Vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1ɑ) in lacrimal gland Adenoid cystic carcinoma: Correlation with clinical outcome.

PURPOSE: VEGF and HIF-1α are important regulators of angiogenesis, overexpressed in various tumors. Lacrimal gland Adenoid cystic carcinoma (ACC) is a malignant tumor whose angiogenic properties remain unexplored. This study was designed to evaluate the expression of HIF-1α and VEGF in lacrimal gland ACC. METHODS: VEGF and HIF-1α immunoexpression was undertaken in 30 lacrimal gland ACC cases. mRNA expression of VEGF and HIF-1α was analysed in 17 cases by quantitative real time PCR. The results obtained were correlated with clinicopathological features and survival of the patients to determine the prognostic significance. RESULTS: Immunoexpression of HIF-1α and VEGF was seen in 36.6% and 46.6% ACC cases. HIF-1α expression showed significant association with advanced T-stage (P = 0.001) and VEGF with intracranial extension (P = 0.014) and solid histological pattern (P = 0.045). HIF-1α mRNA expression was seen in 29.4% cases and showed significant association with perineural invasion (P = 0.027). Recurrence occurred in 60%, distant metastasis in 20% and death in 20% cases. Survival analysis revealed that patients with HIF-1α, VEGF immunoexpression, solid histological pattern, perineural invasion, bone erosion, intracranial extension, metastasis, advanced T-stage, and exenteration had poor survival. On multivariate analysis VEGF immunoexpression (hazard ratio, 16.785; 95% confidence interval, 1.872-150.495; P = 0.012) was the most significant poor prognostic factor. CONCLUSIONS: This study demonstrates that VEGF is a potential predictor for poor clinical outcome in lacrimal gland Adenoid cystic carcinoma.

Prognostic impact of Notch1 receptor and clinicopathological High-Risk Predictors in lacrimal gland adenoid cystic carcinoma.

PURPOSE: Adenoid Cystic Carcinoma (ACC) is an aggressive malignant lacrimal gland tumour associated with poor prognosis. Aberrant Notch signalling has been investigated in various tumours. However, very few studies on Notch signalling in lacrimal gland ACC are reported. The aim of the present study was to evaluate the status of Notch1 receptor and activated Notch1 (NICD1) in lacrimal gland ACC and to correlate it with high-risk clinicopathological features. METHODS: A total of 23 cases of histopathologically proven lacrimal gland ACC, who underwent surgical treatment, were included in this study. Expression of Notch1 receptor and NICD1 was evaluated by immunohistochemistry on formalin fixed paraffin embedded tissues. The results obtained were correlated with clinicopathological high-risk features and survival of the patients. Kaplan-Meier survival and multivariate analysis was performed to determine the prognostic significance. RESULTS: Overexpression of Notch1 receptor and NICD1 was observed in 65% and 39% of lacrimal gland ACC cases, respectively. On Kaplan-Meier survival analysis, patients with Notch1 receptor overexpression had reduced disease free survival. On univariate analysis, male gender, bone erosion, perineural invasion, solid histologic pattern, intracranial extension and advanced tumour stage were also indicators of poor prognosis. On multivariate analysis bone erosion was the most significant poor prognostic indicator. CONCLUSION: Our study demonstrates that overexpression of Notch1 receptor plays a critical role in the biology and aggressive behaviour of lacrimal gland ACC. Bone erosion, solid histologic pattern, advanced T stage, perineural invasion and intracranial extension are other high-risk clinicopathological predictors of lacrimal gland ACC.

Prognostic factors for local recurrence and survival and impact of local treatments on survival in lacrimal gland carcinoma.

