Ocular Lymphoma Research Articles

NCMP-19. SIDE EFFECTS FROM CHEMOTHERAPY VERSUS SYMPTOMS FROM COVID-19 INFECTION

INTRODUCTIONAdverse effects from chemotherapy such as high dose methotrexate (HD-MTX) are seen during and after chemotherapy. During this coronavirus disease 2019 (COVID-19) pandemic period, COVID-19 infection symptoms following chemotherapy due to immune compromise could mimic chemotherapy associated side effects. Differentiation on time is needed for correct management.CASE REPORTA 50-year old male with clinical history of ocular lymphoma underwent HD-MTX therapy. Before admission, his routine COVID-19 test was negative. After receiving HD-MTX, he developed fatigue, nausea and vomiting. The symptoms resolved before discharge. Next day after discharge, he developed diarrhea, fatigue, subjective fever and feeling cold. His temperature was normal. His symptoms have been persistent for 4-5 days and have resolved gradually and spontaneously. Family members have had no symptoms. The patient denies COVID-19 contact history. The above symptoms were considered adverse effects from chemotherapy. The patient did not seek medical attention. Prior to admission for next cycle of HD-MTX, COVID-19 test was found positive. Chemotherapy was on hold. The patient started home quarantine. The patient has been doing well and practiced COVID-19 infection precaution at home.DISCUSSIONThe fatigue, nausea and vomiting during HD-MTX treatment are adverse effects from chemotherapy while the diarrhea, fatigue, subjective fever and chills developed after discharge are symptoms of COVID-19 infection. Our case highlights the importance of keeping in mind and differentiating between side effects from chemotherapy and symptoms of COVID-19 viral infection in cancer patients who receive chemotherapy.

DIAGNOSING SARCOIDOSIS IN THE EYE OF THE STORM

SESSION TITLE: Fellows Diffuse Lung Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Sarcoidosis is a granulomatous disease that typically affects the lungs but can involve all organ systems to a different extent and degree. The diagnosis requires a step wise approach that includes identifying affected organs amenable for biopsy. Up to 30% of patients may present with extra-pulmonary manifestations of sarcoidosis and ocular involvement is seen in up to 25% of these cases. We discuss a case of difficult to diagnose sarcoidosis in a patient with difficult to control asthma that presented with choroidal lesions concerning for ocular lymphoma which prompted additional workup. CASE PRESENTATION: 68 year-old woman with past medical history of difficult-to-treat, severe asthma and obesity with mixed restrictive/obstructive pulmonary functions referred to our institution for a second opinion. She had a long history of asthma since early in childhood that became very difficult to control requiring multiple burst of steroids, use of biologics, and high dose inhaled steroids. She endorsed daily productive cough of white sputum and mild malaise. She denied any other respiratory symptoms. She had undergone an extensive work including serologies and two bronchoscopies with transbronchial and endobronchial biopsies. Chest CT revealed patchy, ill-defined bilateral tree-in-bud opacities without bronchiectasis. Routine exam by her ophthalmologist prompted referral to a regional oncologic ophthalmologist and she was given the presumptive diagnosis of choroidal lymphoma and recommended to undergo choroid biopsy. A PET scan was positive only in the tonsillar beds and biopsy revealed reactive lymphoid hyperplasia. After discussion with ophthalmology the differential diagnosis of choroidal lymphoma, it was decided to proceed to a cryobiopsy of the lung to exclude the possibility of sarcoidosis. She underwent a bronchoscopy and bronchioalveolar lavage revealed 69% lymphocytes with normal flow cytometry. Cryobiopsy revealed non-necrotizing granulomas in a lymphangitic distribution without interstitial inflammation or bronchiolitis. After excluding other causes of granulomatous diseases coupled with eye lesions, patient was diagnosed with systemic sarcoidosis. She was started on oral prednisone with improvement in her respiratory symptoms. DISCUSSION: Sarcoidosis can present with mixed obstructive and restrictive physiology and mimic or exacerbate asthma. It can also present with both anterior and posterior uveitis and is the presenting symptom in 5% of cases. Choroidal and retinal disease can exist without symptoms yet result in blindness. CONCLUSIONS: It is important to recognize this potential presentation of sarcoidosis to start prompt treatment and prevent late complications such as secondary glaucoma and impaired vision. Reference #1: Y. Jamilloux, L. Kodjikian, C. Broussolle, P. Sève. Sarcoidosis and uveitis. Autoimmun Rev. 2014 Aug;13(8):840-9. Epub 2014 Apr 3. Reference #2: B. Bodaghi, V. Touitou, C. Fardeau, C. Chapelon, P. LeHoang. Ocular sarcoidosis. Presse Med, 41 (6 Pt 2) (2012), pp. e349-e354 Reference #3: M. Drent, U. Costabel. European respiratory monograph 32: sarcoidosis. European Respiratory Society (2005) DISCLOSURES: No relevant relationships by Sarah Hackman, source=Web Response No relevant relationships by Jay Peters, source=Web Response No relevant relationships by Jorge Villalpando, source=Web Response

