Correspondence
2457
Mature T cell leukemias which cannot be adequately classified under the new WHO
classification of lymphoid neoplasms
Leukemia (2002) 16, 2457–2458. doi:10.1038/sj.leu.2402715
TO THE EDITOR
Figure 1
Morphologic and immunophenotypic features of a representative case. The Wright–Giemsa-stained peripheral blood smear shows
no prolymphocytoid morphology among the neoplastc lymphocytes. Four-color flow cytometry demonstrates that nearly all of the leukocytes
are an abnormal CD4-positive T cell population with relatively homogeneous expression of CD2, CD3, CD4 and CD7.
We would like to draw attention to rare peripheral blood-and/or marrow-based leukemias of mature T cells which do not fit well within
any of the entities included in the new WHO Classification of Lymphoid Neoplasms, and therefore cannot be adequately classified using
this system. These have all been CD4-positive, mature T cell lymphoproliferative processes without either the prolymphocytoid morphology or associated hepatosplenomegaly and/or generalized lymphadenopathy characteristic of T cell prolymphocytic leukemia (TPLL), and without clinical or morphologic features to suggest adult T
cell leukemia/lymphoma, mycosis fungoides/Sézary syndrome, T cell
large granular lymphocytic leukemia, or an underlying peripheral T
cell lymphoma. Because of the rarity of these cases, we have chosen
to describe them via this letter, rather than wait the 5 to 10 years
likely to be required to accumulate an adequate series for a fulllength manuscript.
In the representative case shown in Figure 1, a 79-year-old female
presented with a WBC count of almost 500 000 per ␮l, yet had no
history of cutaneous or peripheral T cell lymphoma, no history of lymphadenopathy or hepatosplenomegaly, no history of emigration from
an HTLV-1-endemic area, and no prolymphocytoid morphology
among the neoplastic cells. Flow cytometry demonstrated that nearly
all of the circulating leukocytes were an abnormal CD3-positive/CD4positive, mature T cell population. Although cytogenetic evaluation
to rule out the characteristic chromosome 14 abnormality of T-PLL
was not performed in this case, none of the features suggested a TPLL, not even the small cell variant. A second case from a 73-yearold male, which demonstrated a lower leukocyte count but otherwise
similar features, had cytogenetic analysis demonstrating a normal
karyotype.
Under the Revised European–American Lymphoma (REAL) classification previously employed by most hematopathologists,1 these
cases would have fallen within the spectrum of processes known as
T cell chronic lymphocytic leukemia/prolymphocytic leukemia (TCorrespondence: SJ Kussick, Department of Laboratory Medicine, Box
357110, University of Washington Medical Center, 1959 NE Pacific
Street, Seattle, WA 98195, USA; Fax: (206) 598-6189
Received 28 May 2002; accepted 28 June 2002
CLL/PLL), and therefore could have been readily classified for the clinicians treating these patients. However, under the WHO classification
the T-CLL component of the REAL’s T-CLL/PLL category has been
eliminated,2,3 leaving hematopathologists with only the entity known
as T cell prolymphocytic leukemia (T-PLL) for the classification of
cases with the clinical and morphologic features described above.
Because these cases are more similar to those in a 1995 series of 25
cases of T-CLL4 than they are to T-PLL, we feel it is important to
include an entity comparable to T-CLL in any comprehensive lymphoma classification system. Therefore, the REAL classification
appears superior to the WHO system in dealing with these rare cases.
While we agree with the WHO’s decision to separate T-PLL from TCLL in light of the cytogenetic evidence arguing that T-PLL is indeed
a distinct entity, based on our experience we cannot support the
decision to eliminate a T-CLL-like entity.
