Melanoma Treatment (PDQ®) 1/3 —Health Professional Version - National Cancer Institute

Melanoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Melanoma Treatment (PDQ®)–Health Professional Version

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ON THIS PAGE

• General Information About Melanoma
• Cellular and Molecular Classification of Melanoma
• Stage Information for Melanoma
• Treatment Option Overview for Melanoma
• Stage 0 Melanoma Treatment
• Stage I Melanoma Treatment
• Stage II Melanoma Treatment
• Resectable Stage III Melanoma Treatment
• Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment
• Changes to This Summary (04/11/2019)
• About This PDQ Summary

General Information About Melanoma

In This Section

• Incidence and Mortality
• Risk Factors
• Anatomy
• Screening
• Clinical Features
• Diagnosis
• Prognostic Factors
• Related Summaries

Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate, including the uveal tract. Uveal melanomas differ significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment. (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)

Incidence and Mortality

Estimated new cases and deaths from melanoma in the United States in 2019:[1]

• New cases: 96,480.
• Deaths: 7,230.

Skin cancer is the most common malignancy diagnosed in the United States, with 5.4 million cancers diagnosed among 3.3 million people in 2012.[1] Invasive melanoma represents about 1% of skin cancers but results in most deaths.[1,2] The incidence has been increasing over the past 30 years.[1] Elderly men are at highest risk; however, melanoma is the most common cancer in young adults aged 25 to 29 years and the second most common cancer in those aged 15 to 29 years.[3] Ocular melanoma is the most common cancer of the eye, with approximately 2,000 cases diagnosed annually.

Risk Factors

Risk factors for melanoma include both intrinsic (genetic and phenotype) and extrinsic (environmental or exposure) factors:

• Sun exposure.
• Pigmentary characteristics.
• Multiple nevi.
• Family and personal history of melanoma.
• Immunosuppression.
• Environmental exposures.

(Refer to the PDQ summaries on Skin Cancer Prevention and the Genetics of Skin Cancerfor more information about risk factors.)

Anatomy

ENLARGE

Schematic representation of normal skin. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The relatively avascular epidermis houses both basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for basal cell carcinoma and squamous cell carcinoma, respectively. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

Screening

Refer to the PDQ summary on Skin Cancer Screening for more information.

Clinical Features

Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Although melanoma can occur anywhere, including on mucosal surfaces and the uvea, melanoma in women occurs more commonly on the extremities, and in men it occurs most commonly on the trunk or head and neck.[4]

Early signs in a nevus that would suggest a malignant change include the following:

• Darker or variable discoloration.
• Itching.
• An increase in size or the development of satellites.
• Ulceration or bleeding (later signs).

ENLARGE

Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Diagnosis

A biopsy, preferably by local excision, should be performed for any suspicious lesions. Suspicious lesions should never be shaved off or cauterized. The specimens should be examined by an experienced pathologist to allow for microstaging.

Studies show that distinguishing between benign pigmented lesions and early melanomas can be difficult, and even experienced dermatopathologists can have differing opinions. To reduce the possibility of misdiagnosis for an individual patient, a second review by an independent qualified pathologist should be considered.[5,6] Agreement between pathologists in the histologic diagnosis of melanomas and benign pigmented lesions has been studied and found to be considerably variable.[5,6]

Evidence (discordance in histologic evaluation):

1. One study found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 of 140 cases examined by a panel of experienced dermatopathologists. For the histologic classification of cutaneous melanoma, the highest concordance was attained for Breslow thickness and presence of ulceration, while the agreement was poor for other histologic features such as Clark level of invasion, presence of regression, and lymphocytic infiltration.[5]
2. In another study, 38% of cases examined by a panel of expert pathologists had two or more discordant interpretations.[6]

Prognostic Factors

Prognosis is affected by the characteristics of primary and metastatic tumors. The most important prognostic factors have been incorporated into the revised 2009 American Joint Committee on Cancer staging and include the following:[4,7-9]

• Thickness and/or level of invasion of the melanoma.
• Mitotic index, defined as mitoses per millimeter.
• Ulceration or bleeding at the primary site.
• Number of regional lymph nodes involved, with distinction of macrometastasis and micrometastasis.
• Systemic metastasis.
  • Site—nonvisceral versus lung versus all other visceral sites.
  • Elevated serum lactate dehydrogenase level.

