Lymphoma of the Lacrimal Gland - An International Multicenter Retrospective Study.

PURPOSE: To characterize the clinical features of subtype-specific lacrimal gland lymphoma and their effect on patient survival. DESIGN: Multicenter retrospective interventional case series. METHODS: Patient data were collected from 6 international eye cancer centers from January 1, 1980, through December 31, 2017. All patients with histologically verified primary or secondary lymphoma of the lacrimal gland were included. Primary endpoints were overall survival (OS) and disease-specific survival (DSS). RESULTS: A total of 260 patients with lacrimal gland lymphoma were identified. The median age was 58 years and 52% of patients were men. Non-Hodgkin B-cell lymphomas constituted 99% (n = 258) and T-cell lymphomas constituted 1% (n = 2). The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n = 177, 68%), follicular lymphoma (FL) (n = 26, 10%), diffuse large B-cell lymphoma (DLBCL) (n = 25, 10%), and mantle cell lymphoma (MCL) (n = 17, 7%). Low-grade lymphomas (EMZL and FL) were most commonly treated with external beam radiotherapy (EBRT), whereas high-grade lymphomas (DLBCL and MCL) were treated with chemotherapy in combination with rituximab and/or EBRT. The prognosis was relatively good with a 5-year OS and DSS of 73.8% and 87.5%, respectively. Lymphoma subtype was a statistically significant predictor for DSS, with EMZL (5-year DSS: 93.4%) having the best prognosis and DLBCL (5-year DSS: 52.6%) having the poorest. CONCLUSIONS: This is the largest reported collection of data of subtype-specific lacrimal gland lymphoma. The subtype distribution of lacrimal gland lymphoma resembles that of the ocular adnexa. Prognosis is good and the histologic subtype is a significant predictor for disease-specific survival.

Clinicopathological Features of Ocular Adnexal Mantle-Cell Lymphoma in an International Multicenter Cohort.

Importance: To our knowledge, the clinical features of ocular adnexal mantle-cell lymphoma (OA-MCL) have not previously been evaluated in a large multicenter cohort. Objective: To characterize the clinical features of OA-MCL. Design, Setting, and Participants: This retrospective multicenter study included patient data collected from January 1, 1980, through December 31, 2015, at 6 eye cancer centers in 4 countries. Medical records of 55 patients with OA-MCL were reviewed; the median length of follow-up was 33 months. Main Outcomes and Measures: Overall survival, disease-specific survival, and progression-free survival were the primary end points. Results: Fifty-five patients were included; ocular adnexal MCL was found to be most common in older individuals (mean age, 70 years) and men (n = 42 of 55; 76%). Patients with OA-MCL frequently presented with disseminated lymphoma (n = 34 of 55; 62%), and were likely to experience stage IVE disease (n = 35 of 55; 64%), with bilateral involvement (n = 27 of 55; 47%), tumor masses (n = 27 of 36; 75%), and involvement of the orbit (n = 32 of 55; 58%). Chemotherapy with or without external beam radiation therapy was the most frequently used treatment. Overall survival rates for the entire cohort were 65% at 3 years (95% CI, 52%-78%) and 34% at 5 years (95% CI, 21%-47%). Disease-specific survival after 5 years was 38% for the entire cohort (95% CI, 25%-51%); the disease-specific survival adjusted by eye cancer center was better in patients who had received rituximab in addition to the chemotherapy regimen (hazard ratio, 3.3; 95% CI, 1.0-14.7; P = .06). The median progression-free survival was 2.3 years (95% CI, 1.8-2.7 years) in patients who experienced recurrence after primary treatment, and 4.1 years (95% CI, 3.9-4.3 years) in patients who presented with a relapse of systemic lymphoma in the ocular adnexal region. Conclusions and Relevance: These results suggest that the distinctive features of OA-MCL are its appearance in older male individuals, advanced stage and bilateral manifestation at the time of diagnosis, and aggressive course. The prognosis of patients with OA-MCL might be improved by addition of rituximab to chemotherapy treatment.

TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy.

Primary central nervous system lymphoma (PCNSL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) confined to the CNS. TP53 mutations (MUT-TP53) were investigated in the context of MIR34A/B/C- and DAPK promoter methylation status, and associated with clinical outcomes in PCNSL patients. In a total of 107 PCNSL patients clinical data were recorded, histopathology reassessed, and genetic and epigenetic aberrations of the p53-miR34-DAPK network studied. TP53 mutational status (exon 5-8), with structural classification of single nucleotide variations according to the IARC-TP53-Database, methylation status of MIR34A/B/C and DAPK, and p53-protein expression were assessed. The 57/107 (53.2 %) patients that were treated with combination chemotherapy +/- rituximab (CCT-treated) had a significantly better median overall survival (OS) (31.3 months) than patients treated with other regimens (high-dose methotrexate/whole brain radiation therapy, 6.0 months, or no therapy, 0.83 months), P < 0.0001. TP53 mutations were identified in 32/86 (37.2 %), among which 12 patients had hotspot/direct DNA contact mutations. CCT-treated patients with PCNSL harboring a hotspot/direct DNA contact MUT-TP53 (n = 9) had a significantly worse OS and progression free survival (PFS) compared to patients with non-hotspot/non-direct DNA contact MUT-TP53 or wild-type TP53 (median PFS 4.6 versus 18.2 or 45.7 months), P = 0.041 and P = 0.00076, respectively. Multivariate Cox regression analysis confirmed that hotspot/direct DNA contact MUT-TP53 was predictive of poor outcome in CCT-treated PCNSL patients, P = 0.012 and P = 0.008; HR: 1.86 and 1.95, for OS and PFS, respectively. MIR34A, MIR34B/C, and DAPK promoter methylation were detected in 53/93 (57.0 %), 80/84 (95.2 %), and 70/75 (93.3 %) of the PCNSL patients with no influence on survival. Combined MUT-TP53 and MIR34A methylation was associated with poor PFS (median 6.4 versus 38.0 months), P = 0.0070. This study suggests that disruption of the p53-pathway by MUT-TP53in hotspot/direct DNA contact codons is predictive of outcome in CCT-treated PCNSL patients, and concomitant MUT-TP53 and MIR34A methylation are associated with poor PFS.

Conjunctival Lymphoma--An International Multicenter Retrospective Study.

IMPORTANCE: To date, the clinical features of the various subtypes of conjunctival lymphoma (CL) have not been previously evaluated in a large cohort. OBJECTIVE: To characterize subtype-specific clinical features of CL and their effect on patient outcome. DESIGN, SETTING, AND PARTICIPANTS: A retrospective multicenter study was performed. Patient data were collected from January 1, 1980, through December 31, 2010. The dates of the analysis were May 15, 2015, to August 20, 2015. The median follow-up period was 43 months. Seven eye cancer centers were involved in the study. In total, 268 patients with CL were identified, 5 of whom were excluded because of missing clinical data. MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific survival, and progression-free survival were the primary end points. RESULTS: Two hundred sixty-three patients with CL were included in the study. Their mean age was 61.3 years, and 55.1% (145 of 263) were female. All lymphomas were of B-cell type. The most frequent subtype was extranodal marginal zone lymphoma (EMZL) (68.4% [180 of 263]), followed by follicular lymphoma (FL) (16.3% [43 of 263]), mantle cell lymphoma (MCL) (6.8% [18 of 263]), and diffuse large B-cell lymphoma (DLBCL) (4.6% [12 of 263). Conjunctival lymphoma commonly manifested in elderly individuals (age range, 60-70 years old), with EMZL having a female predilection (57.8% [104 of 180]) and MCL having a marked male predominance (77.8% [14 of 18]). Unlike EMZL and FL, DLBCL and MCL were frequently secondary diseases (41.7% [5 of 12] and 88.9% [16 of 18], respectively), with MCL showing a frequent occurrence of stage IVE lymphoma (61.1% [11 of 18]) and bilateral manifestation (77.8% [14 of 18]). Localized disease (stage IE or IIE) was commonly treated with external beam radiation therapy (EBRT) with or without chemotherapy, while widespread lymphoma (stage IIIE or IVE) and MCL of any stage were managed with chemotherapy with or without EBRT. Diffuse large B-cell lymphoma and MCL had a poor prognosis, with 5-year disease-specific survival of 55.0% and 9.0%, respectively, in contrast to EMZL (97.0%) and FL (82.0%). Further survival predictors included age (EMZL), sex (FL), and Ann Arbor staging classification (EMZL and FL). The American Joint Committee on Cancer TNM staging showed limited prognostic usefulness, only being able to predict survival for patients with DLBCL. CONCLUSIONS AND RELEVANCE: Conjunctival lymphoma consists of mainly 4 subtypes of B-cell non-Hodgkin lymphoma: EMZL, FL, MCL, and DLBCL. Mantle cell lymphoma is characterized by a particularly high frequency of secondary disease of stage IVE and bilateral manifestation. The histological subtype is the main outcome predictor, with MCL and DLBCL having a markedly poorer prognosis than EMZL and FL.