To those who would favor the WHO classification by arguing that
T-CLL represents a ‘wastebasket’ entity without a definitive biologic
underpinning, we would reply that most of the REAL and WHO entities lacking a recurrent cytogenetic abnormality are likely to represent
heterogeneous disease processes. For example, nodal diffuse large B
cell lymphoma continues to be largely regarded as single entity under
the REAL and WHO classifications, despite the recent molecular
advances suggesting that DLBCL consists of two or more biologically
distinct entities.5,6 Because our clinician clients need a framework for
making treatment decisions and conducting clinical trials to evaluate
new therapies, we strongly believe that the absence of a unifying biological hallmark of T-CLL does not negate the value of having this
category until sufficient new clinical and/or biological data warrant
refining the concept of T-CLL.
SJ Kussick
BL Wood
DE Sabath
Department of Laboratory Medicine,
University of Washington Medical Center,
Seattle, WA, USA
References
1 Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML,
Delsol G, DeWolf-Peeters C, Falini B, Gatter KC, Grogan TM,
Leukemia
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Isaacson PG, Knowles DM, Mason DY, Muller-Hermelink H-K,
Pileri SA, Piris MA, Ralkiaer E, Warnke RA. A revised European–
American classification of lymphoid neoplasms: a proposal from
the International Lymphoma Study Group. Blood 1994; 84:
1361–1392.
2 Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink H-K,
Vardiman J, Lister TA, Bloomfield CD. World Health Organization
Classification of Neoplastic Diseases of the Hematopoietic and
Lymphoid Tissues: report of the Clinical Advisory Committee
Meeting – Airlie House, Virginia, November 1997. J Clin Oncol
1999; 17: 3835–3849.
3 Jaffe ES, Harris NL, Stein H, Vardiman JW. Pathology and Genetics
of Tumours of the Hematopoietic and Lymphoid Tissues. IARC
Press: Lyon, 2001, pp 195–196.
4 Hoyer JD, Ross CW, Li C-Y, Witzig TE, Gascoyne RD, Dewald
GW, Hanson CA. True T-cell chronic lymphocytic leukemia: a
morphologic and immunophenotypic study of 25 cases. Blood
1995; 86: 1163–1169.
5 Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos I, Rosenwald A,
Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE,
Moore T, Hudson J, Lu L, Lewis DB, Tibshirani R, Sherlock G,
Chan WC, Greiner T, Weisenburger DD, Armitage JO, Warnke J,
Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO,
Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.
6 Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC,
Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval
MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander
ES, Aster JC, Golub TR. Diffuse large B-cell lymphoma outcome
prediction by gene-expression profiling and supervised machine
learning. Nat Med 2002, 8: 68–74.
Isolated granulocytic sarcoma followed by acute myelogenous leukemia type FAB-M2
associated with inversion 16 and trisomies 9 and 22
Leukemia (2002) 16, 2458–2459. doi:10.1038/sj.leu.2402593
TO THE EDITOR
Granulocytic sarcoma (GS), also known as chloroma, are extramedullary tumors composed of immature myeloid cells. They have been
described in a wide variety of anatomical sites, including breast,
ovary, brain, gastrointestinal tract and skull.1,2 They occur at the onset
of acute myelogenous leukemia (AML) or during its evolution. They
may also be the first sign of acute transformation of myelodysplastic
syndromes and chronic myeloproliferative disorders. They are rarely
the first manifestation of AML. GS are observed in only 2 to 8% of
AML, mainly of M2 morphology, although they have also been associated with M3, M4, M5, and M7 morphology.
A 37-year-old man was referred to our hospital in June 1999. He
had a history of ascitis and intestinal occlusion due to three stenotic
lesions of the jejunum. A large peritoneal mass was noted. The patient
had surgery in March 1999 during which a partial resection of the
proximal jejunum was performed. The histologic examination of the
surgical piece was interpreted as a massive lymphomatous infiltration
of the whole intestine wall. In May 1999, he had surgery again
because of necrosis of the tumor with cutaneous fistula. A bone marrow biopsy and a complete blood count were normal. The patient
received two courses of anti-lymphoma chemotherapy.
Because of the lack of response, he was admitted to the hematology
service. The patient had ileus, ascitis, severe deterioration of his health
status and a 13 kg weight loss. A blood count showed a hemoglobin
of 10.5 g/dl, a white blood cell (WBC) count of 4.4 × 109/l and a
platelet count of 343 × 109/l. The leukocyte differential showed 84%
neutrophils, 15% lymphocytes and 1% monocytes.
