Retrospective study on mixed neuroendocrine non-neuroendocrine neoplasms from five European centres

Table 1 Demographic and clinical-pathological characteristics in patients with a diagnosis of mixed neuroendocrine non-neuroendocrine neoplasm

Variable	Category	n (%)	Variable	Category	n (%)
Gender			Predominant component
	Female	25 (36.2)		NE	27 (39.1)
	Male	44 (63.8)		Non-NE	12 (17.4)
				Equal proportion	7 (10.1)
				NA	23 (33.3)
Disease stage			Morphology of NE component
	Localised	37 (53.6)		Large cell	13 (18.8)
	Advanced	30 (43.5)		Small cell	5 (7.2)
	NA	2 (2.9)		Others	1 (1.4)
				NA	50 (72.4)
Primary tumour site			Grading of NE component
	Colon	22 (31.9)		Grade 1	3 (4.3)
	Oesophagus/OGJ	11 (15.9)		Grade 2	14 (20.3)
	Rectum	8 (11.6)		Grade 3	57 (82.6)
	Small bowel/ICJ	8 (11.6)		NA	3 (4.3)
	Pancreas	6 (8.7)
	Stomach	4 (5.8)	Ki-67 of NE component
	Anus	4 (5.8)		Median	70% (55-68)
	Biliary tract	3 (4.3%)		< 55%	19 (27.5)
	Appendix	2 (1.9)		≥ 55%	37 (53.6)
	Unknown	1 (1.5)		NA	13 (18.8)
			Histology of non-NE component
	Lower GI	44 (63.8)		ADC	51 (39.1)
	Upper GI	15 (21.7)		Adenoma	2 (17.4)
	PB	9 (13)		Carcinoma/SCC	1 (10.1)
	Unknown	1 (1.5)		NA	15 (33.3)
			Grading of non- NE component
				Grade 1	10 (14.5)
				Grade 2	14 (20.3)
				Grade 3	20 (29.0)
				Adenoma	2 (17.4)
				NA	23 (33.3)

Note: the sum of the percentages might not reach 100% due to rounding. ECOG: Eastern Cooperative Oncology Group; PS: Performance status; Loc: Localised stage; Adv: Advanced stage; NE: Neuroendocrine; ADC: Adenocarcinoma; SCC: Squamous cell carcinoma; OE: Oesophageal; OGJ: Oesophago-gastric junction; ICJ: Ileo-caecal junction; Lower GI: Lower gastrointestinal tract; Upper GI: Upper gastrointestinal tract; PB: Pancreatico-biliary tract; NA: Not available.

Table 2 Immunohistochemical data on diagnostic samples of mixed neuroendocrine non-neuroendocrine neoplasm

Variable	Category	Number	%
Synaptophysin
	Positive	60	87.0
	Negative	0	0
	NA	9	13.0
Chromogranin A
	Positive	37	53.6
	Negative	16	23.2
	NA	16	23.2
CD56
	Positive	26	37.7
	Negative	10	14.5
	NA	33	47.8
CK-20
	Positive	22	31.9
	Negative	11	15.9
	NA	36	52.2
CK-7
	Positive	24	34.7
	Negative	10	14.5
	NA	35	50.8
CDX-2
	Positive	33	47.8
	Negative	4	5.8
	NA	32	46.4

Note: The sum of the percentages may not reach 100% due to rounding. NA: Not available.

Table 3 Univariate analyses for recurrence-free-survival and overall survival in patients with a diagnosis of localised mixed neuroendocrine non-neuroendocrine neoplasm

