case report promyelocytic leukemia with no retinoic acid...

Case ReportPromyelocytic Leukemia with No Retinoic Acid ReceptorAlpha Abnormality but with RUNX1T1 Insertion toChromosome 7q: A Classification and Management Dilemma

Kathleen Overholt,1 Terri L. Guinipero,1 Nyla A. Heerema,2

Michael R. Loken,3 and Samir B. Kahwash2,4

1Hematology/Oncology and Blood and Marrow Transplant, Nationwide Children’s Hospital, Columbus, OH 43205, USA2Department of Pathology, The Ohio State University, Columbus, OH 43210, USA3Hematologics, Inc., Seattle, WA 98121, USA4Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA

Correspondence should be addressed to Samir B. Kahwash; [email protected]

Received 12 June 2015; Accepted 3 August 2015

Academic Editor: Takashi Sonoki

Copyright © 2015 Kathleen Overholt et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

A case of acute promyelocytic leukemia (APL) with RUNX1T1 insertion to 7q is described and compared to reported cases of APLwith negative retinoic acid receptor alpha (RARA) abnormality. In this report, we describe the case of a 2-year-old boywhopresentedwith bone pain and was found to have pancytopenia. Bone marrow examination showed morphologic and immunophenotypicfindings typical of APL, but conventional cytogenetics, fluorescence in situ hybridization (FISH), and real-time polymerase chainreaction (RT-PCR) showed no evidence of RARA rearrangements. The only cytogenetic abnormality found was a small insertionin 7q, and three copies of RUNX1T1. Gene sequencing results became available after initiating therapy but were not informative.Wedescribe the rarity of such cases and discuss how the typical morphologic and immunophenotypic findings of APL, coupled withthe definite absence of RARA rearrangement (by FISH and RT-PCR), present a diagnostic and classification dilemma, raising thepossibility of an unknown alternative mechanism for the leukemogenesis and maturation arrest seen in other APL variants. Thediagnostic challenges and urgent management issues this unusual case raises may justify including it, along with similar cases, in aseparate subtype of acute myeloid leukemia (AML) in future classifications.

1. Introduction

In this report, we describe a case of acute myeloid leukemia(AML) with morphologic and immunophenotypic findingstypical of acute promyelocytic leukemia (APL), but con-ventional cytogenetics, fluorescence in situ hybridization(FISH), and real-time polymerase chain reaction (RT-PCR)showed no evidence of retinoic acid receptor alpha (RARA)abnormality. The only cytogenetic abnormality found was anadditional copy of RUNX1T1 inserted in 7q.

We discuss how the typical morphologic and immu-nophenotypic findings of APL, coupled with the definiteabsence of RARA rearrangement by FISH and RT-PCR,present a diagnostic and classification dilemma, raising the

possibility of an alternative mechanism for the leukemoge-nesis and maturation arrest seen in APL. We also proposeincluding cases of APL with no RARA abnormality in aseparate subtype in future classifications of AML.

2. Case Report

A 2-year-old, previously healthy male presented with a one-month history of daily fevers (39∘C or greater), fatigue,decreased oral intake, lower extremity pain, and intermittentrefusal to bear weight. He was initially evaluated for possibleleft hip synovitis based on ultrasound findings. Laboratoryfindings at that time were significant for mild normocyticanemia (Hgb, 10.3 g/dL), elevated erythrocyte sedimentation

Hindawi Publishing CorporationCase Reports in HematologyVolume 2015, Article ID 412016, 6 pageshttp://dx.doi.org/10.1155/2015/412016

2 Case Reports in Hematology

rate (ESR) of 27, mildly elevated lactic dehydrogenase (LDH)of 1310 IU/L, and positive antinuclear antibodies (ANA)(1 : 40 in speckled pattern). One week later, he presentedagain with persistence of symptoms. Repeat lab tests showedsimilar results to the prior visit with persistent mild anemia(Hgb, 10.4 g/dL), normal general chemistry tests, normalcoagulation tests, and elevated ESR of 58. Because of concernfor a septic joint or neoplasia, the patient was admitted forevaluation.

