Modern Pathology (2013) 26, 533–543 & 2013 USCAP, Inc. All rights reserved 0893-3952/13 $32.00 533 Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications Russell JH Ryan1, Cem Akin2,3, Mariana Castells2,3, Marcia Wills4, Martin K Selig1, G Petur Nielsen1, Judith A Ferry1 and Jason L Hornick2,5 1Pathology Service, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; 2Mastocytosis Center, Harvard Medical School, Boston, MA, USA; 3Department of Medicine, Harvard Medical School, Boston, MA, USA; 4Seacoast Pathology / Aurora Diagnostics, Exeter, NH and 5Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA Mast cell sarcoma is a rare, aggressive neoplasm composed of cytologically malignant mast cells presenting as a solitary mass. Previous descriptions of mast cell sarcoma have been limited to single case reports, and the pathologic features of this entity are not well known. Here, we report three new cases of mast cell sarcoma and review previously reported cases. Mast cell sarcoma has a characteristic morphology of medium-sized to large epithelioid cells, including bizarre multinucleated cells, and does not closely resemble either normal mast cells or the spindle cells of systemic mastocytosis. One of our three cases arose in a patient with a remote history of infantile cutaneous mastocytosis, an association also noted in one previous case report. None of our three cases were correctly diagnosed as mast cell neoplasms on initial pathological evaluation, suggesting that this entity may be under-recognized. Molecular testing of mast cell sarcoma has not thus far detected the imatinib- resistant KIT D816V mutation, suggesting that recognition of these cases may facilitate specific targeted therapy. Modern Pathology (2013) 26, 533–543; doi:10.1038/modpathol.2012.199; published online 30 November 2012 Keywords: mast cell sarcoma; mastocytosis; urticaria pigmentosa; KIT mutation; imatinib Mast cell neoplasms comprise a clinically and neoplasm. Although relatively common in dogs,2 biologically heterogeneous group of disorders.1 mast cell sarcoma, defined as a malignant mast cell The most common of these are clinically indolent neoplasm presenting as an isolated destructive clonal mast cell proliferations predominantly mass, is exceedingly rare in humans.1 As only involving the skin (cutaneous mastocytosis) and seven cases of mast cell sarcoma have been bone marrow (systemic mastocytosis), whose reported to date in the English language primary symptomatic manifestations are due to the literature,3–9 each representing a single case report, unique paracrine and systemic effects of mast cell there is limited information available regarding the secretory products. Aggressive mast cell neoplasms diagnostic features, clinical behavior, and genetic are rare and are typically variants of systemic aberrations associated with this entity. mastocytosis that diffusely involve the bone Here, we present three new cases of mast cell marrow and other anatomic sites, in some cases sarcoma, and place them in context with the associated with progression to mast cell leukemia, previously reported cases. We find that mast cell or the development of a non-mast cell hematologic sarcoma may present in a broad spectrum of anatomic locations and age groups. The cells of mast cell sarcoma are medium to large, often bizarre- Correspondence: Dr RJH Ryan, MD, Pathology Service, Massa- chusetts General Hospital, Warren Building 225, 55 Fruit Street, appearing epithelioid cells with characteristic mor- Boston, MA 02114, USA. phologic features and a specific immunophenotype. E-mail: [email protected] However, because they bear only limited resem- JL Hornick, MD, PhD, Department of Pathology, Brigham and blance to normal mast cells, none of our cases were Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. E-mail: [email protected] correctly diagnosed on initial pathological evalua- Received 2 September 2012; revised 3 October 2012; accepted 3 tion. We note that KIT genotyped cases of mast cell October 2012; published online 30 November 2012 sarcoma in our series and prior case reports have not www.modernpathology.org Mast cell sarcoma 534 RJH Ryan et al demonstrated the imatinib-resistant KIT D816V biopsy of the mass was felt to be consistent with mutation, but rather showed either an absence of Langerhans cell histiocytosis. The tumor progressed KIT mutations, or mutations in KIT domains intracranially, despite systemic treatment with vin- associated with imatinib sensitivity in other neo- blastine and prednisone. Two debulking surgeries plasms. These findings suggest that accurate diag- were performed. Unfortunately, subsequent radia- nosis of mast cell sarcoma may allow for