Lacrimal Gland Pathology Research Articles

Oculoplastic Conditions in Covid-19 Patients: Case Series and Literature Review.

To investigate oculoplastic conditions in patients diagnosed with coronavirus disease 2019 (COVID-19) seen at ophthalmology departments of three tertiary referral centers in the United Kingdom and the United States, and review of the literature. Retrospective multicenter case series studied over 18 months. A total of four patients developed eyelid, orbital, or lacrimal gland pathology within four weeks of testing positive for COVID-19. All were male, and the mean age at presentation was 49 (range, 31-58 years). Suspected diagnoses included anterior idiopathic orbital inflammation, facial angioedema, dacryoadenitis, and anophthalmic socket inflammation. Three patients recovered fully and one patient recovered partially (mean 2.7 weeks) from ocular manifestations with steroids hastening recovery. Adnexal manifestations of COVID-19 include self-limiting orbital inflammation and eyelid lymphedema.

Clinical, Radiological and Histopathological Features of Patients With Lacrimal Gland Enlargement.

The purpose of this study was to describe the radiologic and histopathologic features of lacrimal gland in patients presenting with lacrimal gland enlargement. We retrospectively retrieved the data of patients with lacrimal gland enlargement in Farabi Eye Hospital between 2012 and 2017. These data included demographics, the patients' facial photographs, orbital CT-scans, and histopathological findings of lacrimal gland biopsies. Forty-seven patients (15 men and 32 women) were enrolled in this study with a median age of 37.9 years (range, 15-79 years). Histopathologic diagnoses were chronic dacryoadenitis in 26 cases (55.32%), IgG4-related disease in 6 patients (12.77%), two cases of acute dacryoadenitis, two cases of non-necrotizing granulomatous inflammation, two cases of Non-Hodgkin's B-cell lymphoma, two cases of adenoid cystic carcinoma and two cases of mixed tumor (4.26% each), as well as one case of conjunctival epithelial cyst, and one case of benign lymphoid tissue and fibrofatty tissue (2.13%). In two samples (4.26%), biopsy revealed normal lacrimal glands. Interestingly, in two cases with relapsing lacrimal gland enlargement, different histopathologic diagnoses were found in biopsies taken from each lacrimal gland at different times. The average size of enlarged lacrimal glands was 19.67 mm × 7.06 mm on axial CT scan and 19.44 mm × 6.20 mm on coronal CT scan. Tissue biopsy is needed for diagnosis of lacrimal gland enlargement because it is difficult to distinguish the type of the lacrimal gland pathology based solely on clinical or radiological presentation.

Asymmetric lacrimal gland enlargement: an indicator for detection of pathological entities other than thyroid eye disease

To examine the clinicopathological characteristics of patients with thyroid eye disease (TED) who showed asymmetric lacrimal gland enlargement. Sixteen patients were included in this retrospective, observational case series. The following data were collected: sex, age, laterality, past medical history, laboratory results for thyroid function and other autoimmune disorders, pathological results, other systemic lesions related to lacrimal gland pathology, and the clinical course after treatment. The results of pathological examinations were consistent with non-specific dacryoadenitis in seven patients, immunoglobulin G4-related dacryoadenitis in four patients, sarcoidosis in two patients, and xanthogranuloma in one patient, respectively. The remaining two patients were proven to be extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tissue type (MALT lymphoma). One patient with sarcoidosis was noted to have another related systemic lesion. After treatment or observation, the lesions were either improved or stable in almost all patients, except for the two patients with MALT lymphoma. Patients with TED who present with asymmetric lacrimal gland enlargement need to be further evaluated. Biopsy of the lacrimal gland and full systemic work-up should be considered as these may lead to detection of other pathological entities, especially malignancies, which could help in saving patients' lives.

Диагностика перфузионно-функциональных соотношений при патологии слезопродуцирующего аппарата

Диагностика перфузионно-функциональных соотношений при патологии слезопродуцирующего аппарата

Efficacy of Trabodenoson in a Mouse Keratoconjunctivitis Sicca (KCS) Model for Dry-Eye Syndrome.