Unmasking of infectious retinitis and intraocular lymphoma in patients after uneventful dropless cataract surgery.

In this case series, 3 unique cases of severe immune-mediated pathologies (primary ocular lymphoma, toxoplasmosis chorioretinitis, and syphilitic retinitis) after dropless cataract surgery with intraocular steroid injection are reported. Patient immune status and subsequent local immunosuppression after dropless cataract surgery played roles in the worsening of these pathologies. This report demonstrates the need for vigilance when administering immunosuppressive agents locally during cataract surgery.

Involvement of Helicobacter Pylori in Ocular Adnexa Lymphoma.

Helicobacter pylori has been proposed as a possible etiologic factor of ocular adnexa lymphoma (OAL), although with conflicting results. To assess the involvement of H. pylori in OAL, as (1) H. pylori DNA positivity on OAL specimens, and (2) prevalence of H. pylori gastric infection in patients with OAL. A systematic review of studies assessing H. pylori in patients with OAL was conducted by searching electronic databases from their inception to May 2019. Pooled positivity for H. pylori in OAL specimens detected by polymerase chain reaction, and pooled prevalence of H. pylori gastric infection, were calculated with 95% confidence interval (CI). Eleven studies with 308 patients were included. Pooled positivity for H. pylori was 16.8% in all OALs and 22.7% in MALT OAL, with high heterogeneity among studies. Pooled prevalence of H. pylori gastric infection in patients with OAL was 34.7%, with low statistical heterogeneity.In conclusion, H. pylori seems to be involved in a subset of OAL, but the heterogeneity found needs to be investigated in further studies. The prevalence of H. pylori gastric infection in patients with OAL does not seem to differ from that of the general population.

Effects of radiation therapy on the meibomian glands and dry eye in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma

BackgroundRadiation therapy (RT) is the treatment of choice in patients with low-grade ocular adenexal mucosa-associated lymphoid tissue lymphoma (OAML) and many of them experience post-RT dry eye with varying severity. The purpose of the present study was to investigate ocular effects of RT on meibomian glands and dry eye by directly visualizing structural changes. Secondly, we focused on the comparison of two groups of patients according to tumor location and radiation technique.MethodsSixty-four eyes with OAML of conjunctiva, orbit, lacrimal gland, or lacrimal sac were grouped into conjunctival lymphoma and “orbital-type” lymphoma (i.e., orbit, lacrimal gland, and lacrimal sac). Subjects were investigated for morphological changes in meibomian glands by meiboscore grading system. Radiation technique was examined and Ocular Surface Disease Index (OSDI) questionnaire, Schirmer’s test, tear film break-up time (TBUT), slit lamp examination of corneal surface and lid margin abnormality were conducted before and after RT.ResultsThe increase in meiboscore was statistically significant over time after RT in both groups (P < 0.001). The extent of increase in meiboscore was significantly greater in the “orbital-type” lymphoma group than in the conjunctival lymphoma group (P < 0.001). The changes in OSDI, TBUT, corneal fluorescein staining score and lid margin abnormality score after RT were significantly different across two groups (P = 0.042, 0.001, 0.035 and 0.001, respectively). Schirmer’s value decreased after RT in both groups. Dry eye symptoms were most severe right after RT in both groups, but a gradual resolution was noted in most patients with conjunctival lymphoma, whereas symptoms persisted in “orbital-type” lymphoma patients. The OSDI score and corneal fluorescein staining score were positively correlated with meiboscore in “orbital-type” patients at post-RT 6 months (r = 0.43, P = 0.04; r = 0.39, P = 0.03, respectively).ConclusionsPatients with OAML had different degrees of morphological changes in meibomian glands according to tumor location and radiation technique. “Orbital-type” lymphoma patients are more likely to experience severe injury to meibomian glands, which eventually leads to persistent dry eye. Patients with “orbital-type” lymphoma should be well informed of post-RT damage on meibomian glands and persistent dry eye.