Differential expression of miR-155 and miR-21 in tumor and stroma cells in diffuse large B-cell lymphoma.

OncomiRs miR-21 and miR-155 have been linked to lymphomagenesis, but information on their implication in diffuse large B-cell lymphoma (DLBCL) is limited. Here, we used locked nucleic acid-based in situ hybridization (ISH) detection techniques on formalin-fixed paraffin-embedded DLBCL tissue samples to identify miR-155 and miR-21 at the cellular level in 56 patients diagnosed with DLBCL, and compared them to miR array data. miR-155 was observed in tumor cells in 19/56 (33.9%) of the samples evaluated by ISH. miR-21 was localized to the stromal compartment in 41/56 (73.2%). A subset of these, 16/56 (28.6%), also showed labeling in tumor cells. When comparing ISH-scores and miR array data, miR-155 in tumor cells, identified by ISH, was associated with miR-155 expression in miR array data (P=0.030). Equally, miR-21 expression by miR array data were highly associated with miR-21 ISH-scores in the stromal cells (P=0.002), whereas no association between miR array data and ISH of miR-21 in tumor cells was observed (P=0.673). We found no association of miR-155 and miR-21 with overall survival or germinal center B-cell-like (GCB) versus non-GCB-like subtypes of DLBCL. In conclusion, miR-ISH added to the biological interpretation of miR expression in DLBCL compared with miR array data, but miR-155 and miR-21 ISH did not add prognostic information in this series.

Follicular lymphoma of the ocular adnexal region: a nation-based study.

PURPOSE: To characterize the clinicopathological features of follicular lymphoma of the ocular adnexal region. METHODS: Retrospective nation-based study of Danish patients with ocular adnexal follicular lymphoma from January 1st 1980 through December 31st 2009. RESULTS: Twenty-four patients with ocular adnexal follicular lymphoma were identified. Fourteen (58%) of the patients were females. The median age was 63 years (range: 42-96 years). Eleven (46%) of the patients had primary ocular adnexal lymphoma, seven (29%) had an ocular adnexal lesion in conjunction with a concurrent systemic lymphoma and six patients (25%) presented with an ocular adnexal relapse. The most frequently affected sites were the lacrimal gland (38%) and the orbit (33%). Thirteen patients (54%) presented with Ann Arbor stage IE lymphoma, four (17%) had stage IIE, two patients (8%) stage IIIE, and five patients (21%) had stage IV lymphoma. Radiotherapy was primarily used in patients with primary lymphoma and those with a stage IE/IIE relapse (82%), while stage IIIE/IV lymphomas most frequently received alkylating chemotherapy (67%). Complete remission was observed in 19 of the patients (79%), but of these 11(58%) had a relapse. The 10-year overall survival for the entire cohort was 59%. The translocation t(14;18) was detected in 16 patients (16/24, 76%). Recurrence was only observed in patients with the t(14;18) (p=0.05, log-rank). CONCLUSIONS: Ocular adnexal follicular lymphoma is more commonly found in elderly female patients. The lacrimal gland is relatively frequently involved. Radiotherapy is the treatment of choice for localized ocular adnexal follicular lymphoma providing a favourable prognosis for majority of patients.

