World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Review

Volume 12, Number 1, February 2021, pages 7-19

Cutaneous Malignant Melanoma: A Review of Early Diagnosis and Management

**Table 1.** Classification of Cutaneous Melanoma According to TNM
Melanoma stage	Description
TNM: tumor-node-metastases.
0 (in situ)	Only the outer or top layer of skin cancer cells.
IA	The tumor is > 0.8 mm but < 1 mm with possible ulceration or without ulceration; the tumor is 0.8 mm thick or less.
IB	The tumor, without ulceration, is > 1 mm but < 2 mm thick.
IIA	The tumor is > 2 mm thick but < 4 mm thick without ulceration or with ulceration, the tumor is > 1 mm thick but < 2 mm thick.
IIB	The tumor is > 2 mm thick with ulceration but < 4 mm thick, or the tumor is > 4 mm thick without ulceration.
IIC	With ulceration, the tumor is more than 4 mm thick.
III	The spread of cancer to one or more lymph nodes close to the initial disease site.
IV	Cancer, also called metastatic melanoma, has spread to other body areas, such as the liver and lungs.

Table 1. Classification of Cutaneous Melanoma According to TNM

Melanoma stage

Description

TNM: tumor-node-metastases.

0 (in situ)

Only the outer or top layer of skin cancer cells.

The tumor is > 0.8 mm but < 1 mm with possible ulceration or without ulceration; the tumor is 0.8 mm thick or less.

The tumor, without ulceration, is > 1 mm but < 2 mm thick.

IIA

The tumor is > 2 mm thick but < 4 mm thick without ulceration or with ulceration, the tumor is > 1 mm thick but < 2 mm thick.

IIB

The tumor is > 2 mm thick with ulceration but < 4 mm thick, or the tumor is > 4 mm thick without ulceration.

IIC

With ulceration, the tumor is more than 4 mm thick.

III

The spread of cancer to one or more lymph nodes close to the initial disease site.

Cancer, also called metastatic melanoma, has spread to other body areas, such as the liver and lungs.

**Table 2.** Various Studies Reported the Patient’s Delay of Diagnosis
	Mean delay, month	< 1 month	1 - 3 month	3 - 6 month	6 - 12 month	> 12 month	No delay
Basnet et al, 2018 [35]	National Cancer Data Base (NCDB) (n = 313,329)	-	59.05%	31.89%	-	9.05%	-	-
Xavier et al, 2016 [31]	Brazil (n = 211)	5	16.6%, (n = 35)	17.1%, (n = 36)	11.8%, (n = 25)	8.1%, (n = 17)	18%, (n = 38)	28.4%, (n = 60)
Tyler et al, 2005 [32]	Canada (n = 176)	4.7	50%, (n = 88)		19.3%, (n = 34)		51.1%, (n = 9)	19.9%, (n = 35)
Betti et al, 2003 [30]	Italy (n = 216)	6.1	-	-	-	-	-	26.6%, (n = 57)
Richarde et al, 1999 [36]	France (n = 590)	2	23.10%, (n = 136)	17.60%, (n = 104)	13.40%, (n = 79)	8.50%, (n = 50)	8.30%, (n = 49)	29.2%, (n = 172)
Rampen et al, 1989 [37]	The Netherlands (n = 284)	-	6.7%, (n = 19)	16.9%, (n = 48)	15.8%, (n = 45)	16.9%, (n = 48)	33.6%, (n = 95)	10.3%, (n = 29)
Doherty er al, 1986 [38]	Scotland (n = 25)	-	16%, (n = 20)		50.4%, (n = 55)		33.6%, (n = 42)
Krige et al, 1991 [39]	South Africa (n = 250)	9.8	16.8%, (n = 42)	18%, (n = 45)	22%, (n = 55)	15.2%, (n = 38)	16.4%, (n = 41)	11.6%, (n = 29)
Schmid-Wendtner et al, 2002 [40]	Germany (n = 233)	-	15.5%, (n = 36)	16.7%, (n = 39)	14.6%, (n = 34)	11.6%, (n = 27)	29.20%, (n = 68)	12.4%, (n = 29)

