Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Boston, MA, USA.
Histopathology. 2023 Oct;83(4):546-558. doi: 10.1111/his.14996. Epub 2023 Jul 16.
While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX-positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1-positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere-specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence.
Two hundred fifty-six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases.
ARX reactivity correlated with worse disease-free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT-positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT-negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX-positive tumours and 7.5% (5/67) of ARX-negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX-positive tumours recurred compared to 0 of 33 ARX-negative tumours and 33.3% (3/9) ALT-positive tumours showed recurrence versus 4.4% (2/45) ALT-negative tumours.
Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low-grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention.
虽然许多胰腺神经内分泌肿瘤（PanNET）表现出惰性行为，但预测小的无功能性 PanNET 的生物学行为仍然是一个挑战。具有类似于胰岛α细胞（ARX 阳性）的表观基因组和转录组的无功能性 PanNET 比类似于胰岛β细胞（PDX1 阳性）的肿瘤更具侵袭性。在这项研究中，我们探讨了 ARX 和 PDX1 的免疫组织化学和端粒特异性荧光原位杂交（FISH）用于替代端粒延长（ALT）的能力，以预测复发。
鉴定了 256 例 PanNET 患者，并进行了 ARX 和 PDX1 的免疫组织化学检测。阳性染色定义为> 5%的肿瘤细胞中存在强烈的核染色。在一部分病例中进行了 ALT 的 FISH。
ARX 反应与无病生存期（DFS）较差相关（P = 0.011），而 PDX1 反应与 DFS 之间无相关性（P = 0.52）。ALT 阳性肿瘤（n = 63，31.8%）的 DFS 明显低于 ALT 阴性肿瘤（n = 135，68.2%）（P < 0.0001）。ARX 反应与 ALT 阳性相关（P < 0.0001）。在无功能肿瘤中，ARX 阳性肿瘤的复发率为 18.5%（30/162），ARX 阴性肿瘤的复发率为 7.5%（5/67）。在 WHO 分级 1 和 2、肿瘤大小≤2cm 的 PanNET 中，ARX 阳性肿瘤的复发率为 14%（6/43），而 ARX 阴性肿瘤的复发率为 0%，33.3%（3/9）的 ALT 阳性肿瘤出现复发，而 4.4%（2/45）的 ALT 阴性肿瘤出现复发。
ARX 和 ALT FISH 状态的免疫组织化学可能有助于区分生物学惰性病例和侵袭性小低级别 PanNET，并有助于识别可能优先受益于手术干预的患者。
