[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.120.181. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Download PDF
Figure 1.
Clinical features of CD56+ lymphoma. A, Solitary tumor of blastic lymphoma on the anterior thigh in patient 2. B, Nasal-type natural killer–cell/T-cell lymphoma manifested as diffuse plaques and nodules in patient 1. C, Subcutaneous movable tumors of subcutaneous panniculitislike lymphoma on the arm of patient 3.

Clinical features of CD56+ lymphoma. A, Solitary tumor of blastic lymphoma on the anterior thigh in patient 2. B, Nasal-type natural killer–cell/T-cell lymphoma manifested as diffuse plaques and nodules in patient 1. C, Subcutaneous movable tumors of subcutaneous panniculitislike lymphoma on the arm of patient 3.

Figure 2.
Histologic features of CD56 lymphoma in the skin. A, Homogeneous infiltrate of blastic cells in patient 4 with blastic CD56+ lymphoma. B and C, Nasal-type natural killer–cell/T-cell lymphoma in patient 1 with an infiltrate composed of pleomorphic small, medium, and large cells. D-F, Subcutaneous panniculitislike CD56+ lymphoma in patient 3. Hematoxylin-eosin used for panels A-D, CD3 stain for panel E, and CD56 for panel F; original magnification ×100 (panel B) and ×400 (panels A, C-F).

Histologic features of CD56 lymphoma in the skin. A, Homogeneous infiltrate of blastic cells in patient 4 with blastic CD56+ lymphoma. B and C, Nasal-type natural killer–cell/T-cell lymphoma in patient 1 with an infiltrate composed of pleomorphic small, medium, and large cells. D-F, Subcutaneous panniculitislike CD56+ lymphoma in patient 3. Hematoxylin-eosin used for panels A-D, CD3 stain for panel E, and CD56 for panel F; original magnification ×100 (panel B) and ×400 (panels A, C-F).

Figure 3.
Kaplan-Meier survival plots for CD56+ lymphoma. The effect of the lymphoma type (A), age in years (B), and degree of involvement (C). Censored events are marked with tick marks on the step curves. SPL indicates subcutaneous panniculitislike lymphoma.

Kaplan-Meier survival plots for CD56+ lymphoma. The effect of the lymphoma type (A), age in years (B), and degree of involvement (C). Censored events are marked with tick marks on the step curves. SPL indicates subcutaneous panniculitislike lymphoma.

Figure 4.
Estimated survival curves for patients with CD56+ lymphoma. A, Survival probability for patients with CD30+ and CD30− lymphomas. The variables included in the model are age, type of lymphoma, presence of extranodal dissemination, presence of Epstein-Barr virus, and CD4 status. B, Survival curves for CD4+ and CD4− lymphomas. CD30 status was removed from this regression model. Censored events are marked with tick marks on the step curves.

Estimated survival curves for patients with CD56+ lymphoma. A, Survival probability for patients with CD30+ and CD30 lymphomas. The variables included in the model are age, type of lymphoma, presence of extranodal dissemination, presence of Epstein-Barr virus, and CD4 status. B, Survival curves for CD4+ and CD4 lymphomas. CD30 status was removed from this regression model. Censored events are marked with tick marks on the step curves.

