• Information
  1. Introduction
  2. Risk Factors
  3. Pathogenesis Of Melanoma
  4. Physical Examination
  5. Classification of Abnormal Pigmented Lesions
  6. Dysplastic Nevi
  7. Indications for Pigmented Lesion Biopsy
  8. Types of Melanoma
  9. American Joint Committee on Cancer
  10. Other Prognostic Factors
  11. Treatment Overview By Stage
  12. Surgical Margins
  13. Other Treatment Modalities

A. Introduction

1. Accounts for 4% of dermatologic tumors, and 80% of deaths from skin cancer
2. Rate of increase in incidence of melanoma exceeds all other cancers
3. Likely ~1:75 persons (over their lifetime) by year 2000
4. In USA, over 44,000 new cases per year with >7200 deaths per year
5. No completely objective screening markers for detecting melanomas
6. Most melanomas probably arise from dysplastic nevi
7. Types of Melanomas
   1. Superficial spreading melanoma (~45% of cases)
   2. Nodular melanoma (~40%)
   3. Acral lentiginous melanoma (~5%)
   4. Other types of melanomas (~10%)
8. ~8% of patients will have 2 or more primary melanomas [3]
   1. Risk factors for 2 or more primary melanomas:
   2. Family history of multiple melanomas
   3. Dysplastic nevi
9. Metastatic melanoma 5 year survival ~14%

B. Risk Factors [4]

1. Greatly Increased Risk (>8 fold)
   1. Personal history of atypical moles, >75-100 moles, and melanoma family history
   2. Previous nonmelanoma skin cancer
   3. Congenital nevus (giant, >20 cm)
   4. History of Melanoma
   5. Strong family history of melanoma in parent, sibling, or children (at least 3 relatives)
   6. Immunosuppression
2. Moderately Increased Risk (3-8 fold)
   1. Clinically atypical (dysplastic) nevi
   2. 51-100 Nevi
   3. 26-50 Nevi
   4. Treatment with UVA + psoralen increases risk about 5 fold after 15 years
   5. Chronic Tanning with UVA light
   6. History of 3 or more severe sunburns (blistering)
   7. Family history but <3 first degree relatives
3. Modest Increased Risk (2-3 fold)
   1. Two Repeated blistering sunburns
   2. Light complexion of hair and eyes
   3. Inability to tan
   4. Single, clinically atypical nevus
   5. Freckling
4. Other Possible Risks
   1. Proximity to Equator
   2. Indoor occupation with outdoor hobbies
5. Familial Melanoma [19]
   1. About 10% of melanoma associated with family history
   2. Hereditary melanoma (high risk alleles) represents ~1% of all melanomas
   3. True hereditary melanoma due to mutations in CDKN2A and CDK4
   4. CDK is cyclin dependent kinase involved in cell cycle regulation
   5. CDKN2A on chromosome 9p21 codes for 16K protein called p16
   6. p16 blocks CDK 4/6 complex from phosphorylating Rb protein
   7. Phosphorylation of Rb protein leads to expression of E2F transcription factors
   8. E2F transcription factors drive G1 to S phase transition of cell cycle
   9. p16 loss leads to hyperphosphorylation of Rb protein and allows cell cycle progression
6. Other Genetic Diseases with Melanoma Risk
   1. Turner's Syndrome
   2. Familial Atypical Mole-Melanoma Syndrome (FAMM)
   3. Familial multiple blue nevi
   4. Carney complex (LAMB or NAME)
   5. Disorders with cafe au lait macules
   6. Disorders with multiple lentigines
7. Cafe au Lait Macules
   1. Mainly with neurofibromatosis 1 and 2
   2. Mc-Cune-Albright Syndrome
   3. Multiple Endocrine Neoplasia (MEN) 1
   4. Tuberous sclerosis
   5. Bloom Syndrome
   6. Ataxia Telangiectasia
   7. Fanconi's Anemia
8. Multiple Lentigines
   1. Peutz-Jeghers Syndrome
   2. Laugier-Hunziker Syndrome
   3. LEOPARD Syndrome
   4. Xeroderma Pigmentosum
9. Epidermal Growth Factor (EGF) [5]
   1. Elevated levels of EGF associated with increased melanoma risk
   2. Alleles with G at position 61 associated with increased EGF production
   3. Genotype G/G has ~5X risk compared with A/A
10. Mutations in CYP2D6 and in melanocortin-1 receptor associated with increased risk [6]

