ORIGINAL ARTICLE
Lymphoma in Taiwan: Review of 1347 neoplasms from a single institution
according to the 2016 Revision of the World Health Organization Classification
Shih-Sung Chuang
a,b,c,*, Shang-Wen Chen
d, Sheng-Tsung Chang
a,e, Yu-Ting Kuo
faDepartment of Pathology, Chi-Mei Medical Center, Tainan, Taiwan
bDepartment of Pathology, Taipei Medical University, Taipei, Taiwan
cDepartment of Pathology, National Taiwan University, Taipei, Taiwan
dDivision of Hemato-Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Lioying, Tainan, Taiwan
eDepartment of Nursing, National Tainan Institute of Nursing, Tainan, Taiwan
fDepartment of Radiology, Chi-Mei Medical Center, Tainan, Taiwan
Received 19 May 2016; received in revised form 9 August 2016; accepted 14 November 2016
KEYWORDS Hodgkin lymphoma;
lymphoma;
lymphoma frequency;
non-Hodgkin lymphoma;
Taiwan
Background/Purpose: Lymphoid neoplasms are heterogeneous and types of lymphoma vary in different geographic regions. In this study, we aimed at classifying the lymphoid neoplasms at our institution in Taiwan and to compare the relative frequency of various types of lymphoma in different countries.
Methods: We retrospectively searched the files of patients diagnosed with lymphoma at our institution from 2000 to 2015 based on the 2016 Revision of the World Health Organization clas- sification.
Results: We identified 1339 patients with lymphoid neoplasms; among them, eight had two distinct types of lymphoid neoplasms. Of the 1347 neoplasms, 6.09% were Hodgkin lymphomas (HLs) and 93.31%, non-HL (NHLs). Among the 1257 NHLs, 82.66% were of B-cell lineage and 17.34% of T-cell lineage. The most common B-cell lymphoma types were diffuse large B-cell lymphoma, follicular lymphoma, and mucosa-associated lymphoid tissue lymphoma. Among T-cell neoplasms, 37% cases were of nodal origin and 63% cases arose in extranodal sites.
The most common nodal and extranodal T-cell neoplasms were angioimmunoblastic T-cell lym- phoma and extranodal natural killer/T-cell lymphoma, nasal type, respectively.
Conclusion: We analyzed the largest series of lymphomas to date from Taiwan and concluded that HL was rare and T-cell neoplasms comprised around 17% of all NHLs in Taiwan. The
Conflicts of interest: The authors declare no conflicts of interest.
* Corresponding author. Department of Pathology, Chi-Mei Medical Centre, 901 Chung-Hwa Road, Yong-Kang District, Tainan 71004, Taiwan.
E-mail address:cmh5301@mail.chimei.org.tw(S.-S. Chuang).
http://dx.doi.org/10.1016/j.jfma.2016.11.006
0929-6646/Copyrightª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Available online atwww.sciencedirect.com
ScienceDirect
journal home page:www.jfma-onl ine.com
relative frequency of the major lymphoma types is similar in East Asian countries, with only a minor difference, but the overall pattern in the East is quite different from that in the West, with the latter showing a higher frequency of HL and a lower rate of T-cell neoplasms.
Copyrightª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/).
Introduction
Lymphoid neoplasms are clonal lymphoproliferations and are heterogeneous in clinical presentation, histopathology, immunophenotype, and prognosis. Characterization and classification of lymphoid neoplasms are challenging and evolve with advances in technology. Currently, the 2008 World Health Organization classification is the gold stan- dard in diagnosis and classification of lymphoid neoplasms.1 Lymphoma types vary across geographic regions, reflecting the impact of ethnicity, socioeconomic status, and various environmental factors on lymphomagenesis.2
In our prior studies with smaller numbers of cases, we showed that the frequency of T and natural killer (NK)/T- cell lymphoma in Taiwan was higher than that in the Western countries and there was an increase in the fre- quency of follicular lymphoma (FL) in the early years of the 21st century in Taiwan.3,4In this study, we aimed to sys- tematically review the cases of lymphoma at our institution in the first 16 years of the 21stcentury and to compare our data with those from different geographical regions.
Materials and methods
We retrospectively searched the files of patients diagnosed with lymphoma at our institution from January 2000 to December 2015. Diagnoses were made according to the 2008 World Health Organization classification of lymphoid neoplasms and the 2016 revision.5 Plasma cell neoplasms were not included. This study was approved by the Internal Review Board of Chi-Mei Medical Center, Tainan, Taiwan and conducted in accordance with the Helsinki Declaration.
