Gallbladder neuroendocrine carcinoma diagnosis, treatment and prognosis based on the SEER database: A literature review

Table 1 Clinicopathological features of GB-NEC and GB-ADC

Clinical variable	GB-NEC (n = 287)	GB-ADC (n = 19 484)	P value
Age, mean (range), yr	68 (32-98)	70 (11-104)	0.175
Race, n (%)			0.372
Black	35 (12.2%)	2187 (11.2%)
White	227 (79.1%)	15121 (77.6%)
Other	25 (8.7%)	2127 (10.9%)
Sex, n (%)			0.239
Female	192 (66.9%)	13679 (70.2%)
Male	95 (33.1%)	5805 (29.8%)
Grade, n (%)			< 0.001
I	9 (3.1%)	2220 (11.4%)
II	7 (2.4%)	5853 (30.0%)
III	98 (34.1%)	5980 (30.7%)
IV	68 (23.7%)	445 (2.3%)
Unknown	105 (36.6%)	4986 (25.6%)
Survival time, median, 95%CI (mo)	8 (6.6-9.4)	7 (6.8-7.2)	0.079
Histologic type, n (%)
Neuroendocrine carcinoma	149 (51.9%)
Large cell neuroendocrine carcinoma	29 (10.1%)
Small cell neuroendocrine carcinoma	109 (38.0%)
SEER Combined Mets at DX-liver, n (%)	53 (18.5%)

Grade: Grade I: well differentiated; differentiated; NOS Grade II: Moderately differentiated; moderately differentiated; intermediate differentiation; Grade IIL: Poorly differentiated; Differentiated Grade IV: Undifferentiated: Anaplastic Surveillance Epidemiology and End Results Combined Mets at DX-liver: The tumor metastasized to the liver. GB-NEC: Gallbladder neuroendocrine carcinoma; GB-ADC: Gallbladder adenocarcinoma; SEER: Surveillance Epidemiology and End Results.

Table 2 2019 World Health Organization and 2017 international Agency for Research on Cancer classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract and hapatopancreatobiliary organs

Terminology	Differentiation	Grade	Mitotic1 rate (mitoses/2 mm2)	Ki-67 index	Molecular differences
NET Gl	Well-differentiated NET (carcinoid)	Low	< 2	< 3%	Mutations in MEN1, DAXX .ATRX
NET G2		Intermediate	2-20	3% - 20%	Mutations in MEN1, DAXX .ATRX
NET G3		High	> 20	> 20%	Mutations in MEN1, DAXX .ATRX
NEC2	Poorly differentiated NEC	High	> 20	> 20%	Mutations in TP53 or RB1
Mixed NENs2	Well or poorly differentiated	Variable3	Variable	Variable

¹Mitotic rates arc expressed as number of mitoses/2 mm² as determined by counting in 50 fields of 0.2 mm² (in a total area of 10 mm²); The Ki-67 proliferation index is determined by counting at least 500 cells in regions of highest labeling (hot-spots) which arc identified at scanning magnification; The Grade is based on whichever of the two proliferation indexes place the neoplasm in the higher grade category[6].

²NEC including {NEC, small-cell lype [SCNEC; NEC; large cell typc (LCNEC)]}; Mixed NENs including [mixed neuroendorine-non-neuroendorine neoplasms (MiNENs)]; Mixed adenoneuroendocrine carcinomas (MANECs).

³Vriablc means: Changeable.

NET: Neuroendocrine tumors; NEC: Neuroendocrine carcinoma.

