CD56+ NK lymphomas:clinicopathological features and prognosis

British Journal of Haematology, 1997, 97, 821–829

CD56þ NK lymphomas: clinicopathological features and prognosis Y. L. K WO N G , A L E X A N D E R C. L. C H A N ,* R AYM O ND L IA N G , A L A N K. S. C H I A NG ,* C. S. C H I M , T. K. C H AN , DAVI D T O D D AN D FA I T H C. S. H O * University Departments of Medicine and *Pathology, Queen Mary Hospital, Hong Kong Received 25 November 1996; accepted for publication 24 March 1997

Summary. The surface molecule CD56 marks a category of malignant lymphoma of putative natural killer (NK) cell origin. We conducted a retrospective analysis of 24 cases of CD56þ NK lymphoma/leukaemia to define the clinicopathologic and prognostic features of this specific group of lymphomas. 56 cases of nasal lymphomas and 204 cases with an initial diagnosis of peripheral T-cell lymphoma were retrospectively analysed. To specifically examine lymphomas of putative NK origin, only those that were negative for surface expression of CD3 but positive for CD56 were analysed. 24 cases were identified. The initial predominant sites of involvement were nasal (n ¼ 18), palate (n ¼ 1), nodal (n ¼ 1) and multi-organ (n ¼ 4). Clinically, in patients with disease localized to one anatomical site (n ¼ 20), most had symptoms confined to the nose, with a high percentage in early stage (I: 91%; IV: 9%). The marrow was not involved in any of these cases. However, patients with multi-organ involvement at presentation (n ¼ 4) behaved differently. All presented acutely with pancytopenia, hepatosplenomegaly, and marrow infiltration with haemophagocytosis.

A leukaemic phase was observed in one case. Anthracycline containing combination chemotherapy resulted in complete remission in 75% of patients with localized disease, but only in 25% with multi-organ involvement. The median survival of patients with localized disease was 12 months, compared with 2 months in the multi-organ group (P ¼ 0.06); the disease-free survival was significantly better in the former (P < 0.01). The overall median survival of all patients was still poor at 11 months. We conclude that CD56þ NK lymphomas could be divided into two main patterns of disease presentations: localized (predominantly nasal), and multi-organ involvement. Each has different clinicopathologic and prognostic features. Conventional chemotherapy appeared ineffective for the majority of patients, and innovative treatment modalities are needed to improve outcome.

Natural killer (NK) cells are cytolytic cells active against tumour cells and cells infected with bacteria and viruses. They develop in the marrow from a bipotential progenitor capable of differentiation into T and NK cells (Spits et al, 1995). Phenotypically, NK cells appear as large lymphocytes with azurophilic granules, and immunophenotypically they express the characteristic marker CD56 (Lanier et al, 1991). Because of a common ontogeny with T cells, NK cells also express some T-cell markers including CD2 and CD7, but not CD5 (Spits et al, 1995). Surface expression of CD3 is absent, but there is cytoplasmic expression of CD3e (Lanier et al, 1992) but not other CD3 proteins. The T-cell receptor (TCR) gene is not rearranged, and the TCR and CD3 proteins are not expressed (Lanier et al, 1992; Spits et al, 1995).

Malignancies derived from putative NK cells have increasingly been recognized as distinct clinical entities (Pandolfi et al, 1984; Imamura et al, 1990; Ho et al, 1990a; Wong et al, 1992; Kanavaros et al, 1993; Sun et al, 1993; Suzumiya et al, 1994; Nakamura et al, 1995; Emile et al, 1996; Macon et al, 1996). Immunophenotypically, these tumours express the membrane phenotype of NK cells, viz positive for surface CD2, CD56 and cytoplasmic CD3, but negative for surface CD3 and CD5 (Chan et al, 1995, 1996; Jaffe et al, 1996). Pathologically, necrosis and angiocentricity were often observed, and the tumour cells varied from small medium to large size. Because of the cytoplasmic expression of CD3, these tumours had originally been classified as T/NK lymphoma ( Jaffe, 1996). However, it is now recognized that, similar to normal NK cells, only CD3e but not the complete CD3 molecule was expressed in these tumours (Chan et al, 1995, 1996). Furthermore, molecular studies have shown

Correspondence: Dr Y. L. Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. q 1997 Blackwell Science Ltd

Keywords: CD56, natural killer cell lymphoma/leukaemia, prognosis.