During admission, MRI of pelvis and bilateral hips wereperformed. Results were significant for scattered areas ofsignal abnormality within the marrow of the pelvis and prox-imal left femur, with associated edematous or inflammatorychanges within soft tissues of the pelvis. Findings were feltto be consistent with inflammatory or infectious etiology,althoughmalignancy could not be excluded.The patient thenunderwent a bone marrow aspirate and biopsy; findings werefelt to represent either aggressive marrow regeneration orearly stages of a myeloproliferative process with no identifieddysplastic features. Flow cytometric analysis demonstrateda predominant maturing myeloid cell population; however,only a very small population, ∼2%, was phenotypic progeni-tor cells.The patient’s symptomswere attributed to an inflam-matory condition and the patient was discharged home onanti-inflammatory medication with primary care follow-up.

Symptoms initially improved, however, over the twoweeks following discharge; his symptoms of fever and bonepain returned. He was seen in the Infectious Disease Clinic,where he was noted to have worsening anemia (Hgb of7.2 g/dL) and thrombocytopenia (42,000 permicroliter), withLDH elevation of 1661 and normal uric acid. He, therefore,underwent repeat bone marrow examination.

3. Pathologic Findings

At the time of this second bone marrow sample, the periph-eral blood was significant for thrombocytopenia (plateletcount of 35,000) with no anemia and normal white bloodcell count; however, the patient had recently been transfusedwith packed red blood cells. The peripheral blood smearmanual differential cell count listed 2% blasts. The bonemarrow aspiratewas hemodilutedwith no significantmarrowelements and no significant number of blasts.

The core biopsy touch imprints also were paucicellular(Figure 1(a)), and flow cytometry showed no significantblast/progenitor cell population. Sections from the corebiopsy were available the following day, revealing a hyper-cellular marrow space with an area of coagulative necrosis(Figure 1(b)). The marrow space was dominated by myeloidcells with somematuration and increased cells with cytoplas-mic granules. There was a marked decrease in erythroid cellsandmegakaryocytes. Immunoperoxidase staining confirmedthe predominance of myeloid cells (positive CD33 andMPO,Figures 1(c) and 1(d)). The negative staining for T-cell, B-cell, CD61, and CD42b helped exclude other hematopoieticmalignancies, andnegative results formast cell tryptase, CD2,and CD25 excludedmastocytosis. A repeat marrow samplingincluding additional core biopsies was recommended inorder to compensate for the inadequate blood-dilute aspirate

and repeat immunophenotyping by flow cytometry on amore representative sample. Additional core biopsies wereobtained, with one core used to generate a cell suspensionof marrow cells by teasing out and disaggregating marrowtissue. This new cell suspension was used for making stainedcytospin slides for cell morphology alongside the touchimprints and was utilized for immunophenotyping by flowcytometry and for cytogenetics.The touch imprints from thissample showed predominance of abnormal promyelocytes,with some showing multiple delicate Auer rods (arrow inFigure 2).

Immunophenotyping by flow cytometry revealed a pre-dominance and abnormal expansion of phenotypic promye-locytes with no significant number of myeloid progenitorcells. The dominant abnormal cells were identified by highright angle scatter showing strong positivity for CD33 andMyeloperoxidase (MPO) but were negative for CD15, HLA-DR, and CD18 (abnormal findings). From this data, thediagnosis of APL was suspected. Molecular and cytoge-netic studies were expedited, but no evidence of a RARAabnormality by karyotyping or FISH was seen. FISH withPML-RARA dual fusion and RARA break-apart probes (allprobes from Abbott Molecular, Des Plaines, IL) were allnormal. Metaphase cytogenetics showed a karyotype of46,XY,ins(7;?)(q22;?). FISH with D7Z1, D7S486, CBFB, andKMT2A were also normal. However, although FISH withthe RUNX1T1-RUNX1 probes did not show typical fusion,three copies of RUX1T1 were present. FISH on metaphasesshowed that RUNX1T1 was present on the abnormal chro-mosome 7, resulting in a reinterpretation of the karyotype to46,XY,der(7)ins(7;8) (q22;q13q22). A marrow specimen wassent for RT-PCR testing, which also did not show RARAabnormalities; however, testing was specific for only PMLfusion partner. Given that morphologic and genetic findingswere not quite clear, genetic sequencing was considered forfurther classification. However, by the time this testing wasdiscussed, our patient had been started on treatment andinitial bone marrow sample was no longer viable.

