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.

Clinical heterogeneity between two subgroups of patients with idiopathic orbital inflammation.

OBJECTIVE: Idiopathic orbital inflammation (IOI) is a group of orbital inflammatory diseases of unknown etiopathogenesis. We investigated whether patients with IOI have clinical heterogeneity based on the presence (typical group) or absence (atypical group) of a unique onset that periocular inflammatory symptoms emerge suddenly but progress slowly. METHODS AND ANALYSIS: This retrospective cohort study included 195 patients diagnosed with IOI. We analysed the clinical data of patients, including the outcomes of corticosteroid treatment, in two subgroups stratified on the basis of the presence (130 patients) or absence (65 patients) of the unique onset. RESULTS: Patients in the typical group were significantly younger at disease onset than those in the atypical group (median age; 52 vs 65 years, p=0.002); had more ocular adnexa-specific lesions, namely, dacryoadenitis, myositis, scleritis and optic perineuritis (78% vs 45%, p=0.00001); and had significantly fewer associations with immune-mediated inflammatory diseases (4% vs 15%, p=0.004). Among 30/119 patients (25%) who were steroid refractory in the typical group, a long period of time from symptom onset to initiation of treatment was a significant steroid-refractory risk factor (OR: 16.7), whereas, among the 18/40 patients (45%) who were steroid refractory in the atypical group, intraconal diffuse lesions were a significant steroid-refractory risk factor (OR: 8.8). CONCLUSION: This cohort study suggests clinical heterogeneity between the two subgroups of patients with IOI.

Long-term outcomes of ocular adnexal lesions in IgG4-related ophthalmic disease.

AIMS: To determine the long-term outcomes of ocular adnexal lesions in immunoglobulin G4-related ophthalmic disease (IgG4-ROD). METHODS: This retrospective, non-randomised exploratory study included 82 patients with ocular adnexal lesions. We evaluated the long-term outcomes in 71 patients during the median follow-up period of 30 months, who underwent either watchful waiting (n=20; range 12-90 months) or systemic corticosteroid treatment, delivered according to consensus guidelines (n=51; range 9- 115 months). We also analysed factors that might contribute to recalcitrance to treatment. RESULTS: Of 82 patients, 40 (49%) were male, and the median patient age was 60 years old. Twenty-one (26%) patients with extraocular muscle (EOM) and/or trigeminal nerve branch (CN V) enlargements had a significantly high frequency of multiple ocular adnexal lesions (p<0.0001, Fisher's exact test). In addition, two patients developed EOM and/or CN V enlargements de novo over time. Twenty patients with solitary lacrimal gland enlargements preferred watchful waiting, due to mild symptoms. Of these, 18 (90%) lesions remained dormant throughout a median follow-up of 27 months. Among 51 patients treated with corticosteroids, 31 (61%) experienced relapses after treatment and required systemic low-dose maintenance treatment. A multivariate analysis indicated that EOM and/or CN V enlargements comprised a risk factor for relapse (HR 2.7; 95% CI 1.1 to 6.7). CONCLUSIONS: This exploratory study showed that different types of ocular adnexal lesions in IgG4-ROD displayed distinct proliferative activities. Our results suggested that EOM and/or CN V enlargements might be secondary lesions that confer refractoriness to systemic corticosteroid treatment recommended by consensus guidelines.

Radiotherapy alone for stage IE ocular adnexal mucosa-associated lymphoid tissue lymphomas: long-term results.