Epidemiology and clinical features of intraocular lymphoma in Singapore.

Intraocular lymphoma is rare. There are very few studies on intraocular lymphoma published from Asian countries. To report our case series of intraocular lymphoma patients from a tertiary eye centre in Singapore. Nine patients with intraocular lymphoma managed between January 2005 and December 2014 were identified from Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) database. Demographic characteristics, clinical presentation, investigations performed and outcomes recorded. There were almost equal distribution between males (four patients) and females (five patients) with mean age of presentation was 60.3 years. Five patients had bilateral involvement and vitreo-retina was the most common site of infiltration. All of our patients had central nervous system involvement although four of them had presented with ocular manifestations initially. Anterior chamber fluid cytology, as a less invasive alternative to vitreous analysis was proven to be useful. The time from ocular presentation to diagnosis of ocular lymphoma was variable; from one day to 18 months. Mortality in our study group was 55% with death occurring 1 month to 8 years from diagnosis of intraocular lymphoma. Intraocular lymphoma is a masquerade syndrome that mimics chronicuveitis and poses a diagnostic challenge. The diagnosis is often delayed and despite the eventual diagnosis, the disease prognosis is poor even with aggressive treatment.

ML-11 DETECTION OF MYD88 MUTATIONS FROM CELL FREE DNA AIDS IN THE DIAGNOSIS OF CENTRAL NERVOUS SYSTEM LYMPHOMAS

BACKGROUNDDiagnosis of primary central nervous system lymphomas (PCNSL) can be challenging. We have shown that the detection of MYD88 mutation in cell free DNA (cfDNA) taken from cerebrospinal fluid (CSF) is reliable (JCO Precision Oncology, 2019; Leukemia and Lymphoma, 2019). We report four cases in which detection of MYD88 mutation aided in the diagnosis.CASE 1A 67-year-old man with a history of systemic B-cell lymphoma, experienced right hemiparesis. MRI showed a slightly enhancing lesion located in the midbrain. MYD88 L265P mutation was found by digital droplet PCR analysis of cfDNA extracted from CSF. The patient underwent a needle biopsy, and was diagnosed as diffuse large B-cell lymphoma.CASE 2A 32-year-old man was diagnosed as having a demyelinating lesion after experiencing severe headaches. A small enhancing lesion was found in the right frontal lobe, and the patient was treated with steroids. The lesions repeatedly disappeared and reappeared and finally, stopped responding to steroids. MYD88 mutation was detected. A biopsy was performed, and the diagnosis was PCNSL.CASE 3A 49-year-old man underwent a biopsy for a right frontal lesion after experiencing memory loss; the pathology showed broad T-cell infiltration but only some perivascular B-cells with slight atypia. The patient was tapered off steroids, and the lesion spread rapidly. An open biopsy was performed, but the pathology was not typical for B-cell lymphoma. The patient’s symptoms rapidly worsened, and whole brain irradiation was performed. At recurrence, MYD88 mutation was detected.CASE 4An 82-year-old man presented with blurred vision. Vitreous humor biopsy was inconclusive for ocular lymphoma. A head MRI showed an intracranial lesion which spontaneously regressed. MYD88 was detected, and the patient is being closely observed.CONCLUSIONDetection of MYD88 mutation from cfDNA extracted from CSF can aid in the diagnosis of CNS lymphoma, especially in atypical cases.

