Departments of 1 Medicine, 2 Pathology and 3 Clinical Oncology, Queen Mary Hospital, Hong Kong
* Correspondence to: Dr Y. L. Kwong, University Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong. Tel: +852-2855-4597; Fax: +852-2974-1165; Email: ylkwong{at}hkucc.hku.hk
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Abstract |
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Methods: Consecutive T-cell and NK-cell lymphomas classified according to the WHO scheme within 10 years in a Chinese population were reviewed.
Results: There were 148 cases, constituting 16.6% (T-cell, n=90, 10.1%, NK-cell, n=58, 6.5%) of all non-Hodgkin lymphomas in this period. There was a male predominance (male:female = 2.5), young age at diagnosis (median age 50 years, range 886) and frequent extranodal presentation. Commonest T-cell lymphomas included anaplastic large cell lymphoma (ALCL, n=25, median age 35 years, nodal 60%, stage I/II 60%), peripheral T-cell lymphoma, unspecified (PTCL, n=24, median age 54 years, nodal 42%, stage I/II 42%), and angioimmunoblastic T-cell lymphoma (AILT, n=19, median age 67 years, nodal 95%, stage I/II 26%). Overall frequencies of T-cell lymphomas were comparable to Western patients. AILT, PTCL and ALCL were aggressive with a poor outcome. NK-cell lymphomas were predominantly extranodal (96%) and aggressive, with a frequency much higher than Western patients.
Conclusions: The apparent high prevalence of T-cell and NK-cell lymphomas in the Chinese was due to more frequent NK-cell but not T-cell lymphomas.
Key words: mature T-cell lymphoma, NK-cell lymphoma, Chinese
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Introduction |
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Natural killer (NK) cells share the same ontogeny with T cells [1]. They characteristically express the NK-cell markers CD56, and variably CD16 and CD57. Cytoplasmic CD3
chain is expressed, but surface CD3 is absent. The EpsteinBarr virus (EBV) is almost invariably found in a clonal episomal form in the tumor cells [11
]. Therefore, the characteristic phenotype is CD3CD3
+CD56+EBV+. NK-cell lymphomas are prevalent in Asian and South American populations, but are exceedingly rare in European and North American people [3
]. In recent years, they have increasingly been reported from Asian patients [12
], although the frequency has remained low in other populations [13
].
Mature T-cell and NK-cell lymphomas are uncommon lymphoid malignancies, reported to constitute about 12% of non-Hodgkin lymphomas [14]. The World Health Organization (WHO) classification scheme groups mature T-cell and NK-cell lymphomas into the same category [2
]. In Asian populations where these lymphomas are regarded as more prevalent, a re-examination and classification according to the WHO scheme will be informative in giving more exact frequencies and clinicopathologic features of these diseases, as well as providing a common basis with which other populations can be compared.
In this study, we analyzed all lymphomas diagnosed within a 10-year period, which fit the WHO classification system for mature T-cell and NK-cell lymphomas. The purpose was to define the frequency, pathologic features and treatment results of these lymphomas in the Chinese population.
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Materials and methods |
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Histopathologic and molecular diagnosis
Diagnostic materials were hematoxylineosin stained and examined histopathologically. Immunophenotyping was performed by immunohistochemical analysis of paraffin-embedded and/or frozen sections after staining with appropriate antibodies directed against a panel of antigens, including CD 2, 3, 4, 5, 7, 8, 10, 19, 20, 22, 23, 25, 30, 45, 56, epithelial membrane antigen, T-cell intracytoplasmic antigen (TIA)-I and the anaplastic large cell lymphoma kinase (ALK). For cases with involvement of the bone marrow or the peripheral blood, flow cytometric analysis was also performed. In situ hybridization (ISH) for EBV-encoded early small RNA (EBER) was done as previously described [15]. EBER positivity was only scored for cases with positive ISH in the neoplastic cells, but not in other reactive cells. TCR gene rearrangement was detected by Southern blot analysis or polymerase chain reaction (PCR), as reported previously [16
]. Molecular analysis was not routinely performed, but was done when the diagnosis was not clear from the histopathologic and immunophenotypic evaluation, particularly when distinction from a reactive condition was necessary.
WHO classification
The histopathologic, immunophenotypic, ISH and molecular findings of the original pathologic reports were reviewed. Over the 10-year study period, the updated Kiel and the REAL classification systems had been used. Where appropriate, the pathologic diagnoses were re-grouped into the corresponding categories in the WHO classification scheme, with strict adherence to the proposed criteria. In cases where uncertainties existed, further immunophenotyping, ISH or TCR gene rearrangement studies were performed until a satisfactory diagnosis could be reached. Cases where a definite diagnosis could not be reached, because of an inadequate initial histopathologic evaluation or a lack of materials for additional tests, were excluded from further analysis.
