|Year : 2018 | Volume
| Issue : 1 | Page : 58-65
|Applicability of 2008 World Health Organization classification system of hematolymphoid neoplasms: Learning experiences
Sushil Modkharkar1, Pooja Navale1, Pratibha Kadam Amare2, Anuradha Chougule3, Nikhil Patkar3, Prashant Tembhare3, Hari Menon4, Manju Sengar4, Navin Khattry4, Shripad Banavali4, Brijesh Arora4, Gaurav Narula4, Siddhartha Laskar5, Nehal Khanna5, Mary Ann Muckaden6, Venkatesh Rangarajan7, Archi Agrawal7, Tanuja Shet1, Sridhar Epari1, PG Subramanian3, Sumeet Gujral8
1 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Cancer Cytogenetics, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Pathology, Hematopathology Laboratory, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
5 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
6 Department of Palliative Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
7 Department of Radiology and Nuclear Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
8 Department of Pathology, Tata Memorial Hospital; Department of Pathology, Hematopathology Laboratory, Tata Memorial Hospital, Mumbai, Maharashtra, India
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|Date of Web Publication||22-Mar-2018|
| Abstract|| |
Background: 2008 World Health Organization (WHO) classification of hematolymphoid neoplasms (HLN) has classified them based on morphology, results of various ancillary techniques, and clinical features. There are no studies looking at the applicability of WHO classification. Aims: The aim of the study was to calculate proportions of all HLN subtypes seen during 1-year period based on 2008 WHO classification of HLN and study applicability and also shortcomings of practices in a tertiary care center in India. Materials and Methods: This was a 1-year retrospective study (January 1st, to December 31st, 2010) where cases were identified using hospital/laboratory electronic records. Old follow-up and referral cases were excluded from the study. Only newly diagnosed cases classified into categories laid down by 2008 WHO classification of HLN included. Results: Out of 2118 newly diagnosed classifiable cases, 1602 (75.6%) cases were of lymphoid neoplasms, 489 (23.1%) cases of myeloid neoplasms, 16 (0.8%) cases of histiocytic and dendritic cell neoplasms, and 11 (0.5%) cases of acute leukemias of ambiguous lineage. Overall, most common HLN subtype was diffuse large B-cell lymphoma (n = 361, 17.0%). Precursor B-lymphoblastic leukaemia/lymphoma (n = 177, 48.2%) was the most common subtype within pediatric age group. Conclusions: All major subtypes of HLN were seen at our center and showed trends almost similar to those seen in other Indian studies. Molecular/cytogenetic studies could not be performed on a significant number of cases owing to logistic reasons (unavailability of complete panels and also cost-related issues) and such cases could not be classified as per the WHO classification system.
Keywords: Extranodal lymphomas, hematolymphoid neoplasms, leukemia, lymphoma, pediatric hematolymphoid neoplasms, World Health Organization classification
|How to cite this article:|
Modkharkar S, Navale P, Amare PK, Chougule A, Patkar N, Tembhare P, Menon H, Sengar M, Khattry N, Banavali S, Arora B, Narula G, Laskar S, Khanna N, Muckaden MA, Rangarajan V, Agrawal A, Shet T, Epari S, Subramanian P G, Gujral S. Applicability of 2008 World Health Organization classification system of hematolymphoid neoplasms: Learning experiences. Indian J Pathol Microbiol 2018;61:58-65
|How to cite this URL:|
Modkharkar S, Navale P, Amare PK, Chougule A, Patkar N, Tembhare P, Menon H, Sengar M, Khattry N, Banavali S, Arora B, Narula G, Laskar S, Khanna N, Muckaden MA, Rangarajan V, Agrawal A, Shet T, Epari S, Subramanian P G, Gujral S. Applicability of 2008 World Health Organization classification system of hematolymphoid neoplasms: Learning experiences. Indian J Pathol Microbiol [serial online] 2018 [cited 2021 Oct 18];61:58-65. Available from: https://www.ijpmonline.org/text.asp?2018/61/1/58/228178
| Introduction|| |
The 2008 classification of hematolymphoid neoplasms (HLN) by the World Health Organization (WHO) is an integrated approach, which besides morphology, incorporates results of various ancillary techniques (such as immunophenotyping and genetic analysis) and clinical features. Although this is supposedly followed by most of the Western world, there are hardly any studies determining incidence/proportions of subsets of HLN defined by this classification. This assumes importance, due to the observation that the prevalence of HLN vary with geographic locations, suggesting various etiological factors playing a role in their pathogenesis.,, Furthermore, there are no studies objectively studying the applicability of this classification in resource-poor countries.
| Materials and Methods|| |
We did a retrospective analysis of 1-year cases of HLN (January 1st, to December 31st, 2010). Cases during this period were identified using hospital/laboratory electronic records. Follow-up and referral cases (which came only for histopathological review and were not investigated further) were excluded from the study. Remaining newly diagnosed cases were classified into categories laid down by 2008 WHO classification of HLN, excluding cases which were nonclassifiable into specific defined entities. These cases were diagnosed by a team of 12 histopathologists (which included three specialist hematopathologists), two liquid hematopathologists, one cytogeneticist, and one molecular hematologist. These cases were discussed in the lymphoma clinics and histopathology was subsequently reviewed by expert hematopathologists on a case-to-case bases.
