Cutaneous Melanoma

Cutaneous Melanoma

Introduction

melanocytes reside at the dermal/epidermal junctionWhen melanoma arises in the skin, it usually arises from melanocytes at the dermal /epidermal junction . There are alternate presentations, mucosal melanomas, ocular melanomas,metastatic melanomas from unknown primary sitespresumed primary visceral melanomas. Each of these has significant differences in presentation and management. The management of malignant melanoma involves prevention, early diagnosis, surgical extirpation, and combination management of metastatic disease.Cutaneous Melanoma Biology

The transition from melanocyte to metastatic melanoma involves several histologic intermediates, including :melanocytic atypia, atypical melanocytic hyperplasia, radial growth phase melanoma, vertical growth phase melanoma, metastatic melanoma.

The RGP : melanoma in situ (MIS) or superficial invasion into the papillary dermis, or both. rarely symptomaticideal time to diagnose melanoma, these lesions typically progress to the VGP,

RGPvery low metastatic capacity. an excellent prognosis mortality risk at the low end of the 0% to 5% range. VGPRisk of melanoma progression is most associated with the presence of VGP, the depth of invasion, and other markers of the malignant phenotype in the VGP component of a melanoma.

the extent of RGP (e.g., clinically, the diameter of the skin lesion) and multiplicity of RGP lesions are not associated with significant risk of metastasis or melanoma-associated mortalitysome melanomas are nonpigmentedOthers develop a VGP in the absence of a RGP (nodular melanoma histology), some melanomas present as metastatic melanoma in lymph nodes, skin, subcutaneous tissue, or visceral sites without an apparent primary cutaneous site. Epidemiology

sixth-most-common U.S. cancer diagnosisOverall 5-year survival rates for melanoma have increased from 82% in the late 1970s (1975 to 1977) to 92% in the more recent era (1996 to 2002).a combined effect of ultraviolet (UV) sunlight exposure and fair skinOcular and nonacral cutaneous melanomas are 50- to 200-fold more likely in white populations than in nonwhite populations, but melanomas in acral and mucosal sites are within twofold of each other across racial groups. Recent data suggest significant molecular differences between acral melanomas and melanomas arising on the skin associated with chronic sun damage, with B-RAF and N-RAS mutations in 81% of melanomas on chronically sun-damaged skin, whereas those mutations were uncommon in melanomas from acral or mucosal sites or from skin without chronic sun damage.

Changes in IncidenceAn increase in age-adjusted melanomaA greater proportion of patients diagnosed at earlier and noninvasive stages of disease.Gender and Age Distributionthe gender ratio of melanoma at diagnosis is approximately 1:1 but is shifting toward a greater proportion of menMelanoma in Children, Infants, and NeonatesCurrent recommendations for management of melanoma in children and infants are the same as for adults, and outcomes are generally believed to be comparable.

Anatomic DistributionThe most common sites in males are on the back and in the head and neck regions. In women, the most common sites are in the lower extremities, commonly below the knee. Lentigo maligna melanoma (LMM) most commonly arises on sun-damaged surfaces of the head and neck in older patients. Etiology and Risk Factors

ultraviolet light exposure the relative role of each type of UV irradiation in melanoma etiology is debated. a combination of fair skin that burns easily and high ultraviolet/sun exposure The role of sunlight intensity and frequency is debated, but both chronic and intermittent exposure may be relevantTherapeutic Radiation as a Risk Factor for Melanoma

Radiation doses greater than 15 Gy delivered to pediatric oncology patients has been shown to increase the risk of developing malignant melanoma In children undergoing scalp irradiation for tinea capitis, scalp basal cell carcinomas were reported to be 30 times more likely to develop than melanomas in adulthood.Pregnancy and Estrogen Useno evidence of any negative (or positive) impact of prior, concurrent, or subsequent pregnancy on clinical outcome.no clear prognostic relevance for birth control pills or estrogen replacement therapy.PregnancyThe general recommendation for treatment of women with melanoma diagnosed during pregnancy is to manage them in the same fashion as nonpregnant patients.

PregnancyThere is no evidence that a subsequent pregnancy adversely impacts outcome. Measures of the risk of future disease progression can be defined based on the initial prognosis and the subsequent elapsed time without recurrence, and such information may help to guide patients with this challenging question.Prevention and ScreeningSun ProtectionScreening for Early DiagnosisSelf-ExaminationManagement of the Patient with Numerous Atypical MolesSun Protection

Ultraviolet exposure and sunburns, in particular, appear to be etiologic in most melanomas. there is no formal proof that sunscreens prevent melanoma. There are some limitations inherent in sunscreen use. Screening for Early DiagnosisSelf-Examinationfamily memberseducating patientsdermatology visits

Management of the Patient with Numerous Atypical Moles

atypical mole syndrom dysplastic nevus syndromeB-K mole syndrome.

These patients have a heightened risk of melanoma, and this is commonly a familial feature.

Management of the Patient with Numerous Atypical MolesThese patients deserve particular attention to melanoma prevention through sun protection and to early diagnosis through aggressive screening. routine skin exams by a dermatologist are usually recommended, as often as every 3 months.dermoscopy(epiluminescent microscopy)

It is tempting to consider excision of all dysplastic nevi. Melanomas may arise de novo in 30% to 70% of cases, and so it is not clear that removal of all suspicious nevi will lead to a meaningful improvement in survival. However, it is certainly appropriate to biopsy any nevus that is suspicious, especially one that is changing.