C. Pathogenesis Of Melanoma [1]

1. UV Damage
   1. Probably Initiates most melanomas
   2. Associated with intense intermittent exposures, not so much cumulative exposure
   3. Other skin cancers are associated with cumulative exposure
2. Solar exposure is major risk factor in significant proportion of Caucasians
   1. Solar exposure strongly contributes to uncommon melanoma, lentigo maligna type (5%)
   2. Solar exposure is unlikely to be associated with melanoma in Blacks or Asians
3. Ultraviolet radiation induces DNA damage
   1. Most or all of this damage is normally repaired by homeostatic processes
   2. DNA repair processes decrease with increasing age
   3. Exposure to sunlight (UV radiation) normally induces repair processes in melanocytes
   4. Melanomas are most likely to occur with intense UV exposure in persons whose baseline UV exposure is low
4. Genes in Melanoma (Table 1, Ref [1])
   1. Ras / MAPK (mitogen activated protein kinase) pathway - oncogene / signal transduction
   2. Cell Cycle: INK4A CDK4, CDKN2A, Cyclin D1, Retinoblastoma (Rb)
   3. P53 and ARF (alternate reading frame): tumor suppressors, control of DNA repair
   4. PTEN and AKT: tumor suppressors / protein kinase
   5. MSH and MITF: pigmentation and signalling, transcription factor
   6. Cell adhesion genes: WNT, ß-catenin, E-cadherin, N-cadherin, alphaVbeta3 integrin
5. Sunscreen use has had no effect on melanoma development [17]

D. Physical Examination [11]

1. Increased risk with the "ABCDE" characteristics:
   1. A=asymmetry
   2. B=border irregularity
   3. C=color variation
   4. D=diameter >6mm
   5. E=evolving (getting larger or other changes over time)
2. If a lesion has any of the above characteristics, it is suspicious for melanoma [11]
   1. Sensitivity of ABCD(E) for any one abnormality in detecting melanoma is >95%
   2. Specificity for this tool has been reported as high (>90%), but this is misleading
3. All persons must perform self skin exams every 1-2 months
4. Spouses, significant others, friends should help with skin exams

E. Classification of Abnormal Pigmented Lesions

1. Type A: sporadic
2. Type B: familial
3. Type C: sporadic with melanoma
4. Type D: Familial dysplastic nevus syndrome with melanoma
5. Spitz Nevi

F. Dysplastic Nevi [8]

1. Characteristics
   1. Macular lesion usually with irregular fuzzy borders
   2. Size usually >5 mm
   3. Color variability carries a high risk for hyistologic dysplasia
2. Prevalence ~12% of population
3. Acquired in adolescence, continue until adulthood
4. Not uncommon in children, where high suspicion should be maintained
5. Associated with ~15 fold increased risk of melanoma and with multiple melanomas
6. Increasing numbers of dysplastic nevi increase risk
7. Distribution
   1. Trunk and upper limbs most common
   2. Buttocks, groin, scalp and breast also
8. Dysplastic Nevus Syndrome
   1. Usually refers to specific syndrome with the following triad:
   2. At least 100 nevi
   3. At least 1 nevus >7mm diameter
   4. At least 1 nevus with clinically atypical features
9. Diagnosis
   1. Requires both cytologic and architectural abnormalities
   2. Universally accepted diagnostic criteria not defined to date
   3. Increasing numbers and atypical properties increase risk for melanoma
   4. Evaluation of families with melanoma for gerline CDKN2A mutations (see above) [25]
10. Prevention
    1. Sunscreens (SPF 15 or higher) may reduce numbers of nevi
    2. Effect of sunscreen use on melanoma incidence is unclear and not major [17]
    3. Avoid peak UV exposure from noon to 4 PM (16:00 hours)
    4. Watch for warning signs of taypical nevi (ABCDE Rule, see above)
11. Prophylactic excision of clinically dysplastic nevi is generally unclear
12. Current estimates only 1 in ~10,000 dysplastic nevi will progress to melanoma per year