Patients who are younger, who are female, and who have melanomas on their extremities generally have better prognoses.[4,7-9]

Microscopic satellites, recorded as present or absent, in stage I melanoma may be a poor prognostic histologic factor, but this is controversial.[10] The presence of tumor infiltrating lymphocytes, which may be categorized as brisk, nonbrisk, or absent, is under study as a potential prognostic factor.[11]

The risk of relapse decreases substantially over time, although late relapses are not uncommon.[12,13]

Related Summaries

Other PDQ summaries containing information related to melanoma include the following:

• Skin Cancer Prevention
• Skin Cancer Screening
• Skin Cancer Treatment
• Intraocular (Uveal) Melanoma Treatment

References

1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed January 23, 2019.
2. Melanoma. Bethesda, Md: National Library of Medicine, 2012. Available online. Last accessed January 31, 2019.
3. Bleyer A, O’Leary M, Barr R, et al., eds.: Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. Bethesda, Md: National Cancer Institute, 2006. NIH Pub. No. 06-5767. Also available online. Last accessed January 31, 2019.
4. Slingluff CI Jr, Flaherty K, Rosenberg SA, et al.: Cutaneous melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1643-91.
5. Corona R, Mele A, Amini M, et al.: Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol 14 (4): 1218-23, 1996. [PUBMED Abstract]
6. Farmer ER, Gonin R, Hanna MP: Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol 27 (6): 528-31, 1996. [PUBMED Abstract]
7. Balch CM, Soong S, Ross MI, et al.: Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7 (2): 87-97, 2000. [PUBMED Abstract]
8. Manola J, Atkins M, Ibrahim J, et al.: Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18 (22): 3782-93, 2000. [PUBMED Abstract]
9. Balch CM, Gershenwald JE, Soong SJ, et al.: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27 (36): 6199-206, 2009. [PUBMED Abstract]
10. León P, Daly JM, Synnestvedt M, et al.: The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg 126 (12): 1461-8, 1991. [PUBMED Abstract]
11. Mihm MC Jr, Clemente CG, Cascinelli N: Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74 (1): 43-7, 1996. [PUBMED Abstract]
12. Shen P, Guenther JM, Wanek LA, et al.: Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences? Ann Surg Oncol 7 (2): 114-9, 2000. [PUBMED Abstract]
13. Tsao H, Cosimi AB, Sober AJ: Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 79 (12): 2361-70, 1997. [PUBMED Abstract]

Cellular and Molecular Classification of Melanoma

In This Section

• Genomic Classification
  • Cutaneous melanoma
  • Uveal melanoma

The descriptive terms for clinicopathologic cellular subtypes of malignant melanoma should be considered of historic interest only; they do not have independent prognostic or therapeutic significance. The cellular subtypes are the following:

• Superficial spreading.
• Nodular.
• Lentigo maligna.
• Acral lentiginous (palmar/plantar and subungual).
• Miscellaneous unusual types:
  • Mucosal lentiginous (oral and genital).
  • Desmoplastic.
  • Verrucous.

Genomic Classification

Cutaneous melanoma

The Cancer Genome Atlas (TCGA) Network performed an integrative multiplatform characterization of 333 cutaneous melanomas from 331 patients.[1] Using six types of molecular analysis at the DNA, RNA, and protein levels, the researchers identified four major genomic subtypes:

• BRAF mutant.
• RAS mutant.
• NF1 mutant.
• Triple wild-type.

Genomic subtypes may suggest drug targets and clinical trial design, as well as guide clinical decision-making for targeted therapies. Refer to Table 1 for more information.

To date, targeted therapies have demonstrated efficacy and received the U.S. Food and Drug Administration approval for the BRAF-mutant subtype of melanoma only. Combination therapies with a BRAF plus a MEK inhibitor have shown improvement in outcomes over a single-agent inhibitor alone; yet, virtually all patients acquire resistance to therapy and relapse. (Refer to the individual treatment sections of this summary for more information). Therefore, clinical trials remain an important option for patients with BRAF-mutant subtype, as well as other genomic subtypes of melanoma.

A variety of immunotherapies have been approved for the treatment of melanoma regardless of genetic subtype. (Refer to the individual treatment sections of this summary for more information.) The benefit of immunotherapy has not been associated with a specific mutation or molecular subtype. The TCGA analysis identified immune markers (in a subset within each molecular subtype) that were associated with improved survival and that may have implications for immunotherapy. Identification of predictive biomarkers remains an active area of research.

