Malignant Melanoma

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Age: 

A more even distribution across age groups. The highest incidence is among people between the ages of 45 and 54.  Forty-two percent of cases present in people younger than age 55.  SCC & BCC have an exponential increase in incidence with age.

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Gender: 

Men are more likely than women to develop melanoma (60% higher incidence).  Prognosis is worse in males (130% higher risk of death from melanoma).

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Location: 

Vast majority arise from cutaneous sites.  Most cases of melanoma and most fatal cases arise from intermittently sun-exposed skin.  A small percentage of melanomas arise on acral surfaces of the hands and feet, which tend to be diagnosed at a later stage.  Melanoma can arise from melanocytes adjacent to the retina or within mucosal surfaces in the oropharynx, sinuses, rectum, or vulva. These lesions typically present with greater local invasion and risk of distant spread than cutaneous melanoma. 

Geography: 

Incidence highest where fair-skinned Caucasians migrated to lower latitudes, with annual sun exposure that is substantially higher than their historically native climates.  Australia, New Zealand, South Africa, and Israel bear a disproportionate burden of skin cancer.

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Race: 

For cutaneous melanomas: Caucasians > Hispanics > Asians > Africans  All racial groups are equally likely to develop melanoma on the acral surfaces of the hands and feet or mucosal surfaces, representing nearly all cases of melanoma in the more darkly pigmented racial groups. 

Survival: 10 yr survival < 1 mm thickness & lack of ulceration

97%

Regional LN (micro/ macroscopic) involvement

30%

Distant metastatic disease

10%

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Genetic predisposition 

Genetic predisposition can only be found in 3% all cases.  Identification of the genes responsible  Patients with multiple dysplastic nevi are at greater risk of developing melanoma . Two highly related genes have discovered to harbor germline mutations in roughly 50% of melanoma pedigrees: CDKN2A and CDK4 . CDKN2A enocodes two products via alternate splicing of messenger RNA: p16INK4A and p14ARF. Each of these tumor suppressor genes exerts an inhibitory effect on cell cycle progression.  Xeroderma pigmentosum is a rare inherited disorder, resulting from mutation in XP gene, in which DNA repair mechanisms are compromised, particularly in response to ultraviolet (UV) light. Squamous cell and basal cell carcinomas and melanoma are prevalent in this population and at a young age.

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Genetic predisposition     

Genetic variability in melanocortin-1 receptor (MC1R) is implicated in pigmentation of skin and hair and, more recently, to melanoma predisposition. It has been known for decades that melanoma is more prevalent among fair-skinned individuals with red or blond hair. Blond-haired individuals with an inability to tan are at substantially greater risk of developing melanoma than blond-haired individuals who tan readily. Polymorphisms, distinct from mutations, in MC1R appear to account for skin and hair color differences among Caucasians. Individuals with melanocortin receptors that have a muted response to increased melanocortin expression following sun exposure suffer the greatest UV-induced genetic damage, leading to a greater risk of melanoma.

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Exposure:     

The acquired or somatic genetic changes that give rise to melanoma occur as a consequence of UV-induced genetic damage. Melanoma arising on intermittently sun-exposed skin (such as the trunk) has its peak incidence among younger individuals and declines severely with increasing age. Melanoma arising from chronically sun-damaged skin (such as the face, neck, and upper extremities) has the highest incidence in older individuals. With the rise in popularity of indoor tanning salons, data indicate that those who use them are at higher risk of melanoma than those who are sun exposed. There is disagreement regarding the constituents of light (UV-A or UV-B) that contribute most to genetic damage. Laboratory studies support a connection for both, and suggest that prevention strategies must take the entire UV light spectrum into account.

UVC

UVB

UVA

X rays 100-280 280-210 310-400 Visible

X-ray

UVB UVC UVA 100-280 280-315 315-400

Visible Light 400-700

Stratosphere - Ozone Layer

Sea Level

Dead Sea Level

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Nevi: 

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Patients with numerous benign nevi or few dysplastic nevi (large, irregularly shaped, and heterogeneously pigmented moles) are at a five-fold increased risk of developing melanoma compared with those with few benign nevi or without dysplastic nevi. Preexisting moles represent a risk factor for melanoma, rather than precursor lesions, in most cases. There is little value in resecting every nevus that appears dysplastic on clinical grounds. Surveying the skin regularly for new or changing moles has been most widely adapted for educating patients and healthcare providers. Beyond the age of 25 to 30, new mole formation warrants clinical examination.

Congenital Nevi: 

Congenital nevi are relatively rare compared with acquired nevi.  They do not suggest a predisposition to melanoma.  A small number of children are born with so-called giant congenital nevi, also referred to as bathing trunk nevi.