BACKGROUND/AIMS: To identify prognostic factors for local recurrence, distant metastasis and disease-specific survival (DSS) for lacrimal gland carcinoma. METHODS: All consecutive patients with lacrimal gland carcinoma treated from January 1998 through December 2018 were included. Log-rank tests and univariate Cox proportional hazards regression models were used to study risk factors and survival. RESULTS: Overall, 55 patients were included in this study, and 5 patients were excluded from the survival analysis. Median age was 46 years (range: 10-76). 43 patients (78%) had adenoid cystic carcinoma (ACC). 31 patients (56%) had T2 disease at presentation. 28 patients (51%) underwent orbital exenteration with or without adjuvant radiotherapy or chemoradiation, 26 (47%) underwent eye-sparing surgery with or without adjuvant radiotherapy or chemoradiation, and 1 received palliative chemoradiation. 11 patients (22%) experienced local recurrence; 14 (29%) experienced distant metastasis. Five- and 10-year local-recurrence-free survival rates were 0.71 (95% CI 0.58 to 0.88), and 5- and 10-year distant-metastasis-free survival rates were 0.67 (95% CI 0.53 to 0.85) and 0.49 (95% CI 0.30 to 0.81), respectively. There was no significant difference in risks of local recurrence, distant metastasis or DSS between ACC patients who had orbital exenteration and those who had eye-sparing surgery. Perineural invasion was negatively associated with local-recurrence-free survival (p=0.02). Among patients with ACC, basaloid/solid histologic type was associated with significantly worse DSS than non-basaloid/solid histologic type (p<0.01). CONCLUSIONS: For lacrimal gland carcinoma, orbital exenteration with adjuvant therapy and eye-sparing surgery with adjuvant therapy are associated with similar recurrence outcomes. Eye-sparing surgery is associated with better DSS. Perineural invasion is a risk factor for local recurrence. ACC with basaloid/solid subtype correlates with worse DSS.

Prognostic factors for relapse and survival among patients with ocular adnexal lymphoma: validation of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM classification.

BACKGROUND/AIMS: To validate the prognostic performance of the American Joint Committee on Cancer (AJCC) eighth edition classification for ocular adnexal lymphoma (OAL). METHODS: We performed a retrospective review of 140 consecutive patients treated for primary OAL between March 2010 and September 2017. Associations between T/N/M categories at presentation and disease-related outcomes, including relapse, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Seventy-nine women and 61 men (median age, 52 (range 20-84) years; median follow-up, 57 (range 7-131) months) were included. Histological subtypes included mucosa-associated lymphoid tissue lymphoma (92.1%, n=129), diffuse large B-cell lymphoma (5.0%, n=7), follicular lymphoma (1.4%, n=2) and mantle cell lymphoma (1.4%, n=2). Patients with ≥T2 disease had significantly higher risks of overall relapse (unadjusted HR)=4.32, p=0.016), decreased PFS (uHR=5.19, p=0.004) and decreased OS (uHR=9.21, p=0.047). Patients with ≥N1 disease had significantly higher risks of overall relapse (uHR=9.17, p<0.001) and decreased PFS (uHR=9.24, p<0.001). M1 disease was significantly associated with higher risks of overall relapse (uHR=3.62, p=0.036), decreased PFS (uHR=5.13, p=0.001) and decreased OS (uHR=9.24, p=0.013). On considering TNM categories as continuous data, the uHRs for per level increase in T, N and M categories were 1.77, 1.83 and 2.30 for overall relapse and 1.72, 1.87 and 2.78 for decreased PFS, respectively (p<0.05 for each comparison). CONCLUSION: The T, N and M categories of the AJCC eighth edition classification have prognostic value for relapse and survival among patients with primary OAL. Particularly, nodal/metastatic involvement at presentation indicated less favourable outcome.

Outcomes in patients with lacrimal gland carcinoma treated with definitive radiotherapy or eye-sparing surgery followed by adjuvant radiotherapy.

