Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136�patients

Abstract

Abstract. The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI-NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI-NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-γ and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD-1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy.

Prognostic impact of CD73 expression and its relationship to PD-L1 in patients with radically treated pancreatic cancer

“…In our study cohort, high CD73 expression in both tumour cells and in stroma was significantly associated with PD-L1 expression in tumour cells. Similar findings have been reported in gastrointestinal neuroendocrine neoplasms [ 35 ]. Deng et al demonstrated a close connection between these two immunosuppressive molecules in their recent mouse experiment concerning head and neck cancer [ 33 ].…”

“…90 was set as a cut off value c Tumour samples were considered positive when >3% of lymphocytes were positive for CD73 d Tumour stroma positivity was considered weak, moderate or strong when < 5%, 5-16% or > 17% of the stromal area was stained, respectively e Due to the strong staining intensity of vascular structures, 95% was set as a cut off value for CD73 positivity of vascular structures In our study cohort, high CD73 expression in both tumour cells and in stroma was significantly associated with PD-L1 expression in tumour cells. Similar findings have been reported in gastrointestinal neuroendocrine neoplasms [35]. Deng et al demonstrated a close connection between these two immunosuppressive molecules in their recent mouse experiment concerning head and neck cancer [33].…”

CD73 expression in normal and pathological human hepatobiliopancreatic tissues

“…PanNET/PanNEC are in accordance with those from a recent report indicating that >70% of gastrointestinal NETs and 40% of NECs are CD73 negative. [59] As pancreatic neuroendocrine neoplasms are considered a heterogeneous entity, with…”

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

“…Thirty to fifty percent of PanNET/PanNEC express mild to moderate CD73 expression and associates with increased malignant potential, which is similar to gastrointestinal (GI)-NET/NECs (80,172,217). In GI-NET/NECs, CD73 expression positively correlates with PD-L1 expression (217), which possibly anti-PD-1/PD-L1 therapy with CD73 and/or A2AR blockade may benefit these patients. Increased expression of CD73 with PanNET also associates with cancer cell stemness (e.g., aldehyde dehydroxygenase expression) and aggressive behavior (80).…”

“…Pancreatic neuroendocrine tumors and carcinomas (PanNET/PanNEC) account for 1-10% of pancreatic tumors (215,216). Thirty to fifty percent of PanNET/PanNEC express mild to moderate CD73 expression and associates with increased malignant potential, which is similar to gastrointestinal (GI)-NET/NECs (80,172,217). In GI-NET/NECs, CD73 expression positively correlates with PD-L1 expression (217), which possibly anti-PD-1/PD-L1 therapy with CD73 and/or A2AR blockade may benefit these patients.…”