Primary Vitreous and retinal lymphoma (PVRL): Risk factor and prognosis

AbstractPrimary Vitreous and retinal lymphoma (PVRL): risk factor and prognosis Pr cassoux PVRL also called primary intra ocular lymphoma (PIOL) is a subset of primary cerebral lymphoma. This lymphoma is part of a heterogeneous group of non‐Hodgkin lymphoma poorly understood and widely incurable. The vast majority of patients are affected by central nervous system diffuse large B cell lymphoma (DLBCL. During the past three decades, there have been consistent reports of an increase in the incidence of NHL worldwide. In the United States, the age‐adjusted incidence rate has almost doubled since the 1970s, from 11.07 per 100 000 in 1975 to 20.20 per 100 000 in 2008 for NHL The etiology of NHL is poorly understood, with the only established risk factors being infection and immune dysregulation. In immunosuppressed patients PVRL is generally associated with EBV infection which is not the case in their immunocompetent counterpart. There is no proofs of the role of environment and exposition to chemical agents had an influence on DLBCL incidence (Interlymph data). Prognosis of PVRL is functional and linked to local progression with a risk of blindness. The poor survival is due to the risk of CNS involvement during evolution. Between 60% and 85% of patients with initially isolated PVRL will develop CNS localization within 29 months of diagnosis PVRL. Until recently, primary central nervous system lymphoma (PCNSL) was associated with a uniformly dismal prognosis. It is now reasonable to anticipate long‐term survival and possibly cure for a significant proportion of patients diagnosed with PCNSL. Poor prognosis is linked to age, performance status and associated comorbidities. A significant number of patients get prolonged survival with intensive chemotherapy plus consolidation.

Prevalence of Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia trachomatis Determined by Molecular Testing in Ocular Adnexa Lymphoma Specimens.

To assess the prevalence of Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia trachomatis in ocular adnexa lymphoma (OAL) determined by molecular testing in different countries and the potential association of Chlamydia infection with mucosa-associated lymphoid tissue (MALT) histotype by performing a systematic review and meta-analysis. Electronic databases were searched for studies assessing the presence of Chlamydia in OAL. Pooled prevalence of the three Chlamydia species was calculated in each country. An odds ratio was calculated for the association between Chlamydia and MALT histotype, with a significant P < .05. Thirty-seven studies with 1,188 OALs were included. Pooled prevalence of C psittaci, C pneumoniae, and C trachomatis by country was done. Chlamydia infection was significantly associated with MALT histotype (odds ratio, 2.183; P = .027). The involvement of C psittaci in OAL is highly variable, with the highest prevalence in Italy and Korea. Chlamydia is associated with MALT histotype.

Primary Ocular Lymphoma: A SEER Database Analysis of Patterns of Involvement and Outcomes

BACKGROUND: Malignant lymphomatous involvement of the eye and its surrounding structures is a rare phenomenon. Due to the unique location, non-specific symptomatology, limitations for invasive procedures, physician experience, and significant effect on the quality of life related to vision, it poses many challenges in the diagnosis and management. Ocular involvement can be primary or secondary in lymphoma. Primary ocular lymphoma, based on its clinical and pathological characteristics, has been divided into 2 main groups: those involving the orbit and adnexal tissues including lacrimal gland, conjunctiva and cornea and, those affecting intra-ocular structures mainly vitreous and retina. We aim to evaluate the SEER database to assess patterns and outcomes in patients with primary ocular involvement with lymphoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients (≥18 years) diagnosed with primary ocular lymphomas between 1975 and 2016. B-cell and T-cell lymphomas with stage I disease and primary site labeled as ocular (orbital, retina, conjunctiva, cornea, choroid, ciliary, lacrimal gland) were included. Treatment effect (surgery, radiation, systemic therapy) was analyzed when available.Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the Log-Rank test. Cox proportional hazards models were used for adjusted survival analyses. RESULTS: We identified 3610 patients with primary lymphoma of the eye and adnexa. The median age was 66 years (18-103). 70% of the patients were Caucasians, followed by Hispanic (10%). Slight female preponderance was noted (55%). Most common site of involvement was orbit (n = 2063; 57%) followed by conjunctiva (n = 986; 27.3%). 8% (n = 292) of the patients were noted to have bilateral involvement. MALT (n = 2208; 61.2%) was the most common histology followed by DLBCL (n = 576; 16%) and follicular lymphoma (n = 519; 14.4%). Other histologies were rare (see Table 1). Most common treatment modality was radiation (n = 2117; 58.6%). Systemic therapy was utilized in only about 25% of the patients. Radiation treatment was associated with improved survival HR = 0.44 (0.23-0.83 95%CI, p = 0.01). Interestingly, patients that received systemic therapy had worse survival in univariate analysis (p&lt;0.05) but was not significant in multivariate analysis. Site-specific survival suggested conjunctiva had the best median OS (19 years [16.3 - 21.7 95% CI]), followed by orbital and lacrimal gland involvement (median OS 12 years [10.92-13.23 95% CI]) - Figure 1. Retina (median OS 1.9 years) and choroid/ ciliary body (median OS 6.3 years) involvement were associated with shorter survival (p&lt;0.05). DISCUSSION: Ocular lymphoma is a rare occurrence. Overall MALT was the most common subtype followed by DLBCL and FL. Very few instances of Burkitt's lymphoma, T-cell, and CLL were identified. Site-specific data in our subset, albeit with low numbers, suggest worse survival in the ciliary body and choroid similar to what is seen within vitreoretinal involvement. Due to small numbers in our subset, this requires confirmation in a larger dataset to identify potential change in management similar to primary vitreoretinal lymphoma, which is now recognized and managed as primary CNS lymphoma. Patients receiving systemic therapy showed a trend towards worse survival, which may be explained by a selection bias for more aggressive disease. Our study highlights the small but relevant prevalence of primary ocular lymphomas and reports the interesting observation of different survival patterns based on the site of involvement. Disclosures Yazbeck: Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Clinical analysis of ocular adnexal mucosa-associated lymphoid tissue lymphoma