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that the T-cell receptor (TCR) gene was in germline configuration (Ho et al, 1990b). Therefore these tumours are now regarded to be of putative NK cell origin ( Jaffe, 1996). They need to be distinguished from several other malignancies, including CD56þ peripheral T-cell lymphoma, hepatosplenic gd T-cell lymphoma, intestinal T-cell lymphoma, aggressive T large granular lymphocyte leukaemia, precursor NK cell leukaemia and lymphomatoid granulomatosis ( Jaffe et al, 1996; Jaffe, 1996). Interestingly, NK lymphomas show a predilection for the nasal cavity and upper aerodigestive tract, although skin and soft tissue infiltration are also observed. Occasionally, tumours with similar histological and immunophenotypic appearances occur in non-nasal sites and are referred to as nasal type NK lymphoma. NK lymphomas are rare in the U.S.A. and Europe, but relatively common in Asian countries. Data pertaining to NK lymphomas are scarce. We have previously reported 100 cases of nasal lymphoma (Liang et al, 1995). These cases were heterogenous, including some cases of B-cell lymphoma and peripheral T-cell lymphoma. We have updated this series and identified nasal lymphoma with an NK phenotype. Furthermore, we also searched for nasal type NK lymphomas in a large cohort of lymphomas with an initial diagnosis of peripheral T-cell lymphoma (PTCL). Finally, to determine if NK lymphomas are clinically and prognostically distinct, we compared the clinicopathological features and treatment outcome of this series of NK lymphomas with that of a cohort of PTCL to which in the past they were often related. MATERIALS AND METHODS Patients. All patients were ethnic Chinese people. 56 cases of nasal lymphoma seen from 1989 to 1995 at the Department of Medicine, Queen Mary Hospital, were reviewed. 204 patients with an initial diagnosis of peripheral T-cell lymphoma (PTCL) seen during the period of 1985–95 were also reviewed. The initial sites of involvements were nodal (146 cases), skin (18 cases) and other extranodal areas (40 cases). For cases to be included in the analysis, adequate data on immunophenotyping, particularly the CD3 and CD56 status, needed to be available. The Ann Arbor staging system was used. Staging procedures included physical examination, complete blood counts, bilateral marrow trephine biopsies, chest X-ray, and computerized axial tomography of the abdomen. Nasal panendoscopy was performed in all patients with nasal lymphoma, and some of the other cases with suspected nasal involvement. Upper endoscopy was performed in patients with suspected gastrointestinal involvement. Histological and immunophenotypic diagnosis. Paraffin sections of formalin or B5-fixed tissue were stained with haematoxylin and eosin to confirm the diagnosis of lymphoma. Immunophenotyping was performed on cryostat sections for cases with available frozen tissue using a panel of monoclonal antibodies. This included antibodies against CD2 (T11), CD3 (Leu 4), CD4 (T4), CD5 (T1), CD7 (T2), CD8 (T8), CD19, CD22, and CD56 (NKH1). Only cases that were CD3¹ , CD56þ were selected for further analysis.

Treatment and statistical analysis. Combination chemotherapy was the primary treatment. A minimum of six courses of chemotherapy were planned for all cases. For patients who reached complete remission after chemotherapy, involved field radiotherapy was given. The dose of radiotherapy was 40–45 Gy using a lateral opposing field covering the nasal region, paranasal cavities, nasopharynx, and the Waldeyer’s ring. The field was extended to cover the cervical region if cervical lymph nodes were present initially. Tumour response was assessed using standard criteria (Hoogstraten, 1984). Disease-free survival was measured from the date of first remission to the date of first relapse. Overall survival time was measured from the data of diagnosis to the date of death or last follow-up. The Kaplan-Meier plot was used to generate disease-free survival and overall survival curves, which were compared for statistical difference with the log-rank analysis. RESULTS Patients Twenty-four patients with CD3¹ , CD56þ lymphomas were identified. These included 20/56 cases of nasal lymphomas, and 4/204 patients with an initial diagnosis of PTCL (Table I). 13 of these patients have previously been described in a report of nasal lymphoma (Liang et al, 1995). The initial sites of presentation were nasal (n ¼ 21), palate (n ¼ 1), nodal (n ¼ 1) and multi-organ (n ¼ 4) (Table I). In the nasal and palate subgroups, symptoms were confined to the local site of involvement, the commonest being nasal obstruction, swelling and bleeding. Lymphadenopathy was not an initial feature in any of the cases. In the only patient who presented with lymphadenopathy there was gross enlargement of the groin lymph node. Skin infiltration was found in two patients (cases 5 and 6) during relapse. On the other hand, in the multi-organ subgroup, patients presented almost uniformly with abrupt onset of systemic symptoms and were very ill on admission. Significant weight loss, pyrexia of 398C or more, jaundice, maculopapular skin rashes, hepatosplenomegaly, multiple lymphadenopathy, pancytopenia, derangement of liver function, and coagulation abnormalities were frequently seen, and all the patients were in stage IVb disease (Table III). A comparison of the clinicopathological features of patients with localized and multi-organ disease is shown in Table II. Pathology and immunophenotyping Localized nasal lymphoma showed diffuse infiltration by medium-sized to large abnormal lymphoid cells with irregular and pleomorphic nuclei. Angiocentricity and coagulative necrosis were common findings (Fig 1). These features were similar to those reported by Jaffe et al (1996). In patients who presented initially with localized disease (nasal, palate, isolated nodal), the bone marrow was not involved histologically. However, in patients who presented with multi-organ involvement the marrow was invariably infiltrated by malignant cells that ranged from 8% to 60% of all nucleated cells. These cells showed azurophilic granules and active haemophagocytosis was observed in all cases. These cells were

