Available online at www.annclinlabsci.org 466 Annals of Clinical & Laboratory Science, vol. 47, no. 4, 2017 Myeloid Sarcoma in a Patient with Associated with del(5q-): Case Report and Literature Review

Josh A. Showalter1, Nidhi Tandon1, Bihong Zhao1, Guilin Tang2, Nghia D. Nguyen1, and L. Jeffrey Medeiros2

1Department of Pathology and Laboratory Medicine, UTHealth McGovern Medical School, Houston, Texas, and 2Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Abstract. Objective. Myeloid sarcoma (MS) is defined in the World Health Organization classification as a tumor mass consisting of with or without maturation and involving any anatomic site other than the . We present a case of MS developing in a patient with 5q- myelodysplastic syndrome (MDS) and review the relevant literature. Methods. A 77-year-old woman with recent diagnosis of MDS associated with del(5q) presented with symptoms and signs attributable to a mass involving the T8 vertebra. of the spinal mass was performed and the specimen was analyzed using routine hematoxylin-eosin stain, immunohistochemical methods, and fluorescence in situ hybridization (FISH). Results. Microscopic examination revealed an infiltrate of intermediate-large cells with basophilic cytoplasm and nuclei contain- ing occasional prominent nucleoli. Immunohistochemical analysis showed that the neoplastic cells were positive for CD4, CD43, CD45, CD68, and CD117, and negative for B- and T-cell antigens supporting the diagnosis of MS. Fluorescence in situ hybridization of the spinal mass showed del(5q) in the neoplastic cells. Conclusion. Although the 5q- syndrome is a clinically indolent form of MDS, a small subset of pa- tients may develop MS as illustrated in this patient. The relevant literature is also reviewed.

Introduction may develop MS which is considered to represent leukemic transformation. Leukemic transforma- Myeloid sarcoma, also known as chloroma or gran- tion in MDS patients occurs in about 15% - 17% ulocytic sarcoma, is defined in the World Health of patients at 5-6 years [5-7]. Organization (WHO) classification as a tumor mass consisting of myeloblasts with or without When patients with prognostically favorable MDS maturation involving any anatomical site other develop MS, it may pose a diagnostic challenge as than the bone marrow. Most often, myeloid sarco- transformation is much less frequent and therefore ma (MS) occurs in patients with acute myeloid leu- may be unexpected. MDS with 5q deletion, also kemia (AML), either at the time of diagnosis or af- known as 5q minus syndrome, is a specific syn- ter therapy [1-3]. Rarely, MS may represent the drome that carries a much better prognosis than initial presentation of an AML and even precede it other MDS categories. Patients with this type of by many years. This phenomenon is well estab- MDS typically have a median prospective survival lished in patients who have AML with recurrent time between 74 and 145 months [5,8]. genetic abnormalities, such as AML with t(8;21) (q22;q22)/RUNX1-RUNX1T1 and AML with In this report, we describe a patient with 5q- syn- inv(16)(p13.1q22) or t(16;16)(p13.2;q22)/CBFB- drome who developed MS involving the vertebra MYH11 [2-4]. Patients with high-risk myelodys- and epidura, and we review the relevant plastic syndrome (MDS) characterized by an ele- literature. vated blast count and/or poor prognosis cytogenetics Case Report

Address correspondence to Josh A. Showalter, MD; Department of Pathology and Laboratory Medicine, The University of Texas Health A 77-year-old woman with a recent diagnosis of MDS Sciences Center at Houston McGovern Medical School, 6431 Fannin classified as 5q- syndrome, treated with lenalidomide Street, MSB 2.212, Houston, TX, 77030, USA; phone: 504 400 7847; fax: 713 500 0712; e mail: [email protected] and supportive transfusions, presented to an outside

0091-7370/17/0400-466. © 2017 by the Association of Clinical Scientists, Inc. Myeloid sarcoma in MDS with 5q- 467 CD99, CD117, ALK-1, BCL-1, MPO, S-100, pancyto- keratin, synaptophysin, chromogranin, TTF1, CDX2, CD56, and CD45.

Fluorescence in situ hybridization analysis was per- formed on the biopsy specimen using fixed, paraffin- embedded tissue sections and the probes D5S721/ D5S23 (5p15, spectrum green) and EGR1 (5q31, spec- trum red) (Abbott Molecular Inc., Abbott Park, IL).