G. Indications for Pigmented Lesion Biopsy

1. Generally, any lesion which is concerning to patient and/or doctor
2. Changing morphology
3. Pruritus
4. Bleeding
5. New lesions
6. Scalp lesions
7. Any characteristics from "ABCDE" which are present

H. Types of Melanoma

1. Superficial Spreading - most common form (~70%)
2. Nodular
3. Lentigo
4. Acral Lentiginous
5. Metastases - skin, lung, liver, brain and bone

I. American Joint Committee on Cancer (AJCC) Clinical Staging [2,10,12]

1. Tumor (T) Node (N) Metastasis (M) System Used
2. Tumor Stage
   1. Tx - indeterminate or unknown primary
   2. Tis - in situ
   3. T1 - <1.01 mm depth
   4. T2 - 1.01-2.0 mm depth
   5. T3 - 2.01-4.0 mm depth
   6. T4 - >4.0 mm depth
3. T Ulceration
   1. Ta - no ulceration
   2. Tb - ulceration present
4. N Stage
   1. N1 - 1 metastatic node
   2. N2 - 2-3 nodes, in-transit metastases or satellite(s) without nodal metastasis
   3. N3 - >3 nodes, matted nodes, satellite(s) or in-transit metastases with metastatic node(s)
5. Nodal Mass
   1. Na - microscopic or clinically occult
   2. Nb - macroscopic or clinical or radiologic with pathologic confirmation
   3. Satellite(s) or in-transit metastases
6. Metastasis
   1. M1a - skin, soft tissues, distant nodes
   2. M1b - lung
   3. M1c - other visceral organs or any distant metastasis and confirmed lactate dehydrogenase (LDH) elevation
7. Staging and Survival
   1. Stage IA - T1a N0 M0; >95% 5 year survival
   2. Stage IB - T1b or T2a, N0 M0; >90% 5 year survival
   3. Stage IIA - T2b or T3a, N0 M0; >75% 5 year survival
   4. Stage IIB - T3b or T4a, N0 M0; >65% 5 year survival
   5. Stage IIC - T4b N0 M0; 45% (increased to 57% with IFNa) 5 year survival
   6. Stage IIIA - Ta, N1a or N2a, M0; 67% (increased to 76% with IFNa) 5 year survival
   7. Stage IIIB - All M0: Ta N1b, Ta N2b, Ta N2c, Tb N1a, Tb N2a; 53-64% 5 year survival
   8. Stage IIIC - All M0: Ta N3, Tb N1b, Tb N2b, Tb N2c,Tb N3; ~26-39% 5 year survival
   9. Stage IV - T(any)N(any)M1 (distant metastases present), ~5% 15 year survival

