杨路路  译，黄文斌  校

伴有t(6;11)(p21;q12)易位的肾细胞癌是一种低级别肾细胞癌，多见于年轻人。该肿瘤典型的特征为少见的的双相形态，表现为较小的细胞群集在基底膜周围，它们再由较大的上皮样细胞巢围绕聚集于腔内。t(6;11)(p21;q12)易位使Alpha (MALAT1)基因和TFEB转录因子基因发生融合，导致TFEB表达上调，该基因表达上调引起这种独特肿瘤的标志性的黑色素细胞标记物的异常表达。本文报道了8例证实有TFEB基因扩增的肾细胞癌，其中6例仅有TFEB基因扩增，2例存在TFEB基因扩增和重排，并证明TFEB过表达后引起的下游反应。结果发现像未扩增的t(6;11) 肾细胞癌，所有TFEB扩增性肾细胞癌均伴有异常的黑色素细胞标记物表达。然而，TFEB扩增性肾细胞与普通的t(6;11) 未扩增性肾细胞癌之间存在明显的不同。首先，与t(6;11)未扩增性肾细胞癌相比，TFEB扩增性肾细胞癌较大（中位年龄64.5岁），而未扩增性肾细胞癌中位年龄为31岁。其次，TFEB扩增性肾细胞癌的形态不总是完全独特的，常表现为高级别上皮样细胞巢，胞质嗜酸性，伴假乳头形成和坏死，或真性乳头形成。这些形态学特征需与高级别透明细胞癌以及乳头状肾细胞癌鉴别。第三，TFEB和黑素色细胞标记物的表达在TFEB扩增性肾细胞癌中更加不一致。8例TFEB扩增性肾细胞癌中，6例免疫组化检测有TFEB蛋白表达，而所有8例均表达melan-A，仅有5例表达cathepsin K，仅3例表达HMB45。第四，TFEB扩增性肾细胞癌具有更强的临床侵袭能力。3例表现为晚期或发生转移，2例随后发生转移，而其他3例随访时间短或无随访。我们的研究结果得到了文献中报道的6例TFEB扩增性肾细胞癌的证实，这些病例来自于1篇个案报道、1个摘要和大的队列肾细胞癌中的2个基因组研究内的4个病例。总之，TFEB扩增性肾细胞癌代表着高级别成人肾细胞癌的一种独特的分子亚型，该亚型具有侵袭性的临床行为，不同的形态学特征和异常的黑色素细胞标记物表达。

Argani P, Reuter VE, Zhang L, et al. TFEB-amplified renal cell carcinomas: An agressive molecular subset demonstrating variable melanocytic marker expression and morphologic heterogeneity. Am J Surg Pathol, 2016,40:1484-1495。

Abstract: Renal cell carcinomas (RCCs) with the t(6;11)(p21;q12) chromosome translocation are low-grade RCC which often occur in young patients. They typically feature an unusual biphasic morphology characterized by nests of larger epithelioid cells surrounding intraluminal collections of smaller cells clustered around basement membrane material. The t(6;11)(p21;q12) translocation fuses the Alpha (MALAT1) gene with the TFEB transcription factor gene, resulting in upregulated expression of intact native TFEB that drives the aberrant expression of melanocytic markers which is a hallmark of this distinctive neoplasm. We now report 8 cases of RCC, which demonstrate TFEB gene amplification (6 without TFEB rearrangement,  2 with concurrent TFEB rearrangement) and demonstrate downstream consequences of TFEB overexpression. Like the unamplified t(6;11) RCC, all TFEB-amplified RCC were associated with aberrant melanocytic marker expression. However, several differences between TFEB-amplified RCC and the usual unamplified t(6;11) RCC are evident. First, TFEB-amplified RCC occurred in older patients (median age, 64.5 y) compared with unamplified t(6;11) RCC (median age, 31 y). Second, the morphology of TFEB-amplified RCC is not entirely distinctive, frequently featuring nests of high-grade epithelioid cells with eosinophilic cytoplasm associated with pseudopapillary formation and necrosis, or true papillary formations. These patterns raise the differential diagnosis of high-grade clear cell and papillary RCC. Third, TFEB and melanocytic marker expression was more variable within the TFEB-amplified RCC. TFEB protein expression by immunohistochemistry was detectable in 6 of 8 cases. While all 8 cases expressed melan-A, only 5 of 8 expressed cathepsin K and only 3 of 8 expressed HMB45. Fourth, the TFEB-amplified RCC were associated with a more aggressive clinical course; 3 of 8 cases presented with advanced stage or metastatic disease, 2 subsequently developed metastatic disease, whereas the other 3 cases had minimal/no follow-up. Our results are corroborated by scant data reported on 6 TFEB-amplified RCC in the literature, gleaned from 1 case report, 1 abstract, and 4 individual cases identified within 2 genomic studies of large cohorts of RCC. In summary, TFEB-amplified RCC represent a distinct molecular subtype of high-grade adult RCC associated with aggressive clinical behavior, variable morphology, and aberrant melanocytic marker expression.