Aa
Ya
b
c
d
e
a
ARRAA
KALB
1
1ptCa[pWppohsf
CT
0d
Leukemia Research 34 (2010) 475–482
Contents lists available at ScienceDirect
Leukemia Research
journa l homepage: www.e lsev ier .com/ locate / leukres
LK-negative anaplastic large cell lymphoma with extensive peripheral bloodnd bone marrow involvements manifested as “leukemic phase”
ing Lua,b, Xiaohui Zhaoa,c, Endi Wangd, Wei Chena,e, Qin Huanga,∗
Department of Pathology, City of Hope National Medical Center, Duarte, CA, United StatesDepartment of Hematology, Ningbo NO 1 Hospital, Ningbo, PR ChinaDepartment of Pathology, University of California, Irvine, CA, United StatesDepartment of Pathology, Duke University Medical Center, Durham, NC, United StatesSir Run Run Hospital, Zhejiang University College of Medicine, PR China
r t i c l e i n f o
rticle history:eceived 18 June 2009eceived in revised form 20 July 2009ccepted 22 July 2009vailable online 19 August 2009
eywords:
a b s t r a c t
CD30-positive anaplastic large cell lymphoma (ALCL) is a distinctive malignant large cell lymphomaof T-cell lineage, often presenting in lymph node or extranodal sites. ALCL cases with extensive bonemarrow and peripheral blood involvement manifested as “leukemic phase” are extremely rare and themost of those cases reported are anaplastic large cell lymphoma kinase (ALK) positive ALCL in childhoodpopulation. Here we report four adult cases of ALK-negative ALCL with extensive bone marrow andperipheral blood involvement manifested as “leukemic phase”. Circulating large lymphoma cells varied
naplastic large cell lymphomaeukemic phaseone marrow and blood
from 20 to 80% in peripheral blood and bone marrow biopsy showed various nodular or interstitialinfiltrates. By reviewing the clinicopathologic data of previously reported ALCL cases with extensivebone marrow and peripheral blood involvement, there appears to be of large variations in regard tothe patient’s age, morphologic variants, immunophenotypic or genotypic characteristics of the disease.While most cases of ALCL with peripheral blood and bone marrow involvement were ALK-positive orcarrying t(2;5) translocation, rare ALK-negative cases were also present. Leukemic ALCL patients usually
osis, r
have unfavourable progn. Introduction
Anaplastic large cell lymphoma (ALCL) was first described in985 as a neoplasm of highly pleomorphic lymphoid cells in aredominantly sinusoidal pattern involved in lymph nodes [1]. Vir-ually all tumor cells were subsequently found to strongly expressD30 antigen and a high percentage of them was identified to haven unique, balanced chromosomal translocation t(2;5)(p23;q35)2,3]. It was recognized as a distinct entity of mature T-cell lym-homa with T- or null-cell immunophenotype by the most recentorld Health Organization (WHO) classification [4]. ALCL com-
rises approximately 3% of all non-Hodgkin’s lymphomas. Therimary systemic ALCL cases commonly involve lymph nodes, with
r without involvement of a variety of extranodal sites. The diseaseas a bimodal age distribution with one peak in children and theecond in older adults [4]. Morris et al. [5] identified a NPM/ALKusion gene, as a consequence of t(2;5) translocation, which results∗ Corresponding author at: Division of Pathology, City of Hope National Medicalenter, 1500 East Duarte Road, Duarte, CA 91010, United States.el.: +1 626 359 8111x62037; fax: +1 626 301 8463.
E-mail address: [email protected] (Q. Huang).
145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.oi:10.1016/j.leukres.2009.07.034
egardless of ALK expression.© 2009 Elsevier Ltd. All rights reserved.
in a translation of an unique chimeric NPM/ALK protein with alteredtyrosine kinase activity. A monoclonal antibodies specific to ALKprotein can be used diagnostically, thus leading to the definitionof this distinctive entity with important clinical and prognosticimplications [6].
Although ALK-positive ALCL has been studied extensively[7–10], approximately 15–20% of systemic ALCL cases are ALK-negative [6], which is less well characterized. Unlike a distinctiveALK-positive ALCL entity, those ALK-negative ALCL cases are con-sidered to be more heterogeneous based on their clinical andepidemiologic features [6]. It is morphologically composed of largerand more pleomorphic cells with some characteristic “hallmark”cells, which are either T- or null-cell immunophenotype, and areuniformly positive for CD30. The older median age and moreaggressive clinical course of ALK-negative ALCL compared to ALK-positive ones support the notion that they may represent twodifferent clinical and pathologic entities, as defined by the current2008 WHO classification [4].
ALCL cases with extensive bone marrow and peripheral bloodinvolvement manifested as “leukemic phase” are extremely rareand have been occasionally reported with the majority being ALK-positive ALCL cases in pediatric population [11–14]. We report herefour adult cases of ALK-negative ALCL with extensive peripheral
476 Y. Lu et al. / Leukemia Research 34 (2010) 475–482
Table 1Clinical features of the current ALK-negative ALCL cases with extensive bone marrow and peripheral blood involvements.