J. Other Prognostic Factors [1]

1. Histopathological examination of lesion tissue is required for diagnosis and prognosis
   1. Distinguish between benign, dysplastic, and malignant lesions
   2. Determine tumor thickness for malignant lesions
   3. Assess other histopathologic characteristics of malignant lesions
   4. Lymph node (LN) and distant site metastasis evaluations
   5. A variety of experimental prognostic markers are undergoing clinical evaluation
2. Tumor Thickness (Breslow)
   1. Appears to be best routinely available prognostic parameter
   2. Thin melanomas have much better prognosis than thicker
   3. Tumors <0.76mm thick had 96% 10 year survival
   4. Tumors 0.76-1.69mm thick had 83% 10 year survival
   5. Tumors 1.70-3.60mm thick had 59% 10 year survival
   6. Tumors >3.60mm thick had 29% 10 year survival
3. Tumor Level (Clark) [12]
   1. Clark I - superficial epidermis only
   2. Clark II - intrapapillary, invasion past basement membrane
   3. Clark III - pan-papillary with compression but not invasion of reticular dermis
   4. Clark IV - reticular dermis invasion
   5. Clark V - subcutaneous fat invasion
4. Lymph Node (LN) Mapping
   1. Regional LN mapping was previously standard of care
   2. Sentinel LN mapping is now considered standard of care for >1mm lesions
   3. Sentinel LN mapping involves dye and radiotracer injection at site of primary tumor
   4. Radiation detector is used to localize the draining LN for the tumor area
   5. Small incision is made at "sentinel" LN site and dye colored LN identified
   6. Pathological or PCR (see below) analysis for tumor in sentinel LN is performed
   7. Positive sentinal LN: 1% for <0.8mm tumor, 8% for 0.8-1.5mm, 23% for 1.5-4.0mm
   8. Positive LN found in 36% of tumors 4.0mm or larger
   9. Sentinal LN removal (after biopsy and detection of micrometastasis) for tumors 1.2mm -
5. 5mm thick associated with improved survival compared with leaving observation [7]
6. Histopathologic Prognostic Factors
   1. Micrometastases are now incorporated into pathologic staging
   2. Mitotic Index - lower index has a better prognosis
   3. Tumor Ulceration - increases recurrence risk 2-3 fold
   4. Presence of tumor infiltrating lymphocytes (TIL) - better prognosis than absence
   5. Loss of expression of melastatin (TRPM1) associated with early metastasis, poorer prognosis [1]
7. Detection of Micrometastases [12]
   1. Usual methods involve pathologic examination of lymph nodes (LN)
   2. Polymerase chain reaction (PCR) detection of melanin producing cells can also be used
   3. PCR amplification of tyrosinase mRNA increases positive nodes by ~50%
   4. It is very likely that Stage IIb tumors have micrometastases
8. Clinical Prognostic Factors
   1. Primary lesion on extremity had better prognosis than primary truncal lesions
   2. Age at diagnosis <60 years predicts better survival
   3. Women survive longer, in general, than men
   4. Presence of macroscopic lymph node metastases is very poor prognostic sign

K. Treatment Overview By Stage [4]

1. Stage Tis (in situ): margins of 0.5-1.0cm around lesion or scar recommended
2. Stage I
   1. Conservative re-excision after biopsy with 1.0cm margins OR
   2. Appropriate surgical excision usually on an outpatient basis with 1.0cm margins
   3. Skin grafting may be done to cover the wound for wide excisions
   4. Sometimes lymph nodes around the tumor may also be removed
3. Stage II
   1. Treatment may be one of the following:
   2. Appropriate surgical excision and examination of the sentinel LN for metastases
   3. For 1.0-4.0mm thick melanomas, margins of 2.0cm if possible (1.0cm if not)
   4. Appropriate surgical excision of the tumor and removal of nearby LN
   5. Clinical trials are further valuating whether removal of LN improves outcome
   6. Trial of wide surgical excision, then adjuvant chemotherapy or biological therapy
   7. A clinical trial of wide surgical excision followed by directed chemotherapy
   8. Directed chemotherapy is given intra-arterialy into the limb where the melanoma was
4. Stage III
   1. Treatment may be one of the following:
   2. Appropriate surgical excision (2cm margins recommended) ± biological therapy
   3. Skin grafting may be done to cover the wound
   4. Nearby LN may be taken out if they contain cancer
   5. Isolated arterial perfusion chemotherapy as above is also under study
   6. Wide surgical excision followed by adjuvant chemotherapy or biological therapy
   7. Interferon alpha 2b has shown activity as adjuvant therapy in Stage III disease
   8. Adjuvant IFN-alpha 2b improves quality adjusted survival
   9. Pegylated IFN-alpha 2b improves 4-year recurrence free (but not overall) survival from 38.9% with observation to 45.6% with average therapy duration of 12 months [27]
   10. In all cases, nearby LN may be taken out if they contain cancer
5. Stage IV
   1. Treatment may be one of the following:
   2. Surgery to remove LN that contain cancer
   3. Surgery to remove tumors that have metastasized to other areas of the body
   4. Radiation therapy to relieve symptoms
   5. Systemic chemotherapy and/or biological therapy (including vaccine based therapies)
   6. Dacarbazine is the only FDA approved chemotherapy, usually used in combination
   7. Autologous T (CD8+ and CD4+) cells expanded in vitro and reinfused have shown benefits [26]