As the morphologic diagnosis of APL could not beconfirmed by molecular and genetic methods, a treatmentprotocol for AML, not otherwise specified (NOS), wasconsidered the best option. The patient was started onchemotherapy treatment per the standard arm of Children’sOncology Group AAML1031 protocol, although not enrolledin the study. Lumbar puncture was performed and noevidence of disease was present. Initial coagulation studieswere within normal limits. However, after initiation of treat-ment, the patient developed bleeding symptoms consistingof epistaxis, guaiac positive stools, and oozing at the site ofcentral line insertion despite maintaining a platelet counthigher than 75,000. Repeat coagulation tests at that timerevealed a mildly elevated prothrombin time (PT) of 15.2(normal 12.4–14.7 seconds), a normal activated prothrombintime (aPTT) of 34 (normal 24–36 seconds), fibrinogen of227mg/dL (normal 170–410mg/dL), elevatedD-dimer of>20(normal <0.50mcg/mL), and a mildly elevated thrombintime of 33.6 (normal range 14.2–18.9 seconds). Due to aprior history of bleeding symptoms, a qualitative Factor XIIIwas performed and found to be within normal limits. von

Case Reports in Hematology 3

(a) (b)

(c) (d)

Figure 1: Initial core biopsy touch imprints. (a)Wright-Giemsa stained blood-dilute touch imprints; note the packedmarrow on the left side.(b) Hemorrhagic necrosis on right side of this H&E stained section. (c) Immunoperoxidase staining of core biopsy for CD33; areas not takingthe stain represent necrotic marrow. (d) Immunoperoxidase staining for Myeloperoxidase of a section from core biopsy.

Figure 2: Wright-Giemsa stained touch imprint showing promye-locytes with fine azurophilic granules. Arrow: a myeloblast withmultiple thin Auer rods typical of APL.

Willebrand panel was obtained on parents (since patient hadreceivedmultiple bloodproducts) and results returnedwithinnormal limits. The patient required multiple transfusionswith platelets and fresh frozen plasma to control bleeding,resulting in symptoms improvement and count recovery.End of induction I bone marrow was performed due to

slow count recovery and showed morphologic blasts at 15%and flow cytometry for measurable residual disease (MRD)identified an abnormal promyelocytes population at 56%(Figures 3(a)–3(c)) exhibiting decreased granularity and noexpression of either HLA-DR or CD11b. The majority ofphenotypic progenitor (blast region) cells were shown tobe lymphoid (8.8% hematogones) and not myeloid. Themyeloid progenitor cells were identified as normal phenotypewith total of 2.7% CD34+ cells. At this time, given thepersistence of an abnormal promyelocytic population, thesample was sent for DNA sequencing (Foundation One)for additional insight into this disease. Results showed onegenomic alteration at CD36/Y325 of unknown significance.

After induction II per AAML1031 high risk arm bonemarrow morphologic examination showed megaloblastoidmaturation with 7% blasts; however, flow cytometric analysisrevealed normal antigen expression on all myeloid precursorsand absence of the abnormal promyelocytic populationidentified earlier. Flow cytometry revealed an MRD of lessthan 0.1% abnormal myeloid cells (Figures 3(d)–3(f)).

The patient started intensification I per AAML1031 highrisk arm which he tolerated without issue. Due to hispoor initial response, the bone marrow transplant team wasconsulted for stem cell transplant. At the time of publicationof this paper, the patient has undergone allogenic stem celltransplantation with a 6 out of 6 matched cord donor and isdoing well more than 100 days post-transplant.


Forward light scatter20 40 60

101

102

103

SSC

Progen.

