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This is a group of aggressive lymphomas that have marked propensity to occur in the nose and paranasal sinuses. They are also known as angiocentric lymphomas and CD56 lymphomas. They are more common in men and peak during the 5th decade. Localized disease may be treated with irradiation with a 77% complete remission rate. In patients relapsing, disseminated disease may involve the skin, regional lymph nodes, lungs, and brain.

Under the microscope, these tumors are composed of a polymorphous mixture of inflammatory cells admixed with atypical lymphocytes having hyperchromatic, enlarged, and convoluted nuclei. These cells have a marked propensity to infiltrate large blood vessels. The identifying trait is found by immunohistochemistry which shows strong immunopositivity for CD56, a marker for natural killer (NK) cell differentiation. Natural killer cells comprise 10-15% of the normal circulating lymphocytes in the peripheral blood and play an important role in the immune system by lysing tumor cells without prior sensitization. These NK cells were once called null cells since they lack most of the usual T and B cell surface antigens.

CD56 is found in a small population of normal T cells. However, other T cell markers including T cell receptor gene rearrangement studies are negative. Epstein-Barr virus is reliably demonstrated indicating a primary pathogenic role for this virus.

SYNONYMS Sinonasal and extra-nasal NK/T-cell lymphoma
Common in Asia and South and Central America

Clinicopathologic and genotypic study of extranodal nasal-type natural killer/T-cell lymphoma and natural killer precursor lymphoma among Koreans.

Ko YH, Ree HJ, Kim WS, Choi WH, Moon WS, Kim SW.

Department of Diagnostic Pathology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.

Cancer 2000 Nov 15;89(10):2106-16 Abstract quote

BACKGROUND: This study aimed to define genotypic profile and to describe the clinicopathologic features of nasal-type natural killer (NK)/T-cell lymphoma of nasal and extranasal origin and NK precursor lymphoma.

METHODS: NK/T-cell lymphomas from the upper aerodigestive tract (n = 45), skin (n = 2), gastrointestinal tract (n = 3), and soft tissue (n = 2) and NK precursor neoplasms (n = 3) were studied. Immunophenotype was analyzed by immunohistochemistry and flow cytometry. In situ hybridization with EBER 1/2 RNA probes was performed. T-Cell Receptor (TCR)-gamma gene rearrangement was analyzed by seminested polymerase chain reaction with heteroduplex analysis. Overall survival rate was correlated with clinicopathologic parameters and compared by Wilcoxon test.

RESULTS: Clonal TCR-gamma gene rearrangement was detected in 3 of 31 upper aerodigestive and 1 of 2 skin tumors. When immunostained using paraffin embedded tissue, 6 upper aerodigestive lymphomas were negative for CD56 in which 4 cases lacked clonal TCR gene rearrangement. Epstein-Barr virus (EBV) mRNA was detected in 33 upper aerodigestive tumors including 26 of 29 nasal tumors (90%), and 7 of 10 extranasal tumors (70%). There was no histologic, immunophenotypic, or genotypic differences according to the lineage and EBV association in upper aerodigestive lymphomas. Among the patients with upper aerodigestive tumors, overall 1-year survival rate was 41%, and correlated well with the stage (P < 0.05) but not with the size of tumor cells, EBV status, and lineage (P > 0.05). Median survival rate of lymphomas from other sites excluding upper aerodigestive tract was not significantly different from that of upper aerodigestive lymphomas with same stage (P > 0.05). Unlike nasal-type NK/T-cell lymphomas, NK precursor lymphoma involved the bone marrow and lymph nodes at initial presentation or in the course of disease. Tumor cells were positive for TdT in all and myeloid markers in two. TCR gene rearrangement was germ line.

CONCLUSIONS: Most upper aerodigestive nasal-type NK/T-cell lymphomas among Koreans are genotypically of NK derivation and few belong to T lineage. Presence or absence of EBV has no significant correlation with the histologic changes and the lineage of these lymphomas.

Sinonasal NK/T-cell Lymphomas in the United States

Karl Gaal, M.D.; Nora C. J. Sun, M.D.; Antonio M. Hernandez, M.D.; Daniel A. Arber, M.D.

From the Departments of Pathology at City of Hope National Medical Center, Duarte, California, (K.G., D.A.A.), Harbor UCLA Medical Center, Torrance, California (N.C.J.S.), and Kaiser Permanente, Los Angeles, California, U.S.A. (A.M.H.).

Am J Surg Pathol 2000;24:1511-1517 Abstract quote

Sinonasal natural killer (NK)/T-cell lymphomas are common in Asia and areas of South and Central America but are rarely seen in the United States, where they have not been as well characterized.

Fifteen cases diagnosed in Southern California were studied with respect to histologic features, immunophenotype, Epstein-Barr virus EBER in-situ hybridization (EBV EBER-ISH), and T-cell receptor gamma chain (TCR-) gene rearrangement. Although ethnic background was available for only seven patients, six were of Asian or Hispanic descent with only one non-Hispanic white known. Twelve presented as sinonasal lesions, but three were limited to the oropharynx. Most cases (11 of 15) demonstrated both necrosis and an angiodestructive pattern. All cases demonstrated cytoplasmic CD3 positivity (15 of 15), and were positive for both TIA-1 and granzyme B (14 of 14). Perforin was positive in 5 of 14. CD56 was expressed in 10 of 15 and CD8 in 3 of 15. EBV EBER-ISH was positive in 14 of 14 and TCR- gene rearrangement was detected in 1 of 14 cases. None (0 of 14) were positive for CD16 or CD57. Although CD16-positive histiocytes were abundant, double-label EBER-ISH/IHC failed to identify CD16 expression on EBV-positive tumor cells. Three cases with pleomorphic large cell morphology showed focal CD30 positivity, raising the differential diagnosis of anaplastic large cell lymphoma, but all were ALK-1-negative and otherwise similar to the other cases of NK/T-cell lymphoma.

Sinonasal NK/T-cell lymphomas in the United States most often occur in ethnic groups from areas of reported high frequency (Asia, Central and South America), although less commonly than in endemic populations, and are otherwise similar phenotypically. A combined approach, including immunohistochemistry, EBV EBER-ISH, and TCR gene rearrangement studies, is most helpful to arrive at the correct diagnosis.


Expression of p53 protein in T- and natural killer-cell lymphomas is associated with some clinicopathologic entities but rarely related to p53 mutations

Hum Pathol 2001:32:196-204

51 cases of these lymphomas for the expression of p53 and its relationship with p53 gene mutations, the expression of the p21 protein as well as the proliferative and apoptotic indices

Overexpression of p53 was found in 19 cases (37%), whereas mutations of the p53 gene were observed in only 5 of 28 tested cases

Anaplastic large cell lymphomas showed a frequent overexpression of p53 (7/8 cases) and p21 (6/8 cases) proteins and rare p53 mutations (1/7 cases)
Nodal peripheral T-cell lymphomas unspecified showed relatively frequent overexpression of p53 protein (5/7 cases), infrequent p21 expression (2/7 cases), and rare p53 gene mutations (1/6 cases)
Angioimmunoblastic lymphomas, the common phenotype was p53–/p21– (15/17 cases), with only a few scattered p53-positive cells, which, on the basis of double staining results, were mostly Epstein-Barr virus-infected B cells. A p53 gene mutation was only found in 1 case (1/8 cases) of angioimmunoblastic lymphoma, Mycosis fungoides showed p53 overexpression in 2 of 4 cases, including 1 case with p53 gene mutation and features of cytologic tumor progression

Nasal NK/T lymphomas showed p53 overexpression in 2 of 5 cases, 1 of which had a p53 gene mutation

All lymphoblastic T-cell lymphomas (5 cases) and hepatosplenic T-cell lymphomas (3 cases) were negative for expression of p53 and p21 proteins.

p53 protein overexpression is a common finding in some entities of T- and T/NK-cell lymphomas, whereas a p53 gene mutation is a rare, sporadic, and rather late event associated with tumor progression in some instances

p53/p21 expression pattern appears to be variable in T- and T/NK-cell lymphoma entities, reinforcing the concept of distinct, entity-related mechanisms of pathogenesis in these tumors

Aggressive NK cell lymphoma/leukemia with clonal der(3)t(1;3) (q12;p25), del(6)(q13) and del(13)(q12q14).

Hamaguchi H, Yamaguchi M, Nagata K, Koike E, Imagunbai M, Tsurukubo Y, Yamamoto K.

Department of Hematology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino, 180-8610, Tokyo, Japan

Cancer Genet Cytogenet 2001 Oct 15;130(2):150-4 Abstract quote

We describe a 54-year-old man with CD2, CD7, and CD56-positive but CD3, CD4, and CD8-negative aggressive NK cell lymphoma/leukemia.