L. Surgical Margins [13,14]

1. Surgery with wide margins of 3-5cm were previously recommended
2. Recent data indicate that such wide margins are generally not beneficial
   1. For 0.8-2.0mm thick lesions, 2cm margins are as good as 5cm margins [15]
   2. Thus, there is no benefit to very wide surgical resection margins for most melanomas
   3. For lesions at least 2.0mm thick, 3cm margins provide better regional control, but not overall survival, than 1cm margins [23]
3. Melanomas on Trunk and Proximal Extremities
   1. <2cm diameter: 1cm margin if <2.0mm thick melanoma; 2.0cm margin for 2-4mm thick
   2. >2cm diameter: 1.5cm margin if <2.0mm thick; 2cm margin for >2-4mm thick
4. Melanomas on Head, Neck, Hands, Feet
   1. <3cm diameter: 1.5cm margin if <2.0mm thick melanoma; 2.0cm margin for 2-4mm thick
   2. >3cm diameter: 2.5cm margin for any lesion <4.0mm thick
5. Surgery provides good palliation even with single site metastatic disease

M. Other Treatment Modalities

1. Regional LN Removal [13,16]
   1. LN dissection is beneficial in specific patients
   2. About 20% of patients without clinical evidence of LN spread are positive on pathology
   3. Identification of sentinal LN may aide in surgical planning [14]
   4. Sentinal LN removal (after biopsy and detection of micrometastasis) for tumors 1.2mm -
2. 5mm thick associated with improved survival compared with leaving observation [7]
   1. Overall, immediate LN removal may cure some patients [7,14]
   2. Patients <60 years with 1-2mm lesions may benefit from regional elective LN removal
   3. Diagnostic markers predicting LN disease would aide in planning LN resection
   4. Immediate lymphadenectomy in sentinal LN+ patients associated with improved disease- free, but not overall, survival [12]
3. Radiation therapy - cutaneous lesions and affected lymph nodes
4. Chemotherapy [18]
   1. Dacarbazine (DTIC) - most active single agent; 15-25% response rates
   2. Cisplatin, carboplatin, and taxol all have limited efficacy against tumors
   3. Paclitaxel has shown ~10% response rates in disseminated melnaoma
   4. Dacarbazine + cisplatin + vinblastine has little benefit over single agent
   5. Only ~2% of patients sustain long term complete remissions
   6. In patients with recurrent disease in a limb, hyperthermic isolated limb perfusion with cytotoxic agent such as melphalan can induce complete response in ~50% [1]
5. Biological Response Modifiers
   1. Interferon alpha (IFNa) - adjuvant or metastatic setting
   2. Interleukin 2 activated killer cells
6. INFa
   1. Only high dose IFNa 2a prolongs survival in advanced melanoma
   2. IFN alpha 2a reduces recurrences and death by ~20% in 1.5-4mm melanomas [20]
   3. IFN alpha 2a is now FDA approved with surgery in patients at high risk for recurrence
   4. Approved for adjuvant use in stages IIb and III melanoma after surgical removal [12]
   5. Very high doses of IFNa given intravenously are used (20 million U/m2)
   6. Lower doses 3 million U three times per week is not effective Stage III disease [21]
   7. Intermediate doses (10 million U five times per week) subcutaneously are not effective adjuvant therapy after surgery in stages IIb and III melanoma [9]
   8. High risk patients likely benefit from IFNa adjuvant therapy (~13% survival increase) [10]
   9. Development of antithyroid, antinuclear, anticardiolipin or anti-DNA antibodies during treatment with intravenous IFNa2b associated with improved survival and response [24]
7. Immune Therapy
   1. Interleukin 2 infusions with tumor infiltrating lymphocytes (TIL)
   2. Melanoma cells express various proteins which are fairly tumor specific
   3. Research ongoing to develop melanoma "vaccines" based on these novel proteins
   4. Monoclonal antibodies against some of these specific proteins have not been effective
   5. Immune therapy is based on documented spontaneous remissions
   6. Autologous GM-CSF expressing melanoma cells for "adjuvant" boost can spur responses
   7. Autologous CD4+ T cells expanded against NY-ESO-1 pulsed autologous dendritic cells with IL2 and IL7 and reinfused lead to complete remission in metastatic resistant melanoma [26]
8. Chemotherapy Resistance
   1. Bcl2 overexpression is common in melanoma
   2. Bcl2 is an antiapoptotic protein that confers resistance to chemotherapy
   3. Antisense olignonucleotides to bcl-2 can be given systemically and reduce bcl2 levels
   4. Augmerosen (one such antisense oligo) appears promising in late stage melanoma [22]
   5. Thus, combination of augmerosen with standard dose dacarbazine gave 40% responses
9. Follow-up Testing after Surgery
   1. Multiple blood tests and radiographs are performed in follow-up
   2. History (symptoms) and physical examination detected ~94% of recurrences
   3. Chest radiographs detected 5% of recurrences
   4. Laboratory results detected some recurrences but were never sole indicated of disease
   5. Therefore, patient self-examination and physician physical are recommended over complex and extensive laboratory evaluations for recurrence

