眼附属器淋巴瘤：亚型特异性临床和遗传特征

Ocular adnexal lymphoma is a relatively rare disease but is one of the most common malignancies in the ocular adnexa, and its incidence is steadily increasing. Ocular adnexal lymphoma consists mainly of four histopathological subtypes of non-Hodgkin B-cell lymphoma: extranodal marginal zone lymphoma (EMZL), follicular lymphoma (FL), mantle cell lymphoma (MCL) and large B-cell lymphoma (LBCL). The clinical characteristics associated with each of the subtypes are not well known due to the sparsity of cases.

Furthermore, a number of molecular and phenotypic features have been identified as recurrent and prognosticating in LBCL but are not yet well documented for the ocular adnexal region: concurrent MYC and BCL2 and/or BCL6 rearrangements, MYC/BCL2 double-expressor phenotype (in diffuse large B-cell lymphomas), and MYD88 and CD79B mutations.

Therefore, the present PhD study aimed to investigate the clinical features of (1) conjunctival lymphoma by subtype and (2) ocular adnexal MCL in an international multicentre cohort of 307 patients and (3) the clinical and genetic features of ocular adnexal LBCL in 34 Danish patients. This was performed by collecting clinical data on the patients and tissue samples of the LBCLs. The tissue samples were analysed immunohistochemically for phenotype, by allele-specific PCR and Sanger sequencing for the presence of the mutations, and by fluorescence in situ hybridisation for the rearrangements. Statistical analyses were performed to detect correlations with clinical features and survival. The analyses revealed that conjunctival EMZL and FL typically presented in individuals in their 60s as localised unilateral tumour masses and had favourable prognoses (5-year disease-specific survival: 82%-97%).

LBCL and MCL were found in all the ocular adnexal structures, with the orbit being the most common location (82% and 58%, respectively). These lymphomas typically presented in patients in their 70s, with MCL having a male predominance. MCLs commonly presented with bilateral lesions and systemic involvement, while LBCLs were unilateral localised tumours. Both subtypes had poor prognoses, with 49%-62% of patients having succumbed to the disease within 5 years.

Ocular adnexal LBCLs had presence of concurrent MYC and BCL2 and/or BCL6 rearrangements in 16% of cases, MYC/BCL2 double-expressor phenotype in 44% of diffuse large B-cell lymphomas, and MYD88 CD79B mutations in 29% of cases. MYC/BCL2 double-expressor phenotype and MYD88 mutations were associated with adverse prognoses. All in all, the results indicate that the histopathological subtype of ocular adnexal lymphoma is a major outcome predictor.

Furthermore, the results underline the importance of analysing the expression of MYC and BCL2 by immunohistochemistry in diffuse large B-cell lymphoma patients and advocate for incorporating the analysis of MYD88 mutations in the routine diagnostic workup of ocular adnexal LBCL. SUMMARY IN DANISH: Lymfomer i jenregionen (orbita, conjunctiva, jenl g, t rekirtel og t resaek) er relativt sjaeldne tumorer, men er blandt de hyppigste cancerformer i denne region og forekomsten er hastigt stigende. Lymfomer i jenregionen best r hovedsageligt af 4 undertyper af non-Hodgkin B-celle lymfom: ekstranodalt marginal zone lymfom, follikulaert lymfom, storcellet B-celle lymfom og mantle celle lymfom.

Grundet sygdommens sjaeldenhed er kliniske karakteristika ved de forskellige lymfomundertyper kun sparsomt unders gt. Endvidere er der blevet identificeret en raekke prognostisk vigtige molekylaere og faenotypiske kendetegn ved storcellede B-celle lymfomer, som endnu ikke er velunders gt i jenregionen.

Det drejer sig om samtidig rearrangement i MYC og BCL2 og/eller BCL6, samtidig overekspression af MYC og BCL2 samt MYD88 og CD79B mutationer. Dette ph. d. -studie havde derfor til form l at unders ge de kliniske kendetegn ved (1) mantle celle lymfomer i jenregionen og (2) de forskellige undertyper af conjunktivale lymfomer i en interna