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Mast Cell Sarcoma in an Infant: a Case Report and Review of the Literature

Mast Cell Sarcoma in an Infant: a Case Report and Review of the Literature

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Mast Cell in an Infant: A Case Report and Review of the Literature

Marnelli A. Bautista-Quach, MD,* Cassie L. Booth, MD,* Albert Kheradpour, MD,w Craig W. Zuppan, MD,* Edward H. Rowsell, MD, PhD,* Lawrence Weiss, MD,z and Jun Wang, MD*

CASE REPORT Summary: diseases comprise a spectrum of disorders This male infant first presented with foul-smelling, purulent including cutaneous , indolent or aggressive systemic otorrhea of the right ear beginning at about 4 months of age. He variants including , and unifocal tumor formations such was treated with antibiotics and ear drops for otitis and the otor- as benign extracutaneous or aggressive mast cell rhea resolved, but he continued to behave as if the ear irritated him. sarcoma (MCS). Many mast cell diseases are associated with Imaging performed at that time, from an outside institution, aberrancy of c-KIT proto- resulting in tyrosine kinase showed a 5-mm mass involving the right distal auditory activity, typically exhibiting point mutation in codon 816. MCS is canal adjacent to the tympanic membrane. No evidence of soft an exceedingly rare clinicopathologic entity characterized by a tissue invasion or bone erosion was seen. Follow-up physical unifocal accumulation of neoplastic mast cells that grow in a examination at 8 months of age showed a large, polypoid, soft locally destructive manner. We report a case in a 2-year-old boy tissue mass causing near complete obstruction of the right external who was initially diagnosed at 8 months of age with atypical auditory canal. A of this mass revealed a subcutaneous cutaneous mastocytoma of the right ear with subsequent aggres- infiltrate of mildly atypical monocytic-like or histiocytic-like cells sive, destructive growth pattern; features that were most consistent with folded or polylobated nuclei admixed with significant numbers with MCS. So far, MCS has been documented in the literature in at of eosinophils (Figs. 1A, B). No Touton-type giant cells were least 6 human cases. To the best of our knowledge, our case rep- identified. At that time, this was interpreted as an “atypical” CM resents the first MCS in an infant. Thorough multimodal approach based on the clinically localized growth without definite evidence of with strict follow-up is relevant in appropriately diagnosing this destructive growth pattern as per outside imaging impression, rare entity, particularly in differentiating this lesion from other positive staining for tryptase (Fig. 1C), CD68, and CD117 that are more likely to occur in infancy. (Fig. 1D), and expression of CD43. Of additional concern was the lack of classic metachromatic granules on Giemsa stain. Immu- Key Words: , mastocytosis, temporal bone nohistochemical (IHC) stains for CD2 and CD25 from the initial (J Pediatr Hematol Oncol 2013;35:315–320) biopsy were both negative. Langerhans cell (LCH), granulocytic sarcoma, and were considered, but were excluded or considered highly unlikely based on negative staining for CD1a protein (Fig. 1E), S100 (Fig. 1F), myeloperox- ast cell disease (MCD) is a group of lesions that idase (MPO), CD34, CD45, and CD163, respectively. Mencompasses cutaneous mastocytosis (CM), systemic At the age of 11 months, 3 months after initial diagnosis, fol- variants, and unifocal tumor formation including extrac- low-up imaging (Fig. 2) revealed rapid disease progression manifested utaneous mastocytoma and mast cell sarcoma (MCS).1,2 by a destructive, 3.33.83.6 cm, lesion arising from the right pet- MCS is an extremely rare entity with only 6 documented rous temporal bone and extending through the skull base, involving human cases in the literature.3–8 We report a case in a now the carotid sheath, and effacing or occluding the right jugular vein. The initial mass had been biopsied but not resected, and no treatment 2-year-old boy who, at 8 months of age, was found to have had been given during this interval. Serum tryptase level was elevated a unifocal right ear mass that was initially diagnosed as at 34.1 ng/mL (reference range, <11.5 ng/mL). atypical CM, and subsequently was demonstrated to Subsequent showed a lesion histologically identical to actually be MCS due to the aggressive and destructive the initial biopsy with the exception of a small, previously unsampled tumor growth pattern. This represents the first case of MCS population of cells (2% to 5%) showing mild to moderate atypia documented in an infant. (Fig. 3A). The tumor cells had a low Ki-67 proliferation index (1% to 2% overall; Fig. 3B) and were positive for CD33, CD68, CD117, and focally reactive for CD25. IHC stains for CD2, CD34, CD45, and S100 were again negative. Flow cytometry analysis of the tumor (Fig. 4) showed a population of cells (B40% of total events) Received for publication December 16, 2011; accepted July 25, 2012. expressing myeloid markers CD11b (Fig. 4B), CD13 (Fig. 4C), and in From the Departments of *Pathology and Laboratory Medicine; particular, CD9, CD33 (Fig. 4D), and CD117 (Fig. 4E), but not w Pediatric Hematology and , Loma Linda University expressing CD15 (Fig. 4C), CD36 (Fig. 4B), CD56 (Fig. 4F), and z Medical Center, Loma Linda, CA; and Clarient Inc., Aliso Viejo, CD25 (Fig. 4E), similar to the CD25 IHC result from the initial CA. M.B.Q., C.L.B., A.K., C.W.Z., E.H.R., L.W., and J.W.: participated in biopsy but was in contrast to the focal CD25 reactivity noted on the the composition of this case report. M.B.Q., C.L.B., C.W.Z., concurrent IHC analysis. This discrepancy was likely secondary to E.H.R., L.W., and J.W.: interpreted the morphologic, special stains sampling variation. Flow cytometry for CD2 yielded an equivocal and IHC findings, performed literature search and review, and result (Fig. 4). A stain for langerin was negative. Electron procured photomicrographs. C.W.Z.: interpreted the EM findings. showed nonspecific cytoplasmic features, with neither typical mast E.H.R.: interpreted the flow cytometry data and provided the scat- cell nor Birbeck granules. Chromosomal studies of the tumor cells tergrams. A.K.: presented additional relevant clinical information. showed a normal 46, XY karyotype. Polymerase chain reaction The authors declare no conflict of interest. analysis on fresh tumor tissue was performed at Stanford University Reprints: Jun Wang, MD, Department of Pathology and Laboratory Medicine, Room 2516, 11234 Anderson Street, Loma Linda, CA Medical Center (Palo Alto, CA). This polymerase chain reaction test 92354 (e-mail: [email protected]). included specific evaluation of c-KIT exons 8 and 17, and no muta- Copyright r 2012 by Lippincott Williams & Wilkins tions were detected.