References

1. Miller AJ and Mihm MC Jr. 2006. NEJM. 355(1):51
2. Thompson JF, Scolyer RA, Kefford RF. 2005. Lancet. 365(9460):687
3. Ferrone CR, Porat LB, Panageas KS, et al. 2005. 294(13):1647
4. Tsao H, Atkins MB, Sober AJ. 2004. NEJM. 351(10):998
5. Shahbazi M, Pravica V, Nasreen N, et al. 2002. Lancet. 359(9304):397
6. Rees J. 2002. Lancet. 360(9332):570
7. Morton DL, Thompson JF, Cochran AJ, et al. 2006. NEJM. 355(13):1307
8. Naeyaert JM and Brochez L. 2003. NEJM. 349(23):2233
9. Eggermont AMM, Suciu S, MacKie R, et al. 2005. Lancet. 366(9492):1189
10. Thome SD, Loprinzi CL, Heldebrant MP. 2002. Mayo Clin Proc. 77:913
11. Abbasi NR, Shaw HM, Rigel DS, et al. 2004. JAMA. 292(22):2771
12. Thompson JF, Hodi FS, Zembowicz A. 2007. NEJM. 356(3):285 (Case Record)
13. Kanzler MH and Mraz-Gernhard S. 2001. JAMA. 285(14):1819
14. Mintzer D. 1999. Am J Med. 106(1):81
15. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. 2000. Cancer. 89(7):1495
16. Cascinelli N, Morabito A, Santinami M, et al. 1998. Lancet. 351(9105):793
17. Dennis LK, Freeman LEB, VanBeek MJ. 2003. Ann Intern Med. 139(12):966
18. Drugs of Choice for Cancer Chemotherapy. 2000. Med Let. 42(1087):83
19. Tsao H, Sober AJ, Niendorf KB, Zembowicz A. 2004. NEJM. 350(9):924 (Case Record)
20. Grob JJ, Dreno B, de la Salmoniere P, et al. 1998. Lancet. 351:1905
21. Cascinelli N, Belli F, MacKie RM, et al. 2001. Lancet. 358(9285):866
22. Jansen B, Wacheck V, Heere-Ress E, et al. 2000. Lancet. 356(9243):1728
23. Thomas JM, Newton-Bishop J, A'Hern R, et al. 2004. NEJM. 350(8):757
24. Gogas H, Ioannovich J, Dafni U, et al. 2006. NEJM. 354(7):709
25. Monzon J, Liu L, Brill H, et al. 1998. NEJM. 338(13):879
26. Hunder NN, Wallen H, Cao J, et al. 2008. NEJM. 358(25):2698
27. Eggermont AM, Suciu S, Santinami M, et al. 2008. Lancet. 372(9633):117