Objective To analyse the features of ocular adnexal mucosa-associated lymphoid tissue(MALT) lymphoma. Methods The clinical and imaging data, histopathological feature of 52 patients with ocular adnexal MALT lymphoma from Jul.2010 to Jul.2015 were retrospectively analyzed. Results There were 24 males and 28 females in the total patients. The age ranged 37-80 years, with a mean of (57.1±11.2) years. The course of disease was 1 month-10 years. Clinical manifestations included eyelid swelling in 35 cases, conjunctival mass in 5 cases, exophthalmos in 15 cases, and epiphora in 1 case. There were 9 cases of diffuse growth and 43 cases of localized growth. There were 10 cases located in the superior-medial quadrant, 7 cases in the inferior-medial quadrant, 23 cases in the upper part of the orbit and 3 cases in the inferior-lateral quadrant. Orbital structures was involved by lymphoma, lacrimal gland in 12 cases, conjunctiva in 5 cases, lacrimal sac in 1 case and extraocular muscle in 1 case. Conclusion The clinical manifestations of ocular adnexal MALT lymphoma are various.Ocular adnexal MALT lymphoma show characteristic imaging manifestations that can improve preoperative diagnosis. Individualized treatment should be adopted based on tumor staging. Key words: Adnexa, ocular; Lymphoma, mucosa-associated lymphoid tissue(MALT); Clinical; Pathology; Imaging

Clinical and histopathological classification of feline intraocular lymphoma.

This retrospective study aimed to describe and classify cats with intraocular lymphoma, determine the proportion of cases with presumed solitary ocular lymphoma (PSOL) compared with ocular manifestations of multicentric disease and assess the clinical outcomes of these patients. One hundred seventy-two cases identified through biopsy submissions were reviewed histologically; 163 of these cases were subtyped according to the WHO classification system. Cases were categorized as having PSOL or ocular lymphoma with suspected systemic involvement (SSI) based on submission forms and follow-up data. The majority of cases exhibited concurrent uveitis (75%) and secondary glaucoma (58%). Diffuse large B-cell lymphoma was the most common subtype (n=86; 53%), followed by peripheral T-cell lymphoma (n=44; 27%). Other subtypes included anaplastic large T- (n=8; 5%) and B-cell (n=4; 2.5%) lymphomas, and 15 cases (9%) were negative for all immunohistochemical markers. In sixty-nine cases (40%), adequate clinical data and sufficient survival data were obtained to distinguish PSOL from SSI. PSOL comprised the majority of cases (64%), while 36% had SSI. When covarying for age at diagnosis, the median survival time was significantly higher (P=0.003) for cases of PSOL (154days) versus those with SSI (69days); hazards ratio of 0.47 for PSOL (95% CI: 0.241-0.937). The subtype of lymphoma did not affect survival time. Cats with PSOL represent a greater proportion of the disease population, and this subset of cats with intraocular lymphoma has a better clinical outcome.

