10 03 02 skin tumors melanoma 2

INTRODUCTION

Melanoma can be cured with simple surgicaltreatment in the vast majority of patients if it isdetected early in its clinical course.

Balch & Milton (1985)1

Over the past 30 years, the incidence of cutane-ous melanoma in the United States has doubled,increasing at a rate of approximately 3% per yearsince 1981. Although melanoma accounts for only4% of all skin cancers, it is responsible for almost80% of skin cancer-related deaths. Estimates arethat in the United States in 2003 there were almost54,000 new cases of melanoma diagnosed and 7600deaths from melanoma.2,3

HISTORY

Melanoma was first described in 1787 by JohnHunter,4 who based his account on the case of a35-year-old man with a recurrent mass behind theangle of the jaw. Hunter did not describe the tumoras a melanoma, but rather as a �“cancerous fungousexcrescence.�” The resected surgical specimen ispreserved in the Hunterian Museum of the RoyalCollege of Surgeons of England, and in 1968 it wasexamined microscopically and found to be a mela-noma.

Rene Laennec first described melanoma as a dis-ease entity in an unpublished paper presented inParis in 1806; 6 years later he first used the word�“melanosis�”.5

In 1820 William Norris6 described the clinicalcourse of a patient who died from widespread mela-noma. Norris became interested in the diseaseand reported 8 cases in 1857.7 Norris noted thatmelanoma often occurs �“in those persons who havemoles on various parts of the body.�” If the attend-ing physician suspected a malignant change in amole, Norris recommended that the surgeon �“im-mediately not only remove the disease, but cutaway some of the healthy parts.�” More than 100years ago, Norris correctly noted the following epi-demiologic features of melanoma and its treatment:8

• there is a relationship between moles and mela-noma

• patients tend to have fair hair and a fair com-plexion

• some patients give a family history of melanomas,indicating a probable hereditary predisposition

• trauma may accelerate tumor growth

• minimal excision often leads to local recurrence

• the tumor should be removed by wide excisionof the lesion and adjacent tissue

• when the disease is widely disseminated, nei-ther medical nor surgical treatment is effective

Isaac Parrish9 reported the first case of mela-noma in America in 1837. In 1853 Sir James Paget10

discussed melanomas in his Lectures on SurgicalPathology.

Sir Jonathan Hutchinson11 first described a sub-ungual melanoma and recommended �“earlyamputation�” for treatment. Later in the 1890s,Hutchinson12,13 presented a series of cases fromwhich the descriptor �“Hutchinson�’s melanoticfreckle�” arose.

In 1907 William Sampson Handley,14 on the basisof observations from a single autopsy, made recom-mendations for surgical treatment of malignant mela-nomas. Handley�’s treatment included wide localexcision of the primary lesion �“about an inch fromthe tumor�” (Fig 1), regional lymph node dissection,and, in selected cases, amputation of the extremity.These recommendations held for the next 50 years.

Handley stated that

SKIN TUMORS II: MELANOMARobert G Anderson MD

Fig 1. Handley�’s recommended incision for melanoma re-moval. (Reprinted from Handley WS: The pathology of melanoticgrowths in relation to their operative treatment. Lancet 1(927):996,1907.)

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A circular incision should be made through theskin round the tumor at what is judged by presentstandards to be a safe and practicable distance.The incision, situated as a rule about an inch fromthe edge of the tumor, should be just deep enoughto expose the subcutaneous fat, is now to beseparated from the deeper structures for about twoinches in all directions round the skin incision. . . .The dotted line . . . represents in section the planesof division of the subcutaneous fat, deep fascia, andmuscle. The knife should nowhere divide any ofthe permeated lymphatics; it will almost certainlydo so unless the skin flaps are freely undermined.

Handley (1907)

It was not until the 1960s that studies weredesigned to determine the clinicopathologicaggressiveness of melanomas and the need for �“de-grees�” of surgical teatment. Over the past fourdecades, several groups have compiled large num-bers of melanoma patients, categorized themaccording to different criteria, and subjected themto various treatment protocols in attempts to deter-mine the most efficacious therapy.15�–19

The first group to study melanoma in depth wasthe World Health Organization (WHO) InternationalMelanoma Group for Clinical Research.15 Many ofthe earlier reports based their recommendationsfor treatment on poorly designed retrospective stud-ies of inadequate numbers of patients followed forinsufficient periods of time. We now have a betterunderstanding of the significance of a number offactors affecting the development of melanomasand their aggressiveness in terms of local recur-rence and metastatic potential.

EPIDEMIOLOGY

A number of individual genetic and environmen-tal factors are believed to play a significant role in thedevelopment of melanoma. These are of interestfrom both an epidemiologic standpoint and in termsof identifying potential high-risk patients who maywarrant a change in life-style and close surveillance.

Incidence

The incidence of cutaneous melanomas in theUnited States is definitely increasing, and melano-mas of the trunk and extremities are rising in fre-quency faster than melanomas of the head and

neck.20,21 In terms of recent rate of increase, infact, melanoma is second only to lung cancer.22

In general, a white American�’s lifetime risk ofdeveloping a melanoma is about 1.4%. The currentmortality rate has increased significantly for elderlywhite males, stabilized in white females, and isdecreasing in younger Americans.3 Dennis2

reviewed the 20-year data of a large melanomaregistry and found a significant increase in the num-ber of thin, localized melanomas and a lesserincrease of thicker, more advanced cases. Thesefindings indicate that the increasing incidence ratesof melanoma are not just due to early detection ofthin melanoma, but represent a true increase inmelanoma incidence.

Ultaviolet Radiation

Sunlight (ultraviolet radiation) is the primary envi-ronmental risk factor in the development of cutane-ous melanoma and non-melanoma skin cancer.23�–26

Over the years numerous epidemiologic studieshave confirmed a direct relationship between actinic(solar) exposure and melanoma.20,21,23,24,27�–34

Koh, Kligler, and Lew35 review the evidence forand against sunlight as a cause of cutaneous mela-noma. Even though sunlight is the major source ofultraviolet radiation, sunlamps and tanning beds emitthe same UVA and UVB radiation and result insimilar biologic and carcinogenic effects.36

Recent studies have shown inconsistent resultsfor the relationship between sunlamp use andmelanoma. Chen et al,23 in an extensive study ofsunlamp use in the northeastern United States,identified several factors related to increased riskof melanoma. After adjusting for the total numberof sunlamp uses, those who first used sunlampsbefore the age of 25 had a higher risk of develop-ing melanoma than those who first used sunlampslater in life. First use of sunlamps after age 25 wasnot associated with melanoma development (ie,did not increase lifetime risk). Those who usedmore than one type of sunlamp had a greater thanthreefold higher risk of melanoma compared withthose who did not use sunlamps. The use of sun-lamps more than 10 times was associated with ahigher risk of melanomas in women but not inmen.23

In Western cultures melanomas tend to occurwith increasing frequency in body areas commonly


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exposed to sunlight. Melanomas are most commonon the skin of the head and neck and least commonin body areas covered by clothing. Women have arelatively higher incidence of lower extremity mela-nomas than men, whereas melanomas of the trunkare proportionately more frequent in men than inwomen.20,21,37�–41

Intermittent, intense exposure to UV radiationcarries a worse prognosis for melanoma develop-ment.25 In fact, Holman and Armstrong31,32 andLew and others33 found that painful or blisteringsunburns during childhood and adolescence wereassociated with subsequent increased risk of devel-oping cutaneous melanoma.

Skin cancer secondary to UV radiation is thoughtto be caused by mutations at sites of incorrectlyrepaired DNA photoproducts. Thymine dimer is aproduct of DNA UV irradiation, and levels of thym-ine dimer rise proportionately with degree of UV-induced DNA damage. Irregular or inadequate useof sunscreen during sunlight exposure is reflectedin thymine dimer production and may lead to DNAmutation and skin cancer.42

Sun Protection

Gallagher and others41,43 stress the importanceof educating parents about sunlight sensitivity (es-pecially in light-skinned children) and starting sunprotection with clothing and effective sunscreensat an early age. This is important in all climates,not just the southern areas of the United States.The authors noted a 100% increase in melanomasin western Canada over a 15-year period41 andcorrelated this rise with changing habits of sun-bathing and outdoor activity. The most frequentsites of melanoma were the trunk in men and thelegs in women.41

In summary, the association between melanomarisk and average annual UVB exposure is strong forboth men and women3 and is affected by numer-ous factors, the most important of which are theintensity of UV radiation, duration of exposure, andskin protection.25

Skin Pigmentation

Although there are no typical melanoma skintypes, the most often described typical melanomapatient has sandy hair, blue eyes, and fair skin.

Melanoma can and does affect all ethnic and racialgroups, but is primarily a disease of whites, espe-cially those of Northern European ancestry.44,45

Among whites, the risk of melanoma is higher inthose with little or no ability to tan.46

Risk Factors

There are distinguishable subpopulations at highrisk for melanoma. The incidence of melanoma is10X higher in whites than in blacks living in a givengeographic area.47,48 The closer to the Equator thatlight-skinned individuals live, the higher the inci-dence of melanoma.27,49 Melanoma occurs mostcommonly on the lower extremities in whitewomen, and on the torso in white men, especiallyon the back. Freckling after exposure to sunlight isassociated with a 1.9X relative risk. Eye color hasbeen shown to have no prognostic significance.50

In 2003 the National Cancer Institute reviewedrisk factors for melanoma.51 All of the following areassociated with increased risk for development ofmelanoma:

MolesNumber - More than 50 ordinary molesAtypical - Dysplastic nevi have a 6-10% lifetime risk of degenerating to melanoma. Biopsy is the only accurate method of confirming the diagno sis of melanoma versus dysplastic nevus.Congenital nevi - 6% lifetime risk of melanoma depending on size; the risk is greater for larger nevi and less for smaller nevi.

Fair skin, freckling, light hairRisk is ~20% higher for Caucasians than African Americans. Greater risk in whites with red or blond hair (Table 1) and fair skin that freckles or burns easily.

TABLE 1Relative Risk of Melnoma According to Hair Color44

Family history52,56

Positive for melanoma in 10% of melanoma patients.


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Up to 8X higher risk depending on the number of affected relatives.

Immunosuppression (regardless of cause)57�–61

AgeMore than 50% of melanomas occur in people older than 50 years of age.Familial melanoma occurs at a younger age.

GenderMale patients are at greater risk.Lifetime risk is 1:57 for men and 1:81 for women.

Xeroderma pigmentosumDefect in enzyme that repairs DNA.High risk of melanoma and non-melanoma skin cancer.More common on sun-exposed skin.

Personal history of melanoma or non-melanoma skin cancer55,62

UV exposure and sunburnSunlight is the major source of ultraviolet radiation (sun lamps, tanning beds, etc).

Minor Factors �— UV radiation intensity, duration, skin protection (clothing, sunscreen)

Intermittent, intense exposures worse.

The atypical mole syndrome (formerly called dys-plastic nevus syndrome, B-K mole syndrome, orfamilial atypical multiple mole melanoma [FAMMM])carries approximately a 10% risk of melanoma. Theatypical mole syndrome has been defined as• !100 melanocytic nevi

• one or more melanocytic nevi that are !8mm insize

• !one melanocytic nevi with clinically atypicalfeatures63

Prevention

Attempts to prevent the development of cutane-ous melanoma are closely tied to protecting theskin from actinic damage. The recommended UVradiation protective measures include the follow-ing:1. Avoid sun exposure from 10:00AM-4:00PM.2. Wear long sleeves, long pants, hat with wide

brim. Best fabrics are those with a tight weaveand dark color.

3. Protect from UV radiation penetrating throughclothing, windshield, windows.

4. Protect from UV radiation reflecting off snow,ice, sand, water.

5. Use a sunscreen product• with broad-spectrum coverage (UVA and

UVB) and high SPF on sunny, hazy, andpartially cloudy days

• apply 20-30 minutes before sun exposure

• reapply sunscreen after water immersionand frequently (every 2 hours).

6. Wear sunglasses with UV absorbing lenses(should block >99% UVB and UVA). Wrap-around sunglasses are best.

7. Avoid using tanning beds and sun lamps.8. Perform careful and frequent skin examinations

on self, children, and significant other.

SKIN CANCER SCREENING PROGRAMS

When public announcements and press releasesemphasize symptoms of and risk factors for mela-noma, the percentage of potentially malignant pig-mented lesions increases among attendees.64 Edu-cation of examiners in the ABCD rules65 and ahow-to approach to organizing skin cancer screen-ings66 have been of major importance in decreas-ing the false-negative findings in these programs.67

The importance of skin cancer screening programsis not limited to identification of malignant skintumors: It extends to increased public awarenessof risk factors and patient identification of earlyneoplasms.

CLINICAL CHARACTERISTICS

Any pigmented lesion >5-10mm in diameter ismore likely to be malignant than benign.1 Besidesbeing smaller than cancerous tumors, benign pig-mented lesions are generally orderly in terms ofcolor, border, and surface. Malignant pigmentedlesions, on the other hand, often have multiple col-ors, irregular borders, and various surface irregu-larities.68 With this in mind, a number of benignpigmented lesions can safely be excluded from con-sideration in the differential diagnosis of cutaneousmelanoma.

Usually lentigo maligna (LM) is so typical inappearance that there is no difficulty in making thediagnosis. Superficial spreading melanoma (SSM)


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and nodular melanoma (NM), on the other hand,may present more of a diagnostic challenge.

There are two groups of melanomas that do notfit the usual description, those that have the typicalappearance of basal cell carcinoma and those thatare hyperkeratotic or verrucous, which Clark classi-fied as �“verrucous melanomas�” in 1967.69 Misdi-agnosis and shave biopsy of these lesions can haveserious consequences for the patient, since shavebiopsy precludes measurement of tumor thickness,the single most important determinant of prognosisand treatment.70,71

BENIGN LESIONS

The most common pigmented lesions in personsof European extraction are benign nevi: junctional,compound, or intradermal.

Junctional nevi are flat and of uniform color thatranges from pale to dark brown.72 The lesions aresmooth, macular, sharply defined, and generallyround. Junctional nevi usually make their appear-ance between ages 4 and 12 and change very littleover the years. If they grow at all, it is at the rate ofabout 1mm/yr during childhood, all the while pre-serving the normal skin markings.

Compound nevi may be darker than junctionalnevi and are palpable. A single nevus may containelements of both junctional and compound nevi.The surface of a compound nevus may be smoothor rough and may have hair. Compound neviusually appear during puberty, remain unchangedfor several years, and gradually fade away as theindividual gets older. A halo nevus is a com-pound nevus surrounded by a depigmented ringof skin.

Intradermal nevi are raised, pale papules thatdistort the normal anatomy of the skin. Most arewithout hair follicles, but hair is more commonwhen the lesion is present from birth.

Blue nevi classically present as a blue-black lump<5mm in diameter. These nevi generally do notchange in size with time. A rare type, the �“cellularblue nevus�”, may degenerate to a malignant mela-noma, the �“malignant blue nevus�”.73,74

The Spitz nevus is a benign compoundmelanocytoma or juvenile melanoma which usu-ally occurs in children and young adults. The lesionis smooth-surfaced, dome-shaped, red or pink, and<6 mm in diameter. A rapid change in size orcolor often brings this lesion to the attention of thephysician.72,75 Microscopically the Spitz nevus is aproliferation of enlarged spindled and/or epithe-lioid melanocytes. Although the majority are benign,these tumors have been associated with metastasisand death.76,77

Lentigo is a general term denoting pigmented,macular skin lesions that exhibit a reticulated pat-tern. The lesion is flat and roughly round, althoughthe pigment may be sharp and jagged at the edges.Simple lentigo is the common brown-to-black mole,clinically indistinguishable from junctional nevi; solarlentigo is a lighter tan to brown, otherwise knownas a �“liver spot�”.

Seborrheic keratoses are multiple, variouslycolored, raised verrucous papules. The surface isgenerally warty and has a �“stuck-on�” appearance;the edges are sharply defined into a round or ovallesion. When removed bluntly, seborrheic kera-toses bleed profusely from multiple finger-like pro-jections into the skin.

Pyogenic granulomas have a characteristiccourse of development over several days to weeks,are raised, and generally have a surrounding areaof inflammation. Although they can occur any-where, pyogenic granulomas are most common onthe hands. The lesions are painless.

Hemangiomas usually remain unchanged formany years unless injured, at which time they maybleed profusely. If clotted, the hemangioma maybe firm to palpation, noncompressible, and resemblea pigmented lesion.

MALIGNANT LESIONS

Unlike benign pigmented skin lesions, melano-mas are characterized by Asymmetry, Border ir-regularity, Color variegation, and Diameter often>6mm (the ABCD of malignancy).34 Clinically thepresence of red, white, or blue variegation in adark brown or black skin lesion is highly suspicious


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for melanoma. The surface of the lesion may beflat, slightly raised, or notched, but the margins arealmost always irregular (Table 2).78 The tumors areusually aymmetrical in color, shape, and outline(Table 3).78

Pigmented basal cell carcinomas are fairlycommon. The lesions are usually raised and mayhave a surrounding ring of smaller nodules. Whenexamined closely, pigmented basal cell carcinomahas the typical appearance of a nonpigmented basalcell tumor. A biopsy may be required to distinguishit from a melanoma. Pigmented squamous cellcarcinomas are rare.

MELANOMA PRECURSORS

By definition, premalignant melanocytic lesionshave atypical melanocytes with a potential formalignant transformation. Three lesions are currentlythought to be precursors of melanoma: dysplasticnevus, lentigo maligna, and melanoma in situ.

Dysplastic Nevus79

Common superficial spreading melanoma isthought to arise either by direct malignant transfor-mation of epidermal melanocytes (60%) or bymalignant transformation of a dysplastic nevus(40%).80 If the latter, melanoma begins as a dysplas-tic nevus, progresses to melanoma in situ, and thengoes on to invasive melanoma.81 Some authors82

consider dysplastic nevi an intermediate phase inthe development of melanoma in situ, althoughprobably only a very small percentage of dysplasticnevi go on to become melanomas.81

Melanocytic dysplasia is a histopathologic termthat implies a disordered and discontinuous prolif-eration of atypical melanocytes. Absolute criteriafor histopathologic diagnosis of melanocytic dyspla-sia are (a) proliferation of intraepidermal melano-cytes arranged singly or in irregular nests in thebasal epidermis or slightly above in the rete ridges,and (b) variable and discontinuous melanocytic cel-lular atypia. In the face of this histopathologic pic-ture, the diagnosis may be dysplastic nevus, atypi-

TABLE 2Comparison of Clinical Features of Cutaneous Melanoma

(Modified from Petersdorf RG (ed), Harrison�’s Principles of Internal Medicine, 10th ed. New York, McGraw-Hill, 1983, p 836.Reprinted with permission from Langley RGB, Fitzpatrick TB, Sober AJ: Clinical characteristics. In: Balch CM, Houghton AN, Sober AJ,Soong S-J (eds), Cutaneous Melanoma, 3rd ed. St Louis, Quality Med Publ, 1998. Ch 5.)


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cal junctional nevus, active junctional nevus, orintraepidermal melanoma; these terms are synony-mous.

Clinically, dysplastic nevi are indistinguishablefrom melanoma in situ.83 Dysplastic nevi exhibitwide variations in shape and color, with irregularborders and several shades of brown or pink in thesame lesion. Whereas junctional nevi seldomexceed 3mm in diameter, dysplastic nevi are often5�–10mm. They may be found anywhere on thebody but are most common on the back. Averageage at first occurrence is 38 years.

The atypical mole syndrome is a hereditary (au-tosomal dominant) disorder characterized by mul-tiple dysplastic nevi that are larger and morenumerous than common nevi.84,85 Average molediameter is 6�–15mm, and the lesions are �“irregu-larly shaped, indistinctly bordered, variably pig-mented nevi that retain a macular or pebbly plaquecomponent.�”85 The nevi are absent at birth, butabout the time of puberty the patient notes anincrease in size and number of moles, which con-tinue to multiply throughout life. Besides the usuallocations, moles in the familial dysplastic nevus syn-drome are often found on the scalp, buttocks, andfemale breast.

Lentigo Maligna

Lentigo maligna is defined as a nonnested prolif-eration of variably atypical melanocytes in an atro-phic epidermis.86 The lesion is regarded by someas a melanoma in situ and by others as a variety ofintraepidermal melanocytic dysplasia in sun-

damaged skin.79 Lentigo maligna may progress tomelanoma in situ and invasive melanoma.87

In one large series, a 5mm margin of resectionwas inadequate in more than 50% of cases;88 inanother study, 38% of cases required two or moreexcisions to obtain tumor-free margins of resec-tion.89 A third study reaffirms the need to obtainhistopathologic confirmation of complete tumorresection in cases of lentigo maligna.90 In elderlypatients with widespread lesions in the facial andneck area, Grenz radiotherapy may be curative fora majority (93%) of patients.91

The term lentigo maligna is synonymous with76,82

Hutchinson�’s frecklemelanotic freckle of Hutchinsonsenile frecklecircumscribed precancerous melanosislentigo malin des Viellardsmelanosis premalignamélanose de Dubreuilhmélanose circonscrite précancéreuse de Dubreuilhmalignant freckleprecancerous melanosispremalignant lentigomelanosis circumscripta preblastomatosaprecancerous nonnevoid melanocytoma

Melanoma in Situ

Melanoma most commonly arises de novo frommelanoma in situ.80 The lesions have intraepidermalmelanocytic proliferation with �“fully evolved cellu-lar atypia that is side-to-side and continuous for asufficient breadth.�”79

TABLE 3Clinical Characteristics of Common Acquired Nevi, Dysplastic Nevi, and Malignant Melanoma

(Adapted from Barnhill RL, Fitzpatrick TB, Fandrey K, et al, Color Atlas and Synopsis of Pigmented Lesions. New York, McGraw-Hill,1995, p 9. Reprinted with permission from Langley RGB, Fitzpatrick TB, Sober AJ: Clinical characteristics. In: Balch CM, Houghton AN,Sober AJ, Soong S-J (eds), Cutaneous Melanoma, 3rd ed. St Louis, Quality Med Publ, 1998. Ch 5.)


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In a histologic study, Sagebiel83 showed themicroscopic gradations from melanocytic hyperpla-sia to melanoma in situ. This report underscoresthe broad spectrum of melanocytic atypia that canbe present in a so-called premalignant pigmentedlesion. While the histologic diagnosis is influencedby the sampling technique and pathologist�’s expe-rience, the degree of cellular atypia often occurs asa continuum from dysplastic nevi to melanoma insitu. Surgeons should read the histologic descrip-tion in addition to the final diagnosis in the pathol-ogy report before recommending treatment of anygiven lesion.

