Testicular follicular lymphoma: let me count the ways

In this issue of Blood Advances, Zhang et al¹ have performed genomic profiling on 8 cases of primary testicular follicular lymphoma (T-FL), with the goal of comparing this lesion to other types of follicular lymphoma (FL). They provide data that clearly place T-FL as a form of follicle center lymphoma, and they provide evidence that warrant its designation as a specific entity.

Interestingly, both phenotypically and genotypically, T-FL is similar to other extranodal forms of FL, in particular primary cutaneous follicle center lymphoma (PCFCL),² and similar lesions involving the vagina and uterine cervix.³ 

The most common genomic aberration in T-FL involved mutation or deletion of TNFRSF14, seen in 57% of cases and a frequent event in primary cutaneous and other extranodal FL.^2,4 Mutations of epigenetic regulators EZH2 and KMT2D were also seen but were less common. FL, in general, is the prototype of a B-cell lymphoma (BCL) with strong dependence on its specialized tumor microenvironment (TME). Extranodal t(14;18)-negative FLs have in common frequent alterations in TNFRSF14, a critical regulator of germinal center B-cell activation, and of immune recognition and modulation.⁵ Accordingly, inactivation of TNFRSF14 has been shown to re-educate the TME, increasing the number of CD4⁺ T follicular helper cells supporting lymphoma cell survival and promoting immune evasion through the exclusion of cytotoxic CD8⁺ T cells. The distinct molecular differences between t(14;18)-negative and t(14:18)-positive FL might contribute to the different clinical presentation (localized vs systemic) and excellent prognosis. These lesions also share a common phenotype, and are positive for BCL6, with weak to negative expression for CD10, and negative expression of BCL2. Interestingly, although the proliferative rate may be high with Ki-67/MIB-1, the clinical behavior is benign. Likewise, PCFCL may show localized satellite lesions, but distant spread beyond the primary site is rare.⁶ 

T-FL is a rare form of FL seen mainly in the pediatric age group, so a major question has been whether it is related to pediatric-type FL (PTFL), a nodal form of FL seen mainly in young males.⁷ Histologically, it shows significant differences with PTFL, typically containing both large centrocytes and centroblasts in well-formed but compact small follicles, rather than the large serpiginous follicles of PTFL, which typically contain a predominance of blastoid cells. Differences also exist in the expression of CD10, which is generally weak to negative in T-FL but strongly positive in PTFL. Although both diseases show frequent TNFRSF14 gene alterations, often associated with IRF8 mutations⁸; significantly, T-FL lacks the most common and characteristic genomic alteration in PTFL, which is mutation of MAP2K1 and other MAPK-pathway genes.^9,10 Thus, the data clearly support separation of T-FL from PTFL (see figure).

This study also adds valuable data for the clinical management of T-FL. Most studies have suggested that orchiectomy is curative in the majority, if not all, patients. Of 6 patients with follow-up data, 5 are alive with no evidence of disease (NED) after orchiectomy alone. Interestingly, 1 patient had a recurrence in the contralateral epididymis, managed locally with surgery and radiation, and remains with NED. Genomic studies indicated a different genomic profile in the “recurrence,” suggesting that it might represent a second primary. The authors do not provide data on comparison of the clonal immunoglobulin gene rearrangements seen in the 2 lesions, so conclusive evidence regarding their clonal identity is lacking. The authors speculate regarding “divergent clonal evolution,” but that hypothesis would require further sequencing and evidence of a common clonal connection in the 2 lesions.

In conclusion, this study provides further evidence supporting the recognition of T-FL as a discrete entity different from PTFL, expanding the family of FL disease entities. T-FL, PTFL, and large BCL with IRF4 rearrangement comprise a group of follicle center cell–derived lymphomas presenting mainly in children and young adults that are biologically and clinically well-defined lymphoma subtypes different from the adult counterpart, both in terms of disease pathogenesis and patient management. Further studies are needed to understand the role of TNFRSF14 alterations in the pathogenesis of the disease.

Conflict-of-interest disclosure: The authors declare no competing financial interests.