Ocular natural killer/T cell lymphoma: a clinicopathologic analysis

Objective: To evaluate the clinicopathological features of ocular natural killer(NK)/T cell lymphoma. Methods: Data of 21 patients (22 eyes) with ocular NK/T cell lymphoma treated at Eye & ENT Hospital of Fudan University from January 2006 to March 2018 were retrospectively analyzed for clinical data, morphology, immunophenotype and outcomes. Results: There were 10 males and 11 females with ages from 3 to 77 years (mean, 43 years). There were 20 unilateral cases (10 left eyes and 10 right eyes) and 1 bilateral case. Except for 1 case of corneal perforation resulting from the involvement of the conjunctiva and cornea, the other cases all involved the orbit (including eyelids and conjunctiva) as demonstrated by radiologic studies, with the lacrimal sac involved in 3 cases, and the nasal cavity or maxillary sinus involved in 2 cases. Three patients had been previously diagnosed sinonasal NK/T cell lymphoma with radiotherapy and chemotherapy. Two patients had a history of ovarian NK/T cell lymphoma with chemotherapy. One patient had multiple ulcers of skin and mucosa at presentation. There were 13 primary ocular NK/T cell lymphomas without evidence of nasal or systemic involvement. All patients presented with eyelid swelling and decreased visual acuity. There were proptosis in 18 cases, motility restriction in 13 cases, eyelid ulceration in 3 cases, and fever in 4 cases. They had all been previously diagnosed as orbital pseudotumor or cellulitis and there was no response to steroids and antibiotics. Pathological examination showed atypical lymphoid infiltration with an angioinvasive growth pattern causing coagulative necrosis. Cytologically, the medium-sized neoplastic cells showed irregular folded nuclei. The neoplastic cells were positive for cytoplasmic CD3ε, CD56, and cytotoxic molecules and Epstein-Barr virus-encoded RNA (EBER) in situ hybridization. Seven patients were lost to follow-up. Ten patients died 2.0 to 17.0 months after diagnosis (mean, 6.3 months) despite treatment with chemotherapy and radiotherapy. Conclusions: Ocular NK/T cell lymphoma is a rare form of ocular lymphoma. There are primary NK/T cell lymphoma and secondary ocular NK/T cell lymphoma with nasal or systemic involvement. The rarity of this tumor and inflammatory signs make it challenging to identify these tumors early. The neoplastic cells are positive for cytoplasmic CD3ε, CD56, cytotoxic molecules and EBER in situ hybridization. Despite aggressive therapy, it demonstrates high lethality with poor prognosis. (Chin J Ophthalmol, 2019, 55: 374-380).

Ocular Adnexa MALT Lymphoma in a 77-year-old Female Controlled by Surgical Resection Alone: A Case Report

Ocular Adnexa MALT Lymphoma in a 77-year-old Female Controlled by Surgical Resection Alone: A Case Report