Melanoma precursors (dysplastic nevi, lentigomaligna and melanoma in situ) can often be distin-guished from each other clinically, however, onlypermanent histopathology can confirm the actualnature of the lesion and therefore define surgicaltreatment.

MELANOMA GROWTH PATTERNS

Melanoma occurs in four principal growth pat-terns: superficial spreading melanoma (SSM), nodu-lar melanoma (NM), lentigo maligna (LM), and acrallentiginous melanoma (ALM). These are all distinctpathologic entities with different prognoses.92�–94 Lesscommon are desmoplastic, amelanotic, and poly-poid melanomas.

Superficial Spreading Melanoma

Superficial spreading melanoma is the most com-mon growth pattern, seen in about 70% ofcases.92,93,95 The lesion usually arises in a preexist-ing nevus, frequently after a history of slow changesfor several years followed by rapid growth in themonths before diagnosis. SSM is perhaps morecommon on the backs of men and the legs ofwomen, but can occur anywhere on the body andat any age, usually after puberty.93

The average size of an SSM is 2cm and its typicalappearance is a darkly pigmented area in a brownjunctional nevus.96,97 The lesions are initially flat andthe fine skin markings are preserved. The dark areasthen expand, with blue, black, gray or white variega-tions and areas of pale regression (amelanosis). Thesurface of the lesion becomes irregular and a crust orscaly plaque may form. The development of a shinynodule within the substance of the melanoma her-

alds the vertical growth phase. The perimeter isnotched and may have a thin pink rim or halo.98

Nodular Melanoma

Nodular melanoma accounts for 15�–30% ofreported melanomas.68,93,95,99 This is an aggressivetumor with a shorter clinical onset than SSM. Nodu-lar melanoma typically arises in uninvolved skin,not from a preexisting nevus. Nodular melanomasare more common in men than in women, occurmost often in middle-age, and frequently on thetrunk and head and neck.

The typical NM is a blue-black papule or nodule,1�–2cm in diameter, either dome-shaped or poly-poidal and resembling a �“blood blister�” or heman-gioma.100 Nodular melanoma lacks a radial (hori-zontal) growth phase and thus tends to be moresharply demarcated from the surrounding normalskin than other types of melanoma.1 About 5% ofNM are amelanotic.

Lentigo Maligna Melanoma

Lentigo maligna makes up 4�–10% of all reportedcases of melanoma. The lesions have a distinctappearance: like a skin stain in multiple shades ofbrown. They are typically flat, large lesions in olderpeople. Vertical growth, although uncommon,results in plaques or nodules. The perimeters of thelesion are generally highly convoluted. LM is thoughtto have a higher correlation with continued, intensesunlight exposure than other types of melanoma,29

and invariably occurs in sun-exposed areas of skinsuch as the face, neck, and dorsum of the hands.101

LM is more common in women than in men. Thetumors are not aggressive, typically exhibit an indo-lent course for 5�–15 years, and have little propen-sity to metastasize.

Acral Lentiginous Melanoma

Acral lentiginous melanomas are most commonon the soles but may also occur on the palms of thehands and nail beds.102�–107 ALM account for only 2-8% of all melanomas in whites108 but up to 35-60%in African-Americans, Asians, and Hispanics.102,109

Plantar melanomas have a similar incidence inwhites and African-Americans, while melanomason other body areas are less frequent in African-


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Americans.110 Average patient age at the time ofdiagnosis is 60.103

The lesions are usually flat and large (avg diam3cm), with an irregular border and multiple colorshades. Tumors present for some time may becomeslightly raised.103

Desmoplastic Melanoma

Approximately 1% of all melanoma cases are des-moplastic (or desmoplastic neurotropic) melanomas.This is a rare variant that has a propensity forperineural invasion, especially in the head andneck.111 It presents as a clinically innocuous, firm,amelanotic plaque or nodule. Immunohistochem-istry is helpful in the diagnosis, with the majorityreactive to S-100 protein.111,112 Regional lymphnode spread is no higher than that of other melano-mas, and treatment recommendation is based onits tendency to recur and spread by perineuralinvasion.113

Amelanotic Melanoma

Amelanotic melanoma is a lesion with no iden-tifiable pigment by light microscopy. The immu-nohistochemical staining technique is useful indiagnosing these tumors. The lesion is usuallydiagnosed in its vertical growth phase and mimicsother cutaneous malignancies.114,115

Other

Other less common types of melanoma includethe polypoid variety, which carries a poor progno-sis. It is not the polypoidal growth pattern per sethat determines prognosis, however, but rather thethickness of the lesion,116 and when survival ratesfrom melanomas of various types are analyzed bythickness alone, the prognosis associated with poly-poidal melanoma is similar to that of other histo-logic forms.

MELANOMA STAGING SYSTEM 2002

Staging systems enable comparisons of treatmentprotocols and analysis of prognostic information.Although clinicians have found it useful to grouptumors for prognostic and treatment purposes, thereis no biologic reason to support �“natural break-

points�” of tumor thicknesses at which survivaldecreases or prognosis worsens.117

The American Joint Committee on Cancer (AJCC)was established in 1959 and regularly reviews thestandard cancer �“staging�” systems.118 Most recentlythe staging criteria of 13 cancers, including melanoma,were reviewed in preparation for the sixth edition ofthe AJCC Cancer Staging Manual. In the original 3-stage melanoma classification system, stage II repre-sented lymph node metastases. In the 1997, revised4-stage classification system, lymph node involvementwas stage III and stage IV included distant metastses,metastases in 2 or more regional nodal basins, 5 ormore in-transit metastases, or nodal metastases thatwere fixed to the surrounding structures or >5cm indiameter.119

The new melanoma staging system is based ondata from more than 17,000 melanoma patientscollected at 13 international centers.19 The newsystem was recently approved by the executive com-mittee of the AJCC and the International UnionAgainst Cancer and became official in 2002. Thisnew system includes both clinical and pathologicstaging and involves numerous changes to the pri-mary tumor, regional lymph nodes, distantmetastases, and the �“groupings�” of various stages.The system relies heavily on pathologic diagnosisincluding Breslow tumor thickness, Clark level ofinvasion, microscopic evidence of ulceration, andthe presence and number of metastatic lymph nodes.Elevated LDH is also now a factor in the metastasisgroup (Table 4).19

The new melanoma staging system120 includesfive major changes:

1. Tumor thickness (Breslow) replaces the level ofinvasion (Clark) as the most important prognos-tic variable of primary tumor invasion that bestpredicts survival.

2. Ulceration of the primary tumor (microscopichistopathologic �“ulceration�”) upstages the dis-ease to the next highest T substage.

3. The number of metastatic lymph nodes replacessize of lymph nodes in the N stage.

4. Lymphatic mapping data (lymphoscintigraphy)and micrometastatic local regional disease withinlymph nodes is incorporated in clinical andpathologic staging.


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TABLE 4Melanoma TNM Classification

(Reprinted with permission from Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer stagingsystem for cutaneous melanoma. J Clin Oncol 19:3635, 2001.)


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TABLE 4 (continued)Proposed Stage Groupings for Cutaneous Melanoma



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5. Subcategorization of stage IV metastatic diseaseis based on anatomic site of the metastasis andelevated serum LDH.Balch and Mihm121 give the following rationale

for the changes:

Primary Tumor (T)

• designation of whole integer breakpoints of 1mm,2mm, 3mm, 4mm is arbitrary; there are no realbreakpoints

• data analysis confirmed that level of invasion(Breslow thickness) is more predictive of sur-vival than tumor thickness only for melanomas"1.0mm

• the designation of T1 "1.0mm is arbitrary; thereare no cut points

• in all melanomas >1.0mm, ulceration is mostpredictive of survival

Nodal Metastases (N)

• nodal status is a significant prognostic factor inmelanoma

• 6 subgroups for node-positive patients improveprognosis prediction

• most studies show that the number of lymph nodeswith metastases has more prognostic significancethan the actual size of the largest metastasis

• micro- and macronodal disease have differentprognoses and are therefore differentiated

• intralymphatic metastasesdefined as clinical or microscopic satellitesaround a primary melanoma or in-transitmetastases between the primary melanoma andthe regional lymph nodes

• poor prognosis with no significant survival dif-ference in either of these situations

• similar prognosis to lymph node metastases

• the combination of both in-transit metastases/satellites plus nodal metstases portends an evenworse prognosis

Distant Metastasis (M)

• only three factors are important in determiningsurvival in advanced disease: metastatic site,number of metastatic sites, and LDH serum level

• survival differences between M categories aresmall, therefore no subgroups of stage IV mela-noma

• LDH elevation is one of the most predictivesurvival factors in all published studies of stageIV melanoma

Sentinel Lymph Node Biopsy

The AJCC Melanoma Committee strongly rec-ommends that all patients with melanoma >1.0mmin thickness with N0M0 have histologic nodal stag-ing with sentinel lymph node biopsy prior to entryinto melanoma clinical trials.

Microstaging

Tumor thickness is the main determinant of prog-nosis in melanoma.122 In 1970 Breslow123 first sug-gested measuring tumor thickness from the uppergranular layer of the epidermis to the deepest partof the tumor. Absolute tumor thickness has provena reliably objective and relatively reproduciblemeasure of future tumor behavior. The Breslowthickness measurement is the current standard formicrostaging melanomas.

The level of microinvasion�—the Clark level�—correlates with tumor thickness,123 histologictype,69,124 and biologic behavior69,122 (Fig 2).

A comparison of Clark�’s and Breslow�’s micro-staging methods demonstrates the advantages ofthe latter in prognostication. Gradations ofBreslow thickness within Clark levels III, IV, andV have been associated with different survivalrates. For example, level IV may include a widerange of tumor thickness (0.6�–12.6mm), and sur-vival from these lesions varies greatly. On theother hand, and excluding other factors such asulceration, vertical growth phase, and regression,patients with tumors of a given thickness haveessentially the same survival regardless of level ofinvasion.

Interobserver Variation in Measurement ofBreslow Depth

A note of caution is in order due to reportedinter- and intra-observer variations in the measure-


13

ment of Breslow depth. Inaccurate measurementof Breslow thickness can be due to the type ofmeasuring instrument, different estimations of thedeepest tumor cell, the presence or absence of acoexisting nevus, and errors in the conversion ofmicrometer units to millimeters. Because mela-noma treatment is based in large part on tumorthickness and ulceration, the prognosis can beadversely affected by faulty measurements of thick-ness and failure to identify ulceration.

Calder, Campbell, and Plastow125 compared threedifferent techniques for measuring tumor thickness:eyepiece reticule, stage Vernier, and projection

image analysis. The authors concluded that theleast variation occurred with the stage Vernier.

Colloby and colleagues126 studied a series of 50malignant melanomas <2.0mm thick that had beencharacterized by experienced clinicians. Theauthors documented differences in inter- and intra-observer measurements of up to 0.86mm over orunder the actual measured thickness. The authorsadvocate taking the �“mean of several measurementsat the point of deepest invasion, made at differenttimes, and if possible comparing them with anotherobserver�’s�” before arriving at the final determina-tion of Breslow thickness (depth of invasion).

Borchez and colleagues127 recorded the variousdiagnoses of suspicious pigmented skin lesions,including both pre-melanoma and melanoma, ren-dered from the same tissue specimens by 20pathologists. Overall specificity was 94% and sen-sitivity was 87%, lower (83%) for thin (<1mm)lesions. False-positive rates were 25% and false-negatives only 3%. Most false positives were in thediagnosis of in situ and thin melanomas.

Staging of Nodal and Distant Metastases

The most sensitive and cost-effective techniquefor detecting metastatic disease in melanoma is athorough history and physical examination. Thepatient should be questioned specifically aboutweight loss, headaches, malaise, and bone and jointpain. A complete physical examination shouldinclude a thorough examination of the skin (entirecutaneous surface), the most likely regional lymphnode basin(s) into which the tumor would drain,and a complete neurologic examination.

In an excellent review of primary staging andfollow-up modalities in 661 melanoma patients,Hofmann and associates128 defined a single institu-tion efficacy of various tests for stage I/II and stageIII melanomas (Table 5).

The use of bone scans and cranial CT scans inthe initial staging of melanomas has been criticizedbecause of the low rate of true positive and thehigh rate of false positives requiring further tests toconfirm the benign nature of the original finding.The above table confirms the high false-positiverates and true negative rates of bone scans andcranial CT scans. At initial staging, no metataseswere diagnosed with 325 bone scans and 282 cra-nial CT scans. The only effective study was lymph

Fig 2. Levels of tumor invasion by the Clark microstaging criteria.(Adapted from McGovern VJ et al: The classification of malignantmelanoma and its histologic reporting. Cancer 32:1446, 1973.)


14

node sonography, with a 16% detection rate. (Sen-tinel lymph node biopsy is considerably more sen-sitive for staging melanomas.)

Gershenwald and colleagues129 list practical rec-ommendations for the initial evaluation of variousmelanoma stages. For local tumor with no evi-dence of regional nodal disease, a physical exami-nation, chest x-ray, LDH, and sentinel lymph nodebiopsy (use guidelines for SLNBx) are recom-mended. The authors note a high (>50%) risk ofsystemic metastases in the face of local recurrenceand/or locoregional (in-transit, satellite or nodal)metastases. In spite of the high false-positive rateand low yield, CBC and more sophisticated radio-logic studies (CT, MRI, PET) are added to the basicworkup for localized melanoma. An elevated LDHmay indicate metastatic disease but is nonspecificand has low sensitivity. In the event of a positivefinding on radiologic studies, unless the lesion ishighly suggestive of a metastasis, close follow-upwith repeat x-ray studies is advised to comfirmstability of the lesion. These diagnostic param-eters basically stage the patient as if distantmetastases were present and serve as a baseline,since a significant number either have or will even-tually develop distant disease. In the case of dis-tant metastases (stage IV), a thorough radiologicexamination is indicated (Table 6). Specializedtests are reserved for symptoms referable to a givenorgan system.

TABLE 5Efficacy of Diagnostic Methods at Initial Staging and in Follow-up of Stage I/II and Stage III

Melanoma Patients

(Reprinted with permission from Hofmann U, Szedlak M, Rittgen W, et al: Primary staging and follow-up in melanoma patients - monocenterevaluation of methods, costs and patient survival. Br J Cancer 87(2):151, 2002.)

TABLE 6Practical Recommendations for Staging

Evaluation Based on Stage at Presentation

(Reprinted with permission from Gershenwald JE, Fischer D,Buzaid AC: Clinical classification and staging. Clin Plast Surg27(3):361, 2000.)


15

PROGNOSIS

Clinical Factors

Age. The median age of patients with stage I or IImelanoma is 45 years. Older patients tend topresent with thicker tumors and have a shorterperiod of survival than younger patients.1

Sex. Several studies document an overall betterprognosis for women,130�–134 who also have a longersurvival for all extremity melanomas.135 Theimproved survival of women is thought to be due tothe greater frequency of extremity melanomas inwomen and a lower incidence of tumor ulceration.1

Anatomic Site. The anatomic site of the tumorhas considerable prognostic importance. Patientswith extremity melanomas have longer survival thanthose with axial tumors.136,137 There are no survivaldifferences between upper and lower extremitytumors or between head and neck and truncaltumors. Melanomas of the hand and feet carry asignificantly worse prognosis. At the other end ofthe spectrum, subungual melanomas can be associ-ated with 5-year survivals as high as 80% if diag-nosed and treated early.1 Patients with scalp tumorshave a worse prognosis than those with lesions onthe face, ear, or neck.135

Tumor Histology

Thickness. Tumor thickness is the most impor-tant determinant of survival for patients with stage Ior II melanoma. Tumor thickness correlates withrisk of local recurrence,71 satellitosis, and in-transitmetastases, and can also be predictive of regionalor distant metastases. Analysis of more than 2600patients shows a continuous direct correlationbetween tumor thickness and mortality.1 Patientswhose tumors are <0.76mm thick have a 10-yearsurvival of 92%, while those whose melanomas are>3mm thick have a 10-year survival of 50%.

Duke University researchers Kalady and associ-ates,138 in a landmark review of more than 10,000melanoma patients studied over a 30-year period,identified 1563 patients with tumor thickness<1.0mm. The characteristics that had the mostsignificant negative prognostic impact were age >45years, male gender, and tumor thickness >0.75

(Fig 3). In-transit, nodal, and distant metastases atthe time of presentation also portended a worseprognosis (Table 7). Recurrences were found to be20% local, 44% in regional lymph node basins and36% in distant sites.

Survival curves for patients with clinically local-ized melanoma, subgrouped according to thick-ness of the primary tumor (T category), further high-light the improved survival of patients with thinnertumors1 (Fig 4, Table 8). A small percentage ofpatients with tumors <0.76mm thick ultimatelydevelop metastases.139�–144

Over the years thin melanomas have been vari-ously classified as <0.76mm or <1.0mm depend-ing on the classification scheme of the reportinginstitution. Within this thin category (<0.76 or<1.0mm), certain subgroups might have a worseprognosis and therefore require more thoroughdiagnostic evaluation and/or more aggressive surgi-cal treatment. Salman and Rogers145 reviewed theliterature for references to factors that might berelevant to prognosis in <0.76mm melanomas. Theauthors list

• patient�’s age

• patient�’s sex

• anatomic site of tumor

• diameter of the primary lesion

• Clark�’s level of invasion

• development of a vertical growth phase

• mitotic index

• ulceration

• regression

• cellular aneuploidy

The significance of these features to a patient�’sprognosis was analyzed and tabulated (Table 9).

Ulceration. The presence of microscopiculceration is thought to predict a more aggressiveform of the disease and a worse prognosis.135,136,146

The 10-year survival of patients with stage I mela-noma that is ulcerated is 50%; without ulceration,78%.1 If the ulcerated area is <6mm wide, thelesion tends to be thinner and 5-year survival isbetter (44%) than when the microscopic ulcerationis >6mm (5-year survival of 5%).147 In the 2002


16

TABLE 7Survival Rates for Melanoma TNM and Staging Categories


Fig 4. Left, disease-free survival based on primary tumor thickness. Right, survival at 15 years for patients with localized melanoma.(Reprinted with permission from Kalady MF, White RR, Johnson JL, et al: Thin melanomas: Predictive lethal characteristics from a 30-yearclinical experience. Ann Surg 238(4):528, 2003 and Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committeeon Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635, 2001. )

Fig 3. Overall survival based on patient population definedas high-risk compared with non high-risk. (Reprinted withpermission from Kalady MF, White RR, Johnson JL, et al: Thinmelanomas: Predictive lethal characteristics from a 30-yearclinical experience. Ann Surg 238(4):528, 2003.)


17

10-year survival rate (54%) than pigmented mela-nomas (73%).1

Growth pattern. Although nodular melanoma isgenerally believed to carry the worst prognosis ofall histologic types, when matched for tumor thick-ness patients who have SSM and NM have similar10-year survival rates. Nodular melanomas tend tobe thicker than other histopathologic types. Len-tigo maligna occurs preferentially in the head andneck region, tends to be thin, and is associated withthe best prognosis for a melanoma. The differencein outcome is not solely attributable to tumor thick-

melanoma staging system, microscopic ulcerationof the primary tumor upstages the disease to thenext highest T substage (Table 10).19

Tumor Mitotic Rate. Tumor mitotic rate is definedas the number of mitoses per square millimeter inthe dermal portion of the tumor. Patients whosetumors have a mitotic rate of 0/mm2 have a signifi-cantly better survival than those with 1/mm2.

Pigmentation. Approximately 7% of melanomasare amelanotic.136 Amelanotic melanomas are usu-ally thicker and therefore associated with a worse

TABLE 8Survival at 5 Years of 5,346 Patients with Melanoma and Clinically Negative Nodes



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ness but rather is a function of histologic type, foreven when LM are matched for tumor thicknesswith NM and SSM, the prognosis for LM is notice-ably better.101 Acral lentiginous melanoma is asso-ciated with a worse prognosis than either SSM orLM. Five-year survival rates are usually less than50% for plantar and palmar lesions of thistype.103,148,149

Vertical growth phase. The presence of a verti-cal growth phase in thin melanomas adversely affectssurvival. Patients whose thin melanomas show his-topathologic evidence of vertical growth phaseshould be considered for sentinel lymph nodebiopsy.38

Histologic level of invasion (Clark level). Sur-vival is inversely related to the level of tumor inva-sion.136 Although the histologic level of invasioncorrelates with prognosis, each level is associatedwith a wide range of tumor thickness, which hasbetter correlation with survival rates.

Lymphocytic infiltration. When tumors arematched for thickness, the prognostic significanceof lymphocytic infiltration disappears.150�–152 Acloser look at lesions with the greatest amount oflymphocytic invasion shows them to be the thin-nest tumors.

TABLE 9Predicted 5- and 10-Year Survival Rates fromInitial Diagnosis for Patients With Localized

Melanoma

(Reprinted with permission from Soong S-J, Weiss HL: Predictingoutcome in patients with localized melanoma. In: Balch CM,Houghton AN, Sober AJ, Soong S-J (eds), Cutaneous Melanoma,3rd ed. St Louis, Quality Med Pub, 1998. Ch 3, p 55.)

TABLE 10Survival at 5 Years of Pathologically Staged Patients Showing Upstaging Effect of Melanoma Ulceration



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Regression. Up to 20% of melanomas will showregression.153 Clinically the epidermis overlyingthe area of regression lacks pigment, creating apale halo around the lesion. Microscopic signs oftumor regression include an increased number ofvessels, increased fibrosis, and scattered dermalmacrophages containing melanin. Although the dataregarding the prognostic value of regression in mela-noma is contradictory,154�–157 the presence of ulcer-ation should direct the surgeon to treat the primarylesion as a thick tumor.

DIAGNOSIS OF THE PRIMARY TUMOR

Accuracy of Clinical Diagnosis

The clinical diagnosis of melanoma is often diffi-cult. Studies have concluded that dermatologistsare better able than nondermatologists to correctlyidentify melanomas.139,147�–150 The correct diagnosisis made in 48�–81% of published reports. Giventhis wide range of accuracy when dealing with apotentially fatal skin cancer, the clinical index ofsuspicion should be extremely high; over-diagnosis(ie, false-positive) is much more desirable than under-diagnosis.

Biopsy

Any lesion that prompts even the slightest suspi-cion of melanoma should be biopsied. Under nocircumstances should a pigmented lesion be treatedwith electrocoagulation or electrodesiccation. Shaveexcision is also contraindicated in suspected mela-noma because it will prevent measurement of tumorthickness. Gentle handling of the specimen isimportant.

