Malignant Melanoma - Professional · PDF fileMalignant Melanoma Raymond L. Barnhill, M.D. ... or malignant, (5) the idea that ... management. Melanoma of Intermittently

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C H A P T E R 1 1

Malignant Melanoma

Raymond L. Barnhill, M.D.Martin C. Mihm, Jr., M.D.George Elgart, M.D.

INTRODUCTION

Malignant melanoma of the skin isincreasingly an important global healthproblem. The reasons for this are imme-diately apparent: (1) The rate of incidenceof cutaneous melanoma continues torise almost inexorably in populations ofEuropean origin worldwide. (2) Diagnosisof melanoma at an early stage is almostcurable. (3) There is currently no effectivetreatment for advanced melanoma. (4)Probably a large proportion of melanomascan be ascribed to a single (modifiable)risk factor—sun exposure. (5) It has notbeen established whether medical inter-vention of any kind influences the out-come in the case of melanoma. Majorinitiatives in recent years have concen-trated on education about sun avoid-ance, the importance of skin awarenessand skin examination, and the screeningof populations at high risk for melanoma.However, it is unclear whether any of thelatter measures have had any significantinfluence on mortality from melanoma.

This chapter discusses the mostsalient clinical and histologic features ofcutaneous melanoma and their differen-tial diagnosis.

CLASSIFICATION AND

ETIOLOGIC CONSIDERATIONS

for many years.1–6 One idea behind such aclassification was that particular intraepi-dermal patterns (also termed radial or hor-izontal growth phases) might correlatewith differences in etiology and possiblyprognosis. Four clinicopathologic sub-types of melanoma were thus proposed(Table 11-1).7,8–14 Nevertheless, an objec-tive assessment of the classification ofmelanoma according to intraepidermalpattern or growth phase is that such aclassification is in many respects artifi-cial.8,15,16 The reasons for this view are: (1)the tremendous morphologic heterogene-ity of melanoma, (2) morphologic pat-terns may correlate with anatomical site,(3) the intraepithelial components ofmany melanoma are not easily classified(because of overlapping features) and clas-sification is not reproducible,17 (4) someintraepithelial components are difficult torecognize as either clearly benign, i.e., apotential precursor such as an atypicalnevus, or malignant, (5) the idea thatnodular melanomas develop as de novoinvasive tumors without any initialintraepithelial melanocytic proliferation13

is theoretically possible but has not beenproved, and (6) after adjustment forBreslow thickness, the pattern of theintraepidermal component has no effecton prognosis.

However, the idea that melanoma isone disease also appears oversimplified,and recent evidence supports the long-standing hypothesis that melanomasindeed seem to have distinct develop-mental pathways that are related toanatomic site, degree of sun exposure,genetics, and potentially other factors.18

MAJOR FORMS OF MELANOMA

Table 11-1

Historical Classification of Malignant

Melanoma

PRESENCE OF RADIAL GROWTH PHASE

• Superficial spreading

• Lentigo maligna

• Acral lentiginous

• Unclassified

ABSENCE OF RADIAL GROWTH PHASE

• Nodular melanoma

BOX 11-3 Summary

• Melanomas of intermittently sun-exposed

skin are found in young adults. It has an

BOX 11-2 Summary

• Melanoma is thought to be one disease,

but this may be an oversimplification

because melanomas have distinct devel-

opmental pathways that are related to

anatomic site, degree of sun exposure,

genetics, and potentially other factors.

BOX 11-1 Overview

• Cutaneous melanoma has become a

major health concern among Caucasian

populations worldwide over the past three

or more decades.

• The principal etiologic factors responsible

for the rapid increase in melanoma inci-

dence rates appear to be most likely

environmental and behavioral, due to

increased recreational sun exposure.

• However, melanoma also seems to have

distinct developmental pathways that are

related to genetic and other host factors

interacting with the environment.

• The major forms of melanoma include

those developing in chronically sun-

exposed skin, intermittently sun-exposed

skin, and sun-protected or completely

shielded sites.