Diagnosis of Primary Melanoma

Characteristics of Primary MelanomaABCD for asymmetry, border irregularity, color variation, and diameter greater than 6 mma wide range in the appearancchange in a lesion over time or new development of a lesionugly duckling sign:amelanotic (nonpigmented)Being different: amelanotic (nonpigmented)hallmarks of a late diagnosissymptomatic,BleedingItching painulceration these usually connote deep vertical growthBiopsy

a full-thickness biopsy of the entire lesion, with a narrow (1 to 2 mm) margin of grossly normal skin. The depth of excision should include the full thickness of dermis and thus should be within the subcutaneous tissue, desmoplastic melanoma often arises from lentigo maligna melanoma and is difficult to diagnose both clinically and histologically. Shave biopsies of these lesions can often lead to failure to appreciate the desmoplastic melanoma in the dermis and may substantially delay diagnosisFor some large lesions (e.g., greater than 2 cm diameter) in cosmetically sensitive locations (e.g., face or genitalia), there may be a rationale for an incisional biopsy, but that also should be performed as a full-thickness skin biopsy. Ideally, it should include the most suspicious area of the lesion and also should include if possible a portion of the edge of the lesion, where it transitions to normal skin, to enable assessment of the junctional change. The incisional biopsy may be an elliptical incision or it may be a full-thickness 4- to 6-mm punch biopsy..Punch biopsies are problematic if too small, if they do not include full-thickness skin, if they are crushed during removal, if they are oriented inaccurately in the paraffin block, or if they are too small to include both the edge of the lesion and the most suspicious or most raised part of the lesionMelanoma Subtypes: Histologic Growth PatternsSuperficial Spreading MelanomaNodular MelanomaAcral Lentiginous MelanomaLentigo Maligna MelanomaLentiginous MelanomaDesmoplastic MelanomaSuperficial Spreading MelanomaThe most common type It is typical for the trunk and extremities, except on acral sites. associated with pagetoid growth of atypical melanocytes in the epidermis. associated with sun exposureNodular Melanoma

Nodular melanomas (NMs) lack a radial growth phase, may be nonpigmented, worst prognosisAcral Lentiginous Melanoma

acral sites (subungual, palmar, plantar) and on mucosal surfaces (anorectal, nasopharyngeal, female genital tract). independent of ultraviolet light exposurea prolonged radial growth phase before vertical growthharder to diagnose DDx subungual hematomas, which can lead to diagnostic delay Lentigo Maligna Melanomaolder individualssun-damaged skin,( face). an extensive radial growth phase When just melanoma in situ, this radial growth phase portion is called lentigo maligna (LM) or Hutchinson's freckle,

Lentiginous MelanomaEarly radial growth phase melanomas Over time, this may represent a growing proportion of melanomas that have traditionally been grouped as SSM, LM, ALM, or unclassified melanomas.

Desmoplastic Melanoma

histologically manifested by dermal melanocytes in a dense stromal responseusually nonpigmented usually stain negative for MART-1/MelanA, gp100, and tyrosinase, but they do stain for S-100. most commonly in the head and neckde novo as a nonpigmented skin papule or as a dermal/vertical growth phase component arising from a pre-existing lentigo maligna or other pigmented junctional lesionDesmoplastic Melanomaa high rate of local recurrence the risk of lymph node metastasis is lower a higher threshold for performing sentinel node biopsy (SNBx) in patients with pure desmoplastic melanoma.Prognostic Factors for Primary Melanomas

Depth of InvasionUlcerationage, angiolymphatic invasion mitotic rateGenderbody site

Depth of InvasionClark defined depth based on the layer of skin to which the melanoma has invaded. Clark level I melanomas are melanomas in situ, limited to the epidermis or dermal/epidermal junction Clark level II melanomas invade into the superficial (papillary) dermis, and these are usually radial growth phase lesions. Clark level III melanomas fill the papillary dermisClark level IV melanomas invade into the deep (reticular) dermis and have significant metastatic risk. Clark level V melanomas are uncommon and contain invasion into the subcutaneous fat.

for thin melanomas, Clark level IV or V is associated with higher risk. Breslow thickness has an effect on survival, local, regional, and systemic recurrence rates,

Thickness is considered in defining the margins of excision for primary melanomas.Ulceration

as an important negative prognostic feature is incorporated in the current staging system the overall stage assignment groups ulcerated lesions with nonulcerated lesions one T level higher (e.g., T2b and T3a are both stage IIA). Melanoma TNM ClassificationTumor (T)

TX:Primary tumor cannot be assessed (e.g., shave biopsy or regressed)T0:No evidence of primary tumorTis:Melanoma in situT1:1 mm in thickness (a. without ulceration or b. with ulceration or level IV or V)T2:1.012 mm in thickness (a. without or b. with ulceration)T3:2.014 mm in thickness (a. without or b. with ulceration)T4:>4 mm in thickness (a. without or b. with ulceration)Nodes (N)

N1: 1 lymph node (a. micrometastasisa or b. macrometastasisb)N2: 23 lymph nodes (a. micrometastasisa or b. macrometastasis) c. Satellite or in-transit metastasis without nodal metastasisN3: 4 nodes; matted nodes; or in-transit metastasis or satellites with metastasis in regional node(s)M1aSkin, subcutaneous tissues, or distant nodesM1bLungM1cAll other visceral or any distant metastasis with elevated LDH

Pathological Stage Grouping for Cutaneous Melanoma C STAGING P STAGING IA T1aN0 M0 IA T1a N0 M0IB T1b-T2aN0 M0 IB T1b-T2aN0 M0IIA T2b, T3aN0 M0 IIA T2b, T3aN0 M0IIB T3b, T4a IIB T3b, T4a IIC T4b IIC T4b

III Any T Any N IIIA T1-T4a N1a T1-T4a N2a IIIB T1-T4b N1a T1-T4b N2a T1-T4a N1b T1-T4a N2b T1-T4a,b N2c

IIIc T1-T4b N1b T1-T4b N2b Any T N3

IV Any TAny NAny M M1a M1b M1cClinically undetectable nodes are those diagnosed only with sentinel node biopsy or elective lymphadenectomy. They are referred to also as micrometastases,

Clinically detectable nodes are also referred to as macrometastases,

Patient Gender and Skin Location of Primary Melanomafor essentially all patient subgroups, the prognosis is better for women than men.Women are more likely to have melanomas on the extremities, the prognostic impact of gender is difficult to distinguish from the impact of tumor location. Patient AgeThe impact of age on prognosis is confusing There is a greater risk of lymph node metastasis in young patients at the time of sentinel node biopsy, especially for patients younger than age 35 years, but the melanoma-associated mortality risk increases with age for all thickness ranges.

Nonetheless, age does appear to have independent prognostic significance for melanoma patients.