BACKGROUND: The optimal treatment for lacrimal gland cancer remains unclear. Eye-preserving surgery, as opposed to exenteration, followed by adjuvant radiotherapy (RT), has recently been reported to deliver satisfactory outcomes, but evidence is sparse. The aim of the present study was to evaluate outcomes in patients with lacrimal gland cancer treated at two tertiary medical centers. METHODS: We retrospectively examined data from patients with lacrimal gland cancer who had received eye-preserving surgical treatment followed by adjuvant RT with or without chemotherapy, or (if the tumor was inoperable) needle biopsy with definitive RT with or without chemotherapy. Baseline clinical and pathological characteristics were considered. Outcomes of interest included post-treatment complications, overall survival (OS), locoregional progression-free survival (LPFS), and distant metastasis-free survival (DMFS). RESULTS: Eighteen patients were included. Two-year OS, LPFS, and DMFS rates were 69.0, 76.7, and 71.4%, respectively. Patients with early-stage (T1-T2) lacrimal gland cancer had significantly better outcomes than those with advanced-stage disease (T3-T4). Two-year OS, LPFS, and DMFS rates were each 100% in patients with disease stages T1-T2, and 37.5, 50, and 37.5%, respectively, in those with disease stages T3-T4 (P < 0.05). Orbital complications were well tolerated. CONCLUSIONS: Eye-sparing surgery with adjuvant RT can achieve satisfactory results in patients with T1-T2 lacrimal gland carcinoma. Disease stage T3 and above was associated with poor outcomes even with post-operative RT, likely due to distant metastasis. Adding neoadjuvant chemotherapy or adjuvant chemotherapy to current treatment strategies might be a suitable choice for this group of patients.

Survival outcomes of eye-sparing surgery for adenoid cystic carcinoma of lacrimal gland.

PURPOSE: To survey adenoid cystic carcinoma of lacrimal glands in Asian population and investigate the predictability in prognosis following the 8th edition American Joint Committee on Cancer (AJCC) staging guideline. STUDY DESIGN: Retrospective study. METHODS: The clinical entities and surgical outcomes of the patients who were histologically confirmed with a diagnosis of lacrimal adenoid cystic carcinoma in National Taiwan University Hospital between January 1995 and December 2015 were retrospectively reviewed. RESULTS: Enrolled were 11 patients. The median follow-up was 7.2 years. Eight patients (72.7%) were diagnosed as T1 or T2 disease, and three patients (27.3%) were diagnosed as T3 or T4 disease according to the AJCC 8th edition guideline. Eye-sparing surgery with radiotherapy was performed in nine patients. Local recurrence was noted in six patients (54.5%) with median disease-free interval of 23.5 months. Six patients (54.5%) developed distant metastases, including lung, bone, and cranial invasions. Overall survival rate during the study period was 54.6%. Five-year overall survival was 81.8% and ten-year overall survival was 68.2%. The Log-rank test for overall survival and disease-free survival between patients with less than T3 disease (p=0.001) and patients with T3 or T4 disease (p=0.006) revealed significant differences. CONCLUSION: This study highlighted the aggressive nature of adenoid cystic carcinoma of lacrimal glands. Eye-sparing surgery with adjunctive radiotherapy may achieve relatively optimal disease control in diseases staged T1 or T2, but in advanced disease metastasis and mortality are usually inevitable.

Cranio-orbital Resection Does Not Appear to Improve Survival of Patients With Lacrimal Gland Carcinoma.

