Lacrimal Adenoid Cystic Carcinoma Research Articles

Non-invasive miRNAs for early detection and diagnosis of lacrimal adenoid cystic carcinoma.

Lacrimal adenoid cystic carcinoma (LACC) is one of the most common malignant epithelial tumors of the lacrimal gland, characterized by high rates of local recurrence, distant metastases, and tumor-related mortality. This malignancy impairs the lacrimal gland's ability to secret tears, thereby disrupting the normal function of the ocular surface. Due to ineffective diagnostic approaches and the complex anatomical location of the lacrimal gland within the orbit, many LACC patients are often diagnosed at the later stages. Therefore, it is urgent to develop a simple and convenient method for early detection of LACC through biomarker analysis by liquid biopsies, such as blood or tears. Various microRNAs (miRNAs) derived from liquid biopsies have been shown to serve as biomarkers for early diagnosis of tumors. In the present study, we screened LACC-specific miRNAs using miRNA microarray analysis in both primary and recurrent patient groups. We then validate their expression by qPCR experiments conducted in tissues, cell lines, tear fluid and serum to explore the association between these miRNAs and LACC development and prognosis. Our findings reveal that hsa-miR-200b-3p, hsa-miR-200c-3p and hsa-miR-141-3p are significantly upregulated in LACC, and the microarray data showed that these three miRNAs were significantly elevated in the recurrence group compared to the primary group. In conclusion, detecting miRNA expression in tear fluid and serum provides non-invasive biomarkers for the early diagnosis of LACC and may facilitate monitoring outcomes related to lacrimal gland diseases.

Molecular Analysis of Salivary and Lacrimal Adenoid Cystic Carcinoma.

Adenoid cystic carcinoma (ACC) of head and neck origin is associated with slow but relentless progression and systemic metastasis, resulting in poor long-term survival rates. ACC does not respond to conventional chemotherapy. Determination of molecular drivers may provide a rational basis for personalized therapy. Herein, we investigate the clinical and detailed molecular genomic features of a cohort of patients treated in Ireland and correlate the site of origin, molecular features, and outcomes. Clinical and genomic landscapes of all patients diagnosed with ACC over a twenty-year period (2002-2022) in a single unit in Ireland were examined and analyzed using fluorescence in situ hybridization, DNA sequencing, and bioinformatic analysis. Fourteen patients were included for analysis. Eleven patients had primary salivary gland ACC and three primary lacrimal gland ACC; 76.9% of the analyzed tumors displayed evidence of NFIB-MYB rearrangement at the 6q23.3 locus; 35% had mutations in NOTCH pathway genes; 7% of patients had a NOTCH1 mutation, 14.3% NOTCH2 mutation, and 14.3% NOTCH3 mutation. The presence of epigenetic modifications in ACC patients significantly correlated with worse overall survival. Our study identifies genetic mutations and signaling pathways that drive ACC pathogenesis, representing potential molecular and therapeutic targets.

Preliminary proteomic analysis of human tears in lacrimal adenoid cystic carcinoma and pleomorphic adenoma.

To detect proteomic differences in tears between adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA). Tear samples were collected from 4 patients with ACC, 5 with PA, and 4 control cases. Label-free analysis and parallel reaction monitoring (PRM) were used to screen and validate the tear proteome. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted for bioinformatics analysis. In total, 1059 proteins in tear samples were identified by label-free analysis. Between ACC and PA, 415 differentially expressed proteins were detected. Based on the GO annotation, enzyme regulator activity and serine-type endopeptidase inhibitor activity in the molecular function category, blood microparticle and extracellular matrix in the cellular component category, and response to nutrient levels in the biological process category were most predominant. By KEGG pathway annotation, the different proteins between ACC and PA mainly participated in complement and coagulation cascades, amoebiasis, African trypanosomiasis and cholesterol metabolism. Eight proteins with mostly significant differences were verified by PRM, and five proteins with more than 10-fold increases in ACC compared with PA, including integrin β, α-2-macroglobulin, epididymal secretory sperm binding protein Li 78p, RAB5C, and complement C5, were identified. The combined tools of label-free analysis and PRM are very effective and efficient, especially for samples such as tears. Some proteomic differences in tears between ACC and PA are identified and these protein candidates may be specific biomarkers for future exploration.