Table 1. 
Summary of Clinical Findings
Summary of Clinical Findings
Table 2. 
Characteristics of the Reports of 177 Cases of CD56+ Lymphoma With Skin Involvement
Characteristics of the Reports of 177 Cases of CD56+ Lymphoma With Skin Involvement
Table 3. 
Clinical Features of 181 Patients With CD56+ Lymphoma
Clinical Features of 181 Patients With CD56+ Lymphoma
Table 4. 
Immunohistochemical and Molecular Characteristics of CD56+ Lymphoma*
Immunohistochemical and Molecular Characteristics of CD56+ Lymphoma*
Table 5. 
Essential Features of CD56+ Lymphoma
Essential Features of CD56+ Lymphoma
1.
Ortaldo  JRMason  ATO'Shea  JJ  et al.  Mechanistic studies of transforming growth factor-beta inhibition of IL-2-dependent activation of CD3- large granular lymphocyte functions: regulation of IL-2β (p75) signal transduction J Immunol. 1991;1463791- 3798
PubMed
2.
Hoyle  CBangs  CDChang  PKamel  OMehta  BNegrin  RS Expansion of Philadelphia chromosome-negative CD3+CD56+ cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice Blood. 1998;923318- 3327
PubMed
3.
Jaffe  ESChan  JKSu  IJ  et al.  Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas: definitions, differential diagnosis, and epidemiology Am J Surg Pathol. 1996;20103- 111
PubMedArticle
4.
Jaffe  ESKrenacs  LKumar  SKingma  DWRaffeld  M Extranodal peripheral T-cell and NK-cell neoplasms Am J Clin Pathol. 1999;111 ((suppl 1)) S46- S55
PubMed
5.
Lin  CWLee  WHChang  CLYang  JYHsu  SM Restricted killer cell immunoglobulinlike receptor repertoire without T-cell receptor gamma rearrangement supports a true natural killer-cell lineage in a subset of sinonasal lymphomas Am J Pathol. 2001;1591671- 1679
PubMedArticle
6.
Kern  WFSpier  CMHanneman  EHMiller  TPMatzner  MGrogan  TM Neural cell adhesion molecule-positive peripheral T-cell lymphoma: a rare variant with a propensity for unusual sites of involvement Blood. 1992;792432- 2437
PubMed
7.
Wong  KFChan  JKNg  CSLee  KCTsang  WYCheung  MM CD56 (NKH1)-positive hematolymphoid malignancies: an aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules, and angiocentricity Hum Pathol. 1992;23798- 804
PubMedArticle
8.
Bagot  MBouloc  ACharue  DWechsler  JBensussan  ABoumsell  L Do primary cutaneous nonT nonB CD4+CD56+ lymphomas belong to the myelo-monocytic lineage? J Invest Dermatol. 1998;1111242- 1244
PubMedArticle
9.
Knudsen  HGronbaek  KThor Straten  P  et al.  A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with theNK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion Br J Dermatol. 2002;146148- 153
PubMedArticle
10.
Chaperot  LBendriss  NManches  O  et al.  Identification of a leukemic counterpart of the plasmacytoid dendritic cells Blood. 2001;973210- 3217
PubMedArticle
11.
Chan  JKSin  VCWong  KF  et al.  Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm Blood. 1997;894501- 4513
PubMed
12.
Chang  SEPark  IJHuh  J  et al.  CD56 expression in a case of primary cutaneous CD30+ anaplastic large cell lymphoma Br J Dermatol. 2000;142766- 770
PubMedArticle
13.
Rakozy  CKMohamed  ANVo  TD  et al.  CD56+/CD4+ lymphomas and leukemias are morphologically, immunophenotypically, cytogenetically, and clinically diverse Am J Clin Pathol. 2001;116168- 176
PubMedArticle
14.
Bekkenk  MWKluin  PMJansen  PMMeijer  CJWillemze  R Lymphomatoid papulosis with a natural killer-cell phenotype Br J Dermatol. 2001;145318- 322
PubMedArticle
15.
Murakami  YNagae  SMatsuishi  EIrie  KFurue  M A case of CD56+ cutaneous aleukaemic granulocytic sarcoma with myelodysplastic syndrome Br J Dermatol. 2000;143587- 590
PubMedArticle
16.
Raspadori  DDamiani  DLenoci  M  et al.  CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis Leukemia. 2001;151161- 1164
PubMedArticle
17.
Suzuki  RKagami  YTakeuchi  K  et al.  Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype Blood. 2000;962993- 3000
PubMed
18.
Gniadecki  RRossen  K Expression of T-cell activation marker CD134 (OX40) in lymphomatoid papulosis Br J Dermatol. 2003;148885- 891
PubMedArticle
19.
Murphy  MSignoretti  SKadin  MELoda  M Detection of TCR-gamma gene rearrangements in early mycosis fungoides by nonradioactive PCR-SSCP J Cutan Pathol. 2000;27228- 234
PubMedArticle
20.
Altman  DG Practical Statistics for Medical Research.  London, England Chapman & Hall1992;
21.
Dummer  RPotoczna  NHaffner  ACZimmermann  DRGilardi  SBurg  G A primary cutaneous nonT, nonB CD4+, CD56+ lymphoma Arch Dermatol. 1996;132550- 553
PubMedArticle
22.
Hofbauer  GFKamarachev  JKempf  WBurg  GPestalozzi  BCDummer  R A CD4+ CD56+ natural killerlike T-cell systemic lymphoma with haemorrhagic cutaneous manifestations Br J Dermatol. 2001;144432- 434
PubMedArticle
23.
Nagatani  TOkazawa  HKambara  T  et al.  Cutaneous monomorphous CD4- and CD56- positive large-cell lymphoma Dermatology. 2000;200202- 208
PubMedArticle
24.
Burg  GDummer  RWilhelm  M  et al.  A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma N Engl J Med. 1991;3251078- 1081
PubMedArticle
25.
Mraz-Gernhard  SNatkunam  YHoppe  RTLeBoit  PKohler  SKim  YH Natural killer/natural killerlike T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course J Clin Oncol. 2001;192179- 2188
PubMed
26.
Adachi  MMaeda  KTakekawa  M  et al.  High expression of CD56 (N-CAM) in a patient with cutaneous CD4-positive lymphoma Am J Hematol. 1994;47278- 282
PubMedArticle
27.
Dargent  JLRoufosse  CDelville  JP  et al.  Subcutaneous panniculitislike T-cell lymphoma: further evidence for a distinct neoplasm originating from large granular lymphocytes of T/NK phenotype J Cutan Pathol. 1998;25394- 400
PubMedArticle
28.
Nakamura  SSuchi  TKoshikawa  T  et al.  Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract Am J Surg Pathol. 1995;19284- 296
PubMedArticle
29.
Takeshita  MKimura  NSuzumiya  J  et al.  Angiocentric lymphoma with granulomatous panniculitis in the skin expressing natural killer cell and large granular T-cell phenotypes Virchows Arch. 1994;425499- 504
PubMedArticle
30.
Noguchi  MKawano  YSato  NOshimi  K T-cell lymphoma of CD3+CD4+CD56+ granular lymphocytes with hemophagocytic syndrome Leuk Lymphoma. 1997;26349- 358
PubMed
31.
Wasik  MASackstein  RNovick  D  et al.  Cutaneous CD56+ large T-cell lymphoma associated with high serum concentration of IL-2 Hum Pathol. 1996;27738- 744
PubMedArticle
32.
Emile  JFBoulland  MLHaioun  C  et al.  CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas Blood. 1996;871466- 1473
PubMed
33.
Petrella  TDalac  SMaynadie  M  et al.  CD4+ CD56+ cutaneous neoplasms: a distinct hematological entity? Groupe Francais d'Etude des Lymphomes Cutanes (GFELC) Am J Surg Pathol. 1999;23137- 146
PubMedArticle
34.
Petrella  TComeau  MRMaynadie  M  et al.  "Agranular CD4+ CD56+ hematodermic neoplasm" (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes Am J Surg Pathol. 2002;26852- 862
PubMedArticle
35.
