Sarah L. von Holstein

Lacrimal gland lesions in Denmark between 1974 and 2007.

Purpose:  To evaluate the incidence rate, distribution, patient characteristics and indications for surgical intervention of lacrimal gland lesions in Denmark between 1974 and 2007.

Adenoid cystic carcinoma of the lacrimal gland: MYB gene activation, genomic imbalances, and clinical characteristics.

PURPOSE To investigate genetic alterations in lacrimal gland adenoid cystic carcinomas (ACCs) with emphasis on the MYB-NFIB fusion oncogene and its downstream targets, MYB rearrangements, and copy number alterations in relation to clinical data and survival. DESIGN Experimental study. PARTICIPANTS AND CONTROLS Fourteen patients with primary lacrimal gland ACC were included. As a control, we also studied the expression of MYB-NFIB in 19 non-ACC lacrimal gland tumors. METHODS The expression and identity of MYB-NFIB fusion transcripts were studied using reverse transcriptase polymerase chain reaction (RT-PCR) and nucleotide sequence analyses. Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to evaluate the expression of MYB/MYB-NFIB target genes. High-resolution array-based comparative genomic hybridization (arrayCGH) and fluorescence in situ hybridization were used to study copy number alterations and MYB rearrangements. MAIN OUTCOME MEASURES mRNA or protein expression of MYB-NFIB, MYB, and its down stream targets; copy number alterations; and genomic rearrangements. RESULTS The median age of the patients was 43 years (equal gender distribution), and the median time of survival was 8.6 years. The MYB-NFIB fusion was expressed in 7 of 14 ACCs. In contrast, all non-ACC tumors were fusion-negative. All 13 ACCs tested stained positive for the MYB protein, and for the MYB targets KIT and BCL2, 12 were positive for MYC and CCNE1, and 9 were positive for CCNB1. Rearrangements of MYB were detected in 8 of 13 cases, including 2 cases with gain of an apparently intact MYB gene. The arrayCGH analysis revealed recurrent copy number alterations with losses involving 6q23-q27, 12q12-q14.1, and 17p13.3-p12, and gains involving 19q12, 19q13.31-qter, 8q24.13-q24.21, 11q12.3-q14.1, and 6q23.3. Neither MYB-NFIB fusion nor any copy number alteration correlated with survival. CONCLUSIONS Lacrimal gland ACCs are frequently positive for the MYB-NFIB fusion, overexpress MYB and its downstream targets, and have genomic profiles characterized by losses involving 6q, 12q, and 17p, and gains involving 19q, 8q, and 11q. Our findings show that lacrimal gland ACCs are genetically and clinically similar to their salivary gland counterparts and that MYB-NFIB is a clinically useful diagnostic biomarker for ACC. Our data also suggest that MYB and its downstream targets are potential therapeutic targets for these tumors. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Lacrimal gland pleomorphic adenoma and carcinoma ex pleomorphic adenoma: genomic profiles, gene fusions, and clinical characteristics.

PURPOSE To study genetic alterations in lacrimal gland pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (Ca-ex-PA) with focus on copy number changes and expression patterns of the translocation target genes PLAG1, HMGA2, and CRTC1-MAML2 in relation to clinical data. DESIGN Experimental study. PARTICIPANTS A total of 36 tumors from 32 patients with lacrimal gland PA or Ca-ex-PA were included in the study. METHODS Genome wide, high-resolution array-based comparative genomic hybridization (arrayCGH) and immunohistochemistry were used to study the genomic profiles and expression patterns of the translocation targets PLAG1, HMGA2, and CRTC1-MAML2. MAIN OUTCOME MEASURES Copy number alterations (gains/losses) and protein expression of PLAG1, HMGA2, and CRTC1-MAML2. RESULTS Genome-wide arrayCGH analysis revealed normal genomic profiles in 10 of 17 PA samples. The average number of genomic imbalances per tumor was 3.25 (range, 1-7) in primary and recurrent PAs with alterations compared with 7.7 (range, 4-12) in Ca-ex-PAs. Five recurrent copy number alterations were identified in PAs, including losses of 1pter-p31.3, 6q22.1-q24.3, 8q24.22-q24.3, and 13q21.31-q21.33, and gain of 9p23-p22.3. Gain of 9p23-p22.3 also was seen in a Ca-ex-PA. In Ca-ex-PA, gain of 22q12.3-qter was the only recurrent alteration. Detailed analysis of the array data identified NFIB and PDGFB as the 2 major candidate target oncogenes that may be activated as a result of copy number gains involving 9p and 22q. Both genes have been implicated in the pathogenesis of PA and other types of salivary gland tumors. Immunohistochemical analysis revealed frequent overexpression of the translocation target gene PLAG1 in PAs and in 1 Ca-ex-PA. In contrast, overexpression of HMGA2 was observed in only a small subset of PAs. The CRTC1-MAML2 fusion oncoprotein was overexpressed in 2 mucoepidermoid Ca-ex-PAs. CONCLUSIONS Lacrimal and salivary gland PAs and Ca-ex-PAs have similar genomic profiles and frequently overexpress the PLAG1 oncoprotein. Copy number gains involving 9p23-p22.3 (NFIB) and 22q12-qter (PDGFB) may be of importance for disease progression in a subset of lacrimal gland PAs.