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FIGURE 2. Magnetic resonance imaging of the head showing a destructive 3.33.8 cm lesion arising from the right petrous temporal bone and extending through the skull base (sagittal view).

FIGURE 1. A and B, Hematoxylin and eosin stain of the initial biopsy of the auditory canal mass showing a subcutaneous infil- trate of monocytoid or histiocytoid cells with folded or poly- lobated nuclei admixed with significant numbers of eosinophils (A: 100, B: 400). Immunohistochemistry showing expression of tryptase (C, 200) and CD117 (D, 400). CD1a (E, 400) FIGURE 3. A, Hematoxylin and eosin stain of the second biopsy and S100 (F, 400) were negative, essentially ruling out Lan- of the destructive mass showing mild to moderate nuclear atypia gerhans cell histiocytosis. (400). B, The neoplastic cells demonstrate a low proliferation index, with Ki-67 nuclear positivity in only about 1% to 2% of tumor cells (200).

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FIGURE 4. Gating is applied on the region as depicted on the flow cytometry scattergram of side scatter versus CD45 (A). A population of cells (B40% of the total events) expresses CD11b and CD13 (B and C, respectively), CD9, CD33 and CD117 (D and E, respectively), but the population of interest do not express CD15, CD36, CD25, and 56 (C, B, E, and F, respectively). CD2 expression was equivocal (F).

