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Brunangelo Falini

New Classification of Acute Myeloid Leukemia and Precursor-related Neoplasms: Changes and Unsolved Issues

Abstract: The World Health Organization (WHO) classification of lympho-hematopoietic neoplasms is increasingly based on genetic criteria. Here, we focus on changes that, as compared to the 2001 edition, were introduced into the 2008 WHO classification of acute myeloid leukemia (AML) and related precursor neoplasms. The category of AML with recurrent genetic abnormalities was expanded to account for 60% of AML by adding three distinct entities, i.e., AML with t(6,9), inv(3), or t(1;22), and two provisional entities, i.e., AML with mutated NPM1 or CEBPA. These changes have greatly modified the approaches to diagnosis and prognostic stratification of AML patients. To emphasize the need of various parameters for diagnosis, including myelodysplasia (MD)-related cytogenetic abnormalities, history of myelodysplasia or myelodysplasia/myeloproliferative neoplasm, and multilineage dysplasia, the category of "AML with multilineage dysplasia" was re-named AML with MD-related changes. Finally, we describe the unique characteristics of myeloid proliferations associated with Down syndrome and blastic plasmacytoid dendritic cell neoplasm.



Introduction

Since 2001, the World Health Organization (WHO) classification of myeloid neoplasms has been oriented towards categorization of disease entities according to underlying genetic alterations as they are usually associated with distinctive clinico-pathological features and may serve as specific diagnostic and prognostic markers (Lowenberg, 2008). This orientation first manifested with the decision to create a category of “AML with recurrent genetic abnormalities.” The 2008 edition has expanded this category to include new distinct and provisional entities (Arber et al, 2008a) that are diagnostically and clinically relevant, with one notable change which is the incorporation of acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) since it accounts for about 30% of AML. Other tumors such as myeloid proliferations associated with Down syndrome and blastic plasmacytoid dendritic neoplasm are not as well characterized genetically but are associated with such unique morphological and clinical features that the 2008 WHO classification designated them distinct entities. There are still some unsolved issues concerning AML with myelodysplasia (MD)-related changes whilst the category “AML, not otherwise specified” remains the most poorly defined entity.

This review discusses the rationale underlying the major changes in the 2008 WHO classification of AML and precursor-related neoplasms (Table 1).

Table 1. Acute Myeloid Leukemia (AML) and Related Precursor Neoplasm
AML with recurrent genetic abnormalities
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Acute promyelocytic leukemia with t(15;17)(q22;q12); PML-RARA
AML with t(9 ;11)(p22;q23); MLLT3-MLL
AML with t(6;9)(p23;q34); DEK-NUP214
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
AML with mutated NPM1*
AML with mutated CEBPA*
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Myeloid sarcoma
Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
*Provisional entities.

AML with Recurrent Genetic Abnormalities

This is genetically the best characterized subgroup of AML in 2008 WHO classification (Arber et al., 2008a). Entities listed in this category are shown in Table 1 and are outlined below.

1). Changes to distinct AML entities, as listed in the 2001 WHO classification

AML that are defined by chromosomal translocations t(15;17), t(8;21), and inv(16) and mixed-lineage leukemia (MLL) gene rearrangements underwent various modifications (Vardiman et al., 2009). First, leukemias carrying either t(8;21)(q22;q22), inv(16)(p13.1q22), or t(15;17)(q22;q12) are considered AML, regardless of the blast cell count. For all other genetic alterations, including AML with t(9;11), AML is diagnosed only if blasts constitute ≥20% of peripheral blood or all nucleated bone marrow cells. Second, AML carrying retinoic acid receptor (RAR) alpha gene rearrangements with partners other than promyelocytic leukemia (PML) gene, as typically observed in acute promyelocytic leukemia (APL) with t(15;17)/PML-RAR alpha, are recognized as separate entities, since they may lack typical APL morphological and clinical features. For example, AML with t(11;17)/PLZF-RAR alpha usually shows a peculiar morphology (regular nuclei, many granules, and absence of Auer rods) and is resistant to all-trans-retinoic acid (ATRA) treatment. Third, the entity formerly known as AML with 11q23 (MLL) abnormalities no longer includes the MLL partial tandem duplication and was re-named “AML with t(9;11)(p22;q23);MLLT3-MLL.” Chromosomal translocations that involve partner genes other than MLLT3 should be specified in the diagnosis.