Case no. Age/sex Initial symptoms Site of involvement Therapies Time to relapse (months) Survival (months)
1 46/M Fever, fatigue, headache LN, BM, PB, CSF CHOP 3 52 38/M Groin cyst LN, BM, PB, CHOP N/A 313 61/F Fever, fatigue, weight loss, LN, BM, PB, spleen, liver CHOP, APBSCT N/A >18
en
L id; CHp
bmcTv
2
2
psvdpcWbt
2
stitFi(E(sawdimRC
TP
I
4 46/M Thrombocytopenia LN, BM, PB, sple
N: lymph node; BM: bone marrow; PB: peripheral blood; CSF: cerebral spinal flueripheral blood stem cell transplant; N/A: not available.
lood (>20% circulating lymphoma cells) and bone marrow involve-ent. One case also showed leptomeningeal spreading, complex
ytogenetic karyotypes and associated with short survival time.his is the first report of ALK-negative ALCL case with central ner-ous system involvement.
. Materials and methods
.1. Clinical case selection and the literature review
Four cases of anaplastic large cell lymphoma with extensive bone marrow anderipheral blood involvement manifested as “leukemic phase” were identified byearching pathology files from City of Hope National Medical Center and Duke Uni-ersity Medical Center. ALCL cases with “leukemic phase” in the current study areefined as more than 20% circulating lymphoma cells of total white blood cells ineripheral blood specimens. ALCL cases with less than 20% circulating lymphomaells were excluded. The pathologic diagnosis was made according to the most recent
HO classification [4]. In addition, we also reviewed ALCL cases with peripherallood and bone marrow involvement manifested as “leukemic phase” reported inhe literature.
.2. Histomorphologic and immunophenotypic studies
Peripheral blood smears, bone marrow aspirate and tough preparations weretained with standard Wright–Giemsa staining (WG) for morphologic examina-ion. Tissue biopsy specimens of lymph nodes and bone marrow core were fixedn formalin and then rapidly decalcified. The specimens were then processed rou-inely, embedded in paraffin, and stained with hematoxylin and eosin (H&E) stain.or immunohistochemistry, 4-�m sections from paraffin-embedded blocks weremmunostained with ALK (1:100, Dako Corporation, Carpinteria, CA, USA), CD31:800, Dako), CD20 (1:40, Novacastra, Burlingame, CA, USA), CD30 (1:2000, Dako),MA (1:40, Boehringer Mannheim Biochemica, Indianapolis, IN, USA), granzyme B1:50, Monosan, USA), and perforin (1:30, Vector, Burlingame, CA, USA), using thetreptavidin–biotin complex method with automated staining equipment (Dakoutostainer; Dako, Carpinteria, CA, USA). In Case 1, cyto-spin of CSF was stained
ith Wright–Giemsa (WG) and brain tissue was fixed in formalin and then embed-ed in paraffin, and stained with hematoxylin and eosin (H&E) stain. In two cases,mmunophenotyping was performed by four-color flow cytometric analysis of bonearrow aspirate with a Coulter Epics XL cytometer (Beckman Coulter, Miami, FL).
elated flow cytometry panels were followed: CD2, CD3, CD4, CD5, CD7, CD8, CD10,D19, CD20, CD22, CD34, CD33, and CD45.
able 2athologic features of the current ALK-negative ALTL cases with extensive bone marrow
Case no. CBC Circulating lymphoma cells Immnod
1 WBC 7.6 × 109/L, Hb 104 g/L,Plt 27 × 109/L
Large cells 40% IHCCD2
2 WBC 110 × 109/L, Hb 76 g/L, Plt29 × 109/L
Large cells 50% IHCCD3CD4CD1
3 WBC 22.3 × 109/L, Hb 89 g/L,Plt 163 × 109/L
Large cells 20% IHCCD3CD4
4 WBC 7.1 × 109/L, Hb 120 g/L,Plt 183 × 109/L
Large cells 80% IHCCD3ALK
HC: immunohistochemistry; FC: flow cytometry.
CHOP 2 2
OP: cyclophosphamide, adriamycin, vincristine, prednisone; APBSCT: autologous
2.3. Cytogenetic analysis
Cytogenetic analysis was performed on peripheral blood or bone marrow spec-imens using standard techniques. GTG banding was used to identify the individualchromosomes.
3. Results
3.1. Clinical features of the present cases
The clinical features of the present four “leukemic phase” ALCLcases were summarized in Table 1. They were included one femaleand three male patients, all adults, with a median age of 48 years.Two patients presented with B symptoms such as fever, fatigueand weight loss, while Case 4 initially presented with thrombo-cytopenia. All of them had lymphadenopathy with various butextensive peripheral blood and bone marrow involvement. Case1 also had severe headache and the cytology of lumbar puncturedemonstrated central nervous system involvement by lymphomacells. Case 3 and Case 4 presented with splenomegaly, suggestingALCL involvement at initial diagnosis. All 4 patients had receivedCHOP based chemotherapy and three of them failed to have goodresponse. Case 1 and Case 4 were expired within 6 months after ini-tial diagnosis, Case 2 had an initial response after chemotherapy,but did not reach complete clinical remission. Case 3 appeared tohave good response to chemotherapy, but was lost in follow-up 18months after initial diagnosis, right after an autologous stem celltransplant (Table 1).