Table 3 Clinical manifestations and laboratory tests of GB-NEC

Clinical features of GB-NEC	Immunohistochemical	Biomarker
Discomfort or pain in the upper abdomen[4,7,10,18,22,33-43]	CgA synaptophysin, CD5 (most frequent)[4,17,22,33,34,44-47]	CA-125[4,18]
Physical examination found[34,39]	cytokeratin 7 (CK7 cytoplasmic positivity)[4,33,37,38,40,41,44,48,49]	CA-199[4,10,18]
Weight loss[27,45,48]	TTF-1[33,38,41,48]	CEA[4,18,36,46]
Poor appetite[4,18,33,50]	Cytokeratin[4,18,38,48]	Blood CgA[45,49]
Jaundice[4,27]	CD117[38]	soluble IL-2 receptor (sIL-2R)[34]
Fever[40]	loss of Rbl expression with intense pl6 labeling[38]	NSE[4,17,34]
Carcinoid syndrome[7,17]	EMA[10,49]
Abnormal liver function[41]	CA199[42]
nausea and vomiting[36]	P53[10]

Immunohistochemical positive markers are described in the second column. Elevated tumor markers in serum are depicted in the third column. GB-NEC: Gallbladder neuroendocrine carcinoma; CgA: Chromogranin A.

Table 4 Application of surgical treatment of GB-NEC

Tumor stage	Treatment
T1aN0M0	Cholecystectomy
T1bNOMO	Cholecystectomy + gallbladder bed cautery/wedge resection1
T2-T3NOMO	Cholecystectomy + wedge resection/cholecystectomy + resection of liver segments (IVb + V/> 3 segments)/hepatectomy + pancreaticoduodenectomy
T1-T3N1MO	Cholecystectomy + resection of liver segments + lymph node resection (D1/D22)/hepatectomy+pancreaticoduodenectomy + lymph node resection (D1/D2)
IVA and IVB (advanced stage)	Systemic comprehensive therapy

¹Wedge resection: Wedge resection of the liver parenchyma of the gallbladder fossa. The specific amount of liver parenchyma to be removed has not yet been determined. In our center, liver parenchyma of 2 cm at the margin of gallbladder fossa is generally removed.

²D1 and D2: D1: Dissection of lymph nodes around the hepatic ligament; D2: Extended dissection of lymph nodes beyond the hepatic ligament.

GB-NEC: Gallbladder neuroendocrine carcinoma.

Table 5 Currently effective chemoradiotherapy regiments that have been tried

Ref.	Chemoradiotherapy regiments
Moris et al[44]	XELOX and Zometaf
Chen et al[36], Meoni et al[45], Furrukh et al[46], Abutaka et al[49]	CBP and ETP
Tidjane et al[39]	ETP+CP four cycles + 5-fluorouracil + oxaliplatin
Okuyama et al[34]	Intravenous CP (60 mg/m2) and DXT (60 mg/m2) every 3 wk for four cycles, followed by intravenous CBP (120 mg/m2) and DXT (60 mg/m2) every 3 wk for three cycles
Duffy et al[3]	VP-16 150 mg/dL; CP 50 mg/dL
Chen et al[4]	Radiotherapy with 10 MV-X-ray and 3D-CRT, (50 Gy/25f)
Shimono et al[10]	3D-CRT (40 Gy/20 fractions per 4 wk and to give 10 Gy/20 fractions per 4 wk, respectively, resulting in a total dose of 50 Gy) + CP + ETP and CAV followed by CP + ETP alone
Shimono et al[10]	Three cycles of CP (50 mg/body) + ETP (80 mg/body) as systemic chemotherapy

CBP: Carboplatin; ETP: Etoposide (VP-16); CP: Cisplatin; 3D-CRT: 3D conformal radiotherapy; DXT: Docetaxel; CAV: Etoposide; cyclophosphamide, adriamycin, and vincristine.

Table 6 Univariate and multivariate Cox regression analysis of prognostic factors for overall survival

Variables	Univariate P value	Multivariate P value	HR (95%CI)
Race	0.842	NA	NA
Histology	0.931	NA	NA
Grade	0.123	NA	NA
Liver metastasis	> 0.001	> 0.001	3.055 (1.839-5.075)
Age	0.004	0.01	1.027 (1.006-1.049)

HR: Hazard ratio; CI: Confidence interval; NA: Not available.