MiR-29a-3p inhibits high-grade transformation and epithelial-mesenchymal transition of lacrimal gland adenoid cystic carcinoma by targeting Quaking.

Lacrimal adenoid cystic carcinoma (LACC) is the most common orbital malignant epithelial neoplasm. LACC with high-grade transformation (LACC-HGT) has higher rates of recurrence, metastasis, and mortality than LACC without HGT. This study investigated the effects of microRNA-29a-3p (miR-29a-3p) in the pathogenesis of LACC-HGT. An Agilent human miRNA microarray was used to screen the differentially expressed miRNAs (DEMs) in LACC and LACC-HGT tumor tissues. Then, the primary cells obtained in previous studies were used to determine the effect of miR-29a-3p. The expression of miR-29a-3p was abnormally lower in LACC-HGT than in LACC. miR-29a-3p can specifically target the 3' UTR of Quaking mRNA and down-regulate Quaking expression, thereby inhibiting the proliferation, migration, and epithelial-mesenchymal transition of LACC cells. This study illustrated that miR-29a-3p functions as a tumor suppressor by down-regulating the expression of Quaking to inhibit the tumorigenesis of LACC cells. This study may also reveal the pathogenesis of HGT in LACC cells and provide a reference for LACC-HGT targeted diagnosis.

Retraction: miR-24-3p Suppresses Malignant Behavior of Lacrimal Adenoid Cystic Carcinoma by Targeting PRKCH to Regulate p53/p21 Pathway.

Retraction: miR-24-3p Suppresses Malignant Behavior of Lacrimal Adenoid Cystic Carcinoma by Targeting PRKCH to Regulate p53/p21 Pathway.

Aberrantly expressed GFRα-1/RET in patients with lacrimal adenoid cystic carcinoma is associated with high recurrence risk: a retrospective study of 51 LACC cases.

Objective:Because of the poor prognosis of lacrimal adenoid cystic carcinoma (LACC), we aimed to investigate the effects of perineural invasion (PNI) and consequent aberrations in GDNF/GFRα-1/RET protein expression on LACC recurrence.Methods:Clinicopathological data for 51 histologically confirmed patients with LACC enrolled between 2001 and 2017 were retrospectively analyzed. Hematoxylin and eosin staining was applied to assess PNI. Tissue-based immunohistochemistry (IHC) detection of GDNF, GFRα-1, and RET proteins was performed on LACC formalin-fixed, paraffin-embedded specimens. We generated semi-quantitative data of the IHC results and compared them with the clinicopathological data for the 51 patients.Results:Of the 51 patients, 19 (37.3%) were PNI positive. Recurrence was more common for LACC with than without PNI (73.7% vs. 37.5%, P = 0.01). GDNF, GFRα-1, and RET proteins were expressed in 62.7%, 62.7%, and 54.9% of the 51 patients with LACC, respectively. The expression of all 3 proteins was more common in patients with than without PNI. In agreement with previous findings, PNI-associated GFRα-1 and RET positivity, as detected by IHC, remained significantly associated with recurrence, whereas GDNF expression, as detected by IHC, was not correlated with LACC recurrence. Specifically, patients with concurrent GFRα-1 and RET expression may have a high risk of PNI (89.5% positivity rate) and recurrence (84.2% positivity rate).Conclusions:PNI may contribute to LACC recurrence. The concurrent expression of GFRα-1 and RET proteins, as detected by IHC, may potentially be associated with LACC PNI and recurrence.

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

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. Retrospective study. 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. 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. 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.

MiR-24-3p Suppresses Malignant Behavior of Lacrimal Adenoid Cystic Carcinoma by Targeting PRKCH to Regulate p53/p21 Pathway.

