Application of the InterLymph Consortium’s Proposed Classification of Lymphoid Neoplasms for Epidemiologic Research to a Large, Nationwide Health Study: Experience in the Women’s Health Initiative
Authors: Edlefsen Kerstin Lara , De Roos Anneclaire , LaCroix Andrea 
Published: April 2020

Abstract
Large cohort studies, such as the Women’s Health Initiative, have traditionally grouped hematopoietic neoplasms (HPN) into disease categories including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and leukemia, however this may not allow for optimal distinction of biologically relevant associations. The 2001 World Health Organization (WHO) classification of HPN represents the current gold standard classification scheme, and has been incorporated into the International Classification of Disease for Oncology, Third Edition (ICD-O-3). In 2007, the International Lymphoma Epidemiology Consortium (InterLymph) proposed a classification of lymphoid neoplasms for epidemiologic research that is based upon the WHO/ICD-O-3 classification (Morton LM, et al. Blood, 2007;110:695–708). Here we report on the application of this proposed classification scheme within the Women’s Health Initiative (WHI), a large, nationwide health study. All incident cases of HPN reported by women in the WHI cohort of 161,808 women were adjudicated by SEER-trained cancer coders according to SEER criteria, including assignment of histology codes based on ICD-O-3 guidelines. Cases were simultaneously assigned to one of the four traditional categories (leukemia, NHL, HL, and MM). Histologic subtypes were then grouped according to the recommendations of InterLymph. A total of 1534 women with incident HPN were identified within the WHI cohort. This included 405 within the general category of leukemia, 853 NHL, 237 MM, and 39 HL. Within the leukemia category, 221 are of lymphoid origin. See Table 1 for the InterLymph classification of the lymphoid neoplasms. These findings highlight the critical importance of appropriately classifying HPN for epidemiologic research. The traditional classification of all blood-based HPN as “leukemias” is particularly problematic, as this grouping includes neoplasms from both the myeloid and lymphoid lineages. In addition, disorders with both leukemic and solid disease phases, such as CLL/SLL, are split between those two traditional categories (leukemia and NHL). These groups also include entities with both indolent and aggressive clinical behaviors. HPN are a heterogeneous group of neoplasms that are known to have distinct phenotypes, presentations, and natural progressions, and they are increasingly recognized to be etiologically heterogeneous. The traditional grouping of these neoplasms into leukemia, NHL, HL, and MM is problematic, and may limit the interpretation of research findings. Classification of these neoplasms according to the recommendations of InterLymph should allow for improved detection of biologically relevant associations.
TABLE 1. All incident lymphoid neoplasms since WHI enrollment, by ICD-0-3 histologic subtype (first column) and by traditional categorization as leukemia (leuk), non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and multiple myeloma (MM).
TOTAL NHL Leuk* MM HL *Leukemia category includes 405 total participants, 177 with myeloid leukemias (116 AML, 40 CML, 14 CMML, 7 other/unclassified) and 7 with leukemias of ambiguous/unspecified lineage ^Chronic lymphocytic leukemia/small lymphocytic lymphoma/pro-lymphocytic leukemia/mantle cell lymphoma Lymphoid neoplasms TOTAL 1350 853 221 237 39 Hodgkin (HL) TOTAL 39 0 0 0 39 Classical Hodgkin (HL, C) 23 23 Hodgkin, not otherwise specified (HL, NOS) 10 10 Nodular lymphocyte-predominant (HL, NLP) 6 6 Non-Hodgkin (NHL) B lineage: TOTAL B-NHL 1259 811 211 237 0 Precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL) 7 7 Mature CLL/SLL/PLL/MCL^ 294 106 188 Lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) 32 23 9 Burkitt lymphoma (BL) 7 6 1 Follicular lymphoma (FL) 208 208 Marginal zone lymphoma (MZL) 88 88 Hairy cell leukemia (HCL) 6 6 Diffuse large B cell (DLBCL) 275 275 Plasma cell neoplasm (PCN) 237 237 B-NHL, not otherwise specified (NOS) 105 105 T lineage: TOTAL T-NHL 47 41 6 0 0 Precursor T-acute lymphoblastic leukemia/lymphoma (T-ALL) 2 2 Mature Mycosis Fungoides(MF)/Sezary syndrome (SS) 7 7 Peripheral T cell lymphoma (PTCL) 30 30 Natural Killer/T cell lymphoma (NK/T) 1 1 Large granular lymphocyte leukemia (T-LGL) 5 5 T-prolymphocytic lymphoma (T-PLL) 2 1 1 Unknown lineage: TOTAL UKNOWN/UNSPECIFIED NHL 5 1 4 0 0 Precursor Acute lymphoblastic leukemia (U-ALL) 1 1 Mature NHL, not other specified (U-NHL) 4 1 3