Clinical outcomes of rare hepatocellular carcinoma variants compared to pure hepatocellular carcinoma

Figures & data

Table 1 Baseline clinicopathologic characteristics of patients

	HCC NOS (pure)	HCC, fibrolamellar	HCC, scirrhous type	HCC, spindle cell variant	HCC, clear cell type	HCC, pleomorphic type	Combined HCC and cholangio (mixed HCC)	p-value
N (%) =80280	78461 (97.7)	310 (0.4)	161 (0.2)	72 (0.1)	487 (0.6)	23 (0.0)	766 (1.0)	-
Age at diagnosis	61.9	37.9	61.4	60.9	64.1	65.9	60.9	<0.001
Sex N (%)	Male: 60370 (76.9) Female: 18091 (23.1)	Male: 170 (54.8) Female: 140 (45.2)	Male: 123 (76.4) Female: 38 (23.6)	Male: 59 (81.9) Female: 13 (18.1)	Male: 303 (62.2) Female: 184 (37.8)	Male: 18 (78.3) Female: 5 (21.7)	Male: 510 (66.6) Female: 256 (33.4)	<0.001
Analytic stage N (%)	I: 26640 (33.9) II: 17888(22.8) III: 19349 (24.7) IV: 14583 (18.6)	I: 85 (27.4) II: 36 (11.6) III: 85 (27.4) IV: 104 (33.6)	I: 49 (30.4) II: 40 (24.9) III: 42 (26.1) IV: 30 (18.6)	I: 17 (23.6) II: 40 (13.9) III: 42 (22.2) IV: 30 (40.3)	I: 180 (36.9) II: 108 (22.2) III: 121 (24.9) IV: 78 (16.0)	I: 6 (26.1) II: 3 (13.0) III: 8 (34.8) IV: 6 (26.1)	I: 187 (24.4) II: 186 (24.3) III: 167 (21.8) IV: 224 (29.2)	<0.001
Race N (%)	Caucasian: 56472 (71.9) African American: 12543 (15.9) Other/missing: 9446 (12.2)	Caucasian: 253 (81.6) African American: 38 (12.3) Other/missing: 19 (6.1)	Caucasian: 137 (85.1) African American: 18 (11.2) Other/missing: 6 (3.7)	Caucasian: 57 (79.2) African American: 12 (16.7) Other/missing: 3 (4.1)	Caucasian: 345 (70.8) African American: 68 (13.9) Other/missing: 74 (15.3)	Caucasian: 16 (69.6) African American: 6 (26.1) Other/missing: 1 (4.3)	Caucasian: 585 (76.4) African American: 97 (12.7) Other/missing: 84 (10.9)	<0.001
Grade N (%)	Well: 10474 (13.4) Moderately: 13857 (17.7) Poorly: 7237 (9.2) Not determined: 46893 (59.7)	Well: 32 (10.3) Moderately: 83 (26.8) Poorly: 22 (7.1) Not determined: 173 (55.8)	Well: 24 (14.9) Moderately: 42 (26.1) Poorly: 26 (16.2) Not determined: 69 (42.8)	Well: 0 (0) Moderately: 4 (5.6) Poorly: 41 (56.9) Not determined: 27 (37.5)	Well: 77 (15.8) Moderately: 172 (35.3) Poorly: 52 (10.7) Not determined: 186 (38.2)	Well: 3 (13.0) Moderately: 3 (13.0) Poorly: 11 (47.8) Not determined: 6 (26.2)	Well: 44 (5.7) Moderately: 193 (25.2) Poorly: 258 (33.7) Not determined: 271 (35.4)	<0.001
Median tumor size (mm)	44	97	42	85	57	75.5	51	<0.001
Year of diagnosis N (%)	2004–2008: 27987 (35.7) 2009–2013: 50474 (64.3)	2004–2008: 145 (46.8) 2009–2013: 165 (53.2)	2004–2008: 66 (40.9) 2009–2013: 95 (59.0)	2004–2008: 22 (30.6) 2009–2013: 50 (69.4)	2004–2008: 203 (41.7) 2009–2013: 284 (58.3)	2004–2008: 14 (60.9) 2009–2013: 9 (39.1)	2004–2008: 397 (51.8) 2009–2013: 369 (48.2)	<0.001

Figure 1 Consort diagram outlining the patient selection.