2). New distinct entities in the 2008 WHO classification

Three new cytogenetically distinct entities are now listed in the category of AML with recurrent genetic abnormalities (Arber et al., 2008a): AML with t(6;9)(p23;q23)/DEK-NUP214, AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1, and AML (megakaryoblastic) with t(1;22)(p13;q13)/RBM15-MKL1. Although rare, these conditions need to be recognized as they are usually characterized by short survival, unless allogeneic stem cell transplantation is performed.

i). AML with t(6;9)(p23;q23)/DEK-NUP214

It is a rare (about 1%) AML whose underlying chromosomal translocation, the t(6;9)(p23;q34), fuses the DEK gene on chromosome 6 with the nucleoporin-encoding gene NUP214(CAN) on chromosome 9 (Soekarman et al., 1992; von Lindern et al., 1992). The encoded fusion protein induces transformation by altering growth characteristics, nucleo-cytoplasmic transport, and protein synthesis of hematopoietic stem cells (Ageberg et al., 2008; Boer et al., 1998; Fornerod et al., 1995). The t(6;9) is the sole chromosome abnormality in the majority of cases; association with complex karyotype is observed in some patients (Arber et al., 2008a). Notably, a high percentage of cases carry an FLT3-ITD mutation (Oyarzo et al., 2004; Thiede et al., 2002).

AML with t(6;9) usually presents with pancytopenia. The most significant morphological changes are basophilia (>2%) (Chi et al., 2008) and multilineage dysplasia (Slovak et al., 2006). The immunophenotype is non-specific. As prognosis is poor (Arber et al., 2008a; Bacher et al., 2009; Harrison et al., 2010; Slovak et al., 2006), allogeneic stem cell transplantation should be considered during the first complete remission (Chalandon et al., 2002).

ii). AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)/RPN1-EVI1

Accounting for 1-3% of AML, the disease may present de novo or after a myelodysplastic phase (Arber et al., 2008a). Chromosomal abnormalities involve the oncogene EVI1 (or its longer form MDS1-EVI1) at 3q26.2, and RNP1 at 3q21 (Shearer et al., 2010). Monosomy 7 is the most commonly associated chromosomal aberration (Lugthart et al., 2010); other karyotypic abnormalities include 5q deletions and complex karyotypes. Most patients present with anemia and a normal platelet count. The morphological features of blast cells encompass all French-American-British (FAB) subtypes except for APL. Multilineage dysplasia is frequent, with an increase in small (≤30 mm) monolobated or bilobated megakaryocytes (Arber et al., 2008a). The immunophenotype is non-specific. Blast cells frequently express CD13, CD33, HLA-DR, and CD34; aberrant expression of lymphoid markers such as CD7 is occasionally observed. Clinically, AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) is an aggressive disease with poor prognosis (Grimwade et al., 2010; Lugthart et al., 2010) that may benefit from allogeneic bone marrow transplantation (Chalandon et al., 2002).

iii). AML t(1;22)(p13;q13)/RBM15-MKL1

This entity accounts for <1% of AML. In most cases, the sole chromosomal abnormality is t(1;22)(p13;q13) which fuses the RNA-binding motif protein-15 (RBM15) gene with the megakaryocytic leukemia-1 (MKL1) gene (Mercher et al., 2003). The encoded fusion protein is thought to induce hematopoietic cell transformation by deregulating transcriptional activity (Mercher et al., 2009). This is usually a de novo AML that typically occurs in infants or young children, with most cases being observed in the first 6 months of life (median, 4 months) (Arber et al., 2008a). The morphological and phenotypic features of blast cells are usually those seen in acute megakaryoblastic leukemia. However, the affected infants or children do not have Down syndrome (Hama et al., 2008). Early reports suggested poor prognosis but intensive chemotherapy was associated with long disease-free survival in more recent studies (Arber et al., 2008a).

3). New provisional entities in the 2008 WHO classification

Two new provisional entities were added to the category of AML with recurrent genetic abnormalities.

