Look into my eyes, please

In this issue of Blood, Bonzheim et al have reported the diagnostic value of the assessment of MYD88 L265P (MYD88) mutations in vitreoretinal lymphoma.¹  In general terms, the diagnosis of lymphoma classically requires standard histopathologic, immunophenotypical, genetic, and molecular criteria that are combined to a variable extent to define individual clinicopathologic entities recognized by World Health Organization classification. These gold standard requisites may not be fulfilled in some rare particular instances, resulting in diagnostic difficulties. One challenging example of this latter occurrence is represented by vitreoretinal diffuse large B-cell lymphoma. The identification of vitreoretinal diffuse large B-cell lymphoma is crucial for 2 main reasons. First, this type of lymphoma is particularly aggressive and must be distinguished from low-grade marginal-zone B-cell lymphomas of the choroid, and second, vitreoretinal diffuse large B-cell lymphoma could represent the intraocular dissemination of a concomitant diffuse large B-cell lymphoma of the central nervous system (PCNSL). PCNSL is another and more frequent type of aggressive B-cell lymphoma that needs to be promptly recognized and treated.

Easy morphologic diagnosis is not the rule in vitreoretinal diffuse large B-cell lymphoma; in fact, the evaluable material is usually obtained by vitreous body aspirate, and this implies that cytologic instead of histologic assessment is often performed in routine practice. Moreover, the diagnosis is further hampered by the low number of cells, the poor conservative status of these free-floating elements in the vitreous, and the prevalent admixture of non-neoplastic components, including smaller lymphocytes. Clearly enough, the most difficult differential diagnosis arises with uveitis and infections. Useful diagnostic tools mainly used in systemic lymphomas, such as flow cytometry and molecular biology, have a limited value in vitreoretinal diffuse large B-cell lymphoma. This is mainly a result of the overall limited amount of material in the case of flow cytometry and the risk of detecting pseudoclonal/oligoclonal B-cell populations by polymerase chain reaction owing to the few cells occurring in the vitreous. Importantly, this latter occurrence may be encountered also in benign/reactive conditions, thus increasing the difficulty in diagnosing vitreoretinal diffuse large B-cell lymphoma. A significant achievement has been reached with the demonstration that increased IL-10 levels are associated with vitreoretinal diffuse large B-cell lymphoma,²  but not all diagnostic laboratories are equipped to measure these levels.

On these grounds, Bonzheim et al introduce a new strategy able to improve the diagnostic accuracy of vitreoretinal diffuse large B-cell lymphoma, through the detection of MYD88 mutations in vitreous aspirates of patients suspected of having vitreoretinal diffuse large B-cell lymphoma. Some cases interpreted as reactive with currently available techniques were reclassified as neoplastic on the basis of the presence of MYD88 mutations and, most importantly, their malignant nature was confirmed by clinical follow-up. Although comparative studies on the diagnostic accuracy between IL-10 levels and MYD88 mutations deserve to be tested in a prospective study, the strategy of the detection of MYD88 mutations is particularly attractive. In fact, it should be taken into account that these molecular assessments are usually already in use within well-equipped diagnostic hematopathology laboratories, because they are equally useful for the recognition of some lymphoproliferative disorders such as lymphoplasmacytic lymphomas often associated with Waldenström macroglobulinemia and diffuse large B-cell neoplasms of activated B-cell-like type, mostly represented by testicular lymphomas, PCNSL, and “leg-type” entities of the skin.³  Therefore, no additional technical efforts would be required to better diagnose vitreoretinal diffuse large B-cell lymphoma.

The results herein provided have further implications. In fact, 65% to 90% of patients with vitreoretinal diffuse large B-cell lymphoma eventually progress to PCNSL,²  and thus it appears critical to assess lymphomatous involvement of the vitreous to properly treat these patients. Another critical feature is that this concept could be extended also to vitreoretinal involvement by systemic or extranodal lymphomas, as confirmed by the experience of Bonzheim et al,¹  who reported the intraocular dissemination by 2 cases of primary testicular lymphomas without a concomitant PCNSL. Because one of these patients developed mutated MYD88 vitreoretinal diffuse large B-cell lymphoma 10 years after the diagnosis of a testicular lymphoma carrying the identical mutation, these results show that this molecular approach also deserves to be tested as a powerful method to detect late relapses and assess the prognostic implications of the occurrence of MYD88 mutations in the vitreous of patients with testicular lymphomas.

Taken together, these issues point toward the need for prospective studies aimed at assessing the actual clinical impact of the detection of MYD88 mutations in primary and secondary vitreoretinal diffuse large B-cell lymphoma.