Growth Patternnodular melanomas have the worst prognosis, associated with their diagnosis at a thicker stage. .Mitotic Ratesix or more mitoses per square millimeter. Ki67Other Prognostic Factorsangiolymphatic invasion has negative prognostic significance

microscopic satellitesUnresolved Issues in Melanoma Staging

Positive Deep Margin on BiopsyLocal Recurrence after Original Incomplete ExcisionSkin or Subcutaneous Lesion without Junctional Involvement and without Known Primary MelanomaPositive Deep Margin on Biopsy

One approach for defining T stage in that setting is to call it TX.The other is to use the T stage of the original depth, even though that is incomplete

Thus, use of TX results in substantial loss of information for patients and their clinicians. The best solution is to avoid shave biopsies, but when they occur, it seems reasonable to stage based on the thickness level that is known, when no residual tumor is found on wide excision, while also noting that there was a positive deep marginLocal Recurrence after Original Incomplete ExcisionSome patients present with melanoma after excisional biopsy or destruction (e.g., cryotherapy) of a pigmented skin lesion that was believed to be benign (clinically or histologically) on initial review. When such a lesion recurs and is found to contain melanoma, re-review of the original biopsy is appropriate, if available. Staging of such recurrent melanomas, when the original lesion was not known to be melanoma, is not well addressed.

Skin or Subcutaneous Lesion without Junctional Involvement and without Known Primary Melanoma Cutaneous or subcutaneous nodules that occur in the absence of junctional melanocytic change, and in the absence of any other known primary They may be in-transit metastases from primary melanomas that spontaneously regressed (stage IIIB), primary melanomas that arose from dermal nevi or that persisted in the dermis after arising from a partially regressed primary melanoma (stage IIB), or a distant metastasis from an unknown primary melanoma (stage IV, M1a). A review of experience with these lesions at the University of Michigan suggests that these are best staged as stage IV by strict application of AJCC terms, but that they behave more like primary tumors arising in the dermis or subcutaneous tissue.

General Considerations in Clinical Management of a Newly Diagnosed Cutaneous Melanoma (Stage I-II)

histologic assessment of skin biopsypresents to a surgeon(T)definitive surgical managementtherapeutic resection and pathologic staging evaluation for regional metastases (N)Clinical Evaluation and Radiologic Studies for Patients with Clinical Stage I-II MelanomaA complete history and physical examBaseline chest x-ray(CBC), for serum chemistries: LFT, and (LDH)PET

microcytic anemia, /GI metastasis of melanoma. Elevated LDH should prompt a more extensive staging workup, and elevated liver function tests should prompt a hepatobiliary ultrasound or computed tomography (CT) scan unless there is another known explanation.PET gained an appropriate role in staging patients with advanced melanoma, The Memorial Sloan-Kettering experience recommends limiting aggressive staging workup (CT scans, PET, magnetic resonance imaging [MRI] of the brain, etc.) after positive SNBx to those patients with thick melanomas and macrometastases.Wide Local Excision for Clinical Stage I-II Melanoma: General Considerations

WLE for: local controlan opportunity to evaluate the tissue adjacent to the primary lesion for microscopic satellites, which, if present, have clinical and prognostic significance.

Appropriate margins of excision for primary melanomas,Intergroup Melanoma Trial:

a 2-cm margin as adequate for melanomas 1 to 4 cm thick?ulceration of the tumor and head-and-neck location as significant negative prognostic features.

British Cooperative Group Trial

excision greater than 1 cm for thicker melanomas? The data from the Melanoma Intergroup study support 2-cm margins for melanomas 2 to 4 mm thick. No data have formally compared 2-cm margins to 3-cm margins for T4 melanomas.

Surgical Staging of Regional Nodespatients who have metastatic disease limited to local and regional sites have substantial chance for cureELND

technique of lymphoscintigraphy to map the actual lymphatic drainage patternsblue dyeradiocolloid lymphoscintigraphygamma probes

radiocolloid lymphoscintigraphy aloneThere is a substantial multicenter and single-center experience with use of radiocolloid alone, which is associated with successful identification of the sentinel node(s) in greater than 99% of patients and with a mean of approximately two sentinel nodes per patient.blue dye aloneThe effectiveness of blue dye alone is limited because some patients have drainage to lymph node basins that may not be predicted (e.g., drainage from the right upper back to the left axilla) or drainage to atypical nodal basins (e.g., the triangular intermuscular space on the back, epitrochlear or popliteal nodes, or subcutaneous in-transit nodes that are outside a traditional nodal basin). In experienced hands, lymphatic mapping should identify a sentinel node in 98% to 100% of cases, and it should be feasible to perform the sentinel node biopsy with minimal morbidity, on an outpatient basis, and in many cases under local anesthesia with sedation. The early reports of sentinel node biopsy stress a long learning curve, but as the technology of gamma probes has improved, the technique is less operator dependent.

advantages(1) It avoids the morbidity of complete node dissection for patients without metastatic nodal disease, (2) it provides to the pathologist a very limited amount of tissue for examination. The rate of missed micrometastases is in the range of 10% to 20% of patients. In contrast, the standard evaluation of a sentinel node includes evaluation of multiple sections of the node, often combined with immunohistochemical staining for melanoma markers (e.g., S100, HMB45, tyrosinase, and/or MART-1/MelanA).with increasing tumor thickness increases rate of positive nodes

In addition, the low morbidity of SNBx supports a threshold for SNBx in thinner melanomas than the 1.5-mm criterion that was used for performance of ELND.