Excisional biopsy is recommended for lesions<1.5cm in diameter that are located in anatomicareas where resection will not be disfiguring.158 Theexcision should be elliptical in most cases and ori-ented to allow wound repair with the most incon-spicuous scar�—ie, in a relaxed skin tension line.This orientation will usually facilitate reexcision ofthe entire biopsy site with a minimum of skin lossand ease of repair. In the head and neck, becauseof esthetic considerations, the long axis of the ellipseshould also be placed in a relaxed skin tension line

to minimize scarring and distortion of importantanatomic landmarks.

The excision should extend into the subcutane-ous tissue but should not violate the underlyingmuscle fascia. The lesion should be excised with a2mm margin (Fig 5).158 A margin of 0.5cm is inad-equate for a malignant tumor and excessive for abenign lesion. If the lesion proves to be a mela-noma, the next step should be formal reexcision ofthe biopsy wound, allowing proper margins accord-ing to the thickness of the tumor.

Fig 5. Technique of excisional biopsy in suspected melanoma.A, Local anesthetic is infiltrated around the lesion. B, Entire lesionis excised with a 1�–2mm rim of normal-looking skin andsubcutaneous fat. Care is taken to avoid crushing the specimenwith forceps. C, Hemostasis is secured and the incision is closed.(Reprinted with permission from Ho VC, Sober AJ, Balch CM:Biopsy techniques. In: Balch CM, Houghton AN, Sober AJ, SoongS-J (eds), Cutaneous Melanoma, 3rd ed. St Louis, Quality MedPubl, 1998. Ch 7, p 136.)

Incisional biopsy is reserved for lesions in ana-tomic locations where skin removal is critical andcould cause disfigurement�—eg, the face, hands,feet�—and for large lesions where excisionalbiopsy is not warranted until the histopathologicdiagnosis is known. A 5�–7mm punch biopsy takenfrom the most raised or irregular portion of thelesion as a full-thickness core of skin and subcuta-neous tissue fulfills the diagnostic needs (Fig 6).158

Again, the underlying muscle fascia should remainundisturbed.


20

Incisional or punch biopsies do not worsen theprognosis but may miss the thickest part of thetumor.159 The decision regarding the definitivesurgical treatment of a melanoma should not bebased on the results of incisional or punch biopsyalone. If biopsy confirms the diagnosis of mela-noma and the final histopathologic study of theresected lesion reveals a tumor that is thicker thanpreviously thought, subsequent treatment must beadjusted accordingly. A melanoma should be con-sidered to be as thick as its thickest part even if thisimplies further wide local excision of the primaryand sentinel lymph node biopsy. Proper planning

at the time of first presentation ensures that theinitial treatment does not compromise possiblefuture intervention.

The effect of incisional biopsy on melanoma prog-nosis has been addressed by Bong, Herd, andHunter160 in a long-term, retrospective study of 265patients (496 controls). The authors found that thebiopsy type (incisional vs excisional) had no signifi-cant effect on recurrence and that melanoma prog-nosis is not affected by incisional biopsy beforedefinitive tumor excision.

Biopsy of a subungual lesion is accomplished byremoving the nail or creating a window in the nailthrough which to do an incisional biopsy. Punchbiopsies of the nail matrix are generally inadequate.Because tumor thickness is not a prognostic factorin subungual melanomas, full-thickness biopsies arenot required.

Biopsy of lesions not thought to be melanomas.How should we biopsy a lesion thought to be abenign nevus, basal cell carcinoma, seborrheic kera-tosis, or other nonmelanoma tumor to obtain a suit-able tissue sample for the pathologist in the eventthe diagnosis actually is melanoma? Witheiler andCockerell161 reviewed 1784 histologically provenmelanomas to evaluate the diagnostic sensitivity ofdifferent biopsy techniques. The authors note that87% of shave biopsies were adequate for �“com-plete and accurate�” diagnosis and the other 13%were too shallow. Overall only 32% of punch biop-sies were considered adequate for diagnosis, eventhough 84% of those >5mm were thought to besatisfactory. The authors concluded that broad (5�–6mm) and deep shave biopsies and wide (5-7mm)punch biopsies extending to the midreticular der-mis allow sufficiently thick tissue sample for com-plete diagnosis.

Since the clinician cannot determine the thick-ness of the biopsy unless the subcutaneous tissue isentered, it is still most advisable to perform a full-thickness skin biopsy on all suspected melanomasand a �“deep�” shave biopsy on lesions not thoughtto be melanomas. Punch biopsies should be 5�–6mm in diameter and shave biopsies >5�–6 mm indiameter.

Fig 6. Technique of punch biopsy in suspected melanoma. A,The area immediately around the lesion is anesthetized and a6mm (or sometimes 4mm) punch is placed over the highestportion of the tumor. A core of tissue is taken by rotating thepunch, taking care to include some subcutaneous tissue formicrostaging. B, The base of the specimen is cut using scissors.C, Cross-section illustrating the proper depth of the biopsywound.


21

Delay in Diagnosis

As might be expected, there are numerous rea-sons for the delayed diagnosis of melanomas. In onestudy the interval from when the patient first noticedthe lesion to diagnosis was a median of 110 days.162

In another study the mean delay was 11.1 months.163

Notice of a change in a nevus by someone otherthan the patient resulted in earlier consultation andtreatment than when the patient self-detected thelesion.164 Melanomas were detected by the patientsthemselves in 67% of women and only 45% of men.Lesions were noticed when they became darker,larger, and thicker. Both misdiagnosis (in 12�–18% ofcases) and mismanagement (consulting physicianchose to observe the lesion) also contributed to delayin diagnosis.164,165 Asymptomatic melanomas diag-nosed incidentally during routine skin surveillancehad a mean thickness of 0.89mm. In contrast, symp-tomatic lesions (bleeding or ulcerated) had a meanthickness of 1.76mm.

Of major concern for delayed diagnosis are mela-nomas arising in hidden body sites166 and on theplantar surface of the foot.167 In one study of 829patients with melanoma, those whose lesions werein hidden body areas tended to be male, older, andhad more advanced tumors. A study on plantarsurface melanomas confirmed the well-known factthat these tumors are usually diagnosed at anadvanced stage, either because of infrequentinspection or because for many people the sole is,for all intents and purposes, a hidden site.

SURGICAL TREATMENT OF THEPRIMARY TUMOR

The benefits of any surgical treatment for mela-noma may not be apparent for many years, there-fore only long-term clinical series give reliableinformation about the superiority of one form oftherapy over another. Many of the early pub-lished reports based their recommendations fortreatment on poorly designed retrospectivereviews of inadequate numbers of patients fol-lowed for insufficient periods of time. We nowhave a better understanding of the significance ofa number of factors affecting the clinical course ofmelanoma in terms of local recurrence and meta-static potential.15,168 The recommendations beloware based on current information, much of it from

the University of Alabama at Birmingham-SydneyMelanoma Unit study. The reader should criti-cally review his or her own rationale for treatmentof melanoma, particularly with respect to surgicalmargins and sentinel lymph node biopsy. Theplan of management of a primary melanoma shouldinclude consideration of the gross disease as wellas subclinical microscopic tumor and any regionalor distant metastases.

Timing

After the diagnosis of melanoma has been estab-lished, definitive surgical treatment may be delayedwith no apparent effect on the 5-year survival.Landthaler and coworkers169 studied more than 300�“delayed-treatment�” melanoma patients who hadnarrow excisional biopsy followed by delayed widelocal excision 21 days or more after diagnosis. The5-year survival of this group was compared withthat of more than 600 patients treated primarily bywide local excision within 21 days of diagnosis.The authors found no effect on overall survival ordisease-free rate of patients whether treatment wasrendered within 21 days or not. Other investiga-tors later confirmed these findings.170�–173

Surgical Margins

Wide surgical margins beyond a certain mini-mum have not been shown to lessen the risk oflocal recurrence. Aitken and associates174 showedno further protection with surgical margins >3cm,and Storm and Mahvi168 emphasize that �“currentlyavailable data do not predict the minimum safemargin�” of resection for specific tumors. How-ever, a local recurrence rate of 60�–70% is seenafter biopsy or curettage alone,175,176 and the riskof metastatic disease is higher when melanomasare excised with very narrow margins.177 Theexcision margin for melanomas should be basedon tumor thickness (Table 11)71,178 Unfortunately,there is no universally accepted consensus on whatconstitutes a safe minimum margin for differentthicknesses of tumor.

Various prognostic factors have been identifiedthat confer a greater malignant potential to thinmelanomas. If a thin melanoma ("1mm) is associ-ated with three or more of the following, it shouldbe treated as a thicker lesion:136,172


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• male sex

• axial location

• !Clark level III

• ulceration

• regression

Melanoma in situ may recur locally but does notmetastasize. A local recurrence can be another insitu lesion or an invasive melanoma.179 The biopsysite of a melanoma in situ should be excised with0.5�–1cm margins.

For lesions measuring <1.0mm in thickness, thesafe minimum margin has not been established, but1cm is considered a satisfactory margin because ofthe minimal risk of local recurrence.168 In a pro-spective randomized study of melanomas <2.0mmthick, Veronesi and associates180 concluded thatlesions <1.0mm thick could be safely excised witha 1cm margin. No conclusions were reachedregarding safe minimum resection margins fortumors >1.0mm.

Balch and colleagues,181 in a randomized pro-spective study of 486 patients with localized mela-noma who were followed for a median of 6 years,determined that excision margins of 2cm are safefor tumors of intermediate thickness�—1.0�–4.0mm.Because melanomas thicker than 4mm are associ-ated with a 20% risk of local recurrence,139,182,183 ifpossible a 3cm surgical margin is recommendedfor lesions >4.0mm in thickness.154 The excep-tion is lentigo maligna, for which a 1cm excisionalmargin is recommended regardless of tumor thick-ness because of the small chance of recurrence.

Although the efficacy of wide local excision formelanoma has not been conclusively established,184

the burden of proof is on those who recommendeven narrower surgical margins than currentlyadvocated.

Depth of Resection

Excision of fascia is controversial and may not bejustified except in deeply invasive lesions or whenthere is little subcutaneous fat under the tumor.The rationale for excising the fascia is to obtain anadditional layer of tissue�—a boundary�—betweenthe surgical margin and the melanoma. Studies canbe found to support the conclusion that excision ofdeep fascia increases the risk of metastatic disease185

and, alternatively, that it has no effect on localrecurrence or long-term survival.186

Treatment by Anatomic Site

Head and Neck. Melanomas of the head andneck constitute 11�–18% of all melanomas reported.Prognostic variables for SSM and NM of the headand neck are tumor thickness, anatomic subsite,and ulceration, particularly for LMM.187 Localrecurrence rates are 2.4% for tumors <2.5mm thick,but climb sharply to 12.3% with tumor thickness>4mm.187

Eyelid (Conjunctival and Cutaneous). Primarymelanoma of the eyelid is rare, occurring almostexclusively among the elderly and white, with anequal distribution between the sexes. The impor-tance of thickness or depth of invasion is uncertainand the recommended treatment is complete sur-gical excision including a margin of normal skinaround the tumor. The afferent periorbital lym-phatics drain mainly to parotid and, to a lesserdegree, submandibular lymph nodes.151 Lympho-scintigraphy and sentinel lymph node biopsy arerecommended for tumors >1.0mm thick. Thinnertumors should be treated according to the usualguidelines and sentinel lymph biopsy.

Ear. Byers and others188 recommend excisionalbiopsy of small suspicious lesions of the ear, fol-lowed by wedge resection of the helix extendingfull thickness to the auditory canal. Minimum treat-ment is excision of the underlying perichondrium,

TABLE 11Excisional Margins for Melanomas

and Melanoma Precursors

(Modified from Ross MI, Balch CM: Surgical treatment of primarymelanoma. In: Balch CM, Houghton AN, Sober AJ, Soong S-J (eds),Cutaneous Melanoma, 3rd ed. St Louis, Quality Med Pub, 1998.)


23

and partial amputation may be necessary for largerlesions. Total auriculectomy is reserved for recur-rent tumors or widespread local disease. Lymphaticdrainage is to the pre- and postauricular, parotid,and jugulodigastric nodes.

Scalp and Neck. Patients with melanomas onthe scalp or neck generally fare worse than thosewith tumors on the face or ears. Melanomas ofthe scalp should be excised with underlyinggalea.189

Urogenital. Urogenital melanoma is rare andcarries a poor prognosis. Lymphoscintigraphy andsentinel lymph node biopsy with wide tumorresection is effective and feasible for vulvar andvaginal melanoma.190 A large review of 219 pri-mary vulvar melanomas in Swedish women showedthe majority of lesions were in the clitoral areaand labia majora (60%) and only 15% in hair-bearing areas. Approximately 35% arose as a poly-poid mass and 27% were amelanotic. Early diag-nosis with biopsy of any changing pigmented ornonpigmented mass may improve the uniformlypoor prognosis.191

Digits. Subungual melanoma represent approxi-mately 0.7-3.5% of all melanomas.192 If the lesion issmall or localized to the nail bed, amputation proxi-mal to the IP joint of the thumb and the DIP joint ofthe fingers is indicated. If the lesion is more exten-sive, amputation of the entire digit is recom-mended.193 Amputation at the metatarsal-phalangeal joint is indicated in the toes.193,194

Melanomas of the proximal fingers or thumb aretreated by excision with recommended soft-tissuemargins and reconstruction with full-thickness skingrafts or flaps.

Sole. Resection of a melanoma on the plantarsurface of the foot should follow the guidelines es-tablished for tumor thickness. Efforts should bedirected at preserving the deep fascia and, if pos-sible, at reconstructing the weight-bearing surfaceswith local flaps and possible ray resection of theunderlying metatarsal bone.195 Foot amputation israrely needed, although isolated limb perfusion maybe of value in large, thick lesions.106

DIAGNOSIS OF METASTASIS TO REGIONALLYMPH NODES

Lymphoscintigraphy

Melanomas in identical locations on differentindividuals may have different drainage patterns.Axillary nodes collect lymph from a large areaextending inferiorly to the iliac crest. Upper backmelanomas may drain to axillary and cervical nodes.Shoulder melanomas have been noted to drain toboth axillae as well as to supra- and infraclavicularsites. Scalp melanomas can drain to occipital orcervical nodes, and drainage may be bilateral. Inother words, the lymphatic drainage of many trun-cal and head and neck melanomas is often unpre-dictable,196 in contrast to the lymphatic drainage inthe extremities which tends to be fairly predict-able.

In 1953 Sherman and Ter-Pogossian197 suggestedlymphoscintigraphy with colloidal gold to locate andmap the lymphatic pattern of cancerous lesions.Sullivan and others196 and Meyer and collabora-tors198 independently reviewed the use of99mtechnetium-antimony trisulfide colloid to iden-tify the primary nodal basin as well as in-transitnodes in melanomas of the trunk, a large percent-age of which showed unexpected lymphatic drain-age. The technique consists of intradermal injec-tion near the melanoma (four to six injections aroundthe periphery of the lesion or biopsy site) after whichthe drainage is imaged several times over a 3�–4 hrperiod.

Norman and associates199 analyzed the results oflymphoscintigraphy in 82 patients with melanomaand noted areas of ambiguous drainage that werelarger than previously reported. The authors199 sug-gest that all patients with head, neck, and shouldermelanomas and all truncal melanomas shouldundergo lymphoscintigraphy.

Although lymphoscintigraphy does not identifythe presence or absence of metastases in melano-mas, it is highly accurate in predicting the nodalbasin to which a given melanoma will metastasize.200

Lymphoscintigraphy is not reliable after wide localexcision or lymph node dissection.201

Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy is a diagnostic stag-ing procedure, not a therapeutic treatment.


24

McMasters, Reintgen, and Ross202 conclude thatsentinel lymph node status is the single most impor-tant predictor of survival in melanomas because itidentifies two groups: (1) those with a relativelyfavorable prognosis requiring no additional treat-ment and (2) high risk patients who might benefitfrom additional surgery (completion lymphadenec-tomy) and interferon.

A sentinel lymph node has been variously definedas the first node in a lymphatic basin draining froma specific primary tumor site203,204 and as �“any nodewith blue-staining afferent lymphatics draining intoa blue-stained node.�”205 The following facts havebeen established regarding sentinel lymph nodes:• Nodal metastases from melanoma follow an

orderly progression.203�–208

• The incidence of �“skip�” metastases in melanomahas been reported to be 0-2%.204

• The histology of the sentinel lymph node reflectsthe histology of the remainder of the lymph nodechain or basin.203,104

• The sentinel lymph node is not necessarily thelymph node closest to the primary tumor.207

• The location of the sentinel node varies amongpatients with same-site melanomas.209

• Sentinel lymph node(s) can be mapped for pri-mary melanomas occurring anywhere on theskin surface.210

• Success in locating the sentinel lymph nodedepends in large part on the experience of thesurgeon.205

Success RateTen studies comprising thousands of patients

report success rates of 97.2�–99.7% with sentinellymph node biopsy. False negative rates rangedfrom 3.6-11%.211�–221

Pediatric Age GroupNeville et al222 report uncomplicated sentinel

lymph node biopsy in 13 pediatric patients, 8 ofwhom had melanomas. The authors conclude thatthe technique is safe in the pediatric age group.222

How Many NodesThe question of how many sentinel lymph nodes

is enough was addressed by Porter and others218 ina study of 633 consecutive patients. In all cases the

histologic status of the lymph node basin was deter-mined by the first or second sentinel lymph nodeharvested. In no case did the removal of more thantwo sentinel lymph nodes upstaged any patient.The sentinel node with the highest gamma count ordeepest blue stain was positive in 95% of cases.

Looking at sentinel lymph nodes from a differentperspective, Temple and colleagues220 attemptedto define sentinel lymph nodes in terms of nodalradioactivity. The study confirms that the the posi-tive sentinel node is not always the most radioac-tive node. If residual radioactive backgroundremains after the first lymph node is removed, thesearch should continue for additional sentinel lymphnodes. Among �“positive�” nodal basins, the �“hot-test�” node was negative and a less radioactive nodewas positive 13% of the time. In addition, 83.6% ofall positive sentinel nodes were stained blue. Theconclusion of this study is that all blue lymph nodesand any lymph node with 10% or more of the exvivo count of the hottest sentinel lymph node shouldbe removed for H&E and immunohistochemistry.

Thin MelanomasIndications for sentinel lymph node biopsy in

thin melanomas is controversial. McMasters et al202

state that it may be indicated in tumor thickness<1.0mm if poor prognostic features such as verticalgrowth phase, ulceration, and Clark level IV arepresent. In another study of 234 consecutive patientswith melanoma, 3.6% with tumors "0.75mm thickhad positive sentinel lymph node(s).223 Bedrosianand coworkers224 reported on 71 patients with mela-nomas "1mm in thickness and histologic evidenceof vertical growth phase, and noted 5.6% of whomhad positive sentinel lymphs. Nahabedian, Tufaro,and Manson225 reviewed the course of 34 patientswith T1 melanomas and concluded that a subset oftumors <0.9mm were at increased risk for earlyregional metastases and late recurrence and wouldbenefit from sentinel lymph node biopsy. The riskfactors included Clark level IV or V, ulceration,regression, positive deep margin on initial biopsy,or a previous melanoma. Muller et al226 studied 75patients with lesions <0.9mm in thickness, all ofwhom had negative sentinel lymph node biopsies.The authors conclude that sentinel lymph nodebiopsy was not indicated in tumors thinner than0.9mm.


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Thick MelanomasHistorically, sentinel lymph node biopsy was not

indicated for staging thick melanomas because ofthe poor prognosis of those patients. A study fromMemorial Sloan Kettering of 126 patients with mela-nomas >4.0mm thick or Clark level V and clinicallynegative nodes documented a median tumor thick-ness of 5.5mm and ulceration in 43%.227 Of thevarious risk factors�—ie, tumor thickness, patient age,ulceration, and sentinel lymph node status�—sentinellymph node status was the strongest predictor ofprognosis.227

A study from the Moffitt Cancer Center of 201patients with melanomas >3.0mm confirmed a sig-nificant disease-free survival and overall survivaladvantage in the sentinel node-negative group.228

At an average follow-up of 51 months, patients whohad positive sentinel lymph node(s) had a disease-free survival of 37%, compared with 73% for thosewhose sentinel lymph nodes were negative.Although not statistically significant, the overall sur-vival difference between sentinel node-positive andnode-negative patients was 70% and 82%, respec-tively. Tumor ulceration was the only histologicparameter other than sentinel lymph node statusthat had a significant impact on survival. The authorsconcluded that the sentinel lymph node status ispredictive of disease-free survival in patients withthick melanomas.

A third study from MD Anderson looked at 131patients with tumor thickness >4.0mm who under-went sentinel lymph node biopsy.229 The strongestpredictor of 3-year disease-free survival was pri-mary tumor ulceration, and the strongest predictorof 3-year overall survival was sentinel lymph nodestatus. The 3-year survival was 86% if the primarytumor was not ulcerated and the sentinel lymphnode was negative, versus 57% if the tumor wasulcerated and the sentinel node was positive.

At present, the consensus is that sentinel lymphnode biopsy is a valid procedure in thick melano-mas, both as a means of prognostication and toidentify candidates for completion lymphadenec-tomy and adjuvant therapy.

Effect on Regional Nodal BasinThe purpose of completion lymphadenectomy

for patients with regional lymph node metastases isto achieve control of the lymph node basin, pro-vide staging for adjuvant therapy and, if possible,

achieve a cure. Gershenwald and colleagues230

found that sentinel lymph node biopsy followed bycompletion lymphadenectomy did not compromiseregional lymph node basin control in patients withmicrometastases.

Improved SurvivalA Multicenter Selective Lymphadenectomy Trial

(MSLT)231 is currently underway to answer the ques-tion of whether routine sentinel lymph node biopsyin patients with newly diagnosed invasive mela-noma is associated with improved survival. In otherwords: Does sentinel node biopsy have a thera-peutic benefit in addition to its diagnostic role?

Effect of Excisional BiopsyIn an effort to determine whether excisional

biopsy of the primary tumor obscured the results ofsentinel lymph node biopsy, 100 patients with mela-nomas received two lymphoscintigrams, one inwhich the radionuclide was injected 2�–5mm dis-tant from the primary tumor and the other in whichthe injection was 10mm from the primary site.232

The tumor identification rate was 94% with theclose injection and 100% with the distant injection.The authors concluded that diagnostic excision ofmelanoma prior to lymphoscintigraphy does notaffect the success of the procedure.

Interval NodesAberrant or interval nodes have been addressed

by several authors.221,233�–235 In a review of 2045patients, interval nodes were identified in 148(7.2%). Of these, 14% were positive for metastaticmelanoma.233 Another study of 379 melanomapatients confirmed interval nodes in 5%, of which2.2% were positive for tumor.221 A large study of4262 patients with melanomas of the distal lowerlimb found popliteal metastases to be rare(0.31%).235 These studies confirm the need toexcise aberrant or interval lymph nodes when iden-tified on lymphoscintigraphy.