Treatment
A variety of chemotherapeutic regimens were used. In general, patients aged 60 years or below were given anthracycline-containing regimens, whereas those older than 60 years were given non-anthracycline regimens (Table 1). In patients reaching a complete remission (CR), involved field consolidation radiotherapy was given. Autologous or allogeneic hematopoietic stem cell transplantations (HSCT) were performed for patients with chemotherapy-responsive relapses. Patients not responding to primary chemotherapy were given salvage regimens (Table 1).
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Results |
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Peripheral T-cell lymphoma (PTCL), unspecified
Twenty-four patients were diagnosed with PTCL, unspecified. Pathologically, these cases were variably described as T-zone lymphoma, lymphoepithelioid cell lymphoma, pleomorphic T-cell lymphoma, small, medium or large sized types, and T-immunoblastic lymphoma; so that there was a broad morphologic spectrum. The immunophenotypic features were also variable (Table 3). However, EBV was found in about 70% of cases. There was a male predominance (male/female = 3.8:1), and the median presentation age was 54.5 years (range 1776). The commonest involved areas were lymph nodes (42%), followed by the skin (16.6%). About 60% of patients presented with stage III/IV disease.
Angioimmunoblastic T-cell lymphoma
Nineteen cases of angioimmunoblastic T-cell lymphomas (AILT) were found. Males were more affected than females (2.2:1), with a median presentation age of 67 years (range 2079), which was the oldest in the whole cohort. The disease was nodal in all but one case. Pathologically, there was a polymorphic lymphomatous infiltrate admixed with reactive lymphocytes, eosinophils, plasma cells and histiocytes, with arborizing high endothelial venules. Systemic manifestations including hepatosplenomegaly, ascites, proteinuria and high fever occurred in 15 cases. Most patients (74%) presented with advanced stage III/IV disease.
Primary cutaneous CD30-positive T-cell lymphoma
Nine patients were diagnosed with this lymphoma. There was a male predominance (male/female = 4:1), with a median presentation age of 59 years (range 3375). Most patients presented with solitary lesion with or without regional lymph node involvement. ALK staining was negative in all but one case. In the only case positive for ALK, the staining was cytoplasmic, and t(2;5) was not detectable cytogenetically. Although on immunophenotypic grounds, particularly with the expression of CD3 and CD5 that are often aberrantly lost in this lymphoma, some of our cases might be considered somewhat unusual. However, the typical histopathologic features, and the clinical course of these cases distinguished them from other T-cell lymphomas.
Lymphomatoid papulosis
Three male patients presented with persistent repeated crops of lesions in the trunk and lower limbs. No treatment other than local excision was required.
Mycosis fungoides
Four patients were referred with either locally advanced mycosis fungoides or disease with systemic spread. However, milder forms of the disease might be treated by dermatologists without oncologic referral. In fact, during the study period, a total of 29 cases of mycosis fungoides were diagnosed in all other centers around Hong Kong [17].
Enteropathy-type T-cell lymphoma
Three patients with this disease presented with chronic diarrhea and weight loss, with gut perforation in two cases. The lymphoma cells showed variable cytologic appearance associated with crypt epithelial infiltration. None of the patients had gluten sensitivity, celiac disease or tropical sprue, and accordingly villous atrophy, crypt hyperplasia and increase in intraepithelial lymphocytes in the surrounding uninvolved mucosae were not observed. None of the patients showed response to multi-agent chemotherapy or autologous HSCT.
Aggressive NK-cell leukemia
Three cases of aggressive NK-cell leukemia were diagnosed, including one case after renal transplantation [18]. Leukemic cells varied from blasts to abnormal lymphoid cells with azurophilic granules. There was marrow infiltration and widespread tissue involvement. Similar to nasal type NK-cell lymphomas, the leukemic cells were CD3CD3
+CD56+EBV+. Patients presented with severe systemic symptoms, including fever, pancytopenia, jaundice and deranged liver function. Mortality was uniform.
Hepatosplenic T-cell lymphoma
One patient diagnosed with this disorder, had a long history of systemic lupus erythematosus with prolonged exposure to steroids and azathioprine. She died shortly after presentation and the lymphoma was diagnosed post-mortem.
Subcutaneous panniculitis-like T-cell lymphoma
One patient was encountered with this diagnosis. Details of this case had previously been reported [19]. The tumor occurred predominantly in the face. Treatment with fludarabine, mitoxantrone and dexamethasone [20
] resulted in a durable CR that had lasted for more than 6 years.