PURPOSE: To ascertain long-term outcome of treatment for primary epithelial malignancies of the lacrimal gland and compare outcomes after cranio-orbital resection or after macroscopic tumor resection with radiotherapy. METHODS: Comparative case series of 79 patients (49 male; 62%) treated for primary epithelial malignancies of the lacrimal gland at Moorfields Eye Hospital between 1972 and 2014. Patients were identified from clinical and pathological databases and, where available, the clinical, pathological, and imaging records reviewed. The primary outcome measures were overall survival after diagnosis, disease-free survival, and final visual acuity for patients having cranio-orbital resection (exenteration plus local bone removal), compared with macroscopic tumor resection plus radiotherapy. RESULTS: The mean age at presentation was 48 years (median: 50 years; range: 13-84 years), with 53 (67%) having adenoid cystic carcinoma, 15 (19%), primary adenocarcinoma, and 11 (14%) carcinoma ex-pleomorphic adenoma (malignant mixed tumor). The overall survival probability of the cohort (79 patients) was 0.59 at 5 years and 0.52 at 10 years, with 36/79 (46%) patients suffering tumor-related deaths; 14 patients died from other causes, and 4 patients were lost to follow up after the minimum follow-up period. The probability of disease-free survival at 5 years for patients with adenoid cystic carcinoma, adenocarcinoma, and malignant mixed tumor was 0.52, 0.4, and 0.64, respectively, with the comparable figures at 10 years being 0.44, 0.40, and 0.64. Most importantly, the 9 patients undergoing cranio-orbital resection and the 44 having solely macroscopic tumor resection plus radiotherapy had similar overall survival (p = 0.59) and disease-free survival (p = 0.89). Subgroup analysis of the 2 treatment modalities for patients with adenoid cystic carcinoma (8 cranio-orbital resection and 32 debulking and radiotherapy) demonstrated similar results for disease-free survival (p = 0.87). Likewise, there were no significant differences between rates of recurrences between the 2 different treatments. For the 50 patients who had eye-preserving surgery and long-term visual acuity data, the final acuity was better or equal to 0.6 logMAR (6/24 Snellen) in 25 (50%). DISCUSSION: There is no difference in either survival or tumor recurrence for lacrimal gland carcinoma treated with cranio-orbital resection, or eye-preserving tumor excision and radiotherapy. The authors, therefore, continue to advocate local resection and radiotherapy for almost all patients with primary epithelial malignancies of the lacrimal gland-this treatment having lower morbidity, causing less disfigurement, and, importantly, preserving useful vision in most patients.

Clinical analysis of 90 cases of malignant lacrimal sac tumor.

PURPOSE: To investigate the pathology, clinical manifestations, and potential risk factors associated with the prognosis of malignant lacrimal sac tumors. In addition, the treatment outcomes and complications were also evaluated. METHODS: Ninety cases of malignant lacrimal sac tumors were retrospectively analyzed at our hospital. Pathological classifications, clinical manifestations, risk factors, and follow-up time were documented. The outcomes and complications were evaluated and compared among the various treatment modalities. RESULTS: The median follow-up time was 50 months (range, 3-258 months). The 5-year overall survival (OS) and progression-free survival (PFS) for all cases were 85.7 and 77.9%, respectively. The 5-year OS and PFS for 69 cases of squamous cell carcinoma were 87.6 and 76.3%, and which were 80.4 and 72.4% for 21 cases of non-squamous cell carcinoma, respectively. There was no difference of 5-year OS and PFS between squamous cell carcinoma and non-squamous cell carcinoma (p = 0.350 and p = 0.946). Positive lymph node status was associated with worse OS (p < 0.001) and PFS (p = 0.020). For the 23.3% of cases (21/90) treated with the definitive radiotherapy, the outcomes were equivalent to that of surgery combined with radiotherapy, with the incidence of treatment-related visual acuity complication not being significant. The addition of chemotherapy to the treatment course had a marginal and non-significant improvement in OS and distant metastasis-free survival. CONCLUSIONS: Lymph node status was found to be a key factor for prognosis. Advanced tumors could benefit from multimodality treatment, with radiotherapy playing an important role. However, the role of chemotherapy requires further investigation.

Eye-Preserving Surgery Followed by Adjuvant Radiotherapy for Lacrimal Gland Carcinoma: Outcomes in 37 Patients.