Radiation Risks For Health Care WorkersThe issue of radiation exposure to personnel han-

dling the technetium 99m-labeled radiocolloid hasbeen addressed in several articles.236�–240 These stud-ies confirm that the radiation workers in nuclearmedicine, surgeons, and pathologists are all exposedto such low levels of radiation that no special proce-


26

dures are required for staff protection. Of interestis that ~90% of the radiocolloid remains at theinjection site.239 The radioactivity of the primarytumor site and sentinel lymph node is detectible for16�–48 hours after injection of the radiocolloid. Themean radiation dose to the hands of surgeons per-forming sentinel lymph biopsy for melanoma is~9.6mrem per operation, as measured by intraglovethermoluminescent dosimeters. A surgeon couldperform literally thousands of sentinel lymph nodebiopsies yearly without exceeding United Statesstandards for radiation exposure.239

Histopathology of Sentinel Lymph NodesThere are numerous methods for detecting

melanoma cells, some investigational and some inclinical practice. Among them are immunohis-tochemistry, antibiodies, and reverse transcriptase-polymerase chain reaction for tyrosinase mRNA(RT-PCR). The Sunbelt Melanoma Trial is cur-rently evaluating conventional histology vs RT-PCRfor the detection of nodal micrometastases.241 TheAJCC Melanoma Staging Committee elected notto include RT-PCR data among its regional basinstaging criteria until the information obtained fromthis more sensitive assay is fully characterized.Sentinel lymph node micrometastasis may ini-tially be identified by another modality, such asimmunohistochemistry, but a patient is consid-ered to have nodal disease only if it can be con-firmed by H&E stain.242�–244 McMasters, Sober,and Kirkwood245 are adamant that the prognosticsignificance of RT-PCR for sentinel lymph nodestaging is unproven, and that its use should berestricted to clinical trials. Clearly, the true inci-dence of metastatic melanoma in sentinel lymphnodes is underestimated because it is limited toidentification by H&E histopathology.245�–251

Current immunohistochemical tests for mela-noma cells include monoclonal antibodies to S-100and HMB-45. The S-100 protein is a sensitivemarker with somewhat limited specificity. The pro-tein is expressed in virtually all malignant melano-mas and melanocytic nevi in addition to a variety ofother tumors. In fact, it is the most sensitive markerfor spindle cell and desmoplastic melanomas. HMB-45 is less sensitive than S-100 but more specific formelanocytic neoplasms. It does not stain desmo-plastic melanoma and staining is variable for spindle-cell melanoma.

Several new monoclonal antibodies to melanocyticdifferentiation antigens include microphthalmia tran-scription factor (Mitf; clone D5), Melan-A (MART-1;clone A103) and tyrosinase (clone T311). Combina-tions (cocktails) of these antibodies result in betteridentification of melanoma metastases than S-100and HMB-45.

Head and Neck MelanomasJansen and associates252 state that sentinel lymph

node biopsy in the head and neck region is techni-cally demanding and is not recommended for thestandard management of head and neck melano-mas. Eicher and coworkers253 express concern thatbecause sentinel lymph nodes are numerous andwidely distributed in the head and neck and oftenoccur in the parotid gland, this may preclude sentinallymph node biopsy in many patients. On the otherhand, Wagner and associates254 report successfulsentinel lymph node biopsy in 99% of 70 patientswith head and neck cutaneous melanomas; the false-negative rate was only 2%. They concluded thatsentinel lymph node biopsy for melanomas in thehead and neck is both safe and reliable.

Factors influencing the success of sentinel lymphnode biopsy in the head and neck include collima-tion of the gamma probe, frequent resection of theprimary tumor prior to performing the node biopsy,and an intimate knowledge of head and neckanatomy, particularly of the facial nerve and lowercranial nerves. The presence of sentinal lymphnodes in the parotid gland (ie, near the facial nerve)should not preclude sentinal lymph node biopsy.

Sentinel lymph nodes are highly predictive ofthe remaining lymph node basin. In early studies ofthe technique of sentinel lymph node biopsy fol-lowed immediately by complete lymph node dis-section, nodal disease was identified in only 1% ofcases with �“negative�” sentinel lymph nodes.255,256

The predictive importance of sentinel lymph nodesas indicators of regional lymph node metastases hasbeen confirmed more recently.257,258

The following techniques are currently recom-mended for the identification and biopsy of senti-nel lymph nodes:• Preoperative lymphoscintigraphy with Tc-99m

radiocolloid to identify the lymph node basin(s)at risk of regional metastases and the location ofthe sentinel lymph node(s) within the respectivelymph node basin(s).


27

• Intraoperative vital blue dye lymphatic mappingfor visual orientation and identification.

• Intraoperative lymphoscintigraphy with a hand-held gamma probe (increases accuracy of thebiopsy by 20%).210

• Histologic examination of the entire sentinellymph node by serial sections of the excisedspecimen.

• Routine H&E and immunohistochemistry with S-100 protein and HMB-45 or a �“melanoma cock-tail�” evaluation of the biopsied sentinel node(s).

Metastases in sentinel lymph nodes may not beidentified on routine H&E sections because thesection of the lymph node studied did not contain adeposit of melanoma cell or the metastatic focuswas too small to be seen without the aid of specialstaining techniques. The detection of micro-metastases can be increased by up to 8% with com-plete serial sectioning of the sentinel node and byup to 18% with immunohistochemical techniquesinvolving the S-100 antibody. Both serial section-ing of the sentinel lymph node and S-100 and HMB-45 immunostaining should be used routinely incases of melanoma.259,260

Biopsy of the sentinel lymph node will identifypatients with subclinical metastatic disease who shouldundergo further surgery. Identification of melanomametastasis in a sentinel lymph node has become thecriterion for removal of the remaining lymph nodesin the involved nodal basin, thus replacing electiveor prophylactic lymph node dissection with �“comple-tion lymphadenectomy.�”261 This ensures that onlythose patients proven to harbor metastatic diseasewill be subjected to the morbidity, in-hospital andconvalescence time, and expense of a regional lymphnode dissection. The entire consideration of �“elec-tive�” lymph node dissection becomes moot. If thesentinel node biopsy is negative, no further surgicaltreatment is necessary. If the sentinel node biopsy ispositive, therapeutic or completion lymphadenec-tomy is performed.

Indications for Sentinel Lymph Node BiopsyAccurate staging defines the indications for sen-

tinel lymph node biopsy. Reintgen and col-leagues261 state that �“it becomes imperative toidentify patients with nodal metastases who maybenefit from [high-dose interferon alfa-2b]. Lym-phatic mapping and sentinel lymph node biopsy is

the least morbid and most cost-effective means ofdetermining which patients with melanoma havelymph node metastases.�”261

Sentinel lymph node biopsy is currently the onlytechnique available for accurate staging of regionallymph node basins and provides202

• prognostication for patient and family• identification of patients who are candidates for

completion lymphadenectomy• identification of candidates for adjuvant therapy

with interferon• identification of homogeneous patient popula-

tions for inclusion in clinical trials

Any limits on the use of lymphoscintigraphy andsentinel lymph node biopsy in the staging of thinmelanomas must take into account that sentinellymph node biopsy is an easily performed proce-dure with low morbidity, and the consequences ofleaving microscopic metastatic nodal disease beara significant impact on survival. Surgeons counsel-ing melanoma patients about treatment options,proposed surgery, anticipated benefits, and poten-tial limitations, risks, and complications of that sur-gery must consider the following:• The tumor thickness on the pathology report

may be inaccurate because of the reported inter-and intra-observer differences in recognition ofactual tumor thickness.

• Additional information such as ulceration,regression, vertical growth phase, and tumormitotic activity may be missing or unavailable.

• Many patients are well-educated and Internet-savvy, and may request sentinel lymph nodebiopsy during their initial evaluation. The inci-dence of nodal metastases in �“thin�” melanomashas been reported to be between 2% and 5.5%.Whereas this figure may be acceptable to some,most patients are extremely distraught over their�“melanoma diagnosis�” and want the full ben-efits of current medical technology. In short,they may not accept a treatment plan that doesnot at least attempt to identify all nodal disease.

• A final consideration is the medicolegal implica-tion of not offering sentinel lymph node biopsyto patients who are in the �“grey�” area betweenthose who absolutely should have it and thosewhose tumors are so thin that it is not even aconsideration.


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The burden of proof must rest on those whopropose more stringent guidelines to limit sentinellymph node biopsy to tumors >0.9-1.0mm in thick-ness. Current pathology reports do not routinelyinclude assessment of ulceration, regression, verti-cal growth phase, and other prognostic factors. Afinal decision has not been made regarding the useof more specific and sensitive histopathologic mark-ers for melanoma cell characterization. Given thisand the fact that adjuvant therapy is now availablefor stage III disease, the use of sentinel lymph nodebiopsy in selected thin melanomas should not becriticized. Surgeons in clinical practice should befree to extend the protocols of large institutionalclinical trials and offer sentinal lymph node biopsyas a diagnostic test to selected patients with thinmelanomas. Reintgen and coworkers201 offer thefollowing protocol for sentinel lymph node biopsy:

Indications for Sentinal Lymph Node Biopsy201

• Male patients with truncal melanoma <0.76mmin thickness (who have up to a 9% incidence ofnodal metastases).

• All patients with melanoma thickness 0.76�–1.0mm (who have a 5% incidence of nodalmetastases and should be offered a choice ofsentinel lymph node biopsy).

• Male patients with �“thin�” melanomas that areClark level III or greater, ulcerated, regressed,or axial in location. (These patients have ~10%risk of metastases and death at 5 years.)

• All melanomas >1.0mm in thickness.261

A word of caution regarding sentinel lymph nodebiopsy is in order. The technique involves morethan acquisition of the gamma probe and vital bluedye. This approach to the treatment of the regionalnodal basin in melanoma surgery requires thecoordination of specialty services in a �“melanomateam.�” All members of the team must understandthe entire concept of sentinel node biopsy, which inbrief consists of appropriate skin marking of the sen-tinel node during lymphoscintigraphy (with thepatient in the surgical position); intradermal blue dyeinjection at surgery; careful dissection of the sentinelnode; and thorough histopathologic examination ofserial sections of the sentinel node with immunohis-tochemical staining to increase the yield of occultlymph node disease.262�–265 Cooperation between

the radiologist, surgeon, and pathologist is essentialto the success of the technique. Without propercoordination of these services, any attempt to designsurgical treatment on the basis of sentinel node biopsymay result in undertreatment of the regional lymphnode basin. If all elements of the team are not avail-able and cooperative, sentinel lymph node biopsyshould not be attempted.

SURGICAL TREATMENT OF REGIONALLYMPH NODES

Current treatment of regional lymph nodes is basedon recommendations for sentinel lymph node biopsy.If suspicion of metastasis is high (clinically enlargedlymph node) and the node in question is in the nodalbasin draining the tumor site (confirmed bylymphoscintigraphy), sentinel lymph node biopsy atthe time of primary tumor resection will inform thedecision about complete lymphadenectomy.Although this approach could be criticized for beingtoo cautious, a therapeutic lymph node dissectionshould not be embarked upon lightly. If the sentinelnode biopsy reveals histopathologically negativenode(s), the patient will have been spared the moreaggressive surgery with its high morbidity, attendantproblems, and probability of chronic lymphedema.Should the sentinel lymph node biopsy be positivefor melanoma, routine completion lymphadenectomyis performed.58 Surgical lymphadenectomy is theonly potential cure for metastatic nodal disease.

[Editor�’s Note: The following sections on ElectiveLymph Node Dissection and Therapeutic LymphNode Dissection should be of historical interest toyounger readers who may not have experiencedthe dilemma of elective versus therapeutic lym-phadenectomy without the benefit of lympho-scintigraphy and sentinel lymph node biopsy.]

Elective Lymph Node Dissection

As recently as mid-1995, McCarthy and others266

were recommending that the technique of sentinelnode biopsy should not be widely disseminatedprior to the demonstration of its reliability throughcontrolled trials. Certainly without the benefit ofsentinel lymph node biopsy, the controversy overelective versus therapeutic lymph node dissectioncould continue indefinitely.267

By definition, elective lymph node dissection(ELND) implies no palpable lymphadenopathy in a


29

patient with clinical stage I or II tumor. The diffi-culty lies in identifying patients within this groupwho are at high risk for developing subclinicalregional metastases and treating those metastasesbefore they spread to distant sites.

Tumor thickness is the single most important fac-tor in determining the potential for regional lymphnode metastases and the need for ELND.130,139,147,152,268

Lymphadenectomy does not alter the clinical courseof patients with thin (<1.0mm) and thick (>4mm)lesions, but does have a profound effect on the ulti-mate fate of patients who have tumors of intermedi-ate thickness.269 Answers to the following questionsmay help identify those patients in whom ELND maybe of benefit:

What is the incidence of regional metastasis bytumor thickness and anatomic site?

Balch and colleagues1 calculated the relative riskof occult regional metastases for extremity andaxial (trunk and head and neck) tumors in menand women (Table 12). The risk of subclinicalmetastases is higher for melanomas of all sites inmen and of axial locations in women. The lowestrisk is with extremity melanomas in women.1,270,271

TABLE 12Estimated Risk of Metastases in Melanoma by

Tumor Location and Thickness

(Reprinted with permission from Balch CM et al: Elective lymph nodedissection: pros and cons. In: Balch CM, Milton GW (eds), CutaneousMelanoma�—Clinical Management and Treatment Results World-wide. Philadelphia, Lippincott, 1985. Ch 8, p 131-157.)

Are there any factors other than tumor thicknessthat influence regional metastases?

When matched for tumor thickness, ulceratedmelanomas are more likely to metastasize thannonulcerated melanomas.152,272�–274

Considering only tumor thickness, is there a differ-ence in patient survival between treatment by widelocal excision versus wide local excision with ELND?

Without question, patients who have tumors ofintermediate thickness have higher survival rateswhen treated by elective lymph node dissection inaddition to wide local excision of their primarymelanoma.150,152,270,274,275 This is particularly truefor tumors 1.50�–3.99mm thick, although theimproved survival conferred by ELND may not beevident for 8�–10 years (Table 13).1

For the first 5 years after treatment there is notmuch difference in survival between patients whoreceived wide local excision only and those whoalso had elective lymph node dissection. By theeighth year, however, the former are still dyingfrom their disease while the ELND group have mini-mal disease-related mortality.1

Is there a difference between elective and thera-peutic lymph node dissection in terms of patientsurvival?

The benefit of prophylactic lymphadenectomyremains one of the most important questionsregarding the current surgical management of pri-mary cutaneous melanoma.276 Proponents of elec-tive node dissection maintain that a properly per-formed lymphadenectomy has low morbidity, andif reserved for patients known to be at high risk ofregional metastases, long-term survival is improved.Opponents of ELND, on the other hand, believethat treatment of regional metastasis is just as effec-tive after the nodes become clinically positive asbefore, when there is only microscopic disease.These investigators claim that many patients aregiven unnecessary lymph node dissections underthe guise of prophylaxis.

In the WHO Melanoma Group Trial, patientswho received a therapeutic lymph node dissectionhad a 10-year survival of only 10% to 20%.15 Thissuggests that many of these patients already hadundiagnosed distant metastases at the time of theirlymphatic resection, further strengthening the casefor ELND in selected patients.


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Karakousis and coworkers277 reviewed the mor-bidity and benefits of elective and therapeutic axil-lary lymph node dissections in 212 patients whohad melanoma. The 5-year survival for patientswith clinically and histologically negative nodes was74%; when the nodes were clinically negative buthistologically positive, it was 73%. Patients whoseclinically palbable nodes were <2cm in diameterhad a 5-year survival of only 46%. As the size andfixation of the nodes increased, survival decreased.This excellent study confirms the fact that once thetumor in the regional lymph node basin reaches asize that makes it clinically palpable, mortalityincreases significantly.

Is there a group of patients who would benefitmost from ELND?

The Intergroup Melanoma Surgical Trial identi-fied subgroups of patients with improved survivalwhen primary treatment included ELND.278,279

These results are an early analysis with need forlonger follow-up. Nonetheless, the patients whobenefited most were under 60 years of age withnonulcerated tumors 1�–2mm in thickness. Otherstudies, including the Mayo Clinic Surgical Trial andthe WHO Melanoma Group Trial, have not dem-onstrated increased survival differences betweenvarious subgroups treated with or without ELND.

Therapeutic Lymph Node Dissection

Patients whose melanomas are diagnosed in clini-cal stage III have a very poor prognosis (10-year

survival of 13%). This is thought to be due to thepresence of subclinical distant metastases at the timeof initial treatment, which invariably consists of widelocal excision of the primary tumor and lymph nodedissection of clinically positive nodes.

Among the factors affecting the survival of patientsin clinical stage III disease are number of positivelymph nodes and thickness of the primarytumor.280,281 Bevilacqua and associates282 evaluatedseveral prognostic variables in node-positive patientsundergoing axillary lymph node dissection. Patientswho had extranodal disease, more than 10% posi-tive nodes, and truncal primary tumors had uni-formly poor outcomes. Although the study was notdesigned to assess the timing of regional lymph nodedissection, it clearly confirms �“the importance ofearly regional control of the disease, which shouldbe achieved by elective node dissection or by shortfollow-up intervals.�”

FOLLOW-UP OF TREATED MELANOMAPATIENTS

The goal of any melanoma follow-up program isthe early detection and treatment of recurrent orresidual disease. Since this topic goes hand-in-hand with the subject of melanoma recurrence, aclear definition of what constitutes �“treatable�”recurrent locoregional melanoma and/or metastaticmelanoma will sort out patients who can be helpedwith treatment and those who cannot. As medicaltechnology advances, so does the cost of healthcare: radiographic studies�—ultrasonography, bone

TABLE 13Ten-Year Survival Rates of Patients With Stage I Melanoma Treated by Wide Local Excision With

and Without Regional Node Dissection

(Reprinted with permission from Balch CM et al: Elective lymph node dissection: pros and cons. In: Balch CM, Milton GW (eds), CutaneousMelanoma�—Clinical Management and Treatment Results Worldwide. Philadelphia, Lippincott, 1985. Ch 8, p 131-157.)


31

scans, CT, MRI, PET, and PET/CT�—and serologicmarkers for recurrence�—LDH, S100b protein, PT-PCR, etc�—may not be cost-effective in certainindividuals.

To put the issue of early diagnosis of recurrenceinto proper perspective, survival after relapse wasanalyzed by mode of detection (Fig 7).128 Therewas no difference in survival after relapse whethernodal disease was detected early by lymph nodesonography or became clinically palpable, whetherthe patient or physician first detected the recur-rence, or whether the (stage III) patients wereasymptomatic or not.

This is not an indictment of efforts to diagnoseearly recurrence of melanoma, but it does speak tothe false sense of urgency to apply all of the latesttechnology to every melanoma patient in a follow-up program. Until our treatment of recurrent mela-

noma catches up to our ability to first detect earlyrecurrence or metastases in various organ systems,efforts should be made to apply reasonable diag-nostic modalities of proven value. Keep in mindthat most recurrent tumors are diagnosed by thepatient or physician through complete history andphysical examination.

Unfortunately, there are problems with variousproposed follow-up schedules. Some authors dono more than report the time of first recurrenceand the relapse-free or disease-free interval fromtime of initial treatment. Others concentrate mainlyon the risk of a second primary tumor. What isgenerally accepted is that regular follow-up duringthe first 5 years after initial treatment is indicatedfor early diagnosis of second primary melanomasand treatable recurrences. Romero and associates283

polled 8 �“melanoma experts�” on their follow-up

Fig 7. Survival after melanoma recurrence is not significantly different regardless of method of detection. (Reprinted with permissionfrom Hofmann U, Szediak M, Rittgen W, et al: Primary staging and follow-up in melanoma patients�—monocenter evaluation of methods,costs, and patient survival. Br J Cancer 87:151, 2002.)


32

schedule for stage I and II (localized invasive) mela-nomas. All agreed that regular follow-up was indi-cated and that the frequency of visits dependedon the thickness of the melanoma: Patients withthicker lesions were followed more frequently thanthose with thinner lesions.284 After 5 years frominitial treatment, it was recommended that allpatients be followed annually for the remainder oftheir lives.

Special tests are reserved for patients who havesigns or symptoms referring to a specific organsystem.181,285,286 Jakowatz and Meyskens285 andHofmann et al128 note �“no impact on survival�”with chest x-rays and liver function studies. Weissand coworkers286 reviewed the records of 145patients with intermediate-thickness and high-riskmelanomas and confirmed the limited value ofthese tests in diagnosing recurrent or metastaticdisease. Only 6% of recurrent lesions were firstdetected by radiographic evaluation (chest films);the other 94% of recurrent melanomas were iden-tified by the patient, through patient history, or onphysical examination.286 Abnormal lab studieswere present in 11% but were never the onlyindicator of recurrence.

Despite these limitations, and considering thefact that certain patients with distant metastasesshould be offered palliation only, many locoregionaland selected distant metastases can be treated forcure or satisfactory control, therefore adequatepatient follow-up for the first 5 years after initialtreatment is recommended.

