Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon type of lymphoma, the diagnosis of which may be impeded by similarities to other conditions, as well as other diagnostic challenges, according to a review recently published in the journal Cancers. The review was written by Sheren Younes, MBBS, PhD, of the Stanford University School of Medicine in Stanford, CA, and colleagues.

“NLPHL is a typically indolent lymphoma with a propensity for recurrence and/or progression,” Dr Younes and colleagues explained in their review.

The annual incidence of NLPHL is 0.1 to 0.2 individuals per 100,000, according to Dr Younes and colleagues. While patients can develop NLPHL at any age, it is most common in younger persons, and it is also more common in males. More than three-quarters of patients with NLPHL have stage I or II disease, and the condition primarily involves peripheral lymph nodes. Although disease recurrence and progression are not uncommon with NLPHL, the 10-year overall survival rate is greater than 80%, according to Dr Younes and colleagues.

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NLPHL can progress to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) or to diffuse large B-cell lymphoma (DLBCL), and consequently NLPHL can be difficult to distinguish from THRLBCL or DLBCL. Other lymphomas, such as classical Hodgkin lymphoma and T-cell lymphomas, and progression transformation of germinal centers can also bear similarities with NLPHL or be difficult to ascertain, adding further complexity to the diagnosis of NLPHL. Variants of NLPHL can also complicate its distinction from other conditions.

NLPHL has a varied presentation, but, as described by Dr Younes and colleagues, it is characterized by large, scarce, sparsely arranged tumor cells. Tumor cells in NLPHL are lymphocyte predominant. The tumor microenvironment associated with NLPHL is also complex and has a high degree of lymphocytes and histiocytes present.

NLPHL also is defined by the presence of some nodularity. NLPHL involves nodules of small lymphoid cells and a follicular dendritic cell meshwork, with neoplastic lymphocyte-predominant cells found within nodules and potentially outside of them.

Several immunohistologic markers are linked to phenotypic features of NLPHL. Additionally, there are several biomarkers for NLPHL that can be evaluated through immunohistochemistry and that can aid in differential diagnosis.

Based on histologic and immunophenotypic features with NLPHL, Dr. Younes and colleagues identified 6 immunoarchitectural patterns with NLPHL. These include classical B-cell-rich nodular, serpigious/interconnected, prominent extranodular lymphocyte predominant, T-cell-rich nodular, diffuse THRLBCL/DLBCL-like, and a B-cell-rich pattern that appears diffuse and moth-eaten.

Recently, genetic analyses have revealed genetic mutations that may be relevant to NLPHL. For instance, transformed NLPHL frequently involves mutations of TET2, JUNB, and NOTCH2 genes. Other genetic patterns appear to exist with NLPHL, and further genomic profiling is expected to reveal more patterns that may influence diagnosis and treatment of NLPHL.


Younes S, Rojansky RB, Menke JR, Gratzinger D, Natkunam Y. Pitfalls in the diagnosis of nodular lymphocyte predominant Hodgkin lymphoma: variant patterns, borderlines and mimics. Cancers (Basel). 2021;13(12):3021. doi:10.3390/cancers13123021