Table 1. Multiplatform Analysis: Mutation, Copy Number, Whole Genome, miRNA/RNA Expression, Protein Expression in Cutaneous Melanomaa

Genomic Subtype	% Samples With Mutation	Increased Lymphocytic Infiltration (%)	Clinical Management Implications for Targeted Therapyc,d
FDA = U.S. Food and Drug Administration; WT = wild type.
aPrimary melanoma with matched normal samples; N = 67 (20%). Metastatic melanoma with matched normal samples; N = 266 (80%). Matched is defined as sample from the same patient.
bTriple WT was defined as a heterogeneous subgroup lacking BRAF, NRAS, HRAS, and KRAS, and NF1 mutations.
cThe indications for immunotherapy are not known to be determined or limited by genomic subtype.
dRisks and benefits of single versus combination therapies are detailed in Treatment Options.
eResearch includes but is not limited to these examples. Clinical trials are posted on clinicaltrials.gov.
fIndicated when mutation is diagnosed by an FDA-approved assay.
			FDA Approved		Researche (single agent or in combination)
BRAFmutant	52	~ 30	BRAF inhibitorsf		CDK inhibitors, PI3K/Akt/mTOR inhibitors, ERK inhibitors, IDH1 inhibitors, EZH2 inhibitors, Aurora kinase inhibitors, ARID2 chromatin remodelers
			– Vemurafenib
			–Dabrafenib
			MEK inhibitors
			–Trametinib
			–Cobimetinib
			Combination of BRAF + MEK inhibitors
			–Vemurafenib + cobimetinib
			–Dabrafenib + trametinib
RASmutant (NRAS, HRAS, andKRAS )	28	~ 25			MEK inhibitors, CDK inhibitors, PI3K/Akt/mTOR inhibitors, ERK inhibitors, IDH1 inhibitors, EZH2 inhibitors, Aurora kinase inhibitors, ARID2 chromatin remodelers
NF1mutant	14	~ 25			PI3K/Akt/mTOR inhibitors, ERK inhibitors, IDH1 inhibitors, EZH2 inhibitors, ARID2 chromatin remodelers
Triple WTb	14.5	~ 40			KIT-mutated/amplified CDK inhibitors (i.e., imatinib and dasatinib), MDM2/p53 interaction inhibitors, PI3K/Akt/mTOR inhibitors, IDH1 inhibitors, EZH2 inhibitors

Uveal melanoma

Uveal melanomas differ significantly from cutaneous melanomas. ln one series, 83% of 186 uveal melanomas were found to have a constitutively active somatic mutation in GNAQ or GNA11.[2,3] (Refer to the PDQ summary on Intraocular (Uveal) Melanoma Treatment for more information.)

References

1. Cancer Genome Atlas Network: Genomic Classification of Cutaneous Melanoma. Cell 161 (7): 1681-96, 2015. [PUBMED Abstract]
2. Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009. [PUBMED Abstract]
3. Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010. [PUBMED Abstract]

Stage Information for Melanoma

In This Section

• Clark Classification (Level of Invasion)
• AJCC Stage Groupings and TNM Definitions

Clinical staging is based on whether the tumor has spread to regional lymph nodes or distant sites. For melanoma that is clinically confined to the primary site, the chance of lymph node or systemic metastases increases as the thickness and depth of local invasion increases, which worsens the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but lungs and liver are common sites.

The microstage of malignant melanoma is determined on histologic examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomic level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm and should always be reported.

Accurate microstaging of the primary tumor requires careful histologic evaluation of the entire specimen by an experienced pathologist.

Clark Classification (Level of Invasion)

Table 2. Clark Classification (Level of Invasion)

Level of Invasion	Description
Level I	Lesions involving only the epidermis (in situmelanoma); not an invasive lesion.
Level II	Invasion of the papillary dermis; does not reach the papillary-reticular dermal interface.
Level III	Invasion fills and expands the papillary dermis but does not penetrate the reticular dermis.
Level IV	Invasion into the reticular dermis but not into the subcutaneous tissue.
Level V	Invasion through the reticular dermis into the subcutaneous tissue.