The overall rate of positive SNBx : 15% to 25%. false-negative SNBx :1.9% to 4%. false-negativeELNDSNBx

FNseeking nodes containing metastases in the remaining nodal basin after a negative sentinel node biopsyby defining patients who return with clinically evident nodal metastases after a prior negative SNBx in the same node basin. it is prudent to follow patients for nodal recurrence even after a negative SNBx.FNThus, the rate of regional control after negative SNBx is similar to that after ELND, with lower morbidityRT-PCRAnother approach under investigation is to perform molecular analysis of sentinel nodes. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay for melanocytic differentiation proteins (e.g., gp100 and tyrosinase) and cancer-testis antigens (e.g., MAGE-A3) permits detection of cells containing those molecules, even when they are present below the limit of detection for current histopathologic sampling and immunohistochemistry.In performing SNBx, melanoma metastases are sometimes clinically evident in the operating room as small pigmented spots just under the capsule of the node .This may be particularly relevant for some large nodes, where the pathologist can be guided to the portion most at risk of metastasis for detailed histologic assessmentRT-PCREarly experience with RT-PCR analysis of sentinel nodes suggested a significant negative prognostic value for RT-PCR positive, histology-negative nodes, and suggested that patients with RT-PCR negative, histology-negative nodes have a remarkably high survival rate.SNBx or observation in addition to WLEThe rationale for performing SNBx for melanoma includes the following:

A negative sentinel node biopsy is a good prognostic indicator that may help low-risk patients feel less vulnerable, especially in the setting of stage I melanomas, in which the prognosis is excellent.A positive sentinel node biopsy for patients with T1-T3a clinically N0 melanomas (clinical stage I-IIA) renders them candidates for adjuvant high-dose interferon therapy, which offers some clinical benefit

The rationale for performing SNBx for melanoma includes the following:

3.Patients with T4 melanomas or with microscopic satellites (N2c, stage IIIB) are further up-staged by the finding of a positive sentinel node, which helps these patients in risk assessment and may make them candidates for selected clinical trials4.Many clinical trials require surgical staging of regional nodes, and, thus, sentinel node mapping makes patients candidates for trials that may prove to be of benefit.5.Identification of melanoma in a sentinel node permits selection of patients for completion lymph node dissection to increase the chance of regional tumor control.6.In patients who are not good candidates for general anesthesia, excision of the sentinel node may be curative if there is no tumor beyond the node, even if completion node dissection is not feasible

Lymphatic mapping and SNBx has been applied generally for all cutaneous sites and may also be useful for melanomas of mucous membranes. A challenging area for SNBx is the head and neck. FN sentinel node biopsies are more

Selection of Patients for Sentinel Node BiopsySentinel node biopsy is generally recommended for patients with melanomas at least 1 mm thickDesmoplastic melanomas

Sentinel Node Biopsy Subsequent to a Prior Wide Local Excision

Sentinel node biopsy should be performed at the same procedure as WLEperforming SNBx after prior WLE, although performing it concurrent with the original WLE is preferredManagement of Clinically Localized Melanoma

Management of Melanoma in situ (Clinical TisN0M0, Stage 0)

wide excision alone. regional nodes should be examined, as should the skin and subcutaneous tissue between the primary site and these regional node basins. No radiologic staging studies. A 5-mm margin or 1 cm, If the margins are positive or close, re-excision to a widely clear margin is recommendedSNB is not indicated. No adjuvant therapy is needed if the margins are widely clear.Clinical Follow-Up after Surgical Treatment of Melanoma in Situ

rarely may be associated with metastasis, NCCN :follow these patients for local recurrence, in-transit metastasis, or regional node metastasis on an annual basis. physical examManagement of Thin Primary Melanoma (Clinical T1a)

studies have shown a continuous risk association with increasing thickness, without an absolute cutoff at 0.76 mm, less than 1 mm thick Clark level of III or less without ulceration. Melanoma Stage Clinical Follow-Upa Radiologic and Laboratory Follow-Up0 Annual None needed IA Annual CXR, CBC, LDH annually; CT scan or other radiologic workup of new findings

IB-IIA Every 3-6 mo , 3 y, then 4-12 mo , 2 y, then annually CXR, LDH, and CBC every 6-12 mo; CT scan or other radiologic workup of new findingsIIB-IIIAEvery 3- 6 mo , 3 y then 4-12 mo ,2 y, then annually CXR, LDH, and CBC every 6- 12 mo; CT scan or other radiologic workup of new findings; if lower-extremity primary, CT pelvis or PET-CT to evaluate iliac nodesIIIB-IIICEvery 3-6 mo , 3 y, then 4-12 mo ,2 y, then annuallyCXR, LDH, and CBC every 6- 12 mo; CT scan or other radiologic workup of new findings; if inguinal nodes had been involved, get CT pelvis (or PET-CT) every 6- 12 mo

IVEvery 2-3 mo , 2 y, then every 3-6 mo 3 y, then annually CT or PET-CT, plus MRI brain, LDH, and CBC every 3-6 mo, especially in areas of prior metastasesA thin melanoma should be examined with a focus on the primary site, the regional nodal basins, and in-transit locations, and a history should elicit any findings that may lead to suspicion of metastases (e.g., weight loss, fatigue, bone pain, headaches, change in appetite(clinical T1a) do not need aggressive radiologic staging studies. (CXR) and an LDH level are adequate

T1a :wide excision with a 1-cm margin (including skin and all underlying subcutaneous tissue, to thedeep fascia). The margin should be measured from the visible edge of the pigmented lesion or from the biopsy scar, whichever is larger. Excisions of this size can almost always be closed primarily, with exceptions being on the face, palms, and feet, where skin grafts or rotation flaps may be needed.

Surgical Methods in Wide Local Excision (Applies for All Primary Melanoma Thicknesses)

For melanomas of the trunk and proximal extremities, wide local excisions should involve measuring the appropriate margin (usually 1 to 2 cm) around the entire scar from the biopsy On the upper back, it is usually best for the scar to run transverse, to minimize tension on it. T1a lesions (nonulcerated, Clark II-III), sentinel node biopsy is not routinely recommended.when the initial biopsy is a shave biopsy ,sentinel node biopsy should be considered. However, if there is no gross residual tumor, it is reasonable to proceed with a 1-cm margin re-excisionClinical Follow-Up for Thin Melanomas (Stage IA)

annual follow-up for many years is recommended rather than frequent follow-up in the first few years. Management of Clinical T2a, T2b Melanomas

an initial history and physical exam CXR and LDH.wide excision with a 1- to 2-cm margin sentinel node biopsy

T2a, T2bWhen it is feasible to take a 2-cm margin without a skin graft (trunk and proximal extremities in most cases), this is recommended to minimize the chance of local recurrence

on the face or distal extremities, a 1- to 1.5-cm margin is acceptable. If a skin graft will be necessary even to close a 1-cm margin (rare), it is recommended that a 2-cm margin be taken because the morbidity and cost of the skin graft will already be needed.for lesions that are barely above 1 mm in depth (e.g., 1.05 mm), it certainly is reasonable to use a 1-cm margin.If the sentinel node biopsy is positive:TX for stage IIIA melanoma (T2a with positive sentinel node biopsy involving one to three nodes) or stage IIIB melanoma (T2b with positive sentinel node biopsy involving one to three nodes).