Table 2. Various Studies Reported the Patient’s Delay of Diagnosis

Mean delay, month

< 1 month

1 - 3 month

3 - 6 month

6 - 12 month

> 12 month

No delay

Basnet et al, 2018 [35]

National Cancer Data Base (NCDB) (n = 313,329)

59.05%

31.89%

9.05%

Xavier et al, 2016 [31]

Brazil (n = 211)

16.6%, (n = 35)

17.1%, (n = 36)

11.8%, (n = 25)

8.1%, (n = 17)

18%, (n = 38)

28.4%, (n = 60)

Tyler et al, 2005 [32]

Canada (n = 176)

4.7

50%, (n = 88)

19.3%, (n = 34)

51.1%, (n = 9)

19.9%, (n = 35)

Betti et al, 2003 [30]

Italy (n = 216)

6.1

26.6%, (n = 57)

Richarde et al, 1999 [36]

France (n = 590)

23.10%, (n = 136)

17.60%, (n = 104)

13.40%, (n = 79)

8.50%, (n = 50)

8.30%, (n = 49)

29.2%, (n = 172)

Rampen et al, 1989 [37]

The Netherlands (n = 284)

6.7%, (n = 19)

16.9%, (n = 48)

15.8%, (n = 45)

16.9%, (n = 48)

33.6%, (n = 95)

10.3%, (n = 29)

Doherty er al, 1986 [38]

Scotland (n = 25)

16%, (n = 20)

50.4%, (n = 55)

33.6%, (n = 42)

Krige et al, 1991 [39]

South Africa (n = 250)

9.8

16.8%, (n = 42)

18%, (n = 45)

22%, (n = 55)

15.2%, (n = 38)

16.4%, (n = 41)

11.6%, (n = 29)

Schmid-Wendtner et al, 2002 [40]

Germany (n = 233)

15.5%, (n = 36)

16.7%, (n = 39)

14.6%, (n = 34)

11.6%, (n = 27)

29.20%, (n = 68)

12.4%, (n = 29)

**Table 3.** Categories of Noninvasive Detectors for Melanoma
Category	Explanation	Devices
Category-I devices	For large-scale screening purposes	Dermoscopy
		Sequential digital dermoscopy
	Total body photography
Evaluation of a few preselected, atypical lesions	Computer-aided multispectral digital analysis
	Electrical impedance spectroscopy
	Raman spectroscopy
Category-III devices	For evaluations by qualified experts of preselected lesions in specialist clinics	Reflectance confocal microscopy
		Multiphoton tomography
Category-IV devices	Experimental development stage, appropriate for the evaluation of a few preselected lesions	Stepwise two-photon-laser spectroscopy
		Quantitative dynamic infrared imaging

Table 3. Categories of Noninvasive Detectors for Melanoma

Category

Explanation

Devices

Category-I devices

For large-scale screening purposes

Dermoscopy

Sequential digital dermoscopy

Total body photography

Evaluation of a few preselected, atypical lesions

Computer-aided multispectral digital analysis

Electrical impedance spectroscopy

Raman spectroscopy

Category-III devices

For evaluations by qualified experts of preselected lesions in specialist clinics

Reflectance confocal microscopy

Multiphoton tomography

Category-IV devices

Experimental development stage, appropriate for the evaluation of a few preselected lesions