MicroRNA (miRNA) may function as an oncogene or a tumor suppressor in tumorigenesis. However, the mechanism of miRNAs in adenoid cystic carcinoma (ACC) is unclear. Here, we provide evidence that miR-24-3p was downreglated and functions as a tumor suppressor in human lacrimal adenoid cystic carcinoma by suppressing proliferation and migration/invasion while promoting apoptosis. miR-24-3p down-regulated protein kinase C eta (PRKCH) by binding to its untranslated region (3’UTR). PRKCH increased the of the cell growth and migration/invasion in ACC cells and suppressed the expression of p53 and p21 in both mRNA and protein level. The overexpression of miR-24-3p decreased its malignant phenotype. Ectopic expression of PRKCH counteracted the suppression of malignancy induced by miR-24-3p, as well as ectopic expression of miR-24-3p rescued the suppression of PRKCH in the p53/p21 pathway. These results suggest that miR-24-3p promotes the p53/p21 pathway by down-regulating PRKCH expression in lacrimal adenoid cystic carcinoma cells.

Clinical significance of post-surgical residual tumor burden and radiation therapy in treating patients with lacrimal adenoid cystic carcinoma.

Retrospective analyses were done on 19 lacrimal adenoid cystic carcinoma (ACC) patients who underwent curative treatment between 1997 and 2013. Nine patients (47.4%) had T1-2 disease and ten (52.6%) had T4 disease. Surgical procedures were globe-preserving tumor resection in 11 patients (57.9%), incisional biopsy in five (26.3%), and orbital exenteration was undertaken in three (15.8%). Residual tumor burdens were R0/1 in 12 patients (63.2%) and R2 in seven (36.8%). Radiation therapy (RT) was recommended to all patients, and 16 (84.2%) completed RT (median 60 Gy). After median follow-up of 57.5 months, seven (36.8%) developed progression and three (15.8%) died. Local recurrence occurred in four patients (21.1%), distant metastasis in one (5.3%), and combined local recurrence and distant metastasis in two (10.5%). Progression-free survival and overall survival rates at 5-years were 64.5% and 82.6%, respectively. Among 12 patients following R0/1 resection, two (16.7%) developed local recurrence and none died, while among seven following R2 resection, five (71.4%) developed progression and three (42.9%) died. RT following R0/R1 resection could reduce progression. Globe-preserving surgery and RT seemed optimal strategy for T1-2 disease. Careful attention should to be paid to minimize residual tumor burden at surgery and effort for safe radiation dose escalation would be desired.

Adjuvant Radiotherapy with Three-Dimensional Conformal Radiotherapy of Lacrimal Gland Adenoid Cystic Carcinoma.

Adenoid cystic carcinoma (ACC) of lacrimal gland is a rare tumour with aggressive behaviour. There is sparse data to address optimum therapy for such tumours. So, the present study was aimed at evaluating the role of adjuvant three dimensional conformal radiotherapy (3D-CRT) in cases of incomplete (R1) resection along with review of literature pertaining to management of lacrimal adenoid cystic carcinoma. We retrospectively reviewed the demographic and treatment data of 10 biopsy proven ACC of lacrimal gland patients, treated from December 2006 to June 2013. They were treated with radiotherapy following surgical resection. Eight patients underwent gross total excision of the tumour mass (enbloc excision) followed by conformal radiotherapy to a dose of 60 Gray/30fractions/ 6 weeks. Two patients with advanced disease were treated with palliative radiotherapy after biopsy. The median age was 32 years. There were equal numbers of male and female patients. The median duration of symptoms was 7 months. At a median follow up of 21 months, eight patients had no evidence of disease and had complete tumour response, two patients worsened, and one of the two had systemic failure with bone metastasis. Despite a small sample size and short follow, enbloc surgical excision with adjuvant radiotherapy is well tolerated and shows good control in ACC of lacrimal gland.