Results

The initial bone owmarr aspiration and biopsy specimens prepared at an outside hospital were re- viewed. The biopsy specimen was hypercellular for age, 85%, and megakaryocytes showed normal numbers with monolobated forms (Figure 2A &B). The percentage of bone owmarr blasts could not be quantified as a result of hypocellular aspirate Figure 1. MRI demonstrating tumor compression and smears. Myeloid precursors showed left shifted pathologic fracture at T7-T8 vertebrae. maturation. Circulating blasts were not seen in the peripheral blood. hospital, with the complaint of persistent back pain for several weeks. Plain radiographic films performed by her primary care were negative. The patient sought immunophenotypic analysis per- further treatment when the pain persisted. formed on bone marrow aspirate could not be in- terpreted due to low cell viability. Conventional At the time of admission to the hospital physical exami- cytogenetics showed a normal female karyotype, 46 nation showed no neurological deficits. A complete XX [20]. blood count showed pancytopenia with a count of 2.4 K/mm3, platelet count 104 K/mm3, Fluorescence in situ hybridization on aspirate hemoglobin 9.1 g/dL, and hematocrit 26.1%. A CT smears showed 5q deletion. The diagnosis of MDS scan revealed a pathologic fracture with partial destruc- with 5q deletion was established. tion of the T8 vertebral body. A MRI was also performed and revealed a lesion replacing the medullary space of T8 with mild wedging and pathologic fracture as well as an The gross specimen from the T8 epidural masswas epidural tumor with extension at T8 causing moderate 2.0x2.0x0.3 cm in aggregate. Routinely stained sec- stenosis of the spinal canal and compression of the spinal tions (Figure 3A-C) showed diffuse infiltration of cord (Figure 1). The patient was subsequently taken to soft tissue by intermediate to large cells with large the operating room and underwent bilateral laminecto- nuclei, occasional prominent nucleoli, and abun- mies, medial facetectomy, and foraminotomies at T7-T9 dant basophilic cytoplasm. with excision and biopsy of the extradural mass. studies showed that the neoplastic cells were posi- tive for CD4, CD43 (Figure 3D), CD45, CD68 Materials and Methods (Figure 3E), and CD117 (Figure 3F) and were negative for all other antibodies tested. Fluorescence This study was ovappr ed by The University of Texas Medical School at Houston Internal Review Board in situ hybridization performed on a fixed, paraffin- Protocol (No: T-15-110) and the authors have no con- embedded tissue section of this specimen showed flicts of interest to disclose. The biopsy specimen was 5q deletion (Figure 4). fixed in formalin without decalcification. Hematoxylin & eosin (H&E) staining was performed on fixed, paraf- Discussion fin-embedded tissue sections. Immunohistochemical analysis was performed with appropriate controls using We present a patient with MDS associated with the following antibody panel: CD2, CD3, CD4, CD5, del(5q), also known as 5q- syndrome, who devel- CD7, CD8, CD20, CD30, CD34, CD43, CD68, oped MS. The development of MS in patients with 468 Annals of Clinical & Laboratory Science, vol. 47, no. 4, 2017

Figure 2. (A) H&E Bone Marrow Biopsy (100x) and (B) H&E of Bone Marrow Biopsy (200x).

Figure 3. (A) H&E Epidural Mass (40x), (B) H&E Epidural Mass (100x), (C) H&E Epidural Mass (200x), (D) CD43, (E) CD68, and (F) CD117.

5q- syndrome is uncommon. In our review of the with excess blasts (RAEB), 25% (2/11) had refrac- literature we identified 23 reported cases of MS in tory with ring sideroblasts (RARS), patients with MDS. Including our patient, only 3 25%(2/11) had MDS 5q- syndrome, and the re- cases with 5q- syndrome have been reported. One of mainder had other MDS [9-15]. these cases also had monosomy 7 which does not fit the currently defined WHO criteria to be designated While it is well established that patients with AML as exclusive deletion 5q syndrome [2, 9-15]. Further have an increased risk of developing MS, little re- analysis of 11 of the cases where location and type search has been conducted to determine if the risk MDS were available, summarized in Table 1, dem- of leukemic transformation can predict the devel- onstrated that 27% (3/11) had refractory anemia opment of MS in patients with AML or MDS. As Myeloid sarcoma in MDS with 5q- 469 count or more than one chromosomal abnormality are not included in the current definition of MDS with isolated del(5q) as defined by the World Health Organization (WHO) classification. Two additional studies, one by Patnaik et. al. and one by Mallo et. al., looking at similar factors showed that patients with 5q- syndrome have a risk of leukemic transfor- mation ranging from 6% [6] to 17% [7].