LymphMono

Myeloid

101

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CD45

Per

CP

103

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Promyel.101

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CD11

b PE

102

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HLA-DR FITC

Forward light scatter20 40 60

101

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SSC

Progen.

Lymph

Mono

Myeloid

101

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CD45

Per

CP

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SSC

Promyel.101

102

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CD11

b PE

102

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HLA-DR FITC

(b) (c)(a)

(e) (f)(d)

Figure 3: (a, b, c) Flow cytometric analysis of the bone marrow, following induction I chemotherapy. The dominant cell population, 56%of nonerythroid cells (green), was consistent with abnormal hypogranular promyelocytes that expressed neither CD11b nor HLA-DR butwere highly autofluorescent. (d, e, f) Similar analysis of bone marrow, following induction II, demonstrated the appropriate right angle lightscatter for promyelocytes (vertical red line) with the majority of maturingmyeloid cells now expressing CD11b, that is, myelocytes-segmentedneutrophils.

4. Discussion

The current WHO classification of hematopoietic malignan-cies [1] does not include a defined subtype for APL caseslacking retinoic RARA abnormality or RARA variants. As aresult, an encounter with one of the rare cases with definitemorphologic and immunophenotypic features of APL but noRARA fusion gene (or its variants) may present a challenge ofdiagnosis, classification, and management. The rarity of suchcases and the variable degrees of sensitivity in detecting thecharacteristic molecular abnormality add more complexity.Detailed documentation will help confirm the existence ofsuch rare cases and further dispel the possibility that theabsence of molecular findings is a result of insufficient work-up or technical failure.

FISH is the most widely used method for the detec-tion of RARA rearrangements, as it is more sensitive thanconventional karyotyping. Detection of RARA abnormalitiesby RT-PCR is usually the next and, in most instances,the last practical step for the few suspected cases of APLthat fail FISH. There are fifteen reported cases of RT-PCRproven RARA rearrangements that failed FISH [2–6] and onereported case where RARA rearrangement was only foundupon genetic sequencing [7].

Our case presented challenges at multiple levels startingwith specimen adequacy and ending with the complexities ofdiscordance between the morphologic and immunopheno-typic findings on one hand and the molecular and geneticsresults on the other.

The initial bone marrow aspirate was suboptimal dueto extreme blood dilution resulting from a combinationof a “packed” marrow and partial marrow necrosis. Thisdemonstrates the requirement for an adequate bone marrowspecimen for proper diagnosis as AML cells may not circulatein the blood. The cell suspension obtained by disaggregatingfreshly obtained core biopsies was utilized to compensate forthis inadequacy andwas used to perform immunophenotypicanalysis by flow cytometry and genetic studies.

A diagnostic and classification dilemma arose after thefull morphologic, immunophenotypic, and genetic work-upwas completed. While classifying this case as APL is appro-priate based on the morphology and immunophenotype,this designation would open the possibility for insufficientmanagement given that the lack of RARA abnormality cor-relates with no response to all trans retinoic acid (ATRA)therapy [8]. Alternatively, it is difficult to fit this case intoanother AML subtype based on morphology, as most ofneoplastic cells are abnormal promyelocytes and not “real”

Case Reports in Hematology 5

FABClassification

of AML

2008 WHOClassification of AML

AML with recurrentcytogeneticsabnormality

AML, NOS AML,MRC

AML,therapyrelated

AML,Down

syndrome

Blasticplasmacytoiddendritic cell

leukemia

Myeloidsarcoma

M0AML, NOS, minimal

differentiation

M1 AML, NOS, withoutmaturation

M2 AML, NOS withmaturation Other M2

M3APL, RARA pos

APL, RARA neg.Other APL

M4 AML, NOSmyelomonocyticOther M4

M5 AML, NOS monocytic/monoblasticOther M5

M6 Erythroid leukemia

M7 AML, megakaryoblasticOther M7

AML, other AML, gene mutation (NPM1; CEBPA)

Normal karyotype

FAB (morphologic diagnosis)WHO (genetics/immunophenotypic/morphologic)

FAB and WHOSuggested new subtype

t(8; 21)

inv16; t(16; 16)

t(9; 11)

t(1; 22)

t(6; 9)

t(3; 3)