Genetic Landscape of Ocular Adnexa Extranodal Marginal Zone Lymphoma

Background: Ocular adnexa lymphomas (OAL) consist of a heterogeneous group of tumors that can arise in the lacrimal gland, orbit, conjunctiva and eyelid. More than 95% of these lymphomas are of B-cell origin and extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue is the most common subtype of OAL, accounting for 55-85% of the cases. Ocular adnexa extranodal marginal zone lymphoma (OA-EMZL) patients have a persistent risk of relapses and in 4% of the cases, the disease transforms into an aggressive lymphoma. A comprehensive list of all somatic nonsilent mutations remains currently unknown thus hampering the complete understanding of the disease and the development of new diagnostic and therapeutic approaches. Previous studies analyzed only a small number of OA-EMZL patients using gene targeted sequencing. In this study we utilized whole-exome sequencing to define the genetic landscape of 69 cases of OA-EMZL. Our data provide an unbiased identification of genetically altered genes and pathways that may play a role in the molecular pathogenesis of OA-EMZL.Methods: GATK HaplotypeCaller was used for joint variant calling on all samples, while MuTect was used to detect somatic variants in seven tumor samples with available paired normal germline DNA. We focused on variants that were exonic, not synonymous, and deleterious (CADD score > 10), while excluding any variants found with a frequency > 1% in control populations. For copy number (CN) analysis we used EXCAVATOR on each sequenced exome in pooled mode against the seven paired normal samples. The output was provided to GISTIC 2.0 to determine recurrent arm-level and gene-level CN changes.Results: We identified 125 candidate cancer driver genes with the following characteristics: 1) have genomic alteration in more than 5% of the cases, 2) are present in the list of COSMIC and DLBCL driver genes, 3) are considered essential genes or tumor suppressor genes as previously defined in a functional CRISPR screen (Reddy et al., Cell 2017). Among the most frequent alterations there were mutations and CN losses of CABIN1 (32%), inactivation of TNFAIP3 (26%) and KMT2D (22%), mutations and CN changes in CARD11 (25%), RHOA (25%), CREBBP (20%) and TBL1XR1 (23%). Gene set enrichment analysis of candidate driver genes showed statistically significant enrichment for genes involved in cell junction, adhesion, cytoskeleton regulation, chromatin organization and for genes harboring at least one highly conserved NFAT binding motif TGGAAA in their promoter. In addition, we identified recurrent lesions affecting several genes belonging to the NFkB, NOTCH and B cell receptor (BCR) signaling pathways. The most frequent alterations in the NFkB pathway included inactivation of TNFAIP3 (26%), mutations and CN alterations of CARD11 (25%), MYD88 (12%), BCL10 (10%) and CRD10 (9%). Mutations affecting NOTCH signaling were found in NOTCH3 (22%), DTX1 (12%), MAML1 (12%), MAML2 (12%), DLK1 (10%) and SPEN (9%). BCR signaling genes alterations were observed in PIK3R2 (12%), VAV1 (10%), PTPN6 (7%) and BTK (4%).CABIN1 was one of the most commonly altered genes. In T cells, CABIN1 is implicated in inhibiting calcineurin-mediated signal transduction, including NFAT activation. In reactive lymph node and tonsil tissue, CABIN1 was expressed in reactive B cells (CD20+ and CD3-) localized mainly in the mantel zone area, as demonstrated by IHC and IF. We hypothesized that it may act as a negative regulator of BCR signaling in MZL. To verify this possibility we used shRNAs to knock down CABIN1 in MZL cell lines and measured NFAT activity in response to IgM stimulation using a luciferase reporter system. IgM stimulation of CABIN1-depleted MZL cells induced a more pronounced activation of NFAT signaling compared to wild-type cells.Conclusions: The genetics of OA-EMZL is characterized by somatic alterations in NFkB, NOTCH, and BCR signaling pathways. Candidate cancer driver genes are implicated in chromatin organization, cytoskeleton regulation and in adhesion, and they are also enriched for NFAT target genes. One of the most altered candidate cancer driver genes was CABIN1, which is a calcineurin inhibitor that acts as a negative regulator of NFAT activity. CABIN1 depletion in MZL cells boosts BCR-stimulated NFAT activity. Our data suggest a widespread dysregulation of NFAT signaling cascade downstream of BCR stimulation as a possible mechanism of OA-EMZL pathogenesis. DisclosuresLossos:Affimed: Research Funding.

Oda A, Messenger KM, Carbajal L, et al. Pharmacokinetics and pharmacodynamic effects in koi carp (Cyprinus carpio) following immersion in propofol. Vet Anaesth Analg 45:529-538, 2018.

This report describes post-traumatic ocular lymphoma in 3 companion rabbits; 2 rabbits with unilateral disease and 1 with bilateral disease. Historical findings suggestive of a traumatic event included either external unilateral ocular trauma or bilateral phacoemulsification. Severe corneal changes, presence of an anterior chamber mass(es), low intraocular pressures, and ocular discomfort were noted on ophthalmic examinations. All eyes were treated for variable courses with standard ophthalmic topical medications (antibiotic, anti-inflammatories, and steroid) and systemic anti-inflammatories. Based upon progression of disease, all affected eyes were ultimately enucleated; lenticular capsular rupture and a round cell neoplasm effacing normal structures with variable mitotic indices were noted on histopathology. Neoplastic lymphocytes strongly expressed CD79a via immunohistochemistry and lacked expression for CD3, indicating B lymphocyte lineage and not of T cell lineage. A single animal had evidence of local metastasis to a regional lymph node. Post-traumatic sarcomas have been reported in this species previously, however, these cases are the first reports of this novel round cell variant, named post-traumatic ocular lymphoma due to the B cell lineage confirmed through immunohistochemistry. Clinicians should be aware of this clinical presentation and the possibility of metastasis when evaluating ocular pathology in this species.