SECOND PRIMARY MELANOMA

The reported incidence of second primarymelanomas is 2�–3.4%.162,287,288 In a prospectivestudy of 3310 patients with AJCC Stage I or IImelanoma,289 114 patients (3.4%) developed a sec-ond primary melanoma. Of those patients in whomaccurate staging information was available for thefirst primary tumor (82), 48% had lower-stage and50% had same-stage second primary tumors. Meantumor thickness and level of invasion decreasedsignificantly in most patients with second primarymelanoma. The authors conclude that careful fol-low-up and patient education allow the earlierdiagnosis of thinner second primary melanomas

and that lifelong follow-up at 2-year intervals isindicated.289

MELANOMA RECURRENCE

Localized (node negative) melanomas recurwithin 2 years of treatment in 67% of cases andwithin 3 years in 81% of cases.290,291 In the remain-ing patients, the tumor may lie dormant for 15-20years, particularly in thin lesions.71,292�–294

A review of the long-term clinical course of 5342patients with localized cutaneous melanomas iden-tified a number of risk factors for recurrence,including tumor thickness and site, ulceration, andpatient gender.295 The probability of cure rangedfrom 17�–80% and the median tumor specific sur-vival (time to death from the tumor) was 2.7�–10years. This extremely wide range varied accordingto risk factors present. For example, half of thedeaths from melanoma in patients with the leastrisk factors (female, extremity site, non-ulcerated,and 0.5mm thickness) occurred more than 10 yearsafter treatment. In all groups the probability of cureincreased to 90% after 15 years of recurrence-freesurvival.295

Thin tumors tend to recur in distant sites inmore than 50% of patients, while thick tumorsrecur locally or metastasize to regional nodes over80% of the time.292 Other reports show that in-transit or nodal metastases occur at the recurrencesite in 2�–16% of cases and distant or visceralmetastases occur at the recurrence site in 20�–26% of cases.290,296,297

Locoregional Recurrence

By definition, in-transit metastases, satellitelesions, and local recurrence are all forms of recur-rent locoreginal disease. Borgstein and associ-ates298 contend that classifying these recurrencesbased on distance from the primary tumor is artifi-cial because their pathophysiology is similar�—thatis, lymphatic invasion. Invasion of the lymphaticchannels is defined as a tumor cell located withinan endothelial-lined space, and can occur anywherebetween the primary tumor and the sentinel lymphnode. Five percent of patients have unequivocalfindings of lymphatic invasion; of these, locoregionalcutaneous recurrence developed in 93% within a


33

median follow-up of 30 months. Among the other94.6% of patients who had no histopathologic evi-dence of lymphatic invasion, locoregional recur-rences were diagnosed in only 1.6% during thesame follow-up period. The authors believe thatlymphatic invasion is a strong predictor of earlylocoregional recurrence.

The overall incidence of in-transit and satellitemetastases is estimated to be less than 5% and isassociated with thicker tumors, ulceration, lowerextremity site, regional nodal metastases,299,300 anddistant metastases. Tumors of intermediate thick-ness (1�–4mm) have a local recurrence rate ofapproximately 2.5%.

Locoregional recurrence portends a poor prog-nosis and ultimately 82% of patients will die of theirdisease.301 Median survival after local recurrenceof melanoma is 10 months to 3 years, and 10-yearsurvival is 20%.183,302,303

Regional Nodal Recurrence

Regional spread of melanoma may manifest aseither in-transit or lymph node metastases. Lymphnodes involved with metastatic melanoma tend tobe firm, rubbery, and nontender. Regionalmetastases may occur at the time of the originaltumor diagnosis (stage III), at a later time (regionalnodal recurrence), or at any time from a melanomaof unknown site. The prognosis is the same in allthree instances if the survival rate is timed from thediagnosis of the nodal metastasis.

Blum and colleagues304 evaluated 1288 mela-noma patients for regional lymph node metastaseswith physical examination and ultrasound.Metastastic disease was diagnosed by ultrasound in263 (20.4%). Histopathology confirmed metatasticmelanoma in >90%, and a second malignancy wasidentified in 3%. The false-positive rate for ultra-sound was only 6%, whereas clinical diagnosis withlymph node palpation had >28% false-negativeresults.

Late Recurrence

Late recurrences of melanoma were reviewedby Crowley and Seigler305 in a study of 7104 patients,168 (2.4%) of whom had recurrence of their dis-ease more than 10 years after diagnosis. Laterecurrences are seen in up to 25% of patients who

have long disease-free intervals, underscoring theneed for continued follow-up. A 10-year disease-free interval in melanoma should not be consid-ered a cure, whereas a relapse-free interval of 15years signifies a 90% probability of cure.306

The cause of late recurrence in melanoma iscontroversial. Numerous factors have been sug-gested, including tumor thickness, influence ofgonadal hormones, location of primary tumor, andinfluence of previous lymph node dissection.Tumor thickness is not an absolute predictor of along disease-free interval. Although the majority oflesions that recur are of intermediate thickness(0.77�–3.99mm; mean 1.6�–2.0mm), some thinlesions also recur late (Table 14) and some patientswith thick lesions survive longer than expected fromthe thickness of their tumors.305

TABLE 14Histologic Characteristics of 168 MelanomasRecurring 10 Years or More After Diagnosis

(Mean 14.3 Years)

(Reprinted with permission from Crowley NJ, Seigler HF: Laterecurrence of malignant melanoma. Analysis of 168 patients. AnnSurg 212:173, 1990.)


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Recurrence After Sentinel Lymph Node Biopsy

Wong and colleagues,307 in a study from theSunbelt Melanoma Trial, evaluated 1183 patientswith tumor thickness !1.0mm and nonpalpableregional lymph nodes. The median follow-up was16 months. The sentinel lymph nodes were exam-ined by routine H&E and S-100 protein stain. Dur-ing the study period the recurrence rate was 15.5%for patients with positive sentinel nodes and 6.0%for those with negative sentinel nodes. The site offirst recurrence was more likely distant in patientswith positive nodes (67%) than in patients with nega-tive nodes (46%). Risk factors for early recurrencein sentinel node-negative patients included tumorthickness, Clark level, and ulceration. After posi-tive sentinel lymph node biopsy and completionlymphadenectomy, early regional nodal basinrecurrence is uncommon and first recurrence ismore likely distant (67%). Patients with positivesentinel lymph nodes are more likely to developearly locoregional and distant metastases than thosewith negative sentinel nodes.

Clary and associates308 describe the pattern ofrecurrence in 357 consecutive patients with local-ized primary cutaneous melanoma who underwentsentinel lymph node biopsy and primary tumorresection. The sentinel node was identified in 93%and was positive in 17%. The 3-year recurrencerate for node-negative and node-positive patientswas 25% and 44%, respectively. In both groups thesite of first recurrence was more often locoregionalthan distant. A reexamination of �“negative�” senti-nel nodes in patients with nodal and in-transitrecurrence confirmed that the sentinel nodes wereactually �“positive�” in 7 of 11 cases. The authorsurge careful histopathologic evaluation of the senti-nel node and directed locoregional follow-upexaminations in these patients.308

Treatment of Locoregional RecurrentMelanoma

The treatment options in locally recurrent mela-noma consist of surgical excision, radiation therapy,and isolated limb perfusion with hyperthermicregional chemotherapy. Excision should be reservedfor the single or multiply clustered local recurrence.Patients with multiple recurrences, either simulta-neous or sequential, and those who have localrecurrence of melanoma and whose primary tumorswere >4mm in thickness or ulcerated are at

increased risk of additional recurrences and in-transit metastases, and may be candidates forregional limb perfusion, intraarterial chemotherapy,or adjuvant systemic therapy. Radiation is usuallyreserved for patients who are not acceptable surgi-cal candidates, have multiple recurrences, or havesymptomatic distant metastatic disease.

The clinical course after recurrence dependsmore on the site of recurrence than on the site ofthe primary tumor. Patients with local and regionalmetastases have a better survival than those withdistant metastases. Annual follow-up examinations,including chest x-ray films and liver function stud-ies, are important because of the extended survivalof many patients after treatment of their recurrentdisease.

DISTANT METASTASES

Patients who have stage I or II melanoma andwho subsequently develop distant metastases do sowithin a median of 34 months from treatment ofthe primary tumor. Patients destined to developremote spread of their cancer who are clinicallynode-positive when their disease is first diagnosedexperience an average interval of less than a yearbetween initial treatment and discovery of theirdistant metastases.309 The median survival afterdiagnosis of distant metastases is only 6�–7.5 months,and the 5-year survival is approximately 6%.136,310

Although melanoma can metastasize to any organ,the first sign of cancer spread usually appears in theskin, subcutaneous tissue, and lymph nodes, fol-lowed by the lungs, liver, brain, bone, and intes-tine.309�–320 Table 15 shows how often these organsare affected in melanoma.

Multiple organ metastases are confirmed in 95%of patients dying from melanoma.309,313 The mostcommon cause of death from melanoma is respi-

TABLE 15Common Sites of Metastases From Melanoma (%)


35

ratory failure due to pulmonary metastases. Thesecond leading cause of death is increased intra-cranial pressure and hemorrhage from brainmetastases.309,313�–320

The management of metastatic melanomadepends on number and site of metastatic lesions,their rate of growth, age and general health of thepatient, previous treatment, and, of course, thepatient�’s wishes. The goal in the face of dissemi-nated disease should be palliation only, since aver-age survival is only about 6 months. Survival iseven shorter with metastases to the liver and brainand with tumor in two or more organs.309

Treatment alternatives for advanced metastaticdisease include no treatment; surgery for isolatedtumor deposits;321 radiotherapy for metastasis tobone, brain, skin, subcutaneous tissue, and lymphnodes;322,323 chemotherapy (primarily with DTIC);and possibly hyperthermia in conjunction withradiotherapy or chemotherapy.324,325 Although 25-40% of patients with cerebral metastases have asingle intracranial lesion, the presence of brainmetastases is usually associated with more wide-spread visceral metastases. Headache and mentaldeficits are common and due to increased intracra-nial pressure from metastatic tumor. The most com-mon physical sign is a focal neurological defect.The best diagnostic test is MRI or CT scan withcontrast enhancement.

Cutaneous and subcutaneous metastatic lesionscan enlarge, ulcerate, and become painful. Treat-ment of these lesions is definitely indicated, andmay involve surgical excision or CO2 laser ablation.After CO2 laser treatment, local recurrence is rareand wound healing is usually complete within 2 to6 weeks.326

Gorenstein and others327 recommend wedgeresection of small peripheral pulmonary metastases.The authors report 25% 5-year survival in 56 patientswith histologically proven pulmonary metastases.

Serologic Markers of Recurrence

Liver function tests, specifically LDH, are recom-mended in the initial work-up of melanoma patients,although an elevated LDH as a first sign of metasta-sis is reported in only 12%. By the time the LDHrise is noted, most patients have clinical symptomsof metastases. An abnormally high LDH level meansthe tumor is stage IV.

The levels of S100b protein in serum and of RT-PCR in sentinel lymph nodes, bone marrow, andperipheral blood are elevated in advanced cases ofmelanoma, and so they are of limited benefit inclinical practice.

METASTATIC MELANOMA OFUNKNOWN PRIMARY

Regional nodal metastases from an unknown pri-mary site account for 4�–12% of metastases frommelanoma.328�–330 Approximately 67% of patientswith unknown primary sites present with regionallymph node disease (most commonly axillary) and33% with distant metastases.330 The source of themetastases is felt to be a primary tumor that sponta-neously regressed.

The average age at diagnosis is 48 years, menoutnumber women 2.6:1, and light-skinned patientsare 42X more numerous than dark-skinned ones.Because survival curves for known and unknownprimary melanoma are similar,331 the recommendedsurgical management is essentially the same�—ie,wide local excision with primary closure or skingraft for stage I and II disease; excision plus regionalnode dissection for stage III; and symptomatic treat-ment for stage IV.

Clinical workup of a suspected unknown primarymelanoma should include a thorough history andphysical examination, to include extensive derma-tologic investigation of all skin lesions and biopsy ofany suspicious area, as well as intraocular,rectovaginal, proctoscopic, and otolaryngologicexaminations. A Wood�’s lamp may expose areas ofdepigmentation or a halo nevus.330,332 Chest x-ray,liver function studies, whole body PET/CT scan, orMRI of the head and neck and CT scan of the chest,abdomen and pelvis may be indicated. Aspirationbiopsy often gives a cytologic diagnosis, and appro-priate lymphadenectomy can be performed. Thediagnosis of unknown primary melanoma is madeon the basis of histologically confirmed subcutane-ous nodule(s) or visceral metastasis without a visiblecutaneous, mucosal, or ocular primary tumor.333

CHILDHOOD MELANOCYTIC NEVI

Small and Medium Congenital Nevi

Congenital nevi occur in 1�–2% of all newborns.All congenital nevi should be considered potential


36

precursors of melanoma, regardless of size.334 Theincidence of malignant degeneration to melanomais unknown in small nevi, but the larger the nevus,the greater the risk. Although the exact risk isunknown, the lifetime risk of developing a mela-noma in a large congenital nevus is 5% to 40%.335�–

340 With small nevi, the prepubertal risk is very low,therefore if prophylactic examination is considered,it is recommended after 10 years of age.335 At thistime there is no evidence to support the routineremoval of all small and medium-sized congenitalmelanocytic nevi.75

Large (Giant) Congenital Nevi

Kopf et al341 describe small nevi as <1.5cm indiameter, medium nevi as 1.5�–20cm, and giantnevi as >20cm. Giant nevi have also beendescribed as

• not easily excised, or

• leaving a defect that cannot be closed primarilywithout a skin graft or flap,334 or

• covering 144in2 on the trunk or extremity, or

• involving a major portion of the face or hand342

Clinically, giant congenital nevi are medium todark brown, have a rough surface, and usually thereis coarse hair growing out of them. With time thelesions often darken and surface irregularitiesincrease. Histologically, giant nevi can have deeplyinfiltrative nevus cells extending into the underly-ing muscle.

The risk of melanomatous transformation inthese nevi has been reported as ranging from 2�–42%337�–340 and is probably about 14%.339 Someinvestigators feel that any congenital nevus, regard-less of size, poses an increased risk of malignantdegeneration because of the concentration of mel-anocytes.343�–346 Due to anesthetic risks, a delay intreatment until the child is at least 6 months old isrecommended.335 Besides melanomas, giant nevican give rise to neurogenic tumors and malignantblue nevi. When giant nevi degenerate into mela-nomas, 60% occur by age 10, 10% in adolescence,and 30% in adult life.338

The treatment of choice for these lesions is pro-phylactic excision. Observation and expectant treat-ment are not recommended because many of those

who develop melanoma subsequently die frommetastatic disease.

CONGENITAL MELANOMA

Although congenital melanoma usually occurs inchildren born to mothers with widespread meta-static melanoma at the time of delivery, it has beenreported to occur in the absence of maternal mela-noma or giant congenital nevus.347

In-utero melanomas not associated with giantcongenital nevi are usually small and may bleedand ulcerate. Transplacental metastases of mela-noma account for 46% of acquired fetal tumors.348

Affected infants often die within days to months ofbirth,349�–351 although spontaneous remissions haveoccurred.

MELANOMA IN CHILDHOOD

Childhood melanoma is defined as a tumor aris-ing in a prepubescent child under 12 years ofage.349,350,352 Melanomas occurring in childhoodare rare and preceded by the same signs and symp-toms as adult melanomas: size and color changes,bleeding, ulceration, crusting, and itching. Approxi-mately 14% of tumors develop in a predisposinglesion; the rest tend to occur in proximity to a small,innocuous skin lesion. In adolescence there is alower association with preexisting cutaneous lesions.

The treatment of childhood melanoma is the sameas that of adult melanoma. All giant congenital nevishould be removed prophylactically if feasible, andif necessary with staged serial excisions.

In the United States the incidence of melanomasin the 15�–19 year-old group increased 85% from1973 to 1996.353 The predominant sites were head,neck, and trunk among males and arms and legsamong females, suggesting that ultraviolet radiationwas a major risk factor in this age group.354

MELANOMA DURING PREGNANCY

Melanoma during pregnancy may be related tohormonal changes thought to stimulate melanocyticproliferation. Although there is no evidence thatpregnancy has an adverse effect on the overall prog-nosis, pregnant patients have a shorter disease-freeinterval and a higher incidence of lymph nodemetastases than nonpregnant patients.


37

Standard surgical treatment includes resection ofthe primary tumor and sentinel lymph node biopsyusing only methylene blue dye even though its safetyin pregnancy has not been determined. If the senti-nel lymph node biopsy is positive for metastatic mela-noma, a therapeutic lymph node dissection is indi-cated�—if allowed by the stage of the pregnancy andthe safety of general anesthesia on the fetus.355�–357

RADIOTHERAPY

Although melanomas have been considered tobe relatively radioresistant, radiotherapy has beenused for various melanoma situations, includingpreoperative and postoperative treatment of theprimary site, unresectable lymph node basins, pal-liative therapy of metastatic disease, and primary,radical, �“curative�” radiotherapy.358�–366

For Primary Tumors

Radiotherapy is rarely indicated as the primarytreatment for cutaneous melanoma. An exceptionto this is lentigo maligna melanoma in the elderly.367

Consideration should also be given to radiotherapyfor primary tumors known to have a high rate oflocal recurrence, such as desmoplastic melano-mas.368

For years European clinicians have used radio-therapy in the treatment of patients with lentigomaligna and lentigo maligna melanoma, with ex-cellent success. One study reported >95% con-trol of lentigo maligna. Because lentigo malignaoften involves wide areas of skin on faces of eld-erly individuals, therapeutic irradiation should cer-tainly be considered for large lesions when surgi-cal resection would be particularly deforming ordebilitating.

The hyperpigmentation of lentigo maligna maytake up to 18 months to resolve. Areas of persistentpigmentation or repigmentation should be biopsiedto rule out invasive melanoma.369

Regional Metastases

Surgery is considered the treatment of choicefor clinically evident regional nodal disease, but asthe indications for formal lymphadenectomy andsentinel lymph node biopsy evolve, the role of

radiation therapy will also evolve. Radiotherapy ofnodal basin(s) may be indicated for patients in whomsurgery would create severe dysfunction, those whobecause of a medical condition cannot tolerate sur-gery, those who are felt to be at high risk of relapseafter surgery, or in the event of microscopic residualdisease identified on histopathologic examination,extranodal tumor spread, or large or multiple posi-tive nodes.

Distant Metastases

The presence of distant metastases usually por-tends a poor prognosis. Treatment must be basedon palliation rather than prolonged survival. Themost commonly treated sites are the brain, bone,lymph nodes, and skin (subcutaneous layer).Attempted long-term control often requires com-bined surgery and radiotherapy for cerebral andsuperficially located pulmonary metastases.370�–372

ADJUVANT THERAPY

Adjuvant therapy in the treatment of tumors isbased on the following considerations:

• the larger the tumor, the less effective the treat-ment

• subclinical micrometastases are more sensitiveto adjuvant therapy than primary tumors

• treatment is more effective against residualmetastatic disease after surgical removal of grossdisease

• a cure requires virtually complete removal of allcancer cells373,374

A major criterion in selecting patients for adju-vant therapy is the relative risk of distant metastases,given that surgery will at best eliminate only local orregional disease. Currently no adjuvant therapy iseffective enough that it can be recommended forroutine treatment, but patients with thick tumorswho are at high risk for locoregional recurrences ordistant metastases should be considered for inclu-sion in various clinical trials. In addition, palliationof symptoms secondary to metastases and prolon-gation of life are definite indications for the use ofbiologic modifiers, vaccines, chemotherapy, or acombination of these modalities.375


38

BIOLOGIC THERAPY

Subclinical micrometastases develop in certainpatients even after aggressive surgical treatmentof the primary tumor and regional nodal disease.It has been postulated that stimulation of thepatient�’s immune system could destroy theseremaining cells, and it is to this end that immuno-therapy is directed. Multiple immunomodulatorshave been tested: bacillus Calmette-Guerin (BCG),Corynebacterium parvum, vaccinia virus, small-pox virus, levamisol, transfer factor, thymosin,isoprinosine, autologous tumor cells, and alpha-,beta-, and gamma-interferons.

Immunologic manipulation is not without com-plication. A number of cases of tumor enhance-ment in association with poor clinical outcome havebeen reported. As such, clinicians must have a fullunderstanding of possible unfavorable responses totherapy before recommending this course of treat-ment to their patients.376�–385

Interferon

Interferon alfa-2b is a recombinant version ofnaturally occurring leukocyte alfa interferon, whichis antiproliferative and has cell-surface antigen-modulator benefits, exerting both antiviral andimmunomodulatory effects on the host. FDAapproval of interferon alfa-2b for the treatment ofmelanoma was granted because of its significantimpact on both relapse-free interval and survival.

The Eastern Cooperative Oncology Group(ECOG) Trial E 1684 reports a disease-free and over-all survival benefit from treatment with interferon.386

ECOG Trial E 1690 confirmed a disease-free sur-vival benefit, but not an overall survival benefit.387

ECOG Trial E 1694 added new evidence regardingthe benefits of high-dose interferon alfa-2b.388

A panel of 13 melanoma specialists (dermatolo-gists, surgical and medical oncologists) reviewedthe available data on high-dose adjuvant interferonalfa-2b therapy for patients with melanoma andissued the following report:389

Intron A was appropriate for patients with:regional nodal and/or in-transit metastasisnode-negative patients with primary melanomas deeper than 4mm

Intron A therapy was uncertain in patients with:

ulcerated intermediate-thickness primary tumors (2.01�–4.0mm in depth)

Intron A therapy was inappropriate for:node-negative patients with non-ulcerated tumors <4.0mm deep389

On the basis of ECOG data from the three trialsabove, Reintgen and coworkers390 state that thereis significant evidence that interferon should be thestandard of care for stage III melanoma.

Immunotherapy

A number of cancer treatment centers aroundthe world are studying melanoma vaccines.Although historically vaccine treatment has beenassociated with a low response rate in advancedmelanoma, improved survival has been reportedwith surgical treatment of the primary tumor andregional nodal disease and postoperative vaccinetherapy. Vaccine therapy for melanomas has notbeen approved by the FDA and is currently avail-able only through clinical trials.

Immunotherapy holds enormous promise in thefuture treatment of melanomas. Coverage of thissubject is beyond the scope of this overview andthe reader is directed to the excellent review byKim et al.391

CHEMOTHERAPY

Numerous clinical trials with single agent andcytotoxic drug combinations have beenreported.392�–396 Since metastatic melanoma is vir-tually always a fatal disease, and chemotherapy isgenerally palliative, response to treatment is ex-pressed in response rate percentage: the fractionof patients experiencing complete remission of allmetastases for at least 1 month plus the fractionwith at least 50% regression of total tumor burdenfor at least 1 month. These regressions or responsesmay last only weeks or months and may be at theexpense of toxic treatments that affect the patient�’squality of life. A thorough discussion of chemo-therapy options is beyond the scope of this over-view. The reader is directed to clinicaltrials.gov, aservice of the National Institutes of Health, for anup-to-date review of current clinical chemotherapytrials for melanoma.


39

1. Milton GW, Balch CM, Shaw HM: Clinical Characteristics. In:Balch CM, Milton GW (eds): Cutaneous Melanoma. ClinicalManagement and Treatment Results Worldwide. Philadel-phia, Lippincott, 1985.

2. Dennis LK: Analysis of the melanoma epidemic, both apparent andreal: data from the 1973 through 1994 surveillance, epidemiol-ogy, and end results program registry. Arch Dermatol 135:275,1999.

3. American Cancer Society: Cancer Facts and Figures 2004.Atlanta, Georgia, Am Cancer Soc, 2004.

4. Bodenham DC: Malignant melanoma. Br J Dermatol 80:190,1968.

5. Halliday A: Case of melanosis. London Med Rep 19:442, 1823.6. Norris W: Case of fungoid disease. Edinburgh Med Surg J 16:562,

1820.7. Norris W: Eight Cases of Melanosis with Pathological and

Therapeutical Remarks on that Disease. London, Longman,1857.