Chromosome analysis of the peripheral blood cells showed clonal aberration consisting of 46,XY,dup(3)(p21p25),der(3)t(1;3)(q12;p25),del(5)(q13q22), del(6)(q13),del(13)(q12q14). The peripheral blood lymphoma cells contained clonal EBV-DNA by Southern blot analysis. The disease was refractory to chemotherapy and the clinical course was aggressive and rapid. Deletion 6q and deletion 13q have been frequently reported in NK cell lymphoma/leukemia.

Thus, some tumor suppressor genes involving NK cell malignancies may be present in these regions.

Differential expression of cytotoxic molecules and killer cell inhibitory receptors in CD8+ and CD56+ cutaneous lymphomas.

Kamarashev J, Burg G, Mingari MC, Kempf W, Hofbauer G, Dummer R.

Department of Dermatology, University Hospital, Zurich, Switzerland.

Am J Pathol 2001 May;158(5):1593-8 Abstract quote

Cutaneous lymphomas of the cytotoxic phenotype, including CD8+ and CD56+ lymphomas, have only recently been recognized. To characterize the phenotypic profile of these lymphomas, we investigated the expression of both cytotoxic molecules and killer cell inhibitory receptors by immunohistochemistry techniques.

Frozen sections from four CD8+ and from three CD56+ cutaneous lymphomas were stained for the cytotoxicity markers including T-cell restricted intracellular antigen-1, perforin, granzyme B, and for expression of the inhibitory receptors including p58.1, p58.2, p70, p140, CD94, NKG2, and leukocyte immunoglobulin-like receptor (LIR-1). Apart from LIR-1, the CD8+ lymphomas in our series express p70 and p140 from the inhibitory receptors and only one or two of the cytotoxic proteins. The CD56+ lymphomas, on the other hand, express only LIR-1 of the set of inhibitory receptors and the whole panel of cytotoxic antigens.

Various subtypes of cytotoxic cutaneous lymphomas (CD8+ and CD56+) differ in regard to their phenotypic and functional profile, which may explain differences in their biological behavior.

Molecular Analysis of Tumor Suppressor Genes, Rb, p53, p16INK4A, p15INK4B and p14ARF in Natural Killer Cell Neoplasms.

Sakajiri S, Kawamata N, Egashira M, Mori K, Oshimi K.

Division of Hematology, Department of Medicine, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.

Jpn J Cancer Res 2001 Oct;92(10):1048-1056 Abstract quote

Natural killer (NK) cell neoplasms, which are derived from mature or precursor NK cells, are rare diseases and are observed predominantly in Asian countries.

We analyzed the status of the Rb, p53, p15INK4B, p16INK4A and p14ARF genes in these diseases by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and western blot analysis.

We used 31 NK cell neoplasms, including four cell lines derived from NK cell neoplasms, 3 myeloid / NK cell precursor acute leukemias, 4 blastic NK cell lymphoma / leukemias, 4 aggressive NK cell leukemia / lymphomas, 4 nasal NK cell lymphomas, and 12 chronic NK lymphocytosis. We found gene amplification of the p53 gene in one nasal NK cell lymphoma, and point mutations of the p53 gene in one blastic NK cell lymphoma / leukemia and one chronic NK lymphocytosis. In addition, homozygous deletions of p15, p16 and p14 genes in 5 out of 31 samples were detected; 3 were from nasal NK cell lymphoma and 2 from blastic NK cell lymphoma / leukemia. Also hemizygous deletion of the Rb gene in one blastic NK cell lymphoma was detected. Rb proteins were highly expressed in one cell line as well as two myeloid / NK cell precursor acute leukemias. In other cell lines, complete loss and an aberrant migration pattern of Rb protein expression were observed. Comparative genomic hybridization suggested that the homozygous deletions of the p15, p16 and p14 were subtle chromosomal deletions and could not be identified by standard karyotyping in some cases.

Although the number of cases we analyzed was not large, alterations identified in the Rb, p53, p16, p15 and p14 genes are of significance and might be associated with tumorigenesis in NK cell neoplasms.

Expression of cytotoxic proteins in peripheral T-cell and natural killer-cell (NK) lymphomas: association with extranodal site, NK or Tgammadelta phenotype, anaplastic morphology and CD30 expression.

Kanavaros P, Boulland ML, Petit B, Arnulf B, Gaulard P.

Department of Pathology, Henri Mondor Hospital AP-HP, Creteil, France.

Leuk Lymphoma 2000 Jul;38(3-4):317-26 Abstract quote

Most peripheral T-cell lymphomas (PTCL) express the alphabeta T-cell receptor (TCR) whereas rare PTCL express the gammadelta TCR. Most if not all gammadelta PTCL are extranodal lymphomas and among them, hepatosplenic gammadelta PTCL constitute a distinct clinicopathological entity. Besides alphabeta and gammadelta PTCL, there is a recently recognized group of extranodal, mainly nasal tumours, which display, in most instances, phenotypic and genotypic features of Natural-Killer cell non-Hodgkin's lymphomas (NK-NHL).

Cytotoxic cells, including NK cells and cytotoxic alphabeta and gammadelta T lymphocytes may induce lysis of the target by using granule-associated cytotoxic proteins such as the T-cell intracellular antigen-1 (TIA-1), perforin and granzyme B. Expression of TIA-1 can be detected in all cytotoxic cells whereas granzyme B and perforin expression can be detected in high levels only in activated cytotoxic cells. Recently, several studies showed that the expression of these cytotoxic proteins in tumour cells of PTCL and NK-NHL is associated with a) extranodal site of clinicopathological presentation b) NK or Tgammadelta-cell phenotype c) CD30 expression in cutaneous T-cell lymphoproliferations and d) anaplastic morphology in nodal PTCL. This latter finding contrasts with the data that only rare Hodgkin lymphomas (HL) express cytotoxic proteins in Hodgkin and Reed-Sternberg cells. Altogether the data of the literature indicate that most extranodal T and NK-NHL are activated cytotoxic lymphomas with the notable exception of hepatosplenic gammadelta PTCL which represent tumours of non-activated cytotoxic cells. On this basis, it is suggested that the expression of cytotoxic proteins may be useful for the identification and classification of extranodal T and NK-cell lymphomas and, to some extent, for the differential diagnosis between HL and CD30+ anaplastic large cell lymphomas. Cytotoxic lymphomas are preferentially localized in extranodal sites such as skin, lung, upper respiratory and gastrointestinal tracts, which are continuously exposed to various antigens.

Since cytotoxic T and NK cells are regarded as first line of defense in these sites, and some cytotoxic tumours such as nasal lymphomas and enteropathy-type intestinal lymphomas are associated with EBV and gliadin, respectively, it is likely that chronic antigen exposure may play a role in the pathogenesis of cytotoxic lymphomas occurring in mucosa and/or skin. Besides chronic antigenic stimulation, chronic immunosuppression may also have pathogenetic significance in cytotoxic lymphomas in view of their increased incidence in immunocompromised patients.



Nasal T-cell/natural killer cell lymphoma: CT and MR imaging features of a new clinicopathologic entity.

Ooi GC, Chim CS, Liang R, Tsang KW, Kwong YL.

Department of Diagnostic Radiology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, China.

AJR Am J Roentgenol 2000 Apr;174(4):1141-5 Abstract quote

OBJECTIVE: Nasal T-cell/natural killer cell lymphoma is a new clinicopathologic entity with a characteristic immunophenotypic profile and distinct clinical features. This study describes the radiologic features of nine cases of proven nasal T-cell/natural killer cell lymphoma.

CONCLUSION: Nasal T-cell/natural killer cell lymphoma is often a locally destructive (T stages 3 and 4) disease, typically presenting with obliteration of the nasal passages and maxillary sinuses. Involvement of the adjacent alveolar bone, hard palate, orbits, and nasopharynx is found in more than 50% of cases and is associated with extensive soft-tissue masses. Presence of bone erosion is suggestive but not diagnostic of the disease.


General Divided into nasal type and extranasal type
Extranasal tumor usually present at high stage with systemic symptoms common

Clinicopathological analyses of 5 Japanese patients with CD56+ primary cutaneous lymphomas.

Kojima H, Mukai HY, Shinagawa A, Yoshida C, Kamoshita M, Komeno T, Hasegawa Y, Yamashita Y, Mori N, Nagasawa T.

Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan.

Int J Hematol 2000 Dec;72(4):477-83 Abstract quote

We analyzed the clinicopathological features of 5 Japanese patients with CD56+ primary cutaneous lymphomas (3 men and 2 women aged 25 to 73 years). Except for 1 patient in whom bone marrow involvement was simultaneously observed, all patients presented with cutaneous lesions.