A review of the original histology found the malignant cells to be
blasts. These cells were shown to contain myeloperoxidase and to
express CD34 and CD68 antigens. Furthermore, immunophenotyping
was partially positive for CD15 and lysozyme. A retrospective diagnosis of isolated granulocytic sarcoma was made. Unfortunately, no
material was available for cytogenetic studies.
The bone marrow aspirate and the blood cell count were still normal. At the end of July 1999, chemotherapy with aracytidine and idarubicin was started, leading to the disappearance of all abdominal
signs and a complete remission. No complementary radiotherapy was
performed because of the small bowel localization of the granulocytic
sarcoma. Then, the patient received a consolidation therapy with high
Correspondence: M De Braekeleer, Laboratoire de Cytogénétique,
Faculté de Médecine, Université de Bretagne Occidentale, 22, avenue
Camille Desmoulins, F-29285 Brest cedex, France; Fax: + 33 298 22
39 61
Received 15 October 2001; accepted 11 February 2002
Leukemia
doses of aracytidine and idarubicin. In December 1999, after
preparative regimen by BEAM, he had an autologous bone marrow
transplantation. No marrow involvement by acute myelogenous
leukemia was detected.
Hematopoietic reconstruction was incomplete, without any signs of
acute leukemia. The patient was hospitalized again at the end of
August 2000 because of the presence of 39% circulating blasts. A
bone marrow aspirate showed hypercellularity with 72% myeloblasts,
some containing Auer rods and showing discrete abnormal granular
maturation, leading to the diagnosis of AML type 2. The blasts were
positive for CD13, CD34, CD117, and myeloperoxidase, but negative
for lysozyme, CD35, and CD15.
A second complete remission was obtained after an induction
course consisting of aracytidine and idarubicin followed, at day 15,
by high-dose aracytidine and amsacrine because of the persistence of
15% blasts in the bone marrow. The abdomen remained normal. In
April 2001, the patient received an allogenic bone marrow transplantation from an HLA-identical familial donor after conditioning using
total body radiation (12 Gy) and cyclophosphamide (120 mg/kg).
Hematopoietic reconstruction was complete but the patient presented
an early acute intestinal graft-versus-host disease requiring immunosuppressive therapy. Complete hematopoietic chimerism was confirmed by cytogenetic analysis. The patient remained in complete
remission until December 2001, at which time he developed a meningeal relapse of AML without medullary involvement.
Cytogenetic analysis of the patient’s bone marrow cells was performed at the time of diagnosis of AML type 2. The chromosomes were
R-banded. We analyzed 25 metaphases: three were 46,XY, one
47,XY,+9, inv(16)(p13q22), 19 48,XY,+9, inv(16)(p13q22), +22 and
(Figure 1) two 49,XYY,+9, inv(16)(p13q22), +22. The FISH study using
partial chromosome paint 16p (pcp(16p) Oncor, Illkirch, France) confirmed the presence of the inv(16) in all the metaphases with trisomy
22 and/or trisomy 9.
The patient reported here is one of the rare cases in which granulocytic sarcoma preceded the onset of overt acute myelogenous leukemia.2–4 In their analysis of the effect of early antileukemic therapy in
isolated chloroma, Imrie et al5 found 83 published cases and added
seven of their own.4 They showed that chemotherapy given at diagnosis of GS delayed the onset of AML (median: 36 months vs 6 months
for non-chemotherapy) and was associated with a better survival.
More than half of the patients were still alive with a median followup of 25 months, compared to a median survival of 13 months for
those who did not receive chemotherapy. The interval between diagnosis of GS and diagnosis of AML was 17 months in our patient, who
is still alive 30 months after GS was diagnosed.
The best results were obtained when anti-AML chemotherapy was
started at the diagnosis of GS. Unfortunately, in many cases, the cell
morphology resembles large cell lymphoma, which may lead to mis-