8. Davis NC: William Norris, M.D.: A pioneer in the study ofmelanoma. Med J Aust 1:52, 1980.

9. Parrish I: Case of melanosis. Am J Med Sci 20:266, 1837.10. Paget J: Lectures on Surgical Pathology, Vol 2. London,

Longman, 1853.11. Hutchinson J: Melanotic disease of the great toe, following a

whitlow of the nail. Trans Pathol Soc London 8:404, 1857.12. Hutchinson J: On tissue dotage. Arch Surg 3:315, 1892.13. Hutchinson J: Lentigo melanosis. Arch Surg 5:253, 1894.14. Handley WS: The pathology of melanotic growths in relation

to their operative treatment. Lancet 1:927,996, 1907.15. Cascinelli N et al: Metastatic spread of stage I melanoma of the

skin. Tumori 69:449, 1983.16. Veronesi U et al: Inefficacy of immediate node dissection in

stage I melanoma of the limbs. N Engl J Med 297:627, 1977.17. Veronesi U et al: Stage I melanoma of the limbs: Immediate

versus delayed node dissection. Tumori 66:373, 1980.18. Veronesi U et al: Delayed regional lymph node dissection in

stage I melanoma of the skin of the lower extremities. Cancer49:2420, 1982.

19. Balch CM, Buzaid AC, Soong SJ, et al: Final version of theAmerican Joint Committee on Cancer staging system for cuta-neous melanoma. J Clin Oncol 19:3635, 2001.

20. Magnus K: Habits of sun exposure and risk of malignantmelanoma: An analysis of incidence rates in Norway, 1955-57,by color, sex, age, and primary tumor site. IN: Magnus K (ed):Trends in Cancer Incidence. Washington, Hemisphere, 1982,p 387.

21. Nectoux J: Time trends: Malignant melanoma of skin. IN:Magnus K (ed): Trends in Cancer Incidence. Washington,Hemisphere, 1982, p 365.

22. Demierre MF, Nathanson L: Chemoprevention of melanoma:an unexplored strategy. J Clin Oncol 21:158, 2003.

23. Chen YT, Dubrow R, Zheng T, et al: Sunlamp use and the riskof cutaneous malignant melanoma: a population-based case-control study in Connecticut, USA. Int J Epidemiol 27:758,1998.

24. Bulliard JL: Site-specific risk of cutaneous malignant melanomaand pattern of sun exposure in New Zealand. Int J Cancer85:627, 2000.

25. Albert MR, Ostheimer KG: The evolution of current medicaland popular attitudes toward ultraviolet light exposure: part 1.J Am Acad Dermatol 47:930, 2002.

26. Fears TR, Bird CC, Guerry D 4th, et al: Average midrangeultraviolet radiation flux and time outdoors predict melanomarisk. Cancer Res 62:3992, 2002.

27. Lee JAH: Melanoma and exposure to sunlight. Epidemiol Rev4:110, 1982.

28. Schottenfeld D, Fraumeni JF Jr (eds): Cancer Epidemiology andPrevention. Philadelphia, Saunders, 1982.

29. Elwood JM et al: Pigmentation and skin reaction to sun as riskfactors for cutaneous melanoma: Western Canada melanomastudy. Br Med J Clin Red Ed 288:99, 1984.

30. Sober AJ, Fitzpatrick TB, Mihm MC Jr: Primary melanoma ofthe skin: Recognition and management. J Am Acad Dermatol2:179, 1980.

31. Holman CDJ, Armstrong BK: Cutaneous malignant melanomaand indicators of total accumulated exposure to the sun: Ananalysis separating histogenic types. JNCI 73:75, 1984.

32. Holman CDJ, Armstrong BK, Heenana PJ: Relationship ofcutaneous malignant melanoma to individual sunlight-expo-sure habits. JNCI 76:403, 1986.

33. Lew RA et al: Sun exposure habits in patients with cutaneousmelanoma: A case control study. J Dermatol Surg Oncol 9:981,1983.

34. Devesa SS et al: Cancer incidence and mortality trends amongwhites in the United States, 1947-84. JNCI 79:701, 1987.

35. Koh HK, Kligler BE, Lew RA: Sunlight and cutaneous malignantmelanoma: Evidence for and against causation. PhotochemPhotobiol 51:765, 1990.

36. Diffey BL: Human exposure to ultraviolet radiation. SeminDermatol 9:2, 1990.

37. Crombie IK: Distribution of malignant melanoma on the bodysurface. Br J Cancer 43:842, 1981.

38. Armstrong BK et al: Trends in melanoma incidence andmortality in Australia. In: Magnus K (ed), Trends in CancerIncidence, Causes and Practical Implications. Washington,DC, Hemisphere, 1982, pp 399-417.

39. Osterlind A, Hou-Jensen K, Jensen OM: Incidence of cutane-ous malignant melanoma in Denmark 1978-1982. Anatomicsite distribution, histologic type, and comparison with non-melanoma skin cancer. Br J Cancer 58:385, 1988.

40. Lee JAH: Trends with time of the incidence of malignantmelanoma of skin in white populations. Pigment Cell 9:1, 1988.

41. Gallagher RP et al: Trends in basal cell carcinoma, squamouscell carcinoma, and melanoma of the skin from 1973 through1987. J Am Acad Dermatol 23:413, 1990.

42. Al Mahroos M, Yaar M, Phillips TJ, et al: Effect of sunscreenapplication on UV-induced thymine dimers. Arch Dermatol138:1480, 2002.

43. Gallagher RP et al: Suntan, sunburn, and pigmentation factorsand the frequency of acquired melanocytic nevi in children.Arch Dermatol 126:770, 1990.

44. Crombie IK: Racial differences in melanoma incidence. Br JCancer 40:185, 1979.

45. Feibleman CE, Maize JC: Racial differences in cutaneous mela-noma incidence and distribution. IN: Ackerman AB (ed): Pathologyof Malignant Melanoma. New York, Masson, 1981, p 47.

BIBLIOGRAPHY


40

46. Dubin N, Pasternack BS, Moseson M: Simultaneous assessmentof risk factors for malignant melanoma and non-melanoma skinlesions, with emphasis on sun exposure and related variables.Int J Epidemiol 19:811, 1990.

47. Muir CS, Waterhouse J, Mack T, eds: Cancer Incidence in FiveContinents. Vol 5. Lyons, Intl Agency for Research on Cancer, 1987.

48. Weinstock MA: Epidemiology of melanoma. Cancer Treat Res65:29, 1993.

49. Crombie IK: Variation of melanoma incidence with latitude inNorth America and Europe. Br J Cancer 40:744, 1979.

50. Elwood JM, Gallagher RP, Hill GB, et al: Pigmentation and skinreaction to sun as risk factors for cutaneous melanoma: WesternCanada Melanoma Study. Br Med J 288:99, 1984.

51. National Cancer Institute: What you need to know aboutmelanoma. Information about detection, symptoms, diagnosis,and treatment of melanoma. NIH Pub No 02-1563, cancer.gov.Posted 3/31/2003; accessed 5/6/04.

52. Newton JA: Familial melanoma. Clin Exp Dermatol 18:5, 1993.53. Ostlere LS et al: Risk of cancer in relatives of patients with

cutaneous melanoma. Int J Dermatol 32:719, 1993.54. Ford D et al: Risk of cutaneous melanoma associated with a

family history of the disease. The International MelanomaAnalysis Group (IMAGE). Int J Cancer 62:377, 1995.

55. Carey WP, Thompson CJ, et al: Dysplastic nevi as a melanomarisk factor in patients with familial melanoma. Cancer 74:3118,1994.

56. Kraehn GM, Schartl M, Peter RU: Human malignant mela-noma�—a genetic disease? Cancer 75:1228, 1995.

57. Rivers JK et al: Malignant melanoma in a man seropositive forthe human immunodeficiency virus. J Am Acad Dermatol20:1127, 1989.

58. Tindall B et al: Malignant melanoma associated with humanimmunodeficiency virus infection in three homosexual men.J Am Acad Dermatol 20:587, 1989.

59. Spatz A, Prade M: Malignant melanoma and Kaposi�’s sarcoma:A possible additional syndrome to AIDS-related complex. AIDS4:264, 1990.

60. Moore GE, Cook DD: AIDS in association with malignantmelanoma and Hodgkin�’s disease. J Clin Oncol 3:1437, 1985.

61. Merot Y, Miescher PA: Cutaneous malignant melanomasoccurring under cyclosporin A therapy. A report of two cases.Br J Dermatol 123:237, 1990.

62. Rivers JK, Kopf AW, Vinokur AF, et al: Clinical characteristicsof malignant melanoma developing in persons with dysplasticnevi. Cancer 65:1232, 1990.

63. Marghoob AA, Kopf AW, Rigel DS, et al: Risk of cutaneousmalignant melanoma in patients with �“classic�” atypical molesyndrome. A case-control study. Arch Dermatol 130:993,1994.

64. De Rooij MJM et al: Skin cancer screening focusing onmelanoma yields more selective attendance. Arch Dermatol131:422, 1995.

65. Nachbar F et al: The ABCD rule of dermatoscopy: highprospective value in the diagnosis of doubtful melanocytic skinlesions. J Am Acad Dermatol 30:551, 1994.

66. Dobes WL: Melanoma skin cancer screenings: a how-toapproach. Cancer 75:705, 1995.

67. Rampen FHJ et al: False-negative findings in skin cancer andmelanoma screening. J Am Acad Dermatol 33:59, 1995.

68. Mihm MC Jr, Clark WH Jr, From L: The clinical diagnosis,classification and histogenic concepts of the early stages ofcutaneous malignant melanomas. N Engl J Med 284:1078,1971.

69. Clark WH Jr: A classification of malignant melanoma in mancorrelated with histogenesis and biologic behavior. In: MontagnaW and Hu F (eds), Advances in Biology of the Skin, Vol VIII.Elmsford NY, Pergamon Press, 1967, pp 621-647.

70. Andersen WK, Silvers DN: Melanoma? It can�’t be melanoma!A subset of melanomas that defies clinical recognition. JAMA266:3463, 1991.

71. Schultz S et al: Time to recurrence varies inversely withthickness in clinical stage 1 cutaneous melanoma. Surg GynecolObstet 171:393, 1990.

72. Reed RJ et al: Common and uncommon melanocytic nevi andborderline melanomas. Semin Oncol 2:119, 1975.

73. Goldenhersh MA, Savin RC, Barnhill RL, et al: Malignant bluenevus. J Am Acad Dermatol 19:712, 1988.

74. Connelly J, Smith JL Jr: Malignant blue nevus. Cancer 67:2653, 1991.75. Roth ME, Grant-Kels JM: Important melanocytic lesions in

childhood and adolescence. Pediatr Clin North Am 38:791, 1991.76. Smith K, Skelton H, Lupton G, et al: Spindle cell and epithelioid

cell nevi with atypia and metastasis (malignant Spitz nevus). AmJ Surg Pathol 13:931, 1989.

77. Barnhill RL, Flotte T, Fleischli M, et al: Childhood melanomaand atypical Spitz tumors. Cancer 76:1833, 1995.

78. Langley RGB, Fitzpatrick TB, Sober AJ: Clinical characteristics.In: Balch CM, Houghton AN, Sober AJ, Soong S-J (eds), CutaneousMelanoma, 3rd ed. St Louis, Quality Med Publ, 1998. Ch 5.

79. Rhodes AR: Potential Precursors of Cutaneous Melanoma. In:Lejeune FJ, Chaudhuri PK, Das Gupta TK (eds), MalignantMelanoma: Medical and Surgical Management. New York,McGraw-Hill, 1994, pp 97�–125.

80. McGovern VJ, Shaw HM, Milton GW: Histogenesis of malig-nant melanoma with an adjacent component of the superficialspreading type. Pathology 17:251, 1985.

81. Rivers JK et al: Clinical characteristics of malignant melanomasdeveloping in persons with dysplastic nevi. Cancer 65:1232, 1990.

82. Allen AC: Skin. In: Kissane JM (ed), Anderson�’s Pathology, 9th

ed. St Louis, CV Mosby, 1990, p1802�–1818.83. Sagebiel RW: Histopathology of borderline and early malignant

melanomas. Am J Surg Pathol 3:543, 1979.84. Elder DE et al: Dysplastic nevus syndrome: A phenotypic association

of sporadic cutaneous melanoma. Cancer 46:1787, 1980.85. Greene MH et al: Acquired precursors of cutaneous malignant

melanoma: The familial dysplastic nevus syndrome. N Engl JMed 312:91, 1985.

86. Clark WH Jr: The Skin. In: Rubin E, Farber JL (eds), Pathology.Philadelphia, J. B. Lippincott, 1988, pp1242�–1252.

87. Ritchie AC: Boyd�’s Textbook of Pathology, Vol II. Philadelphia,Lea & Febiger, 1990, pp 2037�–2043.

88. Agarwal-Antal N, Bowen GM, Gerwels JW: Histologic evaluationof lentigo maligna with permanent sections: implications regard-ing current guidelines. J Am Acad Dermatol 47:743, 2002.

89. Hill DC, Gramp AA: Surgical treatment of lentigo maligna andlentigo maligna melanoma. Australas J Dermatol 40:25, 1999.

90. Carucci JA: Treatment of lentigo maligna. Cutis 67:389, 2001.91. Farshad A, Burg G, Panizzon R, Dummer R: A retrospective

study of 150 patients with lentigo maligna and lentigo malignamelanoma and the efficacy of radiotherapy using Grenz or softx-rays. Br J Dermatol 146:1042, 2002.

92. Clark WH Jr et al: The developmental biology of primary humanmalignant melanomas. Semin Oncol 2:83, 1975.

93. Clark WH Jr et al: The histogenesis and biologic behavior orprimary human malignant melanomas of the skin. Cancer Res29:705, 1969.


41

94. Milton GW: Clinical diagnosis of malignant melanoma. Br J Surg55:755, 1968.

95. McGovern VJ et al: The classification of malignant melanomaand its histologic reporting. Cancer 32:1446, 1973.

96. Mihm JC Jr et al: Early detection of primary cutaneous malignantmelanoma: A color atlas. N Engl J Med 289:989, 1973.

97. Wick MM et al: Clinical characteristics of early cutaneousmelanoma. Cancer 45:2684, 1980.

98. Friedman RJ, Rigel DS, Kopf AW: Early detection of malignantmelanoma: The role of physician examination and self-examination of the skin. New York, Am Cancer Soc, 1985.

99. Clark DA et al: Apparent HL-A5 deficiency in malignantmelanoma. Transplantation 15:326, 1973.

100. Sober AJ et al: Early recognition of cutaneous melanoma. JAMA242:2795, 1979.

101. McGovern VJ et al: Is malignant melanoma arising in aHutchinson�’s melanotic freckle a separate disease entity?Histopathology 4:235, 1980.

102. Seiji M, Takahashi M: Acral melanoma in Japan. Hum Pathol13:607, 1982.

103. Coleman WP III et al: Acral lentiginous melanoma. ArchDermatol 116:773, 1980.

104. Arrinton JH III et al: Plantar lentiginous melanoma: A distinctivevariant of human cutaneous malignant melanoma. Am J SurgPathol 1:131, 1977.

105. Olsen G: Malignant melanoma of the foot. A clinicopathologi-cal study of 125 primary cutaneous malignant melanomas. ActaPathol Microbiol Scand (A) 88:275, 1980.

106. Krementa ET et al: Acral lentiginous melanoma. A clinicopatho-logic entity. Ann Surg 195:632, 1982.

107. Paladugu RR, Winberg CD, Yonemoto RH: Acral lentiginousmelanoma. A clinicopathologic study of 36 patients. Cancer52:161, 1983.

108. Lopansri S, Mihm MC Jr: Clinical and pathological correlationof malignant melanoma. J Cutan Pathol 6:180, 1979.

109. Reintgen DS et al: Malignant melanoma in black American andwhite American populations. A comparative review. JAMA248:1856, 1982.

110. Stevens NG, Liff JM, Weiss NS: Plantar melanoma: Is theincidence of melanoma of the sole of the foot really higher inblacks than whites? Int J Cancer 45:691, 1990.

111. Carlson JA, Dickerson GR, Sober AJ: Desmoplastic neu-rotrophic melanoma. A clinicopathologic analysis of 28 cases.Cancer 75:478, 1995.

112. Anstey A, Cerio R, Ramnarain N, et al: Desmoplastic malignantmelanoma. Am J Dermatopathol 16:14, 1994.

113. Anstey A, McKee P, Jones EW: Desmoplastic malignantmelanoma. A clinicopathologic study study of 25 cases. Br JDermatol 129:359, 1993.

114. Mihm MC, Gouge PB: Problematic Pigmented Lesions: ACase Method Approach. Philadelphia, Lea & Febiger, 1990, pp241-287.

115. Gibson LE, Goellner JR: Amelanotic melanoma: cases studiedby Fontana stain, S-100 immunostain, and ultrastructural exami-nation. Mayo Clin Proc 63:777, 1988.

116. Reed KM et al: Prognosis for polypoidal melanoma is deter-mined by primary tumor thickness. Cancer 57:1201, 1986.

117. Keefe M, Mackie RM: The relationship between risk of death fromclinical stage 1 cutaneous melanoma and thickness of primarytumor: no evidence for steps in risk. Br J Cancer 64:598, 1991.

118. Wright KL: New melanoma staging system reflects key prognos-tic factors. OncoLog Jan 2001 (an M D Anderson Cancer Centerpublication).

119. McCarthy WH, Shaw HM: The influence of prognostic factorson melanoma management. In: Lejeune FJ, Chaudhuri PK,DasGupta TK (eds), Malignant Melanoma: Medical andSurgical Management. New York, McGraw-Hill, 1994. Ch 14,p 171-185.)

120. Kim CJ, Reintgen DS, Balch CM: The new melanoma stagingsystem. Cancer Control 9:9, 2002.

121. Balch CM, Mihm MC: Reply to �“The AJCC staging proposalsfor cutaneous melanoma: comments by the EORTC MelanomaGroup�”. Ann Oncol 13:175, 2002.

122. Kelly JW et al: Thin level IV malignant melanoma�—a subset inwhich level is the major prognostic indicator. Ann Surg 202:98,1985.

123. Breslow A: Thickness, cross-sectional areas and depth ofinvasion in the prognosis of cutaneous melanoma. Ann Surg172:902, 1970.

124. Smith JL Jr: Histopathology and biologic behavior of malignantmelanoma. In: Neoplasms of the Skin and Malignant Mela-noma. Chicago, Year Book, 1976.

125. Calder CJ, Campbell AP, Plastow SR: Measurement techniquesfor melanoma: a statistical comparison. J Clin Pathol 43:922,1990.

126. Colloby PS, West KP, Fletcher A: Observer variation in themeasurement of Breslow depth and Clark�’s level in thincutaneous malignant melanoma. J Pathol 163:245, 1991.

127. Brochez L, Verhaeghe E, Grosshans E, et al: Inter-observervariation in the histopathological diagnosis of clinically suspi-cious pigmented skin lesions. J Pathol 196:459, 2002.

128. Hofmann U, Szediak M, Rittgen W, et al: Primary staging andfollow-up in melanoma patients�—monocenter evaluation ofmethods, costs, and patient survival. Br J Cancer 87:151, 2002.

129. Gershenwald JE, Fischer D, Buzaid AC: Cutaneous melanoma:clinical classification and staging. Clin Plast Surg 27:361, 2000.

130. Balch CM et al: A multifactorial analysis of melanoma:Prognostic histopathological features comparing Clark�’s andBreslow�’s staging methods. Ann Surg 188:732, 1978.

131. Cascinelli N et al: Prognosis of stage I melanoma of the skin.Int J Cancer 26:733, 1980.

132. Shaw HM et al: Histologic features of tumors and the femalesuperiority in survival from malignant melanoma. Cancer45:1604, 1980.

133. Drzewiecki KT, Anderson PK: Survival with malignant mela-noma: A regression analysis of prognostic factors. Cancer49:2414, 1982.

134. Schmoeckel C et al: Low- and high-risk malignant melanoma.I. Evaluation of clinical and histological prognosticators in 586cases. Eur J Cancer Clin Oncol 19:227, 1983.

135. Wells KE, Reintgen DS, Cruse CW: The current managementand prognosis of acral lentiginous melanoma. Ann Plast Surg28:100, 1992.

136. Balch CM, Soong S, Shaw HM, et al: An analysis of prognosticfactors in 8500 patients with cutaneous melanoma. In: BalchCM, Houghton AN, Milton DW, et al (eds), Cutaneous Mela-noma, 2nd ed. Philadelphia, JB Lippincott, 1992.

137. Bennett DR, Wasson D, MacArthur JD, et al: The effect ofmisdiagnosis and delay in diagnosis on clinical outcome inmelanomas of the foot. J Am Coll Surg 179:279, 1994.

138. Kalady MF, White RR, Johnson JL, et al: Thin melanomaspredictive lethal characteristics from a 30-year clinical expe-rience. Ann Surg 238:528, 2003.

139. Balch CM et al: Tumor thickness as a guide to surgicalmanagement of clinical stage I melanoma patients. Cancer43:883, 1979.


42

140. Ketcham AS, Balch CM: Classification and Staging Systems; andBalch CM, Soong SJ, Shaw HM, Milton GW: An Analysis ofPrognostic Factors in 4000 Patients With Cutaneous Melanoma.In: Balch CM, Milton GW (eds), Cutaneous Melanoma. ClinicalManagement and Treatment Results Worldwide. Philadel-phia, Lippincott, 1985, pp 55-62 and 321-352.

141. Slingluff CL, Vollmer RT, Reintgen DS, Seigler HF: Lethal �“thin�”malignant melanoma: identifying patients at risk. Ann Surg208:150, 1988.

142. Shaw HM, McCarthy WH, McCarthy SW, Milton GW: Thinmalignant melanoma and recurrence potential. Arch Surg122:1147, 1987.

143. Prayer L et al: Sonography versus palpation in the detection ofregional lymph-node metastases in patients with malignantmelanoma. Eur J Cancer 26:827, 1990.

144. Elder DE et al: Invasive malignant melanoma lacking compe-tence for metastasis. Am J Dermatopathol 6(Suppl 1):55, 1984.

145. Salman SM, Rogers GS: Prognostic factors in thin cutaneousmelanoma. J Dermatol Surg Oncol 16:413, 1990.

146. Reintgen DS, Cox E, Vollmer R, et al: Mathematical model topredict prognosis for stage I cutaneous melanoma. Surg Forum43:211, 1983.