Based on their Epstein-Barr virus (EBV) status, we categorized these patients into 2 groups, namely EBV-encoded small RNA-1 (EBER-1) (3 patients) and EBER-1- (2 patients). Generalized lymphadenopathy and bone marrow involvement were observed only in EBER-1 patients. Morphologically, angiocentric proliferation was more prominent in EBER-1+ patients and was accompanied by panniculitis-like changes. The lymphomas in EBER-1- patients featured monomorphic proliferation of lymphoblastic cells with no cytoplasmic granules. Phenotypically, CD3-, cytoplasmic CD3 epsilon+, and CD56+ were common findings in both types. The EBER-1- type showed an additional distinguishing feature, CD7+, CD4+, CD8-, HLA-DR+, and terminal deoxynucleotidyl transferase-positive (TdT+) phenotype. The lymphoma was primarily resistant in the EBER-1+ type, and the patients died within 6 months of admission. In contrast, the lymphoma in the EBER-1- patients was originally chemosensitive.

Collectively, we consider there to be at least 2 types of CD56+ primary cutaneous lymphomas, corresponding to nasal-type natural killer (NK)/T-cell lymphomas (EBER-1+) and blastic NK-cell lymphomas (EBER-1-).

Blastoid NK cell leukemia/lymphoma with cutaneous involvement.

Ginarte M, Abalde MT, Peteiro C, Fraga M, Alonso N, Toribio J.

Department of Dermatology, Complejo Hospitalario Universitario, Faculty of Medicine, Santiago de Compostela, Spain.

Dermatology 2000;201(3):268-71 Abstract quote

Malignant neoplasms from natural killer (NK) cells are characterized by their positivity for CD56 and absence of monoclonal TCR gene rearrangement. Recently, they have been classified into four main types (nasal and nasal-type NK cell lymphoma, aggressive NK cell leukemia/lymphoma, and blastoid NK cell leukemia/lymphoma), based on clinical features, racial predisposition, presence of azurophilic granules, immunophenotype and association with Epstein-Barr virus (EBV) infection.

A 72-year-old Caucasian man presented with a malignant neoplasm comprised of blastoid cells without azurophilic granules in the Giemsa stain, with positivity for CD2, CD4, HLA-DR, CD45 and CD56, and negativity for CD3 (surface and cytoplasmic) and CD5. In situ hybridization for EBV and PCR analysis of rearrangement of the T cell receptor gene were negative. Based on these results, a diagnosis of blastoid NK cell lymphoma was made.

In this case the first clinical manifestations were the cutaneous lesions, and, although the disease was already advanced at the diagnosis, the patient responded completely to the treatment and remains asymptomatic 14 months after diagnosis.

Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course.

Mraz-Gernhard S, Natkunam Y, Hoppe RT, LeBoit P, Kohler S, Kim YH.

Departments of Dermatology, Pathology, and Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

J Clin Oncol 2001 Apr 15;19(8):2179-88 Abstract quote

PURPOSE: To describe and identify the clinical and pathologic features of prognostic significance for natural killer (NK) and NK-like T-cell (NK/T-cell) lymphoma presenting in the skin.

PATIENTS AND METHODS: This study was a retrospective review of 30 patients with CD56+ lymphomas initially presenting with cutaneous lesions, with analysis of clinical and histopathologic parameters.

RESULTS: The median survival for all patients was 15 months. Those with extracutaneous manifestations at presentation (11 patients) had a shorter median survival of 7.6 months as compared with those without extracutaneous involvement (17 patients), who had a more favorable median survival of 44.9 months (P =.0001). Age, gender, extent of cutaneous involvement, and initial response to therapy had no statistically significant effect on survival. Seven patients (24%) had detectable Epstein-Barr virus (EBV) within neoplastic cells. The patients with tumor cells that coexpress CD30 (seven patients) have not yet reached a median survival after 35 months of follow-up as compared with those with CD30- tumor cells (20 patients), who had a median survival of 9.6 months (P <.02). Routine histopathologic characteristics had no prognostic significance nor did the presence of CD3epsilon, EBV, or multidrug resistance.

CONCLUSION: NK/T-cell lymphoma is an aggressive neoplasm; however, a subset with a more favorable outcome is identified in this study. The presence of extracutaneous disease at presentation is the most important clinical variable and portends a poor prognosis. The extent of initial skin involvement does not reliably predict outcome. Patients from the United States with NK/T-cell lymphoma presenting in the skin have a low incidence of demonstrable EBV in their tumor cells. Patients with coexpression of CD30 in CD56 lymphomas tend to have a more favorable outcome.

A Case of Primary Cutaneous CD56+, TdT+, CD4+, Blastic NK-Cell Lymphoma in a 19-year-old Woman.

Chang SE, Choi HJ, Huh J, Choi JH, Sung KJ, Moon KC, Koh JK.

Department of Dermatology (S.E.C., J.H.C., K.J.S., K.C.M., J.K.K.) and Pathology (H.J.C., J.H.), Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.

Am J Dermatopathol 2002 Feb;24(1):72-5 Abstract quote

The classification of blastic or blastoid natural killer (NK)-cell lymphoma is controversial.

Reports of primary cutaneous blastic CD56+ NK-cell lymphoma are rare, which necessitates further clinicopathologic definition of this type of lymphoma. Most CD56+ lymphomas display angiocentric histologic features, especially in Asian patients, and these are mostly associated with the presence of Epstein-Barr virus (EBV) genome and with an aggressive clinical course.

We report on a young woman with a primary cutaneous blastic NK lymphoma which showed no angiocentric features but showed an unusual immunophenotype; CD56+, TdT+, CD4+, EBV-, and germline configuration of T-cell receptor gene. This unusual lymphoblastic lymphoma seems to have an immature or progenitor NK cell lineage.

Cutaneous natural killer/T-cell lymphoma

Michael A. Radonich, MD
Rossitza Lazova, MD
Jean Bolognia, MD

New Haven, Connecticut
J Am Acad Dermatol 2002;46:451-6 Abstract quote

Lymphomas are classified as either Hodgkin's or non-Hodgkin's. The 2 subtypes of non-Hodgkin's lymphoma that can present primarily in the skin are cutaneous T-cell lymphoma and cutaneous B-cell lymphoma, both of which tend to be low-grade malignant neoplasms. Recently another distinct subtype of lymphoma was discovered, the natural killer (NK)/T-cell lymphoma, which can involve the skin in a primary or secondary fashion. The NK/T-cell subtype of lymphoma is characterized by the expression of the NK-cell antigen CD56. These CD56+ lymphomas are further subdivided into nasal NK/T-cell lymphomas that commonly present as midfacial destructive disease and non-nasal NK/T-cell lymphomas that often arise in extranodal locations, including the skin.

We report a case of aggressive NK-cell leukemia/lymphoma with numerous secondary cutaneous lesions and review the clinical and histopathologic spectrum of non-nasal CD56+ lymphomas, with an emphasis on the dermatologic findings.

Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells.

Katoh A, Ohshima K, Kanda M, Haraoka S, Sugihara M, Suzumiya J, Kawasaki C, Shimazaki K, Ikeda S, Kikuchi M.

First Department of Pathology, School of Medicine, Fukuoka University, Japan.

Leuk Lymphoma 2000 Sep;39(1-2):97-111 Abstract quote

Gastrointestinal T cell lymphoma (TCL) is a rare subset of peripheral TCL, presenting with or without cytotoxic phenotype, a history of coeliac disease (CD) and enteropathy. However, CD is rare in Japan.

Here, we describe the clinicopathological features of 18 Japanese cases. Lesions were found in the small intestine (n=13), stomach (n=3) and colon (n=2). Seven patients presented with enteropathy but none had a history of CD. Lymphomas appeared as ulceration (n=11), tumour formation (n=6), or polypoid growth (n=1).

Histologically (REAL classification), neoplastic lesions were composed of intestinal type T cell lymphoma (ITCL, n=13, including one case with NK type), anaplastic large cell (ALCL, n=2), adult T cell leukaemia/lymphoma (ATLL, n=2), and lymphoblastic type (n=1). Epstein Barr virus infection was detected by EBER-1 in situ hybridization in 6 of 11 cases with ITCL but not in the other types. ALCL expressed CD30. CD56 was expressed in 3 of 11 cases of ITCL but not in other types. Among the 10 examined cases, 8 were alphabeta T cell type [CD2+, CD3+, T cell receptor (TCR)delta-1-, betaF1+], one was gammadelta T cell type [CD2+, CD3+, TCRdelta-1+, betaF1-], and the remaining case expressed natural killer (NK) cell type [CD2+, CD3-, CD56+, TCRdelta-1-, betaF1-]. Among the 8 examined cases, 3 expressed CD103 molecule, which was associated with extrathymic T cells of intraepithelial lymphocytes. All cases except ATLL expressed the cytotoxicity-associated molecule of TIA-1, and 11 of 14 TIA-1 positive cases expressed activated cytotoxic molecules of perforin, granzyme B, and/or Fas ligand.