The prognosis of patients with MDS with isolated 5q deletion is favorable. Patients with this MDS syn- drome typically have a median prospective survival time between 74 and 145 months for a median fol- low-up time of 67 months [5,8]. It is not clear if these same patients would have a similar prognosis if Figure 4. FISH with cells demonstratingasignal pattern of 1 red and2green which represents clones harboringa5q they subsequently develop a MS. The data on the deletion. prognosis of patients with MS is limited, but of the studies performed, the survival rate is 20% and 30% previously discussed, MS appears to develop more at 3 and 5 years respectively if patients received che- frequently in patients with RAEB. These patients motherapy [3,17,18]. In addition, prognostic mark- have an increased risk of transformation to leuke- ers seen in AML such as NPM1 and FLT3 have been mia, 25% and 33% for RAEB-1 and RAEB2 re- discovered in MS. Typically, patients with NPM1 spectively [16]. In regards to MDS 5q- syndrome, mutations will have a good prognosis while those Germing et. al. examined 381 of such patients. The with FLT3 mutations will have a worse prognosis; authors reported that patients with increased bone however, their role in MS has yet to be determined marrow blast counts, transfusion dependency, and and may require further studies [3,8]. the presence of more than one chromosomal abnor- mality are associated with increased risk of progres- This patient presented with MS involving theT8 sion to AML at a rate of 14.7% at 5 years [5]. This vertebra and the contiguous epidural region. study likely overstates the risk of leukemic transfor- Involvement of the central nervous system (CNS), mation because patients with an elevated blast specifically the spinal cord by MS, does not appear

Table 1. Summary of 11 cases of myeloid sarcoma arising from MDS.

Series Ref. No. Case No. Age/Sex Location MDS Type

Current study 1 77/F Spinal cord MDS 5q- Pileri et al [2] 2 Not provided MDS 5q- Pileri et al [2] 3 Not Provided Skin MDS with 5q- and monosomy 7 Koppisetty et al [9]466/M Prostate RAEB-1 Grantham et al [10] 5 56/M Bladder RAEB-2 Cheng et al [11] 6 57/M Tonsil MDS unclassifiable Paydas et al [12] 7 52/M Lymph nodes Hypoplastic MDS Paydas et al [12] 8 26/M Lymph nodes RARS Geisse et al [13] 9 60/M Tonsils RARS Ravandi-Kashani et al [14] 10 26/M RAEB-2 Cornfield et al [15] 11 79/M Spinal cord MDS with complex cytogenetics

Abbreviations. MDS: Myelodysplastic Syndrome, RAEB: Refractory Anemia with Excess Blasts, RARS: Refractory Anemia with Ring Sideroblasts. Table 2. Summary of 48 Cases of myeloid sarcoma of the spinal cord. 47

Series Ref. No. Case No. Age/Sex Spinal Level Type of disease Symptoms 0 Hu et al [19] 1 43/M C7-T1 MPN with eosinophilia Progressive neck, right upper extremity pain

Joseph et al [20] 2 20/M T4-T9 AML Weakness and numbness in lower extremities Ann

Chamberlain et al [21] 3 23/M S2 AML Pain in left buttock and left posterior thigh al s

Piñán et al [22] 4 61/F T12-L1 APL Progressive loss of muscular strength and paraesthesia in bilateral lower of

extremities, difficulty walking and loss of sphincter control Cl

Baikaidi et al [23] 5 75/F T10-T12 AML t(9;22) Back pain and gait dysfunction in Kyaw et al [24] 6 26/M T2-T4 APL Progressive back pain and bilateral lower extremity weakness, and was ic unable to walk al Cornfield et al [15] 7 79/M T7 MDS with complex cytogenetics Low back pain and lower extremity weakness & Bittencourt et al [25] 8 53/M T6-T8 APL Progressive fatigue, pain and weakness of bilateral lower extremities La Serefhanoglu et al [26] 9 22/M C2-C3, None Progressive backache and weakness in bilateral lower extremities bora

Serefhanoglu et al [26] 10 43/F C6-C7 None Left arm and leg pain to Pacilli et al [27] 11 38/M T6-T8 APL Right chest pain and progressive right paraplegia ry Amalraj et al [28] 12 14/F T3-T11 APL Paraplegia Sc ie

Amritanand et al [29] 13 15/M T8-T10 None Mid-back pain weakness in bilateral lower extremities nc

