key: cord-0005629-yf1vi4np
authors: Reimer, P; Rüdiger, T; Kraemer, D; Kunzmann, V; Weissinger, F; Zettl, A; Konrad Müller-Hermelink, H; Wilhelm, M
title: What is CD4+CD56+ malignancy and how should it be treated?
date: 2003-09-16
journal: Bone Marrow Transplant
DOI: 10.1038/sj.bmt.1704215
sha: 2764ffe80de591762fa622ca85c04d037f5af583
doc_id: 5629
cord_uid: yf1vi4np

CD4+CD56+ malignancy is a rare neoplasm with a typical clinical pattern, an aggressive course and high early relapse rate despite good initial response to chemotherapy. In this review, the impact of different therapeutic approaches on clinical outcome has been studied. We evaluated 91 published cases and our own six patients in terms of clinical features, immunophenotype/cytogenetics and treatment outcome. Treatment was divided into four groups: (A) chemotherapy less intensive than CHOP; (B) CHOP and CHOP-like regimens; (C) therapy for acute leukemia; (D) allogeneic/autologous stem cell transplantation. The median overall survival was only 13 months for all patients. Patients with skin-restricted disease showed no difference in the overall survival from patients with advanced disease (17 and 12 months, respectively). Age ⩾60 years was a negative prognostic factor. Age-adjusted analysis revealed improved survival after high-dose chemo/radiotherapy followed by allogeneic stem cell transplantation when performed in first complete remission. This therapeutic approach should be recommended for eligible patients with CD4+CD56+ malignancy. For older patients the best treatment option is still unknown.

tation; chemotherapy CD4+CD56+ hematopoietic malignancies are now regarded as a distinct clinicopathologic entity. CD4, a glycoprotein expressed on helper T cells and a subset of monocytes and thymocytes, has been found in T cell leukemia/lymphoma and in acute myeloid leukemia. Among leukocytes, the neural cell adhesion molecule CD56 is expressed predominantly on natural killer (NK) cells and on a small subset of T cells (CD8+ cytotoxic/suppressor cells and a subgroup of wd-Tcells). Its expression on leukemia and lymphoma cells characterizes a heterogeneous group of malignancies. Coex-pression of both antigens is very rare. The classification of CD4+CD56+ lymphomas leads to a somewhat confusing terminology for this entity: blastic/blastoid NK-cell lymphoma/leukemia, cutaneous monomorphous CD4+ CD56+large cell lymphoma, agranular NK-cell lymphoma, etc. In the new WHO classification, CD4+CD56+neoplasms are probably included in the ill-defined category of blastic NK-cell lymphomas. CD4+CD56+malignancies must be distinguished from the nasal type of extranodal NK/T cell lymphomas and aggressive NK-cell leukemias that may be closely related entities occurring frequently in the Asian population (Table 1) . While nasal-type NK/T cell lymphoma is characterized by preferential involvement of the nasopharynx with angiocentric and angioinvasive growth resulting in extensive coagulative necroses, aggressive NK-cell leukemia usually presents with constitutional symptoms, and leukemic course. Both tumors show CD2+CD3-CD56+ phenotype and are almost constantly associated with EBV. In contrast to CD4+CD56+ lymphoma, they often present in middle-aged females. [1] [2] [3] [4] The question of tumor cell origin of the CD4+CD56+ neoplasm has been debated for a long time. Some authors proposed precursor NK-cell origin, whereas others suggested that CD4+CD56+ tumor cells derived from myelomonocytic precursor cells. Petrella et al 5 performed extensive flow cytometric analysis in 14 cases and found very high levels of CD123 expression suggesting that this disease derives from plasmacytoid monocytes. Furthermore, some authors have described reactive CD4+CD56+ cells within kidney allografts during tubular necrosis and rejection 6 and within liver biopsies in patients with chronic active hepatitis B. 7 They hypothesized that prolonged antigen stimulation may produce this unusual phenotype. Recently, Chaperot et al 8 using flow cytometry and in vitro assays suggested that CD4+CD56+ malignancies arise from transformed cells of the lymphoid-related plasmacytoid dendritic cell subset.

Little is known about the etiology and pathogenesis of CD4+CD56+ neoplasms. EBV and human herpesvirus-6 are not detectable. Human T cell lymphotropic virus type I (HTLV-I) was found in one case, 9 while others 10-12 failed to detect this virus. In general, (latent) viral infection does not seem to play an important role in the pathogenesis of this disease.

Clinically, CD4+CD56+ neoplasms usually involve the skin, spread rapidly to extracutaneous sites, and have a poor outcome. Therapeutic strategies vary widely from symptomatic treatment and local radiation therapy to allogeneic stem cell transplantation, but optimal treatment remains to be defined.

