This case represents an unusual presentation of infectious mononucleosis with immunophenotypic findings suggestive of in-situ follicular lymphoma. This observation has not, to our knowledge, been previously reported in the English-language medical literature. In 2002 Jaffe et al.  described 25 patients with lymphadenopathy having abnormal BCL-2 overexpression in follicle centers, associated with fairly preserved tissue architecture and residual reactive germinal centers. The term in-situ follicular lymphoma (FLIS) was coined to describe such lesions, and was subsequently incorporated into the World Health Organization classification of hematopoietic neoplasms. A recent study showed that FLIS typically occurs in the 5th or 6th decade of life, with only rare cases reported in patients under 40 years of age. The follicular lymphoma associated t(14;18)(IGH;BCL2) translocation is routinely demonstrated in the vast majority of the abnormal follicles. Patients with FLIS were originally reported as having a very low risk for developing overt follicular lymphoma . Others have suggested that FLIS indicates a possible increased risk of several forms of lymphoid neoplasia, though many patients remain free of malignancy after an extensive follow-up and staging [3, 4]. The diagnosis of FLIS is typically an incidental finding, where lymph nodes are biopsied secondary to reactive follicular hyperplasia or, sometimes, other pathology. To date, very little attention has been paid to potential pathologic mimics of FLIS, although some have shown that FLIS can be seen in association with progressive transformation of germinal centers [5, 6].
Epstein-Barr virus (EBV) is a human herpesvirus with an overall seroprevalence of >90% in all adults. It is thought that in early infection, EBV-infected cells undergo large-scale expansion within the germinal centers. However, the total number of EBV-positive cells even in the acute phase of the disease is low, as previously shown in germinal centers of tonsils from patients with infectious mononucleosis. The EBV infected cells show expression of BCL-6 and CD10, common germinal center markers with variable staining for LMP-1, LMP-2 and EBNA-1, which are EBV latent proteins. EBV also induces upregulation and overexpression of BCL-2 among the B-cells, findings commonly observed in latent EBV infection but also in carcinomas which are EBV positve and EBV+ large B-cell lymphomas [7, 8]. In addition, in experimental cell lines transfected with EBV, LMP-1 was capable of NF-κβ activation leading to BCL-2 over-expression.
The EBV virus has a main pathogenic role in the development of lymphoid and non-lymphoid malignancies [9, 10]. Several studies have shown its association with specific entities such as post-transplant lymphoproliferative disorders of both B and T-cell lineage. Additionally, EBV has a main role in the development of certain B-cell lymphomas, such as endemic Burkitt's lymphoma, certain types of classical Hodgkin lymphoma, EBV-positive diffuse large B-cell lymphoma (DLCBL) of the elderly, DLBCL associated with chronic inflammation and lymphomatoid granulomatosis (among others). It is also related to T/NK malignancies which include aggressive NK cell leukemia, EBV-positive T-cell lymphoproliferative disorders of childhood, extranodal NK/T-cell lymphoma and angioimmunoblastic T-cell lymphomas .
The diagnosis of FLIS is most frequently made in patients who are 50–60 years of age, and older than the reported case. In addition, the serologic findings were confirmatory for the diagnosis of infectious mononucleosis. Even though the immunophenotypic findings were suggestive of FLIS, the absence of a t(14;18) rearrangement, and the presence of EBER and LMP-1 expression were also helpful to exclude FLIS. Some authors have also suggested that the pattern of intensity for CD10 (usually stronger in FLIS) can help distinguish FLIS from other mimickers . In our case, the CD10 intensity was similar in both the BCL-2 coexpressing and non-coexpressing follicles. Further, the patient developed no subsequent lymphadenopathy and had complete resolution of his symptoms. Our case also shows direct immunopathogenic evidence of BCL-2 expression among the EBV-infected cells, which has to our knowledge not been previously documented in vivo. A diagnosis of EBV infection should, therefore, be considered when confronted with BCL-2 expression in germinal centers, particularly in younger individuals, as the diagnosis of FLIS may lead to extensive and invasive haematologic work-ups.
Written informed consent was obtained from the patient for publication of this case report and any accompanying image.