Abe  YMuta  KOhshima  K  et al.  Subcutaneous panniculitis by Epstein-Barr virus-infected natural killer (NK) cell proliferation terminating in aggressive subcutaneous NK cell lymphoma Am J Hematol. 2000;64221- 225
PubMedArticle
36.
Ahn  SJJang  KAChoi  JHSung  KJMoon  KCKoh  JK Nasal and nasal type CD56+ natural killer cell/T-cell lymphoma: a case with rapid progression to bone marrow involvement Br J Dermatol. 2000;1421021- 1025
PubMedArticle
37.
Amo  YYonemoto  KOhkawa  T  et al.  CD56 and terminal deoxynucleotidyl transferase positive cutaneous lymphoblastic lymphoma Br J Dermatol. 2000;143666- 668
PubMedArticle
38.
Ansai  SMaeda  KYamakawa  M  et al.  CD56-positive (nasal-type T/NK cell) lymphoma arising on the skin: report of two cases and review of the literature J Cutan Pathol. 1997;24468- 476
PubMedArticle
39.
Avinoach  IHalevy  SArgov  SSacks  M Gamma/delta T-cell lymphoma involving the subcutaneous tissue and associated with a hemophagocytic syndrome Am J Dermatopathol. 1994;16426- 433
PubMedArticle
40.
Bastian  BCOtt  GMuller-Deubert  SBrocker  EBMuller-Hermelink  HK Primary cutaneous natural killer/T-cell lymphoma Arch Dermatol. 1998;134109- 111
PubMedArticle
41.
Bower  CPStanden  GRPawade  JKnechtli  CJKennedy  CT Cutaneous presentation of steroid responsive blastic natural killer cell lymphoma Br J Dermatol. 2000;1421017- 1020
PubMedArticle
42.
Brody  JPAllen  SSchulman  P  et al.  Acute agranular CD4-positive natural killer cell leukemia: comprehensive clinicopathologic studies including virologic and in vitro culture with inducing agents Cancer. 1995;752474- 2483
PubMedArticle
43.
Chang  SEHuh  JChoi  JHSung  KJMoon  KCKoh  JK Clinicopathological features of CD56+ nasal-type T/natural killer cell lymphomas with lobular panniculitis Br J Dermatol. 2000;142924- 930
PubMedArticle
44.
Chang  SEChoi  JHSung  KJMoon  KCKoh  JK Cutaneous nasal-type CD56+ natural killer/T-cell lymphoma preceded by Epstein-Barr virus antigenaemia Br J Dermatol. 2001;145668- 669
PubMedArticle
45.
Chang  SEChoi  HJHuh  J  et al.  A case of primary cutaneous CD56+, TdT+, CD4+, blastic NK-cell lymphoma in a 19-year-old woman Am J Dermatopathol. 2002;2472- 75
PubMedArticle
46.
Cho  KHOh  JKKim  CWHeo  DSKim  ST Peripheral T-cell lymphoma involving subcutaneous tissue Br J Dermatol. 1995;132290- 295
PubMedArticle
47.
DiGiuseppe  JALouie  DCWilliams  JE  et al.  Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study Am J Surg Pathol. 1997;211223- 1230
PubMedArticle
48.
Feuillard  JJacob  MCValensi  F  et al.  Clinical and biologic features of CD4+CD56+ malignancies Blood. 2002;991556- 1563
PubMedArticle
49.
Hirakawa  SKuyama  MTakahashi  S  et al.  Nasal and nasal-type natural killer/T-cell lymphoma J Am Acad Dermatol. 1999;40 ((2, pt 1)) 268- 272
PubMedArticle
50.
Jang  KAChoi  JHSung  KJ  et al.  Primary CD56+ nasal-type T/natural killer-cell subcutaneous panniculitic lymphoma: presentation as haemophagocytic syndrome Br J Dermatol. 1999;141706- 709
PubMedArticle
51.
Kameoka  JIchinohasama  RTanaka  M  et al.  A cutaneous agranular CD2- CD4+ CD56+ "lymphoma": report of two cases and review of the literature Am J Clin Pathol. 1998;110478- 488
PubMed
52.
Kato  NYasukawa  KOnozuka  TKikuta  H Nasal and nasal-type T/NK-cell lymphoma with cutaneous involvement J Am Acad Dermatol. 1999;40 ((5, pt 2)) 850- 856
PubMedArticle
53.
Kato  NYasukawa  KKimura  K  et al.  CD2CD4+CD56+ hematodermic/hematolymphoid malignancy J Am Acad Dermatol. 2001;44231- 238
PubMedArticle
54.
Ko  YHKim  SHRee  HJ Blastic NK-cell lymphoma expressing terminal deoxynucleotidyl transferase with Homer-Wright type pseudorosettes formation Histopathology. 1998;33547- 553
PubMedArticle
55.
Kojima  HMukai  HYShinagawa  A  et al.  Clinicopathological analyses of 5 Japanese patients with CD56+ primary cutaneous lymphomas Int J Hematol. 2000;72477- 483
PubMed
56.
Marzano  AVBerti  EPaulli  MCaputo  R Cytophagic histiocytic panniculitis and subcutaneous panniculitislike T-cell lymphoma: report of 7 cases Arch Dermatol. 2000;136889- 896
PubMedArticle
57.
Natkunam  YSmoller  BRZehnder  JLDorfman  RFWarnke  RA Aggressive cutaneous NK and NKlike T-cell lymphomas: clinicopathologic, immunohistochemical, and molecular analyses of 12 cases Am J Surg Pathol. 1999;23571- 581
PubMedArticle
58.
Natkunam  YWarnke  RAHaghighi  B  et al.  Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases J Cutan Pathol. 2000;27392- 399
PubMedArticle
59.
Ohtsuka  TYamakage  AYamazaki  S Digital ulcers and necroses: novel manifestations of angiocentric lymphoma Br J Dermatol. 2000;1421013- 1016
PubMedArticle
60.
Paulli  MBoveri  ERosso  R  et al.  CD56/neural cell adhesion molecule expression in primary extranodal Ki-1/CD30+ lymphoma: report of a pediatric case with simultaneous cutaneous and bone localizations Am J Dermatopathol. 1997;19384- 390
PubMedArticle
61.
Radonich  MALazova  RBolognia  J Cutaneous natural killer/T-cell lymphoma J Am Acad Dermatol. 2002;46451- 456
PubMedArticle
62.
Salhany  KEMacon  WRChoi  JK  et al.  Subcutaneous panniculitislike T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes Am J Surg Pathol. 1998;22881- 893
PubMedArticle
63.
Savoia  PFierro  MTNovelli  M  et al.  CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease Br J Dermatol. 1997;137966- 971
PubMedArticle
64.
Shaw  PHCohn  SLMorgan  ER  et al.  Natural killer cell lymphoma: report of two pediatric cases, therapeutic options, and review of the literature Cancer. 2001;91642- 646
PubMedArticle
65.
Uchiyama  NIto  KKawai  KSakamoto  FTakaki  MIto  M CD2-, CD4+, CD56+ agranular natural killer cell lymphoma of the skin Am J Dermatopathol. 1998;20513- 517
PubMedArticle
66.
Yamashita  YTsuzuki  TNakayama  AFujino  MMori  N A case of natural killer/T cell lymphoma of the subcutis resembling subcutaneous panniculitislike T cell lymphoma Pathol Int. 1999;49241- 246
PubMedArticle
67.
Horie  RWatanabe  T CD30: expression and function in health and disease Semin Immunol. 1998;10457- 470
PubMedArticle
68.
Mir  SSRichter  BWDuckett  CS Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells Blood. 2000;964307- 4312
PubMed
69.
Hubinger  GMuller  EScheffrahn  I  et al.  CD30-mediated cell cycle arrest associated with induced expression of p21(CIP1/WAF1) in the anaplastic large cell lymphoma cell line Karpas 299 Oncogene. 2001;20590- 598
PubMedArticle
70.
Camera  APezzullo  LVilla  MR  et al.  Coexistence of two distinct cell populations (CD56+ TcR γδ+ and CD56+ TcR γδ-) in a case of aggressive CD56+ lymphoma/leukemia Haematologica. 2000;85496- 501
PubMed
71.
Yin  ZZhang  DHWelte  T  et al.  Dominance of IL-12 over IL-4 in γδ T cell differentiation leads to default production of IFN-γ: failure to down-regulate IL-12 receptor β2-chain expression J Immunol. 2000;1643056- 3064
PubMedArticle
Study
April 2004