Diagnosis was based on detailed histopathological ex- amination with the aid of immunohistochemistry and/or flow cytometric immunophenotyping. Clonality assay for B- cell and T-cell receptor gene rearrangement was performed for confirmation of clonality and exclusion of morphological mimics of lymphoma/leukemia. In situ hybridization for EpsteineBarr virus (EBV) encoded mRNA was applied for cases of peripheral T-cell lymphoma to exclude extranodal NK/T-cell lymphoma (ENKTL), nasal type as previously described.6Fluorescence in situ hybridization for common lymphoma-associated chromosomal translocation (IGH, BCL2, BCL6, MYC, and CCND1) was performed mainly for the identification of Burkitt lymphoma (BL) and high-grade B-cell lymphoma, NOS (previously called B-cell lymphoma, unclassifiable, with features between diffuse large B-cell lymphoma (DLBCL) and BL), and the differential diagnoses between cyclin D1-positive DLBCL versus mantle cell lym- phoma as previously described.7e9
For primary splenic lymphomas, diagnoses were made based on morphological and flow cytometric immunophe- notyping of the leukemic cells when present and histolog- ical evaluation plus immunohistochemistry of the splenectomy specimens. For those cases of primary splenic lymphoma with leukemic change (confirmed by flow cyto- metric immunophenotyping) but devoid of surgical or bi- opsy specimens, “splenic B-cell lymphoma/leukemia, unclassifiable” was diagnosed, since splenic marginal zone lymphoma (MZL), splenic diffuse red pulp small B-cell lymphoma, and even hairy cell leukemia variant may fall into this category if no splenic tissue can be obtained for histopathological examination.10e12Patients with lympho- cytosis but devoid of organomegaly and not fulfilling the phenotypic criteria of chronic lymphocytic leukemia (CLL;
dim CD20 expression and positivity for CD5, CD23, and CD43) were diagnosed with “unclassifiable small B-cell leukemia”; its neoplastic nature was confirmed by flow cytometric immunophenotyping and/or bone marrow aspi- ration biopsy as mature small B-cell leukemia. We sepa- rated lymphoplasmacytic lymphoma from other mature low-grade B-cell leukemia including “unclassifiable small B-cell leukemia” by: (1) morphological identification of plasmacytoid lymphocytes and plasma cells in addition to small lymphocytes in the marrow aspirate smears; (2) flow cytometric immunophenotyping of these plasmacytoid lymphocytes and plasma cells, which was distinct from the mature B-cell leukemic cells; and (3) presence of immu- noglobulin M monoclonal gammaglobulin.
Transformed lymphoma, either at disease presentation or at relapse, was counted only once at initial diagnosis. For example, Grade 3A FL and DLBCL at the same site was diagnosed as FL. By contrast, coexistence of two distinct lymphomas, either synchronously or metachronously, is defined as two lymphomas. For example, one patient with primary cutaneous peripheral T-cell lymphoma not other- wise specified (PTCL-NOS) and subsequent development of DLBCL during the disease course was diagnosed as two kinds of lymphoma accordingly.
Results
A total of 1347 cases of lymphoid neoplasms were identified among 1339 patients, including eight with two distinct types of lymphoid neoplasms (1 synchronously and 7 met- achronously). Among the 1347 cases, 6.09% (82 neoplasms) were Hodgkin lymphoma (HL), 93.31% (1257) were non-HL (NHL), and 0.59% (8) was other diseases [3 composite lym- phomas, 2 mediastinal lymphoblastic lymphoma of ambig- uous phenotypes (1 mixed T and myeloid and 1 mixed B, T, and myeloid lineages), 1 mediastinal gray zone lymphoma,
1 follicular dendritic cell sarcoma, and 1 Langerhans cell neoplasm].
In this series, HL accounted for around 6% of cases, comparable with the figures given in the East Asian studies of 4e8%, but significantly lower than 15e30% in the West (Table 1).13e18 Interestingly, there was only one case of nodular lymphocyte-predominant HL among a total of 82 cases of HL, which meant that classical HL (CHL) accounted for 99% of all HL cases. The 81 CHL cases in our series were subclassified as nodular sclerosis (38 cases; 47%), mixed cellularity (22; 27%), lymphocyte-rich (18; 22%), and un- classifiable (3; 4%).