3.2. Cytomorphologic and immunophenotypic findings of thepresent cases
The lymph node biopsies in all four cases showed sheets or largeclusters of pleomorphic cells in a characteristic sinusoidal pattern inthe lymph nodes. Many large anaplastic cells contained large irreg-ular nuclear contours and often harbored eccentric kidney shapenuclei, consistent with so-called hallmark cells (Fig. 1A and D).
and peripheral blood involvements.
unophenotype (on lymphe or bone marrow)
Cytogenetics (bone marrow)
: CD30+, EMA focal+, CD3+,0−, ALK−
LN(CC): 86–93, X, +X, Y, del(1) (p32)×2,add(3)(p21)×2, del(6)(q21)×2, −7,add(7)(q32)×2, +8, −9, −10, −11,? del(12q),add(19)(p13.3), add(19)(q13.4), −20, +7,−10mar[cp10]/46, XY[18]
: CD30+, CD45+, CD4+,+, ALK−; FC: CD4+, CD5+,5+, CD7−, CD8−, CD10−,9−, CD20−, CD22−
46, XY
: CD30+, CD2+, CD4+,−, CD5−, CD7−, ALK−; FC:+, CD2+, CD7−, CD5−
N/A
: CD30+, CD2+, CD45+,−, CD5−, CD7−, EMA−,−
46, XY
Y. Lu et al. / Leukemia Research 34 (2010) 475–482 477
Fig. 1. Morphologic and immunophenotypic features of ALK-negative leukemic ALCL cases (Case 2 and Case 3). (A) Case 2: histologic sections of the lymph node biopsyshowing diffuse infiltrates of large, anaplastic lymphoma cells (H&E, 400×); (B) Case 2: histologic sections of the bone marrow biopsy showing extensive infiltrates ofl (H&Ea of thec owingb ×).
ToTcTb8sitaaiecc
arge lymphoma cells admixed with some hematopoietic cells in the marrow spacenaplastic lymphoma cells (Wright–Giemsa, 600×); (D) Case 3: histologic sectionsharacteristic sinusoid pattern (H&E, 200×); (E) Case 3: immunohistochemistry shlood smears showing numerous circulating lymphoma cells (Wright–Giemsa, 600
he peripheral blood smears of each cases demonstrated numer-us circulating anaplastic lymphoma cells (Figs. 2A, 1C and 1F).hese cells were large in size and had lobulated or irregular nuclearontours, lacy to clumped chromatin, and conspicuous nucleolus.he cytoplasm of those cells was moderate to abundant and deeplue. Circulating lymphoma cells in those cases varied from 20 to0% of total white blood cells. The bone marrow biopsies demon-trated extensive involvement with various nodular or interstitialnfiltrates (Fig. 2B). The large neoplastic cells in bone marrowrephine biopsies had pleomorphic nucleoli, some with lobatednd binucleated nuclei, condensed chromatin and intermediate to
bundant cytoplasm. Occasional “hallmark cells” were also seenn admixed with small lymphocytes, histiocytes and hematopoi-tic cells. Mitotic figures were frequently seen (Fig. 1B). In Case 1,erebral spinal fluid contained many pleomorphic large lymphoidells with anaplastic morphology (Fig. 2C). These large atypical cells, 400×); (C) Case 2: peripheral blood smears showing numerous circulating large,lymph node biopsy showing large, anaplastic lymphoma cells in lymph node withlarge, anaplastic lymphoma cells positive for CD30 (400×); (F) Case 3: peripheral
showed similar morphology as described in the peripheral blood.Autopsy findings of this particular case demonstrated that therewere multiple foci of leptomeningeal involvement by anaplasticlarge cell lymphoma, which was further confirmed by positiveparaffin immunohistochemical staining with anti-CD30 antibody(data not shown).
Immunohistochemical studies of the bone marrow core biopsiesdemonstrated that all four cases had strong CD30 expression withcharacteristic nuclear and membranous staining (Figs. 2D and 1E)but all negative for ALK protein expression by immunohistochem-istry. The neoplastic cells in one of the cases were positive for
EMA and two of the cases were positive for CD3 and CD2. Thecytotoxic associated antigens including granzyme B and perforinwere positive in lymphoma cells of Case 1 (Fig. 2E and F). In Case2 and Case 3, flow cytometry demonstrated these two cases haveimmunoprofile consistent with neoplastic T-cells. The histologic
478 Y. Lu et al. / Leukemia Research 34 (2010) 475–482
Fig. 2. Morphologic and immunophenotypic features of ALK-negative leukemic ALCL (Case 1). (A) Peripheral blood smears showing numerous circulating large, anaplasticlymphoma cells with lobulated nuclei (Wright–Giemsa, 1000×); (B) histologic sections of the bone marrow biopsy showing extensive infiltrates of lymphoma cells withadmixed small lymphocytes and myeloid cells in the marrow space (H&E, 400×); (C) cyto-spin of CNS fluid showing numerous anaplastic lymphoma cells (Wright–Giemsa,4 oma cc a cel
aeaa
3
afd++fi
00×); (D) immunohistochemistry of the marrow showing large, anaplastic lymphells positive for perforin (400×); (F) immunohistochemistry showing the lymphom
nd immunophenotypic findings (characteristic hallmark cells andxtensive expression of CD30 and cytotoxic associated antigens)re diagnostic of anaplastic large cell lymphoma, ALK-negative, inll four cases (Table 2).
.3. Cytogenetic findings of the presenting cases
Normal karyotypes were identified in two cases (Case 2nd Case 4) by conventional chromosomal analysis. Case 1 was
ound having a complex karyotype as follows: 86–93, X, +X, Y,el(1)(p32)×2, add(3)(p21)×2, del(6)(q21)×2, −7, add(7)(q32)×2,8, −9, −10, −11,? del(12q), add(19)(p13.3), add(19)(q13.4), −20,7, −10mar[cp10]/46, XY[18]. No t(2;5) translocation was identi-ed.ells positive for CD30 (200×). (E) immunohistochemistry showing the lymphomals positive for granzyme B (400×).