Ocular adnexal diffuse large B-cell lymphoma: a multicenter international study.

IMPORTANCE: The clinical features of diffuse large B-cell lymphoma (DLBCL) subtype of ocular adnexal lymphoma have not previously been evaluated in a large cohort to our knowledge. OBJECTIVE: To investigate the clinical features of ocular adnexal DLBCL (OA-DLBCL). DESIGN, SETTING, AND PARTICIPANTS: This retrospective international cooperative study involved 6 eye cancer centers. During 30 years, 106 patients with OA-DLBCL were identified, and 6 were excluded from the study. The median follow-up period was 52 months. MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific survival (DSS), and progression-free survival were the primary end points. RESULTS: One hundred patients with OA-DLBCL were included in the study (median age, 70 years), of whom 54 (54.0%) were female. The following 3 groups of patients with lymphoma could be identified: primary OA-DLBCL (57.0%), OA-DLBCL and concurrent systemic lymphoma (29.0%), and ocular adnexal lymphoma relapse of previous systemic lymphoma (14.0%). Of 57 patients with primary OA-DLBCL, 53 (93.0%) had Ann Arbor stage IE disease, and 4 (7.0%) had Ann Arbor stage IIE disease. According to the TNM staging system, 43 of 57 (75.4%) had T2 tumors. Among all patients, the most frequent treatments were external beam radiation therapy with or without surgery (31.0%) and rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone (CHOP) or rituximab-CHOP-like chemotherapy with or without external beam radiation therapy (21.0%). The 5-year overall survival among the entire cohort was 36.0% (median, 3.5 years; 95% CI, 2.5-4.5 years). Relapse occurred in 43.9% (25 of 57) of patients with primary OA-DLBCL. Increasing T category of the TNM staging system was predictive of DSS (P = .04) in primary OA-DLBCL, whereas the Ann Arbor staging system was not. However, when taking all 100 patients into account, Ann Arbor stage was able to predict DSS (P = .01). Women had a longer median DSS than men (9.8 years; 95% CI, 1.9-17.7 years vs 3.3 years; 95% CI, 1.6-5.0; P = .03). CONCLUSIONS AND RELEVANCE: Most patients with primary OA-DLBCL were seen with Ann Arbor stage IE and TNM T2 disease. The 5-year overall survival was between 2.5 and 4.5 years, which is the 95% CI around the median of 3.5 years in this cohort. Increasing T category appears to be associated with decreased DSS among patients with primary OA-DLBCL. When taking all patients into account, sex and Ann Arbor stage also seem to be DSS predictors.

Ocular adnexal follicular lymphoma: a multicenter international study.

