J Cutan Pathol 2002 Feb;29(2):88-92 

Large atypical cells of lymphomatoid papulosis are CD56-negative: a study of 18 cases. 

Harvell J, Vaseghi M, Natkunam Y, Kohler S, Kim Y. 

Department of Pathology, Stanford University School of Medicine, CA 94305

     Histologically, diffuse dermal infiltrates of large atypical lymphocytes can be seen in lesions as indolent as type C lymphomatoid papulosis (LyP) to ones as aggressive as NK/T-cell lymphoma. While lesions of lymphomatoid papulosis are definitionally positive for CD30, their ability to express CD56 has not been formally studied. The objective of the current study was to determine whether or not the large atypical cells of LyP express the natural killer cell marker, CD56. METHODS: Biopsies from 18 patients with LyP were studied with monoclonal antibodies to CD30, CD56, CD8, and TIA-1. These included four type C LyP lesions. Clinical information was obtained by chart review and included extent of LyP lesions, presence/absence of disease at follow-up, and any associated hematologic malignancies,. RESULTS: None of the biopsies exhibited CD56 positivity within the large atypical cells of LyP. While some biopsies demonstrated CD56-positive, small, presumably reactive, lymphocytes within the infiltrate, their presence did not correlate with extent of disease, persistence of disease, or propensity for an associated non-LyP hematologic malignancy. CONCLUSIONS: The large atypical cells of types A and C LyP do not exhibit positivity for CD56, and thus a panel of antibodies that includes CD30 and CD56 can readily distinguish between the benign end of the spectrum of CD30-positive lymphoproliferations and aggressive NK/T-cell lymphoma.

Hepatogastroenterology 2002 Jul-Aug;49(46):950-4 

Ulcerative colon T-cell lymphoma: an unusual entity mimicking Crohn's disease and may be associated with fulminant hemophagocytosis. 

Hsiao CH, Kao HL, Lin MC, Su IJ. 

Department of Pathology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei, Taiwan. 

        Primary gastrointestinal T-cell lymphoma is uncommon. Most arise from the small intestine and are usually associated with chronic celiac disease; the so-called enteropathy associated T-cell lymphoma. Primary colon T-cell lymphoma is much more rare. We present two patients with primary colon T-cell lymphoma. Both patients had chronic diarrhea and significant weight loss. Endoscopically, the lymphoma was characterized by the presence of multiple skipped ulcers distributed from the terminal ileum to the descending colon. It was differentiated from Crohn's disease by the absence of fistula or thickening of the intestinal walls. Histologically, the lymphoma was composed of medium to large atypical cells located in the ulcer base with extension to the muscular layer and the adjacent atrophic mucosa. Occasional increased intraepithelial lymphocytes were also seen. Immunohistochemically, the lymphoma cells and intraepithelial lymphocytes were CD3+, CD4-, CD56- and CD8-. It was difficult to diagnosis this unusual lymphoma by biopsy. Because most biopsy specimens showed mixed inflammation within which the lymphoma cell was sometimes hard to identify. Both patients died of fulminant hemophagocytic syndrome and Epstein-Barr virus genome was detected in the lymphoma cells using in situ hybridization on the final surgical specimens. Our study indicates that it is important to recognize this ulcerative colon T-cell lymphoma and to differentiate it from inflammatory bowel disease because of its much more aggressive clinical behavior.

Appl Immunohistochem Mol Morphol 2002 Jun;10(2):163-70 

Comparison of primary and secondary cutaneous CD56+ NK/T cell lymphomas. 

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

Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea. 

        CD56+ NK/T cell lymphoma (NKTL) frequently involves skin and subcutaneous tissue. The characteristics of primary cutaneous nasal-type CD56+ NKTLs and secondary cutaneous involvement of nasal CD56+ NKTLs have not been clearly separated. This retrospective study analyzed 15 cases of NKTL (10 primary CD56+ NKTLs and 5 secondary CD56+ NKTLs) for their clinicopathologic and immunophenotypic characteristics using CD3, CD4, CD20, CD45RO, CD56, TIA-1, CD30, and Ki-67 antigens. In situ hybridization for Epstein-Barr virus RNA (EBERISH) and PCR for T cell receptor (TCR) gamma gene rearrangement were also performed. Clinically, NKTL-P was seen with equal frequency among male (five cases) and female (five cases) patients and presented with subcutaneous nodules without epidermal changes (nine cases), whereas all cases of NKTL-S occurred in male patients and presented with nodules or plaques with distinct epidermal changes (five cases). Microscopically, initial NKTL-P lesions had the panniculitic patterns of small to medium-sized cells (nine cases). NKTL-S lesions were extensive in both subcutis and dermis, with larger and more pleomorphic tumor cells (four cases) that also showed signs epidermotropism (five cases). In initial biopsies of CD56+ NKTL-P, a minority of tumor cells showed signals for EBERISH and in biopsies of CD56+ NKTL-S, virtually every tumor cell showed signals. While all five patients with secondary CD56+ NKTL died of disease with widespread systemic involvement within 16 months after onset of skin lesions, 7 out of the 10 primary CD56+ NKTL patients survived more than 20 months after onset of skin lesions, with slow progression and episodic recurrences. The primary and secondary cutaneous CD56+ NKTLs showed considerable clinicopathologic differences, suggesting differences in pathogenesis.

Virchows Arch 2001 Mar;438(3):271-9 

Nasal 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. 

        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.

Cancer 2001 Feb 1;91(3):525-33 

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. 

        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. Copyright 2001 American Cancer Society.

Blood 1996 Feb 15;87(4):1466-73  

CD5-CD56+ T-cell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas. 

Emile JF, Boulland ML, Haioun C, Kanavaros P, Petrella T, Delfau-Larue MH, Bensussan A, Farcet JP, Gaulard P. 

