Joseph Nancy M, Umetsu Sarah E, Kim Grace E, Terry Merryl, Perry Arie, Bergsland Emily, Kakar Sanjay
Department of Pathology, University of California San Francisco (UCSF), 505 Parnassus Avenue, Room M-559, San Francisco, CA, 94143, USA.
Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA, USA.
Endocr Pathol. 2024 Dec;35(4):325-337. doi: 10.1007/s12022-024-09835-y. Epub 2024 Nov 18.
High-grade or grade 3 epithelial neuroendocrine neoplasms (G3 NEN) are now divided into grade 3 well-differentiated neuroendocrine tumor (G3 NET) and neuroendocrine carcinoma (NEC), both defined by Ki-67 > 20% and/or > 20 mitoses per 2 mm. NET and NEC are thought to be distinct tumors with different genetic profiles: NEC classically harbors co-alteration of TP53 and RB1, whereas NET genetics are site-dependent with frequent alterations in MEN1, ATRX, DAXX, and TSC1/2 in pancreatic NETs. Progression from NET to NEC is considered rare and is not well described. While both TP53 and RB1 alterations were initially thought to be rare in NET, recent work has demonstrated the former in up to 35% of high-grade G3 NET and the latter in rare high-grade NEN that progressed from NET. Here, we describe the clinical, pathologic, and molecular features associated with tumor evolution in a series of five patients that had low-grade NET that progressed to high-grade NEN with co-alteration of RB1 and TP53, similar to NEC. Morphology of the high-grade neoplasms remained well-differentiated in some cases despite RB1/TP53 co-alteration and had some NEC-like features in other cases. All five patients died of disease, with a mean overall survival of 41 months from the first metastatic disease and 12 months from acquisition of RB1/TP53 co-alteration. Our data demonstrate that low-grade NET can progress via the acquisition of both TP53 and RB1 alteration, similar to NEC, but whether this represents a transformation from NET to NEC remains unclear.
高级别或3级上皮性神经内分泌肿瘤（G3 NEN）现分为3级高分化神经内分泌肿瘤（G3 NET）和神经内分泌癌（NEC），两者均由Ki-67＞20%和/或每2mm有＞20个核分裂象定义。NET和NEC被认为是具有不同基因特征的不同肿瘤：NEC通常存在TP53和RB1的共同改变，而NET的基因改变则因部位而异，胰腺NET中MEN1、ATRX、DAXX和TSC1/2常有改变。NET进展为NEC被认为很罕见，且描述不多。虽然最初认为TP53和RB1改变在NET中都很罕见，但最近的研究表明，高达35%的高级别G3 NET存在前者改变，而后者改变则见于罕见的从NET进展而来的高级别NEN。在此，我们描述了5例低级别NET进展为高级别NEN且伴有RB1和TP53共同改变（类似于NEC）患者的肿瘤演变相关的临床、病理和分子特征。尽管存在RB1/TP53共同改变，但部分病例中高级别肿瘤的形态仍保持高分化，而其他病例则具有一些NEC样特征。所有5例患者均死于疾病，从首次出现转移疾病起的平均总生存期为41个月，从出现RB1/TP53共同改变起为12个月。我们的数据表明，低级别NET可通过获得TP53和RB1改变而进展，类似于NEC，但这是否代表从NET向NEC的转变仍不清楚。