AML with mutated nucleophosmin (NPM1)

Accounting for about 30% of AML (50-60% of cases with normal karyotype), this is usually a de novo leukemia (Falini et al., 2005). Nucleophosmin (NPM1) is an essential gene that encodes for a nucleolar protein involved in multiple functions including stabilization of the p14ARF tumor suppressor protein, regulation of ribosome biogenesis, and control of centrosome duplication (Grisendi et al., 2006). Almost all mutations (50 molecular variants so far identified) occur at exon-12 of the NPM1 gene (Falini et al., 2007b) and all of them cause critical changes at the NPM1 protein C-terminus (Falini et al., 2009a). Alterations in NPM1 traffic properties lead to NPM1 mutant accumulation in the cytoplasm of AML cells, which is thought to be critical for leukemogenesis (Bolli et al., 2009). Even though the transformation mechanism is still unclear, the NPM1 mutant may activate the oncogene c-Myc (Bonetti et al., 2008) and increase the degradation of the oncosuppressor Arf (Colombo et al., 2006).

immunoalkaline phosphatase technique. This picture is the same as that provided by the author (B.F.) for the 2008 WHO Classification of Hematological Neoplasms (page 120).

Figure 1. NPM1-mutated AML (synonym: NPMc+ AML), bone marrow biopsy. Leukemic cells are myelo-monocytic in appearance (A; hematoxylin-eosin), CD34-negative (B; note the CD34-positive endothelial cells) and display aberrant cytoplasmic expression of nucleophosmin (C). Nucleus-restricted expression of nucleolin/C23 (D) highlights the difference with the anti-NPM1 staining (C). B, C, and D: immunoalkaline phosphatase technique. This picture is the same as that provided by the author (B.F.) for the 2008 WHO Classification of Hematological Neoplasms (page 120).

The incidence of AML with mutated NPM1 is higher in adults than in children (30% vs. 7%) (Falini et al., 2009b). The patient usually presents with a high white blood cell count; pancytopenia is rare. Most cases show a hypercellular marrow. Leukemic infiltration in a hypoplasic marrow is infrequent as is marrow fibrosis. Blast cells often display myelomonocytic or monocytic features, with dysplasia of two or more cell lineages in about 23% of cases (Falini et al., 2010). Lack, or low expression, of CD34 (Falini et al., 2005) (Figure 1), the most typical immunophenotypic feature (>90% of cases), is independent of leukemic cell maturation. About 85% of cases present with a normal karyotype. Other distinctive features include high frequency of FLT3-ITD (about 40% of cases) (Falini et al., 2005) and unique gene expression (with downregulation of CD34 and upregulation of HOX genes) (Alcalay et al., 2005) and microRNA profiles (Garzon et al., 2008). Diagnosis is based on detection of NPM1 mutations by molecular assays or immunohistochemistry, e.g., detection of aberrant cytoplasmic expression of nucleophosmin (Falini et al., 2006) (Figure 1).

NPM1-mutated AML usually shows an exquisite response to induction therapy (Falini et al., 2005). Unless a concomitant FLT3-ITD mutation is present, prognosis is favorable (Schlenk et al., 2008), resembling that of AML with t(8;21) or inv(16). These features appear to be independent of concomitant chromosomal aberrations (Haferlach et al., 2009) or multilineage dysplasia (Falini et al., 2010). Notably, patients with NPM1-mutated AML without FLT3-ITD do not appear to benefit from allogeneic stem cell transplantation in first complete remission (Schlenk et al., 2008). The NPM1 mutation was recently found to be an important prognostic factor (even independent of FLT3-ITD) in ≥70 year old AML patients (Becker et al., 2010).

CEBPA mutated AML

Usually a de novo leukemia, this disease accounts for about 10% of AML with normal karyotype. Physiologically, the CCAAT/enhancer binding protein alpha (CEBPA) gene encodes for a transcription factor that plays a key role in controlling self-renewal and lineage commitment of hematopoietic stem cells (Reckzeh and Cammenga, 2010). CEBPA mutations contribute to leukemogenesis by inducing proliferation and blocking myeloid lineage commitment (Bereshchenko et al., 2009). The two most frequent mutations are: i) out-of-frame insertions and deletions in the N-terminal region and ii) deletions in the C-terminal region (Pabst and Mueller, 2009). Most cases carry both types of CEBPA mutations, which are usually biallelic; single heterozygous mutations are infrequent.