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define melanoma.[1]

Cancers staged using this staging system include cutaneous melanoma. Cancers not staged using this system include melanoma of the conjunctiva, melanoma of the uvea, mucosal melanoma arising in the head and neck, mucosal melanoma of the urethra, vagina, rectum, and anus, Merkel cell carcinoma, and squamous cell carcinoma.[1]

AJCC Prognostic Stage Groups-Clinical (cTNM)

Table 3. Definition of cTNM Stage 0a

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bThickness and ulceration status not applicable.
0	Tis, N0, M0	Tis = Melanoma in situ.b	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 4. Definition of cTNM Stages IA and IBa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
IA	T1a, N0, M0	T1a = <0.8 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
IB	T1b, N0, M0	T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T2a, N0, M0	T2a = >1.0–2.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 5. Definition of cTNM Stages IIA, IIB, and IICa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
IIA	T2b, N0, M0	T2b = >1.0–2.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T3a, N0, M0	T3a = >2.0–4.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
IIB	T3b, N0, M0	T3b = >2.0–4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T4a, N0, M0	T4a = >4.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
IIC	T4b, N0, M0	T4b = >4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 6. Definition of cTNM Stage IIIa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bFor example, diagnosis by curettage.
cFor example, unknown primary or completely regressed melanoma.
dThickness and ulceration status not applicable.
eDetected by sentinel lymph node biopsy.
III	Any T, Tis, ≥N1, M0	TX = Primary tumor cannot be assessed.b,d	N1a = One clinically occult nodee /in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
		T0 = No evidence of primary tumor.c,d
		Tis = Melanoma in situ.d	N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
		T1a = <0.8 mm/without ulceration.	N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
		T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N2a = Two or three clinically occult nodese/in-transit, satellite, and/or microsatellite metastases not present.
		T2a = >1.0–2.0 mm/without ulceration.	N2b = Two or three nodes at least one of which was clinically detected/in-transit, satellite, and or microsatellite metastases not present.
		T2b = >1.0–2.0 mm/with ulceration.	N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
		T3a = >2.0–4.0 mm/without ulceration.	N3a = Four or more clinically occult nodese/in-transit, satellite, and/or microsatellite metastases not present.
		T3b = >2.0–4.0 mm/with ulceration.	N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
		T4a = >4.0 mm/without ulceration.	N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
		T4b = >4.0 mm/with ulceration.

Table 7. Definition of cTNM Stage IVa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; CNS = central nervous system; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bFor example, sentinel lymph node biopsy not performed, regional nodes previously removed for another reason. (Exception: pathological N category is not required for T1 melanomas, use cN).
IV	Any T, Any N, M1	Any T = See Table 6 for description.	NX = Regional nodes not assessed;b N0 = No regional metastases; ≥N1 = See Table 6 for description.	M1 = Evidence of distant metastasis.
				–M1a = Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes [M1a(0) = LDH not elevated; M1a(1) = LDH elevated].
				–M1b = Distant metastasis to lung with or without M1a sites of disease [M1b(0) = LDH not elevated; M1b(1) = LDH elevated].
				–M1c = Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease [M1c(0) = LDH not elevated; ORM1c(1) = LDH elevated].
				–M1d = Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease [M1d(0) = LDH not elevated; M1d(1) = LDH elevated].

AJCC Prognostic Stage Groups-Pathological (pTNM)

Table 8. Definition of pTNM Stage 0a,b

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; cN = clinical N; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use cN information to assign their pathological stage.
cThickness and ulceration status not applicable.
0	Tis, N0, M0	Tis = Melanoma in situ.b,c	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 9. Definition of pTNM Stages IA and IBa,b