CRTC1-MAML2 gene fusion in mucoepidermoid carcinoma of the lacrimal gland

Epithelial tumors of the lacrimal gland are histologically similar to salivary gland tumors. Here we report on a rare case of mucoepidermoid carcinoma (MEC) in a 73‑year-old man with a swelling of the left lacrimal gland. The tumor had a microscopic appearance consistent with a classical low-grade MEC of the lacrimal gland. There were no signs of recurrence or metastases during a five-year follow-up. Using RT-PCR and FISH we demonstrated that the tumor was positive for the CRTC1-MAML2 gene fusion previously shown to be associated with in particular low-grade salivary MECs with favorable prognosis. By immunohistochemistry we showed that the majority of tumor cells, including epidermoid, intermediate and mucous producing cells, expressed the CRTC1-MAML2 fusion protein. In contrast, 15 non-MEC lacrimal neoplasm were fusion-negative. Our findings show that lacrimal MEC is not only clinically and morphologically but also genetically identical to MECs originating from other exocrine glands, including those of the lung, thyroid, cervix and salivary glands. Taken together, the present and previous studies further emphasize the fundamental biologic and genetic similarities among MECs developing from different anatomical sites and organs. Moreover, our findings indicate that the CRTC1-MAML2 fusion may be a useful diagnostic and prognostic biomarker for lacrimal MEC.

K5/K14-positive cells contribute to salivary gland-like breast tumors with myoepithelial differentiation

Salivary gland-like tumors of the breast show a great variety of architectural patterns and cellular differentiations such as glandular, myoepithelial, squamous, and even mesenchymal phenotypes. However, currently little is known about the evolution and cellular differentiation of these tumors. For that reason, we performed an in situ triple immunofluorescence lineage/differentiation tracing (isTILT) and qRT-PCR study of basal (K5/K14), glandular (K7/K8/18), and epidermal-specific squamous (K10) keratins, p63, and smooth muscle actin (SMA; myoepithelial marker) with the aim to construct and trace different cell lineages and define their cellular hierarchy in tumors with myoepithelial differentiation. isTILT analysis of a series of 28 breast, salivary, and lacrimal gland tumors, including pleomorphic adenomas (n=8), epithelial-myoepithelial tumors (n=9), and adenoid cystic carcinomas (n=11) revealed that all tumor types contained K5/K14-positive progenitor cells in varying frequencies from a few percent up to 15%. These K5/K14-positive tumor cells were found to differentiate to glandular- (K8/18-positive) and myoepithelial-lineage (SMA-positive)-specific cells and were also shown to generate various heterologeous cell differentiations such as squamous and mesenchymal progenies. p63 was co-expressed with K5/K14 in basal-like progenitor cells, myoepithelial, and squamous cells but not in glandular cells. Our results show that the corresponding counterpart tumors of breast and salivary/lacrimal glands have identical cellular compositions. Taken together, our isTILT and RNA-expression data indicate that look-alike tumors of the breast represent a special subgroup of basal-type tumors with benign or usually low malignant potential.

Tumours of the lacrimal gland. Epidemiological, clinical and genetic characteristics.

Tumours of the lacrimal gland are rare, but the prognosis may be grave. To date, no population‐based incidence and distribution data on lacrimal gland tumours exist. In addition, almost nothing is known about the genetic profile of epithelial tumours of the lacrimal gland.