CEBPA-mutated AML usually displays features of either AML with or without cell maturation but some cases may show monocytic or monoblastic features. Myeloid-associated antigens HLA-DR and CD34 are usually expressed, as is CD7 in a significant proportion of patients. About 70% of cases have normal karyotype and approximately 25% carry concomitant FLT3-ITD mutations. Prognosis is favorable, being comparable to AML with inv(16)(p13.1q22) or t(8;21)(q22;q22).

Notably, the distinctive features of CEBPA-mutated AML, i.e., favorable prognosis and unique gene expression profiles, are defined by double, but not single, CEBPA mutations (Dufour et al., 2010; Green et al., 2010; Wouters et al., 2009). This is in agreement with the observation that myeloid precursor cells from healthy carriers with a single germ-line CEBPA mutation evolve to overt AML by acquiring a second sporadic CEBPA mutation (Smith et al., 2004). Notably double CEBPA-mutated cases are mutually exclusive of NPM1 mutations (Green et al., 2010). As in NPM1-mutated AML, the good prognosis of CEBPA-double mutated patients appears to be abrogated by a concomitant FLT3-ITD mutation (Renneville et al., 2009).

AML with Myelodysplasia (MD)-related Changes

In 2001 WHO classification, this entity was listed as AML with multilineage dysplasia. In the revised classification, it was re-named as “AML with myelodysplasia (MD)-related changes” (Arber et al., 2008b), in order to emphasize the biological and clinical importance of parameters other than multilineage dysplasia, when assigning a case to this category. Indeed, a patient is now diagnosed as having AML with myelodysplasia (MD)-related changes if one or more of the following criteria are fulfilled (Arber et al., 2008b): i) a well-documented history of myelodysplasia or myelodysplastic/myeloproliferative neoplasm; ii) presence of an MD-related cytogenetic abnormality; and iii) multilineage dysplasia in bone marrow and peripheral blood smears (defined as dysplasia in >50% of cells in two or more lineages). Patients should not have a history of chemotherapy or radiotherapy for an unrelated disease.

Usually occurring in the elderly, AML with MD-related changes often presents with severe pancytopenia. Due to the heterogeneity of underlying genetic changes, the immunophenotype is quite variable. Cytogenetic abnormalities that permit diagnosis of AML with MD-related changes are listed in Table 2. Borders between AML with MD-related changes and NPM1- or CEBPA-mutated AML are not clearly defined. Recent evidence showing that the distinctive biological and prognostic features of NPM1-mutated AML seem to be independent of concomitant chromosomal aberrations (Haferlach et al., 2009) or multilineage dysplasia (Falini et al., 2010) suggests that NPM1-mutated AML and AML with MD-related changes are distinct entities.

Table 2. Cytogenetic Abnormalities Sufficient to Diagnose AML with MD-related Changes*
Complex Karyotype
** Unbalanced abnormalities
-7/del(7q)
-5/del(5q)
i(17q)/t(17p)
-13/del(13q)
del(11q)
del(12p)/t(12p)
del(9q)
idic(X)(q13)
Balanced abnormalities
t(11;16)(q23;q13.3)#
t(3;21)(q26.2;q22.1)#
t(1;3)(p36.3;q21.1)
t(2;11)(p21;q23)#
t(5;12)(q33;p12)
t(5;7)(q33;q11.2)
t(5;17)(q33;p13)
t(5;10)(q33;q21)
t(3;5)(q25;q34)
* ≥ 20% PB or BM blasts must be present.
** ≥3 unrelated abnormalities.
# Therapy-related AML that frequently associates with these chromosomal abnormalities should be excluded.

Therapy-related Myeloid Neoplasms

The only difference to the 2001 WHO classification was that cases were no longer separated into “alkylating agent related,” “topoisomerase-II-inhibitor related,” or “other.” This is in accordance with the observation that most patients who develop therapy-related AML had been treated with chemotherapy regimens that included both alkylating agents and topoisomerase inhibitors (Vardiman et al., 2009).