4. Discussion
ALCL is an aggressive lymphoproliferative disorder that fre-quently presents with disseminated disease and extranodalinvolvement [16]. Bone marrow involvement was initially consid-ered very uncommon in early studies of this tumor [17,18], butis increased significantly (up to 30%) when immunohistochemi-cal stains for CD30, EMA and ALK are used [24]. Bone marrowinvolvement of ALCL cases has been most frequently seen in ALK-positive ALCL in childhood population [22,27]. However, ALCL cases
with extensive involvement of the bone marrow and peripheralblood manifested as “leukemic phase” (>20% circulating lymphomacells) were considered to be extremely rare and mostly describedas single case reports [13–15]. Nearly all the leukemic ALCL casesreported in the literature were ALK-positive ALCL and mostly seen
Y.Luet
al./Leukemia
Research
34(2010)
475–482479
Table 3Summary of reported leukemic ALCL cases with extensive bone marrow and peripheral blood involvements in the literature.
Source, yearand case no.
Age/sex CBC Site ofinvolvement
Cell type inperipheralblood
Immunophenotype(on LN, PBor BM)
CC and MS Time to relapse(months)
Survival(months)
Wong et al.[17], 1991 Case5
30/F WBC 13.2 × 109/L, Hb117 g/L, Plt 201 × 109/L
LN, BM, PB Intermediate to large cells CD30+, B-cell and T-cell markers NT 1 7
Tamura et al.[18], 1994 Case6
77/F N/A BM, PB Many large cells “leukemicphase”
PB: CD30+, CD25+, HLADR+, CD3+,CD4−, CD8−
NT N/A N/A
Anderson et al.[13], 1996 Case7
36/M WBC 106 × 109/L, Plt82 × 109/L
LN, BM, PB, pleural, CSF, spleen 20% large cells CD30+, EMA+, CD3−, CD20−,CD43−, CD45−; PB: CD2+, CD11c+,CD30+, CD3−, CD5−, CD7−
PB(CC): 46, Y, ADD(X)(p22),t(2;5)(p23;q35); PB(MS): TCR �rearrangement
N/A 4
Villamor et al.[15], 1999 Case8
36/M WBC 21.3 × 109/L LN, PB, liver, spleen 47% small and 4% largeabnormal lymphocytes
CD30+, EMA+, CD3+, CD2+, CD7+,CD8+, CD43+, CD45+, ALK+ in bothlarge and small cells
LN, PB(MS): NPM/ALK+ (RT-PCR) 2 N/A
Bayle et al. [14],1999 Case 9
10/F WBC 54.8 × 109/L, Hb110 g/L, Plt 337 × 109/L
LN, PB 38% lymphocytes with 28%atypical cells
LN: CD45RO+, CD30+, EMA+, ALK+,CD7+, CD3−, CD4−, CD8−
BM(CC): t(2;5)(p23;q35),add10(q26), add16(p13); PB(MS):NPM/ALK+ (Southern)
1.5 >22
Bayle et al. [14],1999 Case 10
18/F WBC 15 × 109/L, Hb 98 g/L,Plt 31 × 109/L
LN, skin, PB 61% lymphocytes with 90%atypical cells
LN: CD30+, EMA+, ALK+, CD7+,CD3+, CD8+; PB: CD2+, CD7+, CD8+,CD3−, CD4−
BM(CC): 46, XX (limited cells);LN(CC): no t(2;5)(p23;q35); BM, PB(MS): TCR rearrangement
2 >18
Bayle et al. [14],1999 Case 11
1.2/F WBC 37.9 × 109/L, Hb97 g/L, Plt 187 × 109/L
LN, liver, spleen 72% lymphocytes with 90%atypical cells
CD45RO+, CD30+, EMA+, ALK+,CD7−, CD3−, CD8−
BM, PB(CC): t(2;5)(p23;q35), 7+;BM, PB(MS): no TCR rearrangement
1 Few
Bayle et al. [14],1999 Case 12
7/M WBC 23.1 × 109/L, Hb103 g/L, Plt 591 × 109/L
LN, skin 22% lymphocytes with 8%atypical cells
CD30+, EMA+, ALK+, CD7−,CD3−/+, CD4−, CD8−
LN(CC): t(2;5)(p23;q35), 47, XXY;PB(MS): NPM/ALK+ (RT-PCR)
N/A >2
Awaya et al.[19], 2002 Case13
63/M WBC 118 × 109/L, Hb134 g/L, Plt 86 × 109/L
BM, PB 71% lymphocytes BM: ALK+, CD30+ in large cells andrare small cells; PB: CD2+, CD3+,CD4+, CD5+, CD7+, CD11b+, CD57+,HLADR+, CD30+ in rare cells, ALK−,CD8−
LN(CC): t(2;5)(p23;q35), 47, XXY;PB(MS): NPM/ALK+ (RT-PCR)
N/A 4
Onciu et al.[28], 2003 Case14
6/F WBC 216 × 109/L Bilateral kidney, lung (diffuse) Small cells 55% CD45RO+, CD2+, CD4+, CD7+,CD16+, CD30+, ALK+
46, XX, t(2;5)(p23;q35),del(10)(q24)[17]/46, idem,−del(10)(q26), +add(10)(q26)[3].NPM/ALK+ (RT-PCR)
N/A >17
Onciu et al.[28], 2003 Case15
9 M/F WBC 35 × 109/L, Hb106 g/L, Plt 417 × 109/L
Lung (diffuse), skin, liver, Small cells 35% CD2+, CD3+, CD4+, CD7+, CD8+,CD30+, ALK+, CD5−
Derivative 2, 5, and 20 8 9
Onciu et al.[28], 2003 Case16
10/M WBC 150 × 109/L, Hb90 g/L, Plt 30 × 109/L
CNS Large cell 60% CD30+, CD4+, CD7+, CD8+, ALK+ t(2;5)(p23;q35) NPM/ALK+(RT-PCR)
N/A 24
Monaco et al.[29], 2007 Case17
13/M WBC 39.5 × 109/L BM, PB Small to medium cells CD45+, CD30+, EMA+, CD56+,CD43+, ALK+, CD3−, CD5−, CD4−,CD8−
t(2;5)(p23;q35) andt(3;8)(q26.2;q24) NPM/ALK+(RT-PCR)
N/A 6
Takahashi et al.[30], 2008 Case18
10/M WBC 26.2 × 109/L, Hb106 g/L, Plt 41 × 109/L
Liver, spleen, pleural, ascites Large cells 50% CD2+, CD3+, CD7+, CD56+, CD45+,CD30+, ALK+
t(4;11)(p12;p15),der(10;18)(q10;q10), +18,t(2;5)(p23;q35)
N/A 2
480Y.Lu
etal./Leukem
iaR
esearch34
(2010)475–482
Table 3(Continued)
Source, yearand case no.
