the tumor cells of blastic nk cell lymphoma ( blastic nkl ) express cd56 antigen with no obvious evidence of b- or t - cell differentiation and some cases expressing cd4 and tdt . committed natural killer ( nk ) cell has been postulated as a cell of origin , because cd56 ( ncam ) is useful marker in detecting nk - related cells ( 1 ) . however , cd56 is not lineage - specific , and its aberrant expression also has been identified in a variety of unrelated hematopoietic malignancies including acute myeloid leukemia with myelomonocytic differentiation and other immature hematopoietic neoplasms of undefined origin . the results of recent studies challenged the terminology " blastic natural killer cell lymphoma " and support that blastic nkl is a tumor of plasmacytoid dendritic cells , not of nk progenitors ( 2 ) . herein we report 4 cd56 + cd4 + non - b , non - t , non - myeloid neoplasms with blastoid morphology . a 45-yr - old man presented with multiple subcutaneous masses in the left upper and lower extremities . at that time , neither lymph nodal involvement nor leukemia was detected . the patient received 6 cycles of chop ( cyclophosphamide , adriamycin , vincristine , prednisolone ) and imvp-16 ( ifosfamide , methotrexate , etoposide , prednisolone ) , but the disease progressed . multiple subcutaneous masses and lymph nodal invasion developed in 10 and 21 months after the first visit . he received adjuvant radiation therapy , but leukemic transformation ( blast , 34% in peripheral blood smear ) and brain involvement also occurred in 23 and 27 months after initial presentation , respectively . in spite of further chemotherapy with daunorubicin , ara - c ( cytosine arabinoside ) , vincristine and prednisolone as well as intrathecal chemotherapy , he died of sepsis 28 months after the diagnosis . a 17-yr - old girl presented with multiple bluish and purpuric maculopatches on the upper and lower extremities and back , and a deep subcutaneous nodule for 2 months . the patient was transferred to another hospital and further follow - up results were not available . an 18-yr - old man was admitted with left inguinal lymphadenopathy , night sweat and weight loss . a computed tomographic scan of the abdomen revealed splenomegaly and the enlarged left para - aortic lymph nodes . peripheral blood findings were as follows : hemoglobin ( hb ) 15.5 g / dl ; white blood cells ( wbc ) 5.410/l ; normal differential counts except increased monocytes ( 10.2% ) . the level of ldh ( 261 iu / l ) and ast ( 144 u / l ) increased . bone marrow aspiration and extraction of a wisdom tooth followed by biopsy of the gum revealed atypical lymphoid infiltration . two months later , he complained of headache and weight loss of 4 kg . on physical examination , he was anemic ( hb 5.6 g / dl , hct 15.7% , reticulocytes 0.08% ) and had severe thrombocytopenia ( 93,000/l ) and leukopenia ( 480/l ) . a computed tomographic scan of the head and neck showed a relatively well demarcated tumor in the right ethmoid sinus which extended into the right orbit , and the maxillary and frontal sinuses . a 22 yr - old male patient was admitted with the multiple lymphadenopathy of the inguinal , cervical , and preauricular lymph nodes , the largest of them measuring 4 cm in diameter . a computed tomographic scan of the abdomen revealed diffuse hepatosplenomegaly and the enlarged paraaortic , common iliac , and external iliac lymph nodes . peripheral blood findings were as follows : hb 15.3 g / dl ; wbc 7.410/l ; normal differential except increased monocytes ( 8.2% ) . after biopsy of the cervical lymph node , he received one cycle of chop chemotherapy without response . then high dose chop chemotherapy subsequently the patient underwent peripheral blood stem cell transplantation , however , the tumor recurred in the bone marrow four months later . tumors of all four cases displayed similar appearance and were composed of diffuse infiltration of monotonous medium - to - large blastoid cells . dense infiltration of tumor cells without necrosis or angiocentric growth was noted in the upper and mid - dermis and occasionally in the dermis