Molecular Genetics in the Diagnosis and Biology of Lymphoid Neoplasms

Hodgkin Lymphomas

CHL is the most common type of Hodgkin lymphoma, representing around 90% of cases, with the remainder representing nodular lymphocyte predominant Hodgkin lymphoma.^[12] Both forms of Hodgkin lymphomas are diagnosed on morphologic and immunophenotypic findings. The primary discriminator is the phenotype of the malignant cells: LP cells express CD20 and other B-cell antigens and express CD30 only rarely and weakly, while HRS cells express CD30, with downregulation of B-cell antigens such as CD20. EBV is implicated in the pathogenesis of CHL. In non-Western countries and in the immunocompromised, it is nearly invariably present and it is more frequent in tumors from patients of lower socioeconomic status and in the elderly. EBV prevalence varies by histologic subtype: it is quite frequent in lymphocyte-depleted CHL and present in the majority of mixed cellularity CHL cases, while it is less common in nodular sclerosis CHL. Due to the paucity of neoplastic cells, molecular studies for immunoglobulin gene rearrangements are not useful in assessing the neoplastic nature of Hodgkin lymphoma. Genomic gains/amplifications of REL, found in over 70% of CHL, BCL3, and MAP3K14 genes are affected by chromosomal gains and rearrangements, leading to activation of the NF-κB pathway. Similarly, mutations in negative regulators of NF-κB, such as NFKBIA encoding IκBa, lead to activation of NF-κB. Activation of the JAK-STAT pathway, mainly due to gain/amplification of JAK2 locus within the 9p24.1 amplicon and inactivating mutations in negative regulators of NF-κB pathway including SOCS1 and PTPN1, are present in CHL. However, genetic analysis does not contribute to diagnosis of Hodgkin lymphoma currently.

Case 158 described a CHL case with a cytotoxic phenotype. Case 278 described a composite FL, grade 2 and 3A, and CHL, which were clonally related based on FISH demonstration of BCL2 rearrangement in both biopsies. Case 141 described a Hodgkin-like transformation in a patient with low-grade FL. Both demonstrated a BCL2 rearrangement. Transformation of CLL/SLL to a CHL-like lymphoma is well described, while other CHL-like transformation of other low-grade lymphomas are less extensively characterized. This case demonstrated that the CHL-like cells demonstrate immunophenotype characteristic of CHL (dim PAX5, CD30, and CD15 expression with absence of OCT2 and BOB1) Table 5.

Am J Clin Pathol. 2019;152(3):277-301. © 2019 American Society for Clinical Pathology