However, if the sentinel node biopsy is negative, then the patient is considered to have been pathologically staged as T2aN0M0 (stage IB) or T2bN0M0 (stage IIA

Management of Clinical T3a Melanomas (Clinical Stage IIA)

a history and physical examination a CXR and serum LDH levelwide excision with a 2-cm margin sentinel node biopsy negative, then no additional surgical or systemic therapy is indicated positive, then management for stage IIIA melanoma should be followed.

115Management of Clinical T3b Melanomas (Clinical Stage IIB)

high-risk localized melanomasa careful history and physical examination at least a CXR and serum LDH levelGiven the higher risk of synchronous metastases that may be detected at diagnosis, more aggressive systemic staging to include CT scans of the chest, abdomen, and pelvis (or PET-CT scan) plus MRI scan of the brain.

Clinical T3bdefinitive management is wide excision with a 2-cm margin and a sentinel node biopsy.IIB (T3bN0M0): no additional surgical therapy is needed. HDIit is available for such patients, whose risk is comparable to that of patients with nonulcerated thick melanomas (T4aN0). Patients with stage IIB melanoma often are also candidates for some experimental adjuvant systemic therapiesManagement of Thick Melanomas (T4a, T4b, Greater Than 4 mm Thick)

a risk of metastasis and mortality in the range of 50% over 5 to 10 years. Ulceration increases this risk T4a melanomas are clinical stage IIBT4b melanomas are clinical stage IIC.T4a, T4bhistory and physical examination CXR, and serum LDH more-aggressive radiologic imaging as indicated by signs and symptoms.

T4a, T4b Definitive management includes wide excision with at least a 2-cm margin plus sentinel node biopsy. strong data supporting the adequacy of 2-cm margins in 1- to 4-mm melanomas may be extrapolated to thicker lesions. T4a, T4b most studies show that sentinel node status has independent prognostic value for patients with thick melanomas. Because these patients have a high risk of sentinel node positivity (approximately 35% to 40%), there is a high chance of regional nodal recurrence, and sentinel node biopsy, followed by completion lymph node dissection, offers the prospect of increasing the chance of regional control.

T4a, T4bIn patients with negative sentinel nodes, adjuvant HDI should be considered because it is approved by the U.S. Food and Drug Administration (FDA) for these patients. Special Considerations in Management of Primary Melanomas

Primary Melanomas of the Head and NeckPrimary Melanomas of the Mucous MembranesPrimary Melanomas of the Fingers and Toes

Primary Melanomas of the Head and Neckanatomic constraints:the optimal margins should be obtained and closed with an advancement flap, skin graft, or limited rotation flap. a large-diameter lentigo maligna on the face that is not amenable it may be treated with superficial or Grenz x-rays with local control rates reported above 90%.topical treatment with imiquimod ointment have also resulted in effective local control of superficial melanomas. Desmoplastic melanomas commonly occur in the head and neck region and may have reported local recurrence rates up to 40% to 60% after resectionHigh local recurrence rates in desmoplastic melanoma :Anatomic constraints in the head and neck amelanotic, histologic appearance of desmoplastic melanoma , especially in fibrotic skin. Thus, in patients with desmoplastic melanoma, every effort should be made to obtain adequate margins. If that is not possible, postoperative adjuvant radiation should be considered with 2- to 3-cm margins around the resected lesion because this may reduce subsequent local recurrences.

Neurotropic melanomas of the head and neck have a propensity to recur at the skull base by tracking along cranial nerves, and postoperative adjuvant radiation including the resection bed and the cranial nerve pathway should be considered for this variant

Primary Melanomas of the Mucous MembranesMucosal melanomas of the head and neck, anorectal region, and female genital tract are usually diagnosed when they are thick. They are associated with high risks of distant metastases and death, approaching 100%. They are also associated with high risks of local recurrence and regional nodal metastases. The depth of invasion is difficult to measure because they are often biopsied in a fragmented way, but they usually are deep lesions, with depths often of 1 cm or more.Primary Melanomas of the Mucous MembranesThey should be resected with wide margins if possible. Resection of melanomas of the nasopharynx, oropharynx, and sinuses is limited by the bony structures of the skull and the base of the brain. Vulvovaginal melanomas may be widely resected in many cases but may also be constrained by efforts to preserve urinary and sexual function. They may also be associated with extensive radial growth in addition to the invasive lesion, which can lead to multifocal local recurrences. Anorectal melanoma may usually be resected widely by an abdominoperineal resection, but this morbid operation is not associated with higher survival rates than local excision only. Adjuvant local radiation therapy may be of value when widely clear margins are not feasible.Primary Melanomas of the Mucous MembranesRT?SNB? Mucosal melanomastheir response to interferon therapy? Primary Melanomas of the Fingers and ToesSubungual melanomasTx:amputation at the interphalangeal joint of the toe ,Even for in situFor melanoma of the toe, amputation of the toe) exception is the great toe(occasionally :wide excision and skin grafting SNB :at least T1b lesions

Clinical Follow-Up for Intermediate-Thickness Melanomas (Stage IB-IIA)

history and focused physical exam :every 3 months -annually, CXR, LDH, and CBC at least annually,other scans Symptomshigh-risk primary (e.g., T4b) on the lower extremitypelvic CT scan orPET-CT :in identifying iliac nodal brain MRI

Stage IB-IIARecurrences: local skin, in-transit skin, or lymph nodes

visceral metastasis : lung and liver, GI, brain, bone, distant skin or nodes, and adrenal glandsheadaches, weight loss, change in appetite, bone pain, or other symptoms that could be associated with these metastatic sites. The diagnostic yield of laboratory tests is low, but elevations of LDH or other liver function tests may signal a liver metastasis or other new metastasis. New microcytic anemia can be a first sign of gastrointestinal blood loss due to a small bowel metastasis.