Since Adachi et al 10 reported the first CD4+CD56+ malignancy in 1994, 91 cases have been published (Table 2) . This review summarizes the clinical and phenotypic features and treatment outcome for the malignancy including our own six patients.

CD4+CD56+ neoplasms generally affect older patients with a median age of 67 years (range 6-89 years). Males are affected almost three times as often as females (m:f ratio: 2.7:1). The clinical manifestations of this disease show a characteristic pattern. The vast majority of patients initially presents with cutaneous lesions of nonspecific morphology and distribution. At diagnosis, in almost 80% of patients, the disease has already spread to extracutaneous sites, most frequently to bone marrow and lymph nodes (450% each), followed by spleen and liver (11-20%) . Other organs such as nasopharynx, tonsils, CNS, lacrimal glands, muscle, or gynecological tract are only sporadically affected.

According to the Ann Arbor classification, 24% of patients are diagnosed in stage I (with only a single skin lesion), 7% patients in stage II, 2% patients in stage III, and 66% patients in stage IV. In contrast to other lymphoid malignancies, B symptoms such as fever, night sweat, and weight loss are rare.

Morphologically, the malignant cells consist of monomorphic medium-sized blasts with finely dispersed chromatin. These cells consistently express CD4 and CD56, while (surface) CD3 and B cell markers are absent. HLA-DR usually is found, whereas CD8 expression is normally negative. Further NK-cell (CD16, CD57) or myeloid (eg CD34) markers are absent. Pan-T cell markers as CD2, CD5, and CD7 are rarely expressed. Phenotypic data are summarized in Table 3 . Expression of T cell markers other than CD4 (eg CD5, CD7, CD8) does not influence clinical course. T cell marker positive and negative patients (balanced according to age and gender) show identical overall survival curves (data not shown). Studies for EBV by immunohistochemistry (latent membrane protein) or in situ hybridization of EBV-encoded RNA (EBER probes) are negative except for two cases indicating no association with EBV infection.

The genetic alterations in CD4+CD56+ neoplasms are largely unknown and in many studies cytogenetic data are missing. However, some authors describe different chromosomal aberrations. In a recent study, Leroux et al 44 using conventional cytogenetic and 24-color FISH analyses identified six chromosomal regions frequently affected in these neoplasms. In their series, reproducible loss of chromosomal material occurred on chromosomes 5q, 6q, 9, 12p, 13q, and 15q in 14 of 21 patients. They concluded that there was no single consistent chromosomal aberration, but that a combination or accumulation of certain genomic imbalances might be specific in CD4+CD56+ malignancy. 44 

Since there is no consensus for optimal treatment in CD4+CD56+ neoplasms, therapeutic approaches for CD4+CD56+ malignancy vary widely from irradiation in localized stages to myeloablative therapy. Although the initial response rate to treatment is high with almost 70% complete remissions (CR) and 10% partial remissions (PR), only about 20% of patients show a sustained remission at Patients with disease limited to the skin only show a slightly better median overall survival than patients with advanced disease (17 and 12 months, respectively), but the difference is not significant (log-rank test, data not shown). In general, outcome is poor with a median overall survival of 13 months reflecting the aggressive course of the disease ( Figure 1 ). To investigate the impact of different therapies on outcome, treatment of published cases can be separated into four groups according to the intensity of the chemotherapy. 1. Local therapy or systemic therapy 'less than CHOP': Primarily older patients are treated with local therapy or CD4 +CD56+ malignancy and its treatment P Reimer et al systemic therapy 'less than CHOP'. The median age in this group is 79 years. Chemotherapy regimens were heterogeneous, but mostly cyclophosphamide-based. Some patients only received local radiation (n ¼ 5), steroid therapy (n ¼ 1), or supportive care (n ¼ 1). Despite an overall high response rate of almost 80% (68% CR, 11% PR), this group showed a very poor outcome. Only two authors reported sustained CR (7%) after this therapy; one young patient with skin-restricted disease had radiotherapy; another, a 72-year-old man with widespread disease, was treated with cyclophosphamide, methotrexate, vincristine and intrathecal prophylaxis. 24, 31 However, the observation time for the two patients was only 14 and 18 months, respectively. The median overall survival for all evaluable patients is only 9 months and Kaplan-Meier curves do not suggest curative potential for this therapeutic approach (Figure 2 ). Table 4 summarizes the clinical data for this treatment group (group A). CD4 +CD56+ malignancy and its treatment P Reimer et al 2. CHOP and CHOP-like regimens: CHOP/CHOP-like chemotherapy was used most frequently in CD4+CD56+ malignancies (group B). However, compared to less aggressive therapies (group A) this moderately intensive treatment did not result in better response rates or survival benefit. The overall response rate in almost 40 evaluable patients was about 70% (55% CR), but sustained CR was only observed in one patient within this treatment group (Table 5 ) with a short follow-up of only 4 months. 39 Taken together, CHOP (-like) therapy, like less aggressive treatments, did not seem to provide curative potential.