Despite the morphological, genetic and phenotypic heterogeneity, prognosis was poor, and 11 of 13 patients with small intestinal lesions died albeit appropriate treatment, but 3 of 4 patients with gastric or colonic lesions were still alive. The main cause of death was intestinal perforation. The latter might be due to the site specificity of small intestine and tumour cytotoxicity.

Expression of killer cell inhibitory receptors is restricted to true NK cell lymphomas and a subset of intestinal enteropathy-type T cell lymphomas with a cytotoxic phenotype.

Dukers DF, Vermeer MH, Jaspars LH, Sander CA, Flaig MJ, Vos W, Willemze R, Meijer CJ.

Department of Pathology, Vrije Universiteit, Amsterdam, The Netherlands.

J Clin Pathol 2001 Mar;54(3):224-8 Abstract quote

BACKGROUND/AIMS: Killer inhibitory receptors (KIR) have a modulating effect on the cytotoxic functions of natural killer (NK) cells and T cells. Because lymphoma cells often have the same receptors as their non-neoplastic counterparts, this study investigated the expression of KIR on well defined groups of NK and T cell lymphomas, with and without a cytotoxic phenotype, from different sites of origin.

METHODS: Nine CD56+/CD3- NK cell lymphomas, 29 CD3+/CD56- T cell lymphomas with a cytotoxic phenotype, and 19 T cell lymphomas without a cytotoxic phenotype were stained for KIR using monoclonal antibodies specific for CD94, CD158a, and CD158b. In addition, the expression of KIR was studied on normal lymphoid tissues.

RESULTS: KIR expression was seen in five of nine true NK cell lymphomas including three of four nasal, one of four cutaneous, and one of one intestinal lymphoma nasal type. Double staining for CD56 and CD94 in normal lymphoid tissues revealed that KIR was predominantly expressed by CD56+ NK cells and sporadically on CD8+ T cells. Moreover, enteropathy-type T cell lymphomas with a cytotoxic phenotype showed KIR expression (three cases expressing CD94 and one case expressing CD158a). All nodal and extranodal nonintestinal T cell lymphomas with or without a cytotoxic phenotype lacked expression of KIR.

CONCLUSIONS: These results show that KIR expression is restricted to CD56+/CD3- true NK cell lymphomas originating from the nose, gut, and skin, as well as in a subset of extranodal T cell lymphomas originating from the small intestine, which possessed a cytotoxic phenotype. Thus, the presence of KIR on NK/T cell lymphomas seems to mimic the distribution of KIR found on NK and T cells in normal lymphoid tissue.

Primary CD56 positive lymphomas of the gastrointestinal tract.

Chim CS, Au WY, Shek TW, Ho J, Choy C, Ma SK, Tung HM, Liang R, Kwong YL.

Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.

Cancer 2001 Feb 1;91(3):525-33 Abstract quote

BACKGROUND: Primary CD56 positive lymphoma of the gastrointestinal (GI) tract is rare. Genotypically, these tumors can be classified into natural killer (NK)-like T-cell lymphoma or NK cell lymphoma by the presence or absence of T-cell receptor (TCR) gene rearrangement. However, they have a considerable degree of morphologic and immunophenotypic overlap, making a definitive diagnosis difficult.

METHODS: The clinicopathologic features of three patients with primary CD56 positive lymphoma of the small and large bowel are presented. This is followed by a review of the English literature from 1966 to the present.

RESULTS: All patients had CD56 positive/CD3epsilon positive disease on paraffin section. Two patients were positive for Epstein-Barr virus-encoded early nuclear RNAs (EBER) according to in situ histochemistry results and were negative for TCR gene rearrangement, consistent with primary NK lymphoma of the GI tract. The other patient was EBER negative with rearranged TCR, consistent with NK-like T-cell lymphoma. There was no clinical or histologic evidence of enteropathy in any of the patients. The major presenting symptoms included fever, weight loss, and intestinal perforation. All patients died between 1 week and 6 months after diagnosis despite undergoing surgery and intensive chemotherapy.

CONCLUSIONS: These results, together with a literature review, suggest that primary NK cell lymphoma of the GI tract may be considered a distinct clinicopathologic entity. Both primary NK and NK-like T-cell lymphoma pursue an aggressive clinical course. EBER and TCR gene rearrangement are useful in distinguishing NK cell lymphoma from NK-like T-cell lymphoma, particularly when frozen tissue is not available for immunophenotyping.


Nasal natural killer cell lymphoma in a post-renal transplant patient.

Mukai HY, Kojima H, Suzukawa K, Hori M, Komeno T, Hasegawa Y, Ninomiya H, Mori N, Nagasawa T.

Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

Transplantation 2000 Apr 15;69(7):1501-3 Abstract quote

Posttransplant lymphoproliferative disorders in organ allograft recipients are most commonly of B-cell origin and only occasionally of T-cell origin.

We present here a case of nasal natural killer cell lymphoma associated with Epstein-Barr virus that occurred in a recipient of a renal transplant 4 years posttransplantation. Immunohistochemically, the lymphoma cells showed CD2-, surface CD3-, cytoplasmic CD3E+, CD56+, CD57-, CD16-, and CD43+ phenotype. Analyses of T-cell receptor beta and gamma genes showed germ line configurations. EBER-1 was detectable in the lymphoma cells. The patient was diagnosed as having natural killer cell lymphoma and was treated with six courses of combination chemotherapy for non-Hodgkin's lymphoma He has been in remission for more than 3 years thereafter.

To the best of our knowledge, this is the first report of a posttransplant NK cell lymphoma associated with Epstein-Barr virus.

Epstein-Barr virus–associated extranodal NK/T-cell lymphoma, nasal type of the hypopharynx, in a renal allograft recipient: Case report and review of literature

Sylvia Stadlmann, MD
Falko Fend, MD
Patrizia Moser, MD
Peter Obrist, MD
Richard Greil, MD
Stephan Dirnhofer, MD

Hum Pathol 2001;32:1264-1268. Abstract quote

Posttransplant lymphoproliferative disorders (PTLPDs) are predominantly B-cell lymphoproliferations, whereas a T-cell origin is rarely observed. In contrast to B-cell PTLPD, T-cell PTLPDs show an inconsistent association with Epstein-Barr virus (EBV). Until now, only 13 cases of EBV-associated T-cell PTLPDs have been reported.

We describe a case of an EBV-associated T-cell PTLPD in a renal allograft recipient 2 years after transplantation. Histologic examination showed medium- to large-sized lymphoid cells with an angiocentric growth pattern and necrosis. The atypical cells showed a CD2+, CD3+, CD7+, CD43+, CD45R0+, CD56+, and CD4–, CD5–, CD8– F1- phenotype with expression of the latent membrane protein (LMP)-1 of EBV. In addition, EBV-specific RNAs (EBER 1/2) were identified by in situ hybridization. Molecular analysis of the T-cell receptor (TCR) chain by polymerase chain reaction (PCR) showed a polyclonal pattern. The morphologic, immunohistochemical, and molecular findings were consistent with a diagnosis of an EBV-associated extranodal natural killer (NK)/T-cell non-Hodgkin lymphoma (NHL) of nasal type.

To our knowledge, this is the first reported case of this rare entity in the posttransplant setting.


Hypersensitivity to mosquito bites as the primary clinical manifestation of a juvenile type of Epstein-Barr virus-associated natural killer cell leukemia/lymphoma

Yoshiki Tokura, MD
Shigehiko Ishihara, MD
Shinichi Tagawa, MD
Naohiro Seo, PhD
Kouichi Ohshima, MD
Masahiro Takigawa, MD

Hamamatsu, Kashiwara, Osaka, and Fukuoka, Japan

J Am Acad Dermatol 2001;45:569-78 Abstract quote

Hypersensitivity to mosquito bites or mosquito allergy is a mysterious disorder that has been reported mainly in Japanese patients (at least 58 patients) in the first two decades of life. The skin lesion at bite sites is typically a bulla that develops into necrosis. Patients simultaneously exhibit a high temperature and general malaise and subsequently may experience lymphadenopathy and hepatosplenomegaly.

Recent studies have revealed that this mosquito hypersensitivity is associated with chronic Epstein-Barr virus infection and natural killer cell leukemia/lymphoma. The natural killer cell, infected with monoclonal (or oligoclonal) Epstein-Barr virus, seems to be involved in the pathogenesis of the hypersensitivity. Half of the patients reported died of hemophagocytic syndrome (or malignant histiocytosis), granular lymphocyte proliferative disorder, or lymphomas.