147. Balch CM et al: The prognostic significance of ulceration ofcutaneous malanoma. Cancer 45:3012, 1980.

148. Rogers GS: Surgical management of stage I malignant mela-noma. Dermatol Clin 9(4):649, 1991.

149. Patterson RH, Helwig EB: Subungual malignant melanoma: Aclinical-pathologic study. Cancer 46:2074, 1980.

150. Balch CM et al: A multifactorial analysis of melanoma. II.Prognostic factors in patients with stage I (localized) melanoma.Surgery 86:343, 1979.

151. McGovern VJ et al: Lymphocytic Infiltration and Survival inMalignant Melanoma. IN: Ackerman AB (ed), Pathology ofMalignant Melanoma. New York, Masson, 1981, p 341.

152. Balch CM et al: A comparison of prognostic factors and surgicalresults in 1786 patients with localized (stage I) melanomatreated in Alabama, USA, and New South Wales, Australia. AnnSurg 196:677, 1982.

153. Evans GRD, Manson PN: Review and current perspectives ofcutaneous malignant melanoma. J Am Coll Surg 178:523, 1994.

154. McGovern VJ, Shaw HM, Milton GS: Prognosis in patients withthin malignant melanoma: Influence of regression. Histopa-thology 7:673, 1983.

155. Gromet MA, Epstein WL, Blois MS: The regressing thinmalignant melanoma: A distinctive lesion with metastaticpotential. Cancer 42:2282, 1978.

156. Paladugu RR, Yonemoto RH: Biologic behavior of thin malig-nant melanomas with regressive changes. Arch Surg 118:41,1983.

157. Trau H et al: Metastases of thin melanomas. Cancer 51:553,1983.

158. Ho VC, Sober AJ, Balch CM: Biopsy techniques. In: Balch CM,Houghton AN, Sober AJ, Soong S-J (eds), Cutaneous Melanoma,3rd ed. St Louis, Quality Med Publ, 1998. Ch 7.

159. Lees VC, Briggs JC: Effect of initial biopsy procedure onprognosis in Stage 1 invasive cutaneous malignant melanoma:review of 1086 patients. Br J Surg 78:1108, 1991.

160. Bong JL, Herd RM, Hunter JA: Incisional biopsy and melanomaprognosis. J Am Acad Dermatol 46:690, 2002.

161. Witheiler DD, Cockerell CJ: Sensitivity of diagnosis of malig-nant melanoma: a clinicopathologic study with a criticalassessment of biopsy techniques. Exp Dermatol 1:170, 1992.

162. Brochez L, Vergaeghe E, Bleyen L, Naeyaert JM: Time delaysand related factors in the diagnosis of cutaneous melanoma. EurJ Cancer 37:843, 2001.

163. Krige JE, Isaacs S, Hudson DA, et al: Delay in the diagnosis ofcutaneous malignant melanoma. A prospective study in 250patients. Cancer 68:2064, 1991.

164. Jansen L, Koops HS, Neiweg OE, et al: Sentinel node biopsy formelanoma in head and neck region. Head Neck 22:27, 2000.

165. Blum A, Brand CU, Ellwanger U, et al: Awareness and earlydetection of cutaneous melanoma: an analysis of factors relatedto delay in treatment. Br J Dermatol 141:783, 1999.

166. Nagore E, Oliver V, Moreno-Picot S, Fortea JM: Primarycutaneous melanoma in hidden sites is associated with thickertumours�—a study of 829 patients. Eur J Cancer 37:79, 2001.

167. Franke W, Neumann NJ, Ruzicka T, Schulte KW: Plantarmalignant melanoma�—a challenge for early recognition.Melanoma Res 10:571, 2000.

168. Storm FK, Mahvi DM: Treatment of Primary Melanoma. In:Lejeune FJ, Chaudhuri PK, Das Gupta TK (eds), MalignantMelanoma: Medical and Surgical Management. New York,McGraw-Hill, 1994. Ch 16, pp 193-203.

169. Landthaler M et al: Excisional biopsy as the first therapeuticprocedure versus primary wide excision of malignant mela-noma. Cancer 64:1612, 1989.

170. Eldh J: Excisional biopsy and delayed wide excision versusprimary wide excision of malignant melanoma. Scand J PlastReconstr Surg 13:341, 1979.

171. Drzewiecki KT et al: Biopsy and prognosis for cutaneousmalignant melanomas in clinical stage I. Scand J Plast ReconstrSurg 14:141, 1980.

172. Drzewiecki KT, Andersen PK: Survival with malignant mela-noma. A regression analysis of prognostic factors. Cancer49:2414, 1982.

173. Lederman JS and Sober AJ: Does wide excision as the initialdiagnostic procedure improve prognosis in patients with cuta-neous melanoma? J Dermatol Surg Oncol 12:697, 1986.

174. Aitken DR et al: The extent of primary melanoma excision. AnnSurg 198:634, 1983.

175. McNeer G, Cantim J: Local failure in the treatment ofmelanoma. Am J Roentgenol 99:791, 1967.

176. Close BM et al: Malignant melanoma of the scalp. Laryngoscope89:1189, 1979.

177. Schmoeckel C et al: Low- and high-risk malignant melanoma.III. Prognostic significance of the resection margin. Eur J CancerClin Oncol 19:237, 1983.

178. Ross MI, Balch CM: Surgical treatment of primary melanoma.In: Balch CM, Houghton AN, Sober AJ, Soong S-J (eds), Cutane-ous Melanoma, 3rd ed. St Louis, Quality Med Publ, 1998.

179. Jones RE Jr, Cash ME, Ackerman AB: Malignant MelanomasMistaken Histologically for Junctional Nevi. IN: Ackerman AB(ed), Pathology of Malignant Melanoma. New York, Masson,1981, p 93.

180. Veronesi U, Cascinelli N: Narrow excision (1-cm margin): asafe procedure for thin cutaneous melanoma. Arch Surg126:438, 1991.

181. Balch CM et al: Efficacy of 2-cm surgical margins for interme-diate-thickness melanomas (1 to 4 mm). Ann Surg 218:262,1993.

182. Elder DE et al: Optimal resection margin for cutaneousmalignant melanoma. Plast Reconstr Surg 71:66,1983.

183. Roses DF et al: Local and in-transit metastases followingdefinitive excision for primary cutaneous malignant melanoma.Ann Surg 198:65, 1983.


43

184. Green MS: The changing controversy over surgical resectionmargins for stage I cutaneous melanoma. Mt Sinai J Med 58:341,1991.

185. Olson G: Removal of fascia�—cause of more frequent me-tastases of malignant melanomas of the skin to regional lymphnodes? Cancer 17:1159, 1964.

186. Kenady DE, Brown BW, McBride CM: Excision of underlyingfascia with a primary malignant melanoma: Effect on recur-rence and survival rates. Surgery 92:615, 1982.

187. Urist MM et al: Head and neck melanoma in 534 clinical stageI patients. A prognostic factor analysis and results of surgicaltreatment. Ann Surg 200:769, 1984.

188. Byers RM et al: Malignant melanoma of the external ear:Review of 102 cases. Am J Surg 140:518, 1980.

189. Shah JP et al: Patterns of regional lymph node metastases fromcutaneous melanomas of the head and neck. Am J Surg 162:320,1991.

190. Abramova L, Rarekh J, Irvin WP, et al: Sentinel node biopsy invulvar and vaginal melanoma: presentation of six cases and aliterature review. Ann Surg 9:840, 2002.

191. Dunton DJ, Berd D: Vulvar melanoma, biologically differentfrom other cutaneous melanomas. Lancet 354:2013, 1999.

192. Levit EK, Kagen MH, Scher RK, et al: The ABC rule for clinicaldetection of subungual melanoma. J Am Acad Dermatol 42:269,2000.

193. Papachristou DN, Fortner JG: Melanoma arising under the nail.J Surg Oncol 21:219, 1982.

194. Pack GT, Oropeza R: Subungual melanoma. Surg GynecolObstet 124:571, 1967.

195. Woltering EA et al: Split-thickness skin grafting of the plantarsurface of the foot after wide excision of neoplasms of the skin.Surg Gynecol Obstet 149:229, 1979.

196. Sullivan DC et al: Lymphoscintigraphy in malignant melanoma:99mTc-antimony sulfur colloid. Am J Roentgenol 137:847, 1981.

197. Sherman A, Ter-Pogossian M: Lymph node concentration ofradioactive colloidal gold following interstitial injection. Can-cer 6:1238, 1953.

198. Meyer CM et al: Technetium-99m sulfur colloid cutaneouslymphoscintigraphy in the management of truncal melanoma.Radiology 131:205, 1979.

199. Norman J et al: Redefinition of cutaneous lymphatic drainagewith the use of lymphoscintigraphy for malignant melanoma.Am J Surg 162:432, 1991.

200. Logic JR, Balch CM: Defining lymphatic drainage patterns withcutaneous lymphoscintigraphy. In: Balch CM, Milton GW (eds),Cutaneous Melanoma. Clinical Management and TreatmentResults Worldwide. Philadelphia, Lippincott, 1985, pp 159-170.

201. Rees WV et al: Altered lymphatic drainage following lym-phadenectomy. Cancer 45:3045, 1980.

202. McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymphnode biopsy for melanoma: controversy despite widespreadagreement. J Clin Oncol 19:2851, 2001.

203. Morton DL, Wen DR, Cochran AJ: Management of early-stagemelanoma by intraoperative lymphatic mapping and selectivelymphadenectomy: an alternative to routine lymphadenectomyor �“watch and wait.�” Surg Oncol Clin North Am 1:247, 1992.

204. Morton DL et al: Technical details of intraoperative lymphaticmapping for early stage melanoma. Arch Surg 127:392, 1992.

205. Albertini JJ et al: Intraoperative radiolymphoscintigraphyimproves sentinel lymph node identification in melanomapatients. In press, 1996.

206. Reintgen D et al: The orderly progression of melanoma nodalmetastases. Ann Surg 220:759, 1994.

207. Ross ML, Reintgen DS, Balch CM: Selective lymphadenec-tomy: emerging role for lymphatic mapping and sentinel nodebiopsy in the management of early stage melanoma. Semin SurgOncol 9:219, 1993.

208. Krag D et al: Minimal-access surgery for staging of malignantmelanoma. Arch Surg 130:654, 1995.

209. Ross MI, Reintgen D, Balch CM: Selective lymphadenectomy:emerging role for lymphatic mapping and sentinel node biopsyin the management of early stage melanoma. Semin Surg Oncol9:219, 1993.

210. Reintgen DS, Jakub JW, Pendas S, et al: The staging of malignantmelanoma and the Florida melanoma trial. Ann Surg Oncol 22(3Suppl):186S, Mar 2004.

211. Muller MG, Borgstein PJ, Pijpers R, et al: Reliability of thesentinel node procedure in melanoma patients: analysis offailure after long-term follow-up. Ann Surg Oncol 7:461, 2000.

212. Hettiaratchy SP, Kang N, O�’Toole G, et al: Sentinel lymph nodebiopsy in malignant melanoma: a series of 100 consecutivepatients. Br J Plast Surg 53:559, 2000.

213. Cafiero R, Peressini A, Percivale PL, et al: Selective lymph nodedissection in patients with intermediate thickness melanoma.Anticancer Res 20:497, 2000.

214. Jansen L, Nieweg OE, Petersen JL, et al: Reliability of sentinellymph node biopsy for staging melanoma. Br J Surg 87:484, 2000.

215. Delhocine T, Pierard GE, Gielen JL, et al: Gamma-probedirected lymphatic mapping and sentinel lymphadenectomy inprimary cutaneous melanoma. Dermatology 204:355, 2002.

216. Harlow SP, Krag DN, Ashikaga T, et al: Gamma probe-guidedbiopsy of the sentinel node in malignant melanoma: a multicenterstudy. Melanoma Res 11:45, 2001.

217. Jacobs IA, Chevinsky AH, Swayne LC, et al: Gamma probe-directed lymphatic mapping and sentinel lymphadenectomyinprimary melanoma: reliability of the procedure and analysis offailures after long-term follow-up. J Surg Oncol 77:157, 2001.

218. Porter GA, Ross MI, Perlman RS, et al: How many lymph nodesare enough during sentinel lymphadenectomy for primarymelanoma? Surgery 128:306, 2000.

219. McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymphnode biopsy for melanoma: how many radioactive nodesshould be removed? Ann Surg Oncol 8:192, 2001.

220. Temple CL, Scilley CG, Zabel PL, et al: Sentinel node biopsyin melanoma using technetium-99m rhenium colloid: theLondon experience. Ann Plast Surg 45:491, 2000.

221. Roozendaal GK, de Vries JD, van Poll D, et al: Sentinel nodesoutside lymph node basins in patients with melanoma. Br J Surg88:305, 2001.

222. Neville HL, Andrassy RJ, Lally KP, et al: Lymphatic mapping withsentinel node biopsy in pediatric patients. J Pediatr Surg 35:961,2000.

223. Wagner JD, Corbett L, Park HM, et al: Sentinel lymph nodebiopsy for melanoma: experience with 234 consecutiveprocedures. Plast Reconstr Surg 105:1956, 2000.

224. Bedrosian I, Faries MB, Guerry D 4th, et al: Incidence ofsentinel node metastasis in patients with thin primary mela-noma (=) with vertical growth phase. Ann Surg Oncol 7:262,2000.

225. Nahabedian MY, Tufaro AP, Manson PN: Sentinel lymph nodebiopsy for the T1 (thin) melanoma: is it necessary? Ann PlastSurg 50:601, 2003.

226. Statius Muller MG, van Leeuwen PA, van Diest PJ, et al: Noindication for performing sentinel node biopsy in melanomapatients with a Breslow thickness of less than 0.9mm. MelanomaRes 11:303, 2001.


44

227. Ferrone CR, Panageas KS, Busam K, et al: Multivariate prognos-tic model for patients with thick cutaneous melanoma: impor-tance of sentinel lymph node status. Ann Surg Oncol 9:637,2002.

228. Cherpelis BS, Haddad F, Messina J, et al: Sentinel lymph nodemicrometastasis and other histologic factors that predict out-come in patients with thicker melanomas. J Am Acad Dermatol44:762, 2001.

229. Gershenwald JE, Mansfield PF, Lee JE, Ross MI: Role forlymphatic mapping and sentinel lymph node biopsy in patientswith thick (=4mm) primary melanoma. Ann Surg Oncol 7:160,2000.

230. Gershenwald JE, Berman RS, Lee JE, et al: Regional nodal basiscontrol is not compromised by previous sentinel lymph nodebiopsy in patients with melanoma. Ann Surg Oncol 7:226,2000.

231. Morton DL, Wen DR: Technical details of intraoperativelymphatic mapping for early stage melanoma. Arch Surg127:392, 1992.

232. Rettenbacher L, Koller J, Kassmann H, et al: Reproducibility oflymphoscintigraphy in cutaneous melanoma: can we accu-rately detect the sentinel lymph node by expanding the tracerinjection distance from the tumor site? J Nucl Med 42:424,2001.

233. O�’Toole GA, Hettiaratchy S, Allan R, Powell BW: Aberrantsentinel nodes in malignant melanoma. Br J Plast Surg 53:415,2000.

234. Uren RF, Howman-Giles R, Thompson JF, et al: Interval nodes:the forgotten sentinel nodes in patients with melanoma. ArchSurg 135:1168, 2000.

235. Thompson JF, Hunt JA, Culjak G, et al: Popliteal lymph nodemetastasis from primary cutaneous melanoma. Eur J Surg Oncol26:172, 2000.

236. Nugent N, Hill AD, Casey M, et al: Safety guidelines forradiolocalised sentinel node resection. Irish J Med Sci 170:236,2001.

237. Morton R, Horton PW, Peet DJ, Kissin MW: Quantitativeassessment of the radiation hazards and risks in sentinel nodeprocedures. Br J Radiol 76:117, 2003.

238. Pelosi E, Arena V, Bello M, et al: Radiolabeled localization ofthe sentinel lymph node: dosimetric evaluation in personnelinvolved in the procedure. Tumori 88:87, 2002.

239. Colgan TJ, Booth D, Hendler A, McCready D: Appropriateprocedures for the safe handling and pathologic examinationof technetium-99m-labelled specimens. CMAJ 164:1868,2001.

240. Miner TJ, Shriver CD, Flicek PR, et al: Guidelines for the safeuse of radioactive materials during localization and resectionof the sentinel lymph node. Ann Surg Oncol 6:75, 1999.

241. Roberts AA, Cochran AJ: Pathologic analysis of sentinel lymphnodes in melanoma patients: current and future trends. J SurgOncol 85:152, 2004..

242. Shivers SC, Wang X, Li W, et al: Molecular staging of malignantmelanoma: correlation with clinical outcome. JAMA 280:1410,1998.

243. Li W, Stall A, Shivers SC, et al: Clinical relevance of molecuarstaging for melanoma: comparison of RT-PCR and immunohis-tochemistry staining in sentinel lymph nodes of patients withmelanoma. Ann Surg 231:795, 2000.

244. Shivers SC, Li W, Lin J, et al: The clinical relevance of molecularstaging for melanoma. Recent Results Cancer Res 158:187,2001.

245. McMasters KM, Sober A, Kirkwood JM: Sentinel lymph nodebiopsy and adjuvant therapy for melanoma: evidence revisited.Arch Dermatol 139:99, 2003.

246. Blaheta HJ, Ellwanger U, Schittek B, et al: Examination ofregional lymph nodes by sentinel node biopsy and molecularanalysis provides new staging facilities in primary cutaneousmelanoma. J Invest Dermatol 114:637, 2000.

247. Blaheta HJ, Schittek B, Breuninger H, Garbe C: Detection ofmicrometastasis in sentinel lymph nodes of patients withprimary cutaneous melanoma. Recent Results Cancer Res158:137, 2001.

248. Blaheta HJ, Ellwanger U, Schittek B, et al: Examination ofregional lymph nodes by sentinel node biopsy and molecularanalysis provides new staging facilities in primary cutaneousmelanoma. J Invest Dermatol 114:637, 2000.

249. Blaheta HJ, Sotlar K, Breuninger H, et al: Does intensivehistopathological workup by serial sectioning increase thedetection of lymph node micrometastasis in patients withprimary cutaneous melanoma? Melanoma Res 11:57, 2001.

250. Sheffield MV, Yee H, Dorvault CC, et al: Comparison of fiveantibodies as markers in the diagnosis of melanoma in cytologicpreparations. Am J Clin Pathol 118:930, 2002.

251. Shidham VB, Qi D, Rao RN, et al: Improved immunohis-tochemical evaluation of micrometastases in sentinel lymphnodes of cutaneous melanoma with �‘MCW Melanoma Cocktail�’�— a mixture of monoclonal antibodies to MART-1, melan-A,and tyrosinase. BMC Cancer 3:15, 2003.

252. Jansen L, Loops HS, Nieweg OE, et al: Sentinel node biopsy formelanoma in the head and neck region. Head Neck 22:27,2000.

253. Eicher SA, Clayman GL, Myers JN, Gillenwater AM: A prospec-tive study of intraoperative lymphatic mapping for head andneck cutaneous melanoma. Arch Otolaryngol Head Neck Surg128:241, 2002.

254. Wagner JD, Park HM, Coleman JJ, et al: Cervical sentinel lymphnode biopsy for melanomas of the head and neck and upperthorax. Arch Otolaryngol Head Neck Surg 126:313, 2000.

255. Morton DL et al: Technical details of intraoperative lymphaticmapping for early stage melanoma. Arch Surg 127:392, 1992.

256. Cochran AJ, Wen DR, Morton DL: Management of the regionallymph nodes in patients with cutaneous malignant melanoma.World J Surg 16:214, 1992.

257. Reintgen D et al: The orderly progression of melanoma nodalmetastases. Ann Surg 6:759, 1994.

258. Thompson JF et al: Sentinel lymph node status as an indicatorof the presence of metastatic melanoma in regional lymphnodes. In press, 1996.

259. Robert ME, Wen DR, Cochran AJ: Pathologic evaluation of theregional lymph nodes in malignant melanoma. Semin DiagnPathol 10:102, 1993.

260. Messina JL: Pathologic examination of sentinel lymph nodes.Techniques 2000, July 25, 1996.

261. Reintgen DS, Rapaport DP, Tanabe KK, Ross MI: Lymphaticmapping and sentinel lymphadenectomy. In: Balch CM,Houghton AN, Sober AJ, Soong S-J (eds), Cutaneous Melanoma,3rd ed. St Louis, Quality Med Pub, 1998.

262. Cho KH et al: Immunohistochemical study of melanocytic nevusand malignant melanoma with monoclonal antibodies againstS-100 subunits. Cancer 66:765, 1990.

263. Walts AE, Said JW, Shintaku IP: Cytodiagnosis of malignantmelanoma: immunoperoxidase staining with HMB-45 anti-body as an aid to diagnosis. Am J Clin Pathol 90:77, 1988.


45

264. International Ludwig Breast Cancer Study Group: Prognosticimportance of occult axillary lymph node micrometastases frombreast cancer. Lancet 335:1565, 1990.

265. Cochran AJ, Wen DR, Herschman JR: Occult melanoma inlymph nodes detected by antiserum to S-100 proteins. Int JCancer 34:159, 1984.

266. McCarthy WH, Thompson JF, Uren RF: Invited commentary on�“Minimal-access surgery for staging of malignant melanoma,�”by DN Krag et al. Arch Surg 130:660, 1995.

267. Urist MM et al: Controversies in the treatment of malignantmelanoma. Contemp Surg 32:99, 1988.

268. Balch CM, Urist MM: Melanoma: When to suspect me-tastases�—and what to do. Your Patient and Cancer, June 1983,p 33.

269. Snow H: Melanotic cancerous disease. Lancet 2:872, 1892.270. Milton GW et al: Prophylactic lymph node dissection in clinical

stage I cutaneous malignant melanoma: Results of surgicaltreatment in 1319 patients. Br J Surg 69:108, 1982.

271. Urist MM et al: Head and neck melanoma in 536 clinical stageI patients: A prognostic factors analysis and results of surgicaltreatment. Ann Surg 200:769, 1984.

272. Balch CM: Surgical management of regional lymph nodes incutaneous melanoma. J Am Acad Dermatol 3:511, 1980.

273. McGovern BJ et al: Ulceration and prognosis in cutaneousmalignant melanoma. Histopathology 6:399, 1982.

274. Reintgen DS et al: Efficacy of elective lymph node dissectionin patients with intermediate thickness primary melanoma. AnnSurg 198:379, 1983.

275. Wanebo HJ, Woodruff J, and Fortner JG: Malignant melanomaof the extremities: A clinicopathologic study using levels ofinvasion (microstage). Cancer 35:666, 1975.

