Blastic NK cell lymphoma has been described under the various names including lymphoblastic lymphoma of NK phenotype, blastoid NK cell lymphoma, and leukemic lymphoma of immature NK lineage, and recently defined as a distinct entity of unknown cellular origin in the new World Health Organization classification (1
). The neoplastic cells are negative for surface CD3 and are positive for CD56. CD4 is usually expressed. CD68 is generally negative, or only weakly and focally expressed. Expression of CD2, cytoplasmic CD3ε, and cytotoxic molecules is variable, but usually negative. Some cases are TdT and/or CD34-positive. Diagnosis of blastic NKL can be made in the absence of commitment to the B-, T-cell or myeloid lineage. Thus the tumor should be negative for TCR gene rearrangement, surface CD3, myeloperoxidase, CD13 and CD33 (1
). In the present study, all cases showed blastoid morphology and expressed CD56 and CD4 with absence of myeloperoxidase expression and TCR gene rearrangement, thus fulfilling the minimum criteria of blastic NKL in the current WHO classification. Similar to previous reports, two cases presented with skin lesions, but the others presented with lymphadenopathy. TdT expression was noted in only one case.
These blastic NKL raises two interesting questions. First, is the term, blastic NKL, appropriate to define these CD4+ CD56+ lineage-negative blastoid neoplasms? Second, what is the pathogenetic implication of TdT expression in blastic NKL?
In the normal developmental pathway of NK cells, pre-NK cells express CD161, immature NK cells express CD161 and CD56, and mature NK cells express CD161, CD56 and CD94. Whereas aggressive NK-cell leukaemia/lymphoma and nasal NK-cell lymphoma, express both CD56 and CD94 with strong NK activity, tumor cells of blastic NKL lack CD94 and CD161 and express CD56 only (6
). That is, blastic NKL does not express any of these mature or immature NK-related markers except CD56. CD56 is not NK-lineage specific marker but often expressed on various types of neoplasia that are not of NK lineage (6
). The only presence of CD56 without other evidence of NK lineage is not sufficient to support the notion that those tumors are of NK blast. Hence, some authors have objected to the term "Blastic NK lymphoma" and proposed other name about these CD56+ CD4+ non-B, non-T neoplasms.
The term "CD56 positive undifferentiated acute leukemia" was suggested by Almasri et al. who denied NK cell origin for this tumor because CD4 is not expressed on normal fetal or adult NK cells (7
). On the other hand, Petrella et al. proposed "CD4+CD56+ hematodermic neoplasm", because these neoplasms mainly involve the skin (2
). In addition, they asserted that CD4+CD56+ hematodermic neoplasm is a tumor of plasmacytoid dendritic cell (pDC) (2
). Likewise Jacob et al. proposed "early plasmacytoid dendritic cell leukemia/lymphoma" for those CD4+CD56+ lineage-negative neoplasm (8
Recently, Karube et al. divided non-B, non-T (lineage negative) neoplasms with lymphoblastic morphology into four types based on immunohistochemistry. They are 1) CD7+ stem cell lymphoma [CD4-, CD7+, CD33+/-, CD56-], 2) blastic NKL [CD4-, CD7+/-, CD33-, CD56+, CD123-], 3) myeloid/NK precursor cell leukemia [CD4-, CD7+, CD33+, CD56+], and 4) CD4+CD56+ hematodermic malignancy [CD4+, CD7+/-, CD33-, CD56+, CD123+]. Based on differences of clinical and phenotypical features, they contended that "CD4-56+ blastic NKL" is clearly distinct from CD4+ CD56+ hematodermic neoplasm (9
pDC is an immature dendritic cell, and represents the key effector cells in the early antiviral innate immune response by producing large amounts of IFN-α/β upon viral infection. pDC induces CD13, CD33, and CD11c myeloid antigens when cultured in GM-CSF or IL-3. This lineage conversion supports the potential of pDCs to differentiate to myeloid lineage as observed in occasional development of acute myelomonocytic leukemia following cutaneous "blastic NKL" (10
Another issue in blastic NKL is an expression of TdT in some but not all the cases. In the blastic NKLs reported previously, TdT was expressed in 19 of 31 CD4+CD56+ cases and 14 of 15 CD4-CD56+ cases (3
). In the study by Petrella et al. (2
), all the 14 CD4+CD56+CD123+ hematodermic neoplasms were negative for TdT. Herling et al. showed 7 cases of CD4+CD56+CD123+ plasmacytoid dendritic cell tumors expressing TdT in variable patterns, and two of their patients had transformation to myelomonocytic leukemia (25
). TdT is a marker for lymphoid blast and expressed in B- and T-lymphoblastic lymphoma, acute lymphoblastic leukemia, and lymphoblastic crisis of chronic myelogenous leukemia. Generally TdT is not expressed in cells of non-lymphoid malignancy, although approximately 20% of acute myeloid leukemia have TdT+ blasts, some of them express both myeloid markers and TdT. Even though there have been no data regarding TdT expression in normal precursors of NK cells and dendritic cells, in vitro studies showed that T, B, NK, and dendritic cells have a common progenitor in the extrathymic and thymic tissue (26
). In conjunction with development of myelomonocytic leukemia in some blastic NKL, expression of TdT in tumor cells suggests that blastic NKL is basically of multipotent cells which can differentiate into dendritic cell, myelomonocyte, and lymphoblast of either T cell or NK cell with the majority committed to plasmacytoid dendritic cell.
Histologically, our Case 3 exhibited rosette-like appearance. Homer-Wright rosettes consisting of neoplastic cells surrounding an eosinophilic fibrillary center without a lumen, is an important finding favoring a neuroepithelial tumor in the differential diagnosis of small round cell malignancy. In the malignant lymphoma, rosette-formation is a rare finding and has been reported in only a few cases.
As for treatment and prognosis, all three cases in the current study except one lost during follow-up, were treated with aggressive chemotherapy with or without radiation therapy. However, the outcomes were dismal. All three patients died from eight to sixty months after diagnosis. Clinical outcomes of our cases were similar to the known poor prognosis of CD56+ CD4+ non-B, non-T neoplasia reported previously (14
). Some other studies revealed that the patients treated with allogenic or autologous stem cell transplantation had a significantly more favorable prognosis than those treated with only chemotherapy and radiation therapy. This finding implies that intensive chemotherapy with stem cell transplantation might improve the prognosis of these types of blastoid lymphomas (8
In summary, we described clinicopathologic findings of 4 cases CD4+CD56+ non-B, non-T neoplasm (Blastic NKL by current WHO classification) which are distinct from other NK/T-cell lymphomas and show characteristic histological and immunophenotypic findings. Because the term "blastic NK cell lymphoma" seems to be a misnomer, we are looking forward to having an appropriate new terminology for this tumor in next WHO classification.