It was, however, argued that since therapy-related myeloid neoplasms usually carry the same chromosomal aberrations as AML with recurrent genetic abnormalities or MD-related changes, they could be assigned to these categories. The case for having them lumped into a distinct category was that, with the exception of AML with inv(16)/t(16;16) or t(15;17), they have a significantly worse prognosis than their de novo counterparts. The 2008 WHO classification recommends that the pathologist indicates the cytogenetic abnormality which has been found associated with a therapy-related myeloid neoplasm (Vardiman et al., 2008).

Acute Myeloid Leukemia, Not Otherwise Specified (AML-NOS)

When cases do not fulfil inclusion criteria for the other AML entities in the WHO classification they are assigned to AML-NOS (Arber et al., 2008c), according to morphological and cytochemical/immunophenotypic criteria (Table 3; Figures 2 and 3). In the 2001 WHO classification, this group of yet poorly characterized leukemias accounted for 50-60% of AML since it included all cases with normal karyotype. In the 2008 edition, AML-NOS accounts for 25-30% of cases, since AML with mutated NPM1 and AML with mutated CEBPA (both of which are mostly associated with normal karyotype) are now listed separately as new provisional entities.

Table 3. Acute Myeloid Leukemia, Not Otherwise Specified (NOS)
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis

Whether the category of AML-NOS was needed was strongly debated because there was no conclusive evidence that the morphological and cytochemical/ immunophenotypic studies that were used to distinguish cases had any clinical impact. However, AML-NOS was maintained to provide a minimum framework for diagnosis (Vardiman et al., 2009). This is especially true for developing countries, where diagnosis of AML is still mainly based on morphology and cytochemistry/immunophenotype. Moreover, these criteria are the only ones available for diagnosis of erythroleukemia (Figure 3).

Morphological variants of AML-NOS are the same as described in the 2001 WHO classification. However, defining criteria for AML diagnosis has now become ≥20% blast cells in the bone marrow or peripheral blood. In AML with monocytic differentiation promonocytes are regarded as blast equivalents.

Other Entities

The 2008 WHO classification now lists three myeloid neoplasms as new distinct entities.

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Figure 2. AML with monoblastic features, AML-NOS (top panel; bone marrow biopsy, hematoxylin-eosin). Blast cells are CD68-positive (middle panel) and show nuclear expression of nucleophosmin (NPM1) (bottom panel), which excludes mutations of the NPM1 gene. Middle and bottom panels: immunoalkaline phosphatase technique.

Myeloid sarcoma

Myeloid sarcoma is a distinct entity in the 2008 WHO classification (Pileri et al., 2008). It is defined as myeloid blasts with or without maturation that grow to form a “tumor mass with effacement of tissue architecture.” In contrast, leukemic infiltrates of any body site (e.g., meningeal) that do not show these characteristics are not regarded as myeloid sarcoma.

Any of the genetic alterations described in AML can be found in myeloid sarcoma, but they are often difficult to be demonstrated due to the fact that, frequently, only small biopsies, usually fixed and embedded in paraffin, are available for molecular studies. At immunohistochemistry, about 16% of cases show aberrant cytoplasmic expression of nucleophosmin, indicating they carry NPM1 mutations (Falini et al., 2007a).

Usually occurring in the elderly, myeloid sarcoma involves mainly the skin, lymph nodes, and bone, although no body site is spared (Campidelli et al., 2009). A de novo presentation should be regarded as AML and treated accordingly. Alternatively, myeloid sarcoma may precede or coincide with AML or even be the initial manifestation of relapse (regardless of peripheral blood or bone marrow findings). In some cases, myeloid sarcoma may represent a blastic transformation of myelodysplasia or a myeloproliferative neoplasm.

Morphological and immunophenotypic features are as described for other AML entities. Differential diagnosis is with a number of pathological conditions, including diffuse large B-cell lymphoma, lymphoblastic lymphoma, small round cell tumors (especially in children), and blastic plasmacytoid dendritic neoplasm (BPDC) (see below). Prognosis is usually poor since many patients, due to delay in the diagnosis, are not treated with intensive chemotherapy.