Among the 1257 neoplasms (NHL), 82.66% (1039 neo- plasms) were of B-cell lineage and 17.34% (218) of T-cell lineage. Table 2 lists the case number and relative fre- quency of all types of B-cell neoplasms. The most common types were DLBCL, FL, and extranodal MZL of mucosa- associated lymphoid tissue (MALT lymphoma). If we classi- fied primary mediastinal large B-cell lymphoma as DLBCL, FL with concurrent DLBCL as FL, and MALT lymphoma, splenic MZL, and nodal MZL as a single category of MZL, the most frequent B-cell neoplasms were DLBCL (50.62%), FL (16.27%), and MZL (12.70%). The second-tier most frequent B-cell neoplasms were CLL/small lymphocytic lymphoma (7.31%), unclassifiable small B-cell leukemia/lymphoma (3.27%), mantle cell lymphoma (2.50%), and BL (2.41%).
Table 3 lists the relative frequency of the 218 T-cell neoplasms. The most common types were angioimmuno- blastic T-cell lymphoma (AITL; 18.3%), ENKTL, nasal type (16.5%), PTCL-NOS (15.1%), and systemic anaplastic large cell lymphoma (ALCL; 10.5%, including 5.0% anaplastic lymphoma kinase (ALK)-positive and 5.5% ALK-negative).
The second-tier most frequent T-cell neoplasms were T- cell large granular lymphocytic leukemia (T-LGL leukemia;
7.3%), adult T-cell leukemia/lymphoma (4.1%), mycosis fungoides (4.1%), and primary cutaneous CD30-positive T- cell lymphoproliferative disorders [4.1%, including 1.4% (3 cases) of primary cutaneous ALCL and 2.8% (6) of lympho- matoid papulosis]. Ten of the 218 T-cell neoplasms were disseminated, involving both nodal and extranodal sites.
They were considered tumors of indeterminate origin. Of the remaining 208 cases, 76 (37%) cases were nodal and 132 (63%) cases arose from extranodal sites. Among the nodal T- cell neoplasms, AITL was by far the most common (53%; 40 cases), followed by PTCL-NOS (21%; 16 cases), and systemic ALCL [17%, including 7 (9%) ALK-positive and 6 (8%) ALK- negative cases]. Of the 132 cases of extranodal T-cell neoplasms, the most common tumor types were ENKTL (35
cases; 26.5%), T lymphoblastic leukemia/lymphoma (18 cases; 13.6%), T-LGL leukemia (16 cases; 12.1%), and PTCL- NOS (10 cases; 7.6%).
Discussion
In this study, we reviewed the 1347 lymphoid neoplasm cases in the first 16 years of the 21st century in a single institution, which is by far the largest series in Taiwan. We confirmed the findings of our previous studies with smaller
Table 1 Hodgkin lymphoma and non-Hodgkin lymphoma in various countries/geographic regions.
Countries/region (case no.)
HL % (case no.) NHL % (case no.) B-cell lymphoma among NHL
T-cell lymphoma among NHL
Reference
USA (103,936) 9.96% (10,042) 90.34% (93,894) 93.37% (86,666/93,894) 6.63% (6228/93,894) [21]
UK (5796) 14.41% (835) 85.59% (4961) 93.79% (4653/4961) 6.21% (308/4961) [16]
Japan (1552) 5.22% (81) 93.62% (1453) 80.25% (1166/1453) 19.75% (287/1453) [15]
Korea (5318) 4.12% (219) 95.88% (5099) 81.60% (4161/5099) 17.16% (875/5099) [14]
China (4638) 8.60% (399) 91.40% (4239) 71.05% (3012/4239) 28.95% (1227/4239) [13]
Taiwan (1347) 6.09% (82) 93.32% (1257) 82.66% (1039/1257) 17.34% (218/1257) Current study HLZ Hodgkin lymphoma; NHL Z Hodgkin lymphoma; UK Z United Kingdom; USA Z United States of America.
Table 2 Relative frequency of 1039 B-cell non-Hodgkin neoplasms in Taiwan.
Lymphoma type No. %
B lymphoblastic leukemia/lymphoma 4 0.38 Chronic lymphocytic leukemia/small
lymphocytic lymphoma
76 7.31
B-cell prolymphocytic leukemia 2 0.19 Unclassifiable small B-cell lymphoma/leukemia 34 3.27 Splenic marginal zone lymphoma 16 1.54
Hairy cell leukemia 1 0.10
Splenic B-cell lymphoma/leukemia, unclassifiable
9 0.87
Spleen-diffuse red pulp small B-cell lymphoma 3 0.29
Hairy cell leukemia variant 1 0.10
Lymphoplasmacytic lymphoma 14 1.35
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)
97 9.34
Nodal marginal zone lymphoma 19 1.83
Follicular lymphoma 153 14.73
Follicular lymphoma with DLBCL 16 1.54
Mantle cell lymphoma 26 2.50
DLBCL 499 48.03
Primary mediastinal large B-cell lymphoma 27 2.60
Primary effusion lymphoma 6 0.58
Burkitt lymphoma 25 2.41
High-grade B-cell lymphoma, NOS 8 0.77
Plasmablastic lymphoma 2 0.19
Unclassifiable high grade B-cell lymphoma/leukemia
1 0.10
BLZ Burkitt lymphoma; DLBCL Z diffuse large B-cell lym- phoma; high-grade B-cell lymphoma, NOSZ the term in the 2016 Revision for “unclassifiable B-cell lymphoma with features intermediate between BL and DLBCL” used in the 2008 WHO classification.