to the subcutaneous tissue ( fig . biopsy of lymph nodes showed effacement of nodal architecture by diffuse proliferation of monomorphic lymphoid cells . peculiarly , in case 3 , tumor cells were arranged around a central fibrillary core , which was very similar to homer - wright type pseudorosettes seen in neuroepithelial tumors ( fig . cd2 ( novocastra , u.k . ) , cd3 ( novocastra , u.k . ) , cd4 ( novocastra , u.k . ) , cd5 ( novocastra , u.k . ) , cd7 ( novocastra , u.k . ) , cd8 ( novocastra , u.k . ) , cd20 ( novocastra , u.k . ) , cd30 ( dako , denmark ) , cd34 ( dako , denmark ) , cd43 ( serotechs , bethesda , md ) , cd56 ( monosan , the netherland ) , cd68 ( dako ) , cd79a ( dako ) , terminal deoxynucleotidyl transferase ( tdt , dako ) , myeloperoxidase ( dako ) , tia-1 ( immunotech , westbrook , me ) , lysozyme ( zymed , u.s.a . ) were used in the present study . ebv in situ hybridization was performed using the fluorescein - conjugated eber1 and 2 oligonucleotides ( dako , denmark ) . briefly , paraffin sections were pretreated with xylene , followed by the treatment with proteinase k and finally hybridized with ebv oligonucleotides . as negative controls we used ebv - negative lymphoid tissues and the hybridization mixture without the ebv oligonucleotides . the results were all negative . for polymerase chain reaction amplification of the t - cell receptor ( tcr ) gamma gene , a 45-yr - old man presented with multiple subcutaneous masses in the left upper and lower extremities . at that time , neither lymph nodal involvement nor leukemia was detected . the patient received 6 cycles of chop ( cyclophosphamide , adriamycin , vincristine , prednisolone ) and imvp-16 ( ifosfamide , methotrexate , etoposide , prednisolone ) , but the disease progressed . multiple subcutaneous masses and lymph nodal invasion developed in 10 and 21 months after the first visit . he received adjuvant radiation therapy , but leukemic transformation ( blast , 34% in peripheral blood smear ) and brain involvement also occurred in 23 and 27 months after initial presentation , respectively . in spite of further chemotherapy with daunorubicin , ara - c ( cytosine arabinoside ) , vincristine and prednisolone as well as intrathecal chemotherapy , he died of sepsis 28 months after the diagnosis . a 17-yr - old girl presented with multiple bluish and purpuric maculopatches on the upper and lower extremities and back , and a deep subcutaneous nodule for 2 months . the patient was transferred to another hospital and further follow - up results were not available . an 18-yr - old man was admitted with left inguinal lymphadenopathy , night sweat and weight loss . a computed tomographic scan of the abdomen revealed splenomegaly and the enlarged left para - aortic lymph nodes . peripheral blood findings were as follows : hemoglobin ( hb ) 15.5 g / dl ; white blood cells ( wbc ) 5.410/l ; normal differential counts except increased monocytes ( 10.2% ) . the level of ldh ( 261 iu / l ) and ast ( 144 u / l ) increased . bone marrow aspiration and extraction of a wisdom tooth followed by biopsy of the gum revealed atypical lymphoid infiltration . on physical examination , protrusion of the right eyeball and enlargement of right neck lymph nodes were found . he was anemic ( hb 5.6 g / dl , hct 15.7% , reticulocytes 0.08% ) and had severe thrombocytopenia ( 93,000/l ) and leukopenia ( 480/l ) . a computed tomographic scan of the head and neck showed a relatively well demarcated tumor in the right ethmoid sinus which extended into the right orbit , and the maxillary and frontal sinuses . a 22 yr - old male patient was admitted with the multiple lymphadenopathy of the inguinal , cervical , and preauricular lymph nodes , the largest of them measuring 4 cm in diameter . a computed tomographic scan of the abdomen revealed diffuse hepatosplenomegaly and the enlarged paraaortic , common iliac , and external iliac lymph nodes . peripheral blood findings were as follows : hb 15.3 g / dl ; wbc 7.410/l ; normal differential except increased monocytes ( 8.2% ) . the level of ldh ( 676 after biopsy of the cervical lymph node , he received