Stepwise two-photon-laser spectroscopy

Quantitative dynamic infrared imaging

**Table 4.** Genetic and Immunohistochemical Markers and Their Diagnostic Methods of Cutaneous Melanoma
Method/marker	Method description	Reference
Comparative genomic hybridization (CGH)	Accurate quantification of DNA copy number variations over a wide dynamic range with detection of single-copy deletions and duplications FFPE	[54]
Analyses of allelic imbalance (AI)	Detects the presence of deletions or gains of specific alleles	[55]
	Uses PCR amplification of microsatellite polymorphic markers followed by gel electrophoresis
	Performed on DNA from formalin-fixed paraffin-embedded tissues (FFPE) tissues
Multiplex ligation-dependent probe amplification (MLPA)	Measures the copy number of up to 45 nucleic acid sequences in one single reaction	[56]
	Performed on DNA extracted from routinely processed
Fluorescence in situ hybridization (FISH)	Utilizes a fluorescent probe or group of probes to search for preselected genomic abnormalities in tumors	[57]
Immunohistochemical markers
S100A6	Part of the family of S100 proteins	[58]
PCNA	A 36-kDa protein that is a cofactor of DNA polymerase d (expressed in all phases of cell cycle proliferation)	[59, 60]
	Proliferation marker
Ki-67	Proliferation marker	[61, 62]
FLIP	Immune modulatory marker	[63]
CD40	Immune modulatory marker-B-cell marker; also a tumor suppressor	[64]
CD26	Immune modulatory marker, an adenosine deaminase receptor	[65]
Cancer/testis antigens	Immune modulatory marker	[66]
	Proteins that are aberrantly expressed in many types of malignancies
Skp2	Cell cycle-related/anti-apoptosis markers	[67]
	F-box protein which aids the formation of a more massive protein complex that degrades p27
Retinoblastoma protein (RB)	Cell cycle-related/anti-apoptosis markers	[68, 69]
P53	Cell cycle-related/anti-apoptosis markers	[69, 70]
P21	Cell cycle-related/anti-apoptosis markers	[6, 70]
P16	Cell cycle-related/anti-apoptosis markers	[61, 72, 73]
HDM2	Cell cycle-related/anti-apoptosis markers	[74]
	90-kDa zinc finger protein that binds to p53 transcription activation domain inhibiting its function and targeting it for degradation by proteasomes
GADD	Cell cycle-related/anti-apoptosis markers	[75]
	Control transcription factors associated with cell cycle arrest, apoptosis, and cellular differentiation
Cyclin D3	Cell cycle-related/anti-apoptosis markers	[71]
Cyclin B	Cell cycle-related/anti-apoptosis markers	[70, 71]
Cyclin A	Cell cycle-related/anti-apoptosis markers	[70, 71]
Cdk2	Cell cycle-related/anti-apoptosis markers	[76]
Bcl-2	Cell cycle-related/anti-apoptosis markers	[77]
Trk-A	Signaling molecule	[78]
	Nerve growth factor receptor tyrosine kinase involved in activation of major oncogenic signaling pathways in melanoma, including the Ras/MAPK and phosphatidylinositol-3 kinase pathways
PTEN	Signaling molecule	[71, 79]

Table 4. Genetic and Immunohistochemical Markers and Their Diagnostic Methods of Cutaneous Melanoma

Method/marker

Method description

Reference

Comparative genomic hybridization (CGH)

Accurate quantification of DNA copy number variations over a wide dynamic range with detection of single-copy deletions and duplications FFPE

[54]

Analyses of allelic imbalance (AI)

Detects the presence of deletions or gains of specific alleles

[55]

Uses PCR amplification of microsatellite polymorphic markers followed by gel electrophoresis

Performed on DNA from formalin-fixed paraffin-embedded tissues (FFPE) tissues

Multiplex ligation-dependent probe amplification (MLPA)

Measures the copy number of up to 45 nucleic acid sequences in one single reaction

[56]

Performed on DNA extracted from routinely processed

Fluorescence in situ hybridization (FISH)

Utilizes a fluorescent probe or group of probes to search for preselected genomic abnormalities in tumors

[57]

Immunohistochemical markers

S100A6

Part of the family of S100 proteins

[58]

PCNA

A 36-kDa protein that is a cofactor of DNA polymerase d (expressed in all phases of cell cycle proliferation)

[59, 60]

Proliferation marker

Ki-67

Proliferation marker

[61, 62]

FLIP

Immune modulatory marker

[63]

CD40

Immune modulatory marker-B-cell marker; also a tumor suppressor

[64]

CD26

Immune modulatory marker, an adenosine deaminase receptor

[65]

Cancer/testis antigens

Immune modulatory marker

[66]

Proteins that are aberrantly expressed in many types of malignancies

Skp2