3. Intensive acute leukemia protocols: Since CD4+CD56+ neoplasms usually show an aggressive course with frequent bone marrow involvement, intensive treatment according to acute leukemia seems an appropriate therapeutic approach (group C). Different protocols were investigated with a high CR rate of 94%. Sustained CR can be achieved with these regimens in about one-third of patients. Although median observation time for these responders was only 7.5 months, Falca˜o et al 29 reported a young boy continuing in CR for seven years following therapy for acute lymphoblastic leukaemia. Table 6 shows the data for this treatment group. 4. Myeloablative therapy: Experience with myeloablative therapy in CD4+CD56+ malignancy is limited to 10 patients (four autologous and six allogeneic transplants) that are summarized in Table 7 . All patients in whom data on myeloablative therapy were evaluable underwent total body irradiation and all but one received high-dose cyclophosphamide (alone or in combination with other chemotherapeutic agents). The entire group (group D) had a median survival of 31.5 months. However, only two of the six patients receiving allogeneic transplant relapsed (median overall survival 38.5 months) compared to three relapses in the four patients with autologous transplant (median survival 16.5 months). Autologous peripheral blood stem cell transplantation (APBSCT) with one exception did not lead to long-lasting disease-free survival. However, in the allogeneic setting, all but one patient remained disease-free, if the transplantation has been performed in first remission. However, this treatment is restricted to younger patients as reflected by the median age of 28.5 years in this group.

Taken together, overall response rate (CR and PR after initial therapy) is high regardless of therapy and does not show pronounced differences in the four groups. On the CD4 +CD56+ malignancy and its treatment P Reimer et al other hand, maintenance of CR is better, with more aggressive treatment (group A: 7%, group B: 3%, group C: 35%, and group D: 50%, respectively). Figure 2 shows Kaplan-Meier survival curves for the different treatment groups. The overall survival between groups C and D was significantly higher than in groups A and B. Group D alone was also significantly superior to groups A, B, and C. However, age X60 years was a negative prognostic factor in CD4+CD56+ neoplasms that strongly influences outcome ( Figure 3 ) and median age decreased when more intensified therapy was provided: 79 years (group A), 67.5 years (group B), 52 years (group C), and 28.5 years (group D), respectively. Elderly patients survived for a median of 9 months (range 2-40 months) compared to younger patients with a significantly longer median survival of 18 months (range 2-84 months; Po0.0001). Older age in less aggressive treatment groups might at least partly explain poor outcome. Therefore, we performed an age-adjusted evaluation that revealed significant superiority in the overall survival only for allogeneic stem cell transplantation in the first remission ( Figure 4 ).

CD4+CD56+ neoplasms are a distinct entity with a characteristic CD4+CD56+CD3-phenotype, usually with rapid and aggressive course and poor outcome. Since skin- restricted disease shows no better outcome than primarily disseminated disease, CD4+CD56+ neoplasms must be considered as a primarily systemic disease. Despite initial good response to various (chemo-) therapies, median overall survival is only 13 months and therapeutic guidelines are not yet defined, mainly because of its rare occurrence. Treatment that is more aggressive than the CHOP regimen (groups C and D) results in better response rates compared to less intensive therapies (groups A and B). While intensive therapy for acute leukemia (group C) only enhances the rate of sustained CR, myeloablative treatment (group D) also leads to a marked increase of median survival of 38.5 months. However, age X60 years is a negative prognostic factor, which is consistent with findings in malignant lymphoma and myeloid malignancies. In an age-adjusted evaluation only allogeneic stem cell transplantation in first CR showed significant superiority in terms of the overall survival compared to all other treatments in patients o60 years. Since allogeneic stem cell therapy is limited to younger patients and most patients with CD4+CD56+ malignancy are in their seventh decade of life, the vast majority of patients are not eligible for this otherwise promising therapeutic option. Our own experience confirms the above results (Table 8) . Patients initially were treated either with CHOP or combination chemotherapy designed for acute leukemia. All patients died with a median survival of 15.5 months including one patient who underwent autologous PBSCT in the first remission. Another patient who relapsed after autologous PBSCT achieved a second CR following allogeneic peripheral stem cell transplantation, but died as a complication of treatment on day +52. To our knowledge, this is the first patient with CD4+CD56+ malignancy who received peripheral allogeneic stem cell transplantation and who underwent both autologous and allogeneic stem cell transplantation.