Figure 4: An approximate correlation between FAB and WHO 2008 classifications of AML subtypes, including suggested new subtypes“APL, NOS, and RARA negative.” FAB, French-American-British; WHO, World Health Organization; AML, acute myeloid leukemia; NOS,not otherwise specified; APL, acute promyelocytic leukemia; RARA, retinoic acid receptor alpha; MRC, myelodysplasia related changes.

myeloblasts. In fact, myeloblasts would not have reached the20% threshold needed to diagnose most AML subtypes, ifabnormal promyelocytes were not added to blast count.

Based on the facts illustrated by this case, it became evi-dent that the current WHO classification has no appropriatesubtype that would fit this case. Hence, there exists a needto create a subtype that accommodates such cases. This newcategory would help classify these rare cases in a manneranalogous to classifying cases of Myelomonocytic Leukemia(AML-M4 in French-American-British classification or FAB)[9] asAML,NOS,Myelomonocytic (inWorldHealthOrgani-zation classification or WHO), if they do not exhibit a recur-rent cytogenetic abnormality. This is also similar to the man-ner cases of (AML-M2 in FAB) are classified as AML, NOS,myeloid with maturation (in WHO) after excluding t(8;21).An approximate correlation between the subtypes of themorphology-based FAB classification and the current WHOclassification ofAML, including the suggested subtype ofAPLwith negative RARA, is shown in Figure 4. A suggested termfor the new subtype is “APL, NOS, and RARA negative.”

Suggested criteria for inclusion in this new subtype are(1) morphologic and immunophenotypic features typical ofAPL, (2) myeloblasts and abnormal promyelocytes constitut-ing aminimumof 20% of bonemarrow cells, and (3) negativeRARA by FISH and RT-PCR.

Clinically, the initial diagnostic dilemmas seen in this caseresulted in treatment plan quandary, given that treatment andprognosis for APL and AML are very different. Given thecompelling need to alleviate symptoms, it was felt thatmovingforward with induction per traditional AML therapy, whilewaiting for confirmatory testing, was the most appropriatecourse for this patient. While the patient did not have theclassical clinical findings of RARA positive APL, he did alsonot fit the typical bone marrow morphologic findings of anyother AML subtype. End of induction I bone marrow wasperformed due to slower than expected count recovery, andhe was found to have positive MRD, as described earlier inthis report. The new clinical onset of bleeding tendency andthe pathologic findings were additional reasons to give pauseand consider future treatment options. We proceeded per


high risk standard AML treatment and moved forward withstem cell transplantation.

At the genetic level, the presence of three copies ofRUNX1T1 in this case supports a malignant process; however,the significance of this finding in the context of APL is notknown. Whether the inserted gene is juxtaposed to anothergene thus altering its expression is not known.

There are a few reported cases of morphologic APL thatdescribe alternative translocations noted in the literature.Sainty et al. described work done by the European Work-ing Group in 2000, where 90 cases of morphologic APLlacking the typical translocation t(15;17) were reviewed [10].The results of the study indicated that, in the majority ofcases (49 of 67 eligible cases), the traditional PML-RARArearrangement could be identified by further moleculardetection. The other 18 cases studied included 11 cases ofmorphologic APL with a t(11;17)(q23;q21) that coded for thePLZF-RARA fusion gene. These cases differed immunophe-notypically from the traditional t(15;17) by the addition ofCD56 positivity, and, clinically, these latter cases uniformlydid not respond to ATRA therapy. One case was identifiedwith t(5;17), resulting in theNPM-RARA rearrangement withno clinical or morphologic difference to typical t(15;17) APLand 1 case of unbalanced der(5)t(5;17). In 5 cases, no RARArearrangements could be detected byRT-PCR, and thesewereunder review at time of publication.These 5 cases were felt torepresent mutations or alternations of pathways that mediatethe differentiation of cells characteristic of APL either bymutation or epigenetic changes [10].