• Unusual variants of melanoma meriting

attention because of difficulty of diagnosis

include amelanotic melanoma, desmo-

plastic-neurotropic melanoma, “nevoid”

melanoma, small-cell melanoma, and

melanoma resembling or developing in

cellular blue nevus.

• The principal clinical criteria for melanoma

include the ABCDEs: Asymmetry, irregular

and notched orders, irregular or “varie-

gated” or jet black Color, D iameter often

�5–6 mm, Elevation from the Bskin

surface, a persistently Evolving lesion,

ulceration, and bleeding.

• Histopathologic diagnosis usually involves

several criteria including asymmetry,

diameter �5–6 mm, organizational

aberrations including pagetoid melanocy-

tosis, prominent confluence and high

cellular density of melanocytes, diminished

or absent maturation, effacement or

ulceration of epidermis, significant cyto-

logic atypia, and mitoses in the dermal

component.

• Lesions suspicious for melanoma should

be biopsied by excision, if possible, for

histopathologic examination.

• The principal prognostic factors are the

stages of melanoma, e.g., localized pri-

mary melanoma, regional lymph node or

distant metastatic disease and Breslow

thickness for localized melanomas.

• Surgery is the only effective therapy at

present and may be virtually curative for

many melanomas measuring less than 1

mm and without other adverse prognostic

indicators.

• There is no objective evidence that any

medical intervention influences the course

of advanced melanoma (or perhaps

melanoma at any stage).

Because almost all melanomas are initiallylocalized to squamous epithelium forsome period of time, a classification ofmelanoma based on the presence orabsence and patterns of intraepidermalinvolvement was described and utilized

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Continued research is needed to validatedifferences among the latter variants andto identify clearly avenues for preven-tive and therapeutic intervention thathave real impact on patient sufferingand mortality from melanoma. Suchsubstantiation of unique differencesamong melanomas that provide thebasis for meaningful intervention is theonly rationale for the continued use ofany classification of melanoma. Other-wise, there is no real rationale for re-cording descriptive information inpathology reports other than informa-tion such as Breslow thickness and mar-gins, etc. that has been validated to havea direct bearing on prognosis and patientmanagement.

Melanoma of Intermittently Sun-Exposed Skin

This group of melanomas which accountfor the great majority of melanomas inCaucasians often (but not always) havean adjacent pagetoid intraepidermalcomponent, a frequent association withBRAF mutations and melanocytic nevi(also with BRAF mutations), and devel-opment in relatively young adults.18

Lentigo Maligna (Solar) Melanoma

Melanomas of chronic sun-damaged skinare distinct from other forms of mela-noma irrespective of intraepidermal pat-tern of melanocytic proliferation becauseof their strong correlation with cumula-tive sunlight exposure, onset in olderpersons, uncommon association withmelanocytic nevi, and finally, the patternof genomic aberrations. This group ofmelanomas seems to have significantly

fewer chromosomal aberrations as com-pared to acral and mucosal melanomas,in general an absence of BRAF muta-tions, frequent gains in CCND1 andregions of chromosome 22, and lossesfrom chromosome 4q.18

Acral (and Mucosal) Melanoma

These melanomas also appear distinctivesince they develop in relatively or com-pletely sun-protected sites, have infre-quent BRAF mutations, and show greaternumbers of chromosomal aberrations ascompared to the latter melanomas.18

Nodular Melanoma

This descriptive term refers to mela-nomas with no adjacent intraepithelialcomponent and is thought to simplyindicate a heterogenous group of mela-noma showing rapid tumor progressionirrespective of intraepithelial pattern orlocation.13,18

GENERAL CLINICAL FEATURES

OF CUTANEOUS MELANOMA

In general, cutaneous melanoma mostcommonly affects adult Caucasians andis rarely observed before puberty.19,20

Men and women are equally affectedalthough some European studies havesuggested a higher incidence in females.Patients are diagnosed with melanomamost commonly in the fourth throughseventh decades. The most commonsites include the trunk (back) followedby the upper extremities and head andneck for men and the lower extremitiesfollowed by the back, upper extremities,and head and neck for women. Grossmorphologic features of melanoma in-clude size often �1 cm (range 2 mm to�15 cm), irregular or notched borders,asymmetry, complexity of color includinga variable admixture of tan, brown, blue,black, red, pink, gray, and white, andulceration and bleeding (Fig. 11-1).19,20