PURPOSE: To describe the clinical outcomes of eye-preserving surgery followed by adjuvant radiotherapy in patients with lacrimal gland carcinoma. METHODS: Thirty-seven patients with lacrimal gland carcinoma who underwent eye-preserving surgery were studied. RESULTS: At last follow up, 32 patients were alive without disease, 3 patients were alive with disease with distant metastasis, 1 patient had died of disease, and 1 patient had died of other cause. The 5-year recurrence-free survival rate was worse in patients without than in patients with adjuvant radiotherapy (p = 0.001) and worse in patients with T3-T4 tumors than in patients with T1-T2 tumors (p = 0.027). At last follow up, 25 patients (68%) had visual acuity of 20/40 or better. CONCLUSIONS: In patients with lacrimal gland carcinoma, eye-preserving surgery and adjuvant radiotherapy is associated with reasonable local control rates and visual and ocular function. Postoperative adjuvant radiotherapy seems to enhance local control rates.

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.

Management of Lacrimal Gland Carcinoma: Lessons From the Literature in the Past 40 Years.

PURPOSE: To review the published literature on management strategies for lacrimal gland carcinomas. METHODS: Review of relevant articles in PubMed published in English from the year of 1970 through September 2014. RESULTS: A review of literature suggests that treatment strategies for adenoid cystic carcinoma of lacrimal gland are varied, but local control does not necessarily prevent future delayed distant relapse. Tumor size and histologic features of lacrimal gland carcinoma seem to be important prognostic features. With improved imaging modalities providing better tumor diagnosis and staging, and availability of more focused radiation delivery techniques, multimodality globe sparing management of lacrimal gland carcinomas may be possible in selected cases. The availability of targeted drugs based on the molecular signature of an individual lacrimal gland carcinoma may offer possible targeted treatments for patients with nonresectable or metastatic disease. CONCLUSION: Given the rarity of lacrimal gland carcinoma, multi-institutional studies and consistent reporting of size and histologic type of tumors in the literature may be prudent. Particularly, multimodality globe-sparing treatment strategies should be studied further.

Lesión linfoproliferativa del saco lagrimal: caso clínico / Lacrimal sac lymphoproliferative lesion: Case report

CASO CLÍNICO: Se presenta el caso de una mujer de 51 años con tumoración firme a nivel del canto interno del ojo derecho de 5 años de evolución. La biopsia excisional mediante dacriocistectomía estableció el diagnóstico de lesión linfoproliferativa de bajo grado (hiperplasia linfoide reactiva). DISCUSIÓN: Los tumores del saco lagrimal son muy raros, con un pico de incidencia en la quinta década de la vida. La clínica en fases iniciales es parecida a la obstrucción lagrimal por otras causas, de ahí que hasta un 40% de estos tumores no se sospechen y sean diagnosticados durante la realización de una dacriocistorrinostomía

CASE REPORT: The case is presented of a 51 year-old woman with a firm mass at the medial canthus of the right eye of five years onset. A low-grade lymphoproliferative lesion (reactive lymphoid hyperplasia) was diagnosed from an excisional biopsy. DISCUSSION: Lacrimal sac tumors are rare, with a peak incidence in the fifth decade of life. The initial clinical features are epiphora and medial canthus swelling. As it mimics nasolacrimal duct obstruction, up to 40% of these tumors are misdiagnosed until undergoing surgery

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.

Neutron radiotherapy for adenoid cystic carcinoma of the lacrimal gland.