specific tion therapy did not produce a response, and the targeted therapy for this aggressive malignancy. patient developed local progression involving the skull. At this time, the pathology was reviewed at a Materials and methods second institution, and an unspecified histiocytic or myeloid neoplasm was favored. She was treated Cases of mast cell sarcoma were retrieved from the with multiple courses of chemotherapy, including consultation files of two of the authors (J.A.F. and 2CDA/Ara-C, ICE, clofarabine, ALCL 99, idarubicin/ J.L.H). Formalin-fixed, paraffin-embedded tissue velcade/Ara-C, and decitabine over 27 months was stained immunohistochemically using the anti- following initial presentation. Although the tumor bodies listed in Table 1. showed an initial response, there was subsequent Tissue for electron microscopy was extracted from intracranial progression near the left sphenoid and formalin-fixed, paraffin embedded tissue blocks, transverse venous sinus. soaked in 100% xylene overnight, rehydrated in a The pathology was then reviewed at a third series of ethanol solutions, rinsed in sodium institution, and a conclusive diagnosis of a malig- cacodylate buffer, and fixed for 1.5 h with 2.5% nant mast cell neoplasm was rendered. Of note, a glutaraldehyde, 2.0% paraformaldehyde, and total of five bone marrow biopsies had been 0.025% calcium chloride, in a 0.1 M sodium caco- performed in the 20 months following initial dylate buffer, pH 7.4. Tissues were further processed diagnosis, all of which were negative for involve- in a Leica Lynx automatic tissue processor. Briefly, ment by systemic mastocytosis, even on retrospec- tissues were post fixed with osmium tetroxide, tive review. The patient was treated with radiation dehydrated in a series of ethanol solutions, en bloc and imatinib mesylate, and scheduled for allogeneic stained during the 70% ethanol dehydration step for hematopoietic stem cell transplantation. Serum one hour, infiltrated with propylene oxide epoxy tryptase levels have remained markedly elevated mixtures, embedded in pure epoxy, and polymer- (ranging from 122 ng/ml to 4200). At last follow-up, ized over night at 60 1C. Thin sections were stained the patient is alive with persistent disease 45 with lead citrate and examined with an FEI months following initial presentation. Morgagni transmission electron microscope. Images Histologically, all biopsies and excision speci- were captured with an AMT (Advanced Microscopy mens showed similar morphologic findings Techniques) digital CCD camera. (Figure 1). There was a dense proliferation of The study protocols were approved by the morphologically heterogeneous, medium-sized to Institutional Review Board of Partners Healthcare. large cells, with well-defined cell borders, clear to palely eosinophilic cytoplasm, and irregular nuclei. A prominent, patchy infiltrate of eosinophils was Results also present. Scattered very large epithelioid cells Patient 1 were also present; these often showed bizarre features, including multilobated nuclei and multi- Patient 1 was a 12-year-old female who initially nucleation. There was occasional emperipolesis of presented with a large left middle ear mass. A eosinophils within the large cells. Mitotic activity Table 1 Antibodies used for immunohistochemistry Antigen Clone Antigen retrieval Dilution Source KIT YR 145 Ventana CC1, 30 min Ready to use Cell Marque, Rocklin, CA KIT Polyclonal None 1:200 Dako, Carpinteria, CA Mast cell tryptase G3 Ventana CC1, 30 min Ready to use Ventana, Tucson, AZ Mast cell tryptase AA1 Trypsin 1:500 Dako, Carpinteria, CA Chymase CC1 EDTA þ steamer 1:1000 Abcam, Cambridge, MA CD2 AB75 Ventana CC1, 30 min 1:50 Leica, Buffalo Grove, IL CD4 4B12 Ventana CC1, 30 min Ready to use Leica, Buffalo Grove, IL CD25 4C9 EDTA þ steamer 1:200 Novocastra, Newcastle upon Tyne, UK CD30 BerH2 Ventana CC1, 30 min Ready to use Ventana, Tucson, AZ CD43 DFT-1 Ventana CC1, 30 min 1:40 Biogenex, Fremont, CA CD68 KP-1 Ventana CC1, 30 min Ready to use Ventana, Tucson, AZ MITF D5 Ventana CC1, 60 min 1:30 Lab Vision/Neomarkers, Fremont, CA Ki-67 30-9 Ventana CC1, 30 min Ready to use Ventana, Tucson, AZ Modern Pathology (2013) 26, 533–543 Mast cell sarcoma RJH Ryan et al 535 Figure 1 Representative histological images from the intracranial tumor in case 1. Note the dense infiltration of eosinophils, tumor cells with well-defined cell borders and lobulated nuclei, and scattered multinucleated tumor cells (a–b). The tumor cells show variable expression of KIT (c), and strong membranous CD25 (d). Mast cell tryptase was also positive (not shown). varied from 2 per 10 high power fields in the initial until a few months before presentation. The patient