An update on tumors of the lacrimal gland

Lacrimal gland tumors are rare and constitute a wide spectrum of different entities ranging from benign epithelial and lymphoid lesions to high-grade carcinomas, lymphomas, and sarcomas with large differences in prognosis and clinical management. The symptoms and findings of a lacrimal gland lesion are a growing mass at the site of the lacrimal gland, including displacement of the eyeball, decreased motility, diplopia, and ptosis. Pain is the cardinal symptom of an adenoid cystic carcinoma. Radiological findings characteristically include an oval, well-demarcated mass for benign lesions whereas malignant lesions typically display calcifications, destruction of bone, and invasion of adjacent structures. The diagnosis ultimately relies on histology, as does the choice of treatment and the prognosis. In recent years, the understanding of the biology of numerous types of lacrimal gland neoplasia has improved and the choice of treatment has changed accordingly and holds further promise for future targeted therapies. Treatment of benign epithelial lesions is surgical excision whereas carcinomas often require adjuvant radiotherapy and/or chemotherapy. In contrast, the cornerstone in management of lymphoid lesions is chemotherapy, often including a monoclonal antibody. This article presents an update on the clinical, radiological, histological, and molecular features, along with treatment strategies for tumors of the lacrimal gland.

Granular cell tumour of the lacrimal gland

Purpose To report the clinical and histopathological characteristics of a patient with a granular cell tumour (GCT) of the lacrimal gland. Methods Surgical excision and histological examination. Results A 38-year old male presented with a painful swelling located temporally in the right upper eyelid. Clinical examination revealed proptosis and displacement of the right eye and a tumour was palpated at the site of the lacrimal gland. MRI scan revealed a solid tumour in the lacrimal fossa. The tumour was excised. Microscopically the tumour was composed of tumour cells with coarsely granular cytoplasm. The tumour cells were arranged in clusters and ribbons separated by collagen bundles and no necrosis or mitosis were present. The granules were PAS positive, diastase resistant and the tumour cells expressed focal staining for S100. Electron microscopy showed numerous secondary lysosomes. The diagnosis is consistent with a GCT. Conclusion This case presents for the first time a GCT of the lacrimal gland.

Tumors of the lacrimal gland

Tumors of the lacrimal gland comprise a wide spectrum, of which the most common demonstrate epithelial and lymphoid differentiation. The diagnosis of lacrimal gland tumors depends primarily on histological evaluation, as do the choice of treatment and prognosis. For some lacrimal gland neoplasms, such as adenoid cystic carcinoma, the outlook is grave. Optimal treatment for several lacrimal gland tumors is also a matter of controversy. However, recent progress has been made in the molecular and genetic understanding of tumorigenesis for such lesions. This article presents an overview of the histopathology of lacrimal gland tumors, together with their epidemiological features, clinical characteristics, and treatment strategies.

Adenoid cystic carcinomas of the salivary gland, lacrimal gland, and breast are morphologically and genetically similar but have distinct microRNA expression profiles

Adenoid cystic carcinoma is among the most frequent malignancies in the salivary and lacrimal glands and has a grave prognosis characterized by frequent local recurrences, distant metastases, and tumor-related mortality. Conversely, adenoid cystic carcinoma of the breast is a rare type of triple-negative (estrogen and progesterone receptor, HER2) and basal-like carcinoma, which in contrast to other triple-negative and basal-like breast carcinomas has a very favorable prognosis. Irrespective of site, adenoid cystic carcinoma is characterized by gene fusions involving MYB, MYBL1, and NFIB, and the reason for the different clinical outcomes is unknown. In order to identify the molecular mechanisms underlying the discrepancy in clinical outcome, we characterized the phenotypic profiles, pattern of gene rearrangements, and global microRNA expression profiles of 64 salivary gland, 9 lacrimal gland, and 11 breast adenoid cystic carcinomas. All breast and lacrimal gland adenoid cystic carcinomas had triple-negative and basal-like phenotypes, while salivary gland tumors were indeterminate in 13% of cases. Aberrations in MYB and/or NFIB were found in the majority of cases in all three locations, whereas MYBL1 involvement was restricted to tumors in the salivary gland. Global microRNA expression profiling separated salivary and lacrimal gland adenoid cystic carcinoma from their respective normal glands but could not distinguish normal breast adenoid cystic carcinoma from normal breast tissue. Hierarchical clustering separated adenoid cystic carcinomas of salivary gland origin from those of the breast and placed lacrimal gland carcinomas in between these. Functional annotation of the microRNAs differentially expressed between salivary gland and breast adenoid cystic carcinoma showed these as regulating genes involved in metabolism, signal transduction, and genes involved in other cancers. In conclusion, microRNA dysregulation is the first class of molecules separating adenoid cystic carcinoma according to the site of origin. This highlights a novel venue for exploring the biology of adenoid cystic carcinoma.