CD56+ Lymphoma With Skin InvolvementClinicopathologic Features and Classification

Author Affiliations

From the Departments of Dermatology (Drs Gniadecki, Thomsen, and Skovgaard) and Pathology (Dr Rossen), Bispebjerg Hospital, and Departments of Pathology (Dr Ralfkier) and Hematology (Dr Jønsson), The National University Hospital, Copenhagen, Denmark. The authors have no relevant financial interest in this article.

Arch Dermatol. 2004;140(4):427-436. doi:10.1001/archderm.140.4.427
Abstract

Background  Extranodal lymphomas expressing CD56 (neuronal cell adhesion molecule) are characterized by a high incidence of cutaneous involvement and a very aggressive clinical course. Knowledge about the prognosis and clinicopathologic features of CD56+ lymphomas with skin involvement is very limited.

Objectives  To determine survival and prognostic factors for extranodal CD56+ lymphomas with skin involvement and to describe their clinicopathologic features.

Design  Retrospective literature survey and case studies.

Patients  A total of 181 patients with CD56+ lymphoma involving the skin: 177 cases from the literature and 4 new cases.

Main Outcome Measure  Survival and its dependence on the following putative prognostic factors: staging, histopathologic findings, lymphocyte markers, T-cell receptor gene rearrangement, Epstein-Barr virus infection, treatment modality.

Results  Three major subtypes of CD56+ lymphoma in the skin were distinguished: blastic lymphoma, nasal-type natural killer–cell/T-cell lymphoma, and subcutaneous panniculitislike lymphoma. The disease disseminated readily, mainly to lymph nodes, bone marrow, the central nervous system, and the liver, but 45% of patients had a purely cutaneous disease at presentation. All subtypes had a very aggressive course with a median survival of 14 months. The main risk factors were age older than 55 years (hazard ratio [HR], 2.5; 95% confidence interval [CI], 1.8-3.2), systemic dissemination at presentation (HR, 2.0; 95% CI, 1.5-3.3), and lack of CD30 (HR, 3.8; 95% CI, 1.4-4.9) or CD4 expression (HR, 1.56; 95% CI, 1.06-2.57). The different treatment modalities did not improve survival.

Conclusions  CD56+ lymphomas involving the skin are rare and extremely aggressive regardless of their histologic presentation and the extent of skin involvement. No effective treatment is available. The risk of death is particularly increased in older patients with CD30CD4 lymphomas.

