Cancer Genetics and Cytogenetics 195 (2009) 186e188

Letter to the editor

Philadelphia chromosomeepositive blastic plasmacytoiddendritic cell leukemia

The Philadelphia chromosome t(9;22)(q34;q11.2), whilebeing the defining cytogenetic feature of chronic myeloidleukemia (CML) [1], has also been well described as a cyto-genetic abnormality associated with acute lymphoblasticleukemia (ALL) [2], mixed phenotype acute leukemia[3], and less frequently, de novo acute myeloid leukemia(AML) [4,5].

We describe the first recorded case of blastic plasmacy-toid dendritic cell leukemia with Philadelphia chromosome,as evidenced with fluorescence in situ hybrization (FISH),reverse-transcription polymerase chain reaction (RT-PCR),and cytogenetic analysis.

Our patient, a 29-year-old male, presented to his localhospital with hip pain and difficulty walking long distances,with onset after walking down a set of stairs. Upon directquestioning, he admitted to loss of appetite and a 4-kgweight loss over the last week, with associated vague, poorlylocalized abdominal pain. He denied night sweats or fevers.He had an otherwise unremarkable medical history, and wastaking no regular medications before this presentation.

Clinical examination revealed no hepatosplenomegaly,lymphadenopathy, or skin lesions, and was remarkable onlyfor localized tenderness over the right pubis.

Plain-film X-ray was performed of the hips and pelvis,which identified a 4.5-cm lytic lesion in the pubicsymphysis, extending to the right pubic ramus, associatedwith a pathologic fracture. Further imaging was performed,with computed tomographic (CT) and magnetic resonanceimaging, which identified a soft-tissue mass measuring53� 30� 40 mm involving the adductors of the right hipwith cortical bone destruction, showing gadoliniumenhancement, and a pathologically enlarged right obturatorlymph node 32� 14 mm.

After referral to our institution, he underwent biopsy ofthe lesion, which revealed a hemopoietic-appearingneoplasm with features suggestive of a natural killer(NK)-cell neoplasm or a blastic plasmacytoid dendritic cellneoplasm. A further CT-guided biopsy, lymph node biopsy,and bone marrow examination were performed, and at thistime, the previously normal biochemical parametersevolved to a rapidly rising lactate dehydrogenase, withhypercalcemia and slightly elevated uric acid, thought torepresent early tumor lysis syndrome. Hematologic param-eters were within normal ranges, except for a slight neutro-philia, and the blood film appeared normal.

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Core biopsy of the lesion and excisional biopsy of theobturator node showed infiltration by a population of cellswith irregular nuclei, fine chromatin, and multiple nucleoli.Immunohistochemical stains revealed that the cells werepositive for CD43, CD56, LCA, BCL-2, and CD30(weakly), and showed weak focal CD4 positivity. Theywere negative for CD3, CD5, CD8, CD10, CD15, CD20,CD79a, CD138, and TIA. Flow cytometry performed onthe specimen revealed two populations of blasts, the firstof which comprised 23% total cells and expressed thephenotype CD4, CD7, CD13, CD34, CD56, CD117,CD123, and were HLA-DR negative, and a second popula-tion which expressed cytoMPO, but which were CD56 andCD117 negative.

Bone marrow examination revealed hypercellular frag-ments with 12% blasts, which were characterized by theirlarge-size, high nuclear/cytoplasm ratio, deeply basophiliccytoplasm, as well as prominent, multiple cytoplasmicvacuoles. Trephine biopsy showed an interstitial infiltrateof immature cells, mild myeloid hyperplasia, and preserva-tion of erythroid and megakaryocytic lineages. Flow cy-tometry revealed that the blast population expressed CD4,CD13, CD33, CD34, CD56, CD117, and CD123, and wereHLA-DR and MPO negative.

Cytogenetic analysis of the lymph node and bone marrowrevealed a complex karyotype: 16/20 dividing cells showeda hypotriploid cell line with 58 chromosomes, includingtrisomies 7, 10, 12, 13, 14, 15, and 21; tetrasomy 8 and 19;additional material attached to chromosome 1; a t(9;22), re-sulting in the Philadelphia (Ph) chromosome and one extracopy of the Ph chromosome. The karyotype was:58,XY,add(1)(p34),þ7,þ8,þ8,t(9;22)(q34;q11.2),þ10,þ12,þ13,þ14,þ15,þ19,þ19,þ21,der(22)t(9;22) (Fig. 1), andwas annotated according to the International System ofHuman Cytogenetic Nomenclature (ISCN 2005) [6].58,XY,add(1)(p34),þ7,þ8,þ8,t(9;22)(q34;q11.2),þ10,þ12,þ13,þ14,þ15,þ19,þ19,þ21,der(22)t(9;22)] (Fig. 1), andwas annotated according to the International System ofHuman Cytogenetic Nomenclature (ISCN 2005) [6].