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; cN = clinical N; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use cN information to assign their pathological stage.
IA	T1a, N0, M0	T1a = <0.8 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T1b, N0, M0	T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.
IB	T2a, N0, M0	T2a = >1.0–2.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 10. Definition of pTNM Stages IIA, IIB, and IICa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
IIA	T2b, N0, M0	T2b = >1.0–2.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T3a, N0, M0	T3a = >2.0–4.0 mm/without ulceration.
IIB	T3b, N0, M0	T3b = >2.0–4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T4a, N0, M0	T4a = >4.0 mm/without ulceration.
IIC	T4b, N0, M0	T4b = >4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 11. Definition of pTNM Stages IIIA, IIIB, IIIC, and IIIDa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bDetected by sentinel lymph node biopsy.
cFor example, unknown primary or completely regressed melanoma.
dThickness and ulceration status not applicable.
IIIA	T1a/b–T2a, N1a or N2a, M0	T1a = <0.8 mm/without ulceration/T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present; OR N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
		T2a = >1.0–2.0 mm/without ulceration.
IIIB	T0, N1b, N1c, M0	T0 = No evidence of primary tumor.c,d	N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
	T1a/b–T2a, N1b/c or N2b, M0	T1a = <0.8 mm/without ulceration/T1b <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present;/N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present; OR	M0 = No evidence of distant metastasis.
		T2a = >1.0–2.0 mm/without ulceration.
			N2b = Two or three nodes at least one of which was clinically detected/in-transit, satellite, and or microsatellite metastases not present.
	T2b/T3a, N1a–N2b, M0	T2b = >1.0–2.0 mm/with ulceration/T3a = >2.0–4.0 mm/without ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
			N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.
IIIC	T0, N2b, N2c, N3b, or N3c, M0	T0 = No evidence of primary tumor.c,d	N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present; OR
			N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
	T1a–T3a, N2c or N3a/b/c, M0	T1a = <0.8 mm/without ulceration/T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present; OR	M0 = No evidence of distant metastasis.
		T2a = >1.0–2.0 mm/without ulceration.
		T2b = >1.0–2.0 mm/with ulceration.
			N3a = Four or more clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
		T3a = >2.0–4.0 mm/without ulceration.	N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
	T3b/T4a, Any N ≥N1, M0	T3b = >2.0–4.0 mm/with ulceration/T4a = >4.0 mm/without ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
			N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.
			N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
			N3a = Four or more clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
			N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
	T4b, N1a–N2c, M0	T4b = >4.0 mm/with ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
			N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.
			N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
IIID	T4b, N3a/b/c, M0	T4b = >4.0 mm/with ulceration.	N3a = Four or more clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
			N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.

Table 12. Definition of pTNM Stage IVa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; cN = clinical N; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bFor example, sentinel lymph node biopsy not performed, regional nodes previously removed for another reason. (Exception: pathological N category is not required for T1 melanomas, use cN).
cPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use cN information to assign their pathological stage.
dThickness and ulceration status not applicable.
IV	Any T, Tis, Any N, M1	Any T = See Table 6 for description.	NX = Regional nodes not assessed;d N0 = No regional metastases; ≥N1 = See Table 6 for description.	M1 = Evidence of distant metastasis.
		Tis = Melanoma in situ.b,c		–M1a = Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes [M1a(0) = LDH not elevated; M1a(1) = LDH elevated].
				–M1b = Distant metastasis to lung with or without M1a sites of disease [M1b(0) = LDH not elevated; M1b(1) = LDH elevated].
				–M1c - Distant metastasis to on-CNS visceral sites with or without M1a or M1b sites of disease [M1c(0) = LDH not elevated; OR M1c(1) = LDH elevated].
				–M1d = Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease [M1d(0) = LDH not elevated; M1d(1) = LDH elevated].

References

1. Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.

Treatment Option Overview for Melanoma

In This Section

• Excision
  • Lymph node management
• Adjuvant Therapy
• Limb Perfusion
• Systematic Treatment for Unresectable Stage III, Stage IV, and Recurrent Disease
  • Immunotherapy
  • Signal-transduction inhibitors
  • Chemotherapy
  • Palliative local therapy

Table 13. Standard Treatment Options for Melanoma

Stage (TNM Staging Criteria)	Standard Treatment Optionsa
aClinical trials are an important option for patients with all stages of melanoma because advances in understanding the aberrant molecular and biologic pathways have led to rapid drug development. Standard treatment options are available in many clinical trials. Information about ongoing clinical trials is available from the NCI website.
Stage 0 melanoma	Excision
Stage I melanoma	Excision +/− lymph node management
Stage II melanoma	Excision +/− lymph node management
Resectable Stage III melanoma	Excision +/− lymph node management
	Adjuvant therapy
Unresectable Stage III, Stage IV, and Recurrent melanoma	Intralesional therapy
	Immunotherapy
	Signal-transduction inhibitors
	Chemotherapy
	Palliative local therapy

Excision

Surgical excision remains the primary modality for treating melanoma. Cutaneous melanomas that have not spread beyond the site at which they developed are highly curable. The treatment for localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion.

Lymph node management

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB can be considered to assess the presence of occult metastasis in the regional lymph nodes of patients with primary tumors larger than 1 to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections and individuals who may benefit from adjuvant therapy.[1-6]

To ensure accurate identification of the sentinel lymph node, lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[1,6-11] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)

Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II (NCT00297895) to determine whether CLND affects survival. SLNB should be performed before wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

High-dose interferon alpha-2b was approved by the U.S. Food and Drug Administration (FDA) in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but are considered to be at a high risk of relapse (stages IIB, IIC, and III). However, prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon improve relapse-free survival but do not improve overall survival (OS).