IMPORTANCE: The clinical features of the follicular subtype of ocular adnexal lymphoma (OAL) have not been previously evaluated in a large cohort. OBJECTIVE: To characterize the clinical features of follicular OAL. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective multicenter study that involved 6 eye cancer centers from January 1, 1980, through December 31, 2010. A total of 105 patients with follicular OAL were identified, of which 7 patients were excluded because of missing clinical data. The median follow-up time was 52 months (range, 13-118 months). MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific, and progression-free survivals were the primary end points. RESULTS: Ninety-eight eligible patients with follicular OAL were included; 60 (61%) were women. The median patient age was 63 years (range, 32-96 years). Sixty-nine patients (70%) had primary OAL, 19 (19%) had OAL in conjunction with a concurrent systemic lymphoma, and 10 (10%) presented with an ocular adnexal relapse. The lacrimal gland (28%), conjunctiva (28%), and orbit (28%) were the most frequently involved sites. Of the 69 patients with primary follicular lymphoma, 38 (55%) presented with Ann Arbor stage IE lymphoma, and 31 (45%) had stage IIE lymphoma. Patients with disseminated lymphoma had stage IIIE (9 of 19 [47%]) and stage IV (10 of 19 [53%]) disease, whereas patients with a relapse of systemic lymphoma presented with stage IE (8 of 10 [80%]), stage IIE (1 of 10 [10%]), and stage IIIE (1 of 10 [10%]) disease. Patients with primary follicular lymphoma (n = 69) and those with isolated ocular relapse (n = 9) were treated with external beam radiation therapy (EBRT) (35 of 78 [45%]) or EBRT plus chemotherapy (22 of 78 [28%]). Patients presenting with stage IIIE-IV follicular lymphoma (n = 20) most frequently received chemotherapy (9 of 20 [45%]) or EBRT plus chemotherapy (4 of 20 [20%]). The 10-year overall survival for the entire study cohort was 60%. Primary patients treated with EBRT had a better disease-specific survival compared with patients receiving ERBT plus chemotherapy (10-year disease-specific survival, 94% vs 40%; P = .02 by log-rank test). CONCLUSIONS AND RELEVANCE: Follicular OAL was more commonly found in elderly female patients. These tumors were equally noted to involve the conjunctiva, lacrimal gland, and orbit. Patients with ocular adnexal follicular lymphoma primarily treated with EBRT had a more favorable long-term disease-specific survival.

Diffuse large B-cell lymphoma of the ocular adnexal region: a nation-based study.

PURPOSE: To characterize the clinicopathological features of diffuse large B-cell lymphoma (DLBCL) of the ocular adnexal region. METHODS: The present series of orbital and adnexal DLBCLs were found by searching the Danish Registry of Pathology between 1980 and 2009. Histological specimens were re-evaluated using a panel of monoclonal antibodies. Clinical files from all patients with confirmed DLBCL were collected. RESULTS: A total of 34 patients with DLBCL of the ocular adnexal region were identified. Eighteen of the patients were men. The patients had a median age of 78 years (range 35-97 years). Ninety-seven per cent of the patients had unilateral ocular adnexal region involvement, and the orbit (76%) was the most frequently affected site. Nineteen patients (56%) presented with Stage I lymphoma. Of these, 18 were diagnosed with primary lymphoma. Four patients (12%) had Stage II, one patient (3%) had Stage III and ten patients (29%) presented with Stage IV lymphoma. The 5-year overall survival (OS) rate for the whole study group was 20%. The patients with Stage I lymphoma had a significantly better 5-year OS rate (28%) than patients in Stage II-IV (5-year OS rate, 9%). In Cox regression analysis, concordant bone marrow involvement and the International Prognostic Index (IPI) score were prognostic factors for OS. CONCLUSIONS: Diffuse large B-cell lymphoma of the ocular adnexal region is mainly prevalent in elderly patients. Most patients had unilateral orbital involvement. The overall prognosis is poor. Concordant bone marrow involvement and the IPI score were independent prognostic factors for mortality.

Malignant lymphoma of the lacrimal gland: a nation-based study.