PURPOSE: Lacrimal gland adenoid cystic carcinomas are rare, aggressive orbital tumors that share histopathologic similarities with salivary gland malignancies. Neutron radiotherapy may be useful for treatment due to its high biological effectiveness for salivary malignancies. METHODS: The authors retrospectively reviewed the outcomes for 11 lacrimal gland adenoid cystic carcinoma patients treated with neutrons from 1988 to 2011. Most had undergone surgery prior to radiation therapy. However, gross residual disease was present in 8 patients. The most common American Joint Committee on Cancer stage was T4cN0M0. Four patients with skull base involvement received a radiosurgery boost and 1 received a proton therapy boost. RESULTS: Median follow up was 6.2 years. Median overall survival was 11.1 years and median disease-free survival was 6.3 years. Five-year local control was estimated by the Kaplan-Meier method as 80%. Three patients had a local recurrence; 4 developed distant metastases. Six patients died. Seven patients had intact vision in the affected eye before neutron radiation. Two required enucleation for a painful dry eye. Of the 5 who avoided an enucleation, 3 had either severe visual impairment (20/400) or only light perception and 2 were without known vision compromise or complications at the time of their death. One patient developed asymptomatic frontal lobe radionecrosis after 2 courses of radiation therapy. CONCLUSIONS: Neutron radiation therapy achieved excellent 5-year local control in this series of high-risk patients, with most cases having gross residual disease. Late recurrences and distant metastases remain a challenge. Meaningful ipsilateral vision preservation was not possible in most cases in the long term, although only 2 patients required an enucleation for treatment effects.

Clinicopathologic and immunohistochemical features of primary ductal adenocarcinoma of lacrimal gland: five new cases and review of literature.

BACKGROUND: A primary ductal adenocarcinoma of the lacrimal gland is a rare epithelial malignant tumor, and its clinicopathological and immunohistochemical features have not been well determined. The purpose of this study was to determine the clinicopathological characteristics of lacrimal duct carcinomas and to determine their long-term prognosis. METHODS: We performed immunohistochemical studies of biological and proliferative markers of primary ductal adenocarcinomas of the lacrimal gland in five patients, and followed their long term prognosis. We also reviewed nine published cases of primary ductal adenocarcinomas of the lacrimal gland. RESULTS: All specimens were positive for the androgen receptor, and three of five specimens overexpressed the HER-2/neu protein. Nuclear immunostaining for p53 ranged from 10% to 95% and that of Ki-67 from 20% to 70% in the tumor cells. Four of five patients had distant metastases and three patients died from the disease during the 5-year follow-up. CONCLUSIONS: Our findings indicate that primary ductal adenocarcinomas of the lacrimal gland express androgen receptors and a wide range of proliferative markers. Their long-term prognosis is poor.

Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma.

PURPOSE: To compare the long-term outcomes after intra-arterial cytoreductive chemotherapy (IACC) with conventional treatment for lacrimal gland adenoid cystic carcinoma (ACC). DESIGN: Retrospective case series. PARTICIPANTS: Nineteen consecutive patients treated with IACC, followed by orbital exenteration, chemoradiotherapy, and intravenous chemotherapy. INTERVENTIONS: Analyses of the histologic characteristics of biopsy specimens, extent of disease at the time of diagnosis, diagnostic surgical procedures, incidence of locoregional recurrences or distant metastases, disease-free survival time, response to IACC, tumor margins at definitive surgery, and toxicity and complications. MAIN OUTCOME MEASURES: Disease relapse, disease-free survival, and chemotherapeutic complications. RESULTS: Eight patients with an intact lacrimal artery had significantly better outcomes for survival (100% vs. 28.6% at 10 years), cause-specific mortality, and recurrences (all P = 0.002, log-rank test) than conventionally treated patients from the University of Miami Miller School of Medicine. These 8 patients (group 1) had cumulative 10-year disease-free survival of 100% compared with 50% for 11 patients (group 2) who had an absence of the lacrimal artery or deviated from the treatment protocol (P = 0.035) and 14.3% for conventionally treated patients (P<0.001). Likewise, group 2 was associated with lower cause-specific mortality than the institutional comparator group (P = 0.038). Prior tumor resection with lateral wall osteotomy, delay in IACC implementation or exenteration, and failure to adhere to protocol are risk factors for suboptimal outcomes. CONCLUSIONS: Neoadjuvant IACC seems to improve overall survival and decrease disease recurrence. An intact lacrimal artery, no disruption of bone barrier or tumor manipulation other than incisional biopsy, and protocol compliance are factors responsible for favorable outcomes. The chemotoxicity complication rate is limited and manageable.