Dysplastic Nevus

Benign Nevi

Giant congenital nevi

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Personal history of melanoma: 

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10 times risk compared to general population of developing a new primary.

Congenital Nevi: 

Congenital nevi are relatively rare compared with acquired nevi.  They do not suggest a predisposition to melanoma.  A small number of children are born with so-called giant congenital nevi, also referred to as bathing trunk nevi.

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ABCD of melanoma:     

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Skin examination: 

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A:Asymmetry of pigmented lesion B: Border indistinct or irregular C: Color black, dark brown or blue D: Diameter of 6 mm or greater Some primary melanomas do not produce melanin and therefore lack the classic appearance.

Skin examination of the entire body should be performed for any patient who presents with numerous benign-appearing nevi, any dysplastic nevi, or a history of even a single melanoma, as the entire body is at risk for melanoma.

Lymph node examination: 

Closest LN basin most important.  Palpable LN warrants FNAC.  Sentinel LN biopsy for melanoma greater than 1 mm thickness.

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Biopsy techniques: 

Excisional biopsy: ▪ For lesions that can be entirely excised without concern for causing an unacceptable cosmetic result. Local anesthesia is required. ▪ Narrow margins of 1 to 2 mm are sufficient when making an initial diagnosis of skin cancer. ▪ The biopsy should extend to the subcutaneous tissue to provide an adequate estimate of the depth of invasion, particularly for melanoma.

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Incisional biopsy: ▪ ▪ ▪ ▪

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For large lesions (greater than 1 cm in diameter). In the case of possible melanoma lesions, the most abnormal appearing area should be biopsied. Biopsy should include subcutaneous tissue to allow an estimation of thickness. A punch biopsy, of sufficient diameter to encompass the most abnormal appearing area, is the preferred method.

Techniques to avoid: ▪ Shave biopsies and serial thin section techniques (such as Mohs surgery) are strictly contraindicated. ( difficult assessment of margins & IHC) ▪ Frozen biopsy assessment is inadequate for the diagnosis of melanoma and does not allow adequate material for review in difficult pathologic cases.

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Microstaging / microscopic depth of invasion: 

In the absence of known distant metastatic disease, the most important prognostic factor is regional lymph node involvement.  Overall 85% of melanoma patients present with clinically normal lymph nodes.  In clinically node-negative patients, most investigators have found the microscopic degree of invasion of the melanoma, or microstaging, to be of critical importance in predicting outcome.  Two methods of microstaging described: ▪ Clark’s level: ▪ Classification according to the level of invasion relative to histologically defined landmarks in the skin. ▪ Clark’s levels correlate with prognosis (lesions with deeper levels of invasion have a greater propensity for recurrence). ▪ The inherent problem with Clark’s system is that the thickness of the skin and hence the distance between the various landmark dermal layers varies greatly in different parts of the body. ▪ Furthermore, except for Clark’s level I (melanoma in situ), there is no scientific rationale for considering these landmarks to be biologic barriers to tumor growth.

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Microstaging / microscopic depth of invasion: ▪ Breslow’s thickness: ▪ Obviates some of the problems associated with Clark’s levels. ▪ In this method, the thickness of the primary tumor is measured from the top of the granular layer of the epidermis to the deepest contiguous tumor cell at the base of the lesion using a micrometer in the microscope eyepiece. ▪ Many investigators have documented an inverse correlation between Breslow’s tumor thickness and survival. ▪ Several studies have demonstrated that tumor thickness conveys more prognostic information than does Clark’s level of invasion. ▪ The measurement of tumor thickness is generally more reproducible and less subjective than is the determination of Clark’s level. ▪ Occasionally, Breslow’s thickness is impossible to determine and only the Clark’s level is available for microstaging, usually because of technical factors related to the performance of the biopsy (shave biopsy) or the preparation of the histologic specimen.

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Ulceration: 

One of the strongest negative predictive factors for long-term survival.  Ulceration is defined as the lack of a complete epidermal layer overlying the melanocytic lesion.  The presence of ulceration essentially upstages affected patients to the next highest T level.  Likelihood of finding ulceration is directly related to tumor depth: ▪ Thin melanomas ( 1 mm) have a 6% rate of ulceration ▪ Melanomas > 4-mm have a 63% incidence of ulceration

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Regional LN involvement: 

Strongest prognostic indicator in the staging of melanoma.  There is a direct relationship between the depth of invasion of the primary lesion and the potential for lymph node involvement.  The number of involved lymph nodes is inversely related to long-term survival. ▪ 5-year survival rate of approx 60% for single LN involvement than those who have multiple nodes (20%–25%).