Fluorescence in situ hybrization studies using the BCR/ABL dual-fusion probe showed two fusion signals in 60/100 interphase cells, and three fusion signals in 26/100interphase cells, consistent with the extra copy of the Phil-adelphia chromosome detected cytogenetically and sugges-tive of clonal evolution. Molecular analysis by RT-PCR

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Fig. 1. Full karyogram showing t(9;22), marked with arrows, in addition to other abnormalities.

187Letter to the editor / Cancer Genetics and Cytogenetics 195 (2009) 186e188

confirmed the existence of the BCR-ABL1 transcript, withboth b2a2 and b3a2 transcripts detected.

The patient was started on induction chemotherapy,and while pancytopenic, he developed febrile neutropeniawith no source identified. Empirical antibiotic therapywas started, but the patient developed severe bilateralleg pain, initially with no associated signs upon clinicalexamination and resistant to analgesia. Over the courseof several hours, the patient became progressively moreunwell, with signs of cardiovascular shock that requiredICU admission and a noradrenaline infusion to maintainblood pressure. The cause of the leg pain subsequentlydeclared itself, upon demonstration of crepitation onpalpation of the legs, and pale, pulseless, anaesthetizedcalves and feet. Bilateral compartment syndrome wasdiagnosed secondary to clostridial necrotizing fasciitis.The rapidly ascending crepitus, with associated ultrasoundevidence of gas tracking to the level of the inguinal liga-ment was deemed too extensive for surgical intervention,and palliative measures were instituted. The patient diedwithin 2 hours.

Blastic plasmacytoid dendritic cell leukemia/lymphomais an uncommon disease, representing less than 1%leukemia/lymphoma cases, with an aggressive clinicalcourse [7]. Diagnosis relies on the demonstration of co-expression of CD4þ, CD56þ, and CD123þ in the absenceof any specific myeloid, B-, T-lymphoid, or NK lineagemarkers [8]. Although complex karyotypes are common,

and several major recurrent chromosomal abnormalitieshave been recognized [9], to our knowledge, this is the firstcase reported to have the Philadelphia chromosome associ-ated with blastic plasmacytoid dendritic leukemia.

Acknowledgments

The authors are grateful to Professor Barbara Bain forher insights and encouragement to document this case.

Rebecca L.C. AdamsHematology RegistrarPathology Queensland

Princess Alexandra HospitalIpswich Road

Woolloongabba QLD 4102Australia

Tel.: þ61 7 3240 2166; fax: þ61 7 3240 7042E-mail address: Rebecca_l_adams@health.qld.gov.au

Catherine McCarthyCytogenetics Laboratory

Pathology QueenslandRoyal Brisbane and Womens Hospital

Herston QLD 4006Australia

Tel.: þ61 7 3636 8582E-mail address: Catherine_mccarthy@health.qld.gov.au

188 Letter to the editor / Cancer Genetics and Cytogenetics 195 (2009) 186e188

Robert J. BirdHematology Department

Pathology QueenslandPrincess Alexandra Hospital

Ipswich RoadWoolloongabba QLD 4102 Australia

Tel.: þ61 7 3240 2425; fax: þ61 7 3240 7042E-mail address: Robert_bird@health.qld.gov.au

References

[1] Nowell P, Hunderford D. A minute chromosome in human chronic

granulocytic leukemia. Science 1960;132:1497.

[2] Radich JP. Philadelphia chromosome-positive acute lymphocytic

leukemia. Hematol Oncol Clin North Am 2001;15:21e36.

[3] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H,

Thiele J, Vardiman JW, editors. WHO Classification of Tumors of

Haemopoietic and Lymphoid Tissues. Lyon: International Agency

for Research on Cancer, 2008.

[4] Mitelman F. Johannson B, Mertens F, editors. Mitelman Database of

Chromosome Aberrations in Cancer. 2009. Available at: http://www.

cgap.nci.nih.gov/Chromosomes/Mitelman. Accessed on 6 June 2009.

[5] Huret J-L, editor. Atlas of genetics and Cytogenetics in Oncology and

Haematology. 2009. Available at: Ghttp://www.atlasgeneticsoncology.

org. Accessed on 6 June 2009.

[6] ISCN. In: Shaffer LG, Tommerup N, editors. An International System

for Human Cytogenetic Nomenclature. Basel: S. Karger, 2005.

[7] Jacob MC, Chaperot L, Mossuz P, Feiullard J, Valensi F,

Leroux D, Bene MC, Bansa JC, Briere F, Plumas J. CD4 þCD56þ lineage negative malignancies: a new entity developed

from malignant early plasmacytoid dendritic cells. Haematologica

2003;88:941e55.

[8] Garnache-Ottou F, Feuillard J, Saas P. Plasmacytoid dendritic cells

leukaemia/lymphoma: towards a well defined entity? BJH 2007;136:

539e48.

[9] Leroux D, Mugneret F, Callanan M, Radfor-Weiss I, Dastugue N,

Feuillard J. CD4(þ) CD56(þ) DC2 acute leukaemia is characterised

by recurrent clonal chromosomal changes affecting 6 major targets:

a study of 21 cases by the Groupe Francais de cytogenetique Hemato-

logique. Blood 2002;99:4154e9.