The CD56 antibody recognizes the neuronal cell adhesion molecule, which in physiologic conditions is expressed on virtually all peripheral natural killer (NK) cells, a subset of monocytes and peripheral CD8+ T cells. Lymphocyte activation in the presence of several cytokines (interleukin 2, interferon [IFN] γ, and tumor necrosis factor α) may result in an increased expression of CD56 on both CD8+ and CD4+ cells (the so-called cytokine-induced killer cells), and this process may take place during the antitumor response.1,2

It has long been recognized that CD56 is expressed in a well-defined type of neoplasm, the NK/T-cell nasal lymphoma.3,4 This lymphoma is most common in populations from Asia (Korea, Hong Kong, and Japan) and South America and is consistently associated with the Epstein-Barr virus (EBV). It presents clinically with the destructive nasal or midline facial tumor. Recent molecular studies on the clonality of killer cell immunoglobulinlike receptors confirm the origin of this neoplasm from NK cells.5

In 1992, Kern et al6 and Wong et al7 reported expression of CD56 in extranodal lymphomas that are histologically similar to nasal lymphomas but do not occupy the nasopharyngeal region (nonnasal CD56+ lymphomas). These lymphomas run a very aggressive clinical course and have a weaker association with EBV than the true nasal lymphomas. Skin is often the site of the initial ivolvement. The cellular origin of this lymphoma type is unknown, but NK cells, T cells, or plasmacytoid monocytes have been proposed.4,810

Owing to the extreme rarity of the disease, information about nonnasal CD56+ lymphoma is limited. Histopathologically, nonnasal CD56+ lymphoma has been divided into 2 types: (1) nasal-type NK/T-cell lymphoma (named by some authors as the pleomorphic, small, medium, and large cell type) and (2) blastic NK/T-cell lymphoma.3,4,11 Moreover, an additional entity of the aggressive NK-cell lymphoma/leukemia of an extremely malignant course has been proposed.11 Further complexity is added to the classification by the fact that CD56 may be expressed in other types of lymphomas and leukemias such as anaplastic large-cell lymphomas, lymphomatoid papulosis, hepatosplenic γδ T-cell lymphomas, subcutaneous panniculitislike (SPL) γδ T-cell lymphomas, B-cell and T-cell lymphoblastic lymphomas, or myeloid leukemias with or without skin involvement.2,1217

In the present article, we report 4 new cases of CD56+ lymphoma where the skin was the primary site of presentation. Moreover, we review the available literature on CD56+ lymphomas involving the skin and provide data on prognosis and clinical and pathologic variants. This article includes nonnasal lymphomas only. Other well-defined types of lymphomas expressing CD56 have also been excluded.

METHODS

Since the inclusion of CD56 staining in the routine phenotyping of cutaneous lymphomas in 1997, we identified 4 cases of CD56+ lymphoma. In all patients, skin symptoms were the primary reason for referral. The cases were classified as CD56+ lymphomas on the basis of positive immunoperoxidase staining with the CD56 antibody and the inability to classify the tumor into other established T- or B-cell lymphoma categories.

IMMUNOPHENOTYPING AND BIOCHEMICAL ANALYSES

Routine histopathologic studies were done on 4-µm-thick sections stained with hematoxylin-eosin and reviewed by 2 of us with expertise in hematopathology and cutaneous pathology (K.R. and E.R.). The immunophenotyping was performed on paraffin and cryostat sections using antibodies against CD34, terminal deoxynucleotidyl transferase, CD56, CD3, CD4, CD8, T-cell intracellular antigen-1, granzyme B, CD79a, and CD30 (Ber-H2).9,18

Interferon γ concentration was determined in a serum sample from patient 3 using the Quantikine human IFN-γ immunoassay (R&D Systems, Abingdon, England), according to the manufacturer's protocol. For the assessment of the T-cell receptor (TCR) rearrangement status, genomic DNA was amplified using consensus primers for TCR-γV (5′-CTTCCAACTTGGAAGGGAGAA-3′ covering TCR-γV1-5, 7, and 9) and TCRJ (5′-CCAGGCGAAGTTACTATGAGC-3′ covering TCR-γJ1 and 2) yielding an amplification product of approximately 350 base pairs that was subsequently analyzed by single-strand conformational polymorphism.19 For detection of EBV-encoded small nuclear ribonucleic acid (EBER), a mixture of fluorescein-conjugated oligodeoxyribonucleotides complementary to the 2 EBERs was used (EBER; DAKO, Glostrup, Denmark).

Sections were dewaxed and rehydrated, digested with proteinase K, and postfixed for 20 minutes in 4% paraformaldehyde. Subsequently, the sections were allowed to prehybridize for 60 minutes at 45°C in a solution consisting of 50% formamide, 20% dextran sulfate, 0.2% polyvinyl pyrrolidone, 0.2% Ficoll, 0.1% sodium pyrophosphate, 5mM sodium edetic acid, and 50mM Tris hydrochloride at pH 7.6. After overnight hybridization at 37°C, the sections were incubated with alkaline phosphatase-conjugated rabbit anti-FITC (fluorescein isothiocyanate–conjugated) antibody (Roche Diagnostics, Basel, Switzerland) and developed with Fast Red TR (Sigma, St Louis, Mo). As positive controls, we used sections from lymph nodes with known EBV-associated Hodgkin disease.

SEARCH STRATEGY AND SELECTION OF THE MATERIAL

The aim was to find all published cases of CD56+ lymphomas presenting in the skin. The PubMed database was searched up to September 2002 using MeSH terms "Antigens," "CD56 AND Lymphoma," and "Non-Hodgkin AND (skin OR cutaneous OR subcutaneous)" (38 references) and the phrase "CD56 AND Lymphoma AND (skin OR subcutis OR cutaneous OR subcutaneous OR panniculitis)" (127 references). Obviously irrelevant articles, such as those presenting no clinical data or reporting on lymphomas without skin involvement, were rejected. The selected 73 articles were read by 1 of us (R.G.) who further selected the articles reporting as a minimum the main clinical features, survival and the cause of death of individual patients, CD56 positivity of the lymphoma, and histopathologic description. At this stage, 50 articles were found. An additional reference (congress abstract) was identified from the literature lists of these articles, but this communication contained data already included in a separate publication.

CLASSIFICATION OF CASES

Cases of CD56+ lymphoma with skin involvement were classified as previously described.4 Blastic lymphomas were defined as those showing a dense nonepidermotropic dermal infiltrate composed of cells resembling lymphoblasts with finely granular chromatin, inconspicuous nucleoli, and a sparse to moderate amount of cytoplasm. The lymphomas showing dermal and sometimes subcutaneous infiltrates of atypical pleomorphic cells (small, medium, or large) containing variable amounts of cytoplasm were considered to represent nasal-type NK/T-cell lymphomas. The SPL lymphomas showed similar histologic features to the nasal-type NK/T-cell lymphomas and were defined by the presence of clinical features of panniculitis and subcutaneous tumors. In all cases, the positivity of tumor cells for CD56 was required for diagnosis.

STATISTICAL ANALYSIS

The stardard error and confidence intervals (CIs) for proportions were computed as described by Altman.20 The analysis of 2 × 2 frequency tables was done by the χ2 test with the Yates correction. Analysis of survival times was done by life table analysis and the log-rank test and by the Cox backward stepwise regression model. Disease-related survival was defined as the number of months from the establishment of the diagnosis to the death event that was related to the lymphoma. Patients who died due to unrelated diseases or were lost to follow-up were considered to be censored at the time of the last contact. Median survival time, defined as the time when the cumulative probability of survival equals 0.5, was established from the Kaplan-Meier step-function curves. Calculations were performed with the Unistat statistical package (Unistat Corp, London, England), GraphPad Prism (GraphPad Software, San Diego, Calif), and SPSS statistical software (SPSS Science, Chicago, Ill).