We propose that this disease, defined as the triad of hypersensitivity to mosquito bites, chronic Epstein-Barr virus infection, and natural killer cell leukemia/lymphoma, is a clinical entity mostly seen in Asians.

Aggressive Epstein-Barr Virus-Associated, CD8+, CD30+, CD56+, Surface CD3–, Natural Killer (NK)-Like Cytotoxic T-Cell Lymphoma

Jianguo Tao, M.D. , Ph.D. ; Suresh G. Shelat, M.D. , Ph.D. ; Elaine S. Jaffe, M.D. ; Adam Bagg, M.D.

From the Department of Pathology and Laboratory Medicine (J.T., S.G.S., A.B.), University of Pennsylvania, Philadelphia, Pennsylvania; and the Laboratory of Pathology (E.S.J.), NIH-NCI, Bethesda, Maryland, U.S.A.

Am J Surg Pathol 2002;26:111-118 Abstract quote

We report an unusual case of aggressive natural killer (NK)-like cytotoxic T-cell lymphoma in a previously healthy immunocompetent West African male.

He presented with a fever of unknown origin, subsequently developed erythematous skin nodules, generalized lymphadenopathy, and hepatosplenomegaly, and then died of multiple organ failure. A skin nodule and lymph node biopsy showed an infiltrate of pleomorphic atypical medium and large lymphoid cells with extensive necrosis and prominent apoptosis. Peripheral blood and ascites also harbored these cells, with cytology revealing irregular nuclear folding and basophilic cytoplasm, and some with azurophilic cytoplasmic granules. Flow cytometry and immunohistochemistry demonstrated the expression of CD2, CD7, CD8, CD30, CD56, and cytoplasmic but not surface CD3. In situ hybridization demonstrated Epstein-Barr virus transcripts. A monoclonal T-cell receptor chain gene rearrangement was detected by polymerase chain reaction.

This is the first reported case of an NK-like T-cell lymphoma with these unusual features, making precise classification difficult. Some features suggest an NK1.1 or NKT lymphocyte origin. Because the earliest clinical manifestation was splenomegaly and abnormal liver function, the normal cellular counterpart may be a distinct subset of NK1.1 cells normally present in hepatosplenic sinusoids. This tumor disseminated early and pursued a fulminant clinical course, thus emphasizing the importance of early recognition and diagnosis.


GENERAL Broad cytologic spectrum
Nuclei often irregular with granular chromatin
Moderate amount of pale to clear cytoplasm
Azurophilic granules in Giemsa touch preparations
Many admixed inflammatory cells
Angiocentric and angiodestructive growth common
Fibrinoid necrosis of blood vessels
Extensive coagulative necrosis and apoptosis common
Epithelium may be infiltrated by lymphoma cells

Am J Surg Pathol 1996;20:103-11.
Pathol Pattern 1999;111(Suppl 1):S46-S55.
Am J Surg Pathol 1997;21:242-8.
Am J Surg Pathol 1997;21:1223-30.
Am J Surg Pathol 1998;22:135-7.

Three major groups of natural killer (NK) cell-associated hematolymphoid malignancy:
Nasal and nasal-type NK-cell lymphoma
Aggressive NK-cell lymphoma/leukemia
Blastic NK-cell lymphoma/leukemia


Am J Surg Pathol 1995;19:284-96.
Arch Dermatol 1996;132:550-3
Am J Surg Pathol 1999;23:137-46.

Another group of patients with unique immunohistochemical characteristics has been reported:
Express both the T helper/inducer cell marker CD4 and the NK-cell marker CD56
Suggest a T-cell origin, but the negativity of the CD3 (surface and cytoplasmic) and the other T-cell-related antigen, CD2, and the absence of clonal rearrangement of the T-cell receptor (TCR) gene are against this hypothesis


Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study.

DiGiuseppe JA, Louie DC, Williams JE, Miller DT, Griffin CA, Mann RB, Borowitz MJ.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6417, USA.

Am J Surg Pathol 1997 Oct;21(10):1223-30 Abstract quote

The classification of natural killer (NK)-cell and NK-like T-cell malignancies has undergone significant evolution in recent years. Although examples of NK-cell tumors resembling acute leukemia have been described anecdotally as blastic, blastoid, or monomorphic NK-cell leukemia/lymphoma (NKL/L), the clinical and pathologic features of these tumors have not been systematically defined.

We report four patients with blastic NKL/L and describe the clinical, pathologic, and immunophenotypic findings in these cases. All patients were elderly (58-82 years) and presented with cutaneous plaques. Two patients also had adenopathy, and three patients had marrow involvement at presentation. Biopsy of cutaneous lesions showed atypical superficial and deep dermal lymphoid infiltrates. Involved lymph nodes were architecturally effaced by an interfollicular infiltrate with blastic cytologic features. In Wright-Giemsa-stained blood or marrow smears, tumor cells had finely distributed nuclear chromatin, many with nucleoli, and variable amounts of cytoplasm. In contrast to many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent or inconspicuous. The tumor cells were immunophenotypically distinctive. They expressed intermediate density CD45, as is characteristic of blasts; in addition, the cells were positive for HLA-DR, CD2, CD4, and the NK-associated antigen CD56. Surface CD3, cytoplasmic CD3, and CD5 were negative in all cases tested, whereas CD7 was expressed in two cases. In formalin-fixed tissue, tumor cells marked with antibodies to CD43, but not with other T- or B-lineage-related antibodies. All three cases studied for Epstein-Barr viral RNA by in situ hybridization were negative. Although treatments varied, all three patients with clinical follow-up died within months of the diagnosis. The clinical course in two patients culminated in an overtly leukemic phase.

These findings suggest that blastic NKL/L represents a distinct clinicopathologic entity, characterized by cutaneous, nodal, and marrow involvement by blastic cells with immunophenotypic characteristics of true NK cells. The disease afflicts elderly patients, pursues an aggressive course, and may culminate in overt leukemia.

Blastic Natural Killer Cell Lymphoma/Leukemia A Report of Seven Cases

Michael G. Bayerl, MD
Christiane K. Rakozy, MD
Anwar N. Mohamed, MD
Trieu D. Vo, PhD
Michael Long, PhD
David Eilender, MD
and Margarita Palutke, MD

Am J Clin Pathol 2002;117:41-50 Abstract quote

Only a few blastic natural killer (NK) cell leukemias and lymphomas have been reported. As such, the clinicopathologic spectrum of this disease is incompletely understood. We report 7 cases of blastic NK cell lymphoma/leukemia. All patients were men, 5 white and 2 Arab American.

All cases exhibited blastic morphologic features and were CD3– and CD56+ with germline T-cell receptor genes. Five cases were CD4+ and involved the skin. Both CD4– cases never involved the skin. Other markers of mature NK cells such as CD16, CD57, and TIA-1 were expressed infrequently. Three cases were CD33+. One CD33+ case had a clonal rearrangement of the immunoglobulin heavy chain gene.

Skin and lymph nodes were involved most often, with frequent evolution to a leukemic phase. Initial responses to therapy were achieved in most patients, but the tumors invariably recurred.


T-cell/natural killer cell lymphoblastic lymphoma with an unusual coexpression of B-cell antigens.

Gloeckner-Hofmann K, Ottesen K, Schmidt S, Nizze H, Feller AC, Merz H.

Institute of Pathology, Medical University of Luebeck, Germany.

Ann Hematol 2000 Nov;79(11):635-9 Abstract quote

Lymphoblastic lymphomas are usually B- or T-cell neoplasms. There exists a small group of T-cell lymphomas additionally coexpressing cytotoxic or natural killer (NK)-cell markers, supporting the hypothesis of a common T/NK-cell precursor and respective neoplasms. Clinically, lymphatic neoplasms of T/NK-cell phenotype are either extranodal lymphomas or acute leukemias. The clinical course of these T/NK neoplasms cannot be predicted by morphology and/or phenotype alone. However, the expression of a heterogeneous (T + NK or myeloid) marker profile or of "early" antigens (such as TdT, CD10, RAG1, RAG2) render them more likely to be in the acute leukemia group.

We present a case of a 63-year-old woman with a bone marrow infiltrate, enlarged lymph nodes, and B-symptoms. A cervical lymph node biopsy showed a monomorphic blastic infiltrate with a T-cell phenotype, coexpressing NK markers (CD56, CD57, NK1) and B-cell antigens (CD20, CD79).

To the best of our knowledge, this is a newly recognized phenotype that has not been reported before. T/NK-cell lymphomas, including blastic NK-cell leukemia/lymphoma and T-lymphoblastic lymphomas, have to be included in the differential diagnosis. Both groups have a different clinical behavior and prognosis. In particular, T/NK-cell lymphomas associated with an Epstein Barr virus infection are clinically very aggressive neoplasms.