Ocular adnexal lymphoma staging and treatment: American Joint Committee on Cancer versus Ann Arbor.

PURPOSE: To evaluate the prognostic utility of the American Joint Committee on Cancer (AJCC) staging system for ocular adnexal lymphoma (OAL).
 METHODS: A multicenter, consecutive case series of patients with biopsy-proven conjunctival, orbit, eyelid, or lacrimal gland/sac lymphoma was performed. The electronic pathology and clinical records were reviewed for new or recurrent cases of ocular adnexal lymphoma. The main outcome measures included pathology and clinical staging (AJCC and Ann Arbor systems), treatment, and recurrence (local and systemic). Statistical analysis included demographic evaluations and the Kaplan-Meier survival probability method.
 RESULTS: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue were the most common (n=60/83, 72%). The most common Ann Arbor clinical stages were IE (76%) followed by IIE (17%) and IIIE (7%). Pathology identified 13 cases (15%) that were upstaged to group IV (p=0.017). Similarly, AJCC clinical stages were cT1NOMO (21.7%), cT2NOMO (44.6%), cT3N0M0 (5%), and cT4NOMO (2.4%). Local control was achieved in 75% of treated patients. There were 19 local recurrences from which 14 (74%) belonged to the non-radiation treatment groups. Lower-risk groups (T1 and T2 without lymph node involvement or metastatic disease of AJCC and IE of Ann Arbor) had longer disease-free survival than the higher-risk groups (AJCC T1, T2 with nodal involvement or metastatic disease, T3, and T4 as well as Ann Arbor II, III, and IV). The overall mean follow-up was 43.3 months (range 6-274).
 CONCLUSIONS: Regardless of stage, recurrence and disease-free survival were more closely related to treatment and histopathology rather than tumor size or site-specific location.

Outcomes of malignant tumors of the lacrimal apparatus: the University of Texas MD Anderson Cancer Center experience.

BACKGROUND: Malignant epithelial neoplasms of the lacrimal apparatus are rare and are typically treated with surgery and occasionally adjuvant radiation therapy (RT). The purpose of this study was to assess treatment outcomes by type of surgery (orbital exenteration vs eye-sparing surgery) and clarify the role of adjuvant RT for this rare disease. METHODS: Forty-six patients with malignant epithelial neoplasms of the lacrimal apparatus were treated at a single institution from 1945 through 2008. Twenty-seven patients (59%) were treated with orbital exenteration and 19 (41%) with eye-sparing surgery; 64% of the orbital exenteration group and 83% of the eye-sparing surgery group also received adjuvant RT (median dose, 60 grays). Median follow-up time for all patients was 38 months (range, 3-460 months). RESULTS: For the orbital exenteration and eye-sparing surgery groups, the 5-year overall survival (OS) rates were 59% and 62%, and the 5-year disease-free survival (DFS) rates were 49% and 39%, respectively (P = .56, P = .35). Tumor status (T1-2 vs T3-4) was associated with OS (P = .02), and tumor size (<3.5 vs >3.5 cm) with DFS (P = .015). Median time to locoregional recurrence was 85 months for orbital exenteration, and 123 months for eye-sparing surgery. All patients who did not receive RT experienced local recurrence, and RT extended time to locoregional recurrence (median 460 vs 30 months, P = .009). Seven grade ≥3 complications were experienced after adjuvant RT. CONCLUSIONS: For appropriately selected patients, an eye-sparing surgery for lacrimal apparatus tumors can achieve similar survival outcomes to those in patients treated with an orbital exenteration. Adjuvant RT should be considered for all patients presenting with these rare tumors.

Localized orbital mucosa-associated lymphoma tissue lymphoma managed with primary radiation therapy: efficacy and toxicity.