To determine the efficacy of trabodenoson, an adenosine mimetic with highly selective adenosine A1 receptor binding properties, in a preclinical mouse model for dry-eye disease. Dry-eye disease was induced in adult male C57BL/6 mice using a combination of desiccating environment and transdermal administration of scopolamine. Mice were treated concurrently and twice daily with either vehicle, 6% trabodenoson, or 0.05% cyclosporine (Restasis). Efficacy (P < 0.05 versus vehicle) was determined by clinical assessment of dry-eye symptoms using corneal fluorescein staining and tear volumes and histopathologically by quantifying lacrimal gland pathology and conjunctival goblet cells. Twice-daily topical (ocular) administration of trabodenoson increased tear levels and reduced corneal fluorescein staining (P < 0.05) as compared with vehicle-treated eyes in a mouse model of dry-eye disease. Furthermore, significant infiltration of immune cells in the lacrimal gland and reduced number of mucin-producing conjunctival goblet cells were noted in both untreated and vehicle-treated eyes. Comparatively, trabodenoson treatment significantly reduced lacrimal gland infiltration and increased the number of goblet cells (P < 0.05 for both versus vehicle). These trabodenoson-related effects on lacrimal gland pathology and goblet cells were similar to or better than the effects observed with cyclosporine treatment. Topical ocular delivery of trabodenoson significantly improves the clinical and histopathological signs associated with dry-eye disease in mice. This improvement appears to be related to anti-inflammatory effects from targeting adenosine signaling and represents a novel therapeutic approach to develop for the management of dry-eye disease.

The “Wedge Sign”: An Imaging Sign for Aggressive Lacrimal Gland Disease

Lacrimal gland carcinoma can form a triangle of tissue back to the orbital apex, intraconal spread apparently being prevented by the intermuscular septum. The "wedge sign" frequency is assessed in lacrimal carcinoma, lacrimal lymphoma, or dacryoadenitis. Retrospective masked review of images from patients with biopsy-proven lacrimal gland pathology. For each patient, the presence of a triangle of tissue between the lateral rectus and lateral orbital wall and the superior rectus and the orbital roof was assessed by masked review of computed tomography or magnetic resonance imaging. For the lateral compartment, the wedge was classified as "grade 1" if it just reached the sphenoidal trigone and "grade 2" if it was a complete triangle reaching the orbital apex. Comparison of proportions was made using the Fisher exact test, using an α risk of 0.05 as clinically significant. Imaging for 116 patients was reviewed: 39 with lacrimal gland carcinoma, 37 with lymphoma, and 40 with dacryoadenitis. The lateral wedge (grade 1 or 2) was most common in patients with carcinoma (16/39; 41%), was present in 11 of 37 patients (30%) with lymphoma, and was rarest in patients with dacryadenitis (6/40; 15%) (P= 0.033). The proportion in patients with carcinoma (41%) was similar to that in patients with lymphoma (30%) (P= 0.345); the proportion in patients with lymphoma (30%) was similar to that in patients with dacryoadenitis (15%) (P= 0.170), but carcinoma (41%) was significantly different from dacryoadenitis (15%) (P=0.013). The proportions for malignant lesions (carcinoma and lymphoma; 27/76, 36%) and benign dacryoadenitis (15%) were significantly different (P= 0.029). Likewise, a superior wedge, of any extent, was present in 10 of 39 carcinomas (26%), 2 of 40 dacryoadenitis (5%), and 6 of 37 lymphomas (16%) (P= 0.033). The "wedge sign" is most common in lacrimal gland carcinoma, but can occur in patients with severe forms of dacryoadenitis or lymphoma and generally indicates life-threatening lacrimal gland pathology that requires urgent biopsy. It is significantly more common in lacrimal gland carcinoma compared with dacryoadenitis and in malignancy (lymphoma and carcinoma) compared with inflammation.

Review of 268 lacrimal gland biopsies in an Australian cohort.