Despite a milder degree of cellular atypia than described in cell lineage disease, aggressive systemic mastocytosis, and previous cases,3–8 and the absence of the most common c-KIT (MCL) are more commonly observed in mutations in MCD, the clinical, radiologic, histologic, and immu- adults. Other variants consist of a unifocal infiltrate of nophenotypic characteristics were most consistent with MCS. neoplastic mast cells without evidence of systemic involve- Complete staging work-up showed no evidence of or ment. Examples of the latter include MCS and extracuta- peripheral blood involvement. He underwent tumor debulking surgery followed by a month-long trial of imatinib (150 mg/d) with neous mastocytoma (ECM), with the former characterized no clinical or radiographic evidence of tumor response. He was by a destructive pattern of growth, typically showing high- subsequently placed on an investigational oral regimen, protein grade cytomorphology, whereas ECM demonstrates a kinase C-412 (PKC412; 40 mg, tid) and has recently completed 12 nondestructive growth pattern and low-grade cytology.1,2 months of therapy with no significant adverse effects. Minimal Mutations of c-KIT oncogene in the tyrosine kinase decrease in residual tumor size, evident from subsequent radio- domain, expressing substitution from aspartate to valine at graphic impressions, from 2.12.7 to 2.12.4 cm was noted after codon 816 (D816V) have been detected in most cases of the first 6 months of treatment with the aforementioned agent. systemic mastocytosis (SM).9,10 Table 1 summarizes the This decrease in tumor size has allowed possibility for further typical features of the different subtypes of MCD.1,11 debulking surgery. Subsequent showed residual tumor MCS is an aggressive, exceedingly rare condition with cells limited to the right middle ear in a background of moderate 3–8 fibrosis and mixed inflammatory cells. The patient is now 2 years only 6 human cases reported in the literature so far. old, and has experienced mild right-sided cranial nerve VII palsy Patients’ ages ranged from 4 to 74 years, and 4 were and possible right-sided hearing deficit since the initial subtotal females. All patients presented with a unifocal, destructive resection, but no worsening of these deficits or new clinical symp- mass without initial evidence of systemic involvement. Each toms have emerged. patient had no reported history of any MCD before diag- nosis of MCS. Three4,6,8 of the 6 cases documented c-KIT DISCUSSION mutation analysis but none showed the typical D816V Mastocytosis is a diverse group of diseases exhibiting mutation commonly seen in SM. The only mutation unifocal or multifocal proliferation of clonal mast cells.2 detected, present in 1 case, was in exon 17 with substitution Different subtypes are characterized by differing clinical of asparagine to lysine at codon 822.8 Four of the 6 patients symptoms and distribution of abnormal mast cell clusters.1 underwent tumor resection with subsequent Isolated CM often occurs in children, whereas systemic with or without radiation.4,5,7,8 Despite aggressive treat- forms such as indolent systemic mastocytosis, systemic ment, all patients showed disease persistence and/or mastocytosis with associated clonal hematological nonmast recurrence, with 3 of 6 patients developing MCL.3,4,7 Four r 2012 Lippincott Williams & Wilkins www.jpho-online.com | 317 Bautista-Quach et al J Pediatr Hematol Oncol Volume 35, Number 4, May 2013

TABLE 1. Typical Features* of Mast Cell Diseases1,11 CM ECM ISM SM-AHNMD ASM MCL MCS Location Skin Lung Skin + 1 or 1 or more organs 1 or more Bone marrow Variable, more organs (usually organs and blood; hematolym- (usually bone hematolym- (usually skin phoid marrow) phoid); skin bone uncommon uncommon uncommon marrow and ); skin uncommon Extent Usually Unifocal Multifocal Multifocal/ Multifocal/ Disseminated Unifocal with multifocal, disseminated disseminated frequent can be secondary unifocal dissemination/ leukemic transformation Population Children Adults Adults Adults >children Adults Adults Adults >children >adults >children >children >children Histology Aggregates Monomorphic, Skin lesions Variable; must Focal and Dense, diffuse- Atypical mast of rounded mast similar to show multifocal diffuse compact cells with rounded cells; those of CM mast cell infiltration infiltrate of bizarre nuclei mast cells nondestruc- plus compact infiltrates and by atypical, atypical, and prominent surround- tive growth infiltrates of morphologic spindled round mast nucleoli ing dermal round to features of mast cells cells. Often blood spindle mast AHNMD blast-like vessels and cells with morphology adnexal reactive bone with structures marrow monocytoid changes or lobulated nuclei Metachromatic Strong Strong Present Present (mast cells) Absent Absent Absent granules IHC (+) tryptase, (+) tryptase, (+) tryptase, (+) tryptase, (+) tryptase, (+) tryptase, (+) tryptase, CD117 CD117 CD117, CD117, CD25 CD117, CD117, CD117 CD25 CD25 CD25 Variable Variable CD2 Usually (+) Variable CD2 Variable CD25 CD25 CD2 and CD2 Serum tryptase Normal to NA Persistent Persistent Persistent Often marked Often elevated slightly elevation elevation elevation (>200 ng/ (>20 ng/mL) elevated (>20 ng/mL) (>20 ng/mL), (>20 ng/ mL) often marked mL), usually (>200 ng/mL) marked (>200 ng/ mL)

