of the main points of discussion concerning this rare disease is still differential diagnosis. According to the most recent pooled analysis, published last year, 11 out of 100 cases reviewed have had an erroneous pathological diagnosis.12 Differential diagnosis is based on clinical, cytomorphological, ultrastructural and immunohystochemical analyses. From the morphological point of view, interdigitating dendritic tumor cells are composed of fusiform spindle cells with indistinct cell border, abundant slightly eosinophilic cytoplasm, oval nuclei, finely dispersed chromatin and small nucleoli; occasionally multinucleated cells are found. The tumor architecture can be organized with a storiform, whorled or fascicular growth pattern.20 Cytologic atypia is variable ranging from moderate to severe, while marked pleomorphism is occasionaly reported. The mitotic figures are variable but usually few in number (less than 5 per 10 high-power fields).21 Tumors that could be morphologically indistinguishable from interdigitating cell sarcoma include inflammatory pseudotumor, follicular dendritic cell sarcoma, malignant Langerhans cell histiocytosis, anaplastic large-cell lymphoma, melanoma and sarcoma.1 As in the case we report, in consideration of S-100 positivity, melanoma should be always considered for differential diagnosis. Most melanomas show a nesting growth pattern and an epithelioid morphology associated with positivity for HMB45 and Melan-A. However, metastatic amelanocitic sarcomatoid melanoma represents a major diagnostic challenge. In contrast to Langerhans cells sarcoma, interdigitating tumor cells have not ultrastructural Birbeck granules,22 but they present complex interdigitating cytoplasmatic processes and lysosomes may be found.1 The immunophenotype of interdigitating cell sarcoma is characterized by strong immunoreaction with S-100 protein, while expression of CD1a, CD21 and CD35 is absent and CD68 is variable. The cells are also negative for cytokeratins, ephitelial membrane antigen (EMA), B-cell markers, T-cell markers, CD30, CD34 and myeloperoxidase.1 They are characterized by weak staining for esterase, alkaline phosphatase and ATPase.23 In contrast to lymphoma cells, Ig and t cell receptor (TCR) gene rearrangements are usually not detected, but t(14,18) translocation with B-cell lymphoma 2 (BCL2) rearrangement has been reported in a single case of dendritic cell sarcoma developed from follicular lymphoma6 and chromosome 12 trisomy with heavy immunoglobulin (IgH) rearrangement has been detected in a case developed from chronic lymphocytic leukemia.24 These previously published findings underline the complex and not
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fully understood relationship between haematopoietic malignancies and dendritic cell sarcoma. As far as molecular alterations typical of solid tumors are concerned, the presence of anaplastic lymphoma kinase (ALK) rearrangements have been investigated in the 2 published cases and no positive results have been reported.25,26 Even though p53 mutations have been detected more frequently in interdigitating cell sarcoma than other dendritic malignancies, the data are still overall controversial and the prognostic value of p53 mutations has not been established.27 A recent analysis has also reported higher frequency of acetylated histone H3 (H3Ac) expression in interdigitating dendritic cell and Langerhans cell sarcoma, when compared to Langerhans cell histiocytosis, being considered as the benign variant of the neoplasm.28 Finally, an American study published in 2010 has showed that histiocytic and dendritic cell neoplasms consistently express T cell immunoglobulin mucin 3 (TIM-3) and T cell immunoglobulin mucin 4 (TIM-4), which have been thus suggested as markers of these malignancies.29 Till now, no therapeutic approach has demonstrated consistent clinical efficacy. For localized disease, surgical resection is usually considered as the mainstay of treatment. There is no consensus on the role of adjuvant therapy. Although some indications of potential clinical benefit of adjuvant radiotherapy have been reported,30-32 the data on its role are still considered as controversial 2,5 and the latest pooled analysis published in 2013 has confirmed there is no statistically significant survival difference between patients treated with or without adjuvant radiotherapy.12 For advanced disease, chemotherapy has been usually administered, without precise guidelines available, due to the rarity of the disease and the absence of prospective clinical data. On the basis of published case and series reports, several schedules have been used including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), DHAP (dexamethasone, cisplatin, highdose cytarabine), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), ICE (ifosfamide, carboplatin, etoposide) and combination of cisplatin and epirubicin. Limited response, short duration of clinical benefit and a 2-year overall survival rate of about 30% have been reported.5,6,33 In 3 patients high-dose chemotherapy and autologous bone marrow transplantation have been tried without any benefit,34-36 whereas a case report has described one complete radiological response after a chemotherapy regimen for Hodgkin lymphoma (ABVD) in metastatic disease.37 Ultimately, the most used chemotherapy combinations contain alkylating agents and anthracyclines; in this context chemotherapy combinations indicated for sarcomas such as epirubicin and ifosfamide thus appear as a reasonable option. The study of prognostic molecular markers could help in individualizing systemic treatment even in the absence of prospective clinical trials, according to a modern view for rare diseases. On the basis of previously published series,2,12 prognostic markers should be studied separately in the different subtypes of dendritic cell sarcomas, thus making more and more difficult their identification and clinical validation.