To review the distribution of pathology in lacrimal gland biopsies performed in an Australian cohort. Retrospective review. Two hundred sixty-eight lacrimal gland biopsies from 263 patients. Pathology archives in South Australia and Victoria were searched for lacrimal gland biopsies performed between 1 January 1997 and 31 December 2012. Data retrieved included the year of biopsy, the histopathological diagnosis, patient age and gender. Distribution of pathology affecting the lacrimal gland; patient age and gender. The distribution of lacrimal gland pathology was: inflammations and vasculitides 50.0%, lymphomas 19.8%, lymphoid hyperplasias 12.3%, benign epithelial tumours 7.8% (all pleomorphic adenomas), malignant epithelial tumours 4.1%, dacryops 3.0% and miscellaneous 3.0%. The mean age was 52 years, with lymphoma affecting the oldest patient group (64.6 years) and sarcoidosis the youngest (40.6 years). Of the patients with biopsy-confirmed dacryoadenitis, biopsy revealed a specific diagnosis in 34% of cases. Immunoglobulin G4-related disease was the most common 'specific' dacryoadenitis. Significantly more pleomorphic adenomas were diagnosed in the period 1997-2004 than the period 2005-2012 inclusive, but there were no other significant changes in the distribution of pathology over time. Two thirds of dacryoadenitis was 'non-specific', two thirds of epithelial tumours were pleomorphic adenomas and approximately two thirds of all lacrimal gland biopsies were accounted for by inflammations and lymphoid hyperplasias. The ratio of inflammations to neoplasias will be significantly influenced by the clinician's threshold for biopsying patients presenting with features of dacryoadenitis.

The Frequency of Granulomatous Lacrimal Gland Inflammation as a Cause of Lacrimal Gland Enlargement in Patients Without a Diagnosis of Systemic Sarcoidosis

Purpose: To determine the rates of orbital sarcoidosis in patients with clinical lacrimal gland enlargement and no history of sarcoidosis.Methods: This was a retrospective study of patients from the Orbital Surgery Service at Wills Eye Institute who underwent lacrimal gland incisional biopsy from 1994–2009 for lacrimal gland enlargement. Patients were excluded if they had a history of sarcoidosis, other autoimmunities, or lacrimal gland enlargement thought to be malignant in etiology. Subject charts were reviewed for pathology results, as well as clinical and demographic data. Rates of sarcoidosis in a patient population presenting with isolated lacrimal gland enlargement were thereby analyzed.Results: 75 patients fulfilling study criteria had lacrimal gland biopsies. 67 (89)% had benign lacrimal gland pathology and 8 (11)% had malignant lacrimal gland pathology. Sarcoidosis was found histologically in 15 (20%). The most frequent pathologic finding was non-specific chronic non-granulomatous inflammation, seen in 32 (43%) studies specimens. Age and gender were not statistically different between sarcoid positive and sarcoid negative patients. Patients with a positive biopsy were more likely to be African American. 26 (35%) of the studied patients had ACE levels obtained. The average ACE level was statistically greater in patients with sarcoidosis-positive biopsies than in those with negative biopsies.Discussion: In patients with clinical lacrimal gland enlargement, incisional biopsy led to a diagnosis of sarcoidosis in 20% of patients. An elevated ACE level may help predict which patients have a greater diagnostic yield with biopsy.

Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome

IntroductionIn Sjögren's syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface. We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögren's syndrome.MethodsMale NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mouse antibody MOPC-21. Extra-orbital lacrimal glands were analyzed by immunohistochemistry for high endothelial venules (HEV), by Affymetrix gene-array analysis and real-time PCR for differential gene expression, and by ELISA for CXCL13 protein. Leukocytes from lacrimal glands were analyzed by flow-cytometry. Tear-fluid secretion-rates were measured and the integrity of the ocular surface was scored using slit-lamp microscopy and fluorescein isothiocyanate (FITC) staining. The chemokine CXCL13 was measured by ELISA in sera from Sjögren's syndrome patients (n = 27) and healthy controls (n = 30). Statistical analysis was by the two-tailed, unpaired T-test, or the Mann-Whitney-test for ocular integrity scores.ResultsLTBR blockade for eight weeks reduced B-cell accumulation (approximately 5-fold), eliminated HEV in lacrimal glands, and reduced the entry rate of lymphocytes into lacrimal glands. Affymetrix-chip analysis revealed numerous changes in mRNA expression due to LTBR blockade, including reduction of homeostatic chemokine expression. The reduction of CXCL13, CCL21, CCL19 mRNA and the HEV-associated gene GLYCAM-1 was confirmed by PCR analysis. CXCL13 protein increased with disease progression in lacrimal-gland homogenates, but after LTBR blockade for 8 weeks, CXCL13 was reduced approximately 6-fold to 8.4 pg/mg (+/- 2.7) from 51 pg/mg (+/-5.3) in lacrimal glands of 16 week old control mice. Mice given LTBR blockade exhibited an approximately two-fold greater tear-fluid secretion than control mice (P = 0.001), and had a significantly improved ocular surface integrity score (P = 0.005). The mean CXCL13 concentration in sera from Sjögren's patients (n = 27) was 170 pg/ml, compared to 92.0 pg/ml for sera from (n = 30) healthy controls (P = 0.01).ConclusionsBlockade of LTBR pathways may have therapeutic potential for treatment of Sjögren's syndrome.