q 1997 Blackwell Science Ltd, British Journal of Haematology 97: 821–829

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Table I. Clinical features of 24 cases of CD3 , CD56 NK lymphomas.

Case

Sex/age

Primary site

Marrow involvement

Initial stage

Treatment

DFS (months)

Survival (months)

Cause of death

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

M/37 M/17 M/35 M/37 F/45 M/42 M/55 M/58 F/84 M/73 M/41 M/68 F/17 M/34 F/32 M/72 F/59 M/76 F/18 M/35 F/30 M/56 M/32 F/60

L, S L, S, LN L, S, LN L, S, LN LN N N N N N N N N N P N N N N N N N N N

þve þve þve þve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve ¹ve

IV IV IV IV I I I I I I IV (*) I I I I I I I I I I I I I

CHOP, IMVP16 m-BACOD, 2-CDA CEOP CEOP CHOP m-BACOD m-BACOD m-BACOD, L17M, IMVP16 CP COPP m-BACOD, L17M m-BACOD CHOP CHOP m-BACOD, L17M COPP, L17M CHOP CEOP CHOP m-BACOD m-BACOD m-BACOD m-BACOD m-BACOD

3 0 0 0 17 7 2 10 0 0 17 0 20þ 4 76þ 57þ 5 0 107þ 97þ 12 12 4 0

14 2 1 0.1 23 12 2 18 0 0 18 0 27þ 8 76þ 63þ 5 1 107þ 99þ 20 12 12 4

Relapse Infection Hepatic failure Hepatic failure Local relapse Local relapse Local relapse Infection Local disease Local disease Infection Local disease — Local relapse — — Infection Myocardial infarction — — Local relapse Infection Local relapse Local relapse

L: liver; S: spleen; LN: lymph node; N: nasal; P: palate; * Stage IV because of lung involvement. CHOP: cyclophosphamide 750 mg/m2 , adriamycin 50 mg/m2 , vincristine 1.4 mg/m2 , prednisone 100 mg/m2 × 5. m-BACOD: bleomycin 4 mg/m2 , adriamycin 45 mg/m2 , cylophosphamide 600 mg/m2 , vincristine 1 mg/m2 , dexamethasone 6 mg/m2 × 5, methotrexate 200 mg/m2 × 2. IMVP16: ifosfamide 1 g/m2 × 5, methrotrexate 30 mg/m2 × 2, etoposide 100 mg/m2 × 3. L17M: vincristine 1.4 mg/m2 × 4, adriamycin 20 mg/m2 × 4, prednisone 60 mg/m2 × 28, cyclophosphamide 600 mg/m2 . COPP: cyclophosphamide 450 mg/m2 × 2, vincristine 1.4 mg/m2 × 2, procarbazine 100 mg/m2 × 14, prednisone 40 mg/m2 × 14. CEOP: cyclophosphamide 450 mg/m2 × 2, vincristine 1.4 mg/m2 × 2, epirubicin 60 mg/m2 , prednisone 100 mg/m2 × 5. 2-CDA: 2-chlorodeoxyadenosine 0.09/kg/d × 7.

different from large granular lymphocytes in showing scanty cytoplasm and pleomorphic nuclear morphology with open lacy chromatin. In one patient a leukaemic phase with active haemophagocytosis in the peripheral blood was observed

(Fig 2). Liver biopsy performed in all of these cases also showed lymphoma infiltration (Fig 3), with occasional haemophagocytosis also observed. Immunophenotypically, all cases (except case 5) showed a characteristic phenotype:

Table II. Localized and multi-organ subgroups of nasal and nasal-type NK lymphomas.