Early melanomas especially those in-volving chronic sun-exposed and acralsites may be completely flat but withprogression usually develop a papular ornodular component (Figs. 11-2 to 11-4).Melanomas lacking pigment (amelan-otic melanoma) and those resemblingkeratoses are particularly difficult todiagnose without a high index of suspi-cion (Fig. 11-5). Acral melanoma,although accounting for 5% or less ofmelanomas among Caucasians, is the

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diagnose without a high index of suspicion

• Acral melanoma is the most frequent form

of melanoma among Asians, Africans, and

other ethnic groups of color.

• Subungual melanoma (SM) is a distinctive

variant of acral melanoma that most often

involves the nail bed of the great toe or

thumb.

� FIGURE 11-1 Melanoma of intermittently sun-exposed skin. Note the asymmetry, large

diameter, irregular borders, and complex coloration.

adjacent pagetoid intraepidermal compo-

nent and a frequent association with

BRAF mutations.

• Lentigo maligna (solar) melanoma has a

strong correlation with sunlight exposure,

onset in older persons, uncommon asso-

ciation with melanocytic nevi and a pat-

tern of genomic aberrations.

• Acral and mucosal melanomas develop

in relatively or completely sun-protected

sites, have infrequent BRAF mutations,

and show greater numbers of chromoso-

mal aberrations.

• Nodular melanoma is a descriptive term

that refers to melanomas with no adja-

cent intraepithelial component. This is

thought to indicate simply a heteroge-

nous group of melanoma showing rapid

tumor progression.

BOX 11-4 Summary

• Most commonly affects adult Caucasians,

and the incidence is essentially equal

between men and women.

• The most common sites that melanomas

are found include the trunk (back) fol-

lowed by the upper extremities and head

and neck for men; and the lower extremi-

ties followed by the back, upper extremi-

ties, and head and neck for women.

• Amelanotic melanoma and those resem-

bling keratoses are particularly difficult to


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most frequent form of melanoma amongAsians, Africans, and other ethnic groupsof color (Fig. 11-3).7,13,18,19 However,approximately the same incidence of acralmelanoma occurs in all ethnic groups.Subungual melanoma (SM) is a distinctivevariant of acral melanoma that most ofteninvolves the nail bed of the great toe orthumb21–25 where it commonly presentsas an ulcerated tumor.22 However, the ini-tial manifestations may include a longitu-dinal pigmented band of the nail plate(frequently �9 mm wide) or a mass underthe nail plate (Fig. 11-6).25 A useful clinicalsign is pigmentation extending from thenail onto the surrounding periungual skin(Hutchinson’s sign).

GENERAL HISTOPATHOLOGIC

FEATURES

� FIGURE 11-2 Solar melanoma (melanoma of chronically sun-exposed skin). This lesion

involves the cheek. The lesion has macular and papular components, asymmetry, large diam-

eter, irregular borders, and complex coloration.

� FIGURE 11-3 Acral melanoma. This lesion demonstrates macular and large nodular

components.

� FIGURE 11-4 ”Nodular” melanoma. Melanoma on the scalp, without demonstrable sur-

rounding component. Melanomas with this configuration may develop on any anatomic site

with or without a clearly identifiable adjacent intraepithelial proliferation of melanoma.

Intraepithelial Component

Almost all melanomas begin as a prolif-eration of melanocytes initially confinedto the epidermis (Fig. 11-7).1–16 The lat-ter proliferation may develop with orwithout a detectable melanocytic nevus.Estimates of the frequency of melanomasdeveloping in continuity with a nevus ofany kind vary widely. Approximately athird of melanomas have nevus rem-nants. The duration of this intraepider-mal phase ranges from months to manyyears, during which these proliferativelesions show progressive degrees ofarchitectural and cytologic atypicality.

