COMMENTARY

B-acute leukemic lymphoblasts versus hematogones: the wolf in sheep’sclothing?

ANNA KALFF & SURENDER JUNEJA

Department of Diagnostic Haematology, Royal Melbourne Hospital, Parkville, Melbourne, Australia

Hematogones are normally occurring, immature B-

lineage cells which resemble malignant lymphoblasts

morphologically and by expression of immature B-

cell phenotype. These B-cell precursors are found in

small numbers in most marrow specimens, however

are reported to be present in larger numbers in

healthy infants and young children and may be

particularly prominent in the regeneration phase

following chemotherapy or bone marrow transplan-

tation (sometimes constituting 5% to more than 50%

of cells) [1].

Distinction of hematogone-rich lymphoid re-

generation from B-acute leukemic lymphoblasts

(B-ALL) is critical – precise identification of hema-

togones and leukemic blasts increases sensitivity of

minimal residual disease (MRD) detection and may

aid in development of more definitive therapeutic

targeting.

Hematogones have an extremely high phenotypic

stability unaffected by disease or therapy, or to their

coexistence with leukemic cells; in a recently

published study by Babusikova et al. [2] the pattern

of sequence and intensity of antigen expression was

virtually identical in all cases (669 patient samples) –

see Table I. Three stages of hematogone maturation

have been described – types 1, 2 and 3, with

characterised varying expression of antigens and

side scatter as demonstrated in Figure 1.

In contrast to this stability, neoplastic lympho-

blasts demonstrate multiple immunophenotypic

aberrancies [3], including maturational arrest (uni-

form expression of TdT and/or CD34), immuno-

phenotypic asynchrony (co-expression of early and

late antigens normally mutually exclusive in hema-

togones), over-expression or under-expression of

normally expressed antigens and frequent expression

of cross-lineage antigens (e.g. CD19 and CD33).

Despite these distinguishing phenotypic features,

and topographic differences like interstitial disper-

sion without significant clustering in the bone

marrow trephine biopsy [4], there may remain

significant overlap between hematogones and leuke-

mic lymphoblasts resulting in the challenging situa-

tion of distinguishing between these cell types. It is

the type 1, or immature hematogones that most often

pose the greatest challenge of distinguishing between

benign regenerative change from B-leukemic blasts.

Type 1 hematogones are TdTþ, CD34þ and

demonstrate low CD45 expression, all similar to B

lymphoblasts. These similarities can make assess-

ment of patients for MRD following chemotherapy/

bone marrow transplantation or diagnosis of

early relapse with small volume disease difficult to

interpret.

Sevilla [5], report in this issue of Leukemia and

Lymphoma the reproducible spectrum of expression

of cytoplasmic IgM in the context of the three

currently recognised maturational stages of hemato-

gones, highlighting the complementary role this

marker may have in further distinguishing between

these benign cells and the leukemic B-lymphoblasts.

They have demonstrated that as hematogones

mature, they acquire cytoplasmic IgM in conjunction

with brighter expression of CD19, decreased expres-

sion of CD10 and loss of TdT and CD34. This

acquisition of cytoplasmic IgM was found to occur

early during the transition to the intermediate

stage (type 2 hematogones). Cytoplasmic IgM is

expressed on lymphoblasts in the most mature

precursor B differentiation stage (pre-B ALL), and

Correspondence: Anna Kalff, Department of Diagnostic Haematology, Royal Melbourne Hospital, Parkville, Melbourne, Australia.

E-mail: akalff@hotmail.com

Leukemia & Lymphoma, April 2009; 50(4): 523–524

ISSN 1042-8194 print/ISSN 1029-2403 online � 2009 Informa Healthcare USA, Inc.

DOI: 10.1080/10428190902725839

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is generally not expressed on pro-B or common-B

lymphoblasts [6].

The caveat to this, however, is the well described

phenomenon of ‘phenotypic switch’ in relapsed

leukemic blasts, particularly, in B-ALL. Essentially,

all cases of B-ALL demonstrate multiple immuno-

phenotypic aberrancies relative to their normal

counterpart (hematogones) and stability of these

aberrancies has relevance to follow-up MRD analy-

sis. Loss or gain of aberrancy occurs in a high

proportion of patients (70% and 60%, respectively)

[3] with B-ALL. The analysis of cytoplasmic IgM

was not performed in this larger analysis by Chen

et al. [3] and the sample size (n¼ 25) in this current

study by Sevilla [5], did not permit such analysis.

So, the reproducible expression of cytoplasmic

IgM on hematogones becomes an additional anti-

genic marker to aid in the distinction of hematogones

from leukemic blasts. However, the problem of

phenotypic switch still remains, and results should

never be interpreted in isolation, but in conjunction

with other parameters – such as morphologic features

and molecular studies.

Declaration of interest: The authors report no

conflicts of interest. The authors alone are respon-

sible for the content and writing of the article.

References

1. McKenna RW, Washington LT, Acquino DB, Picker LJ,

Kroft SH. Immunophenotypic analysis of hematogones (B-

lymphocyte precursors) in 662 consecutive bone marrow

specimens by 4-color flow cytometry. Blood 2001;98:2498–

2507.

2. Babusikova O, Zeleznikova T, Kirschnerova G, Kankuri E.

Hematogones in acute leukemia during and after therapy. Leuk

Lymphoma 2008;49:1935–1944.

3. Chen W, Karandikar NJ, McKenna RW, Kroft SH. Stability of

leukemia-associated immunophenotypes in precursor B-lym-

phoblastic leukemia/lymphoma: a single institution experience.

Am J Clin Pathol 2007;127:39–46.

4. Rimsza LM, Larson RS, Winter SS, Foucar K, Chong YY,

Garner KW, Leith CP. Benign hematogone-rich lymphoid

proliferations can be distinguished from B-lineage acute

lymphoblastic leukemia by integration of morphology, immu-

nophenotype, adhesion molecule expression, and architectural

features. Am J Clin Pathol 2000;114:66–75.

5. Sevilla DW, Emmons FN, Bai X, Colovai A, Bhagat G, Alobeid

B. The pattern of cytoplasmic IgM expression in the context of

the three currently recognised maturational stages of hemato-

gones. Leuk Lymphoma 2009;50:642–644.

6. WHO classification of tumours of haematopoietic tissue and

lymphoid tissues. Swerdlow SH CE, Harris NL, Pileri SA,

Stein H, Thiele J, Vardiman JW, editor. Lyon, France:

International Agency for Research on Cancer (IARC); 2008.

Table I. Antigen expression of B-leukemic lymphoblasts and all

three maturational stages of hematogones.

B-leukemic

lymphoblasts

Hematogones

1 2 3

CD10 þ/7 Bright þ þCD19 þ/7 þ þ þþCD20 þ/7 7 þ Bright

CD22 þ/7 þ þ þCD34 þ/7 þ 7 7CD38 þ þ þ þCD45 Low Low þ Bright

nTdT þ þ 7 7Cytoplasmic IgM + 7 þ þþ

Adapted from Babusikova et al. [2].

Figure 1. CD45 versus side scatter flow cytometric histogram.

Demonstrates varying expression of CD45 and side scatter and the

changes with maturation from the most immature hematogones –

type 1 (HG1 pink) [low CD45 and low side scatter], through to

type 2 (HG2 green) and to the most mature – type 3 (HG3 red).

A normal lymphoid gate is also demonstrated (blue).

524 A. Kalff & S. Juneja

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