Cytologic subtypes of grade 3 follicular lymphoma

Histologic grading of follicular lymphoma poses a dilemma. On one hand, there are data to support the notion that histologic grade (no matter what system of grading is used) correlates to some extent with clinical outcome. Furthermore, those patients with the highest grade of follicular lymphoma (follicular large-cell lymphoma by the Working Formulation, or follicular lymphoma grade 3 by the REAL and WHO classifications) show favorable response rates more akin to those seen in diffuse large-cell lymphoma when treated with anthracycline-based multiagent chemotherapy regimens. On the other hand, there is poor consensus on exactly which grading criteria should be used and poor interobserver reproducibility of grading on a case-by-case basis. This dilemma is inherent in any system that attempts to establish discrete groups using what amounts to a continuous variable (in this case the number of large cells within neoplastic follicles).

Since the Rappaport classification was published more than 40 years ago, grading has been a part of follicular lymphoma diagnosis. Until the recent publication of the WHO classification of hematopoietic neoplasms, however, no single grading scheme was officially sanctioned by a widely used classification system. The WHO officially recommends utilizing the grading system of Mann and Berard, in which grade is assigned based upon the quantification of larged transformed lymphocytes (centroblasts) within neoplastic follicles per high power microscopic field (0.159 mm²) based on a formal count of 10 fields. When using this grading system, 2 patterns may be encountered: follicular lymphoma with sufficient centroblasts to warrant a grade 3 designation but with many residual small cells; and follicular lymphoma with monotonous sheets of centroblasts. The WHO classification recognizes this histologic dichotomy and assigns a grade of “3a” to the former case and “3b” to the latter. This distinction makes intuitive sense to many, since grade 3a cases would be assumed to overlap significantly with low-grade follicular lymphoma with respect to treatment response and outcome. Potential biologic differences between grades 3a and 3b have been evaluated in previous studies, but this grading system has never been formally evaluated for clinical relevance.

The article by Hans et al (page 2363) is the first to formally (albeit retrospectively) analyze differences in clinical outcome between follicular lymphoma grades 3a and 3b by WHO criteria. The authors conclude that the 3a-3b distinction does not correlate with response to treatment or with clinical outcome. But the presence and extent of a diffuse large-cell component does correlate with behavior of the disease. The latter finding appears to justify the WHO-sanctioned practice of rendering a separate diagnosis of diffuse large B-cell lymphoma in such cases.