samples that showed a lower frequency (around 6%) of HL and a higher frequency of T-cell neoplasms (around 16% of all lymphoid neoplasms and 17% of all NHLs) as compared with the Western ones.3,4,16 Furthermore, we identified eight patients with two distinct lymphomas, occurring at a frequency of 0.60% among 1339 patients with lymphoid neoplasms.
HL accounts for 15e30% of all lymphoid neoplasms in the West.18 The great majority (90e95%) are CHL, with the
remaining being nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) which accounts for 3e8% of HLs in Western countries.19 The incidence of CHL is higher in affluent, industrialized nations than in developing coun- tries.18As shown inTable 1, the frequency of HL is much lower in the East Asian countries as compared with the West; and the frequency of NLPHL is extremely low in the East, ranging from 1.2% to 3.7% among all HLs.13e16Inter- estingly, the frequency of NLPHL among all HLs is lower in the East as compared with the West.
Table 4summarizes the relative frequency of the more common B-cell neoplasms in different geographic region- s.13e16,20e22 DLBCL is the most common type, accounting for four to five out of 10 lymphoma diagnoses. Among the East Asian countries, FL is the second most common B-cell neoplasms in Taiwan and Japan (16% and 24%, respec- tively). The reason for the increasing trend of FL in Taiwan is currently unknown. In a recent study, we used the epidemiological data during 1993e2012 from the Taiwan National Cancer Registry Database and confirmed a distinct increasing trend of FL with a strong birth-cohort effect in Taiwan, suggesting that lifestyle alternation is an important factor for the pathogenesis of FL (Wu et al, manuscript in preparation). Interestingly, the frequency of FL was exceedingly low in Korea and China (3% and 4%, respec- tively). In these two countries, MALT lymphoma was the second most common B-cell lymphoma type, most likely due to a higher prevalence of Helicobacter pylori infection and gastric MALT lymphoma in these two countries and the national endoscopy screening program for gastric cancer in Korea.23,24In Taiwan, the decreasing frequency of MZL was mostly due to the decreased frequency of gastric MALT lymphoma, the most common type of MZL. The main reason was probably due to the early eradication of H. pylori by gastroenterologists for patients with H. pylori-related chronic active gastritis and gastric ulcer. The eradication might lead to the decreased frequency of gastric MALT lymphoma, the well-known late complication of H. pylori- related gastritis.
Table 3 Relative frequency of 218 T-cell non-Hodgkin neoplasms in Taiwan.
Lymphoma type No. %
T lymphoblastic leukemia/lymphoma 21 9.6 Angioimmunoblastic T-cell lymphoma 40 18.3 Extranodal NK/T-cell lymphoma, nasal type 36 16.5 Peripheral T-cell lymphoma, unspecified 33 15.1 Anaplastic large cell lymphoma, ALK-positive 11 5.0 Anaplastic large cell lymphoma, ALK-negative 12 5.5 T-cell large granular lymphocytic leukemia 16 7.3 Monomorphic epitheliotropic intestinal
T-cell lymphoma
6 2.8
Adult T-cell leukemia/lymphoma 9 4.1 Aggressive natural killer cell leukemia 6 2.8
Mycosis fungoides 9 4.1
Lymphomatoid papulosis 6 2.8
Primary cutaneous anaplastic large cell lymphoma
3 1.4
Hepatosplenic T-cell lymphoma 3 1.4
Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder
2 0.9
Subcutaneous panniculitis-like T-cell lymphoma
2 0.9
Systemic EBVþ T-cell lymphoma of childhood 2 0.9 T-cell prolymphocytic leukemia 1 0.5 ALKZ anaplastic lymphoma kinase; EBV Z EpsteineBarr virus;
NKZ natural killer.
Table 4 Relative frequencies of the common B-cell lymphoma types among all B-cell non-Hodgkin lymphoma (NHL) in various countries/geographic regions.
Countries/region (case no.)
DLBCL (case no.) FL (case no.) MALT lymphoma (case no.)
CLL/SLL (case no.)