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Patients with clinically enlarged or matted nodes at the time of diagnosis have a worse prognosis than those with microscopic disease.

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Other prognostic factors: 

Age: ▪ Whether age is truly an independent predictor of survival remains unclear. ▪ Patients who are 65 years old have a survival rate that is decreased by 10%–15% compared with their younger counterparts. ▪ Data from the prospective Sunbelt Melanoma Trial and retrospective studies reveal that younger patients are significantly more likely to harbor nodal disease than older patients with similar lesions. Age, therefore, deserves consideration in management decisions regarding surgical evaluation of nodal basins.

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Gender: ▪ Many studies have identified a trend toward improved survival in women compared with men with melanoma. ▪ As an independent predictor of survival, however, this has frequently not reached statistical significance.

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Other prognostic factors: 

Location: ▪ Location of the primary melanoma has not stood out as an independent predictor of prognosis in multivariate analysis. ▪ Lesions on the back, upper arms, neck, and scalp (BANS area) have a worse prognosis than those with lesions on the extremities. This may be due to the simple fact that these lesions cannot be evaluated easily by the patient. ▪ Men are more likely to develop truncal melanomas, whereas women are most likely to develop melanoma on their extremities. ▪ Acral lesions carry a worse prognosis than other extremity lesions.

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Desmoplastic Melanomas: ▪ Represent a less common but clinically distinct spindle cell variant of melanoma with dense fibrosis and frequent neurotropism. ▪ Clinically, they are raised, firm nodules that are amelanotic in up to 40% of patients, leading to a common delay in diagnosis. ▪ Likely because of their neurotropism, these tumors have local recurrence rates as high as 40%, which has led many clinicians to advocate local radiation therapy following excision.

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Other prognostic factors: 

Angio lymphatic invasion: ▪ Uncommon in malignant melanoma. ▪ Multiple large studies have shown worsened long-term survival and more frequent lymph node involvement in patients with angioinvasive melanomas. ▪ 5-year survival is reduced by as much as 50% with vascular invasion.

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Regression: ▪ Represents host immune response to invasive melanoma. ▪ Areas where invasive cells may have once existed are replaced by inflammatory reaction and fibrosis, which may make it impossible to determine the precise depth of the initial lesion histologically. ▪ There is continuing debate regarding the prognostic importance of regression ▪ Many clinicians believe that thin lesions that show signs of regression should be given higher consideration for surgical nodal staging, given the fact that the initial lesion may have originally been more deeply invasive.

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Other prognostic factors: 

Angiogenesis: ▪ An independent factor in long-term survival as well as local recurrence. ▪ Angiogenesis is a marker of invasive potential..

Tumor (T) classification  TX Primary tumor cannot be assessed (eg, shave biopsy, regressed primary)  Tis Melanoma in situ  T1 < or = 1.0 mm  

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T2  

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T3  

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T4  

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a: without ulceration and level II/III* b: with ulceration or level IV or V*

1.01-2.0 mm a: without ulceration b: with ulceration

2.01-4.0 mm a: without ulceration b: with ulceration

>4.0 mm a: without ulceration b: with ulceration

* Clark's levels: level II: invades the papillary dermis; level III: invades to the papillary-reticular dermal interface; level IV: invades the reticular dermis; level V: invades subcutaneous tissue.

Node (N) classification  N1 One lymph node  

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N2   

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a: micrometastases (clinically occult) b: macrometastases (clinically apparent)

2-3 lymph nodes a: micrometastases b: macrometastases c: in-transit met(s)/satellite(s) without metastatic lymph nodes

N3 4 or more metastatic lymph nodes, or matted lymph nodes, or in-transit met(s)/satellite(s) with metastatic lymph node(s)

Metastasis (M) classification  M1a Distant skin, subcutaneous, or lymph node metastases, normal LDH  M1b Lung metastases, normal LDH  M1c All other visceral metastases, normal LDH Any distant metastases, elevated LDH

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Micrometastases are diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable lymph node metastases confirmed by therapeutic lymphadenectomy or when any lymph node metastasis exhibits gross extracapsular extension.

 Excision of primary lesion: Recommendations  For lesions > 1 mm in thickness, the recommended excision margin is 1 cm.  For lesions 1–4 mm in thickness, a 2-cm margin is recommended.  At least a 2-cm margin should be taken for lesions > 4 mm in thickness. Important consideration  Regardless of the recommended margin, a histologically negative margin is necessary. If the pathology report reveals melanoma cells or atypical melanocytic hyperplasia at the margins, further excision is indicated.  When the anatomic location of the primary tumor precludes excision of the desired margin (eg, on the hands and feet or the face), at least 1 cm should be taken as long as the margins are histologically negative.  If a minor compromise in excision margin can allow primary closure without a skin graft, it is worthwhile.