Age/sex CBC Site ofinvolvement
Cell type inperipheralblood
Immunophenotype(on LN, PBor BM)
CC and MS Time to relapse(months)
Survival(months)
Matsushita etal. [32], 2008Case 19
81/M WBC 26.5 × 109/L, Hb94 g/L, Plt 156 × 109/L
Liver, lung, BM Large cells 10% CD2+, CD3+, CD7+, CD8+, CD30+,ALK+
47, XY, +X, t(2;5) (p23;q35),der(10) t(1;10) (q23;q24) [20]
2d
Grewal et al.[31], 2007 Case20
29/M WBC 81.3 × 109/L, Hb153 g/L, Plt 210 × 109/L
BM, Liver, spleen, pleura, CNS Rare large cells CD2+, CD3+, CD5+, CD7+, CD8+,CD30+, CD45+, EMA+, ALK+
46, XY, t(2;5)(p23;q35)[5] and 47,idem, +X[5]
5 8
Grewal et al.[31], 2007 Case21
11/M WBC 26.5 × 109/L, Hb94 g/L, Plt 156 × 109/L
BM, liver, spleen Small cells CD2+, CD3+, CD5+, CD7+, CD43+,CD30+, CD45+, EMA+, CD4+, ALK+
46, XY, t(2;5)(p23;q35)[12], 46–47,idem, +7, +19[cp2]. 46, XY,t(2;5)(p23;q35), der(2),t(2;18)(p23;q11.2), +7,add(17)(p11.2), −18[15]
2 3
Grewal et al.[31], 2007 Case22
59/F WBC 26.5 × 109/L, Hb94 g/L, Plt 156 × 109/L
BM, liver, spleen, lung, kidney Intermediate large cells CD3+, CD7+, CD13+, CD30+, CD45+,ALK+
46, XX, t(2;5)(p23;q35) and 46, X,add(X) (p22.1), t(2;5)(p23;q35)
1 1
Kong et al. [34],2007 Case 23
32/F WBC 76.4 × 109/L, Plt326 × 109/L
LN, BM, liver, spleen, pleura, CNS Small cells CD2+, CD3+, CD5+, CD7+, CD30+,ALK+
46, XX, t(2;5;13)(p23;q35;q14)[6]/46, idem,add(19)(q13.3)[3]/46, XX[14]
2 2
Nguyen et al.[37], 2009 Case24
26/M WBC 529 × 109/L, Plt174 × 109/L
LN, BM Small cells CD4+, CD5+, CD30+, EMA+, ALK+ 46, XY, t(2;5)(p23;q35),add(18)(q21)
2.5 2.5
Meech et al.[35], 2001 Case25
1.5/M WBC 11 × 109/L, Hb100 g/L, Plt 281 × 109/L
BM, liver, spleen, pleura Small cells CD13+, CD25+, CD30+, CD45+,CD45RO+, HLA−DR+, CD56+ ALK+,EMA+, CD3−
46, XY, t(2;19)(p23;p13.1),der(5)t(5;19)(p15.3;q13.1) TPM4−,ALK+ (RT-PCR)
>14 >14
Dalal et al. [36],2005 Case 26
52/M WBC 15.5 × 109/L, Plt145 × 109/L
Skin, LN, liver, spleen, Large cells CD2+, CD8+, CD45+, CD30+, CD25+,CD43+, CD38+, granzyme B+, ALK−,CD3−, CD20−
Complex karyotypic abnormalitywith involvement of chromosomes1, 2, 5, 7, 8, and 15. However, herewas no evidence of the t(2;5)translocation
N/A N/A
esear
iwnarwluaes
ftnaaaTsvsawp
cAppAtdR(Agtulcrc
iaAradootips3cbar1
mhi
Y. Lu et al. / Leukemia R
n pediatric patients, except one leukemic ALK-negative ALCL caseas described [36]. We report here four unusual leukemic ALK-egative ALCL cases, which may represent an uncommon group indult population with extensive peripheral blood and bone mar-ow involvement. The diagnosis of ALK-negative ALCL in our casesas clearly made by the combination of characteristic morpho-
ogical features of neoplastic cells (hallmark cells), the strong andniform CD30 expression and positivity for the cytotoxic associatedntigens (granzyme B and perforin), which could be easily differ-ntiated from those of peripheral T-cell lymphoma, not otherwisepecified (PTCL-NOS).