RESULTS
CLINICAL CHARACTERISTICS

The crucial characteristics of our 4 cases of CD56+ lymphoma are summarized in Table 1 and illustrated in Figure 1 and Figure 2. The data gathered for further analysis came from 177 additional cases retrieved from published reports (Table 2).8,9,11,14,2166

During the preliminary analysis of the data, we confirmed the practical feasibility of the previously suggested classifications of blastic lymphomas and nasal type NK/T-cell lymphomas.4 Moreover, a group of patients presented with CD56+ lymphoma that manifested as panniculitis. Cytologically, the malignant cells of these tumors resembled those of pleomorphic lymphoma, but since this type had specific clinical features, we decided to analyze these cases as a separate subtype, CD56+ SPL lymphoma. The major characteristics of these 3 categories are summarized in Table 3. There was a marked male predominance in the cases of blastic and pleomorphic lymphoma, whereas the SPL type seemed to affect mostly women. The median age at diagnosis was 55 years and did not differ significantly between lymphoma subtypes.

The skin lesions included plaques and tumors, sometimes with hemorrhage and necrosis. Patients with SPL lymphoma also showed features of panniculitis. When all individuals with CD56+ lymphoma were analyzed as a single group, most patients (53%; 95% CI, 45%-61%) presented with widespread skin lesions. Only 30% (95% CI, 22%-38%) had a single lesion, and 17% (95% CI, 11%-24%) had several lesions confined to a single anatomic region. Virtually any region of the skin could be affected, but the CD56+ SPL lymphoma tended to be localized on the extremities and the buttocks. A very rare but clinically characteristic presentation of CD56+ lymphoma was bruiselike lesions that tended to occupy the face and in 1 case were associated with paraneoplastic hemorrhagic diathesis.2123 Bruiselike lesions seem to be characteristic of blastic lymphoma.

Virtually all patients with SPL lymphoma had systemic symptoms: weight loss, fever, general weakness, and arthralgia, which have been attributed to the increased synthesis of proinflammatory cytokines such as IFN-γ.24 Also, our patient with SPL lymphoma (case 3) had an increased concentration of IFN-γ in the blood (2859 pg/mL; normal concentration in human plasma is <15 pg/mL). Systemic symptoms were less frequent (17% of cases) in the 2 other types of CD56+ lymphoma. Extracutaneous involvement was often encountered (52% of patients). The most frequent sites of dissemination were bone marrow (26%) followed by lymph nodes and/or spleen (20%), visceral organs (mostly liver) (11%), and the central nervous system (7%). Visceral dissemination was slightly less frequent in cases of SPL lymphoma than in the 2 remaining subtypes (Table 3).

HISTOPATHOLOGIC AND MOLECULAR CHARACTERISTICS

In the nasal-type NK/T-cell lymphomas and blastic lymphomas, the infiltrate of the malignant cells was localized in the dermis and often in the subcutis. Epidermotropism was noted in only few cases.25 Angiocentricity and blood vessel invasion was present in approximately 60% of nasal-type NK/T-cell lymphomas and SPL lymphomas, but was absent in blastic lymphomas. In general, the histopathologic features were in accordance with previous descriptions.3,4

Immunohistochemical and molecular features are listed in Table 4. No specific single set of markers could be associated with the lymphoma subtypes; nonetheless, some regularity was observed. Malignant cells did not express B-cell markers (CD19, CD20, or immunoglobulin gene rearrangement) or NK-cell marker CD57 and only rarely expressed the stem-cell marker CD34. Likewise, expression of CD8 was noted in only 4 patients,2628(patient 5),29(patient 2) and expression of CD2, CD5, and CD7 was highly variable. Only in 3 cases did the malignant cells demonstrate a mature T-cell phenotype, CD3+CD4+CD8, and have rearranged TCR genes.3032(patient 31)

The most common phenotype of the blastic CD56+ lymphoma was CD3CD4+ present in 78% of the cases (P = .001, χ2 test). Terminal deoxynucleotidyl transferase was sometimes detected in this subtype, but the expression was often equivocal, and the number of patients investigated for this marker was too small to draw meaningful conclusions. Epstein-Barr virus was present only in few cases (Table 3), and in 2 cases the TCR rearrangement was detected.

Nasal-type NK/T-cell lymphoma was often associated with EBV infection. The most common phenotype was CD3+CD4 (52.2%), which is significantly more than expected by chance association (P = .02, χ2 test).

The characteristics of SPL lymphoma were similar to those of the nasal-type NK/T-cell lymphoma: 84% of patients had the phenotype CD3+CD4 (P = .001, χ2 test), and a substantial proportion of patients had detectable EBV and rearranged TCR genes (Table 3 and Table 4). In all but 1 case, the TCR-γδ but not TCR-αβ genes were rearranged. In all cases of SPL lymphoma that were examined for expression of cytotoxic markers, the presence of at least 1 marker (T-cell intracellular antigen-1, granzyme B, or perforin) was noted.

SURVIVAL

Kaplan-Meier survival curves revealed that the median survival for all patients with CD56+ lymphoma was 14 months and did not differ significantly between the different subtypes (Figure 3). To determine whether any clinical characteristic predicts survival, we chose the following variables: age, sex, race, presence of extracutaneous dissemination at presentation, and extent of skin involvement (single lesions, local involvement, widespread lesions). These variables have been shown to be important in various types of non-Hodgkin lymphomas, including cutaneous T-cell lymphomas. Only age and the presence of extracutaneous dissemination were strong negative predictors of survival (Figure 3). Patients younger than 55 years (the median age of onset of CD56+ lymphoma) had twice as long survival as those older than 55 years (25 months vs 10 months; P = .003; hazard ratio, 0.53; 95% CI, 0.32-0.71). Lymph node involvement did not have a measurable negative effect on survival, while dissemination into bone marrow and/or visceral organs had a strong negative effect, decreasing survival from a median of 25 months to 8 months (P<.001; hazard ratio, 2.0; 95% CI, 1.48-3.31).

There was no survival difference between patients with CD3+ tumor cells and those with CD3 lymphomas. There were too few patients with CD8+ lymphomas to perform a reliable analysis. T-cell receptor TCR rearrangement did not have any prognostic importance either. However, EBV status, CD4 expression, and CD30 expression were related to survival in the single-variable model. To elucidate the importance of these phenotypic markers for survival, we performed the backward stepwise Cox regression analysis to account for possible associations between the variables. The following variables were selected: age at diagnosis, type of lymphoma, extranodal dissemination, and presence of EBV, CD4, and CD30. Of these, only age, CD4, and CD30 were identified as significant variables (P = .01, P = .03, and P = .004, respectively). Presence of CD30 was the strongest predictor of survival (Figure 4A). The importance of CD4 was also investigated (in a model from which the CD30 status was removed to increase the number of patients in the model). Interestingly, in this regression model, the presence of visceral dissemination was also a significant predictor (P<.001; Figure 4B).

Therapy did not seem to affect survival. The patients who received treatment were classified into 4 categories: (1) those who received CHOP (cyclophosphamide-doxorubicin-vincristine-prednisone combination therapy); (2) those who received another doxorubicin-based therapy; (3) those who received another combination chemotherapy; and (4) those who received local radiation, systemic steroids, or no therapy. There were no differences in survival among these 4 groups of patients.