Breslows thickness

Risk of nodal metastasis

< 1 mm

< 5%

1 – 4 mm

20 – 25%

1 mm

15%

4 mm

55%

> 4 mm

60%

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Management of regional LNs: 

Patients with melanoma having Breslow depth 1 mm are candidates for surgical evaluation of nodal involvement using SLNB techniques.  Patients with thinner melanomas may also be candidates for SLNB if adverse prognostic factors are identified in their primary tumor. 

The first step in evaluating palpable nodes is generally FNA. Positive cytology is sufficient to mandate complete nodal dissection.  A negative or inadequate sample FNA may be repeated, with image guidance if necessary, or may lead directly to an open node biopsy, followed by complete lymphadenectomy in the event of a positive frozen section or touch-prep cytologic determination of metastasis.

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Management of regional LNs: 

In patients with 1-4 mm thickness melanomas, an alternative approach of wide excision alone with observation and serial physical examination of nodal basins has been advocated by some clinicians and has not been shown to reduce long-term survival if complete lymph node dissection is performed at the identification of clinically positive nodes.  The use of SLNB vs observation continues to be an area of intense debate.  

Sentinel LN: The first draining lymph node receiving lymph from the primary tumor bed

SLNB: Dermal injection of vital blue dye (Lymphazurin) surrounding the primary melanoma site allows visualization of the draining lymphatics and the “sentinel” node. Also technetium 99m –labeled sulfur colloid is injected into the primary site preoperatively, and the potentially involved lymph basins are identified with a gamma camera. The patient is then taken to the operating room, where a hand-held gamma probe is used to identify the sentinel node(s).  This technique, in combination with the use of vital blue dye, has led to a success rate exceeding 99% in most large current trials.

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Management of regional LNs: RT-PCR for identification of sub-microscopic metastatic nodal disease:  It is unknown whether submicroscopic metastatic disease has clinical relevance in the long-term survival of patients with melanoma.  Although a number of retrospective studies have suggested that RT-PCR analysis has a role to play in predicting outcome for patients with histologically negative sentinel nodes, a recent study with longer follow-up suggested that this prognostic value was lost over time.  This observation stresses the importance of prospective evaluation of candidate prognostic tests such as RT-PCR.  These issues are currently being prospectively investigated in the Sunbelt Melanoma trial.

Ocular melanomas   

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Generally do not have access to lymphatic channels, so the surgical principles outlined previously do not apply here. Have unique propensity to metastasize hematogenously, often to the liver after a long relapse-free interval – Different tumor biology ? Some small melanomas situated peripherally in the retina can be excised with minimal loss of vision, but most cannot. For larger lesions, treatment options are enucleation (total removal of the eye) or implanted radiotherapy with a radioactive gold plaque fitted to the back of the eyeball immediately behind the tumor. A multi-institution, randomized trial comparing implanted radiotherapy with enucleation for local disease control and overall survival by the Collaborative Ocular Melanoma Study Group showed that both techniques provide similar outcomes for all sizes of tumors.

Melanomas of anus and vulva 

Excision of primary tumors in these areas should not be overly radical.  Abdominoperineal resection or radical vulvectomy is unnecessarily deforming and is not associated with improved survival compared with wide local excision.  Abdominoperineal resection is indicated only for locally recurrent melanomas after prior sphincter-conserving excision or for melanomas with radiographic evidence of mesorectal node involvement. 

In case of inguinal LN involvement, both the primary site and regional nodes should be removed.

Nasal sinuses or Nasopharyngeal melanomas 

Wide excision to include adjacent bony structures, if needed.  Node dissection is reserved for patients who have proven nodal involvement.  Radiation therapy should be considered for those patients whose primary tumor cannot be fully removed from this site with adequate margins.

Immunotherapy  Interferon-alpha-2b (IFN-; Intron A) is the established standard adjuvant therapy Node dissection is reserved for patients who have proven nodal involvement.  Trials 

ECOG 1684: Interferon-alpha-2b was administered by intravenous infusion, 20 mU/m2for 5 consecutive days every 7 days for 4 weeks during the “induction” phase AND for a subsequent 48 weeks, 10 mU/m2 were administered by subcutaneous injection on alternate days for a total of three doses every 7 days in the “maintenance” phase. This “high-dose” regimen was compared with observation.  OS improved by 25% and RFS by 50% in interferon arm.(p