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The existence of molecular or pathological prognostic factors is currently controversial. The only confirmed prognostic factors for interdigitating dendritic cell sarcomas are clinical: tumors involving the abdomen or measuring more than 5 cm in diameter have been described as more aggressive.2 On the other hand, histopathologic features such as mitotic count, presence of necrosis, nuclear pleomorphism have been studied as potential prognostic factors in little retrospective series but neither of them demonstrated to be related to outcome.6,18 Some studies have reported that high proliferation index Ki-67 is correlated to poor survival.18,20,38 In addition, p53 positivity could be associated with poor survival,6,18 although the role of p53 mutations still remains controversial. The B-RAF gene encodes for a serine-threonine kinase belonging to the MAP-kinase signaling pathway. RAS activation induces RAF phosphorylation, which, in turn, activates MEK and ERK. Activated ERK translocates to the nucleus where it acts phosphorylating transcription factors with stimulating effects on cell survival and proliferation. In melanoma, B-RAF is mutated in 40–60% of cases and about 40 different mutations have been detected. The most frequent mutation, found in about 90% of cases, causes the substitution of valine with glutamic acid at codon 600. Functionally, the mutation implies constitutive activation of ERK. B-RAF V600E mutation has been found in specific forms of histiocytosis: Langerhans cell histiocytosis (57% of studied cases) 39 and Erdheim-Chester disease (54%).40 Also B-RAF V600K was detected in one case of Langerhans cell histiocytosis.40 After the first findings, a potential role for B-RAF mutation in the pathogenesis of histiocytic and dendritic cell tumors has been studied and 129 cases of histiocytic, dendritic cell sarcomas and other related lesions were reviewed from the archives of 10 hospitals in Korea and analyzed for the presence of B-RAF mutations. According to this study, histiocytic sarcoma exhibites the highest positivity rate (5/8; 62.5%), followed by Langerhans cell tumor (7/28; 25%) and follicular dendritic cell sarcoma (5/27, 18.5%). Other dendritic cell sarcomas did not harbor B-RAF mutations but only one case of interdigitating cell sarcoma was included in the retrospective analysis. In this series of patients, B-RAF mutations’ carriers did not show any specific clinico-pathological features.10 More recently, one B-RAF V600E mutation was detected in a case of interdigitating dendritic cell sarcoma, characterized by aggressive clinical behavior and lack of responsiveness to chemotherapy.41 As far as hematological malignancies are concerned, B-RAF mutations have been found in the majority of hairy cell leukemia, but not in other B-cell malignancies. In this disease a potential pathogenetic role has been suggested and some experiences of targeted treatment have been published.42-44 Vemurafenib is a kinase inhibitor of B-RAF approved for the treatment of patients with metastatic melanoma carrying B-RAF V600 mutations. After the discovery of B-RAF genetic alterations in histiocytosis and dendritic cell sarcomas, little experiences of specific targeted therapy have been published. Haroche et al. have recently reported 3 cases of patients with systemic histiocytosis, carrying B-RAF V600E mutation and treated with
