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Mast Cell Sarcoma: New Cases and Literature Review www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 40 Review Mast cell sarcoma: new cases and literature review Jilliana Monnier1,*, Sophie Georgin-Lavialle1,2,*, Danielle Canioni2,3, Ludovic Lhermitte2,3, Michael Soussan4, Michel Arock5,6, Julie Bruneau2,3, Patrice Dubreuil2,7, Christine Bodemer2,8, Marie-Olivia Chandesris2, Olivier Lortholary2, Olivier Hermine2,9 and Gandhi Damaj2,10,11 1 Service de Médecine Interne, Hôpital Tenon, Université Paris VI, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France 2 Centre de Référence des Mastocytoses, Faculté de Médecine et AP-HP Necker-Enfants Malades, Paris, France 3 Laboratoire d’Anatomie-Pathologie, Université Paris Descartes, Paris Sorbonne Cité, Faculté de Médecine et AP-HP Necker- Enfants Malades, Paris, France 4 Département de Médecine Nucléaire, Hôpital Avicenne, AP-HP et Université Paris 13, Bobigny, France 5 Laboratoire d’Hématologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France 6 LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France 7 Inserm, U1068, CRCM, [Signaling, Hematopoiesis and Mechanism of Oncogenesis], Institut Paoli-Calmettes, Marseille, Aix- Marseille Univ, CNRS UMR7258, Marseille, France 8 Service de Dermatologie de l’Hôpital Necker Enfants-Malades, AP-HP, Paris, France 9 Service d’hématologie Adulte, Université Paris Descartes et Institut Imagine, Hôpital Necker-Enfants Malades, Paris, France 10 Institut d’Hématologie de Basse Normandie, Centre Hospitalier Universitaire, Caen, France 11 Microenvironnement Cellulaire et Pathologies, Normandie Univ, Unicaen, MILPAT, Caen, France * These authors have contributed equally to this work Correspondence to: Gandhi Damaj, email: [email protected] Keywords: mast cell, mastocytosis, mast cell sarcoma, KIT mutations, targeted therapies Received: March 06, 2016 Accepted: August 24, 2016 Published: Spetember 01, 2016 ABSTRACT Mast cell sarcoma (MCS) is a rare form of mastocytosis characterized by the presence of solid tumor(s) comprising malignant mast cells that harbor destructive infiltration capability and metastatic potential. Here, we present an extensive literature review and report on 23 cases of MCS, including 3 new cases from the French National Reference Center for Mastocytosis. From our analysis, it appears that MCS can occur at any age. It can manifest de novo or, to a lesser extent, may evolve from a previously established mastocytosis. Bone tumor is a frequent manifestation, and symptoms of mast cell activation are rare. Histological diagnosis can be difficult because MCS is frequently composed of highly atypical neoplastic mast cells and can thus mimic other tumors. Unexpectedly, the canonical KIT D816V mutation is found in only 21% of MCS; therefore, complete KIT gene sequencing is required. The prognosis of patients with MCS is poor, with a median survival time of less than 18 months, and progression to mast cell leukemia is not unusual. Because conventional chemotherapies usually fail, the role of targeted therapies and bone marrow transplantation warrants further investigation in such aggressive neoplasms. INTRODUCTION Mast cell sarcoma (MCS) is an exceedingly rare and malignant form of solid tumor composed of highly Mast cell neoplasms comprise a clinically atypical MCs and characterized by destructive infiltration and biologically heterogeneous group of disorders and metastatic potential. Clinical presentation is variable characterized by abnormal accumulation of atypical mast and proper diagnosis may be very difficult due to multiple cells (MCs) in one or several organs [1]. differential diagnoses [2]. Genetic features are barely www.impactjournals.com/oncotarget 66299 Oncotarget Table 1: Clinical and biological characteristics of MCS patients as obtained from the literature review All MCS with pediatric Adult MCS mastocytosis MCS n = 23 n = 5 n = 18 Age at diagnosis of MCS (years) 41 8 55 median (range) (1 – 77) (1 – 15) (19 – 77) Gender (Female/Male) 13/10 3/2 10/ 8 Familial mastocytosis, n (%) 1/23 (4.3) 1/5 (0.2) 0/18 (0) Median time from symptoms to diagnosis 15 0,2 20 (range, months) (0-21) (0 – 1) (0 –216) History of mastocytosis, n (%) 2/23 (9) 0/5 (0) 2/18 (11) Organ Involvement, n (%) Bones 18 /23 (78) 5/5 (100) 13/18 (72) Digestive tract 8/23 (35) 0/5 (0) 8/18 (45) Lymph nodes 7/23 (30) 0/5 (0) 7/18 (38) Skin (UP) 7/23 (30) 0/5 (0) 7/18 (38) Splenomegaly 6/23 (26) 1/5 (20) 5/18 (28) Hepatomegaly 5/23 (22) 1/5 (20) 4/18 (22) MCAS, n (%) 7/23 (30) 1/5 (20) 6/18 (33) KIT mutation*, n 14 3 11 WT KIT, n (%) 7 (50) 2 (67) 5 (46) other mutation, n (%) 4 (29) 1 (33) 3 (27) D816V KIT mutation, n (%) 3 (21) 0 3 (27) Laboratory data, median (range) Tryptase (ng/L) 236 (8,6 – 900) 145 (34 – 200) 233 (8,6 – 900) Hemoglobin (g/dL) 10,6 (8 – 14) 11,6 (9,6 – 14) 11,25 (8 – 14) Platelets (G/L) 309 (30 – 486) 