PURPOSE: To evaluate the clinical outcomes and late effects of radiation therapy (RT) in localized primary orbital mucosa-associated lymphoma tissue (MALT) lymphoma (POML). METHODS AND MATERIALS: From 1989 to 2007, 89 patients with Stage IE POML received RT. The median age was 56 years old. Sites involved conjunctiva (59 patients [66%]), lacrimal gland (20 patients [23%]), and soft tissue (10 patients [11%]). Megavoltage beam(s) was used in 91%, electrons in 7%, and orthovoltage in 2% of cases. The dose given was 25 Gy in 97% and 30 Gy in 3% of patients. Lens shielding was possible in 57% of patients. RESULTS: The median follow-up was 5.9 years. Complete response or unconfirmed complete response was seen in 88 patients (99%). Relapse occurred in 22 patients (25%). First relapse sites were local (2 patients [9%]), in the contralateral orbit (5 patients [23%]), and distant (15 patients [68%]). The 7-year overall survival (OS), cause-specific survival (CSS), relapse-free survival (RFS), and local control (LC) rates were 91%, 96%, 64%, and 97%, respectively. Radiation-related late sequelae were documented in 40 patients (45%). Cataracts were observed in 22 patients (Grade 1 in 2 patients; Grade 3 in 20 patients). The incidence of Grade 3 cataract at 7 years was 25%. Other late sequelae (n = 28) were dry eye(s) (22 patients [Grade 1 in 14 patients; Grade 2 in 2 patients; Grade 3 in 2 patients; n/s in 4 patients), keratitis (3 patients), macular degeneration/cystoid edema (2 patients), and vitreous detachment (1 patient). Five patients developed Grade 3 noncataract late effects. Lens shielding reduced the incidence of Grade 3 cataract and all Grade ≥2 late sequelae. Seventeen patients (16 with cataracts) underwent surgery; 23 patients were treated conservatively. The outcome for managing late effects was generally successful, with 30 patients completely improved, and 9 patients with persisting late sequelae (10%). CONCLUSIONS: POML responds favorably to moderate doses of RT but results in significant late morbidity. The majority of late effects were successfully managed. Lens shielding reduced the risk of cataracts and other late sequelae.

Hepatitis C virus infection in ocular adnexal lymphomas.

OBJECTIVE: To assess the influence of hepatitis C virus (HCV) infection on disease appearance and outcome of ocular adnexal non-Hodgkin lymphoma (ONHL). DESIGN: Retrospective comparative study (from January 1, 1992, through December 31, 2006). METHODS: The medical records of 129 patients with ONHL were retrospectively reviewed. All the patients were tested serologically for the presence of HCV infection. Patients were divided into 2 groups according to the presence or absence of HCV infection. MAIN OUTCOME MEASURES: Prevalence of HCV infection, staging to evaluate the extent of disease at the onset, and clinical outcome data on overall and disease-free survival. RESULTS: The prevalence of HCV infection among the patients with ONHL was 17.8%. Seropositivity for HCV infection was significantly associated with extraorbital lymphoma at the onset (P = .006). High prevalence of mucosa-associated lymphoid tissue disease (79.8%) was registered. Protocol therapy included radiotherapy and chemotherapy, depending on the stage of the disease. Complete remission was achieved in 99 patients (76.7%). A total of 23.6% of patients with HCV-seronegative status and 21.7% of those with HCV-seropositive status experienced relapse of the lymphomatous disease. No significant differences in the 5-year overall survival and disease-free survival between the 2 groups were observed. CONCLUSIONS: Prevalence of HCV infection in patients with ONHL is a relevant issue, accounting for 17.8% of the examined patients. Infection with HCV may influence the initial appearance of ONHL because it is associated with more widespread disease at the onset. However, the overall and disease-free survival of the infected patients are not statistically different than that of patients who are not infected.