*The most common features of each disease are included; however, mast cell disorders are highly variable in their presentation and not all potential presentations are described. ASM indicates aggressive systemic mastocytosis; CM, cutaneous mastocytosis; ECM, extracutaneous mastocytoma; IHC, immunohistochemistry; ISM, indolent systemic mastocytosis; MCL, mast cell leukemia; MCS, mast cell sarcoma; NA, data not available; SM-AHNMD, systemic mastocytosis with an associated clonal hematologic nonmast cell lineage disorder. of the 6 patients succumbed to the disease.3–5,7 As with with the experimental agent PKC412, allowing for further MCS, MCL does not always show the D816V mutation, debulking surgery. Histologic findings from the most recent however, recent studies revealed alternate mutations of the surgery mainly demonstrated fibrosis and mixed inflam- c-KIT gene in several MCL cases.12–15 It is probable that mation, with evidence of residual tumor limited to the right full sequencing of the c-KIT gene in cases of aggressive middle ear. To the best of our knowledge, this represents MCDs such as MCS or MCL that lack the commonly the first reported occurrence of MCS diagnosed in an tested mutations will show alternate or new abnormalities. infant. Table 2 shows a brief summary of MCS reported in Several IHC stains are helpful in identifying mast cells humans.1,11 We report a case in a 2-year-old boy with a and differentiating them from other cell lineages. In addi- unifocal right ear mass, initially diagnosed as CM with tion to positivity for CD68, reactivity with c-KIT or CD117 atypical features, showing rapid increase in tumor size and and tryptase are frequently observed, and are required for subsequently exhibiting destructive growth pattern; findings the diagnosis of mast cell lesions. In fact, among hema- that are most consistent with MCS. It is likely that the topoietic neoplasms, these 3 markers (tryptase, CD117, and initial diagnosis of “atypical” CM corresponded to early CD68) are distinctive of MCD.17 Neoplastic mast cells phase of MCS. Our case showed rapid disease progression typically coexpress CD2 and/or CD2518 in addition to initially with no evident tumor response with imatinib. CD117 and tryptase. Bcl-2 expression has been reported in However, minimal decrease in tumor size with disease sta- some MCL cases.19 Mast cells are typically negative for bilization was achieved after the first 6 months of treatment MPO, most myelomonocytic, and lymphoid antigens.18–22

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TABLE 2. Summary of Mast Cell Sarcoma Cases in Humans Disease Persistence/ Recurrence Age at c-KIT After Case Diagnosis Sex Site Mutation Treatment Treatment MCL Progression Outcome Current 11 mo Male Right ND Subtotal resection, Disease No evidence of Minimal decrease in case temporal imatinib, oral persis- MCL at tumor size with bone regimen tence with diagnosis PKC412 treatment, (PKC412)16 imatinib with histologic followed by evidence of limited debulking surgery residual tumor Brcic 4 y Male Right tibia NM AML-BFM Yes Yes Death; 18 mo after et al3 diagnosis Chott 8 y Female Brain: ND Subtotal resection, Yes Yes Death; 13 mo after et al4 tempoparie- radiation and diagnosis tal area polychemotherapy Kojima 32 y Female Ascending NM Resection with node Yes ND, but Death; 2 y after et al5 colon dissection, dissemination to diagnosis predonine, nonhemato- radiation poietic organs was detected Ma 39 y Female Uterus ND Combination Stable No evidence of Stable disease currently et al6 chemotherapy, disease; MCL at imatinib ongoing diagnosis treatment with imatinib Horny 74 y Female Larynx: NM Total resection, Yes Yes Death; 4 y after et al7 subglottis bleomycin, diagnosis radiation, modified De Vita chemotherapy Bugalia Elderly Male Asn-822- Complete resection, Yes: disease No evidence of Disease resolution with et al8 (specific Lys in imatinib, INF recurrence MCL at INF a-2b age exon 17 a-2b only with diagnosis NM) imatinib

AML-BFM indicates acute -Berlin-Frankfurt-Munster 2004 therapy protocol; Asn, asparagine; INF a-2b, interferon a-2b; Lys, lysine; MCL, mast cell leukemia; ND, not detected; NM, not mentioned; PKC, protein kinase C clinical trial.