OBJECTIVE: To characterize the clinicopathologic features of lacrimal gland lymphoma. METHODS: All cases of lacrimal gland lymphoma from January 1, 1975, through December 31, 2009, were retrieved from The Danish Registry of Pathology. Histologic specimens were reevaluated using a panel of monoclonal antibodies. Clinical files from all patients with confirmed lymphoma were collected. RESULTS: Twenty-seven patients with lacrimal gland lymphoma were identified. Eight of the patients were men and 19 were women; the median (range) age was 69 (43-87) years. The distribution of lymphoma subtypes was as follows: extranodal marginal zone lymphoma, 10 (37%); follicular lymphoma, 5 (19%); diffuse large B-cell lymphoma, 4 (15%); mantle cell lymphoma, 3 (11%); chronic lymphocytic leukemia/small lymphatic lymphoma, 2 (7%); and unclassified B-cell lymphoma, 3 (11%). Twenty-two patients (81%) had stage I or II lymphoma, 1 patient (4%) had stage III lymphoma, and 4 patients (15%) had stage IV lymphoma. Patients with stage I or II lymphoma were treated with radiotherapy (15 [67%]), chemotherapy (3 [14%]), chemotherapy plus radiotherapy (1 [5%]), and surgery (3 [14%]). Patients presenting with stage III or IV lymphoma were treated with chemotherapy alone. Complete remission was observed in 23 of the patients (85%), although 12 (44%) of these had a relapse, independent of subtype, stage, or treatment. The 5-year overall survival was 70%. CONCLUSIONS: Malignant lymphoma of the lacrimal gland is relatively rare and is mostly prevalent in elderly women. The distribution of lacrimal gland lymphoma subtypes resembles that of lymphoma subtypes of the salivary glands. The majority of lacrimal gland lymphomas are low grade, and the prognosis is relatively good.

Extranodal marginal zone lymphoma in the ocular region: clinical, immunophenotypical, and cytogenetical characteristics.

PURPOSE: To evaluate clinical, immunophenotypical, and cytogenetical characteristics of 116 patients with a diagnosis of extranodal marginal zone lymphoma (EMZL) presenting primarily in the ocular region. METHODS: Specimens from all patients with a diagnosis of ophthalmic lymphoma in Denmark during the period 1980 to 2005 were reviewed and reclassified according to the World Health Organization (WHO) classification. Cases reclassified as EMZL were selected and reviewed with respect to clinical characteristics and outcome. The presence of translocations involving IGH and/or MALT1 was investigated in 42 specimens by fluorescence in situ hybridization (FISH). RESULTS: Median age was 69 years. Most lymphomas were located in the orbit. Approximately one fourth of the patients had disseminated disease at presentation. One third experienced a relapse or progression of disease after initial therapy, and relapses were frequently found at extraocular sites. Five-year progression-free survival and overall survival (OS) rates were 71% and 75%, respectively. Translocations involving the IGH- or MALT1-gene loci were detected in 2 (5%) of 42 specimens. In Cox regression multivariate analysis, IGH-translocation was the only factor associated with PFS, whereas a favorable International Prognostic Index (IPI) score was the most reliable predictor of OS. CONCLUSIONS: EMZL presenting in the ocular region usually runs an indolent course, but relapses are frequently seen. The IPI-score was the most reliable independent parameter for estimating risk of death in our cohort of patients. Furthermore, we found that the frequency of translocations involving the MALT1- and IGH-gene loci is low in ocular region EMZL.

Increasing incidence of ophthalmic lymphoma in Denmark from 1980 to 2005.

PURPOSE: To evaluate patient characteristics and incidence of ophthalmic lymphoma in Denmark during the period 1980 to 2005. METHODS: All patients in Denmark with a diagnosis of ophthalmic lymphoma during the period 1980 to 2005 were retrieved from three different population-based registries. Specimens from all patients were collected and reclassified according to the World Health Organization (WHO) classification system. Incidence rates were calculated by using Poisson regression models. RESULTS: A total of 228 patients with a histologically verified diagnosis of ophthalmic lymphoma were included. There was an equal distribution of males and females. The most frequent lymphoma subtype was extranodal marginal zone B-cell lymphoma (MALT [mucosa-associated lymphoid tissue] lymphoma, 55.5%) and most cases were located in the orbit (56.8%). High-grade lymphoma subtypes were found more frequently in males than in females. Incidence rates were highly dependent on the patient's age. For all ages, a statistically significant annual average increase of 3.4% during the 26-year period was found. This increase was primarily due to a rise in the incidence of MALT lymphoma. CONCLUSIONS: In the Danish population ophthalmic lymphoma consists primarily of orbital MALT lymphoma. Although it is a rare disease in mostly elderly patients, the incidence of ophthalmic lymphoma is increasing at a rapid pace.