Nomogram Incorporating the WNT/β-Catenin Signaling Pathway for Predicting the Survival of Cutaneous Melanoma

Figures & data

Table 1 Criteria for Immunohistochemistry Score

Variables	1 Point	2 Points	3 Points
β-catenin	<1/3	1/3–2/3	>2/3
VEGF	<10%	10–50%	>50%
DKK1	<25%	25–50%	>50%

Abbreviations: VEGF, vascular endothelial growth factor, DKK1, Dickkopf 1.

Figure 1 Immunohistochemical staining of CM and control tissue. In the CM tissue, positive VEGF expression (A), positive β-catenin expression in the cytoplasm and nuclei (B), and negative DKK1 expression (C) were displayed. In the control tissue, negative VEGF expression (D), positive β-catenin expression in the cell membrane (E), and positive DKK1 expression (F) were displayed. Positive cells exhibited brown cytoplasmic staining (at 400 × magnification).

Abbreviations: CM, cutaneous melanoma; VEGF, Vascular Endothelial Growth Factor; DKK1, Dickkopf 1.

Figure 2 KM analysis for the OS probability of CM patients. The 1-, 3-, 5- year OS rates in the training cohort (78.4%, 56.3%, 43.9%) and the validation cohort (77.8%, 51.6%, 41.0%) were similar.

Abbreviations: KM, Kaplan-Meier; OS, overall survival; CM, cutaneous melanoma.

Table 2 Association of Survival with Clinical and Pathological Parameters in CM Patients Within 5 Years

Variables		N (%)	1-Year OS Rate	3-Year OS Rate	5-Year OS Rate	χ^2	P
Age	≥55	120 (63.2%)	76.8%	55.3%	40.0%	1.232	0.281
	<55	70 (36.8%)	81.4%	64.3%	42.9%
Sex	Male	97 (51.1%)	78.4%	56.3%	38.9%	0.223	0.638
	Female	93 (48.9%)	83.1%	63.6%	45.5%
Ulceration	Yes	108 (56.8%)	61.0%	28.0%	17.1%	49.541	<0.001
	No	82 (43.2%)	91.7%	77.8%	55.6%
Lymph node metastasis	Yes	75 (39.5%)	58.7%	22.7%	6.7%	90.293	<0.001
	No	115 (60.5%)	91.3%	78.3%	60%
Distant metastasis	Yes	61 (32.1%)	60.7%	18.0%	0%	95.581	<0.001
	No	129 (67.9%)	86.8%	74.4%	56.6%
Breslow thickness	<1mm	44 (23.2%)	90.9%	77.3%	68.2%	29.240	<0.001
	1–2mm	74 (38.9%)	83.8%	70.6%	44.1%
	>2mm	72 (37.9%)	66.7%	32.1%	38.9%
Pathologic type	Supericial type	100 (52.6%)	94.6%	81.1%	45.9%	7.013	0.132
	Nodular type	37 (19.5%)	70.0%	42.0%	34.0%
	Acrotype	53 (27.9%)	78.4%	55.3%	38.9%
Clark level	I–IV	150 (77.3%)	83.1%	67.6%	46.6%	30.550	<0.001
	V	40 (20.6%)	61.9%	16.7%	0%
Satellite lesions	Yes	88 (46.3%)	75.4%	53.6%	36.2%	2.201	0.143
	No	102 (52.6%)	86.5%	63.5%	46.2%
Dermal mitoses	<1/mm^2	45 (23.68%)	88.9%	73.3%	66.7%	14.625	<0.001
	≥1/mm^2	145 (77.32%)	75.2%	51.0%	30.3%
History of misdiagnosis	Yes	32 (16.8%)	77.8%	54.4%	36.1%	2.613	0.109
	No	158 (83.2%)	81.3%	65.6%	53.1%
Range of surgical resection	<1cm	55 (28.9%)	48.3%	26.7%	16.7%	46.224	<0.001
	1–2cm	58 (30.6%)	86.2%	46.6%	27.6%
	>2cm	77 (40.5%)	97.2%	88.9%	66.7%
Interferon therapy	Yes	91 (47.9%)	83.5%	59.3%	41.8%	0.890	0.345
	No	99 (52.1%)	73.7%	53.5%	36.4%
VEGF	Positive	121 (63.7%)	67.2%	36.2%	15.5%	70.741	<0.001
	Negative	69 (36.3%)	95.9%	87.8%	75.7%
β-catenin	Positive	103 (54.2%)	62.4%	28.7%	11.9%	87.230	<0.001
	Negative	87 (45.8%)	95.5%	85.4%	69.7%
DKK1	Positive	69 (36.3%)	90.9%	78.5%	58.6%	26.593	<0.001
	Negative	121 (63.7%)	63.8%	37.7%	18.8%

Abbreviations: CM, cutaneous melanoma; VEGF, vascular endothelial growth factor; DKK1, Dickkopf 1.

Figure 3 KM analyses of indicators in predicting the prognosis of CM patients within 5 years. KM curves at different classifications of age (A), sex (B), ulceration (C), lymph node metastasis (D), distant metastasis (E), Breslow thickness (F), pathologic type (G), Clark level (H), satellite lesions (I), history of misdiagnosis (J), range of surgical resection (K), dermal mitoses (L), interferon therapy (M), VEGF (N), β-catenin (O), and DKK1 (P) were shown. It revealed that ulceration, distant metastasis, lymph node metastasis, Breslow thickness, Clark levels, dermal mitoses, β-catenin, VEGF, and DKK1 were associated with the OS.

Abbreviations: KM, Kaplan-Meier; CM, cutaneous melanoma; VEGF, vascular endothelial growth factor; DKK1, Dickkopf 1; OS: overall survival.

Figure 4 Multivariate COX regression analysis of independent indicators in predicting the prognosis of CM patients.

Abbreviations: CM, cutaneous melanoma; VEGF, vascular endothelial growth factor; DKK1, Dickkopf 1; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 5 Nomogram predicting the prognosis of CM patients.

Abbreviations: CM, cutaneous melanoma; VEGF, vascular endothelial growth factor; DKK1, Dickkopf 1; HR, hazard ratio; 95% CI, 95% confidence interval.

Figure 6 Internal and external validation of the nomogram predicting the OS of CM patients. The AUCs in the training cohort and validation cohort were 0.914, 0.852, 0.785 (A–C) and 0.904, 0.840, 0.773 (G–I), respectively, indicating good discrimination. The calibration plots in the training and validation datasets were shown in (D–F) and (J–L). Both indicated that the nomogram-predicted prognosis compared well with the actual prognosis.

Abbreviations: OS, overall survival; CM, cutaneous melanoma; AUC, area under the curve.

Figure 7 ROC curves of different models predicting the 1-, 3-, and 5- year OS of CM patient (A–C). The AUCs of the nomogram with the Wnt/β-catenin signaling pathway (0.914, 0.852, 0.785) were highest compared with the nomogram without the Wnt/β-catenin signaling pathway (0.693, 0.640, 0.615) and the TNM stage (0.726, 0.693, 0.673).

Abbreviations: ROC, receiver operating characteristic, OS, overall survival, CM, cutaneous melanoma, AUC, area under the curve, TNM, Tumor-Node-Metastasis.