Morphologic assessment included microscopic evaluation of lymph node and other tissue biopsies, resection specimens, peripheral blood smear, bone marrow (BM) biopsy/aspirate, and body fluid cytology. Immunohistochemistry was done using a comprehensive antibody panel on paraffin block material. Flow cytometric immunophenotyping (using six color flow cytometric analysis) was done on freshly collected peripheral blood, BM aspirate, and other body fluids (and lymph nodes in some selected cases). Conventional cytogenetics, metaphase-interphase fluorescent in situ hybridization, and other molecular tests were performed based on morphologic/immunophenotypic interpretation and targeted requisitions by the clinicians. Waldeyer's ring was considered extranodal site, as was the case in most of the studies we used for comparison, though controversy exists.
Most studies quoted here do not meet criteria set by 2008 WHO classification of HLN. They were used for comparison since extensive literature search did not come up with any comprehensive, all-inclusive study.
| Results|| |
A total of 3912 cases of HLN were seen during the study period. Among them, 337 cases were for follow-up and/or previously treated and 1187 cases were referred to our hospital for histopathological opinion only. Another 270 cases could not be classified into specific defined entities applying 2008 WHO classification and were excluded from the study. Thus, we had a final total of 2118 classifiable cases in this retrospective study.
Lymphoid neoplasms (n = 1602, 75.6%)
- Precursor lymphoid neoplasms (n = 408, 25.5%) - Demographic details are given in [Table 1]. Precursor B-acute lymphoblastic leukaemia/lymphoma (B-ALL/LL) constituted 277 (67.9%) cases and precursor T-lymphoblastic leukaemia/lymphoma (T-ALL/LL) constituted 131 (32.1%) cases. Among T-ALL/LL, 18 (13.7%) cases were of precursor T-lymphoblastic lymphoma (where peripheral blood and BM were uninvolved)
- Hodgkin lymphoma (HL) (n = 216, 13.5%) - Demographic details are given in [Table 2]. Among these, nodular lymphocyte predominant HL constituted 15 (6.9%) cases, whereas classical HL (CHL) constituted the remaining 201 (93.1%) cases
- Mature B-cell neoplasms (n = 890, 55.6%) - Demographic details are given in [Table 3]. The most common subtypes were diffuse large B-cell lymphoma (DLBCL) (n = 361, 40.6%) followed by plasma cell neoplasms (PCN) (n = 127, 14.3%). DLBCL was also the overall most common HLN subtype in the present study (17.0%)
- Mature T-cell and NK-cell neoplasms (n = 88, 5.5%) - Demographic details are given in [Table 4]. Anaplastic large cell lymphoma (ALCL) (n = 43, 48.9%) was the most common subtype, followed by peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) (n = 17, 19.3%).
|Table 1: Demographic characteristics of precursor lymphoid neoplasms in this study|
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|Table 3: Demographic characteristics of mature B-cell neoplasms in this study|
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|Table 4: Demographic characteristics of mature T-cell and NK-cell neoplasms in this study|
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Myeloid neoplasms (n = 489, 23.1%)
Demographic details are given in [Table 5]. Myeloproliferative neoplasms (MPN) was the largest subgroup among myeloid neoplasms in this study.
- Myeloproliferative neoplasms (n = 275, 56.2%) - All these cases were of BCR-ABL 1-positive chronic myelogenous leukaemia (BCR-ABL1 + CML). Three cases which were BCR-ABL1 negative were not completely investigated and so were excluded from the study
- Acute myeloid leukemias (AML) and related precursor neoplasms (n = 202, 41.3%) - Within these, AML with recurrent genetic abnormalities was the most common category (n = 120, 59.4%).
Histiocytic and dendritic cell neoplasms (HDN) (n = 16, 0.8%)
Demographic details are given in [Table 6]. Langerhans cell histiocytosis (LCH) (n = 11, 68.8%) was the most common HDN subtype, with most cases (n = 9, 81.8%) seen in pediatric age group (median age = 6 years).
|Table 6: Demographic characteristics of acute leukaemias of ambiguous lineage and histiocytic/dendritic cell neoplasms in this study|
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| Discussion|| |
Ours is a tertiary care cancer center getting referral cases from all over. Thus, these data are biased and may not be true representative of national data.
