Ophthalmic symptoms, clinical signs and diagnostic delay in infants diagnosed with brain tumours in Denmark between 2007 and 2017.

PURPOSE: To investigate ophthalmic onset manifestations and the impact of diagnostic delay on the prognosis in infants (<1 year) diagnosed with a brain tumour. METHODS: A retrospective population-based nationwide study of infants diagnosed with a brain tumour between 2007 and 2017 in Denmark. Data was retrieved from the Danish Childhood Cancer Registry, the National Danish Health registries, and medical files. Primary outcome measures included symptoms, clinical findings, time to diagnosis and survival. RESULTS: Thirty-seven infants were diagnosed with a brain tumour in Denmark between 2007 and 2017. In total, 19/37 infants (51%, 95% CI: 34-68) had ophthalmic manifestations at any time prior to or at diagnosis; and in 6/37 (16%, 95% CI: 6-32) ophthalmic manifestations were the initial symptom. The most common ophthalmic manifestations were strabismus (n = 7), sunset eyes (n = 6), nystagmus (n = 4), reduced pupillary light reflex (n = 4), and/or decreased vision (n = 4). The median number of symptoms per infant at the time of diagnosis was three (range 0-9). The median diagnostic delay was 26 days (range 0-283, IQR: 6;90). 5-year survival rate was 75% (95% CI: 61-90) and all children with diagnostic delay > 100 days (n = 9, 24%) were still alive at the end of follow-up (median 6.3 years, range 2.2-10.2). CONCLUSION: We provide an overview of symptoms and clinical signs in a nation-wide series of infants with CNS tumours and demonstrate that ophthalmic manifestations are frequently observed in infants prior to diagnosis, but, often in combination with other clinical signs. The diagnostic delay was substantial for a large part of the infants, but this was not associated with increased mortality.

Nystagmus in children with primary brain tumours in Denmark between 2007 and 2017.

BACKGROUND: The aim of the study was to evaluate the prevalence, clinical characteristics, and diagnostic importance of nystagmus in children with brain tumours. METHODS: A nation-wide retrospective review of all children diagnosed with a brain tumour between January the 1st, 2007 and December 31st, 2017, in Denmark. Data is based on information from the Danish Childhood Cancer Registry, hospital records from paediatric- and ophthalmological departments, and records from private ophthalmologists. RESULTS: Nystagmus was observed in 13.7% (60/437) of children with a brain tumour. In 50/60 children (83.3%) nystagmus was an incidental finding at the clinical examination and only in 10/60 children (16,7%) were nystagmus noticed by patient/caregivers prior to the clinical examination. In 38/60 children nystagmus was observed before the brain tumour diagnosis, most often (16/38, 42%) the same day as the diagnosis was made. In 22/60 children nystagmus was found after the brain tumour diagnosis (prior to any treatment) with a median of four days (range 0-47) after the brain tumour diagnosis. Nystagmus was most commonly binocular (56/60, 93.3%) and gaze-evoked (43/60, 71.7%). The median number of additional symptoms and/or clinical findings was five (range 0-11). CONCLUSION: Nystagmus is frequent in children with brain tumours and is typically accompanied by other symptoms and clinical signs. However, nystagmus is often first recognized by the ophthalmologist late in the time course. Therefore, raising awareness of the importance of looking for nystagmus in children with unspecific neurological symptoms might contribute to increased suspicion of brain tumour and thereby faster diagnosis.

Epidemiology and clinical characteristics of congenital choristomas in the ocular adnexa of pediatric patients.

PURPOSE: To investigate the epidemiology and clinical characteristics of infants presenting with conjunctival, palpebral, or orbital congenital choristomas (dermolipomas, epidermoids, and dermoid cysts) and children undergoing surgery for congenital choristomas in the ocular adnexa. METHODS: We reviewed the medical files of congenital choristomas in children seen in The Capital Region of Denmark during a 5-year period (2014-2018). Children (< 18 years) were divided into two groups: those referred < 1 year of age (Group I) and those undergoing surgery to remove the lesion (Group II). Group I was used to calculate a population-based incidence of congenital choristomas by comparing our data to birth statistics from the Danish Medical Birth Registry. RESULTS: A total of 97 children were included, 43 in Group I and 70 in Group II (including 16 patients from Group I). The total incidence of congenital choristomas was 1 in 2537 live born children. Most lesions were palpebral choristomas (27/43, 63%) located in the superotemporal region (17/27, 63%), followed by the superonasal region (7/27, 26%). The main reasons for surgical removal of a congenital choristoma were growth (28/70, 40%) or cosmesis (25/70, 36%). CONCLUSION: The total incidence of congenital choristomas in the ocular adnexa of infants < 1 year of age, including both conjunctival and palpebral congenital choristomas, is about 1 in 2537 live born children in The Capital Region of Denmark. Hence, congenital choristomas are common masses found in the ocular adnexa.