Olcay et al [30] 14 12/M L4-Conus Acute Myeloblastic Progressive swelling of the left cheek, bilateral lower extremity, fecal and e,

medullaris urinary incontinence vo Verra et al [31] 15 45/M L5-S2 AML Back pain and difficulty walking l. Jerse et al [32] 16 75/F T3-T6 ET Spinal cord compression 47 ,

Balleari et al [33] 17 76/F C7-T2 AML with Maturation Hyposthenia and hypoesthesia bilateral upper extremities. no

Widhalm et al [34] 18 35/F T3-T5, S1-S4 None Sensorimotor paraparesis from T-5 downward, along with sphincter . dysfunction and urinaryretention 4, Chauhan et al [35] 19 53/F T10-T12 CML Progressive weakness in bilateral lower extremities associated with radicular 20 pain radiating down the right leg 17 Seo et al [36] 20 59/M T8-T11 AML with Maturation Back pain, paresthesias, and bilateral lower extremity paraplegia. Meltzer et al [37] 10/M T2-T6 Acute myeloblastic Midback pain, bilateral lower extremity paraparesis, leukemia and paresthesias. Shiozawa et al [38] 21 2/M L3 None External genital and lower extremity pain foramonth with difficulty standing or walking Kalayci et al [39] 22 24/F T3-T5 None Localized back pain with bilateral lower extremity weakness, numbness, and urinary retention Howell et al [40] 23 11/M T1-T5 None Progressively worsening lower extremity weakness and paresthesias, and mild pain in his upper back and scapular regions. Chalhoub-Hachem 24 19/M Not Specified CML Spinal cord compression et al [41] Siddiqui et. al. [42] 25 9/F Not Specified Acute Myeloblastic Leukemia Rapidly progressive paraparesis Ugras et. al. [43] 26 13/M T11-L1 None Hypoalgesia and hypoesthesia below L1 Buckland et. al. [44] 27 35/F Not Specified None Rapidly progressive triplegia Graham et. al. [45] 17/F C6-Conus AML Medullaris Spastic paraplegia and sensory loss at T10 Graham et. al. [45] 40/M S1 None Paresthesia and numbness of right hand with bilateral sciatica and altered sensation in feet. Myeloid sarcoma in MDS with 5q- 471 c . to be an uncommon phe- ti of ne e as

a nomenon. Review of the lit- to th pl si d n. of ys

of erature reveals at least 48 cases ter he io s an s. ss st od it nc r with CNS involvement sum- es y, lo el re hi lysi ur it we . l d pa ct ra sp marized in Table 2. Most pa- lo My akn ro on an em d al pa th mi ti nt S: tr

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yt or non-contiguous. Most of li , hi oc ia these patients, 58%, had on . em nop AML prior to, concurrent si ) ) ) ) rd om uk el co 21 21 21 21 with or shortly after the diag- Eo 8; 8; 8; 8; ic le al c My t( t( t( t( nosis. Only 27% were aleu- yt in ni e L L L L L L L L L L L L L sp ne ne ne ro kemic, and only 1 patient had ut e eloc AM Ch No AM AM AM No AM AM No AM Ac CM AM AM AM AM AM th MDS as in our patient further of demonstrating the rarity of a 3 1 promy -S ed om -T e this entity in patients with rc ifi ut L5 T2 al S1

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ia sis is currently a convenient of as s em se and reliable means for diag- /M /F /M /M /M /M /M /M /M /M /M /M /M /M /M /M /F F uk Ca neopl 17 32 49 19 12 70 10 14 19 47 18 48 55 17 6/ 29 70 54 nosing MS. Studies suggest le e d 48 iv that the IHC workup for MS oi of el y

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: CD117, CD163, and myelo- 1] ti [4 [4 . s [5 . 4] . . . et. et. et. MP [5 . al et. et. et. et. et. et. et. al al on [5 on i i i , . al al peroxidase as well as other . i i i i i i i al . . . ti . . al sk sk sk . et et al av av av av av av av me . ia et et markers that can suggest et in in in . n af af af af af af af et ro e2 (c ev nt wa et dz dz dz st st st st st st st me me granulocytic versus monocyt- ok le bl br m za nd Sy Ab Wo Ma et De Ai Brow Ki Ko Wo Wo De Ta Mo Mo Mo Bu Mo Mo Mo Mo ic lineage [4,55,56]. 472 Annals of Clinical & Laboratory Science, vol. 47, no. 4, 2017

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