BACKGROUND: To evaluate the long-term efficacy and toxicity of radiation therapy in patients with Stage IE primary ocular adnexal mucosa-associated lymphoid tissue lymphoma. METHODS: We designed a retrospective analysis to evaluate 81 patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma treated with radiation therapy between 2006 and 2016. The median radiation dose was 30 Gy (range, 30-36 Gy in 15-18 fractions). Local control, progression-free survival, overall survival, and cumulative incidence of Grade 3 cataract were calculated by using the Kaplan-Meier method. RESULT: The median follow-up time was 74 months (range, 4-157 months). The 5-year local control was 100%. Although local relapse was suspected in 3 patients after radiation therapy, 2 patients were pathologically diagnosed as IgG4-related inflammation and in 1 patient as intense inflammatory cell infiltration. The 5-year progression-free survival was 94.4%. Five patients had relapse at distant sites. The 5-year overall survival was 98.8%. Twenty patients had Grade 3 cataract. The 5-year cumulative incidences of Grade ≥ 3 and Grade ≥ 2 cataract for 58 patients treated without a lens shield were 38 and 40%, respectively. The incidence of Grade ≥ 3 cataract was 42% for 50 patients treated with 6-MV X-rays (estimated lens dose: 29 Gy) and 17% for 8 patients treated with 9-MeV electrons (estimated lens dose: 24 Gy). CONCLUSIONS: Radiation therapy alone yielded excellent local control and long-term survival in Stage IE ocular adnexal mucosa-associated lymphoid tissue lymphoma. Long-term observation with careful attention to relapse at distant sites is necessary. In the case of suspected local relapse, IgG4-related disease should be carefully ruled out.

A female patient with retinoblastoma and severe intellectual disability carrying an X;13 balanced translocation without rearrangement in the RB1 gene: a case report.

BACKGROUND: Female carriers of a balanced X; autosome translocation generally undergo selective inactivation of the normal X chromosome. This is because inactivation of critical genes within the autosomal region of the derivative translocation chromosome would compromise cellular function. We here report a female patient with bilateral retinoblastoma and a severe intellectual disability who carries a reciprocal X-autosomal translocation. CASE PRESENTATION: Cytogenetic and molecular analyses, a HUMARA (Human androgen receptor) assay, and methylation specific PCR (MSP) and bisulfite sequencing were performed using peripheral blood samples from the patient. The patient's karyotype was 46,X,t(X;13)(q28;q14.1) by G-banding analysis. Further cytogenetic analysis located the entire RB1 gene and its regulatory region on der(X) with no translocation disruption. The X-inactivation pattern in the peripheral blood was highly skewed but not completely selected. MSP and deep sequencing of bisulfite-treated DNA revealed that an extensive 13q region, including the RB1 promoter, was unusually methylated in a subset of cells. CONCLUSIONS: The der(X) region harboring the RB1 gene was inactivated in a subset of somatic cells, including the retinal cells, in the patient subject which acted as the first hit in the development of her retinoblastoma. In addition, the patient's intellectual disability may be attributable to the inactivation of the der(X), leading to a 13q deletion syndrome-like phenotype, or to an active X-linked gene on der (13) leading to Xq28 functional disomy.

Ocular adnexal mucosa-associated lymphoid tissue lymphoma with polyclonal hypergammaglobulinemia.

PURPOSE: To determine the characteristics of patients with primary ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma associated with polyclonal hypergammaglobulinemia. DESIGN: Case series study. METHODS: Among 81 Japanese patients with primary ocular adnexal MALT lymphoma, seven patients (9%) were diagnosed with polyclonal hypergammaglobulinemia. Patient clinical data included a history of autoimmune disease and dissemination. Peripheral blood collected from all patients was analyzed for serum levels of rheumatoid factor, soluble interleukin-2 receptor (sIL-2R), and immunoglobulins at the time of diagnosis and after each treatment. RESULTS: Seven patients with polyclonal hypergammaglobulinemia had elevated serum levels of rheumatoid factor, sIL-2R, immunoglobulin G (IgG), and immunoglobulin E (IgE) at the time of diagnosis. One patient had Sjogren syndrome. Six patients (86%) had a dissemination of the MALT lymphoma or lymphadenopathy at the time of diagnosis. Histopathologic examination of the patients with lymphadenopathy revealed not only MALT lymphoma but also secondary follicles. None of the seven patients showed improvement in serum levels of IgG, rheumatoid factor, or sIL-2R in spite of complete regression of the ocular lesions after radiotherapy. After administration of cyclophosphamide/doxorubicin/vincristine/prednisone and/or rituximab to three patients, all three showed improved serum levels of IgG, rheumatoid factor, and sIL-2R. CONCLUSIONS: Patients with ocular adnexal MALT lymphoma and polyclonal hypergammaglobulinemia have elevated serum levels of rheumatoid factor, sIL-2R, and IgE, and high dissemination or lymphadenopathy. These unique characteristics may correlate with the systemic immunologic imbalances.