CD2–CD4+CD56+ hematodermic/hematolymphoid malignancy

J Am Acad Dermatol 2001;44:231-8

Japanese patient with a unique hematolymphoid malignancy characterized by an involvement of skin, nasopharyngeal region, bone marrow, lymph node, and a CD4+ CD43+ CD56+ CD2–CD3–CD8– and terminal deoxynucleotidyl transferase phenotype

Clinically, the cutaneous eruptions were purplish, hard, multiple nodules

Histologically, a massive proliferation of atypical pleomorphic cells with medium-sized nuclei were observed throughout the dermis

No clonal rearrangement of T-cell receptor (TCR)- gene or immunoglobulin heavy chain J gene was found, and no positive identification of EBV by in situ hybridization for EBV-encoded small nuclear RNA was found

Patient underwent high-dose chemotherapy with autografting of peripheral blood stem cells; however, the tumors quickly relapsed

Additional data from 17 cases of lymphoid malignancy from the literature sharing immunophenotypic and genotypic features similar to those of this case, including CD2–CD4+CD56+ and germline rearrangement of TCR

Although the cellular origin could not be decided, this malignancy was found to have 100% affinity for skin, a short course, and poor prognosis

CD56+/CD4+ Lymphomas and Leukemias Are Morphologically, Immunophenotypically, Cytogenetically, and Clinically Diverse

Christiane K. Rakozy, MD,1 Anwar N. Mohamed, MD,1 Trieu D. Vo, PhD,2 Ghada Khatib, MD,1 P. Michael Long, PhD,1 David Eilender, MD,3 and Margarita Palutke, MD

Am J Clin Pathol 2001;116:168-176 Abstract quote

CD56, a neural adhesion molecule, is a marker of natural killer (NK) lymphocytes as well as a subgroup of CD8+ T cells. Normal lymphocytes with a CD56/CD4 phenotype are scarce. Physiologic increases may occur in patients with immunosuppression, chronic inflammation, and autoimmune disorders.

We report 4 cases of lymphomas/leukemias with the unusual CD56/CD4 phenotype. Two were of T-cell and 2 of true NK-cell origin. The T-cell lymphomas had large granular lymphocyte morphologic features and splenomegaly. One patients had a benign course; the other died within months of the leukemia diagnosis. The 2 NK cell lymphomas had blastic morphologic features, initially involved skin, and had a very aggressive clinical course; 1 patient died of acute leukemia, and 1 had recurrence after bone marrow transplantation. Cytogenetic analyses did not show a consistent pattern of abnormalities. The NK lymphoma with acute leukemia had a t(2;5) but was CD30– and anaplastic lymphoma kinase negative.

Although CD56+/CD4+ lymphomas/leukemias are a heterogeneous group, there may be a distinct subgroup of NK lymphoblastoid lymphomas of the skin, judging from our cases, as well as those previously reported.

Agranular CD4+CD56+ blastic natural killer leukemia/lymphoma.

Kimura S, Kakazu N, Kuroda J, Akaogi T, Hayashi H, Nishida K, Abe T.

Division of Hematology, Kyoto Second Red Cross Hospital, Japan.

Ann Hematol 2001 Apr;80(4):228-31 Abstract quote

Blastic natural killer cell leukemia/lymphoma (blastic NKL/L) is characterized by blastic morphology and a distinctive immunophenotype combining blastic features and cytologically resembling acute myeloid or lymphoid leukemia. The clinical, pathologic, and cytogenetic features of blastic NKL/L have not yet been systematically identified.

We report herein a case of blastic NKL/L with skin lesion, adenopathy, and systemic lymphoadenopathy. The identified tumor cells were positive for CD4 and CD56, and negative for T-cell, B-cell, and myeloid markers. T-cell receptor beta, gamma, delta, and immunoglobulin heavy chain genes in the bone marrow cells showed germ-line configurations. Southern blot analysis with a terminal probe did not reveal any Epstein-Barr virus infection.

Although patients diagnosed as blastic NKL/L have generally shown chemotherapy resistance and poor prognosis, our patient was treated with a combined chemotherapy, which is also used for acute lymphoblastic leukemia, and has maintained complete remission (CR) for more than 13 months. In addition to clinical investigations, we thoroughly analyzed his karyotype by using a combination of G-banding and a new technique, spectral karyotyping. The karyotype was described as 45, XY, der(1)t(1;20)(p32;q11.2), der(6) (1pter-->1p32:: 6p21.1-->6q13:: 7q11.2-->7qter), der(7) t(7;20)(q11.2;q11.2), t(13;14)(q14;q32), der(13)t(6;13) (p21.1; q14), -20.


Nasal natural killer cell/t-cell lymphoma showing cellular morphology mimicking normal lymphocytes.

Chinen K, Kaneko Y, Izumo T, Ohkura Y, Matsubara O, Tsuchiya E.

Departments of Pathology (Drs Chinen, Izumo, Ohkura, and Tsuchiya) and Cancer Chemotherapy (Dr Kaneko), Saitama Cancer Center, Ina-machi, Japan; and the Department of Pathology, National Defense Medical College, Tokorozawa City, Japan (Dr Matsubara).

Arch Pathol Lab Med 2002 May;126(5):602-5 Abstract quote

We report the autopsy case of a 34-year-old Japanese man with a nasal natural killer (NK)-cell/T-cell lymphoma.

The patient developed the disease at 32 years of age, and a biopsy of the nasopharynx revealed pleomorphic lymphoma cell proliferation. Radiotherapy was performed, but the patient eventually died of respiratory failure. After radiotherapy, no histologic evidence of malignancy was obtained with biopsy materials featuring lymphocytic infiltration. Autopsy studies, including in situ hybridization for Epstein-Barr virus-encoded RNA, revealed generalized infiltration of normal lymphocyte-like, UCHL-1-positive, and Epstein-Barr virus-encoded RNA-positive lymphoma cells. Monoclonal proliferation of the Epstein-Barr virus-carrying cells was verified by means of Southern blot analysis.

Retrospectively, we concluded that the normal lymphocyte-like presentation of the lymphoma cells, probably influenced by radiotherapy, prevented pathologists from recognizing the lymphoma. The utility of in situ hybridization for Epstein-Barr virus-encoded RNA in identification of tumor cells is emphasized with respect to the present case.


Special stains  
CD45RO, CD43
CD3, cytoplasmic
Cytotoxic molecules (perforin, granzymeB, TIA-1)
Epstein-Barr virus
>90% of nasal type cases but figure may be lower in Caucasians
High proliferative rate, usually >80%
TCR genes

Immunoreactivity of B-cell markers (CD79a, L26) in rare cases of extranodal cytotoxic peripheral T- (NK/T-) cell lymphomas.

Blakolmer K, Vesely M, Kummer JA, Jurecka W, Mannhalter C, Chott A.

Department of Clinical Pathology, General Hospital Vienna, University of Vienna, Austria.

Mod Pathol 2000 Jul;13(7):766-72 Abstract quote

The monoclonal antibodies L26 (CD20) and CD79a are very useful reagents for the immunohistochemical assessment of B-cell lineage in lymphoproliferative disorders. Although very few CD20-positive peripheral T-cell lymphomas (PTL) have been reported, comprehensive analyses of CD79a reactivity in extranodal PTL and NK/T-cell lymphomas have not been performed previously.

This study investigated CD79a (clone JCB117) and CD20 reactivity in 94 extranodal non-B-cell lymphomas (enteropathy-type intestinal T-cell lymphoma [n = 52], nasal NK/T-cell lymphoma [n = 11], and primary cutaneous PTL [n = 31]) and in 17 cases of nodal PTL, unspecified.

In four cases (enteropathy-type intestinal T-cell lymphoma [n = 3] and nasal NK/T-cell lymphoma [n = 1]), the majority of tumor cells stained for CD79a (all CD20 negative) and one cutaneous PTL, unspecified, was CD20 positive (CD79a negative). Extensive immunophenotyping and polymerase chain reaction-based molecular analyses revealed that all five B-cell marker-positive extranodal lymphomas had a cytotoxic phenotype and did indeed represent monoclonal peripheral T-cell proliferations.

To minimize the risk of misinterpretation of lymphoma cell lineage, especially in cases of extranodal, lymphoproliferative disease, we suggest the use of both CD79a and CD20 in combination with a panel of antibodies reactive to T cells, such as betaF1 and CD5, and to T cells and NK cells, such as CD3, CD2, CD56, and TIA-1.

Electron microscopy (EM)  

Comparative ultrastructural study of cytotoxic granules in nasal natural killer cell lymphoma, intestinal T-cell lymphoma, and anaplastic large cell lymphoma.