Table 2 Treatment options and sequence of treatments

	HCC, NOS(Pure)	HCC, fibrolamellar	HCC, scirrhous	HCC, spindle cell variant	HCC, clear cell type	HCC, pleomorphic type	Combined HCC and cholangio(Mixed HCC)	p-value
Surgery at primary site N (%)	Ablation: 7696 (9.8) Surgery without transplant: 8291 (10.6) Surgery with transplant: 7945 (10.1)	Ablation: 6 (1.9) Surgery without transplant: 170 (54.8) Surgery with transplant: 10 (3.2)	Ablation: 14 (8.7) Surgery without transplant: 16 (9.9) Surgery with transplant: 26 (16.2)	Ablation: 3 (4.2) Surgery without transplant: 24 (33.3) Surgery with transplant: 5 (6.9)	Ablation: 25 (5.1) Surgery without transplant: 168 (34.5) Surgery with transplant: 43 (8.8)	Ablation: 0 (0) Surgery without transplant: 8 (34.8) Surgery with transplant: 2 (8.7)	Ablation: 30 (3.9) Surgery without transplant: 228 (29.8) Surgery with transplant: 111 (14.5)	<0.001
Surgical margin N (%)	Positive: 1457 (1.9) Negative: 15483 (19.7)	Positive: 21 (6.8) Negative: 148 (47.7)	Positive: 2 (1.2) Negative: 42 (26.1)	Positive: 7 (9.7) Negative: 19 (26.4)	Positive: 17 (3.5) Negative: 185 (37.9)	Positive: 1 (4.4) Negative: 8 (34.8)	Positive: 31 (4.0) Negative: 300 (39.2)	<0.001
Radiation N (%)	No: 70768 (90.2) Yes: 7023 (9.0)	No: 285 (91.9) Yes: 23 (7.4)	No: 136 (84.5) Yes: 24 (14.9)	No: 63 (87.5) Yes: 9 (12.5)	No: 436 (89.6) Yes: 47 (9.7)	No: 21 (91.3) Yes: 2 (8.7)	No: 691 (90.2) Yes: 69 (9.01)	0.586
Chemotherapy N (%)	No: 43426 (55.4) Yes: 33169 (42.3)	No: 173 (55.8) Yes: 128 (41.3)	No: 106 (65.8) Yes: 50 (31.1)	No: 44 (61.1) Yes: 26 (36.1)	No: 301 (61.8) Yes: 173 (35.5)	No: 15 (65.2) Yes: 8 (34.8)	No: 443 (57.8) Yes: 295 (38.5)	0.005
Systemic therapy before surgery N (%)*	4577 (5.8)	13 (4.2)	9 (5.6)	3 (4.2)	22 (4.5)	2 (8.7)	54 (7.1)	<0.001
Systemic therapy after surgery N (%)*	1695 (2.2)	25 (8.1)	5 (3.1)	7 (9.7)	16 (3.3)	0 (0)	57 (7.4)	<0.001

Notes: *These two rows are from the same systemic vs surgery sequence variable, and the other subgroups were not listed. They share the same p-value. Systemic therapy includes: Chemotherapy (NAACCR Item #1390), Hormone Therapy (NAACCR Item #1300), Immunotherapy (NAACCR Item #1410) and Hematologic Transplant and Endocrine Procedure (NAACCR Item #3250). In addition, surgery includes transplantation.