T-cell prolymphocytic leukemia
One patient was diagnosed with this disease. Details of this case had been reported before [21].
Occurrence of mature T-cell and NK-cell lymphomasin different extranodal sites
Table 4 shows the distribution of mature T-cell and NK-cell lymphomas at major extranodal sites. In the nose, skin and muscle, T-cell and NK-cell lymphomas accounted for more than half of all the non-Hodgkin lymphomas diagnosed in these areas. At other anatomical sites, B-cell lymphomas predominated.
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Discussion |
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The WHO classification of lymphomas, in bringing together clinical characteristics, and morphologic, immunophenotypic and molecular features, has addressed most of these issues. This report is, to date, the first comprehensive study of mature T-cell and NK-cell lymphomas classified by the WHO criteria in Chinese people. These lymphomas share some common features, including a male predominance (male to female ratio from 1.5 to 4:1) not observed in B-cell lymphomas, and presentation at a relatively younger age (median at the fifth decade). However, the initial sites of involvement showed more variation, with AILT and ALCL being almost exclusively nodal, NK/T-cell lymphoma, nasal type almost exclusively extranodal, and PTCL unspecified both nodal and extranodal. Furthermore, distinct features existed for different subtypes of lymphomas, underlining the importance of considering each mature T-cell and NK-cell lymphoma as a discrete entity.
In this study, T-cell lymphomas constituted 10.1% of all non-Hodgkin lymphomas diagnosed within the 10-year period, a frequency much lower than that of about 20% previously reported in Chinese and Japanese populations [3, 9
]. This difference is probably due to improvement in diagnosis instead of changes in disease epidemiology. The inclusion of consecutive cases in this report, instead of a selected subset of cases chosen specifically for study purposes [3
, 9
, 22
], also contributed to this difference. Furthermore, the increased use of immunophenotyping enabled real T-cell lymphomas to be distinguished from other non-T-cell lymphomas, particularly T-cell-rich B-cell lymphomas. In some subtypes of T-cell lymphomas, including AILT and PTCL unspecified, the lymphomatous infiltrate is heterogeneously mixed with reactive inflammatory cells, making it possible that in the past, reactive conditions in the lymph node might sometimes be inappropriately considered lymphomatous. In this study, the judicious use of TCR gene rearrangement has helped to exclude reactive lymphoid disorders and improve the diagnostic accuracy. Moreover, the general improvement of diagnostic capabilities in hospital pathology laboratories means that fewer cases might be referred to a tertiary center such as ours, thereby decreasing the referral bias that might have been observed in previous studies [3
, 9
, 22
]. Furthermore, human T-cell lymphotrophic virus I infection is not found in our population, so that adult T-cell leukemia/lymphoma has not been observed. Finally, the denominator of the total number of lymphomas was raised by the increasing recognition in Chinese patients of indolent B-cell lymphomas [23
, 24
], a disease formerly thought to be rare. Therefore, these factors combined to decrease the overall frequency of T-cell lymphomas, which became comparable to those reported in Western patients.
There was also a decrease in the frequency (at 2.69%) of PTCL unspecified in this series, compared with 5.18.6% in previous reports from other Chinese/Asian populations [3, 10
, 25
]. Again, this probably reflects a change in diagnosis rather than disease epidemiology. PTCL, unspecified (or not otherwise specified, PTCL-NOS), used to be the diagnostic label for any lymphoma that showed a purported T-cell immunophenotype, but which did not fit into other well-defined lymphoma entities. Owing to a broad spectrum of morphologic appearances, there are wide interobserver variations in the diagnosis of PTCL unspecified [22
]. Moreover, in the REAL classification, PTCL-NOS was considered a provisional entity with no specific criteria proposed for its recognition [26
]. These factors make the frequencies of PTCL-NOS reported in previous studies difficult to interpret. Finally, many of the PTCL-NOS included in these reports occurred in the nasal/para-nasal areas and the upper aerodigestive tract [10
]. Although true T-cell lymphomas do occasionally occur in these sites (in this series, 2.4% of all non-Hodgkin lymphomas in the nose were true T-cell lymphomas), these PTCL were more likely an inappropriate diagnosis for nasal NK-cell lymphomas. This is because NK-cells show cytoplasmic CD3
that is detectable by polyclonal anti-CD3 antibodies on immunohistochemical staining of paraffin sections, leading to the misinterpretation of a T-cell immunophenotype. The problem is now better resolved by immunophenotyping of lymphoma cells on cryostat sections for the detection of surface CD3, which is typically absent on NK-cells [27
]. Furthermore, angiocentricity and angio-destruction in NK-cell lymphomas are often helpful features. Hence, when strict criteria are used, PTCL unspecified has become a rarity in our Chinese population, with only about two cases diagnosed every year.