276. Morton DL: Current management of malignant melanoma(editorial). Ann Surg 212:123, 1990.

277. Karakousis CP et al: Axillary node dissection in malignantmelanoma. Am J Surg 162:202, 1991.

278. Balch CM, Soong SJ, Milton GW, et al: A comparison ofprognostic factors and surgical results in 1786 patients withlocalized (stage I) melanoma treated in Alabama, USA, and NewSouth Wales, Australia. Ann Surg 196:677, 1982.

279. Balch CM, Soong JS, Bartolucci AA, et al: Efficacy of an electiveregional lymph node dissection of 1-4 mm thick melanomas forpatients 60 years of age and younger. Ann Surg 224:255, 1996.

280. Cox EB, Vollmer RJ, Seigler HF: Melanoma in the SoutheasternUnited States. Experience at the Duke Medical Center. In:Balch CM, Milton GW (eds), Cutaneous Melanoma. ClinicalManagement and Treatment Results Worldwide.. Philadel-phia, Lippincott, 1985, pp 404-418.

281. Morton DL, Roe DJ: Melanoma in the Western United States.Experience with Stage II melanoma at the UCLA MedicalCenter. In: Balch CM, Milton GW (eds), Cutaneous Melanoma.Clinical Management and Treatment Results Worldwide.Philadelphia, Lippincott, 1985, pp 419-430.

282. Bevilacqua RG et al: Axillary dissection in melanoma. Prog-nostic variables in node-positive patients. Ann Surg 212:125,1990.

283. Romero JB, Stefanato CM, Kopf AW, Bart RS: Follow-uprecommendations for patients with Stage I malignant mela-noma. J Dermatol Surg Oncol 20:175, 1994.

284. Schultz S et al: Time to recurrence varies inversely withthickness in clinical stage I cutaneous melanoma. Surg GynecolObstet 171:393, 1990.

285. Jakowatz JG, Meyskens FL Jr: Evaluation and treatment of thepatient with early melanoma. Compr Ther 21:46, 1995.

286. Weiss M et al: Utility of follow-up tests for detecting recurrentdisease in patients with malignant melanomas. JAMA274(21):1703, Dec 6, 1995.

287. Garbe C: A rational approach to the follow-up of melanomapatients. Recent Results Cancer Res 160:205, 2002.

288. Dicker TJ, Kavanagh GM, Herd RM, et al: A rational approachto melanoma follow-up in patients with primary cutaneousmelanoma. Scottish Melanoma Group. Br J Dermatol 140:249,1999.

289. DiFronzo LA, Wanek LA, Morton DL: Earlier diagnosis of secondprimary melanoma confirms the benefits of patient educationand routine postoperative follow-up. Cancer 91:1520, 2001.

290. McCarthy WH, Shaw HM, Thompson JF, et al: Time andfrequency of recurrence of cutaneous stage I malignant mela-noma with guidelines for follow-up study. Surg Gynecol Obstet166:497, 1988.

291. Crowley NJ, Seigler HF: Relationship between disease-freeinterval and survival in patients with recurrent melanoma. ArchSurg 127:1303, 1992.

292. Milton GW et al: Tumour thickness and the site and time of firstrecurrence in cutaneous malignant melanoma (stage I). Br J Surg67:543, 1980.

293. Briele HA et al: Late recurrence of cutaneous melanoma. ArchSurg 118:800, 1983.

294. Griffiths RW, Briggs JC: Long term follow-up in cutaneousmalignant melanoma: The relationship of maximal tumourthickness to disease-free survival, disease recurrence anddeath. Br J Plast Surg 37:507, 1984.

295. Gamel JW, George SL, Edwards MJ, Seigler HF: The long-termclinical course of patients with cutaneous melanoma. Cancer95:1286, 2002.

296. Slingluff CL, Dodge RK, Stanley WE, et al: The annual risk ofmelanoma progression. Cancer 70:1917, 1992.

297. Gadd MA, Coit DG: Recurrence patterns and outcome in 1019patients undergoing axillary or inguinal lymphadenectomy formelanoma. Arch Surg 127:1412, 1992.

298. Borgstein PJ, Meijer S, van Diest PJ: Are locoregional cutaneousmetastases in melanoma predictable? Ann Surg Oncol 6:315,1999.

299. Singletary SE, Balch CM: Recurrent regional metastases andtheir management. In: Balch CM, Houghton AN, Milton DW,et al (eds), Cutaneous Melanoma. 2nd ed. Philadelphia, JBLippincott, 1992.

300. Calabro A, Singletary SE, Balch CM: Patterns of relapse in 1001consecutive patients with melanoma nodal metastases. ArchSurg 124:1051, 1989.

301. Karakousis CP, Balch CM, Urist M, et al: Local recurrence inmalignant melanoma: Long-term results of the multi-institu-tional randomized surgical trial. Ann Surg Oncol 3:446, 1996.

302. Elias EG et al: A clinicopathologic study of prognostic factors incutaneous malignant melanoma. Surg Gynecol Obstet 144:327,1977.

303. Urist MM, Balch CM, Milton GW: Surgical Management of thePrimary Melanoma. In: Balch CM, Milton GW (eds), CutaneousMelanoma. Clinical Management and Treatment ResultsWorldwide. Philadelphia, Lippincott, 1985.

304. Blum A, Schlagenhauff B, Stroebel W, et al: Ultrasoundexamination of regional lymph nodes significantly improvesearly detection of locoregional metastases during the follow-up of patients with cutaneous melanoma: results of a prospec-tive study of 1288 patients. Cancer 88:2534, 2000.

305. Crowley NJ and Seigler HF: Late recurrence of malignantmelanoma. Analysis of 168 patients. Ann Surg 212:173, 1990.


46

306. Gamel JW, George SL, Edwards MJ, Seigler HF: The long-termclinical course of patients with cutaneous melanoma. Cancer95:1286, 2002.

307. Chao C, Wong SL, Ross MI: Patterns of early recurrence aftersentinel lymph node biopsy for melanoma. Am J Surg 184:520,2002.

308. Clary BM, Brady MS, Lewis JJ, Coit DG: Sentinel lymph nodebiopsy in the management of patients with primary cutane-ous melanoma: review of a large single institutional expe-rience with an emphasis on recurrence. Ann Surg 233:250,2001.

309. Balch CM, Soong SJ, Murad TM, et al: A multifactorialanalysis of melanoma. IV. Prognostic factors in 200 mela-noma patients with distant metastases (stage III). J Clin Oncol1:126, 1983.

310. Barth A, Wanek LA, Morton DL: Prognostic factors in 1512melanoma patients with distant metastases. J Am Coll Surg181:193, 1995.

311. Amr MH, Al-Sarraf M, Vaitkevicius VK: Clinical presentation,natural history and prognostic factors in advanced malignantmelanoma. Surg Gynecol Obstet 149:687, 1979.

312. Budman DR, Camacho E, and Wittes, RE: The current causesof death in patients with malignant melanoma. Eur J Cancer14:327, 1978.

313. Das Gupta T and Brasfiels, R: Metastatic melanoma: Aclinicopathological study. Cancer 17:1323, 1964.

314. Einhorn LH et al: Prognostic correlations and response totreatment in advanced metastatic malignant melanoma. CancerRes 34:1995, 1974.

315. Meyer JE, Stolbach L: Pretreatment radiographic evaluation ofpatients with malignant melanoma. Cancer 42:125, 1978.

316. Patel JK et al: Metastatic pattern of malignant melanoma: Astudy of 126 autopsy cases. Am J Surg 135:807, 1978.

317. Stehlin JS Jr, Hills WJ, Rufino C: Disseminated melanoma:Biologic behavior and treatment. Arch Surg 94:495, 1967.

318. Roth JA et al: Radionuclide photoscanning: Usefulness inpreoperative evaluation of melanoma patients. Arch Surg110:1211, 1975.

319. Finck SJ, Giuliano AE, Morton DL: LDH and melanoma. Cancer51:840, 1983.

320. de la Monte SM, Moore, GW, Hutchins GM: Patterneddistribution of metastases from malignant melanoma in hu-mans. Cancer Res 43:3427, 1983.

321. Huffman TA, Sterin WK: Ten-year survival with multiplemetastatic malignant melanoma: Primary site unknown. ArchSurg 106:234, 1973.

322. Habermalz HJ, Fisher JJ: Radiation therapy of malignantmalanoma: Experience with high individual treatment doses.Cancer 38:2258, 1976.

323. Strauss A et al: Radiation therapy of malignant melanomas: Anevaluation of clinically used fractionation schemes. Cancer47:1262, 1981.

324. Storm FK et al: Thermochemotherapy for melanoma metastesesin liver. Cancer 49:1243, 1982.

325. Kim JH, Hahan EW, Ahmed SA: Combination hyperthermia andradiation therapy for malignant melanoma. Cancer 50:478,1982.

326. Waters RA, Clement RM, Thomas JM: Carbon dioxide laserablation of cutaneous metastases from malignant melanoma. BrJ Surg 78:493, 1991.

327. Gorenstein LA et al: Improved survival after resection ofpulmonary metastases from malignant melanoma. Ann ThoracSurg 52:204, 1991.

328. Huffman TA, Sterin WK: Ten-year survival with multiplemetastatic malignant melanoma, primary site unknown. ArchSurg 106:234, 1973.

329. Baab GH, McBride CM: Malignant melanoma: the patient withan unknown site of primary origin. Arch Surg 110:896, 1975.

330. Giuliano AE, Moseley HS, Morton DL: Clinical aspects ofunknown primary melanoma. Ann Surg 191:98, 1980.

331. Reintgen DS et al: Metastatic malignant melanoma with anunknown primary. Surg Gynecol Obstet 156:335, 1983.

332. Chang P, Knapper WH: Metastatic melanoma of unknownprimary. Cancer 49:1106, 1982.

333. Santini H, Byers RM, Wolf PF: Melanoma metastatic to cervicaland parotid nodes from an unknown primary site. Am J Surg150:510, 1985.

334. Rhodes AR, Weinstock MA, Fitzpatrick TB, et al: Risk factorsfor cutaneous melanoma. A practical method for recognizingpredisposed individuals. JAMA 258:3146, 1987.

335. Sober AJ, Burstein JM: Precursors to skin cancer. Cancer75:645, 1995.

336. Kaplan EN: The risk of malignancy in large congenital nevi. PlastReconstr Surg 53:421, 1974.

337. Pack GT, Davis J: The pigmented mole. Postgrad Med 27:370,1960.

338. Mark CJ et al: Congenital melanocytic nevi of the small andgarment type. Hum Pathol 4:395, 1973.

339. Moss ALH, Briggs JC: Cutaneous malignant melanoma in theyoung. Br J Plast Surg 39:537, 1986.

340. Moss ALH: Congenital �“giant�” naevus: A preliminary reportof a new surgical approach. Br J Plast Surg 40:410, 1987.

341. Kopf AW, Bart RS, Hennessey P: Congenital nevocytic nevi andmalignant melanomas. J Am Acad Dermatol 1:123, 1979.

342. Greeley PW, Middleton AG, Curtin JW: Incidence of malig-nancy in giant pigmented nevi. Plast Reconstr Surg 36:26, 1965.

343. Kaplan EM: The risk of malignancy in large congenital nevi. PlastReconstr Surg 53:421, 1972.

344. Solomon LM: The management of congenital melanocytic nevi.Arch Dermatol 116:1017, 1980.

345. Rhodes AR, Melski JW: Small congenital nevocellular nevi andthe risk of cutaneous melanoma. J Pediatr 100:219, 1982.

346. Pers M: Naevus pigmentosus giganticus. Ugeskr Laeger125:613, 1963.

347. Ishii N et al: Congenital malignant melanoma. Br J Dermatol124:492, 1991.

348. Ceballos PI, Maldonado RR, Mihm MC: Melanoma in children.N Engl J Med 332:656, 1995.

349. O�’Lerman RI et al: Malignant melanoma of childhood: Aclinicopathologic study and a report of 12 cases. Cancer 25:436,1970.

350. Trozak DJ, Rowland WD, Hu F: Metastatic malignant melanomain prepubertal children. Pediatrics 55:191, 1975.

351. Skov-Jensen T, Hastrup J, Lambrethsen E: Malignant melanomain children. Cancer 19:620, 1966.

352. Boddie AW Jr, Smith JL Jr, McBride CM: Malignant melanomain children and young adults: Effect of diagnostic criteria onstaging and end results. South Med J 71:1074, 1978.

353. Hamre MR, Chuba P, Bakhshi S: Cutaneous melanoma inchildhood and adolescence. Pediatr Hematol Oncol 19:309,2002.

354. Bader JL, Li FP, Olmstead PM: Childhood malignant melanoma:incidence and etiology. Am J Pediatr Hematol Oncol 7:341,1985.

355. Slingluff CL Jr et al: Malignant melanoma arising duringpregnancy. A study of 100 patients. Ann Surg 211:552, 1990.


47

356. Shiu MH, Schottenfeld D, McLean B, et al: Adverse effect ofpregnancy on melanoma. Cancer 37:181, 1976.

357. Wong JH, Sterns EE, Kopald KH, et al: Prognostic significanceof pregnancy in stage I melanoma. Arch Surg 124:1227, 1989.

358. Harwood AR: Conventional fractionated radiotherapy for 51patients with lentigo maligna and lentigo maligna melanoma.Int J Radiat Oncol Biol Phys 9:1019, 1983.

359. Harwood AR: Conventional radiotherapy in the treatment oflentigo maligna and lentigo maligna melanoma. J Am AcadDermatol 6:310, 1982.

360. Harwood AR: Melanomas of the head and neck. J Otolaryngol12:64, 1983.

361. Harwood AR, Dancuart F, Fitzpatrick PJ, Brown T: Radiotherapyin nonlentiginous melanoma of the head and neck. Cancer48:2599, 1981.

362. Benediktsdottir K et al: Pre-operative irradiation of malignantmelanoma. A multifactorial analysis of survival. Acta RadiolOncol 23:315, 1984.

363. Ang KK et al: Regional radiotherapy as adjuvant treatment forhead and neck malignant melanoma. Preliminary results. ArchOtolaryngol Head Neck Surg 116:169, 1990.

364. Johanson CR, Harwood AR, Cummings BJ, Quirt I: 0�–7�–21radiotherapy in nodular melanoma. Cancer 51:226, 1983.

365. Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy formetastatic malignant melanoma: brain metastases, bone me-tastases, and spinal cord compression. Int J Radiat Oncol BiolPhys 15:859, 1988.

366. Salmi R, Holsti P: Effects of roentgen irradiation on humanmelanoma metastases in the skin. Acta Oncologica 26:37,1987.

367. Harwood AR: Conventional fractionated radiotherapy for 51patients with lentigo maligna and lentigo maligna melanoma.Int J Radiat Oncol Biol Phys 9:1019, 1983.

368. Walsh NMG, Roberts JT, Orr W, et al: Desmoplastic malignantmelanoma. Arch Pathol Lab Med 112:922, 1988.

369. Harwood AR, Cummings BJ: Radiotherapy for malignantmelanoma: a re-appraisal. Cancer Treat Rev 8:271, 1981.

370. Carella RJ et al: Value of radiation therapy in the managementof patients with cerebral metastases from malignant melanoma.Cancer 45:679, 1980.

371. Cooper JS: Radiotherapy of malignant melanoma. DermatolClin 3(2):341, 1985.

372. Cooper JS, Carella R: Radiotherapy of intracerebral metastaticmalignant melanoma. Radiology 134:735, 1980.

373. Schabel FM Jr: Concepts for systemic treatment ofmicrometastases. Cancer 35:15, 1975.

374. Schabel FM Jr: Rationale for adjuvant chemotherapy. Cancer39:2875, 1977.

375. Mastrangelo MJ, Bellet RE, Kane MJ, Berd D: Chemotherapyof melanoma. In: Perry MC (ed), Chemotherapy Source Book.Baltimore, Williams & Wilkins, 1992. Ch 50, pp 886-907.

376. Meyskens FL Jr, Loescher L, Serokman R, Moon TE: Potentialuses of biological response modifiers (BRM) in the adjuvanttreatment of melanoma and results from a trial of BCG+/�–vitamin A. Adjuv Ther Cancer 4:583, 1984.

377. Colmerauer ME, Koziol JA, Pilch YH: Enhancement of metasta-sis development by BCG-immunotherapy. J Surg Oncol 15:235,1980.

378. Costanzi JJ: Chemotherapy and BCG in the treatment ofdisseminated malignant melanoma. In: Terry WD, WindhorstD (eds), Immunotherrapy of Cancer: Present Status of Trialsin Man. New York, Raven Press, 1978, pp 87-93.

379. Ishibashi T et al: Inhibition and promotion of tumor growth byBCG. Evidence for stimulation of humoral enhancing factors byBCG. Int J Cancer 21:67, 1978.

380. Levy NL, Mahaley MS, Day ED: Serum-mediated blocking ofcell-mediated antitumor immunity in a melanoma patient:association with BCG immunotherapy and clinical deteriora-tion. Int J Cancer 10:244, 1972.

381. McIllmurray MB et al: Controlled trial of active immunotherapyin management of stage II B malignant melanoma. Br J Med2:540, 1977.

382. Piessens WF, Lachapelle FL, Legros N, Heuson JC: Facilitationof rat mammary tumor growth by BCG. Nature 228:1210, 1970.

383. Hedley DW, McElwain TJ, Currie GA: Specific active immu-notherapy does not prolong survival in surgically treatedpatients with stage II-B malignant melanoma and may promoteearly recurrence. Br J Cancer 37:491, 1978.

384. Gershon RK, Metzler CM: Regulation of the immune response.In: Towney JJ, Good RA (eds), The Immunopathology ofLymphoreticular Neoplasms. New York, Plenum Press, 1979,pp 23-51.

385. Patt YZ, Hersh EM, Reuben J, et al: The need for immuneevaluation prior to Thymosin-containing chemoimmunotherapyfor melanoma. Cancer Immunol Immunopathol 7:131, 1979.

386. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferonalfa-2b adjuvant therapy of high-risk resected cutaneous mela-noma: the Eastern Cooperative Oncology Group Trial EST1684. J Clin Oncol 14:7, 1996.

387. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High- and low-doseinterferon alfa-2b in high-risk melanoma: first analysis ofintergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444,2000.

388. Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose inter-feron alfa-2b significantly prolongs relapse-free and overallsurvival compared with the GM2-KLH/QS-21 vaccine in pa-tients with resected stage IIB-III melanoma: results of inter-group trial E1694/S9512/C509801. J Clin Oncol 19:2370,2001.

389. Dubois RW, Swetter SM, Atkins M, et al: Developing indica-tions for the use of sentinel lymph node biopsy and adjuvanthigh-dose interferon alfa-2b in melanoma. Arch Dermatol137:1217, 2001.

390. Reintgen D, Cruse CW, Glass F, Fenske N: In support of sentinelnode biopsy as a standard of care for patients with malignantmelanoma. Dermatol Surg 26:1070, 2000.

391. Kim CJ, Dessureault S, Gabrilovich D, et al: Immunotherapy formelanoma. Cancer Control 9:22, 2002.

392. Seeber A, Binder M, Steiner A, et al: Treatment of metastaticmalignant melanoma with dacarbazine plus fotemustine. EurJ Cancer 34:2129, 1998.

393. Daponte A, Ascierto PA, Gravina A, et al: Cisplatin, dacarbazine,and fotemustine plus interferon alfa in patients with advancedmalignant melanoma. A multicenter phase II study of the ItalianCooperative Oncology Group. Cancer 89:2630, 2000.

394. Bajetta E, Del Vecchio M, Bernard-Marty C, et al: Metastaticmelanoma: chemotherapy. Semin Oncol 29:427, 2002.

395. Rossi CR, Lejeune FJ, Pontes L, et al: Phase I-II study on isolationantiblastic fotemustine perfusion after dacarbazine chemo-sensitization for advanced melanoma of the extremities. Mela-noma Res 13:293, 2003.

396. Avril MF, Aamdal S, Grob JJ, et al: Fotemustine compared withdacarbazine in patients with disseminated malignant mela-noma: a phase III study. J Clin Oncol 22:1118, 2004.


48

Gershenwald JE, Fischer D, Buzaid AC: Clinical classification and staging. Clin Plast Surg 27(3):361,2000.

Hofmann U, Szedlak M, Rittgen W, et al: Primary staging and follow-up in melanoma patients �—monocenter evaluation of methods, costs and patient survival. Br J Cancer 87:151, 2002.

Sheffield MV, Yee H, Dorvault CC, et al: Comparison of five antibodies as markers in the diagnosis ofmelanoma in cytologic preparations. Am J Clin Pathol 118:930, 2002.

Intenzo CM, Kim SM, Patel JI, et al: Lymphoscintigraphy in cutaneous melanoma: a total body atlas ofsentinel node mapping. Radiographics 22:491, 2002.

Kalady MF, White RR, Johnson JL, et al: Thin melanomas. Predictive lethal characteristics from a 30-yearclinical experience. Ann Surg 238:528, 2003.

McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymph node biopsy for melanoma: controversydespite widespread agreement. J Clin Oncol 19:2851, 2001.

Borgstein PJ, Meijer S, van Diest PJ: Are locoregional cutaneous metastases in melanoma predictable?Ann Surg Oncol 6:315, 1999.

Gershenwald JE, Mansfield PF, Lee JE, Ross MI: Role for lymphatic mapping and sentinel lymph nodebiopsy in patients with thick (=4 mm) primary melanoma. Ann Surg Oncol 7:160, 2000.

Kim CJ, Reintgen DS, Balch CM, for the AJCC Melanoma Staging Committee: The new melanomastaging system. Cancer Control 9:9, 2002.

Statius Muller MG, Borgstein PJ, Pijpers R, et al: Reliability of the sentinel node procedure in melanomapatients: analysis of failures after long-term follow-up. Ann Surg Oncol 7:461, 2000.

DiFronzo LA, Wanek LA, Elashoff R, Morton DL: Increased incidence of second primary melanoma inpatients with a previous cutaneous melanoma. Ann Surg Oncol 6:705, 1999.

Dubois RW, Swetter SM, Atkins M, et al: Developing indications for the use of sentinel lymph nodebiopsy and adjuvant high-dose interferon alfa-2b in melanoma. Arch Dermatol 137:1217, 2001.

Sotomayor MG, Yu H, Antonia S, et al: Advances in gene therapy for malignant melanoma. CancerControl 9:39, 2002.

Kim CJ, Dessureault S, Gabrilovich D, et al: Immunotherapy for melanoma. Cancer Control 9:22, 2002.

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