Table 3 Univariate and multivariate association with overall survival (from diagnosis)

Predictors	Univariate Analysis Hazard Ratio (95% CI)	Multivariate Analysis Hazard Ratio (95% CI)
Mixed HCC Pleomorphic Clear cell Spindle cell Scirrhous FLHCC Pure HCC*	1.13; 1.04–1.23; p=0.003 1.63; 1.07–2.51; p=0.025 0.92; 0.83–1.02; p=0.127 1.76; 1.37–2.24; p<0.001 0.97; 0.81–1.16; p=0.732 0.61; 0.53–0.71; p<0.001	1.18; 1.09–1.28; p<0.001 1.61; 1.05–2.47; p=0.029 1.11; 1.00–1.23; p=0.049 1.31; 1.03–1.68; p=0.030 0.83; 0.69–1.00; p=0.045 0.77; 0.66–0.89; p<0.001
Female Male*	0.87; 0.86–0.89; p<0.001	0.90; 0.88–0.92; p<0.001
Diagnosis between 2009–2013 Diagnosis between 2004–2008*	0.87; 0.86–0.89; p<0.001	0.88; 0.86–0.90; p<0.001
Treatment at academic center Treatment at comprehensive community cancer program*	0.55; 0.54–0.56; p<0.001	0.77; 0.75–0.78; p<0.001
Well differentiated Moderately differentiated Poorly differentiated/undifferentiated*	0.57; 0.55–0.59; p<0.001 0.59; 0.57–0.60; p<0.001	0.64; 0.62–0.66; p<0.001 0.79; 0.76–0.82; p<0.001
Positive surgical margin Negative surgical margin*	2.60; 2.44–2.77; p<0.001	1.52; 1.42–1.62; p<0.001
Stage I Stage II Stage III Stage IV*	0.21; 0.20–0.21; p<0.001 0.25; 0.24–0.25; p<0.001 0.60; 0.59–0.62; p<0.001	0.32; 0.31–0.33; p<0.001 0.41; 0.40–0.43; p<0.001 0.73; 0.71–0.75; p<0.001
Chemotherapy No chemotherapy*	0.76; 0.75–0.77; p<0.001	0.52; 0.51–0.53; p<0.001
Systemic therapy before surgery No systemic therapy and/or no surgery*	0.25; 0.24–0.26; p<0.001	1.43; 1.35–1.52; p<0.001
Systemic therapy after surgery No systemic therapy and/or no surgery*	0.60; 0.57–0.64; p<0.001	1.62; 1.52–1.73; p<0.001
Surgery without transplant No surgery*	0.31; 0.30–0.32; p<0.001	0.25; 0.24–0.26; p<0.001
Ablation No surgery*	0.40; 0.39–0.41; p<0.001	0.36; 0.34–0.38; p<0.001
Surgery with transplant No surgery*	0.13; 0.12–0.13; p<0.001	0.15; 0.14–0.15; p<0.001
Radiation No radiation*	1.09; 1.06–1.12; p<0.001	0.63; 0.61–0.65; p<0.001

Note: *Reference

Table 4 Multivariate survival analysis of OS by chemotherapy* – stratified by histology

Covariate	Level	Hazard Ratio (95% CI)	HR p-value
Comparisons stratified by histology:	Chemotherapy:	REF: No	–
Combined HCC and cholangio (Mixed HCC)	Yes vs No	0.59 (0.49–0.69)	<0.001
HCC, pleomorphic type	Yes vs No	0.71 (0.29–1.77)	0.464
HCC, clear cell type	Yes vs No	0.52 (0.42–0.64)	<0.001
HCC, spindle cell variant	Yes vs No	0.58 (0.34–0.99)	0.046
HCC, scirrhous	Yes vs No	0.75 (0.51–1.12)	0.161
HCC, fibrolamellar	Yes vs No	0.65 (0.48–0.87)	0.004
HCC, NOS(Pure)	Yes vs No	0.52 (0.51–0.53)	<0.001

Notes: *Chemotherapy (NAACCR Item #1390). Prior to 2013, targeted therapies that invoke an immune response, such as Herceptin, had been coded as chemotherapy. Effective with cases diagnosed January 1, 2013, and forward these therapies are classified as biological response modifiers. Coding instructions for these changes have been added to the remarks field for the applicable drugs in the SEER*RX Interactive Drug Database (http://seer.cancer.gov/tools/seerrx/).

Figure 2 Survival curves by histology.