Basal cell cystadenoma of the lacrimal gland: diagnostic pitfalls of a basaloid pattern in lacrimal tumours

An 85-year-old male experienced a painless swelling along the left lateral orbit for one year. A computed tomography scan demonstrated a cystic mass in the orbit adjacent to the lacrimal gland. There was a concern for malignancy considering the large size and the patient's age, so the tumour was excised. Histopathology of the tumour showed nests with basaloid patterns, but a definitive diagnosis was not rendered. The uncertainty of tissue diagnosis coupled with the basaloid pattern, which carries a grim prognosis in some salivary gland tumours, led us to refer this case to an authority on lacrimal gland pathology, who suggested that this tumour be called a basal cell cystadenoma. To the best of our knowledge, a basal cell cystadenoma of the lacrimal gland has not been reported in the literature. We present histopathological features that distinguish this tumour from malignant tumours with a basaloid pattern. We also discuss the management differences associated with basaloid patterns in lacrimal tumours.

Sjögren’s Syndrome-Like Ocular Surface Disease in Thrombospondin-1 Deficient Mice

Thrombospondin-1 (TSP-1) is a major activator of latent transforming growth factor-beta in vitro as well as in vivo. Mice deficient in TSP-1, despite appearing normal at birth, develop a chronic form of ocular surface disease that is marked by increased apoptosis and deterioration in the lacrimal gland, associated dysfunction, and development of inflammatory infiltrates that result in abnormal tears. The increase in CD4(+) T cells in the inflammatory infiltrates of the lacrimal gland, and the presence of anti-Sjögren's syndrome antigen A and anti-Sjögren's syndrome antigen B antibodies in the serum resemble autoimmune Sjögren's syndrome. These mice develop an ocular surface disorder dry eye that includes disruption of the corneal epithelial layer, corneal edema, and a significant decline in conjuctival goblet cells. Externally, several mice develop dry crusty eyes that eventually close. The inflammatory CD4(+) T cells detected in the lacrimal gland, as well as those in the periphery of older TSP-1 null mice, secrete interleukin-17A, a cytokine associated with chronic inflammatory diseases. Antigen-presenting cells, derived from TSP-1 null, but not from wild-type mice, activate T cells to promote the Th17 response. Together, these results indicate that TSP-1 deficiency results in a spontaneous form of chronic dry eye and aberrant histopathology associated with Sjögren's syndrome.

Epithelial tumors of the lacrimal gland: an update

The goal of this article is to offer an update on the treatment and prognosis of the most common epithelial tumors of the lacrimal gland, report on new pathological entities and offer a review of the classification of lacrimal gland tumors. Improvements have been made in the understanding of lacrimal gland lesions with the knowledge that lacrimal gland tumors compare to the more common counterparts of the major salivary glands. Therefore, the WHO's classification of salivary gland tumors has been adapted to the lacrimal gland pathology. Until recently, primary adenocarcinomas of the lacrimal gland were not further subclassified, but they can now be divided into low-grade and high-grade malignancies. The adjunctive use of intra-arterial cytoreductive chemotherapy for the management of adenoid cystic carcinoma is one of the most important advancements on the management of these aggressive tumors. Another important step forward has been taken on carcinoma ex pleomorphic adenoma of the lacrimal gland, which is subclassified into noninvasive carcinoma, with an excellent prognosis after complete excision and invasive carcinoma for which the prognosis is still guarded despite adjunctive radiotherapy. This article offers an update on diagnosis, classification and treatment of common and rare epithelial lacrimal gland tumors.

Lacrimal Gland Prolapse: Management During Aesthetic Blepharoplasty: Review of the Literature and Case Reports

Prolapse of the lacrimal gland is an acquired clinical condition caused mainly by relaxation of the local suspending ligaments. Before an aesthetic blepharoplasty, there should be a preoperative clinical suspicion of lacrimal gland pathology for patients with bulging lateral thirds of the upper eyelids. It should be borne in mind that inadvertent removal of the lacrimal gland can lead to important alterations in ocular lubrication. This report describes two clinical cases of patients with lacrimal gland prolapse associated with dermatochalasis and their treatment.