Hence, granulocytic sarcoma may be distinguished from mastocytosis and MCL.16 Moreover, PKC412 has been MCD by MPO staining. Nevertheless, a prior study dem- discovered to inhibit activation and subsequent release of onstrated a subset of atypical mast cells in CM that showed chemical mediators by binding of immunoglobulin-E in positivity for MPO,17 further imposing challenge in differ- basophils and mast cells, thus minimizing adverse effects entiating MCD from other myeloid tumors. LCH is one of from these mediators during treatment.27 Although mini- the more common histiocytic disorders of childhood and mal decrease in tumor size, based on subsequent radio- may morphologically mimic MCD. CD1a, , graphic impressions, was observed in our patient after the and langerin are characteristically positive in LCH23 but first 6 months of treatment with PKC412, this has permit- negative in MCD. ted feasibility of performing further resection, which Available cytoreductive treatment for SM and its showed histologic evidence of limited residual disease. subtypes includes interferon-a (IFN-a) with or without Nonetheless, insufficient data are available at present on corticosteroids, hydroxyurea, imatinib mesylate,24 or 2- long-term response to PKC412. chlorodeoxyadenosine (2-CdA or cladribine).24,25 Of these agents, IFN-a and 2-CdA or cladribine have shown modest response rates; thus, both have been recommended as first CONCLUSIONS line agents in SM.24 SM with c-KIT tyrosine kinase D816V MCS in infants is extremely rare, and must be histo- activating mutation has demonstrated resistance to imati- pathologically distinguished from a number of the more nib26; however, this drug was recently reported to show a common tumors of infancy, including LCH, benign local- reasonable disease response in 1 MCS case.6 Although our ized mastocytoma, , neuro- patient lacked the D816V mutation, a trial of imatinib was blastoma, , central nervous system pursued. However, no appreciable decrease in tumor size neoplasms, and acute leukemia, or granulocytic sarcoma. A was noted with imatinib treatment. A clinical trial of a multimodal approach, including clinical, radiographic, and protein kinase inhibitor, PKC412 (midostaurin) is in immunophenotypic correlation is necessary to make these progress, and has revealed some promise in the treatment of distinctions. Although most systemic MCDs demonstrate aggressive forms of SM such as aggressive systemic activating mutations of the c-KIT tyrosine kinase domain, r 2012 Lippincott Williams & Wilkins www.jpho-online.com | 319 Bautista-Quach et al J Pediatr Hematol Oncol Volume 35, Number 4, May 2013 particularly substitutions in exons 8 and/or 17; a c-KIT 13. Akin C, Fumo G, Yavuz AS, et al. A novel form of abnormality has been documented in only 1 case of MCS in mastocytosis associated with a transmembrane c- mutation humans.8 MCS may harbor mutations in the c-KIT gene and response to imatinib. Blood. 2004;103:3222–3225. other than the usually tested aforementioned abnormalities. 14. Mital A, Piskorz A, Lewandowski K, et al. A case of mast cell leukaemia with exon 9 KIT mutation and good response to Hence, a full c-KIT gene sequence analysis may be helpful, imatinib. Eur J Haematol. 2011;86:531–535. and perhaps may lead to the investigation of other treat- 15. Spector MS, Iossifov I, Kritharis A, et al. Mast-cell leukemia ments for MCS, including targeted gene therapy. exome sequencing reveals a mutation in the IgE mast-cell receptor beta chain and KIT V654A. Leukemia. 2011;26: ACKNOWLEDGMENT 1422–1425. 16. Gotlib JR. Phase II PKC412 in aggressive systemic masto- The authors thank Dr Tracy George and her team from cytosis and mast cell leukemia. February 17, 2011. Available Stanford University Medical Center for conducting the c-KIT at: http://clinicaltrials.gov/ct2/show/NCT00233454. Accessed exons 8 and 17 mutation analysis. June 21, 2011. 17. 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