The current ALCL cases studied showed some clinicopathologiceatures as follows: first, they were all ALK-negative ALCL cases inheir late stage, with involvements of both lymph nodes and extra-odal sites including peripheral blood, bone marrow, spleen, liver,nd central nervous system. Second, two cases presented moder-te and high leukocytosis, indicating that these leukemic ALCL casesre frequently associated with increased in white blood cell count.hirdly, the histologic features of these four leukemic cases demon-trated classic ALCL cellular morphology rather than its small cellariant. Finally, the outcome in our cases (two of them had veryhort survival and one failed to have good response to chemother-py) was relatively poor, suggesting that those ALK-negative ALCLith “leukemic phase” is often associated with a unfavourablerognosis.
Because of the rarity of such leukemic presentation in ALCLases, the reasons that why they are seen mostly in ALK-positiveLCL rather than ALK-negative ALCL cases have not emerged. Oneossible explanation is that the majority of ALCL cases are ALK-ositive, while ALK-negative ALCL cases are relatively uncommon.n alternative explanation is that as defined by the WHO classifica-
ion, ALK-positive and ALK-negative ALCL cases may represent trulyifferent entities with different clinical and pathologic features.ecently, gene expression and comparative genomic hybridizationCGH) studies have established that ALK-positive and ALK-negativeLCL lymphomas have their unique gene expression signatures andenomic imbalances, further supporting that they belong to dis-inct entities at a molecular and genetic level [33]. To have a betternderstanding of the clinical and pathologic features of ALCL with
eukemic phase within these two entities, we also reviewed thelinicopathologic data of all well-documented leukemic ALCL caseseported in the literature (Table 3), and compared it to that of theurrent four cases.
Interestingly, 19 out of 22 (86.3%) leukemic ALCL patientsncluded in the review (the data of case 5 and case 6 was unavail-ble while case 26 was ALK-negative)(Table 3) were ALK-positiveLCL and they had a mean age of 28.5 years with a male/femaleatio of 12/7. These age and sex features fall in the pediatric,dolescent, and young adult age groups with a marked male pre-ominance as described by previous studies [7,20]. In contrast, 4ut of 5 ALK-negative leukemic ALCL cases were over 45-year-ld, with a median age of 48.6 years, which is consistent withhe notion that ALK-negative ALCL cases occurs most commonlyn relatively older ages [4]. Furthermore, it is reported that ALK-ositive ALCL patients have longer failure free survival and overallurvival than ALK-negative ALCL patients (5 years OS: 70–80% vs.3–49%) [27]. However, in our review including the present fourases, ALCL patients with extensive bone marrow and peripherallood involvement manifested as “leukemic phase” revealed over-ll poor prognosis regardless of ALK expression. The survival timeanged from 1 to 31 months with the majority being less than
year.Based on the available data, all leukemic ALCL patients showedoderate anemia with variable platelets counts. Most patients
ad mild to moderate leukocytosis and more than 20% circulat-ng ALCL lymphoma cells at their initial presentation or during the
ch 34 (2010) 475–482 481
disease course (Table 3). The histologic features of those leukemicALCL cases in our review include the common type, monomorphic,sarcomatoid, giant cell-rich, small cell variant, lymphohistiocyticvariant, and Hodgkin’s-like ALCL [7,19]. The common type con-stitutes 75% or more of the cases [23]. In the present four casesas well as several other reported cases, the neoplastic cells inthe peripheral blood were large cells with characteristic anaplas-tic morphology, which correspond to the cell types found intheir respective lymph nodes and bone marrows. Eight leukemicALK-positive cases revealed a prominent component of small atyp-ical lymphoid cells, belonging to the small cell variant of ALCLcases [12,14,15,21,28,34,35,37]. In particular, it was reported thatthe small cell variant of ALCL had a tendency to be associatedwith a leukemic picture and the patients with small-cell variantsappeared to have a worse prognosis than that of common type ALCL.[11,13,14]. But in our review, it seems that there is no significant dif-ference of survival between the common type and small cell variantin leukemic ALCL cases, indicating that the prognostic significancesof ALCL with different morphologic variants need to be furtherinvestigated.
Immunophenotypic analysis is extremely useful and required inthe accurate diagnosis of ALCL [7]. The hallmark of ALCL is definedby strong expression of CD30, though it is not specific. By defini-tion, ALCL is of T-cell origin [25]. However, the cells may exhibitnull-cell phenotype or an aberrant phenotype with loss of many ofthe T-cell associated antigens [26]. In our review and the presentcases, all the cases had CD30 expression and the majority of themhad CD2 and CD4 positivity, which is consistent with the notion inthe literature [6]. It is reported that CD3 which is the most widelyused pan T-cell marker, is negative in more than 75% of the T/nullALCL cases, and CD7 are often negative in these cases as well [4],However, in our study, it is interesting to note that over half ofthe cases (13/25) showed CD3 positivities and most patients in thisgroup showed relatively older age and poorer prognosis than thosewith CD3 negative phenotype. We also found that CD7 expression isfrequently identified in 13/21 ALK-positive ALCL cases rather thanALK-negative ALCL cases, suggesting these two entities might havesome distinctive immunophenotypic characteristics.
