Pathology of Other Myeloid Related Precursor Neoplasms

Updated: Mar 13, 2014
  • Author: Cherie H Dunphy, MD, FCAP, FASCP; Chief Editor: Cherie H Dunphy, MD, FCAP, FASCP  more...
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Overview

Overview

Myeloid-related precursor neoplasms derive from precursor cells that have at least one form of myeloid differentiation. Plasmacytoid monocytes are seen in blastic plasmacytoid dendritic cell (BPDC) neoplasm; and myeloid cells are seen in stem cell leukemia/lymphoma (SCLL), which is also known as 8p11 myeloproliferative syndrome (EMS).

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Disorders

See the list below:

  • Blastic plasmacytoid dendritic cell neoplasm
  • Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)
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Definition

Blastic plasmacytoid dendritic cell neoplasm

BPDC neoplasm is composed of cells with a lymphoblastlike morphology; the tumor derives from the precursors of plasmacytoid dendritic cells (ie, plasmacytoid monocytes). Previous terms for this disorder have included CD4+CD56+ hematodermic tumor (HDT) and blastic natural killer (NK) cell lymphoma.

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

Stem cell leukemia/lymphoma (SCLL), which is also known as the 8p11 myeloproliferative syndrome (EMS), is characterized in its typical form by the occurrence, either simultaneously or sequentially, of a bcr/abl-negative myeloproliferative disorder and a lymphoma, usually a precursor T-cell lymphoblastic lymphoma. The presence of the characteristic chromosomal translocation always involving the fibroblast growth factor receptor 1 (FGFR1) gene at chromosome 8p11 in both the myeloid and lymphoid malignancies suggests bilineage differentiation from an affected pluripotent stem cell.

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Epidemiology

Blastic plasmacytoid dendritic cell neoplasm

BPDC neoplasm is a rare disorder without any known racial or ethnic predilection. This condition is more common in male patients (male-to-female ratio, 3.3). Although BPDC neoplasm occurs more frequently in the elderly, the tumor may occur in patients of any age, including pediatric patients.

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

SCLL is a relatively rare disorder that occurs more frequently in male patients (male-to-female ratio, 3:2), and the disease may arise in patients of any age (age range, 3-84 y).

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Clinical Features

Blastic plasmacytoid dendritic cell neoplasm

Frequent sites of occurrence of BPDC neoplasm include the skin (60-100%), as well as the peripheral blood (PB) and bone marrow (BM) (60-90%). Patients may present with cytopenia (particularly thrombocytopenia).

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

Clinical features typical of SCLL include the following: constitutional symptoms at presentation; an aggressive lymphoma with generalized lymphadenopathy, which generally spares the mediastinum (splenomegaly and variable hepatomegaly are also frequent findings); and peripheral blood neutrophilic leukocytosis and eosinophilia arising during the course of the disease.

Hemoglobin levels vary; they may be elevated, depending on the particular hematologic entity present. Platelet counts are rarely elevated. As with chronic myelogenous leukemia (CML), the myeloproliferative aspect of SCLL has a chronic phase that transforms into a myeloblastic phase, typically within 1 year of diagnosis. The acute leukemia is resistant to conventional chemotherapy.

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Morphologic Features

Blastic plasmacytoid dendritic cell neoplasm

BPDC neoplasm is characterized by a monotonous infiltration by medium-sized blasts with irregular nuclei, fine chromatin, and a variable number of inconspicuous nucleoli, as seen in the image below. The associated cytoplasm is scant, agranular, and grayish-blue. Angioinvasion and coagulative necrosis are distinctly and importantly absent. Scattered mitoses may be present in varying number.

Skin involvement by blastic plasmacytoid dendritic Skin involvement by blastic plasmacytoid dendritic cell neoplasm.

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

Early in the course of SCLL, bone marrow morphology most often displays features of an atypical myeloproliferative disorder, although it may manifest considerable variability. Findings consistent with chronic myelomonocytic leukemia have been noted in at least several patients. [1, 2, 3] In an unusual case, a 20-year-old man was reported to have had preexisting polycythemia vera for 8 years before transformation to acute myelomonocytic leukemia (AML-M4) with t(6;8)(q27; p11). [4]

There have been reports of several patients with SCLL whose bone marrow findings at the time of diagnosis of SCLL showed acute myeloid leukemia, either alone (see the following image), [5, 6] concurrent with precursor T-cell lymphoblastic lymphoma (T-LBL), [7] or as a bilineage acute leukemia together with precursor B-cell acute lymphoblastic leukemia (B-ALL). [8, 9] In at least 3 instances, patients presented with ALL alone; 2 patients presented with precursor B-ALL, [10, 11] and 1 patient presented with precursor T-ALL. [12] Lymph node findings at diagnosis have been more consistent, with most cases demonstrating morphologic and phenotypic features of precursor T-LBL, with or without eosinophils. In rare cases, findings are consistent with myeloid (granulocytic) sarcoma. [13, 14]

Blasts of stem cell leukemia. Blasts of stem cell leukemia.
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Immunophenotypic Features and Methods

Blastic plasmacytoid dendritic cell neoplasm

The neoplastic cells in BPDC neoplasm are typically positive for CD45, HLA-Dr, CD43, CD4, CD56, and cutaneous lymphocyte-associated antigen (CLA). [15] The pDC markers, CD123 (strong, >90% of cases), TCL-1 (90% of cases), CD45RA, blood dendritic cell antigen (BCDA)-2 (expressed in more mature cases), and myxovirus A (MxA) may be detected by flow cytometric immunophenotyping (FCI) and/or immunohistochemical (IHC) staining. [16] Some cases demonstrate CD2 positivity, weak CD7 positivity, weak CD33 positivity, TdT positivity (up to 50% of cases), and CD68 positivity.