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Vemurafenib. All the 3 patients experienced clinical improvement within some days after the beginning of the treatment and radiological responses associated with reduced FDG –uptake through PET-CT have been recorded.45 No data on the activity of Vemurafenib or other B-RAF inhibitors in dendritic cell sarcoma have been published until now. To the best of our knowledge, here we report the first case of interdigitating dendritic cell sarcoma carrying B-RAF V600E mutation and treated with specific targeted therapy. Pathological diagnosis criteria, clinical presentation, time and pattern of relapse are consistent with previously published series. After chemotherapy, following brain and systemic progression, the patient has been treated with Vemurafenib according to molecular characterization. Treatment with Vemurafenib obtained clear clinical response, but radiological response could not be evaluated due to fatal brain hemorrhage, probably related to rapid tumor shrinkage. Toxicity experienced by our patient is consistent with published literature data about B-RAF inhibition. Grade 4 toxicity with associated ECG abnormalities forced us to discontinue the drug even in the presence of evident clinical benefit and we were not able to assess the effect of the interruption on the course of the disease. References 1. Jaffe HS, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press 2001; International Agency for Research on Cancer, Lyon, France. 2. De Pas T, Spitaleri G, Pruneri G, Curigliano G, Noberasco C, Luini A, Andreoni B, Testori A, de Braud F. Dendritic cell sarcoma: an analytic overview of the literature and presentation of original five cases. Crit Rev Oncol/Hematol 2008; 65:1-7; PMID:17658269; http://dx.doi.org/10.1016/j. critrevonc.2007.06.003 3. Jayaram G, Mun KS, Elsayed EM, Sangkar JV. Interdigitating dendritic reticulum cell sarcoma: cytologic, histologic and immunocytochemical features. Diagn Cytopathol 2005; 33:43-8; PMID:15945093; http:// dx.doi.org/10.1002/dc.20275 4. Weiss LM, Beckstead JH, Warnke RA, Wood GS. Leu6-expressing cells in lymph nodes: dendritic cells phenotypically similar to interdigitating cells. Hum Pathol 1986; 17:179-84; PMID:3081423; http://dx.doi.org/ 10.1016/S0046-8177(86)80291-X 5. Kairouz S, Hashash J, Kabbara W, McHayleh W, Tabbara IA. Dendritic cell neoplasms: an overview. Am J Hematol 2007; 82:924-8; PMID:17636477; http://dx. doi.org/10.1002/ajh.20857 6. Gaertner EM, Tsokos M, Derringer GA, Neuhauser TS, Arciero C, Andriko JA. Interdigitating dendritic cell sarcoma. A report of four cases and review of the literature. Am J Clin Pathol 2001; 115:589-97; PMID:11293908; http://dx.doi.org/10.1309/M95G7DQ2-TLQL-7Q11 7. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417:949-54; PMID:12068308; http://dx.doi.org/10.1038/nature00766 8. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New Engl J
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With the above-mentioned limitations, our reported experience represents a proof-of-concept of a new approach to rare disease in oncology and hematology. The treatment of rare malignant disease is frequently based on single-center experiences and little retrospective series reports. Therapeutic approach often refers to evidence obtained for more frequent tumors with similar histological or clinical features. The wide diffusion of genetic characterization could completely change the perspective on rare disease by tailoring treatment more on molecular targets than on histological and clinical definition. Even in the absence of histological certain diagnosis, molecular target identification could lead the treatment choice and extend to rare diseases the outcome improvement associated with targeted therapy. In conclusion, the reported case represents the first published experience of B-RAF targeted therapy in malignant dendritic cell sarcoma. Molecular characterization could open new perspectives of treatment in dendritic cell sarcomas and overall in very rare disease, warranting further study on this approach and specifically designed clinical trials. Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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