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.

Recurrent rearrangements of the PLAG1 and HMGA2 genes in lacrimal gland pleomorphic adenoma and carcinoma ex pleomorphic adenoma.

PURPOSE: Lacrimal gland tumours constitute a wide spectrum of neoplastic lesions that are histologically similar to tumours of the salivary gland. In the salivary gland, pleomorphic adenoma (PA) is frequently characterized by recurrent chromosomal rearrangements of the PLAG1 and HMGA2 genes, a genetic feature retained in carcinoma ex pleomorphic adenoma (ca-ex-PA) that makes it possible to distinguish ca-ex-PA from de novo carcinomas. However, whether PLAG1 and HMGA2 gene rearrangements are found in lacrimal gland PA and ca-ex-PA is not known. METHODS: Twenty-one lacrimal gland PAs and four ca-ex-PAs were retrospectively reviewed and subjected to break-apart fluorescence in situ hybridization (FISH) for rearrangements of the PLAG1 gene. Cases without PLAG1 abnormalities were subjected to HMGA2 break-apart FISH. Immunohistochemical staining for PLAG1 and HMGA2 protein was performed and correlated with gene status. RESULTS: Sixteen of 21 PAs showed rearrangement of PLAG1 and were all positive for PLAG1 protein. Two of the remaining five PAs showed rearrangement of HMGA2 and were the only cases positive for HMGA2 with immunohistochemistry. The three FISH-negative PAs expressed PLAG1 protein. All four ca-ex-PAs showed rearrangement of PLAG1 and expressed PLAG1 protein. None of the de novo carcinomas showed rearrangement of either of the two genes or expression of the two proteins. CONCLUSION: Rearrangement of PLAG1 and HMGA2 and expression of the corresponding proteins are frequent and specific findings in lacrimal gland PA and ca-ex-PA. The mechanism for PLAG1 overexpression in FISH-negative PAs is yet to be clarified.

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.

Breast carcinoma metastasis to the lacrimal gland: Two case reports.

A 77-year-old female, with proptosis, reduced eye motility and diplopia which had developed over two to three months and a 69-year-old female with proptosis, oedema of the eyelid, reduced motility and ptosis, which had developed over three weeks, are presented in the present study. Computed tomography scans revealed irregular lacrimal gland tumours in the two patients. The two patients had history of breast cancer. The first breast cancer metastasis in the lacrimal gland demonstrated a cribriform growth pattern containing ductal elements. The epithelial tumour cells stained positive for cytokeratin (1-8, 10, 14-16, 18 and 19), oestrogen receptor, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA) and gross cystic disease fluid protein 15 (GCDFP-15). The second metastatic tumour was positive for EMA and estrogen receptor, but variably positive for CEA and GCDFP-15. The metastasis in the lacrimal gland was a pleomorphic tumour. The tumour cells were positive for EMA and variably positive for oestrogen and CEA. Metastases to the lacrimal gland are extremely rare, and metastases to the lacrimal gland should be considered in the diagnoses of lacrimal gland tumours. The present study aimed to describe two such cases and draw attention to breast carcinomas as a differential diagnosis and the most frequent cause of lacrimal gland metastasis.

Genetic analysis of an orbital metastasis from a primary hepatic neuroendocrine carcinoma.

A 71-year-old female with a known history of primary hepatic neuroendocrine carcinoma, presented with a visual defect, proptosis and restricted eye movements of the right eye. Biopsies from the orbit and from the primary hepatic neuroendocrine carcinoma showed similar morphological and immunohistochemical features, and high-resolution, array-based comparative genomic hybridization demonstrated loss of one copy each of chromosomes 3 and 18, and gain of 1q both in the primary hepatic neuroendocrine carcinoma and in the orbital tumour. The orbital mass was diagnosed as a metastasis from the primary hepatic neuroendocrine carcinoma. Primary hepatic neuroendocrine tumours are extremely rare, and the orbit is an extremely rare location for a neuroendocrine carcinoma metastasis. This is the first reported case of an orbital metastasis with origin from a primary hepatic neuroendocrine carcinoma.

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.

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.