Regionally Metastatic Melanoma (Stage III): Lymph Node Metastasis, Satellite Lesions, and In-Transit Metastasesa high propensity to regional metastasis a negative prognostic there is some chance of long-term disease-free survival and cure for patients with regional metastases, and they should be managed with curative intent whenever feasible.

Regional metastases are defined as follows:

Local recurrence is best defined as recurrence of melanoma in the scar from the original excision or at the edge of the skin graft if that was used for closure. Satellites metastases either may occur simultaneous with the original diagnosis or arise subsequent to original excision. Typically, recurrences that are separate from the scar but within 2 to 5 cm of it are considered satellite metastases

Regional metastasesRegional recurrences beyond 5 cm of the scar but proximal to regional nodes are considered in-transit metastases Regional node metastases are typically in a draining nodal basin that is near the lesion.

Management of Local Recurrence

Local recurrence is common after a primary lesion is inadequately excised. This type of local recurrence thus represents a failure of initial surgical management and may not represent the same high risk of distant metastasis and mortality that is associated with local recurrence after what is otherwise considered adequate surgical resectionManagement of Local Recurrencere-resect the entire scar down to the level of fascia, and perhaps including fascia, because there may be more tumor in the scar than is clinically evident, and this type of resection can generally be performed with minimal morbidity. Excision with a 1- to 2-cm margin is reasonable if the recurrences are limited to the scar satellite metastases, more extensive resection may be appropriate, with a skin graft In patients with concurrent distant disease, a less aggressive approach to the local recurrence may be justified, and simple excision to a clear margin may be acceptable.

Management of Local RecurrenceSNBThis is usually successful even if there has been a prior sentinel node biopsy or even a prior complete lymph node dissection. This may enable regional control in such high-risk patients, in whom the sentinel nodes may be positive in up to 50% of cases.

Unresectable recurrent lesions should be considered for palliative radiation therapy.

Management of Satellite and In-Transit Metastases

clinical outcomes similar to with palpable nodal metastases. When a patient presents with a solitary in-transit metastasis or a localized cluster of in-transit metastases it is reasonable to perform excision of this along with sentinel node biopsy. The margin of excision should be adequate to obtain free margins. This usually requires a 5- to 10-mm margin. A fairly frequent clinical scenario that is difficult to manage is the patient with multiple in-transit metastases. Satellite and In-Transit Metastasesthere is no reliable systemic therapy for this processsurgery remains the first best option for regional control, when feasibleSatellite and In-Transit Metastasesto excise them under local anesthesia. Follow-up every 2 to 3 months new, small in-transit metastases often can be excisedFor the isolated in-transit metastases:sentinel node biopsyRadiation therapy should be considered after surgical resection in this settingRegional options for satellite and In-Transit MetastasesIntralesional therapy withInterferon - Interleukin -2Bacillus Calmette-Guerin (BCG) Topical treatment of superficial metastases with imiquimodManagement of Satellite and In-Transit MetastasesUsual recommendations :limited excisions If that fails isolated limb perfusion or infusion Amputation of the extremity?Isolated Limb Perfusion and Infusion

Melphalan TNF-complete responses in 60% to 90% of patients, Retreatment with isolated limb perfusion or infusionIsolated limb perfusionMelphalan+TNF-? compared to melphalan aloneadjuvant ?Management of Regional Lymph Node Metastasesprognosis is related to tumor burden in the nodes and the number of nodes involved with tumor. clinically occult metastases (sentinel node positive, clinically negative) and clinically positive (palpable) metastatic nodes. This was a significant prognostic distinction.

Management of Patients after a Positive Sentinel Node Biopsy (Stage IIIA If Nonulcerated Primary Lesion, One Positive Node)

Several studies have identified features of the positive sentinel node (SN) that predict a low risk of a positive CLND:the number of positive SNs the tumor burdenthe location of tumor in the node features of the primary melanomaSNBxA much more rigorous histopathologic approach than non-SNs, multiantigen RT-PCR the current limited data suggest that the true rate of positive non-SNs after a positive SNBx may be somewhere between 15% and 50%.The standard recommendation is to perform CLND of any lymph node basin with a positive SN for melanoma.Medical contraindications for CLNDvery low tumor burden in the SNobservation after positive SNBx

For those patients who refuse CLND or who are not good medical candidates for it, it is reasonable to combine imaging evaluation with ultrasound or PET-CT to identify recurrences at an early stage if possible.Management of Palpable Metastatic Melanoma in Regional Nodes: Therapeutic or Completion Lymphadenectomylymphadenopaty : after a negative sentinel node biopsy after observation of a nodal basinfrom an unknown primary melanoma after a prior complete dissection

stage IIIstage III (A, B, or C) disease is associated with a subsequent risk of distant metastasis in the range of 40% to 80%. there is a significant chance of cure after complete lymphadenectomy for stage III melanoma, with overall 25-year survival rates of 35%. in the future, there is benefit in achieving regional control, which is obtained in about 90% of patients. As discussed earlier, aggressive staging studies are of very low yield in patients with micrometastases found on sentinel node biopsy. However, for patients with thick melanomas or with macrometastases or palpable clinical nodes, the yield is higher. Preoperative staging is recommended for those patients, using MRI of the brain and with CT or PET-CT.Axillary Dissection

Axillary dissection should include all node-bearing tissue in levels I, II, and III.Tx of Lymphedema:compression sleeve and/or massage therapy

Inguinal and Iliac DissectionFor patients with metastatic melanoma to inguinal nodes, complete groin dissection is indicated. Patients with known inguinal metastases should undergo CT scan of the pelvis or PET-CT scanThe risk of lymphedema with inguinal or ilioinguinal dissection is greater than for axillary or cervical node dissectionsIt may require a fitted compression stocking or massage therapy approachesCervical DissectionA modified radical neck dissection should be performed, Melanomas of the face, ear, or anterior scalp often drain to parotid or periparotid nodes. In such cases, superficial parotidectomy is indicated as part of a modified radical neck dissection.