Myeloid proliferations related to Down syndrome

The 2008 WHO edition recognizes two clinical forms of myeloid proliferations associated with Down Syndrome (DS) (Baumann et al., 2008): i) Transient abnormal myelopoiesis (TAM) ; and ii) AML associated with DS, which is usually megakaryoblastic in type.

i). Transient abnormal myelopoiesis (TAM)

Approximately 10% of DS newborns present with a hematological disorder known as TAM. Genetic alterations (presence of GATA1 mutations) (Cabelof et al., 2009) and morphological and laboratory findings may be the same as typical DS-associated AML. In 70-80% of cases, TAM resolves spontaneously over a period of several weeks to 3 months, whilst in the remaining cases a non-transient AML (see below), usually of megakaryoblastic type, develops 1 to 3 years later (Kitoh et al., 2009; Roy et al., 2009). Indications for chemotherapy in TAM are not clearly defined (Baumann et al., 2008).

ii). AML associated with Down syndrome

Children with DS have an approximately 50-fold increased risk of developing AML in the first 5 years of life (Malinge et al., 2009), as compared to those without DS. About 1-2% of children with DS develop AML, with the great majority being megakaryoblastic. In contrast, this morphological variant of AML is very rare (about 5% of AML) in children of corresponding age without DS.

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Figure 3. Pure erythroid leukemia, AML-NOS. Left panel (bone marrow biopsy; hematoxylin-eosin): leukemic cells show features of atypical erythroid precursors, some times with multi-lobated nuclei (arrow). Right panel: leukemic cells express glycophorin A. Right panel: immunoalkaline phosphatase technique. This picture is the same as that provided by the author (B.F.) for the 2008 WHO Classification of Hematological Neoplasms (page 135).

DS-associated AML develops predominantly in the first 3 years of life. In most cases it occurs de novo but is occasionally preceded by a history of TAM (see above). In some cases, a pre-leukemic phase which is morphologically comparable to refractory cytopenia of childhood may last for several months before AML develops (Baumann et al., 2008). In patients with frank AML, blast cells often have basophilic cytoplasm with coarse basophilic granules and cytoplasmic blebs suggesting megakaryoblasts. Bone marrow trephine is an important diagnostic tool since it usually reveals a dense network of reticulum fibres (responsible for frequent “punctio sicca“) and a marked increase in megakaryocytes with clusters of dysplastic small forms, micromegakaryocytes, and less frequently megakaryoblasts. Blasts are CD117+, CD13+, CD33+, CD7+, CD41+, CD61+, CD14-, myeloperoxidase-, and glycophorin-negative. CD34 is expressed in about 50% of cases. At immunohistochemistry on bone marrow paraffin sections, monoclonal antibodies directed against fixative-resistant epitopes of the CD41 and CD61 and LAT molecules are particularly helpful in detecting cells of megakaryocytic lineage. As in TAM, blast cells carry mutations of the gene encoding the GATA1 transcription factor. AML in children with DS who are over 5 years old and do not bear GATA1 mutations should be regarded as “conventional” AML.

The clinical outcome of GATA1-mutated AML in young children with DS is characterized by excellent response to chemotherapy and very favorable prognosis compared with AML in children without DS. However, there is an ongoing debate on what should be the best chemotherapeutic schedules for these patients (Kudo et al., 2010; Tandonnet et al., 2010).

Blastic plasmacytoid dendritic neoplasm (BPDC)

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Figure 4. Blastic plasmacytoid dendritic cell neoplasm (BPDC). Multiple, violaceous skin lesions of the dorsum (top panel). The dermis is massively infiltrated by blast cells (middle panel, hematoxylin-eosin) that express CD4 (bottom panel) and other plasmacytoid dendritic cells markers (not shown). Panel C: immunoalkaline phosphatase technique.