Departement de Pathologie, Hopital Henri Mondor, Creteil, France. 

Non-Hodgkin's lymphomas are divided into B- and T-cell neoplasms. The existence and the clinical relevance of lymphomas derived from the third lymphocyte lineage, ie, natural killer (NK) cells are still controversial. NK cells are lymphocytes that mediate cytotoxicity without prior sensitization. NK cells also have phenotypic and genotypic characteristics: they express the NK-related antigen CD56, T-cell markers such as CD2 and CD7, but do not express CD5 and T-cell receptor (TCR) proteins, and their TCR locus is not rearranged. Therefore, if NK cell lymphomas exist, they should express some T-cell markers, but not alpha beta or gamma delta TCR proteins. Such lymphomas are actually called TCR silent peripheral T cell lymphomas (PTCL). To detect and characterize NK cell lymphomas, we investigated the immunophenotype and immunogenotype of 35 patients with TCR silent PTCL. The first group included 16 patients with a lymphoma of CD5-CD56+ phenotype, which is identical to normal NK cells. These patients had either a nasal/nasopharyngeal lymphoma (11 cases) or a lymphoma with predominant non-nasal/non-nodal initial involvement (five cases). Eight of the nine cases for which immunogenotypic data were available lacked clonal rearrangement of the TCR gamma genes. Thus, these tumors are likely to be NK cell lymphomas. The second group of 15 cases had a CD5+ phenotype (14 were CD56-, and 1 was CD56+) and clonal rearrangement of TCR gamma genes, indicating that they were true PTCL with unproductive TCR rearrangement. The four remaining cases were CD5- CD56- lymphomas and disclosed either a clonal (two cases) or no clonal (two cases) rearrangements of the TCR gamma genes. Altogether these findings show that CD5-CD56+ so-called "TCR silent PTCL" bear the immunophenotype and immunogenotype of normal NK cells and display peculiar clinical features distinct from true PTCL.

Int J Cancer 1997 Nov 4;73(3):332-8 

Nasal T/natural killer (NK)-cell lymphomas are derived from Epstein-Barr virus-infected cytotoxic lymphocytes of both NK- and T-cell lineage. 

Chiang AK, Chan AC, Srivastava G, Ho FC. 

Department of Pathology, The University of Hong Kong, Hong Kong. 

The cellular nature of nasal T/natural killer (NK)-cell lymphomas (NLs) remains controversial. It is still debatable whether these represent T-cell lymphomas with extensive loss of surface antigens or are, in fact, true NK-cell lymphomas. They are associated closely with Epstein-Barr virus (EBV), to the extent that EBV-encoded small non-polyadenylated RNAs (EBER) expression can be used as a marker for the neoplastic cells. The cell lineage of this group of lymphomas was examined further by correlating immunophenotype, genotype and EBV status with the expression of cytotoxic granule-associated proteins, perforin and T-cell intracellular antigen-1 (TIA-1) in 13 cases of NL. Combined immunophenotypic and gene rearrangement analyses demonstrated that NLs can be identified clearly as either NK-cell or T-cell tumours. Nasal NK-cell lymphomas lacked clonal rearrangement of both T-cell receptor (TCR) gamma and immunogloulin heavy chain (IgH) genes and were either CD3(Leu4)-CD56+ (8 cases) or CD3(Leu4)+CD56+ (2 cases), whereas nasal T-cell lymphomas had rearranged TCRgamma and germ-line IgH genes and were either CD3(Leu4)+CD56+ (2 cases) or CD3(Leu4)+CD56- (1 case). Immunohistochemical (IH) studies showed that both perforin and TIA-1 were expressed universally in NL, irrespective of NK- or T-cell lineage. Dual labelling of TIA-1 by IH and EBER by in situ hybridisation demonstrated that the granule proteins were expressed predominantly by the EBER+ tumour cells. Our results indicate that NLs are derived from EBV-infected cytotoxic lymphocytes of both NK- and T-cell lineage. We postulate that cytotoxic lymphocytes generated during the cellular immune response to EBV infection or re-activation at the nasal region themselves may become targets for EBV infection and subsequent transformation.

Am J Surg Pathol 1996 Jan;20(1):103-11 

Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology. 

Jaffe ES, Chan JK, Su IJ, Frizzera G, Mori S, Feller AC, Ho FC. 

Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA. 

A workshop jointly sponsored by the University of Hong Kong and the Society for Hematopathology explored the definition, differential diagnosis, and epidemiology of angiocentric lymphomas presenting in the nose and other extranodal sites. The participants concluded that nasal T/natural killer (NK) cell lymphoma is a distinct clinicopathologic entity highly associated with Epstein-Barr virus (EBV). In situ hybridization for EBV an be very valuable in early diagnosis, especially if tissue is sparse. The cytologic spectrum is broad, ranging from small or medium-sized cells to large transformed cells. Histologic progression often occurs with time. Necrosis is nearly always present, and angioinvasion by tumor cells is seen in most cases. Nasal T/NK cell lymphoma has a characteristic immunophenotype: CD2-positive, CD56-positive, but usually negative for surface CD3. Cytoplasmic CD3 can be detected in paraffin sections. Clonal T-cell receptor gene rearrangement is not found. Tumors with an identical phenotype and genotype occur in other extranodal sites, most commonly in the skin, subcutis, and gastrointestinal tract, and should be referred to as nasal-type T/NK cell lymphomas. The differential diagnosis includes lymphomatoid granulomatosis, blastic or monomorphic NK cell lymphoma/leukemia, CD56-positive peripheral T-cell lymphoma, and enteropathy-associated T-cell lymphoma.

Back to CD56        

Settembre 2002