With the decrease in PTCL unspecified, ALCL has become the commonest T-cell lymphoma in this series. These lymphomas have distinct histologic and immunophenotypic features, which enable them to be distinguished readily from other lymphomas. Expression of ALK is an important diagnostic and prognostic marker in this group of lymphomas [28]. ALK-positive ALCLs occurred in younger patients (mean age <30 years), were mostly nodal and associated with low-risk International Prognostic Index (IPI) score, and had a favorable treatment outcome (5-year survival ranging from 71% to 100%) [29
31
]. On the other hand, ALK-negative ALCL occurred in older patients (mean age >50 years), were associated with high IPI scores, and had an unfavorable outcome (5-year survival between 10% and 45%) [28
, 30
, 31
]. ALK positivity was shown in a few of our cases in this study. Although fluorescence in situ hybridization for t(2;5) and molecular studies may add to the analysis of our patients, materials suitable for these tests were not available to us. Therefore, better phenotypic and genotypic studies are required to characterize fully ALCL in our population.
AILT in our patients showed features typical of this disorder, namely, older age at presentation (the oldest group in this study), predominant nodal involvement, frequent systemic manifestations and a poor treatment outcome. Few series on AILT have been reported, mainly because they are usually considered together with ALCL and PTCL unspecified in large series of T-cell lymphomas [32, 33
]. The prognosis is typically poor, with a 5-year survival of 2036% [32
, 33
].
For rare forms of T-cell lymphoma, including mycosis fungoides, subcutaneous panniculitis-like T-cell lymphoma and hepatosplenic T-cell lymphoma, isolated cases were observed at frequencies comparable to those previously reported in Western patients. Enteropathy-type T-cell lymphoma was observed in three cases. There was no association with pre-existing enteropathy, consistent with the rarity of enteropathy in the Chinese.
The other major lymphoma subtype in this study was putative NK-cell lymphomas, which constituted 6.5% of all lymphomas diagnosed within the study period. The clinicopathologic features and treatment outcome of these lymphomas have been described previously [12, 34]
These lymphomas show a racial predilection, being found almost exclusively in patients of Asian or South American descent [35
]. Formerly classified as angiocentric lymphoma in the REAL classification, nasal type NK/T-cell lymphoma is now more clearly defined in the WHO classification by its histopathology and immunophenotype, instead of angiocentricity, which is a helpful but not constant feature of this lymphoma. Distinction from a T-cell lymphoma may not be easy, as aforementioned. In cases where the specimen is limited in size, or the immunophenotypic features are not typical, TCR gene rearrangement studies may be required. The recognition of this lymphoma entity carries important diagnostic significance. In Western patients, lymphomas of the sinonasal areas are mostly diffuse large B-cell lymphomas. Instead, we showed that in Chinese patients, about 40% of lymphomas in this area are NK-cell lymphomas. They should be distinguished from B-cell lymphomas because of their rapidly progressive nature and poor prognosis. Aggressive treatment together with high-dose therapy and hematopoietic stem cell transplantation are needed to improve treatment outcome [36
].
The T-cell immunophenotype is regarded as imparting a poor prognosis. In several large series of patients from which this conclusion was made, the exact classification of the lymphomas was not well explained [37]. Furthermore, the diagnosis of PTCL-NOS might be as frequent as 50% [38
]. In this series, AILT and PTCL unspecified had apparently the worst outcome, followed by NK/T-cell lymphoma and ALCL, although owing to the relatively small number of cases in each category, a definitive conclusion could not be reached. However, the results were similar to those reported before [28
33
]. Thus, different lymphomas within the mature T-cell and NK-cell lymphoma group have distinct clinicopathologic and biological features, and different treatment outcome. It is no longer adequate to consider all lymphomas within this category as a single group. Furthermore, recent results have shown that even within each lymphoma type, the prognosis might be affected by the expression of different biological molecules or T-cell activation markers, including caspase 3, bcl-2 and PI-9 in ALK-negative ALCL [39
], and T-cell activation markers in unspecified PTCL [40
]. These results underscore the importance of careful pathologic classification and clinical evaluation of these lymphomas.
Therefore, the apparent high incidence of mature T-cell and NK-cell lymphomas in the Chinese people is due to a high frequency of NK-cell but not T-cell lymphomas. A diligent classification of T-cell and NK-cell lymphomas is needed for patient treatment and prognostication.
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Acknowledgements |
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Received for publication July 3, 2004. Revision received September 1, 2004. Accepted for publication September 3, 2004.
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