Frequency Clinical Primary sites

Symptoms Clinical staging Treatment response Pathological Pancytopenia Marrow infiltration Organ infiltration

Localized

Multi-organ

83.3% (20/24)

16.6% (4/24)

Nasal (18) Palate (1) Nodal (1) Local due to obstruction or ulceration Mostly stage IAE Fair to poor

Nodal, skin and hepatosplenic

Systemic with weight loss, pyrexia, jaundice Stage IVB Very poor

Rare Negative Negative

Always Positive Positive

q 1997 Blackwell Science Ltd, British Journal of Haematology 97: 821–829

M/37

M/17

M/35

M/37

1

2

3

4

WBC

1.4

2.9

0.4

3.8

Hb

11.1

9.5

5.8

8.8 10

12

157

82

Plats

60

40

35

8

%

Yes

Yes

Yes

Yes

HP

Pyrexia, jaundice (bili: 546) Skin rash, liver 7 cm Spleen 1 cm, ascites Multiple lymph nodes

Pyrexia, jaundice (bili: 384) Liver 3 cm Spleen 9 cm, ascites Multiple lymph nodes

Pyrexia, jaundice (bili: 209) Skin rash, liver 3 cm, Spleen 4 cm, ascites Multiple lymph nodes

Pyrexia, jaundice (bili: 60) Skin rash, liver 6 cm Spleen 2 cm Abdominal lymphadenopathy

Clinical features

Liver + Lymph node +

Liver + Lymph node +

Liver + Lymph node +

Liver + Lymph node + Skin +

Tissue biopsy

CEOP

CEOP

m-BACOD 2-CDA

CHOP IMVP16

Treatment

Hb: haemoglobin (g/dl); WBC: white blood cells (×109/l); Plats: platelets (×109/l); Bili: bilirubin in mmol/l; HP: haemophagocytosis.

Sex/age

Case

Marrow involvement

Table III. Clinical features of four cases of CD3¹ , CD56þ aggressive multi-organ NK lymphoma on initial presentation.

No

No

No

3 months

Remission

3d

1 month

2 months

14 months

Survival

Disseminated disease, liver failure

Disseminated disease, liver failure

Disseminated disease

Disseminated disease

Cause of death

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q 1997 Blackwell Science Ltd, British Journal of Haematology 97: 821–829

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Table IV. Immunophenotyping of 24 cases of CD3 , CD56 lymphomas.

NK

Case

CD2

CD3*

CD4

CD5

CD7

CD8

CD16

CD56

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

þ þ þ þ ¹ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ

¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹

¹ ¹ ¹ ND þ ¹ ¹ ¹ ¹ ¹ ND ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹

¹ ¹ ND ND ¹ ¹ ¹ ¹ ND ¹ ND ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹

þ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ND þ ND ¹ ¹ þ ¹ ¹ ¹ ¹ ¹ ¹ þ ¹ ¹ ¹

¹ ¹ ¹ ND þ þ ¹ ¹ ¹ ¹ ND ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹ ¹

¹ ¹ ND ND ND ¹ ¹ ND ¹ ¹ ND ¹ ¹ ¹ ¹ ND ¹ ¹ ¹ ND ¹ ¹ ND ND

þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ

CD3*: surface CD3 detected by Leu-4. ND: not done.

CD2þ , CD3¹ , CD56þ . Case 5 (nodal, stage I) had an aberrant phenotype: CD2¹ , CD3¹ , CD4þ , CD5¹ , CD7¹ , CD8þ , CD56þ (Table IV), and the tumour cells were more monomorphic and blastic in appearance, resembling the ‘blastic’ form of NK lymphoma as reported by Jaffe et al (1996). Treatment and outcome Anthracycline-containing combination chemotherapy was given to 21 patients, but not in three cases because of advanced age and impaired cardiopulmonary status (Table I). Patients who presented with multi-organ involvement had a very poor outcome. Three of four patients never achieved a remission, with a median survival of