one cycle of chop chemotherapy without response . subsequently the patient underwent peripheral blood stem cell transplantation , however , the tumor recurred in the bone marrow four months later . tumors of all four cases displayed similar appearance and were composed of diffuse infiltration of monotonous medium - to - large blastoid cells . dense infiltration of tumor cells without necrosis or angiocentric growth was noted in the upper and mid - dermis and occasionally in the dermis to the subcutaneous tissue ( fig . biopsy of lymph nodes showed effacement of nodal architecture by diffuse proliferation of monomorphic lymphoid cells . peculiarly , in case 3 , tumor cells were arranged around a central fibrillary core , which was very similar to homer - wright type pseudorosettes seen in neuroepithelial tumors ( fig . cd2 ( novocastra , u.k . ) , cd3 ( novocastra , u.k . ) , cd4 ( novocastra , u.k . ) , cd5 ( novocastra , u.k . ) , cd7 ( novocastra , u.k . ) , cd8 ( novocastra , u.k . ) , cd20 ( novocastra , u.k . ) , cd30 ( dako , denmark ) , cd34 ( dako , denmark ) , cd43 ( serotechs , bethesda , md ) , cd56 ( monosan , the netherland ) , cd68 ( dako ) , cd79a ( dako ) , terminal deoxynucleotidyl transferase ( tdt , dako ) , myeloperoxidase ( dako ) , tia-1 ( immunotech , westbrook , me ) , lysozyme ( zymed , u.s.a . ) were used in the present study . ebv in situ hybridization was performed using the fluorescein - conjugated eber1 and 2 oligonucleotides ( dako , denmark ) . briefly , paraffin sections were pretreated with xylene , followed by the treatment with proteinase k and finally hybridized with ebv oligonucleotides . as negative controls we used ebv - negative lymphoid tissues and the hybridization mixture without the ebv oligonucleotides . the results were all negative . for polymerase chain reaction amplification of the t - cell receptor ( tcr ) gamma gene , 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 ) . expression of cd2 , cytoplasmic cd3 , and cytotoxic molecules is variable , but usually negative . 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 . 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 ) . 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-/ 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 , 9 - 24 ) . in the study by petrella ( 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 , 27 ) . 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 . 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 . clinical outcomes of our cases were similar to the known poor prognosis of cd56 + cd4 + non - b , non - t neoplasia reported previously ( 14 , 28 ) . 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 , 9 ) 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 .
blastic natural killer ( nk ) cell lymphoma is a rare neoplasm characterized by blastoid tumor cells expressing cd4 and cd56 , with predominant skin involvement . 
 although this tumor has been regarded as a neoplasm related to nk cell , recent studies suggested that it is derived from plasmacytoid dendritic cells , but not from nk cell . 
 herein we report 4 cases of cd4+cd56 + lineage marker- blastic nk cell lymphomas with a review of literatures . 
 the patients were 3 men and one woman . 
 three of them were young ( 17 , 18 , and 22 yr old ) . 
 three patients had skin lesions , at initial presentation in two patients and during the course of disease in other patient . 
 histologically , tumors consisted of monotonous medium to large blastoid cells showing no necrosis , angiocentric growth or epidermotrophism . 
 all four tumors were cd4 + and cd56 + . 
 three expressed cd68 antigen . 
 lineage specific markers for b- and t cell were negative . 
 all tumors did not express myeloperoxidase . 
 t - cell receptor gene rearrangement , ebv , cd13 and cd33 were negative . 
 in one patient , tumor cells arranged in homer - wright type pseudorosette and expressed terminal deoxynucleotidyl transferase ( tdt ) . despite the standard lymphoma chemotherapy , the tumors , except one lost during follow - up , progressed and relapsed . 
 the patients died 8 - 60 months after diagnosis .