All cases are otherwise negative for Epstein-Barr virus (EBV) (assayed using in situ hybridization for EBV-encoded RNA [EBER-ISH]), B-cell, T-cell, myeloid, and NK cell markers, as well as for cytotoxic proteins (assayed using IHC). Granzyme B may be demonstrated by FCI. [17, 18] The neoplastic cells are also negative for nonspecific esterase and myeloperoxidase enzyme cytochemical stains.

It should be noted that in rare cases, test results for CD56 are negative; such a finding does not exclude the diagnosis of BPDC neoplasm, provided there is expression of CD4, CD123, and TCL1 by the neoplastic cells. However, tumors that share some but not all immunophenotypic features of BPDC neoplasm may better be classified as acute leukemia of ambiguous lineage.

FCI allows for multicolor analysis, which is particularly important in defining the "lineage-negative" immunophenotype of the neoplastic cells of BPDC neoplasm. Although FCI offers the advantage of defining the lineage-negative immunophenotype in this disorder, paraffin IHC may be useful in limited biopsy specimens and for the evaluation of markers not available for, or routinely analyzed by, FCI (ie, BDCA-2, MxA protein, EBV-EBER-ISH, cytotoxic granule-associated proteins). Paraffin IHC also plays an important role in the differential diagnosis.

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

The immunophenotypic features of SCLL depend on and are reflective of the particular hematologic entity and the particular type of lymphoma.

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Molecular/Genetic Features and Methods

Blastic plasmacytoid dendritic cell neoplasm

T-cell receptor–[gamma] (TCR γ ) gene rearrangement is absent in cases of BPDC neoplasm. Although clonal rearrangements of the TCR genes are lacking, occasional cases with clonal or oligoclonal TCR-gamma or TCR-delta chain gene rearrangements have been reported; these rearrangements are perhaps related to the blast stage and the expression of TdT. [19, 20] Although no single defining genetic abnormality has been described, complex structural chromosomal abnormalities have been demonstrated.

By far, the most frequently observed abnormality is deletion 5q (found in up to 72% of cases), followed in order of decreasing frequency by alterations of 13q, 12p, and 6q, and by losses of chromosomes 15 and 9. [21, 22, 23, 24, 25, 26] Trisomies of chromosomes 8 and 21 and monosomy 7 are rare, in contrast with acute myeloid leukemia and myelodysplastic syndromes (MDS). [27, 28]

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

The defining cytogenetic abnormality, a translocation at the 8p11 locus, always involves the fibroblast growth factor 1 (FGFR1) gene. To date, 8 partner genes have been identified in association with FGFR1 rearrangements. The most frequent FGFR1 translocation partner is the zinc finger gene ZNF198, located at 13q11. The t(8;13)(p11;q11) disrupts intron 8 of the FGFR1 gene and fuses proline-rich and zinc finger domains of the ZNF198 gene with the cytoplasmic tyrosine kinase domain of FGFR1. Oligomerization of the fusion protein occurs, with subsequent activation of downstream signal transduction pathways, culminating in neoplastic cell transformation.

Through review of reported karyotypes in SCLL, it is evident that gain of an additional copy of chromosome 21 is a nonrandom cytogenetic event apparently associated with progression of this disease. This abnormality was reported in only 5 of 47 (10.6%) karyotypes from the time of diagnosis; in follow-up, however, it was reported in 10 of 13 (76.9%) karyotypes. These karyotypes were mostly derived during clinical deterioration.

In addition, a case was recently reported of a precursor T-LBL with prominent eosinophilia; examination of a bone marrow biopsy specimen showed severe myeloid hyperplasia with eosinophilia, increased reticulin fibers, and an absence of evidence of lymphoma involvement. [29] Cytogenetic analysis showed a 46,XY,t(8;12)(q11;p12) karyotype in all of the 15 mitoses that were analyzed. Polymerase chain reaction (PCR) displayed rearrangement of TCR-gamma; PCR results were negative for the bcr-abl translocation, JAK-2 mutation, and the FIP1L1/PDGFRA fusion gene. [29]

The report concluded that SCLL is not associated solely with 8p11 but may also be associated with other genetic alterations, such as t(8;12)(q11;p12). [29] This case involving an unusual chromosomal abnormality also demonstrated a rapid development of resistant leukemia.

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Prognosis and Predictive Factors

Blastic plasmacytoid dendritic cell neoplasm

The overall prognosis of patients with BPDC neoplasm is poor (median survival, 12-14 mo), despite multiagent chemotherapy and/or radiation therapy. The clinical course is characterized by invariable relapses, and a fulminant leukemic phase ultimately develops in most patients. [30] Sporadic cases, usually involving young patients who underwent treatment of acute leukemia with therapeutic regimens and subsequent allogeneic stem cell transplantation, have been reported. [31, 32, 33]

Stem cell leukemia/lymphoma (8p11 myeloproliferative syndrome)

SCLL most often terminates in AML that is resistant to conventional chemotherapy. As mentioned previously, gain of an additional copy of chromosome 21 is a nonrandom cytogenetic event that is apparently associated with progression of this disease.

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