Increasing cytologic atypia of mel-anocytes accompanies the aberrantarchitectural appearance. The melano-cytes vary in degree of atypia and theproportion of cells with nuclear atypia.However, atypical melanocytes usuallyhave enlarged nuclei that exhibit varia-tion in nuclear shapes and chromatin

BOX 11-5 Summary

• Essentially all melanomas begin as a pro-

liferation of melanocytes initially confined

to the epidermis.

• Increasing cytologic atypia of melanocytes

accompanies the aberrant architectural

appearance of melanomas.

• After the period of intraepidermal prolifer-

ation, there is often invasion of the papil-

lary dermis, primarily as single cells and

small aggregates of cells.

• Breslow thickness (in mm) of melanoma is

one of the most important factors deter-

mining prognosis and theraphy.

• Melanomas with prominent invasive compo-

nents may display polypoid morphologies.


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patterns, and may have large nucleoli.Thickening of nuclear membranes andirregular nuclear contours are also char-acteristic features. The cytoplasm ofsuch melanocytes may be abundantwith a pink granular quality, may con-tain granular or finely divided (“dusty”)melanin (Figs.11-7 to 11-9), or show re-traction, resulting in a clear space aroundthe nuclei. Melanocytes with scant cyto-plasm typically have high nuclear-to-cytoplasmic ratios. Such proliferationshave been variously labeled atypicalmelanocytic hyperplasia, premalignantmelanosis, melanocytic dysplasia, and“pagetoid melanocytic proliferation,” aswell as melanoma in situ.26,27

Invasive Melanoma

After the period of intraepidermal prolif-eration, there is often invasion of thepapillary dermis, primarily as single cellsand small aggregates of cells (Table 11-2).Microinvasive melanoma is also remark-able for a striking host response in thepapillary dermis, typically a dense cellu-lar infiltrate of lymphocytes and mono-cyte/macrophages. Presumably, in con-sequence of this host reaction, regression,often focal, is common in up to 50% ofmicroinvasive melanomas (see the fol-lowing sections).28

The term “vertical growth phase”(“VGP”) has been used by some to describethe proliferation of invasive melanomacells as cohesive aggregates (Fig. 11-10).29,30

It has been postulated that the so-calledVGP may signify the onset of the metasta-tic phenotype since it may be indistin-guishable from metastatic melanoma.30

However, melanomas lacking the mor-phology of the VGP have resulted inmetastases.

Melanomas with prominent invasivecomponents may display polypoid mor-phologies such that more than half (ses-sile forms) or virtually all (pedunculatedforms) of the tumor is above the epider-mal surface. Amelanotic variants alsomay develop in any type of melanoma.

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� FIGURE 11-5 Amelanotic “nodular” melanoma. This type of lesion may

develop at any location and is indistinguishable from metastatic melanoma.

� FIGURE 11-6 Subungual melanoma. Note broad irregularly pigmented band involving nail

plate. Pigmentation extends onto periungual skin (Hutchinson’s sign).

Table 11-2

Anatomic Levels of Invasion

Level I Entirely intraepidermal; melanoma

in situ

Level II Microinvasive into papillary dermis

Level III Expansion of papillary dermis by

cohesive cellular nodule or

plaque (but confined to papil-

lary dermis)

Level IV Invasion of reticular dermis

Level V Invasion of subcutaneous fat


• Clinical Features• In general onset after puberty but all ages

affected• Most frequent ages 30–70 years• Caucasians affected much greater than

Africans, Asians• Women � men• Most common sites are lower extremities

and trunk of women and• Trunk (back) of men• Pain, pruritus• Size often �1 cm (range 2 mm to �15 cm)• Initially macular, later stages may be

papular and nodular

Pagetoid spread (transepidermal migra-tion of cells in a manner analogous toPaget’s disease of the breast)1–9,31 refers tosingle cells and small groups of cells arerandomly scattered throughout the epi-dermis reaching the granular layer andstratum corneum. The melanoma cellsoften have an epithelioid cell appearance,i.e., they resemble epithelial cells becauseof abundant cytoplasm that is usuallygranular and eosinophilic or contains144

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MELANOMAS OF

INTERMITTENTLY SUN

EXPOSED SKIN

� FIGURE 11-7 Melanoma of intermittently sun-exposed skin (pagetoid melanoma)

Scanning magnification shows pagetoid spread of epithelioid melanoma cells.