High Frequency of MYD88 L265P Mutation in Primary Ocular Adnexal Marginal Zone Lymphoma and Its Clinicopathologic Correlation: A Study From a Single Institution

The pathogenesis of primary ocular adnexal marginal zone lymphoma (POAMZL) remains unclear. The reported associations with Chlamydia psittaci infection and MYD88 mutations are highly variable. To examine MYD88 L265P mutation in ocular marginal zone lymphomas and correlate with clinicopathologic features and Chlamydia infection. Presence of MYD88 L265P mutation and Chlamydia infection in lymphoma was analyzed by using sensitive polymerase chain reaction (PCR) methods. The MYD88 L265P mutation was identified in 8 of 22 POAMZLs (36%), including 2 of 3 cases in which PCR failed to detect clonal IGH gene rearrangement; none of the 4 secondary marginal zone lymphomas were positive. Test results for Chlamydia were negative in all cases. Patients with and without the MYD88 mutation had similar clinicopathologic features. The MYD88 mutational analysis provides important information in diagnostic workup of POAMZL. The frequent MYD88 mutation suggests a critical role of this aberration in the pathogenesis of POAMZL and may serve as a therapeutic target for patients with progressive disease.

Intraocular involvement is associated with a high risk of disease relapse in primary central nervous system lymphoma

The aim of the present study was to prospectively evaluate the recurrence and survival outcome of primary central nervous system lymphoma (PCNSL) with intraocular involvement. For this purpose, a prospective cohort of 103 pathologically confirmed patients with PCNSL was enrolled in this study. Ophthalmologic examinations were performed both at diagnosis and during follow‑up. The patients with PCNSL with suspected intraocular involvement underwent vitrectomy for confirmation. Patients who presented with intraocular involvement either at diagnosis or during disease progression were allocated to the intraocular lymphoma (IOL) group. All patients with PCNSL received systemic methotrexate (MTX)‑based chemotherapy with or without radiotherapy. MTX intravitreal injection combined with systemic MTX‑based chemotherapy was recommended once ocular lesions were confirmed. Recurrent intraocular and central nervous system (CNS) events, progression‑free survival (PFS) and overall survival (OS) outcomes were analyzed. The findings of this study revealed that 21patients with PCNSL exhibited intraocular involvement. One patient with IOL presented with isolated ocular lymphoma at the initial diagnosis, and the others presented with ocular involvement along with CNS invasion during the course of the disease. A total of 14patients received systemic MTX‑based chemotherapy prior to the diagnosis of IOL. The recurrence rates in patients with or without intraocular involvement were 71.4 and 46.3%, respectively (P=0.04) and the relapse sites in the patients with IOL included the brain (3patients), eyes (6patients), and both brain and eyes (6 cases). The median PFS was 13months in the IOL group and 19months in the patients without intraocular involvement (non‑IOL) (P=0.019). The median OS was 51months vs. 56months, respectively (P=0.312). There was no significant difference in the 2‑year PFS and OS rates between the 2groups (23.8% vs. 23.2%, P=0.951; and 61.9% vs. 41.4%, P=0.093, respectively). On the whole, the findings of this study suggest that patients with IOL have a high risk of relapse and a poor PFS compared to patients without IOL, but a similar OS.

Correction: The mutational landscape of ocular marginal zone lymphoma identifies frequent alterations in TNFAIP3 followed by mutations in TBL1XR1 and CREBBP.

[This corrects the article DOI: 10.18632/oncotarget.14928.].

Ocular non-Hodgkin lymphoma: a report of two cases and review of the literature

In this article, two cases of non-Hodgkin lymphomas (NHL) occurring at an unusual site were reported. The first case was a male patient aged 60 years hailing from Debidwar, Comilla came with the complaint of gradually increasing mass in the left eyelid for two years. Fine-needle aspiration (FNA) and histopathology of his lesion revealed NHL, which on immunohistochemistry showed to be of B-cell origin. A debulking operation was done in National Institute of Ophthalmology &amp; Hospital, Dhaka and he was sent for chemotherapy. The second case was also a male aged 35 years from Muladi, Barisal who presented with gradually increasing bilateral masses on both the upper eyelids for six months. The results of FNA of the eyelid tumors were suggestive of NHL that was subsequently confirmed by histopathology. Immunohistochemistry showed the tumor to be of B-cell origin.Mediscope Vol. 5, No. 2: Jul 2018, Page 36-41