Sadahira Y, Akisada K, Sugihara T, Hata S, Uehira K, Muraki N, Manabe T.

Department of Pathology, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan.

Virchows Arch 2001 Mar;438(3):280-8 Abstract quote

Comparative immunohistochemical and ultrastructural studies were performed on five nasal natural killer (NK) cell lymphoma cases, two intestinal T-cell lymphoma cases, and eight anaplastic large cell lymphoma (ALCL) cases to clarify morphological differences in cytotoxic granules among these cytotoxic lymphomas.

Nasal NK-cell lymphomas and intestinal T-cell lymphomas had fine azurophilic granules and displayed dot-like immunostaining of granzyme B- and T-cell intracellular antigen 1 (TIA-1), predominantly in the central area of the cytoplasm. Ultrastructurally, these NK-cell lymphomas and intestinal T-cell lymphomas had two types of cytotoxic granules, type-I granules (dense core granules) and type-II granules (multivesicular bodies), which have been demonstrated in normal large granular lymphocytes in peripheral blood. However, ALCLs did not have azurophilic granules, and only type-II cytotoxic granules were found ultrastructurally, even though they showed similar dot-like immunostained patterns of granzyme B and TIA-1, as seen in NK-cell lymphomas and intestinal T-cell lymphomas. Immunoelectron microscopy revealed that TIA-1 was primarily located at the periphery of the cytoplasmic granules in the NK-cell lymphoma and ALCL cases.

These findings suggest that malignant lymphomas with a cytotoxic phenotype can be divided into two types, (azurophilic granule)+, (type-I granule)+, (type-II granule)+ lymphomas and (azurophilic granule)-, (type-I granule)-, (type-II granule)+ lymphomas.



Solitary primary cutaneous CD30+ large cell lymphoma of natural killer cell phenotype bearing the t(2;5)(p23;q35) translocation and presenting in a child.

Gould JW, Eppes RB, Gilliam AC, Goldstein JA, Mikkola DL, Zaim MT, Wood GS.

Department of Dermatology, Case Western Reserve University, and the Veterans Administration Medical Center, Cleveland, Ohio 44106, USA.

Am J Dermatopathol 2000 Oct;22(5):422-8 Abstract quote

Primary cutaneous CD30+ large cell lymphoma is an unusual tumor most commonly seen in adults. Most of these lymphomas are of T-cell origin and carry a good prognosis.

We present the case of a 4-year-old girl with stage IEA CD30+ large cell lymphoma with a CD56+ natural killer cell phenotype and the t(2;5)(p23;q35) translocation. After excision, the patient has been free of disease for 44 months. Primary cutaneous CD30+ large cell lymphoma is uncommon in children. To our knowledge, primary cutaneous CD30+ natural killer type lymphoma has not been reported previously. The indolent behavior of this tumor indicates its similarity to other primary cutaneous CD30+ large cell lymphomas and its difference from other CD56+ lymphomas involving the skin, which often exhibit an aggressive clinical course.

Cases such as this one illustrate why the use of a single, or even a few, immunohistochemical stains can be misleading in regard to lymphoma classification and prognostication.


Lymphomatoid papulosis with a natural killer-cell phenotype.

Bekkenk MW, Kluin PM, Jansen PM, Meijer CJ, Willemze R.

Department of Dermatology, Leiden University Medical Centre, Albinusdreef 2, 2300 RC Leiden, the Netherlands.

Br J Dermatol 2001 Aug;145(2):318-22 Abstract quote

Lymphomatoid papulosis (LyP) is defined as a recurrent self-healing papulonodular eruption with the histological features of a (CD30+) cutaneous T-cell lymphoma. The atypical cells usually have a CD3+/-, CD4+/-, CD8-, CD30+, CD56- T-cell phenotype.

We report an unusual case of LyP, in which the atypical cells expressed a CD3-, CD4-, CD8-, CD30+, CD56+ phenotype. Detailed phenotypic and genotypic analysis confirmed that these cells had a natural killer (NK)-cell phenotype. Lymphomas with an NK-cell phenotype usually have a poor prognosis.

However, the waxing and waning of papular lesions for more than 20 years and the excellent response to low-dose oral methotrexate in this patient suggest similar clinical behaviour to LyP cases with a T-cell phenotype.


CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms.

Liu Q, Ohshima K, Sumie A, Suzushima H, Iwasaki H, Kikuchi M.

Department of Pathology, School of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonanku, Fukuoka 814-01, Japan.

Virchows Arch 2001 Mar;438(3):271-9 Abstract quote

CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration.

Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas.

Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.



Angiocentric nasal T/natural killer cell lymphoma: a single centre study of prognostic factors in 108 patients.

Aviles A, Diaz NR, Neri N, Cleto S, Talavera A.

Departament of Hematology, Oncology Hospital, National Medical Center, Mexico.

Clin Lab Haematol 2000 Aug;22(4):215-20 Abstract quote

Angiocentric T cell/natural killer (NK) nasal lymphoma remains a rare clinical presentation in North America and Europe but is more common in Asia and Latin America.

We have reviewed 108 cases of angiocentric T/NK cell lymphoma of the nasal cavity with a view to establishing prognostic factors. Most patients were high or high intermediate clinical risk and had additional poor prognostic factors such as bulky disease, high levels of beta 2 microglobulin, advanced stage and multiple extranodal involvement. At 8 years, overall survival was 82%, 90% and 84% for low-intermediate, high-intermediate and high clinical, respectively. Disease free survival was very similar: 79%, 83% and 80%, respectively.

Multivariate analysis did not identify any factor influencing overall survival and disease-free survival. There was no evidence that the international prognostic index (IPI) was applicable in these patients and it appears that angiocentric T/NK cell lymphoma is an independent prognostic factor itself.

Clinicopathological features of Epstein-Barr virus-associated nasal T/NK cell lymphomas in southern Japan.

Seki D, Ueno K, Kurono Y, Eizuru Y.

Department of Otolaryngology, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.

Auris Nasus Larynx 2001 Jan;28(1):61-70 Abstract quote

OBJECTIVE: Nasal T/natural killer cell lymphomas (NTCL) are highly prevalent among Oriental populations. However the characteristic immunophenotype of NTCL is still controversial and it can be difficult to make a firm histologic diagnosis of malignancy. Therefore, 14 cases of NTCL in patients from southern Japan were evaluated for clinicopathological features and immunophenotypic status. Furthermore, the genetic variations in the latent membrane protein 1 (LMP-1) gene of Epstein-Barr virus (EBV)-related NTCL were evaluated.

METHODS: Biopsy specimens were fixed in formalin and embedded in paraffin before examination using in situ hybridization for EBV-encoded RNA-1 (EBER-1) as well as immunohistochemical staining for CD3, CD3epsilon, CD4, CD8, CD43, CD45RA, and CD45RO. To detect genetic variations, single-strand conformation polymorphism (SSCP) analysis and DNA sequencing were applied.

RESULTS: Clinically, 14 cases were divided into two groups. The first group consisting of eight patients showed good prognosis. The other group consisting of six patients showed poor prognosis. The vast majority of neoplastic cells in NTCL were EBER-1 positive. These cells did not express CD4, CD8, or CD45RA, but often expressed CD43 and CD45RO. In addition, they were negative for CD3 when stained with a mouse monoclonal antibody but stained for CD3epsilon when a rabbit polyclonal was used. The 3'-terminal of LMP-1 gene of seven cases were amplified and all of them have 30 base pair (bp) deletion.

CONCLUSION: NTCL are a heterogeneous mix of cell types although EBV-associated NTCL in patients from southern Japan appear to originate from natural killer cells rather than T cells, and also prognosis is variable and not always poor. The ability to make a firm diagnosis can be enhanced through the combined use of in situ hybridization and immunohistochemistry. High prevalence of the 30-bp deletions of the LMP-1 gene in EBV-related NTCL may also reflect the prevalence of the deletion variant in the normal population in Japan.


Bone marrow involvement by nasal NK cell lymphoma at diagnosis is uncommon.

Wong KF, Chan JK, Cheung MM, So JC.

Dept of Pathology, Queen Elizabeth Hospital, 30 Gascoigne Rd, Kowloon, Hong Kong SAR, China.

Am J Clin Pathol 2001 Feb;115(2):266-70 Abstract quote

To look for subtle evidence of marrow involvement in nasal NK cell lymphoma at diagnosis, we retrospectively studied trephine biopsy specimens from 25 consecutive patients by 2 sensitive techniques: CD56 immunohistochemistry and Epstein-Barr virus-encoded RNA in situ hybridization (EBER ISH).