B-ALL/LL (n = 277, 67.9%) was the most common precursor lymphoid neoplasm subtype, in keeping with the findings of studies from Korea (69.0%) and Mexico (73.2%). Hyperdiploidy was the most common recurrent cytogenetic abnormality for B-ALL/LL (n = 79, 37.4%), similar to the findings of Safaei et al. and Mrózek et al.
The proportion of HL (13.5%, n = 216) in this study was higher than those noted in the studies from Australia (9.6%) and East Asia (9.1% and 4.1%)., The mean age for HL (31.1 years) closely matched with that reported by Arora et al. (31.9 years), Sun et al. (32.9 years,) and Yoon et al. (38.8 years). Bimodal age distribution of CHL seen in the studies from Europe  and America  was not seen in this study and in another Indian study by Patkar et al. Mixed cellularity was the most common CHL subtype (n = 67, 33.3%), as also seen in the Indian study by Arora et al., as well as in East Asian studies., This was in contrast to American study by Morton et al., where nodular sclerosis was the most common subtype.
Mature B-cell neoplasms constituted the largest lymphoid neoplasm subgroup in the present study (n = 890, 55.6%), in keeping with the findings of Jayasekara et al. (81.9%), Morton et al. (79.7%), and Yoon et al. (66.9%). [Table 7] gives comparison between proportions of mature B-cell neoplasms in the present study and other comparable studies. DLBCL was the most common mature B-cell neoplasm subtype (n = 361, 40.6%) in this study, which correlated with the studies from India and across the world, where they constituted 26.9% to 61.2%.,,,,, PCN was the second most common (n = 127, 14.3%), similar to that reported by Morton et al. (23.4%) and Jayasekara et al. (23.3%), whereas in East Asian studies, extranodal marginal zone lymphoma (ENMZL) was the second most common mature B-cell neoplasm and showed high proportions (12.5% and 18.6%)., However, the proportion of ENMZL was much lower (n = 11, 1.2%) in this study. Most mature B-cell neoplasm subtypes were seen in older age group, except for Burkitt lymphoma (BL) and anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK + LBL), which were seen in relatively younger age group (mean ages: 28.4 and 34.6 years, respectively), as also seen in the Indian study by Arora et al. (mean ages for BL = 22.1 years and ALK + LBL = 37.5 years) and the Chinese study by Sun et al. (BL, mean age = 25.6 years).
|Table 7: Comparison between proportions of mature B-cell neoplasms in this study with other studies|
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[Table 8] gives comparison between proportions of mature T-cell neoplasms in the present study and other comparable studies. ALCL was the most common mature T-cell neoplasm subtype in the Indian study by Naresh et al. (40.0%), which correlated with this study (n = 43, 48.9%), whereas it was the second most common (28.2%) in another Indian study by Arora et al., the most common being PTCL, NOS (33.0%). In the present study, PTCL, NOS was the second most common mature T-cell neoplasm (n = 17, 19.3%). Extranodal NK/T-cell lymphoma (ENKTL) was the most common mature T-cell neoplasm in the East Asian studies (53.4% and 56.6%)., ENKTL is rare in Indian subcontinent, as seen in this study (n = 8, 9.1%) and in other similar Indian studies., Mycosis fungoides/Sezary syndrome were the most common mature T-cell neoplasm subtypes in the American study by Morton et al. (46.1%) and in the European study by Novelli et al. (36.4%) (along with PTCL, NOS), whereas it was only third most common in the present study. ALCL and hepatosplenic T-cell lymphoma (HSTL) were seen in relatively younger age group (mean ages: 32.2 and 27.5 years, respectively) as compared to other mature T-cell neoplasms, similar to that noted by Arora et al. (mean ages for ALCL and HSTL being 35.1 and 34.3 years, respectively) and in the East Asian studies.,,
|Table 8: Comparison between proportions of mature T-cell and NK-cell neoplasms in this study with other studies|
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The proportion of extranodal lymphomas (ENL) (32.2%) noted in this study correlated with those reported by Arora et al. (32.9%), Krol et al. (34.0%), and Zucca et al. (24.0%–48.0%). However, much higher proportions were seen in Chinese studies by Sun et al. (63.5%) and Yang et al. (53.5%). DLBCL was the most common ENL subtype (n = 174, 55.2%) in the present study, as also noted by Sun et al. (38.0%), Yang et al. (42.5%), and Arora et al. Gastrointestinal tract (GIT) was the most commonly involved extranodal site (n = 90, 28.6%), as also reported by Arora et al., Sun et al., Krol et al., and Zucca et al. The most common ENL subtype affecting GIT was DLBCL (n = 54, 60.0%), similar to the findings of Sun et al. and Ghimire et al.