Higher magnification demonstrating pagetoid pattern and the beginnings of dermal

invasion by melanoma cells.

BOX 11-6 Summary

• Asymmetrical• Irregular and often notched borders• Complexity and variation in color often

with admixtures of tan, brown, black, blue,

gray, white, red• May be entirely skin-colored (amelanotic)

or black• Ulceration and bleeding may be present

• Histopathologic Criteria• Architecture

➤ Asymmetry

➤ Heterogeneity of lesion

➤ Large size (�6 mm) but many exceptions

➤ Poor circumscription of proliferation

➤ Melanin not uniformly distributed

➤ Organizational abnormalities of intraepi-

dermal component

➤ Pagetoid spread

– Upward migration of melanocytes in

random pattern, single cells predomi-

nate over nests

– Cells often reach granular and corni-

fied layers

➤ Lentiginous melanocytic proliferation

– Melanocytes reach confluence

– Nesting of melanocytes (sun-dam-

aged skin)

– Melanocytes not equidistant

– Proliferation of melanocytes along

adnexal epithelium

➤ Nested pattern

– Variation in size, shape, placement of

nests

– Nests replace large portions of

squamous epithelium

– Diminished cohesiveness of cells in

nests

– Confluence of nests

➤ Loss of epidermal rete pattern

(effacement)

➤ Mononuclear cell infiltrates, often

band-like

➤ Fibroplasia of papillary dermis

➤ Regression frequently present• Cytology

➤ Nuclear changes

– Majority of melanocytes uniformly

atypical

– Nuclear enlargement

– Nuclear pleomorphism (variation in

sizes and shapes)

– Nuclear hyperchromasia with coarse

chromatin

– One or more prominent nucleoli

➤ Cytoplasmic changes

– of cytoplasm

➤ Mitoses (in dermal component)

➤ Atypical mitoses

➤ Necrotic cells

• Invasive Component in Dermis• Architecture

➤ Tumefactive cellular aggregates

➤ Pushing, expanding pattern without

regard for stroma

➤ Hypercellularity

➤ Less host response• Cytology

➤ As above

➤ Increased nuclear to cytoplasmic

ratios

➤ Mitoses in dermal component

➤ Atypical mitoses

➤ Necrotic cells


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finely divided (“dusty”) melanin (Figs. 11-7 to 11-9). The cells are usually larger than(sometimes two to three times) the sur-rounding keratinocytes. The epidermismay be hyperplastic, the epidermal retepattern is often lost (effaced), and the sur-face of the epidermis abutting the intraepi-dermal tumor may exhibit a characteristi-cally scalloped contour. Melanoma cellsoften proliferate as variably sized nestsand horizontally disposed aggregatesimmediately underneath this scallopedepidermis. These aggregates have fre-quently large size and diminished cohe-

sion of cells. In some instances, the latterproliferative pattern may predominatewith little or no pagetoid spread.

The most common cell in the invasivecomponent is epithelioid (Fig. 11-10).Less frequently, spindle cells, small cellsor large bizarre mononuclear or multin-ucleate cells may predominate or maybe admixed with the other cell types.Many melanomas show considerableheterogeneity of cell type, such that thecells vary in nuclear size and shape andthe amount of cytoplasm from onefocus to another.

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Pagetoid melanocytosis with large epithelioid melanoma cells.

� FIGURE 11-10 Melanoma of intermittently sun-exposed skin (pagetoid melanoma).

Invasive component- containing epithelioid melanoma cells.

The differential diagnosis of melanomaswith pagetoid intraepidermal compo-nents includes various melanocytic pro-liferations: markedly atypical (dysplas-tic) nevi (AMN), halo nevi, Spitztumors, pigmented spindle cell tumors,recurrent/persistent melanocytic nevi,and congenital nevi, particularly in thefirst year of life. Nevi associated withprominent pagetoid spread are com-monly confused with melanoma.