COMMENT

The CD56+ lymphoma is known to be one of the most aggressive neoplasms affecting the skin. However, because of its rarity, little is known about its clinicopathologic features and prognostic factors. CD56+ lymphomas frequently affect the skin, and the dermatologist is often the first physician to see the patient. Unfortunately, knowledge about this lymphoma is not widespread, which is reflected in the fact that most published case reports originate from few academic centers with long-term interest in cutaneous oncology and malignant hematology. The true prevalence of CD56+ lymphoma is unknown because the CD56 antibody is not routinely used for lymphoma phenotyping by all centers. The fact that 4 cases were encountered over 3 years in a relatively small center like ours (population base, approximately 1.5 million) may suggest that this lymphoma is more prevalent than expected.

For the present article, we critically assessed 177 published cases of CD56+ lymphoma together with our own 4 cases. One must be aware of possible limitations of this design. There is a theoretical possibility that the same group will describe the same patient multiple times without making reference to other publications. In several cases we identified clinical data of the same patient in several communications, mostly posters or congress abstracts followed by full articles. We were aware of this possibility and worked to exclude patients who may have been described multiple times by checking for identical age, sex, survival, and clinical characteristics in patients reported in multiple publications by the same researchers.

Another limitation is that the characteristics of the described patients are not representative of all patients with CD56+ lymphoma. The CD56 marker is not routinely used by all dermatopathologists, and there might be a tendency to perform this staining for more aggressive or histopathologically unclear lymphomas. However, owing to the rarity of CD56+ lymphoma, prospective studies have not been performed. To date, the present article is the largest survey on this type of lymphoma.

The data confirm an extreme aggressiveness of this tumor and a median survival of approximately 1 year after diagnosis despite chemotherapy and radiation therapy. The data confirm the usefulness of the accepted classification of these lymphomas: blastic and nasal-type NK/T-cell lymphomas. In addition, CD56 is also expressed in a subset of SPL lymphomas (Table 5).

The male preponderance of CD56+ lymphoma has been noted previously.11,25,28,33,34 This predominance holds true for blastic and nasal-type NK/T-cell lymphomas, while CD56+ SPL lymphoma seems mainly to affect women. However, sex is not a factor that affects survival.

The 3 most important independent predictors of survival are age at diagnosis and the expression of CD30 and CD4. Of these, CD30 expression has the strongest positive prognostic importance, independent of other possible confounders such as age, clinical stage, lymphoma subtype, and the presence of EBV in the lesions. This surface molecule belongs to the tumor necrosis factor receptor family and is also expressed in other cutaneous lymphomas such as lymphomatoid papulosis and the anaplastic large cell lymphomas that run a favorable clinical course.67 The role of CD30 in cutaneous lymphomas is puzzling because nodal CD30+ anaplastic lymphomas are very aggressive—especially those not carrying the t(2;5) chromosomal aberration—in contrast to their cutaneous counterparts. CD30 molecules exert pleiotropic biological effects on lymphoma cells, which depend largely on the cellular context.67 In anaplastic lymphoma, stimulation of CD30 leads to cell growth arrest and apoptosis via signaling mechanisms involving p21CIP1/WAF1 and antagonizing the activity of nuclear factor κB.68,69 In contrast, activation of CD30 has a mitogenic effect in Hodgkin lymphoma that constitutively expresses nuclear factor κB.67,68 The favorable prognostic importance of CD30 in CD56+ lymphomas has previously been suggested by Mraz-Gernhard et al25 and was confirmed in the present study. The reason for the predictive value of CD4 is unclear. It is possible that the absence of CD4 heralds a less mature and hence more aggressive phenotype.

In the Cox survival model based on 33 patients with known variables (age, lymphoma subtype, presence or absence of extranodal dissemination, EBV status, and expression of CD4 and CD30), the presence of extranodal dissemination was not a significant predictor. We were puzzled by this finding and considered the possibility that the number of patients was too low to detect this effect. Therefore, we constructed another regression survival model that did not include the CD30 status. This analysis was made on 129 patients and showed statistical significance for extranodal dissemination. Although we consider it likely that the clinical stage is predictive for survival, we cannot exclude the possibility that this variable is correlated with (and dependent on) the expression of CD30.

The cellular origin of CD56+ lymphomas is still a matter of debate; NK cells, T cells, and monocytes have been suggested as relevant cell types. Recent research has provided evidence that blastic CD56+ lymphomas originate from plasmacytoid monocytes that under normal conditions may act as precursors of antigen-presenting cells.10,34 However, in a recent case of CD56+ lymphoma,9 the expression of the NK-receptor complex CD94/NKG2 was found, which suggests an NK-cell origin of this neoplasm. The malignant cells in SPL lymphomas seem to be related to γδ T cells. In fact, the clinical and histologic features of CD56+ and CD56γδ T-cell lymphomas are indistinguishable, and a significant proportion of SPL CD56+ lymphomas express TCR-γδ. It seems that TCR-γδ+ and TCR-γδ lymphomas originate from a common T-cell precursor, but developmental arrest occurs earlier the TCR-γδ type. Another observation supporting this concept is the coexistence of TCR-γδ+ and TCR-γδ populations in patients with CD56+ leukemia/lymphoma syndrome.70 An interesting feature of SPL lymphomas, demonstrated for the first time by Burg et al24 and also shown in our case 3, is the presence of systemic symptoms (fever, weight loss, general weakness, and/or arthralgia) that may be related to the production of IFN-γ by tumor cells. Like αβ T cells, γδ cells may differentiate into IFN-γ (T helper 1–like) and interleukin 4 (T helper 2–like) producing cells. However, γδ T cells differentiate by default toward the type 1 cytokine–producing cells,71 and this maturational pathway may be caricatured in SPL lymphoma.

Back to top
Article Information

Corresponding author and reprints: Robert Gniadecki, MD, DMS, Department of Dermatology D, Bispebjerg Hospital, Bispebjerg bakke 23, DK-2400 Copenhagen NV, Denmark (e-mail: rg01@bbh.hosp.dk).

Accepted for publication July 2, 2003.