High incidence of autoimmune disease in Japanese patients with ocular adnexal reactive lymphoid hyperplasia.

PURPOSE: To determine the incidence of autoimmune disease in Japanese patients with ocular adnexal lymphoid proliferations. DESIGN: Case series study. METHODS: The authors investigated the incidence of autoimmune disease in 88 patients with primary ocular adnexal lymphoid proliferations. Southern blot analysis was used to determine the presence of B-cell clonality in reactive lymphoid hyperplasia (RLH) associated with autoimmune disease. RESULTS: Histopathologic analysis indicated that 15 (17%) patients had RLH, 62 (70%) patients had mucosa-associated lymphoid tissue lymphoma (MALToma), and 11 (13%) patients had primary lymphomas. The incidence of autoimmune disease was seven (47%) of 15 patients with RLH, two (3%) of 62 patients with MALToma, and zero (0%) of 11 patients with primary lymphoma. B-cell clonality was detected in one (14%) of seven RLH patients with autoimmune disease. CONCLUSIONS: Ocular adnexal RLH with or without B-cell clonality is highly associated with autoimmune disease.

Assessment of inflammation in idiopathic orbital myositis with fat-suppressed T2-weighted magnetic resonance imaging.

PURPOSE: To evaluate the inflammation in idiopathic orbital myositis by fat-suppressed T2-weighted magnetic resonance imaging (MRI). DESIGN: Observational case series. METHODS: The inflammation in nine patients with orbital myositis was evaluated with fat-suppressed T2-weighted MRI within three weeks of onset. Patients were mainly treated with steroid pulse therapy and followed to the acute improvement or chronic ocular motility restriction phases. RESULTS: Each patient was found to have localized inflammations in the extraocular muscles or associated fascial structures. Of the five patients with acute improvement, none had inflammation of the extraocular muscles, whereas the four patients with chronic ocular motility restriction had inflammation of the extraocular muscles. CONCLUSION: These results suggest that acute or chronic pattern in orbital myositis is correlated with the localized inflammation. The inflammation in the extraocular muscles may be one of the factors that lead to the chronic ocular motility restriction.

Low efficacy of 18F-FDG PET for detection of uveal malignant melanoma compared with 123I-IMP SPECT.

UNLABELLED: Earlier investigations showed that N-isopropyl-p-123I-iodoamphetamine SPECT (123I-IMP SPECT) is useful for the diagnosis of uveal malignant melanoma, whereas the feasibility and usefulness of 18F-FDG PET in uveal malignant melanoma have not yet been established. We compared the usefulness of 123I-IMP SPECT and 18F-FDG PET for the detection of uveal malignant melanoma on the same subjects. METHODS: Nineteen patients (10 men, 9 women) with suspected uveal malignant melanoma were examined by 123I-IMP SPECT. Thirteen of them were also examined by 18F-FDG PET. 123I-IMP SPECT was performed at 15 min or at 3 and 24 h after intravenous administration of 123I-IMP. RESULTS: In 12 of 19 study patients, 123I-IMP SPECT obtained at 24 h after intravenous administration of 123I-IMP delineated an area of increased uptake in the site corresponding to the ocular tumor. All of the ocular tumors in the 12 123I-IMP SPECT-positive patients were confirmed histopathologically and clinically to be uveal malignant melanoma. The other 7 123I-IMP-SPECT-negative patients have been monitored under the diagnosis of choroidal nevus, choroidal hemangioma, hyperplasia of the pigment epithelium of the retina, or idiopathic inflammatory lesions without any complications. In a total of 13 patients examined by 18F-FDG PET, 9 of whom were 123I-IMP SPECT positive and 4 were negative, only 1 patient showed abnormal uptake of 18F-FDG PET in the site corresponding to the ocular tumor. Therefore, 8 of 9 patients with uveal malignant melanoma showed false-negative results in 18F-FDG PET. The 18F-FDG PET-positive patient with uveal malignant melanoma had the largest tumor mass with a short diameter of 12 mm, a long diameter of 17 mm, and a height of 7 mm. In the other 8 18F-FDG PET-negative patients, the tumors had a dimension of 11 x 13 x 7 mm or less. CONCLUSION: 123I-IMP SPECT is a sensitive and accurate method for the detection of uveal malignant melanoma, whereas the efficacy of 18F-FDG PET for this purpose is low because of a high incidence of false-negative results. 123I-IMP SPECT is far more superior in comparison with 18F-FDG PET in detecting uveal malignant melanoma.