AMN with pronounced atypia maybe misdiagnosed as melanoma becauseof focal or minimal pagetoid spread,confluence of cellular aggregates alongthe dermal/epidermal junction, promi-nent variation in nesting pattern, signif-icant cytologic atypia, entrapment ofnests of dermal nevus cells in the papil-lary dermis, and dense mononuclearcell infiltrates. On occasion, the distinc-tion of AMN from melanoma is exceed-ingly difficult. Nonetheless, discrimina-tion of melanoma from AMN is usuallypossible because of the larger size,greater asymmetry, disorder, cellularity,and cytologic atypia encountered inmelanoma. Usually AMN will maintainan overall symmetry, a nevic appearanceas exemplified by fairly organized junc-tional nesting, a basilar proliferation ofmelanocytes that is still concentratedalong the epidermal rete and with greaterdensity toward the lower poles of therete. Thus, the intervening epidermisbetween rete will contain a lesser densityof melanocytes compared to that on theepidermal rete. If pagetoid spread is pre-sent, this architectural pattern is oftenmore prominent about epidermal reteand confined to the lowermost epider-mis. Occasionally, AMN exhibit efface-ment of the epidermal rete pattern andconfluence of melanocytic cells along thedermal/epidermal junction in this zone.The latter changes are commonly associ-ated with dense mononuclear cell infil-trates and may strongly suggestmelanoma. These findings must be care-fully interpreted in the overall context ofthe lesion. AMNs are generally character-ized by variable or discontinuous

Differential Diagnosis

BOX 11-7 Summary

• Markedly atypical (dysplastic) nevi

• Halo nevi

• Spitz tumors

• Pigmented spindle cell melanocytic

tumors

• Recurrent/persistent melanocytic nevi

• Congenital nevi


• Clinical Features• Age 60–70 years

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cytologic atypia, i.e., the degree of nuclearenlargement, pleomorphism, and hyper-chromatism varies from cell to cell.9 Thiscytologic feature is very helpful in discrim-inating AMN from the more uniform orcontiguous cytologic atypia of melanoma.

A finding that raises the possibility ofmelanoma is entrapment of atypicalnevus cells in a fibrotic papillary dermisof an AMN. Such findings may evensuggest partial regression of melanoma.A distinction from melanoma should bebased on an assessment of all the cyto-logic and architectural characteristics ofthe lesion. Importantly, the dermalnevus cells in question usually lack themarked and uniform cytologic atypia,especially manifested as hyperchroma-sia, of melanoma cells.

In general, halo nevi have densemononuclear cell infiltrates, histologicregression in some instances, and vary-ing degrees of architectural and cyto-logic atypia that may suggest melanoma.The typical halo nevus of children andadolescents is characterized by smallsize, overall symmetry, orderly appear-ance, and little or no cytologic atypia.9

The lymphoid cells that permeate thedermal nevus have a uniform densityand regular horizontal contour. Thenevus cells of halo nevi may demon-strate cellular enlargement with promi-nent eosinophilic cytoplasm, but theirnuclear details are usually little altered.In contrast, there is a variant of halonevus that has aprominent pattern andcellular atypia, and is perhaps best cate-gorized as an AMN. The discussion ofAMN (above) is relevant to this form of(atypical) halo nevus.

The misdiagnosis of other melanocyticnevi including acral nevi, Spitz tumors(see Chapter 19), pigmented spindle celltumors, congenital nevi, recurrent mel-anocytic nevi, and nevi in children asmelanoma is primarily related to misin-terpretation of patterns of pagetoidspread. Overall symmetry and a well-organized appearance, as well as little orno cytologic atypia, favor a benignmelanocytic proliferation. Pagetoidspread in benign melanocytic nevi isgenerally characterized by an orderlypattern and is generally limited to thelower epidermis and aggregates of cellspredominate over single cells.