MPN was the largest myeloid neoplasm subgroup in the present study (n = 275, 56.2%), as also seen in the studies by Maynadie et al. (38.0%) and Osca-Gelis et al. (36.7%). While in the studies by Sant et al. (39.7%) and Jayasekara et al. (35.0%), AML was the most common subgroup. The proportion of myelodysplastic syndromes (MDS) (n = 5, 1.0%) among all myeloid neoplasms in this study was much lower than that seen in the Australian study by Jayasekara et al. (25.7%) and in the European studies by Maynadié et al. (22.0%) and Osca-Gelis et al. (34.4%). This was probably due to referral bias, where older patients were less likely to be referred to a tertiary care center in a resource-poor country. The median age for BCR-ABL1 + CML was between 60 and 65 years in most European countries; however, lower median age was seen in countries with younger population  and in the American study by Lee et al. (39.0 years), as also noted in this study (40.0 years). BCR-ABL1 + CML constituted <5% of all pediatric leukaemias, in the world literature,, which correlated with our study, where they constituted 3.2% (n = 9).
The median age for AML and related precursor neoplasms was 28 years in this study, in contrast to the Western literature, where incidence of AML was highest in older age group (median age = 65.0–70.0 years).,, This may be attributed to similar referral bias, noted above, in case of MDS. Among AML and related precursor neoplasms, AML, not otherwise specified was the most common category in the studies from Europe,,, whereas it was AML with recurrent genetic abnormalities in the present study (n = 120, 59.4%). AML constituted 15.4% (n = 43) of all pediatric leukaemias in this study, which correlated with the findings of Aquino et al. (15.0%–20.0%) and Linabery et al. (18.0%).
Histiocytic and dendritic cell neoplasms
The median age for LCH (6 years) seen in this study was higher than that seen in the study by Bhatia et al. (1.8 years) and peak age of presentation noted by Broadbent et al. (1–3 years). Bone was the most common site affected (n = 5, 45.5%), which correlated with studies across the world.,,
Pediatric hematolymphoid neoplasms
Precursor lymphoid neoplasms were more common in pediatric patients in this study (n = 222, 60.5%), similar to that reported by Morton et al., Jayasekara et al., and Kaatsch et al.
 Among mature B-/T-cell neoplasms, BL (n = 33, 71.7%) was the most common subtype, in keeping with the world literature., While within HL, mixed cellularity was the most common subtype (n = 13, 39.4%), similar to the East Asian studies,, and in contrast to western studies where nodular sclerosis was the most common subtype.,
Lacunae in this study (unclassifiable cases)
The WHO classification system is evidence based and should be followed in an ideal clinical setting. The recent most classification incorporates new genetic and biologic information gathered since the publication of 2001 edition, refining the criteria for the diagnosis of some previously established entities, as well as introduction of new previously unrecognized entities., This has helped in better classification of disease, thereby aiding in specific treatment decisions.
However, in resource-poor countries, it is difficult to adhere to all the guidelines put forward by the WHO system. Reasons for this are mainly two-fold technical and financial. Technical reasons included small biopsy size (leading to tissue depletion for further studies) and suboptimal quality review material (especially in referred cases, where suboptimal tissue processing and fixation, resulted in poor antigen preservation, affecting immunohistochemistry results). Financial reasons included economic constraints leading to inadequate reagents and panels in molecular and cytogenetic testing, resulting in these tests being performed only in a few selected cases. In our study, among the newly diagnosed cases of HLN, 270 cases (11.3%) were nonclassifiable due to same reasons. Similar constraints in adequate characterization of HLN were encountered by Naresh et al.
We do not have any comprehensive reporting formats for HLN. Various laboratories report individually and there is no methodology to have an upfront complete diagnosis. It is left to the clinician to relate various reports of histopathology, BM, flow cytometry, cytogenetics, and molecular diagnostics.
| Conclusions|| |
We have tried to classify various subtypes of HLN based on 2008 WHO classification of HLN. All major subtypes of HLN were seen at our center, showing trends almost similar to those seen in other Indian studies, with some variations from studies outside India. Few subtypes of HLN have not been included owing to inadequate workup. For more correct data, we need to work with multiple registries all across India. Workup may be done in centralized laboratories so as to make it financially viable. Many of the methodologies are expensive and difficult to be applicable on a large scale in a resource-poor country like India, against the basic mandate of classification system. We had these deficiencies, despite being a tertiary care center.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Hematopathology Laboratory, 727, 7th Floor, Annexe Building, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]