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. We collected specimens and clinical files on all biopsied lacrimal gland lesions in Denmark over a 34-year period and re-evaluated the diagnosis to provide updated population-based incidence rates and epidemiological characteristics. Clinical data regarding symptoms, clinical examinations, treatment and follow-up were collected for patients with adenoid cystic carcinoma (ACC), pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (Ca-ex-PA) and mucoepidermoid carcinoma (MEC). Using RT-PCR, FISH, immunohistochemistry, Q-PCR and high-resolution array-based comparative genomic hybridization (arrayCGH) we explored the genetic characteristics including copy number alterations (CNA) in ACC, PA, Ca-ex-PA and MEC. The incidence of biopsied lacrimal gland lesions was 1.3/1,000,000/year, and ~50% were neoplastic lesions. Of these, 55% were malignant tumours with epithelial tumours as the most frequent. The overall incidence was increasing, and this was caused by an increase in biopsied non-neoplastic lesions. We found that 10/14 ACCs either expressed the MYB-NFIB fusion gene and/or had rearrangements of MYB. All ACCs expressed the MYB protein. ACC was characterized by recurrent copy number losses involving 6q, 12q and 17q and gains involving 19q, 8q and 11q. ArrayCGH revealed an apparently normal genomic profile in 11/19 PAs. The remaining 8 PAs had recurrent copy number losses involving 1p, 6q, 8q and 13q and gain involving 9p. PA expressed PLAG1 in all tumours whereas only 2/29 tumours expressed HMGA2. Ca-ex-PA was characterized by recurrent copy number gain involving 22q. PLAG1 was expressed in 3/5 Ca-ex-PA whereas none of these tumours expressed HMGA2. MEC expressed the CRTC1-MAML2, and this fusion was found to be tumour-specific for lacrimal gland MEC. In conclusion, lacrimal gland lesions that require pathological evaluation are rare in the Danish population, and the incidence rate of biopsied benign lesions is increasing. Epithelial tumours of the lacrimal gland are molecularly very similar to their salivary gland counterparts in the expression of the tumour-specific fusion genes and in their genomic imbalances as demonstrated by arrayCGH. MYB-NFIB is a useful biomarker for ACC and MYB, and its downstream target genes may be potential therapeutic targets for these tumours.

Epithelial tumours of the lacrimal gland: a clinical, histopathological, surgical and oncological survey.

Epithelial tumours of the lacrimal gland represent a large spectrum of lesions with similarities in clinical signs and symptoms but with different biological behaviour and prognosis. They are rare, but with aggressive malignant potential. Tumours of the lacrimal gland may present with swelling of the lacrimal gland, displacement of the eyeball, reduced eye motility and diplopia. Pain and symptoms of short duration before the first ophthalmic consultation are characteristic of malignant tumours. The histological diagnosis determines the subsequent treatment regimen and provides important clues regarding the prognosis. The purpose of this paper is to describe the various primary epithelial tumours of the lacrimal gland. In the first part of the review, the frequency, demographics, clinical presentation and diagnostic features are described. In the second part, primarily tumour-specific histological characteristics are given. Finally, treatment modalities including surgical procedures and medical oncology as well as prognosis are discussed.

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. MATERIAL AND METHODS: All biopsied/surgically removed lacrimal gland lesions in Denmark during the period 1974-2007 were identified by searching two population-based registries. Specimens were collected and re-evaluated. The following data were collected: age, gender, indications for surgical intervention and local recurrence. RESULTS: A total of 232 lesions from 210 patients with a histologically verified lesion of the lacrimal gland were included. The incidence rate of lacrimal gland lesions was 1.3/1 000 000/year. The overall annual age- and gender-adjusted incidence rate more than doubled during the study period, owing to an increase in non-malignant lesions. Approximately half of the lesions were neoplasms (119) and 55% (66) of these were malignant. Dacryops constituted 10% (24), inflammatory lesions 27% (62), normal tissue 12% (27), benign tumours 23% (53) and malignant tumours 29% (66). Patients with malignant neoplasms were significantly older than patients with benign neoplasms (63 versus 48 years, p < 0.001). The indication for surgical intervention was suspicion of a tumour in more than 90% of the neoplastic lesions and in 30% of the non-neoplastic lesions. CONCLUSION: Lacrimal gland lesions that require surgical evaluation are rare in the Danish population and represent a wide spectrum of diagnoses, mostly benign. The overall incidence rate of biopsied lacrimal gland lesions is increasing.

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 73­year-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.