ALK protein expression detected by immunohistochemicalstaining is practically useful and a specific marker for the diagnosisof ALK-positive ALCL [6,22]. It is noted that three cases includedin our reviews were reported prior to the introduction of poly-clonal and monoclonal antibodies against ALK protein [6]. ALLother 19 cases were reported to have immunohistochemistry data,which showed all except one were ALK-positive [14,15]. In contrast,the current four cases were all lacking ALK expression detectedby immunohistochemistry, suggesting that while the majority ofleukemic ALCL cases are ALK-positive, leukemic ALK-negative casesalso exist.
By the literature review, while many leukemic ALK-positiveALCL cases showed evidence of t(2;5) as a sole cytogeneticabnormality, 2 out of 4 cases demonstrated normal karyotypesin ALK-negative group by conventional chromosomal analysis.Furthermore, nearly 70% of leukemic ALCL cases demonstratedadditional cytogenetic abnormalities with +7 and abnormal sexchromosomes being the most common alterations. One of thepresent cases (Case 1) and Case 26 in Table 3 also revealed complexcytogenetic abnormality. These observations suggest that thoseacquired additional cytogenetic abnormalities may directly con-tributed to more aggressive clinical course of those leukemic ALCLpatients.
Conflict of interest
None.
4 esear
R
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
[
82 Y. Lu et al. / Leukemia R
eferences
[1] Stein H, Mason DY, Gerdes J, O’Connor N, Wainscoat J, Pallesen G, et al.The expression of the Hodgkin’s disease-associated antigen Ki-1 in reac-tive and neoplastic lymphoid tissue: evidence that Reed–Sternberg cells andhistiocytic malignancies are derived from activated lymphoid cells. Blood1985;66:848–58.
[2] Rimokh R, Magaud JP, Berger F, Samarut J, Coiffier B, Germain D, et al. Atranslocation involving a specific breakpoint (q35) on chromosome 5 is char-acteristic of anaplastic large cell lymphoma (“Ki-1lymphoma”). Br J Haematol1989;71:31–6.
[3] Kaneko Y, Frizzera G, Edamura S, Maseki N, Sakurai M, Komada Y, et al. A noveltranslocation, t(2;5)(p23;q35), in childhood phagocytic large T-cell lymphomamimicking malignant histiocytosis. Blood 1989;73:806–13.
[4] Mason DY, Harris NL, Delsol G. Anaplastic large cell lymphoma, ALK-negative.In: Swerdlow S, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors.World Health Organization Classification of Tumours. Pathology and Geneticsof Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008.p. 317–9.
[5] Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL,et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994;263:1281–4.
[6] Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud D, et al. Detectionof anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin(NPM)-ALK proteins in normal and neoplastic cells with the monoclonal anti-body ALK1. Blood 1997;89:1394–404.
[7] Jaffe ES. Anaplastic large cell lymphoma: the shifting sands of diagnostichematopathology. Mod Pathol 2001;14:219–28.
[8] Downing JR, Shurtleff SA, Zielenska M, Curcio-Brint AM, Behm FG, Head DR, etal. Molecular detection of the (2;5) translocation of non-Hodgkin’s lymphomaby reverse transcriptase-polymerase chain reaction. Blood 1995;85:3416–22.
[9] Shiota M, Nakamura S, Ichinohasama R, Abe M, Akagi T, Takeshita M, etal. Anaplastic large cell lymphomas expressing the novel chimeric proteinp80NPM/ALK: a distinct clinicopathologic entity. Blood 1995;86:1954–60.
10] Lamant L, Meggetto F, Al Saati T, Brugières L, de Paillerets BB, Dastugue N,et al. High incidence of the t(2;5)(p23;q35) translocation in anaplastic largecell lymphoma and its lack of detection in Hodgkin’s disease: comparison ofcytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. Blood 1996;87:284–91.
11] Greer JP, Kinney MC, Collins RD, Salhany KE, Wolff SN, Hainsworth JD, et al.Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma. J ClinOncol 1991;9:539–47.
12] Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME. A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J SurgPathol 1993;17:859–68.
13] Anderson MM, Ross CW, Singleton TP, Sheldon S, Schnitzer B. Ki-1 anaplas-tic large cell lymphoma with a prominent leukemic phase. Hum Pathol1996;27:1093–5.
14] Bayle C, Charpentier A, Duchayne E, Manel AM, Pages MP, Robert A, et al.Leukemia presentation of small cell variant anaplastic large cell lymphoma:report of four cases. Br J Haematol 1999;104:680–8.
15] Villamor N, Rozman M, Esteve J, Aymerich M, Colomer D, Aguilar JL, et al.Anaplastic large-cell lymphoma with rapid evolution to leukemic phase. AnnHematol 1999;78:478–82.
16] Tilly H, Gaulard P, Lepage E, Dumontet C, Diebold J, Plantier I, et al. Primaryanaplastic large-cell lymphoma in adults: clinical presentation, immunophe-notype, and outcome. Blood 1997;90:3727–34.
17] Wong KF, Chan JK, Ng CS, Chu YC, Lam PW, Yuen HL, et al. Anaplastic large cellKi-1 lymphoma involving bone marrow: marrow findings and association withreactive hemophagocytosis. Am J Hematol 1991;37:112–9.