MCL (case no.) BL (case no.) Reference
USA (nZ 498,057) 38.92%
(193,855)
20.48%
(101,997)
9.94% (49,508) 22.28%
(110,944)
4.91% (24,456) 1.92% (9543) [22]
CSA (nZ 809) 45.8% (371) 23.4% (189) 7.9% (64) 4.3% (35) 5.7% (46) 3.3% (27) [20]
UK (nZ 5488) 43.24% (2373) 16.82% (923) 17.91% (983) Not included 4.50% (247) 1.88% (103) [16]
Japan (nZ 1166) 51.37% (599) 24.10% (281) 7.89% (92) 1.29% (15)b 3.00% (35) 0.60% (7) [15]
Korea (nZ 3399)a 47.75% (1623) 2.68% (91) 19.45% (661) 2.85% (97) 2.88% (98) 3.27% (111) [14]
China (nZ 3012) 55.78% (1680) 4.48% (135) 11.78% (355) 5.74% (173) 3.75% (113) 1.56% (47) [13]
Taiwan (nZ 1039) 48.03% (499) 16.27% (169) 7.89% (82) 7.31% (76) 2.50% (26) 2.41% (25) Current study BLZ Burkitt lymphoma; CLL Z chronic lymphocytic leukemia; CSA Z Central and South America; DLBCL Z diffuse large B-cell lymphoma;
FLZ follicular lymphoma; MALT Z mucosa-associated lymphoid tissue; MCL Z mantle cell lymphoma; SLL Z small lymphocytic lym- phoma; UKZ United Kingdom; USA Z United States of America.
aIn this Korean study, plasma cell neoplasms (762 among a total of 4161 cases) were included. In the current table, plasma cell neoplasms were excluded for the purpose of comparison.
bIn this Japanese study, only small lymphocytic lymphoma SLL but not CLL was included.
The relative frequency of the more common T-cell neoplasms in various geographic regions is listed inTable 5.
ENKTL is strikingly common in China, accounting for half of the T-lineage tumors, and is also numerous in Korea (about one third of the cases). The reason is unknown, although lifestyle and environmental factors such as farming, pesti- cide exposure, and living near incinerators might be risk factors.25In addition, the strong EBV association and racial predisposition suggest a genetic defect in the host immune response to EBV infection.26,27 AITL is less common than PTCL-NOS in most East Asian countries. However, the relative frequency of AITL has increased in recent years in Taiwan when compared with the data from our previous studies.3,28In France AITL is currently the most common T- cell lymphoma as reflected in two new data sets.29One of the reasons for the increasing frequency of AITL might be a better understanding and recognition by pathologists of this entity, which was originally considered as an atypical im- mune response.30Since the better definition of this entity in the past two decades,31e33 the frequency of this lym- phoma type seems to be increasing. The prior low fre- quency of AITL in some studies might be “falsely” low as they might have been misdiagnosed as reactive/atypical lymphoid hyperplasia, particularly in the earlier lesions or partial nodal involvement with presence of residual germinal centers.3,28,31e33
The weakness of this study is that the data spanned 16 years and were from a single center in Taiwan, which may not be representative of the whole population in Taiwan. The other limitation was that one study author (SSC) was in charge of the diagnostic flow cytometric immunophenotyping and might have picked up more mature lymphoid leukemia cases (such as T-LGL leukemia) as compared with other pathology laboratories, which relied only on biopsy specimens for lymphoma diagnosis.
Accordingly there might be a higher proportion of mature lymphoid leukemia in this study. However, the strength of the study is that we have longitudinal data, since one study author (SSC) has been continuously registering/filing all lymphoma cases for more than 20 years, which enables us to clearly subtype neoplasms in cases with two different types of lymphoid neoplasms.
In conclusion, we analyzed the largest series of lym- phoma so far from Taiwan. We showed that HL was rare, accounting for around 6% of all lymphoid neoplasms, and T- cell neoplasms comprised around 17% of all NHLs. The frequency is similar to that in East Asian countries, with only a minor difference, but the overall pattern in the East is quite different from that in the West, where a higher frequency of HL and a lower rate of T-cell neoplasms were observed.
Acknowledgments
Dr SS Chuang is grateful to his mentors, Professor Chin-Yang Li and Peter G. Isaacson, for their teaching and inspiration in hematopathology. The authors thank Professor Shigeo Nakamura, Koichi Oshima, and Ryo Ichinohasama for consultation and assistance with challenging cases, and thank Professor Ming-Qing Du, Dr Hongxiang Liu, and Dr Hongtao Ye for assistance in molecular diagnosis.
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