Abstract and Introduction
Classical Hodgkin lymphoma and ALK− anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK− anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK− anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.
Classical Hodgkin lymphoma and anaplastic large cell lymphoma are both characterized by the presence of CD30-positive tumor cells.[1,2] Furthermore, anaplastic large cell lymphoma is divided into ALK+ cases, presenting with a translocation affecting the ALK locus,[3–5] and ALK− cases, in which translocations involving DUSP22 have been described in a fraction of cases. Whereas classical Hodgkin lymphoma often presents in young adults, anaplastic large cell lymphoma arises at various ages. ALK+ anaplastic large cell lymphoma is more frequently found in children and adolescents, whereas ALK− anaplastic large cell lymphoma is often observed in older patients.[7,8] Classical Hodgkin lymphoma can be cured in about 90% of patients with currently applied treatment approaches. However, ALK− anaplastic large cell lymphoma often shows poor outcome, particularly in the elderly. Therefore, a correct diagnostic classification of both diseases is mandatory for an appropriate therapeutic strategy.
Although classical Hodgkin lymphoma is a B-cell neoplasm, the tumor cells, Hodgkin, and Reed-Sternberg cells—have largely lost their B-cell phenotype.[11,12] Anaplastic large cell lymphoma is a T-cell neoplasm, but the tumor cells often present with a null phenotype and can be negative for all T-cell markers.[13,14] In ALK+ anaplastic large cell lymphoma immunohistochemical detection of ALK expression is a decisive marker for the differential diagnosis, but this marker cannot be applied for ALK− anaplastic large cell lymphoma. In some cases of anaplastic large cell lymphoma cytotoxic molecules like TIA1, perforin, and granzyme B are expressed. However, there are rare Hodgkin lymphoma cases in which expression of these cytotoxic molecules can also be found in Hodgkin and Reed-Sternberg cells.[15,16] In the past years, the B-cell transcription factor PAX5 has been discovered to be still expressed at low level in Hodgkin and Reed-Sternberg cells of most classical Hodgkin lymphoma cases.[11,17,18] Classical Hodgkin lymphoma can therefore in most cases reliably be distinguished from ALK− anaplastic large cell lymphoma. However, some PAX5-negative classical Hodgkin lymphoma cases are difficult to be distinguished from ALK− anaplastic large cell lymphoma. Ancillary molecular studies showing rearrangements of B- or T-cell receptors can be helpful in these cases. However, owing to a low tumor cell content, mostly observed in Hodgkin lymphoma and sometimes also found in anaplastic large cell lymphoma, they do not always give indicative results.
Therefore, the aim of the present study was to identify a set of characteristic markers, which can successfully be applied in the differential diagnosis of classical Hodgkin lymphoma and ALK− anaplastic large cell lymphoma.
Mod Pathol. 2014;27(10):1345-1354. © 2014 Nature Publishing Group