	RFS				OS
	n	Median (mo)	95%CI	P value	n	Median (mo)	95%CI	P value
Primary tumour site
Lower GI	25	15.70	10.1-NR	0.28	25	29.6	19.1-NR	< 0.001
PB	4	8.11	2.9-NR		4	8.6	7.6-NR
Upper GI	5	14.89	8.0-NR		5	20.4	9.4-NR
Unknown	0				0
Age at diagnosis
< 70 yr	22	15.5	11.5-NR	0.023	22	32.6	20.7-NR	0.017
≥ 70 yr	12	9.2	6.5-NR		12	16.1	8.6-NR
ECOG PS
0-1	27	12.7	9.2-NR	0.29	27	29.6	18.3-NR	0.34
≥ 2	5	18.5	5.7-NR		5	28.6	14.3-NR
Gender
Female	14	7.0	4.2-NR	0.081	14	11.9	8.6-NR	0.037
Male	20	15.5	11.5-NR		20	32.6	19.1-NR
Predominant component
ADC	9	11.5	6.4-NR	0.99	9	20.7	15.9-NR	0.66
EQUAL	2	8.1	-		2	-	-
NE	14	12.7	7.0-NR		14	20.4	18.3-NR
Grading NE component
G1	2	-	-	0.16	2	-	-	0.24
G2	2	33.7	24.4-NR		2	36.7	29.6-NR
G3	29	11.5	8.0-18.5		29	20.7	15.9-NR
Ki-67 of NE component
< 55%	9	17.1	2.9-NR	0.67	9	28.6	8.6-NR	0.83
≥ 55%	17	9.2	7.0-NR		17	19.1	14.3-NR
pN+
No	4	-	-	0.015	4	-	-	0.069
Yes	16	10.1	6.5		16	28.6	14.3-NR
Periop-treatment
No	13	14.0	7.0-NR	0.375	13	28.6	16.1-NR	0.24
Yes	19	14.9	8.0-NR		19	20.4	14.3-NR

RFS: Recurrent free survival; OS: Overall survival; 95%CI: 95% confidence interval; NR: Not reached; Lower GI: Lower gastrointestinal tract; Upper GI: Upper gastrointestinal tract; PB: Pancreatico-biliary tract; PS: Performance status; ECOG: Eastern Cooperative Oncology Group; ADC: Adenocarcinoma; EQUAL: Equal proportions of the two histologies; NE: Neuroendocrine component; pN+: Presence of metastatic loco-regional lymph nodes on post-operative pathological examination; Periop: Perioperative (adjuvant and/or neoadjuvant chemotherapy and/or radiotherapy) .

Table 4 Univariate analysis of progression-free survival and overall survival in patients with advanced mixed neuroendocrine non-neuroendocrine neoplasm

	PFS				OS
	n	Median (mo)	95%CI	P value	n	Median (mo)	95%CI	P value
Primary tumour site
Lower GI	35	6.6	4.6-7.4	0.008	37	9.6	5.21-15.2	< 0.001
PB	7	4.4	0.8-NR		7	4.4	2-NR
Upper GI	11	9.5	5.1-NR		11	9.5	5.1-NR
Unknown	1	1.3	-		1	1.3	-
Age at diagnosis
< 70 yr	32	5.9	4.3-9.5	0.19	32	9.5	5.2-16.3	0.23
≥ 70 yr	22	5.6	3.8-8.0		22	9.0	4.6-14.7
ECOG PS
0-1	36	6.9	4.6-8.2	0.9	36	9.6	5.216.3	0.45
≥ 2	13	5.9	3.4-NR		13	5.9	4.6-NR
Gender
Female	20	5.2	2.6-9.1	0.5	20	7.9	3.7-19.8	0.96
Male	34	6.9	4.6-9.5		34	9.0	5.2-15.2
Predominant component
ADC	11	4.4	2.6-NR	0.08	11	4.4	2.6-NR	0.14
EQUAL	6	9.5	4.4-NR		6	34.2	12.4-NR
NE	23	5.6	4.3-7.2		23	7.2	5.2-13.7
Grading NE component
G1	0				0
G2	5	6.9	5.2-NR	0.65	5	53.8	5.2-NR	0.34
G3	49	5.6	4.4-7.4		49	9.0	5.2-13.4
Ki-67 of NE component
< 55%	14	7.0	5.3-12.9	0.78		10.7	5.6-NR	0.6
≥ 55%	32	4.7	3.9-8.0			7.2	5.15-13.4
First line active treatment
No	13	2.2	1.6	< 0.001		3.7	2.0	< 0.001
Yes	40	7.1	5.2-9.8			13.4	9.0-16.3

PFS: progression free survival; OS: overall survival; 95%CI: 95% confidence interval; NR: Not reached; Lower GI: Lower gastrointestinal tract; Upper GI: Upper gastrointestinal tract; PB: Pancreatico-biliary tract; PS: Performance status; ECOG: Eastern Cooperative Oncology Group; ADC: Adenocarcinoma; EQUAL: Equal proportions of the two histologies; NE: Neuroendocrine component; Note: Advanced mixed neuroendocrine non-neuroendocrine neoplasms include both patients who presented with advanced disease at diagnosis and those who developed advanced recurrent disease after initial curative treatment. First line active treatment includes palliative surgery alone, palliative surgery combined with chemotherapy, chemotherapy alone, chemo-radiotherapy.