18] Tamura K, Tashiro H, Kondoh S, Kisanuki A, Sumiyoshi A, Suzumiga J, et al. Ki-
1 (CD30)-positive large cell lymphoma present with leukemia: a case report.Fukuoka Igaku Zasshi 1994;85:366–71.19] Awaya N, Mori S, Takeuchi H, Mori S, Sugano Y, Kamata T, et al. CD30 and theNPM-ALK fusion protein (p80) are differentially expressed between peripheralblood and bone marrow in primary small cell variant of anaplastic large celllymphoma. Am J Hematol 2002;69:200–4.
[
[
ch 34 (2010) 475–482
20] Falini B, Pileri S, Zinzani PL, Carbone A, Zagonel V, Wolf-Peeters C,et al. ALK+ lymphoma: clinico-pathological findings and outcome. Blood1999;93:2697–706.
21] Clavio M, Rossi E, Truini M, Carrara P, Ravetti JL, Spriano M, et al. Anaplastioclarge cell lymphoma: a clinicopathologic study of 53 patients. Leuk Lymphoma1996;22:319–27.
22] Fraga M, Brousset P, Schlaifer D, Payen C, Robert A, Rubie H, et al. Bone mar-row involvement in anaplastic large cell lymphoma. Immunohistochemicaldetection of minimal disease and its prognostic significance. AM J Clin Pathol1995;103:82–9.
23] Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, et al. ALK-positive lymphoma: a single disease with a broadspectrum of morphology. Blood 1998;91:2076–84.
24] Delsol G, Saati T, Gatter K, Gerdes J, Schwarting R, Caveriviere P, et al. Coexpres-sion of epithelial membrane antigen (EMA), Ki-1, and interleukin-2 receptorby anaplastic large cell lymphomas: diagnostic value in so-called malignanthistiocytosis. Am J Pathol 1988;130:59–70.
25] Foss HD, Anagnostopoulos I, Araujo I, Assaf C, Demel G, Kummer JA, et al.Anaplastic large-cell lymphomas of T-cell and null-cell phenotype expresscytotoxic molecules. Blood 1996;88:4005–11.
26] Wellmann A, Otsuki T, Vogelbruch M, Clark HM, Jaffe ES, Raffeld M, etal. Analysis of the t(2;5)(p23;q35) translocation by reverse transcription-polymerase chain reaction in CD30+ anaplastic large-cell lymphomas, inother non-Hodgkin’s of T-cell phenotype, and in Hodgkin’s disease. Blood1995;86:2321–8.
27] Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, et al.ALK-anaplastic large-cell lymphoma is clinically and immunophenotypicallydifferent from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwisespecified: report from the International Peripheral T-Cell Lymphoma Project.Blood 2008;111:5496– 504.
28] Onciu M, Behm FG, Raimondi SC, Moore S, Harwood EL, Pui CH, et al.ALK-positive anaplastic large cell lymphoma with leukemic peripheral bloodinvolvement is a clinicopathologic entity with an unfavorable prognosis: reportof three cases and review of the literature. Am J Clin Pathol 2003;120:617–25.
29] Monaco S, Tsao L, Murty VV, Nandula SV, Donovan V, et al. Pediatric ALK+anaplastic large cell lymphoma with t(3;8)(q26.2;q24) translocation and c-mycrearrangement terminating in a leukemic phase. Am J Hematol 2007;82:59–64.
30] Takahashi D, Nagatoshi Y, Nagayama J, Inagaki J, Itonoaga N, Takeshita M, et al.Anaplastic large cell lymphoma in leukemic presentation: a case report and areview of the literature. J Pediatr Hematol Oncol 2008;30(9):696–700.
31] Grewal JS, Smith LB, Winegarden 3rd JD, Krauss JC, Tworek JA, Schnitzer B.Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemicphase and multi-organ involvement: a report of three cases and a review of theliterature. Ann Hematol 2007;86:499–508.
32] Matsushita H, Nakamura N, Asai S, Yabe M, Hayama N, Kondo Y. A leukemicchange as an initial manifestation of the common variant type of ALK-positiveanaplastic large cell lymphoma in a patient with lung adenocarcinoma. InternMed 2008;47:2057–62.
33] Lamant L, de Reynies A, Duplantier MM, Rickman DS, Sabourdy F, Giuriato S,et al. Gene-expression profiling of systemic anaplastic large-cell lymphomareveals difference based on ALK status and two distinct morphologic ALK+subtypes. Blood 2007;109:2156–64.
34] Kong SY, Cho HJ, Suk JH, Tak EY, Ko YH, Kim K, et al. A novel complext(2;5;13)(p23;q35;q14) in small cell variant type anaplastic large cell lym-phoma with peripheral involvement. Cancer Genet Cytogenet 2004;154:183–5.
35] Meech SJ, McGavran L, Odom LF, Liang X, Meltesen L, Gump J, et al. Unusualchildhood extramedullary hematologic malignancy with natural killer cellproperties that contains tropomyosin 4-anaplastic lymphoma kinase gene
fusion. Blood 2001;98:1209–16.36] Dalal BI, Chhanabhai M, Horsman DE, LeHuquet J, Coupland R. Anaplastic large-cell lymphoma presenting as acute leukemia. Am J Hematol 2005;79:164–5.
37] Nguyen JT, Condron MR, Nguyen ND, De J, Medeiros LJ, Padula. Anaplastic largecell lymphoma in leukemic phase: extraordinarily high white blood cell count.Pathol Int 2009;59(May (5)):345–53.
