Disease Morphology and Immunohistochemistry

Although the morphologic appearance of GZL is highly variable, the key feature indicative of the disease is high tumor cell content that frequently appears in confluent sheets, which is dissimilar to most classic Hodgkin lymphomas. Another defining feature of GZL is the absence of fibrous bands and a nodular growth pattern. Focal fibrosis may also be present, but compared with classic Hodgkin lymphoma, these regions are infrequently seen and are without neutrophilic infiltrate, which is often seen in classic Hodgkin lymphoma.

Despite the distinguishing features of GZL’s morphology, immunophenotyping can make GZL classification challenging. For example, some patients may show morphology indicative of classic Hodgkin lymphoma, but their immunophenotype may suggest otherwise. Other questions include whether Epstein-Barr virus-positive patients should be considered as having an Epstein-Barr virus-related disease or GZL.

Continue Reading

Related Articles

Current immunohistochemical recommendations for diagnosis includes testing for CD3, CD15, CD20, CD30, CD79a, PAX5, MUM1, and EBER. Some studies have shown benefit in testing for programmed death-ligand 1 in the relapse setting, as the majority of these patients express this ligand. With respect to histology, an excisional biopsy is preferred over a core needle biopsy because of extensive dissimilarity in histomorphology.

Differential Diagnosis and Prognosis

In general, low tumor cell content in the absence of the exclusion of other related malignancies makes a diagnosis of GZL doubtful. Once excluded, however, there are limited differential diagnoses. The most common differential diagnoses include T-cell/histiocyte-rich large B-cell lymphoma, primary mediastinal (thymic) large B-cell lymphoma, classic Hodgkin lymphoma, DLBCL with CD30 expression, and Epstein-Barr virus-positive DLBCL (not otherwise specified).

Because of a high degree of disease misclassification and treatment heterogeneity, prognostication of GZLs is very challenging, particularly in a prospective manner. At present, prognostic data have been sparse and limited to findings from retrospective studies alone. Results from one study indicated that higher expression of CD30 may be associated with worse progression-free survival, whereas the administration of frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was associated with superior progression-free survival. Other reports have shown benefits with higher-intensity chemotherapy regimens, such as etoposide, prednisolone, vincristine, cyclophosphamide, and hydroxydaunorubicin with rituximab (EPOCH-R).

To improve the diagnosis and classification of GZLs, as well as to provide optimal treatment for patients with this disease, further prospective studies are needed.

“A prospective randomized trial comparing R-CHOP with EPOCH-R will clarify the most appropriate regimen for GZL in the frontline setting,” the review authors concluded.


1. Parker K, Venkataraman G. Challenges in the diagnosis of gray zone lymphomas. Surg Pathol Clin. 2019;12(3):709-718. doi:10.1016/j.path.2019.03.014

2. Swerdlow SH, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th edition. Lyons (France): IARC press; 2008.

3. Swerdlow SH, Campo E, Harris NL, et al, editors. WHO classification of tumours of haematopoietic and lymphoid tissues (Revised 4th edition). Revised 4th edition. Lyons (France): IARC; 2017.

4. Evens AM, Kanakry JA, Sehn LH, et al. Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. Am J Hematol. 2015;90(9):778-783. doi:10.1002/ajh.24082