Influence of Ginkgo biloba extract on proliferation of ACC-2 cell, Survivin and TIP30 gene expression in adenoid cystic carcinoma of lacrimal gland

Exploring the influence of extract of Ginkgo biloba (EGB) on the proliferation, apoptosis of ACC-2 cell in lacrimal adenoid cystic carcinoma and analyzing the influence of EGB on the gene expression of Survivin and TIP30 based on the levels of the gene and protein. ACC-2 cell in human with ACC of lacrimal gland disposed by EGB of different concentration was in vitro cultured. MTT method was used for cell proliferation detection. Annexin V/PI double-staining flow cytometer was used to detect cell apoptosis and cell cycle. Survivin and TIP30 gene expression together with protein expression were analyzed by RT-PCR and Western blotting. And it is indicated that EGB has inhibitory effect on the proliferation of ACC-2 cell in vitro. Furthermore, the dose-effect relationship was significant. Compared with the control group, it had statistical difference (P <0.01). The inhibitory concentration 50% (ICso) is 88 mg . L-1. By flow cytometer examination, it was indicated that EGB can gradually increase ACC-2 cell in G0-G1 stage and decrease it in G2-M and S stage. With the increase of dose, the apoptosis rate of ACC-2 cell obviously increased (P <0.05 or P <0.01). Both of the expression results of RT-PCR and Western hybrid proteins have showed that the concentration of EGB increased, it could be seen a significant decrease in Survivin gene expression (P <0.01). Meanwhile, the TIP30 gene expression got a significant increase. Therefore, EGB can effectively inhibit ACC-2 cell Survivin gene expression in human with adenoid cysistic carcinoma of larcrimal gland as well as promoting TIP30 gene expression, inducing the ACC-2 cell apoptosis and inhibiting tumor cell proliferation, which provided a certain theoretical and experimental basis for the application of Chinese herbal medicinal ingredient in the treatment of tumors.

Isolation and identification of cancer stem cells from human LACC cell line

To find ways to isolate and culture lacrimal adenoid cystic carcinoma (LACC) stem cells from human LACC cell line and to identify their biological properties. Experimental research. LACC cells were digested, centrifuged and suspended in specific serum free medium (SFM) to get LACC cancer stem cell spheres. Limiting dilution analysis and monoclonal formation assay were performed to determine the proportion of cancer stem cells in LACC cell line. MTT assay was used to determine the proliferation and chemotherapeutic drug resistance of stem cell spheres. The expressions of cell surface markers CD44⁺/CD24⁻ were detected by flow cytometry. Stem cell spheres differentiation were induced by dropping serum medium into SFM and the morphologic changes were observed. The IC₅₀ and UV optical density of two kinds of cells were tested by Student's t-test. About (0.92 ± 0.02) % cells were clonogenic in LACC cell line. They could survive and proliferate to form free-floating cell spheres in SFM, which could stably passaged. The IC₅₀ values of cancer stem cells and LACC cell line were 22.53 mg/L and 11.06 mg/L (t = 37.94, P < 0.05), which suggested that cancer stem cells were more resistant to cis-platinum than LACC cell line. In flow cytometry assay, 84.25% stem cell spheres were CD44⁺/CD24⁻ cells, comparing with 23.77% in LACC cell line. Stem cell spheres could differentiate into normal adenoid cystic carcinoma cells in medium with serum. LACC stem cell spheres, containing a large number of cancer stem cells, could be obtained by serum free suspension culture. This provide us an ideal model system for cancer stem cell research.

Neoadjuvant intra-arterial chemotherapy in patients with primary lacrimal adenoid cystic carcinoma.