Therapies that have improved OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.

Limb Perfusion

A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary stage I limb melanoma did not show a disease-free survival or OS benefit from isolated limb perfusion with melphalan, when compared with surgery alone.[5]

Systematic Treatment for Unresectable Stage III, Stage IV, and Recurrent Disease

Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase pathway—have demonstrated improvement in OS in randomized trials in comparison to dacarbazine (DTIC). Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.

Immunotherapy

Checkpoint inhibitors

Three checkpoint inhibitors—pembrolizumab, nivolumab, and ipilimumab—are now approved by the FDA. Each has demonstrated the ability to impact OS against different comparators in unresectable or advanced disease. (Refer to the Pembrolizumab, the Nivolumab, and the Ipilimumab sections in the Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment section of this summary for more information.) Multiple phase III trials are in progress to determine optimal sequencing of immunotherapies, immunotherapy with targeted therapy, and whether combinations of immunotherapies or immunotherapy plus targeted therapy are superior for increasing OS.

Interleukin-2 (IL-2)

IL-2 was approved by the FDA in 1998 because of durable complete response (CR) rates in a minority of patients (6%–7%) with previously treated metastatic melanoma in eight phase I and II studies. Phase III trials comparing high-dose IL-2 with other treatments and providing an assessment of relative impact on OS have not been conducted.

Signal-transduction inhibitors

Studies to date indicate that both BRAF and MEK inhibitors can significantly impact the natural history of melanoma, although they do not appear to be curative as single agents.

BRAF inhibitors

Vemurafenib

Vemurafenib, approved by the FDA in 2011, has demonstrated an improvement in progression-free survival (PFS) and OS in patients with unresectable or advanced disease. Vemurafenib is an orally available, small-molecule, selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test.[11]

Dabrafenib

Dabrafenib, an orally available, small-molecule, selective BRAF inhibitor that was approved by the FDA in 2013, showed improvement in PFS when compared with DTIC in an international, multicenter trial (BREAK-3 [NCT01227889]).

MEK inhibitors

Trametinib

Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2 that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations. Trametinib demonstrated improved PFS over DTIC.

Cobimetinib

Cobimetinib is an orally available, small-molecule, selective MEK inhibitor that was approved by the FDA in 2015 for use in combination with the BRAF inhibitor vemurafenib. (Refer to the Combination signal-transduction inhibitor therapy section of this summary for more information.)

c-KIT inhibitors

Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[12-14] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.

Combination signal-transduction inhibitor therapy

In 2014, the combination of dabrafenib and trametinib received accelerated approval from the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600K mutation. The combination demonstrated improved durable response rates over single-agent dabrafenib. Full approval is pending completion of ongoing clinical trials and demonstration of clinical benefit on OS.

In 2015, the combination of vemurafenib and cobimetinib was also approved by the FDA for patients with unresectable or metastatic melanomas that carry the BRAF V600E or V600 K mutation. Published phase III data support improved PFS using another combination of BRAF and MEK inhibitors versus BRAF inhibitor plus placebo—dabrafenib plus trametinib compared with dabrafenib plus placebo. OS data are immature.

Chemotherapy

DTIC

DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[15-18] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.

Temozolomide

Temozolomide, an oral alkylating agent, appeared to be similar to intravenous DTIC in a randomized phase III trial with a primary endpoint of OS; however, because the trial was designed to demonstrate the superiority of temozolomide, which was not achieved, the trial was left with a sample size that was inadequate to provide statistical proof of noninferiority.[16]

Palliative local therapy

Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[19-21]

References

1. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000. [PUBMED Abstract]
2. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
3. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000. [PUBMED Abstract]
4. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998. [PUBMED Abstract]
5. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
6. Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012. [PUBMED Abstract]
7. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996. [PUBMED Abstract]
8. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000. [PUBMED Abstract]
9. Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372 (9633): 117-26, 2008. [PUBMED Abstract]
10. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004. [PUBMED Abstract]
11. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
12. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008. [PUBMED Abstract]
13. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011. [PUBMED Abstract]
14. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011. [PUBMED Abstract]
15. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999. [PUBMED Abstract]
16. Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000. [PUBMED Abstract]
17. Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004. [PUBMED Abstract]
18. Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011. [PUBMED Abstract]
19. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000. [PUBMED Abstract]
20. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999. [PUBMED Abstract]
21. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001. [PUBMED Abstract]