References
1.
Ortaldo  JRMason  ATO'Shea  JJ  et al.  Mechanistic studies of transforming growth factor-beta inhibition of IL-2-dependent activation of CD3- large granular lymphocyte functions: regulation of IL-2β (p75) signal transduction J Immunol. 1991;1463791- 3798
PubMed
2.
Hoyle  CBangs  CDChang  PKamel  OMehta  BNegrin  RS Expansion of Philadelphia chromosome-negative CD3+CD56+ cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice Blood. 1998;923318- 3327
PubMed
3.
Jaffe  ESChan  JKSu  IJ  et al.  Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas: definitions, differential diagnosis, and epidemiology Am J Surg Pathol. 1996;20103- 111
PubMedArticle
4.
Jaffe  ESKrenacs  LKumar  SKingma  DWRaffeld  M Extranodal peripheral T-cell and NK-cell neoplasms Am J Clin Pathol. 1999;111 ((suppl 1)) S46- S55
PubMed
5.
Lin  CWLee  WHChang  CLYang  JYHsu  SM Restricted killer cell immunoglobulinlike receptor repertoire without T-cell receptor gamma rearrangement supports a true natural killer-cell lineage in a subset of sinonasal lymphomas Am J Pathol. 2001;1591671- 1679
PubMedArticle
6.
Kern  WFSpier  CMHanneman  EHMiller  TPMatzner  MGrogan  TM Neural cell adhesion molecule-positive peripheral T-cell lymphoma: a rare variant with a propensity for unusual sites of involvement Blood. 1992;792432- 2437
PubMed
7.
Wong  KFChan  JKNg  CSLee  KCTsang  WYCheung  MM CD56 (NKH1)-positive hematolymphoid malignancies: an aggressive neoplasm featuring frequent cutaneous/mucosal involvement, cytoplasmic azurophilic granules, and angiocentricity Hum Pathol. 1992;23798- 804
PubMedArticle
8.
Bagot  MBouloc  ACharue  DWechsler  JBensussan  ABoumsell  L Do primary cutaneous nonT nonB CD4+CD56+ lymphomas belong to the myelo-monocytic lineage? J Invest Dermatol. 1998;1111242- 1244
PubMedArticle
9.
Knudsen  HGronbaek  KThor Straten  P  et al.  A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with theNK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion Br J Dermatol. 2002;146148- 153
PubMedArticle
10.
Chaperot  LBendriss  NManches  O  et al.  Identification of a leukemic counterpart of the plasmacytoid dendritic cells Blood. 2001;973210- 3217
PubMedArticle
11.
Chan  JKSin  VCWong  KF  et al.  Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm Blood. 1997;894501- 4513
PubMed
12.
Chang  SEPark  IJHuh  J  et al.  CD56 expression in a case of primary cutaneous CD30+ anaplastic large cell lymphoma Br J Dermatol. 2000;142766- 770
PubMedArticle
13.
Rakozy  CKMohamed  ANVo  TD  et al.  CD56+/CD4+ lymphomas and leukemias are morphologically, immunophenotypically, cytogenetically, and clinically diverse Am J Clin Pathol. 2001;116168- 176
PubMedArticle
14.
Bekkenk  MWKluin  PMJansen  PMMeijer  CJWillemze  R Lymphomatoid papulosis with a natural killer-cell phenotype Br J Dermatol. 2001;145318- 322
PubMedArticle
15.
Murakami  YNagae  SMatsuishi  EIrie  KFurue  M A case of CD56+ cutaneous aleukaemic granulocytic sarcoma with myelodysplastic syndrome Br J Dermatol. 2000;143587- 590
PubMedArticle
16.
Raspadori  DDamiani  DLenoci  M  et al.  CD56 antigenic expression in acute myeloid leukemia identifies patients with poor clinical prognosis Leukemia. 2001;151161- 1164
PubMedArticle
17.
Suzuki  RKagami  YTakeuchi  K  et al.  Prognostic significance of CD56 expression for ALK-positive and ALK-negative anaplastic large-cell lymphoma of T/null cell phenotype Blood. 2000;962993- 3000
PubMed
18.
Gniadecki  RRossen  K Expression of T-cell activation marker CD134 (OX40) in lymphomatoid papulosis Br J Dermatol. 2003;148885- 891
PubMedArticle
19.
Murphy  MSignoretti  SKadin  MELoda  M Detection of TCR-gamma gene rearrangements in early mycosis fungoides by nonradioactive PCR-SSCP J Cutan Pathol. 2000;27228- 234
PubMedArticle
20.
Altman  DG Practical Statistics for Medical Research.  London, England Chapman & Hall1992;
21.
Dummer  RPotoczna  NHaffner  ACZimmermann  DRGilardi  SBurg  G A primary cutaneous nonT, nonB CD4+, CD56+ lymphoma Arch Dermatol. 1996;132550- 553
PubMedArticle
22.
Hofbauer  GFKamarachev  JKempf  WBurg  GPestalozzi  BCDummer  R A CD4+ CD56+ natural killerlike T-cell systemic lymphoma with haemorrhagic cutaneous manifestations Br J Dermatol. 2001;144432- 434
PubMedArticle
23.
Nagatani  TOkazawa  HKambara  T  et al.  Cutaneous monomorphous CD4- and CD56- positive large-cell lymphoma Dermatology. 2000;200202- 208
PubMedArticle
24.
Burg  GDummer  RWilhelm  M  et al.  A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma N Engl J Med. 1991;3251078- 1081
PubMedArticle
25.
Mraz-Gernhard  SNatkunam  YHoppe  RTLeBoit  PKohler  SKim  YH Natural killer/natural killerlike T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course J Clin Oncol. 2001;192179- 2188
PubMed
26.
Adachi  MMaeda  KTakekawa  M  et al.  High expression of CD56 (N-CAM) in a patient with cutaneous CD4-positive lymphoma Am J Hematol. 1994;47278- 282
PubMedArticle
27.
Dargent  JLRoufosse  CDelville  JP  et al.  Subcutaneous panniculitislike T-cell lymphoma: further evidence for a distinct neoplasm originating from large granular lymphocytes of T/NK phenotype J Cutan Pathol. 1998;25394- 400
PubMedArticle
28.
Nakamura  SSuchi  TKoshikawa  T  et al.  Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract Am J Surg Pathol. 1995;19284- 296
PubMedArticle
29.
Takeshita  MKimura  NSuzumiya  J  et al.  Angiocentric lymphoma with granulomatous panniculitis in the skin expressing natural killer cell and large granular T-cell phenotypes Virchows Arch. 1994;425499- 504
PubMedArticle
30.
Noguchi  MKawano  YSato  NOshimi  K T-cell lymphoma of CD3+CD4+CD56+ granular lymphocytes with hemophagocytic syndrome Leuk Lymphoma. 1997;26349- 358
PubMed
31.
Wasik  MASackstein  RNovick  D  et al.  Cutaneous CD56+ large T-cell lymphoma associated with high serum concentration of IL-2 Hum Pathol. 1996;27738- 744
PubMedArticle
32.
Emile  JFBoulland  MLHaioun  C  et al.  CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas Blood. 1996;871466- 1473
PubMed
33.
Petrella  TDalac  SMaynadie  M  et al.  CD4+ CD56+ cutaneous neoplasms: a distinct hematological entity? Groupe Francais d'Etude des Lymphomes Cutanes (GFELC) Am J Surg Pathol. 1999;23137- 146
PubMedArticle
34.
Petrella  TComeau  MRMaynadie  M  et al.  "Agranular CD4+ CD56+ hematodermic neoplasm" (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes Am J Surg Pathol. 2002;26852- 862
PubMedArticle
35.
Abe  YMuta  KOhshima  K  et al.  Subcutaneous panniculitis by Epstein-Barr virus-infected natural killer (NK) cell proliferation terminating in aggressive subcutaneous NK cell lymphoma Am J Hematol. 2000;64221- 225
PubMedArticle
36.
Ahn  SJJang  KAChoi  JHSung  KJMoon  KCKoh  JK Nasal and nasal type CD56+ natural killer cell/T-cell lymphoma: a case with rapid progression to bone marrow involvement Br J Dermatol. 2000;1421021- 1025
PubMedArticle
37.
Amo  YYonemoto  KOhkawa  T  et al.  CD56 and terminal deoxynucleotidyl transferase positive cutaneous lymphoblastic lymphoma Br J Dermatol. 2000;143666- 668
PubMedArticle
38.
Ansai  SMaeda  KYamakawa  M  et al.  CD56-positive (nasal-type T/NK cell) lymphoma arising on the skin: report of two cases and review of the literature J Cutan Pathol. 1997;24468- 476
PubMedArticle
39.
Avinoach  IHalevy  SArgov  SSacks  M Gamma/delta T-cell lymphoma involving the subcutaneous tissue and associated with a hemophagocytic syndrome Am J Dermatopathol. 1994;16426- 433
PubMedArticle
40.
Bastian  BCOtt  GMuller-Deubert  SBrocker  EBMuller-Hermelink  HK Primary cutaneous natural killer/T-cell lymphoma Arch Dermatol. 1998;134109- 111
PubMedArticle
41.
Bower  CPStanden  GRPawade  JKnechtli  CJKennedy  CT Cutaneous presentation of steroid responsive blastic natural killer cell lymphoma Br J Dermatol. 2000;1421017- 1020
PubMedArticle
42.
Brody  JPAllen  SSchulman  P  et al.  Acute agranular CD4-positive natural killer cell leukemia: comprehensive clinicopathologic studies including virologic and in vitro culture with inducing agents Cancer. 1995;752474- 2483
PubMedArticle
43.
Chang  SEHuh  JChoi  JHSung  KJMoon  KCKoh  JK Clinicopathological features of CD56+ nasal-type T/natural killer cell lymphomas with lobular panniculitis Br J Dermatol. 2000;142924- 930
PubMedArticle
44.
Chang  SEChoi  JHSung  KJMoon  KCKoh  JK Cutaneous nasal-type CD56+ natural killer/T-cell lymphoma preceded by Epstein-Barr virus antigenaemia Br J Dermatol. 2001;145668- 669
PubMedArticle
45.
Chang  SEChoi  HJHuh  J  et al.  A case of primary cutaneous CD56+, TdT+, CD4+, blastic NK-cell lymphoma in a 19-year-old woman Am J Dermatopathol. 2002;2472- 75
PubMedArticle
46.
Cho  KHOh  JKKim  CWHeo  DSKim  ST Peripheral T-cell lymphoma involving subcutaneous tissue Br J Dermatol. 1995;132290- 295
PubMedArticle
47.
DiGiuseppe  JALouie  DCWilliams  JE  et al.  Blastic natural killer cell leukemia/lymphoma: a clinicopathologic study Am J Surg Pathol. 1997;211223- 1230
PubMedArticle
48.
Feuillard  JJacob  MCValensi  F  et al.  Clinical and biologic features of CD4+CD56+ malignancies Blood. 2002;991556- 1563
PubMedArticle
49.
Hirakawa  SKuyama  MTakahashi  S  et al.  Nasal and nasal-type natural killer/T-cell lymphoma J Am Acad Dermatol. 1999;40 ((2, pt 1)) 268- 272
PubMedArticle
50.
Jang  KAChoi  JHSung  KJ  et al.  Primary CD56+ nasal-type T/natural killer-cell subcutaneous panniculitic lymphoma: presentation as haemophagocytic syndrome Br J Dermatol. 1999;141706- 709
PubMedArticle
51.
Kameoka  JIchinohasama  RTanaka  M  et al.  A cutaneous agranular CD2- CD4+ CD56+ "lymphoma": report of two cases and review of the literature Am J Clin Pathol. 1998;110478- 488
PubMed
52.
Kato  NYasukawa  KOnozuka  TKikuta  H Nasal and nasal-type T/NK-cell lymphoma with cutaneous involvement J Am Acad Dermatol. 1999;40 ((5, pt 2)) 850- 856
PubMedArticle
53.
Kato  NYasukawa  KKimura  K  et al.  CD2CD4+CD56+ hematodermic/hematolymphoid malignancy J Am Acad Dermatol. 2001;44231- 238
PubMedArticle
54.
Ko  YHKim  SHRee  HJ Blastic NK-cell lymphoma expressing terminal deoxynucleotidyl transferase with Homer-Wright type pseudorosettes formation Histopathology. 1998;33547- 553
PubMedArticle
55.
Kojima  HMukai  HYShinagawa  A  et al.  Clinicopathological analyses of 5 Japanese patients with CD56+ primary cutaneous lymphomas Int J Hematol. 2000;72477- 483
PubMed
56.
Marzano  AVBerti  EPaulli  MCaputo  R Cytophagic histiocytic panniculitis and subcutaneous panniculitislike T-cell lymphoma: report of 7 cases Arch Dermatol. 2000;136889- 896
PubMedArticle
57.
Natkunam  YSmoller  BRZehnder  JLDorfman  RFWarnke  RA Aggressive cutaneous NK and NKlike T-cell lymphomas: clinicopathologic, immunohistochemical, and molecular analyses of 12 cases Am J Surg Pathol. 1999;23571- 581
PubMedArticle
58.
Natkunam  YWarnke  RAHaghighi  B  et al.  Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases J Cutan Pathol. 2000;27392- 399
PubMedArticle
59.
Ohtsuka  TYamakage  AYamazaki  S Digital ulcers and necroses: novel manifestations of angiocentric lymphoma Br J Dermatol. 2000;1421013- 1016
PubMedArticle
60.
Paulli  MBoveri  ERosso  R  et al.  CD56/neural cell adhesion molecule expression in primary extranodal Ki-1/CD30+ lymphoma: report of a pediatric case with simultaneous cutaneous and bone localizations Am J Dermatopathol. 1997;19384- 390
PubMedArticle
61.
Radonich  MALazova  RBolognia  J Cutaneous natural killer/T-cell lymphoma J Am Acad Dermatol. 2002;46451- 456
PubMedArticle
62.
Salhany  KEMacon  WRChoi  JK  et al.  Subcutaneous panniculitislike T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes Am J Surg Pathol. 1998;22881- 893
PubMedArticle
63.
Savoia  PFierro  MTNovelli  M  et al.  CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease Br J Dermatol. 1997;137966- 971
PubMedArticle
64.
Shaw  PHCohn  SLMorgan  ER  et al.  Natural killer cell lymphoma: report of two pediatric cases, therapeutic options, and review of the literature Cancer. 2001;91642- 646
PubMedArticle
65.
Uchiyama  NIto  KKawai  KSakamoto  FTakaki  MIto  M CD2-, CD4+, CD56+ agranular natural killer cell lymphoma of the skin Am J Dermatopathol. 1998;20513- 517
PubMedArticle
66.
Yamashita  YTsuzuki  TNakayama  AFujino  MMori  N A case of natural killer/T cell lymphoma of the subcutis resembling subcutaneous panniculitislike T cell lymphoma Pathol Int. 1999;49241- 246
PubMedArticle
67.
Horie  RWatanabe  T CD30: expression and function in health and disease Semin Immunol. 1998;10457- 470
PubMedArticle
68.
Mir  SSRichter  BWDuckett  CS Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells Blood. 2000;964307- 4312
PubMed
69.
Hubinger  GMuller  EScheffrahn  I  et al.  CD30-mediated cell cycle arrest associated with induced expression of p21(CIP1/WAF1) in the anaplastic large cell lymphoma cell line Karpas 299 Oncogene. 2001;20590- 598
PubMedArticle
70.
Camera  APezzullo  LVilla  MR  et al.  Coexistence of two distinct cell populations (CD56+ TcR γδ+ and CD56+ TcR γδ-) in a case of aggressive CD56+ lymphoma/leukemia Haematologica. 2000;85496- 501
PubMed
71.
Yin  ZZhang  DHWelte  T  et al.  Dominance of IL-12 over IL-4 in γδ T cell differentiation leads to default production of IFN-γ: failure to down-regulate IL-12 receptor β2-chain expression J Immunol. 2000;1643056- 3064
PubMedArticle
×