Pazopanib monotherapy in a patient with a malignant granular cell tumor originating from the right orbit: A case report.

Granular cell tumors are uncommon, usually benign tumors of Schwann cell origin. The malignant variant is extremely rare, representing <2% of all granular cell tumors. Therefore, standard systemic chemotherapy for this disease does not exist. The present study reports the case of a 40-year-old female with a malignant granular cell tumor that originally arose in the right orbit and subsequently relapsed. The patient was started on pazopanib monotherapy following treatment with two investigational drugs, a smoothened inhibitor and then a phosphatidylinositol 3-kinase inhibitor, as part of a clinical trial. Although additional radiotherapy for local control was necessary, the lung metastases remained stable during the pazopanib monotherapy, which lasted for 7 months, following which a clinically stable disease state was determined. This case suggests that pazopanib can be a treatment option for the stabilization of disease progression in metastatic malignant granular cell tumor.

Ocular changes in a limited form of Wegener's granulomatosis: patient with cutaneous ulcer of upper eyelid.

BACKGROUND: We report a patient with a limited form of Wegener's granulomatosis (WG) who presented with ocular changes and an eyelid ulcer in her left eye. CASE: A 56-year-old woman complained of ocular pain and discharge. Upon examination, we found evidence of ulcerative keratitis, a mass in the orbit, and an eyelid skin ulcer in her left eye. OBSERVATIONS: The antineutrophil cytoplasmic antibody test was negative, and systemic evaluations showed no specific changes. A biopsy specimen of the left orbit demonstrated necrosis, granulomatous inflammation, and vasculitis. A diagnosis was made of a limited form of WG, whilethe biopsy specimen of the left upper lid demonstrated granulomatous inflammation without vasculitis. CONCLUSION: Although the eyelid ulcer was contiguous with the orbital mass, histopathology showed they had distinctive pathological features.

Serologic factors in early relapse of IgG4-related orbital inflammation after steroid treatment.

PURPOSE: To determine whether serologic factors correlate with early relapse in cases of IgG4-related orbital inflammation, a lymphoproliferative disorder. DESIGN: Retrospective cohort study. METHODS: We examined the orbital images and serum data of 30 patients with (n=24) or without (n=6) corticosteroid treatment before and after corticosteroid treatment and 6 months after discontinuation of corticosteroid treatment. RESULTS: Seven patients (23%) (all with corticosteroid treatment) had elevated serum levels of rheumatoid factor. Of the 24 patients with corticosteroid treatment, 24 (100%) showed regression of the lesion, but 8 of the 24 (33%) showed relapse. The serum IgG4 levels before and after corticosteroid treatment were not significantly different between the relapsed and nonrelapsed groups (P=.5 and P=.2, respectively). However, the incidence of patients who were rheumatoid factor-positive was significantly higher in the relapsed group (P=.02). The 6 patients without corticosteroid treatment showed minor proliferation or regression of the lesion at the 6-month follow-up. CONCLUSIONS: The serum rheumatoid factor level may correlate with proliferative activity in IgG4-related orbital inflammation.

Orbital IgG4-Related Disease: Clinical Features and Diagnosis.

Orbital IgG4-related disease, which can occur in adults of any age, is characterized by IgG4-positive lymphoplasmacytic infiltrations in ocular adnexal tissues. The signs and symptoms include chronic noninflammatory lid swelling and proptosis. Patients often have a history of allergic disease and elevated serum levels of IgG4 and IgE as well as hypergammaglobulinemia. Orbital IgG4-related disease must be differentiated from idiopathic orbital inflammation and ocular adnexal marginal zone B-cell lymphoma to ensure appropriate and effective treatment. Systemic steroid therapy decreases the size of the lesions, but relapse often occurs when systemic steroid therapy is discontinued.