von Holstein Sarah Linéa
Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Acta Ophthalmol. 2013 Nov;91 Thesis 6:1-28. doi: 10.1111/aos.12271.
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.
泪腺肿瘤较为罕见，但预后可能很严重。迄今为止，尚无基于人群的泪腺肿瘤发病率和分布数据。此外，对于泪腺上皮肿瘤的基因特征几乎一无所知。我们收集了丹麦34年间所有经活检的泪腺病变的标本和临床档案，并重新评估诊断结果，以提供最新的基于人群的发病率和流行病学特征。收集了腺样囊性癌（ACC）、多形性腺瘤（PA）、多形性腺瘤恶变（Ca-ex-PA）和黏液表皮样癌（MEC）患者的症状、临床检查、治疗及随访等临床数据。我们采用逆转录聚合酶链反应（RT-PCR）、荧光原位杂交（FISH）、免疫组织化学、定量聚合酶链反应（Q-PCR）和基于高分辨率芯片的比较基因组杂交（arrayCGH）技术，探索了ACC、PA、Ca-ex-PA和MEC的基因特征，包括拷贝数改变（CNA）。经活检的泪腺病变发病率为每年1.3/1000000，其中约50%为肿瘤性病变。其中，55%为恶性肿瘤，上皮性肿瘤最为常见。总体发病率呈上升趋势，这是由经活检的非肿瘤性病变增加所致。我们发现，14例ACC中有10例表达MYB-NFIB融合基因和/或发生MYB重排。所有ACC均表达MYB蛋白。ACC的特征是6号染色体长臂（6q）、12号染色体长臂（12q）和17号染色体长臂（17q）反复出现拷贝数缺失，19号染色体长臂（19q）、8号染色体长臂（8q）和11号染色体长臂（11q）出现拷贝数增加。ArrayCGH显示19例PA中有11例基因组图谱明显正常。其余8例PA存在1号染色体短臂（1p）、6q、8q和13q反复出现拷贝数缺失，9号染色体短臂（9p）出现拷贝数增加。所有PA肿瘤均表达PLAG1，而29例肿瘤中只有2例表达HMGA2。Ca-ex-PA的特征是22号染色体长臂（22q）反复出现拷贝数增加。5例Ca-ex-PA中有3例表达PLAG1，而这些肿瘤均未表达HMGA2。MEC表达CRTC1-MAML2，且发现该融合基因是泪腺MEC特有的。总之，在丹麦人群中，需要进行病理评估的泪腺病变很少见，经活检的良性病变发病率在增加。泪腺上皮肿瘤在肿瘤特异性融合基因表达和arrayCGH显示的基因组失衡方面，在分子水平上与唾液腺上皮肿瘤非常相似。MYB-NFIB是ACC和MYB的有用生物标志物，其下游靶基因可能是这些肿瘤的潜在治疗靶点。