Management of Regional Metastases in Patients with Visceral or Other Distant Disease

Management of regional metastases can be important for clinical management even in the setting of distant disease, There are three general types of regional metastasis: satellite metastasis, in-transit metastasis, and regional lymph node metastasis. The Role of Radiation Therapy in the Management of Regional Nodal Disease

Adverse risk factors that increase the risk for nodal basin recurrence after therapeutic nodal dissection to 30% to 50%.lymph node extracapsular extension large lymph nodes (greater than 3 cm in diameter) four or more involved lymph nodesRecurrent disease after previous lymph node dissection

postoperative adjuvant radiation delivered to nodal basins:recurrent unresectable nodal disease with pain, ulceration, bleeding, and lymphedema,

Retrospective reports from several centers report 5-year locoregional control rates after radiation ranging from 80% to 93%

Postoperative adjuvant irradiationhigh-dose per fraction or conventional fractionation ?

locoregional control rates appear to be equivalent,

Radiation complicationLymphedema fibrosis nerve plexopathiesOsteonecrosisIn summary, review of retrospective data reveals that postoperative adjuvant radiation for stage III patients results in acceptable locoregional control with reasonable complication rates and no obvious survival benefit.

Adjuvant Systemic Therapy (Stages IIB, IIC, and III)

High-dose interferon alpha is the only agent to have gained FDA approval for the treatment of resected stage IIB and stage III melanomaThe most common severe side effectsFatigueAsthenia fever depressionelevated liver transaminases. Cytotoxic Chemotherapy and Combination Chemotherapies in Adjuvant Therapy of MelanomaArguably, single-agent chemotherapy or combination chemotherapies regimens have not been comprehensively evaluated for the adjuvant treatment of melanoma. To date, however, they have not caused significant improvement in survival. Neoadjuvant Therapy for Resectable Stage III or IV Melanoma

Neoadjuvant therapy for resectable stage III or stage IV melanoma remains an investigational approach. Adjuvant ImmunotherapyThere is substantial evidence that the immune system responds naturally to melanoma and that immune modulation can be therapeutic for advanced melanoma. In the last 20 years, there have been dramatic and durable clinical tumor regressions with high-dose interleukin-2 therapy, now approved for use in advanced melanoma, and recent experience with antibody to the CTLA-4 moleculeThe WHO Trial 6 enrolled 761 patients after lymphadenectomy for regional node metastasis and randomized them to a four-arm trial including BCG and DTIC. Those four arms were surgery only (S), surgery + BCG (B), surgery + DTIC + BCG (DB), and surgery + DTIC (D). Granulocyte-Macrophage Colony-Stimulating Factor(GM-CSF) as attracted attention as a vaccine adjuvant in murine studies.in patients with high- to extremely high risk melanoma.A single-arm study was performed in high-risk melanoma patients in which GM-CSF was administered subcutaneously daily at 125 mcg/m2 for 14 days, followed by a 14-day rest period and with repeat of that cycle for 1 year. This has been a well-tolerated regimen. Clinical Follow-Up for Patients with Regionally Metastatic Melanomas (Stage III)

history and focused physical exam :every 3 months and as infrequently as annually, CXR, LDH, and CBC at least annuallyCT or PET-CT is not likely to have much yield if the other studies and clinical exam are all unremarkable.high-risk primary (e.g., T4b) on the lower extremity, pelvic CT scan or PET-CT may be helpful in identifying iliac nodal recurrences that are difficult to detect on exam.brain MRI may be helpful in detecting small brain metastases when they are asymptomatic and amenable to treatment with gamma-knife radiation therapy.

Management of Distant Metastases of Melanoma (Stage IV)

very poor prognosis, with median survivals of 6 to 15 months.M1a, (M1b) ,(M1c)Timing of Distant MetastasesIn general, the interval to detection of distant metastases is shorter for patients who initially present with high-stage disease (e.g., stage IIB-III) and is longest for patients who present with clinically localized thin melanomas (e.g., stage IA). Often, metastases become evident within 2 to 3 years of diagnosis, Patterns of Metastases

Approximately 60% to 80% of first metastases are at local or regional sites including regional nodes. Common visceral sites of metastasis are lung, liver, brain, gastrointestinal tract (especially small bowel), bone, and adrenal gland.

Prognostic Factors in Distant Metastatic Melanoma (Stage IV)

Negative prognostic factors in stage IV melanoma:a large number of metastatic sites elevated LDH levelpoor performance status.

There is little evidence that the available therapies significantly alter the natural history of melanomaClinical Evaluation of Patients with Distant Metastasis (Stage IV)

The initial steps are to perform full restaging studiesMRI scan of the brain total-body PET-CT scan CT scans of the chest, abdomen, and pelvis. Other scans or imaging studies (bone scan, soft tissue MRI, ultrasound, or plain films) may be indicated to evaluate known areas of metastasis (e.g., soft tissue masses in extremities) or to evaluate symptoms (e.g., plain films or bone scans for bony symptoms).

PET-CT scansdistinguishing tumor from scar For small bowel metastases lymph node metastases that are borderline in size PET-CT scan may also be helpful in assessing patients for resectability when there is limited disease on initial assessmentHistologic or Cytologic Diagnosis

tissue confirmation of metastatic melanoma is usually recommended. Fine-needle aspiration biopsy BiopsyCore -needle biopsy, when feasible, can improve diagnostic accuracy further. IHC stains for S100, HMB45, tyrosinase, and MART-1/MelanA can all be helpful in confirming a diagnosis of melanoma.