In summary, allogeneic stem cell transplantation in the first CR should be recommended for younger patients with CD4+CD56+ neoplasms with curative intent. For patients not eligible for allogeneic stem cell transplantation, the best therapy still is unknown. Owing to a high early relapse rate, we would not recommend autologous PBSCT for these patients. Whether nonmyeloablative therapy followed by allogeneic transplantation or maintenance therapy will improve outcome remains to be evaluated.

Natural killer cell neoplasms

Report of the workshop on nasal and related extranodal angiocentric T/natural killer cell lymphomas: Definitions, differential diagnosis, and epidemiology

World Health Organization Classification of Tumours. Pathology & Genetics. Tumours of Hematopoietic and Lymphoid Tissues

Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the non-Hodgkin's lymphoma classification project

Agranular CD4+ CD56+ hematodermic neoplasm' (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmocytoid monocytes

Homing of CD4+CD56+ T lymphocytes into kidney allografts during tubular necrosis or rejection

Selective expansion of cytotoxic T lymphocytes with a CD4+CD56+ surface phenotype and a helper type 1 profile of cytokine secretion in the liver of patients chronically infected with hepatitis B virus

Identification of a leukemic counterpart of the plasmacytoid dendritic cells

A case of neural cell adhesion molecule-positive peripheral T-cell lymphoma associated with human T-cell lymphotrophic virus type 1 showing an unusual involvement of the gastrointestinal tract during the course of the disease

High expression of CD56 (N-CAM) in a patient with cutaneous CD4-positive lymphoma

and the Groupe Franc¸ais d'Etude des Lymphomes Cutane´s (GFELC). CD4+ CD56+ cutaneous neoplasm: A distinct hematological entity?

CD56-positive cutaneous lymphoma: a poorly recognized entity in the spectrum of primary cutaneous disease

Acute agranular CD4-positive natural killer cell leukemia

Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract

Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract

CD3À, CD56/NCAM+ malignant lymphoma with TCRb gene rearrangement: a case report

A primary cutaneous non-T, non-B CD4+, CD56+ lymphoma

CD5À CD56+ Tcell receptor silent peripheral T-cell lymphomas are natural killer cell lymphomas

Blastic natural killer leukemia/lymphoma: A clinicopathologic study

CD3ÀCD56+ Non-Hodgkin's lymphomas with an aggressive behaviour related to multidrug resistance

CD56+ agranular natural killer cell lymphoma of the skin

Do primary cutaneous non-T non-B CD4+CD56+ lymphomas belong to the myelomonocytic lineage? (letter)

A cutaneous agranular CD2À CD4+ CD56+ 'lymphoma'

Primary cutaneous natural killer/T-cell lymphoma

Blastic NK-cell lymphoma expressing terminal deoxynucleotidyl transferase with Homer-Wright type pseudorosettes formation

High-dose chemotherapy with peripheral blood stem cell rescue in blastoid Natural Killer cell lymphoma

Natural killercell lymphoma involving the gynecologic tract

Cutaneous monomorphous CD4-and CD56-positive large-cell lymphoma

Blastic CD4 NK cell leukemia/lymphoma: a distinct clinical entity

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

CD56+/CD4+ lymphomas and leukemias are morphologically, immunophenotypically, cytogenetically, and clinically diverse

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

Agranular CD4+CD56+ blastic natural killer leukaemia/lymphoma

CD56-and CD4-positive non-Hodgkin's lymphoma of probable T-cell origin

Blastic natural killer cell leukemia/lymphoma presenting as overt leukaemia

CD2ÀCD4+CD56+ hematodermic/hematolymphoid malignancy

Blastic NK-cell lymphoma/leukemia with T-cell receptor g rearrangement

Clinical and biological features of CD4+CD56+ malignancies

CD56+ TdT+ Blastic natural killer cell tumor of the skin. A primitive systemic malignancy related to myelomonocytic leukemia

Blastic natural killer cell leukaemia/ lymphoma

A case of primary cutaneous CD56+, TdT+, CD4+, blastic NK-cell lymphoma in a 19-year-old woman

Blastic natural killer cell lymphoma/leukemia

on behalf of Groupe Franc¸ais de Cytoge´ne´tique He´matologique. CD4, CD56+ DC2 acute leukaemia is characterized by recurrent clonal chromosomal changes affecting 6 major targets: a study of 21 cases by the Groupe Franc¸ais de Cytoge´ne´tique He´matologi-que