300 (300 – 300) 300 (30 - 486) Leukocytes (G/L) 9,3 (2,8 – 15) 12 (12 – 12) 7,8 (2,8 - 15) Outcome MCL evolution, n (%) 7/23 (30) 2/5 (40) 5/18 (28) Death, n (%) 12/20 (60) 2/2 (100) 10/18 (55) Median survival time; (range; months) 17 (1-45) 22,2 (12-45) 15,5 (1– 40) MCAS; symptoms of MC activation (including flushing, fever, malaise, diarrhea and tachycardia); MCL: mast cell leukemia; MCS: mast cell sarcoma; UP; urticaria pigmentosa; WT: wild-type; * Asp 822 Lys (exon 17), Leu 799 Phe (exon 17), Val 560 Gly (exon 11), Del D419 (exon 8) known and therapeutic options are limited. The prognosis (range: 19-77). The disease appears to be sporadic, and of patients is dismal, and the tumor is most often fatal only one familial case has been described [3]. De novo within a few months [2, 3]. The majority of the available MCS was the most frequent presentation, representing information on MCS is based only on case reports. For 91% of the cases (21 patients). Only two patients (9%) this reason, we aimed to review all published data on MCS had a history of cutaneous mastocytosis, and they were and, in addition, included 3 previously unpublished French considered to have secondary MCS. The age of onset of cases. Therefore, this review includes 23 cases of SM: 20 cutaneous lesions in these two patients were 1 and 10 cases from the literature and three new French cases from years, respectively. These two latter cases are of clinical the French National Reference Center for Mastocytosis. interest and highlight the need for providing medical The goal of this extended review is to help better define advice if new symptoms appear and for long-term follow- the clinical and biological presentation of MCS as well as up of patients with mastocytosis. their prognostic profiles and outcomes. CLINICAL MANIFESTATIONS EPIDEMIOLOGY MCAS were observed in nearly one-third (7/23, MCS was described as early as 1986 by Horny et al 30%) of patients. These symptoms included flushing, [4]. It is an exceedingly rare subcategory of mastocytosis fever, malaise, diarrhea and tachycardia. The most and accounts for less than 0.5% of all French cases of common organ involved was bone (78%), with masses mastocytosis reported in the CEREMAST database. found in the thoracic vertebrae, pelvis, tibia, femur, The median patient age at diagnosis was 41 years ankle and skull; followed by the gastro-intestinal tract (range: 1-77) with a slight predominance of females (13 (35%) (Figure 1); lymph nodes (30%); skin (30%); females/10 males). After excluding 5 pediatric cases, the spleen (26%); and liver (22%) (Table 1). Sarcoma may median age of the adult group at diagnosis was 55 years also be localized in the uterus (n = 1), testicles (n = 1), www.impactjournals.com/oncotarget 66300 Oncotarget oropharyngeal tract (including the lips, ears and larynx (n 309 G/L (range 30-486) and 9.3 G/L (range 2.8-15), = 3)) and eyes (n = 1). Of note, all 5 pediatric cases had respectively. Serum tryptase levels were increased in the bone localization (Table 1), and 80% (n = 4) of these had majority of cases, with a median level of 236 ng/L (range: cephalic bone localization, including the temporal bone, 8.6-900) (Table 1); external auditory tract and ear. This could suggest that careful clinical long-term follow-up of children and young Histological findings and immunohistochemistry adults with mastocytosis is necessary and may include (IHC) of MCS examinations of the head, ears and skull for the children. LABORATORY CHARACTERISTICS Mast cells in MCS rarely share histologic features encountered in systemic mastocytosis, such as spindle- shaped MCs and MCs with an eccentric oval nucleus or hypogranulated cytoplasm. Indeed, in MCS, MCs Biological features presented more frequently as medium to very large pleomorphic or sometimes epithelioid cells, as having The median hemoglobin level, platelet and oval or bilobed nuclei, or even as multinucleated cells. leukocyte counts were 10.6 g/dl (range: 8-14), Granules can be observed in abnormal MCs using Giemsa Figure 1: Endoscopic findings of a gastro-intestinal mast cell sarcoma (# 23).There is a burgeoning polylobar tissue lesion of the right colon (arrow). www.impactjournals.com/oncotarget 66301 Oncotarget stain. In some cases, MCs were highly heterogeneous and The presence of atypical cells should cause the differed from site to site within the same patient. Tumor pathologist to test for both tryptase and CD117 to identify infiltration by eosinophils is frequently encountered and MCs, which is the major step of the diagnostic process. may be marked. All of the reported cases were at least CD117 and/or Highly atypical MCs found in MCS usually tryptase positive. Thus, immunohistochemistry is strongly expressed tryptase, KIT (CD117) and CD68. However, recommended to obtain the correct diagnosis of sarcoma CD25 was haphazardly expressed.
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