“Blastic plasmacytoid dendritic cell neoplasms” (BPDC) (Facchetti et al., 2008) was originally inappropriately named “agranular CD4+/CD56+ hematodermic neoplasm” and “blastic NK-cell lymphoma.” Subsequent studies proved the tumor cells were myeloid in origin, deriving from the so-called plasmacytoid dendritic cells. This specialized dendritic cell subset (Jegalian et al., 2009a) plays an immunomodulatory role as it secretes copious amounts of Interferon alpha and other cytokines, including IL-6, IL-8, and TNF alpha. Consequently, the 2008 WHO classification lists BPDC among myeloid and related neoplasms. The underlying genetic alteration is still unknown. Clinically, BPDC is an aggressive tumor characteristically presenting as asymptomatic, solitary, or multiple skin lesions (Figure 4) which are associated with lymphadenopathy in about 20% of cases (Facchetti et al., 2008). Although minimal at presentation, bone marrow involvement invariably develops during disease progression. Morphologically, BPDC is characterized by diffuse proliferation of medium-sized blast cells with irregular nuclei that are usually reminiscent of lymphoblasts (Figure 4). In the skin, neoplastic proliferation is confined to the dermis, sparing the epidermis; there is no angioinvasion or coagulative necrosis. Tumor cells are negative for myeloperoxidase and express a constellation of markers, including CD68 (50% of cases), CD4 (Figure 4), CD43, CD45RA, CD56, and the plasmacytoid dendritic cell-associated antigens CD123, BDCA-2/CD303, TCL1, CLA, and CD2AP (Herling and Jones, 2007; Marafioti et al., 2008; Petrella et al., 2004; Pilichowska et al., 2007). Extensive immunohistochemical studies are mandatory before BPDC can be diagnosed because hematological malignancies such as AML and extranodal NK/T-cell lymphoma, nasal type, with and without skin involvement, may express CD56 with or without CD4. Immunostaining for nucleophosmin (NPM1) differentiates between BPDC and NPM1-mutated AML presenting with skin involvement. In the former, NPM1 is always nucleus-restricted while in the latter it is aberrantly expressed in leukemic cell cytoplasm (Facchetti et al., 2009).

Recognition of BPDC is of great clinical importance since patients respond poorly to conventional chemotherapy. Initial response is invariably followed by relapse involving skin alone or skin plus other sites. Long-lasting remission was occasionally achieved only after allogeneic stem cell transplantation (Assaf et al., 2007). Prognosis in pediatric patients appears more favorable, even without allogeneic stem cell transplantation (Jegalian et al., 2009b).

Conclusions and Future Perspectives

One major, unresolved issue is the nature of the underlying genetic alterations in approximately 40% of AML cases with normal karyotype that are now lumped into the AML-NOS category of the revised classification. The increasing availability of genome-wide sequencing technologies for analysis of human neoplasms (Ley et al., 2008; Mardis et al., 2009) promises to unravel new genetic lesions, so that in the near future the number of patients that are presently classified as AML-NOS will certainly diminish and eventually disappear. It will also be important to establish which genetic lesions are founder, driving events defining disease entities and which are secondary alterations related to tumor progression. The prognostic impact of each newly discovered recurrent genetic alteration will also have to be assessed.

bone marrow aspirate stained with the anti-PML (PG-M3) monoclonal antibody. Leukemic promyelocytes show nuclear “microgranular” positivity for PML protein (double arrow) characterized by very numerous nuclear dots that are difficult to count. In contrast, normal residual hematopoietic cells display a speckled PML positivity (single arrow) characterized by a few nuclear dots that are easy to count. Immunoalkaline phosphatase technique.

Figure 5. Acute promyelocytic leukemia with t(15;17)/PML-RARα: bone marrow aspirate stained with the anti-PML (PG-M3) monoclonal antibody. Leukemic promyelocytes show nuclear “microgranular” positivity for PML protein (double arrow) characterized by very numerous nuclear dots that are difficult to count. In contrast, normal residual hematopoietic cells display a speckled PML positivity (single arrow) characterized by a few nuclear dots that are easy to count. Immunoalkaline phosphatase technique.

Another important challenge is how to create a genetically based classification of myeloid neoplasm that can be used worldwide. One attractive approach is to find simple, low-cost surrogates for molecular studies that are not readily available in developing countries. Notably, immunohistochemistry for PML (Falini et al., 1997) (Figure 5) and NPM1 (Falini et al., 2006) already recognizes about 40% of AML genetically. The increasing use of wide genome sequencing techniques is expected to identify new mutated genes whose protein products may be targeted by monoclonal antibodies. The final hope is that a more genetic-oriented classification of AML will contribute to a better classification of myeloid neoplasms, improve risk-adapted stratification of leukemic patients, and develop new classes of anti-leukemic drugs for targeted therapy.

Disclosure

B. Falini applied for a patent on clinical use of NPM1 mutants. Other authors have none to disclose.

(Corresponding author: Prof. Brunangelo Falini, Institute of Hematology, University of Perugia, Perugia, Italy.)

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(53):281-292, October 2010.]

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