Only 2 patients had marrow involvement by NK cell lymphoma at diagnosis. In 3 additional patients, marrow involvement developed during or after systemic recurrence. All 5 positive cases were revealed by EBER ISH, but only 3 cases showed CD56 immunoreactivity. Among the 5 cases, only 2 were recognized by morphologic assessment. All 5 patients died, often within a short period, compared with a mortality of 50% for patients without demonstrable marrow involvement.

Marrow involvement is distinctly uncommon in nasal NK cell lymphoma at diagnosis, and EBER ISH is the most sensitive technique for the demonstration of occult NK cell lymphoma.

Despite the low frequency of marrow involvement in nasal NK cell lymphoma, EBER ISH is worthwhile to identify the minor subgroup of patients with a high likelihood of early death due to disease and when autologous bone marrow or peripheral blood stem cell transplantation is contemplated.


Successful treatment of advanced natural killer cell lymphoma with high-dose chemotherapy and syngeneic peripheral blood stem cell transplantation.

Nawa Y, Takenaka K, Shinagawa K, Deguchi S, Matsumura N, Koyama S, Hiramatsu Y, Omoto E, Yoshino T, Harada M.

Second Department of Internal Medicine, Okayama University Medical School, Japan.

Bone Marrow Transplant 1999 Jun;23(12):1321-2 Abstract quote

CD56+ angiocentric lymphoma has currently been recognized as a distinct clinical entity which is the prototype of the putative NK cell lymphomas.

A 16-year-old Japanese girl with advanced CD56+ angiocentric lymphoma received high-dose chemotherapy supported with syngeneic peripheral blood stem cell transplantation (PBSCT). Prior to syngeneic PBSCT, she received six cycles of conventional chemotherapy before transplantation, resulting in a partial response. PBSC were mobilized with granulocyte colony-stimulating factor (G-CSF) and collected from her identical twin. High-dose cyclophosphamide, MCNU, etoposide, and carboplatin were used for pretransplant conditioning. Syngeneic PBSCT was well tolerated. She achieved complete remission and is now surviving in continuous complete remission for more than 30 months after syngeneic PBSCT.

Thus, marrow-ablative chemotherapy facilitated by autologous or allogeneic PBSCT should be considered as part of the primary therapy for poor prognosis NK cell lymphomas.

High-dose chemotherapy with peripheral blood stem cell rescue in blastoid natural killer cell lymphoma.

Mukai HY, Kojima H, Suzukawa K, Hori M, Komeno T, Hasegawa Y, Ninomiya H, Mori N, Nagasawa T.

Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

Leuk Lymphoma 1999 Feb;32(5-6):583-8 Abstract quote

A 25-year-old man was referred because of skin rash, lymphadenopathy and anemia. Laboratory examinations revealed severe anemia (Hb, 4.8 g/dl) and elevated levels of GOT, GPT, LDH and soluble interleukin-2 receptor.

Work-up studies disclosed the involvement of lymphoma cells in lymph nodes, skin, bilateral kidneys and bone marrow. Lymph node biopsy revealed diffuse proliferation of medium- to large-sized lymphoblastic cells. Bone marrow aspiration showed massive infiltration of large blastic cells with no cytoplasmic granules. The lymphoma cells in bone marrow and lymph node showed surface CD3-, cytoplasmic CD3epsilon+, CD4+, CD8-, CD56+, CD57-, CD16- and CD43 (MT-1)+ phenotype. Analyses of T cell receptor beta and gamma genes showed germ line configurations. EBER-1 was not detectable in the lymphoma cells. He was diagnosed as having blastoid natural killer (NK) cell lymphoma. In spite of several courses of combination chemotherapy, the lymphoma was progressive. He was then treated with high-dose chemotherapy and peripheral blood stem cell rescue, achieving remission which has now lasted for more than 12 months.

We consider that blastoid NK cell lymphoma is an extremely aggressive subtype of CD56-positive lymphomas, and high-dose chemotherapy with peripheral blood stem cell rescue should be included for the choice of the treatment.

Successful treatment of disseminated nasal NK/T-cell lymphoma using double autologous peripheral blood stem cell transplantation.

Sasaki M, Matsue K, Takeuchi M, Mitome M, Hirose Y.

Department of Medicine, Kameda General Hospital, Kamogawa, Japan.

Int J Hematol 2000 Jan;71(1):75-8 Abstract quote

Nasal natural killer (NK)/T-cell lymphoma is a rare disease with an aggressive clinical course. Prognosis is generally poor and the disease is invariably fatal after systemic dissemination.

We report a patient with aggressive nasal NK/T-cell lymphoma who was resistant to therapy and developed systemic dissemination involving the intestine, skin, and stomach. Epstein-Barr virus (EBV) was detected by Southern blotting with EBV-terminal repeat probe and by in situ EBV-encoded small nuclear early region-1 hybridization. The patient was treated using double high-dose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). Pretransplant conditioning for the first auto-PBSCT was MCVC (high-dose ranimustine, carboplatin, etoposide [VP16], and cyclophosphamide), and for the second auto-PBSCT, modified ICE (high-dose ifosfamide, VP16, and carboplatin). The patient obtained a complete remission and has been free of disease for 3.0 years since the second PBSCT.

These observations suggest that double high-dose chemotherapy with PBSCT support may be effective in resistant nasal NK/T-cell lymphoma.

Killer T-cell induction in patients with blastic natural killer cell lymphoma/leukaemia: implications for successful treatment and possible therapeutic strategies.

Yamada O, Ichikawa M, Okamoto T, Park C, Motoji T, Mizoguchi H, Shibuya A.

Department of Haematology, Tokyo Women's Medical University, Japan.

Br J Haematol 2001 Apr;113(1):153-60 Abstract quote

A rare form of putative natural killer (NK) cell lymphoma called blastic NK cell lymphoma appears to be clinicopathologically distinctive in showing a homogenous lymphoblast, variable expression of CD2, CD4, CD56 and TdT, negative for surface CD3, T-cell receptor antigen, CD16, CD34 and lack of association with Epstein-Barr virus (EBV).

We report two patients with blastic NK cell lymphoma and describe the interesting clinical studies. The patients presented with cutaneous plaques. Both patients had adenopathy, and one had marrow involvement at presentation. Unlike in many NK and NK-like T-cell disorders, azurophilic cytoplasmic granules were absent. They expressed intermediate density CD45. In addition, the cells were positive for HLA-DR, CD2, CD4, CD56 and TdT, and negative for EBV transcripts. In spite of the advanced clinical stage, complete remission was achieved by conventional chemotherapy.

After interleukin 2 expansion of tumour-infiltrating bone marrow and lymph node cells from the patients, cytotoxic T-cell lines with rearranged T-cell receptor genes were established. They showed specific killing activity against autologous tumour cells in an MHC-restricted fashion, with possible implications for treatment. In addition, upon cessation of maintenance chemotherapy, one patient developed overt leukaemia with blasts expressing CD33 antigens, suggesting a continuous spectrum of blastic NK cell lymphoma to myeloid/NK cell precursor acute leukaemia.

Natural killer cell lymphoma: report of two pediatric cases, therapeutic options, and review of the literature.

Shaw PH, Cohn SL, Morgan ER, Kovarik P, Haut PR, Kletzel M, Murphy SB.

Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois 60614, USA.

Cancer 2001 Feb 15;91(4):642-6 Abstract quote

BACKGROUND: Natural killer (NK) cell lymphomas are rapidly fatal malignancies that to the authors' knowledge are rare in children. In the current study, the authors report the cases of two boys with NK cell lymphomas with refractory disease who both were salvaged with high dose chemotherapy and stem cell transplantation and compare these patients with those in the published experience.

METHODS: A comprehensive literature review was performed to identify other cases of pediatric patients with NK cell lymphomas, their treatment, and outcome.

RESULTS: One of the patients in the current study developed two recurrences and the other patient experienced early disease progression during front-line treatment. Both then were treated with high dose chemotherapy followed by stem cell rescue. At last follow-up, the patients remained free of disease at 15 months and 16 months, respectively, after transplantation (48 months and 22 months, respectively, from the time of diagnosis). In addition to the 2 patients in the current study, the authors found 13 pediatric patients reported in the literature to date. Of the 7 patients with localized (Stage I-II) disease, 5 patients (71%) were reported to be alive 1-107 months after diagnosis. Of the 6 patients with Stage IV disease, only the 2 patients who received high dose chemotherapy and stem cell rescue (33%) were alive at the time of last follow-up (at 30 months and 12 months, respectively). Including the patients reported in the current study, 9 of 15 children with NK cell lymphoma (all stages) (60%) were reported to be alive at the time of last follow-up.

CONCLUSIONS: Although pediatric NK cell lymphomas rapidly can become fatal, it appears that high dose chemotherapy followed by stem cell transplantation is effective therapy, especially in patients with advanced or resistant disease. Further follow-up is needed to determine whether this treatment approach will be curative.

Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

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