Surgery for Distant Metastases (Stage IV)

Patient Selection and Prognostic FactorsCases in which the benefit of surgery is clear

Anemia due to occult bleeding from intestinal metastasisBowel obstruction due to small bowel metastasisCutaneous or subcutaneous metastasis or metastases with ulceration, pain, or impending ulcerationLymph node metastasis with neurologic symptomsSymptomatic brain metastasisLife-threatening hemorrhage from metastasis

Metastase to GI tractCT scan ?enterclysis study ?PET-CT is the bestNonetheless, when a patient presents with GI blood loss or obstruction associated with a small bowel (or other GI) metastasis of melanoma, operation is almost always indicated. If the tumor involves the mesenteric nodes and is matted, then it may not be feasible or appropriate to resect the operation for Metastase to GI tract

if the patient can be rendered surgically free of disease, then there may be long-term survival greater than 5 years in as many as 25% of patients and mean survival greater than 2 years.Cutaneous, subcutaneous, and nodal metastasessubstantially decreases the quality of life for patients. Even in the setting of low-volume distant visceral disease, resection of cutaneous lesions can benefit patients by avoiding tumor-associated skin ulceration and drainageExtensive lymph node metastasis with neurologic symptomsThe morbidity of surgery may include lymphedema complications, wound healing issues, and brief perioperative discomfort,The major risks of continued tumor growth include paralysis or major neurologic dysfunction of the extremity, intractable lymphedema, disabling pain, and unresectability.Brain metastasessurgerySteroid therapy spontaneous hemorrhagein metastatic melanomacan be trivialcan be massive In such cases, resection of the hemorrhagic mass may diminish future risk of bleeding, decrease pain, and delay death.

cases in which the benefit of surgery is likely

Solitary asymptomatic visceral metastasis resectable with minimal morbidityBony metastasis with pain or joint involvement, unresponsive to radiationSolitary brain metastasis without symptomsLarge nodal metastasis in the absence of symptoms and with concurrent low-volume systemic disease.Extensive skin and soft tissue metastases in the absence of visceral metastasesIsolated growing metastasis in the setting of stable or regressing metastases after systemic therapy

Solitary visceral metastasisexcision can be both therapeutic and diagnostic

to enroll in an experimental therapeutic trial to take an approved systemic therapy in the hope of clinical responseBone metastasesRadiation therapy is usually the first choice for therapeutic intervention if significant pain exists.impending fracture, orthopedic stabilization should be considered before radiation. However, if the lesion does not respond to radiation or is solitary, resection with bone grafting or joint replacement can be considered. Brain metastasisAn asymptomatic solitary brain metastasis Stereotactic radiosurgery

surgeryextensive lymph node basin diseaseIn the presence of large-volume visceral disease, systemic therapy is the best option, if there is low-volume asymptomatic visceral disease, it is often likely that the nodal disease will cause disabling symptoms before the visceral disease does. extensive regional skin and subcutaneous metastasesThus selection of these patients for surgery depends on multiple considerationsMultiple metastasesTx systemic Resecting the one or several tumor deposits that are progressingCases in which some patients may benefit from surgery but risk and benefit are closely balancedMore than one visceral metastasis, without symptomsMultiple lung nodulesBilateral adrenal metastasesExtensive skin and soft tissue metastases in the setting of visceral disease

A Situations that may push the patient and the clinician toward such an aggressive surgical approach include(1) prior failure of systemic therapy (2) a young patient for whom perioperative morbidity is not a major concern, (3) disease sites that are particularly amenable to surgery through limited surgery

Adjuvant Therapy for Resected Stage IV MelanomaThere is no standard or approved adjuvant therapy after resection of metastatic melanoma (stage IV). Interferon ?Therefore, observation remains the standard management of patients in this setting.

Treatment of Unresectable Metastatic (Stage IV) Melanoma

Single-Agent Chemotherapy

Alkylating agents Dacarbazine ,Temozolomide ,

Nitrosoureas Lomustine ,Fotemustine ,

P latinum analogs Cisplatin ,Carboplatin

Microtubule-stabilizing/destabilizing Paclitaxel ,Docetaxel ,Vincristine ,Vinblastine ,VindesineImmunotherapy for Systemic Treatment of Stage IV Melanoma

Interleukin-2

The intravenous administration of high-dose interleukin-2 (IL-2; aldesleukin) represents the most effective treatment for patients with metastatic melanoma and the treatment most likely to provide long-term complete responses in these patients. IL-2 has no direct effect on cancer cells, and all of its antitumor activity is a function of its ability to modulate immunologic responses in the host.

IL-2an intravenous bolus infusion of 600,000 to 720,000 IU/kg every 8 hours to tolerance using two cycles separated by approximately 10 days (maximum of 15 doses per cycle). Results of this treatment are evaluated at 2 months after the first dose, and if tumor is regressing or stable, a second course is then administered. FDA Approved The durability of complete responses is the hallmark of IL-2 therapy, and greater than 80% of complete responders are likely cured, with ongoing complete regression in many series now beyond 15 years.

Regimens of IL-2high-dose bolus IL-2 alone is superiorsubcutaneous administrationcontinuous infusion

Although the Surgery Branch of the NCI uses a dose of 720,000 IU/kg, most centers use a dose of 600,000 IU/kg, and both are approved by the FDA. There is no clear evidence favoring one dose regimen over the other.

High -dose bolus IL-2 Only in selected patients younger than the age of 70 years with an ECOG performance status of 2 or less do not have active systemic infections or other major medical illness of the cardiovascular respiratory or immune system.normal serum creatinine and serum bilirubin. The toxicities of IL-2 administration are transient, and virtually all returning to baseline after IL-2 administration is stopped.

Toxicities of IL-2 Administration

Supportive measures are often required for patients during treatmentIL-2 can be administered to patients with metastatic melanoma with a treatment related-mortality expected to be less than 0.5%Most Common and Most Severe Adverse Events with High-Dose Interleukin-2 TherapyCardiovascular Hypotension Tachycardia Supraventricular Ventricular Myocardial infarction Myocardial ischemia Gastrointestinal Nausea Vomiting Diarrhea Stomatitis Neurologic Confusion Somnolence Coma Pulmonary Dyspnea Adult respiratory distress syndrome, pulmonary edema Hepatic Elevated bilirubin levelsElevated transaminase levels ,Elevated ALK-PRenal Oliguria ,Increased creatinine levels ,Anuria , Hematologic Thrombocytopenia ,Anemia 1