In addition to this large working study, there have beenrare reports of other genetic alterations not including theRARA gene. A recent report by Duan et al. describes an adultpatient with isolated i(17q) without t(15;17) and with negativePML-RARA by RT-PCR exhibiting morphology consistentwith APL but responded poorly to traditional therapy [11].

Kim et al. reported one case of FISH negative APL withcryptic PML-RARA rearrangement detected by long distancePCR and noted only 12 such cases were reported in theliterature at that time [2].

To our knowledge, there is no well documented casereport of a typical APL that exhausted all levels of moleculardetection of RARA and exhibited only an insertion of mate-rial from chromosome 8q in 7q as in this case.The diagnosticand management complexities that this and similar RARAnegative cases present should justify creating a new AMLsubtype in future classification schema.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

Theauthorswould like to thankMariaNunez andFloraYazigifor their help in preparing this paper.

References

[1] J. W. Vardiman, J. Thiele, D. A. Arber et al., “The 2008 revisionof the World Health Organization (WHO) classification ofmyeloid neoplasms and acute leukemia: rationale and impor-tant changes,” Blood, vol. 114, no. 5, pp. 937–951, 2009.

[2] M. J. Kim, S. Y. Cho, M.-H. Kim et al., “FISH-negative crypticPML-RARA rearrangement detected by long-distance poly-merase chain reaction and sequencing analyses: a case study andreview of the literature,” Cancer Genetics and Cytogenetics, vol.203, no. 2, pp. 278–283, 2010.

[3] J. S. Welch, P. Westervelt, L. Ding et al., “Use of whole-genomesequencing to diagnose a cryptic fusion oncogene,”The Journalof the American Medical Association, vol. 305, no. 15, pp. 1577–1584, 2011.

[4] J. Koshy, Y.-W. Qian, G. Bhagwath, M. Willis, T. W. Kelley,and P. Papenhausen, “Microarray, gene sequencing, and reversetranscriptase-polymerase chain reaction analyses of a crypticPML-RARA translocation,”Cancer Genetics, vol. 205, no. 10, pp.537–540, 2012.

[5] A. M. Gruver, H. J. Rogers, J. R. Cook et al., “Modified array-based comparative genomic hybridization detects cryptic andvariant PML-RARA rearrangements in acute promyelocyticleukemia lacking classic translocations,” Diagnostic MolecularPathology, vol. 22, no. 1, pp. 10–21, 2013.

[6] E. M. Blanco, C. V. Curry, X. Y. Lu et al., “Cytogeneticallycryptic and FISH-negative PML/RARA rearrangement in acutepromyelocytic leukemia detected only by PCR: an exceedinglyrare phenomenon,” Cancer Genetics, vol. 207, no. 1-2, pp. 48–49,2014.

[7] C. C. Yin, N. Jain, M. Mehrotra et al., “Identification of anovel fusion gene, IRF2BP2-RARA, in acute promyelocyticleukemia,” Journal of the National Comprehensive Cancer Net-work, vol. 13, no. 1, pp. 19–22, 2015.

[8] A. Melnick and J. D. Licht, “Deconstructing a disease: RAR𝛼,its fusion partners, and their roles in the pathogenesis of acutepromyelocytic leukemia,” Blood, vol. 93, no. 10, pp. 3167–3215,1999.

[9] J.M. Bennett, D. Catovsky,M. T.Daniel et al., “Proposed revisedcriteria for the classification of acute myeloid leukemia,”Annalsof Internal Medicine, vol. 103, no. 4, pp. 620–629, 1985.

[10] D. Sainty, V. Liso, A. Cantu-Rajnoldi et al., “A newmorphologicclassification system for acute promyelocytic leukemia distin-guishes cases with underlying PLZF/RARA gene rearrange-ments,” Blood, vol. 96, no. 4, pp. 1287–1296, 2000.

[11] Y. Duan, J. Nie, Z. Zhang et al., “A rare case with typicalacute promyelocytic leukemia morphology associated withisolated isochromosome 17q without RAR𝛼 rearrangement,”Hematology/Oncology and Stem Cell Therapy, vol. 6, no. 1, pp.42–45, 2013.

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