BackgroundWe describe four cases of primary lacrimal adenoid cystic carcinoma (ACC) treated with neoadjuvant intra-arterial chemotherapy (NAIC).MethodsThe outcomes and complications of NAIC were reviewed. Several treatment-related local and/or systemic complications were noted.ResultsOne patient experienced ipsilateral eyelid and eyeball necrosis and permanent facial palsy; the second patient developed ipsilateral facial swelling and jaw claudication; and the third patient had febrile neutropenia, cellulitis, and phlebitis. These three patients underwent total exenteration. The fourth patient experienced neutropenia and thrombocytopenia and underwent tumour removal without exenteration. All patients were followed for more than 4 years and were alive at the last follow-up.ConclusionNeoadjuvant intra-arterial chemotherapy may be an alternative treatment that will improve the survival rate of ACC. However, careful and close observation is needed to minimise the risk of side effects. Further investigations are needed to justify the use of chemotherapy-related treatments and the associated costs.

Adenoid cystic carcinoma of the lacrimal gland metastatic to the kidney: case report and review of the literature

Adenoid cystic carcinoma (ACC) is a malignant neoplasm that arises within secretory glands. It rarely occurs in the lacrimal gland. Kidney metastases are very rare. We report a case of a 76-year-old female patient treated with right radical nephrectomy because of the tumour mass of the right kidney. Well-circumscribed, firm, grey mass was found on the lower pole of the kidney. Histologically, tumour was considered to be ACC. Retrospective history data showed ACC of the lacrimal gland surgically treated 14 years before with metastasis to the lung operated seven years before. Our diagnosis was metastatic ACC to the kidney. ACC has a remarkable capacity for recurrence. To our knowledge, in the English-speaking area (PubMed), 10 cases of ACC metastatic to the kidney have been described to date, and this is the second reported case of kidney metastasis from primary lacrimal ACC.

Primary culture and morphological characteristics of human lacrimal adenoid cystic carcinoma cells

To explore a method of primary culturing human adenoid cystic carcinoma cells of lacrimal gland. Experiment research. Tumor tissue was obtained from the surgical material of a patient diagnosed as lacrimal adenoid cystic carcinoma in Tianjin Medical University Eye Hospital during May 16th to June 1st.We gained primary cells via tissue culture techniques. Mixed cells were removed through several ways.Observed cell morphological characteristics by phase contrast microscope, scanning electron microscope and transmission electron microscope. Cyto-immunochemical staining was applied to detect the expressions of vimentin, desmin, S-100, cytokeratin, pan and CD34. Their expressions were also detected in the tumor tissue except CD34. Made cell growth curve and calculated cell doubling time. The outgrowth of cells was observed by day 5 after seeding tissues, and then cells generated slowly. The first passage proceeded by day 32, and the classical epithelioid cell colonies was observed by day 69 after inoculation. Purified cells of human lacrimal adenoid cystic carcinoma were obtained after the removal of mixed cells through several ways, which have been successfully subcultured for more than 100 passages. The 25th passage LACC cells appeared to be typically epithelioid cells, they showed contact inhibition as the density high enough.SEM and TEM showed the 25th passage LACC cells were malignant tumor cells poorly differentiated. They showed positive reaction with vimentin, cytokeratin (pan) as well as S-100, but negative reaction with desmin and CD34, which were consistent with the tumor tissue. The cell growth curve turned like a sigmoid one, and the cell doubling time was 37.1 h. We gained purified LACC cells, and understood the morphological characteristics, laying the foundation for the establishment of a human lacrimal adenoid cystic carcinoma cell line.

Lacrimal Gland Adenoid Cystic Carcinoma with High-Grade Transformation to Myoepithelial Carcinoma: Report of a Case and Review of Literature

Adenoid cystic carcinoma (AdCC) is the most frequent malignant neoplasm of the lacrimal glands. Like its salivary gland counterpart, lacrimal AdCC can rarely undergo high-grade transformation ("dedifferentiation"). We herein report the clinical, radiographic and microscopic findings of a lacrimal gland AdCC with high grade transformation, occurring in a 39-year-old female patient. In contrast to salivary gland AdCC with high-grade transformation, which usually shows a high grade component with "ductal" differentiation, in the case presented, the "dedifferentiated" component showed morphologic and immunohistochemical features of myoepithelial differentiation.