Role of Heat Shock Protein 47, a Collagen-Binding Chaperone, in Lacrimal Gland Pathology in Patients with cGVHD

Uncontrolled fibrosis due to excessive accumulation of extracellular matrix proteins in the lacrimal glands of patients with chronic graft-versus-host disease (cGVHD) is well documented. Heat-shock protein 47 (HSP47) is involved in the molecular maturation of collagen and has been shown to have a fibrogenic role in various fibrotic diseases. In this study, the role of HSP47 in the pathogenesis of lacrimal gland of patients with cGVHD was investigated. The expression of HSP47, Ki67 (a proliferation marker), types I and III collagen, and alpha-smooth muscle actin (alpha-SMA) was examined in tissue sections and in primary cultures of fibroblasts obtained from the lacrimal glands of patients with cGVHD (n = 8) and Sjögren's syndrome (SS; n = 7). Tissue sections of the lacrimal glands of patients with cGVHD showed markedly increased expression of HSP47 in fibroblasts around the medium-sized ducts than did those from patients with SS. The elevated expression of HSP47 in patients with cGVHD was mostly detected in Ki67-positive fibroblasts and was associated with increased accumulation of types I and III collagen in and around the fibrotic areas. Primary fibroblast cultures generated from cGVHD lacrimal gland showed higher HSP47 mRNA expression than did fibroblasts isolated from SS biopsy tissue, as determined by RT-PCR (P < 0.05). In contrast, alpha-SMA was higher in the SS than cGVHD fibroblasts at both mRNA and protein levels, and more lacrimal gland fibroblasts in the SS were positive for alpha-SMA than cGVHD (P < 0.01). In cGVHD, increased expression of HSP47 may promote excessive collagen assembly in and around the periductal areas where fibroblasts are mostly in an active state. The less alpha-SMA in the cGVHD lacrimal gland fibroblasts suggests a relative lack of myofibroblastic transformation. It is likely that fibroblasts incapable of myofibroblastic transformation are the main source of HSP47 and collagen production, and the resultant effect is the periductal fibrotic changes seen in lacrimal glands of patients with cGVHD.

Production of a severe cystic fibrosis mutation in mice by gene targeting.

We have used gene targeting in embryonic stem cells to introduce an HPRT mini-gene into the coding sequence of the murine cystic fibrosis gene (cftr). This insertion introduces a termination codon in frame with the cftr coding sequence to terminate prematurely the CFTR protein within the first nucleotide binding domain. Animals homozygous for the cftr disruption fail to thrive and display a range of symptoms including meconium ileus, distal intestinal obstructions, gastrointestinal mucus accumulation and blockage of pancreatic ducts. The animals also show lacrimal gland pathology. Tracheal and caecal transepithelial current measurements demonstrate the lack of a cAMP activatable Cl- channel. These animals will prove useful for the evaluation of new therapeutic drugs and gene therapy strategies.

Antigenic profile of the human lacrimal gland.

The antigenic profile of 13 normal formalin-fixed, paraffin-embedded human main and accessory lacrimal glands, biopsied from patients aged 11 to 78 years, was studied using a panel of 27 polyclonal and monoclonal antibodies. Secretory cells of lacrimal acini reacted with antibodies to S-100 protein and simple epithelium-type cytokeratins CK 7, CK 8, CK 18, and CK 19. Their luminal membranes were labeled with antibodies to carcinoembryonic antigen, epithelial membrane antigen, and epithelial glycoproteins recognized by Ber-EP4. Myoepithelial cells were often immunopositive for S-100 protein, vimentin, glial fibrillary acidic protein (GFAP), and alpha-smooth muscle actin. More rarely, they reacted with antibodies recognizing CK 5, CK 13, and CK 14, which consistently labeled the basal cells of lacrimal ducts. Unlike myoepithelial cells, basal ductal cells were immunopositive for CK 7, CK 8, CK 18, and CK 19. In main excretory ducts, dendritic melanocyte-like cells co-expressing vimentin and S-100 protein intermingled with ductal epithelial cells. The luminal cells of lacrimal ducts basically paralleled secretory cells in their antigenic profile, although they lacked Ber-EP4 and were immunopositive for CK 4. Antibodies to neuron-specific enolase and synaptophysin reacted with nerve fibers among negatively reacting secretory acini. This antigenic profile closely parallels that of salivary glands and provides a basis for studies of lacrimal gland pathology.