LENTIGO MALIGNA (SOLAR)

MELANOMA

Lentigo maligna (also known as mela-noma with adjacent predominately lentig-inous intraepidermal component of sun-exposed skin (historically lentigo malignamelanoma; Hutchinson’s melanoticfreckle.) is a confusing term since it hasbeen used to describe a histologic spec-

trum from slightly increased numbers ofbasilar melanocytes with variable, low-grade cytologic atypia,1–9,32,33 that is notclearly melanoma in situ, to a contiguousand often nested intraepidermal prolifera-tion of highly pleomorphic melanocyticcells, that is, melanoma in situ.32,33

Furthermore, some pathologists considerall lentigo maligna to be melanoma insitu16 while others obviously do not,9,34,35

hence the confusion. Irrespective of ter-minology used, the pathologist mustclearly communicate to the clinician themeaning of the pathologic terms used todescribe these lesions. For clarity, theauthor recommends the term “solarintraepidermal melanocytic proliferation”with atypia (SIMP) (atypia may be gradedas slight, moderate, or severe according toguidelines proposed for atypical nevi) forlesions judged to fall short of melanoma insitu; otherwise, solar melanoma in situshould be used for lesions showing suffi-ciently disordered melanocytic prolifera-tion and cellular atypia, i.e., contiguousproliferation of uniformly markedly atyp-ical melanocytes.

In addition to a mainly basilar prolif-eration of melanocytes (Figs. 11-11 and11-12), this form of melanoma is alsocharacterized by atrophy and effacementof the epidermis, involvement ofappendageal structures, and markedsolar elastosis.1–9,32,36,37 However, thepresence of the latter changes may sim-ply be related to anatomic site, i.e., theskin of the cheek in older individualsusually exhibits a flattened epidermisand prominent solar elastosis. There maybe prominent involvement of appendagealepithelium with large cellular nests.Recognition of prominent appendagealinvolvement by melanoma is of criticalimportance because the lesion should notbe misdiagnosed as invasive rather thansimply as intraepithelial or in situ. Themost typical cell type has retracted cyto-plasm and often an elongate, stellate, orspindled configuration1–9,36 and a highnuclear-cytoplasmic ratio. The nuclei arecommonly pleomorphic and hyperchro-matic. With progression, the cells be-come more epithelioid in appearance andexhibit nuclear enlargement and promi-nent nucleoli. Another characteristic fea-ture is the presence of prominent spindlecell differentiation with formation ofconfluent fascicles of spindle cells alongthe dermal–epidermal junction and ap-pendages. One particular variant mayclosely simulate pigmented spindle celltumor.9

Extension of melanoma into the der-mis may be difficult to recognizebecause of prominent cellularity of the

• Men � women• Sun-exposed surfaces: cheek (most com-

mon), nose, forehead, ears, neck,• Dorsal surfaces of hands• 0.2–20 cm• Initial tan macule suggesting a varnish-like

stain• Tan, brown, black macule or patch (black

flecks characterisitic) (early lesions)• Pink, gray, white with progression and

areas of regression• Papule or nodule, pigmented or amelanotic

(advanced)• Ulceration and bleeding• Asymmetry• Irregular, notched borders

• Histopathologic Criteria• Effacement and thinning of epidermis

common• Prominent solar elastosis

• Solar Intraepidermal Melanocytic Neoplasia

(Lentigo Maligna)• Solar intraepidermal melanocytic

proliferation (insufficient for melanoma

in situ)

➤ Lentiginous melanocytic

proliferation

➤ Pleomorphic melanocytes (variable cyto-

logic atypia)

➤ Extension of melanocytic proliferation

downward along appendages

➤ Usual absence of nesting and pagetoid

spread• Melanoma in situ

➤ Contiguous or near contiguous lentigi-

nous melanocytic proliferation

➤ Intraepidermal nesting of melanocytes

➤ Pagetoid spread

➤ Promient extension of melanocytic prolif-

eration downward along appendages,

often with nesting

➤ Significant cytologic atypia

➤ Melanocytes somewhat spindled to

increasingly epithelioid

• Pigmented spindle cell variant (often on ears)• Prominent intraepidermal discohesive nest-

ing of atypical spindle cells• Spindle cells often comprise invasive com-

ponent but polygonal, small cells common• Appendage-associated nesting of atypical

melanocytes suggests invasion and may be

florid (not true invasion)• Partial regression relatively common• Precursor nevus present ~3% of cases• Desmoplasia, neurotropism, angiotropism

common

BOX 11-8 Summary


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stroma, activation of mesenchymal cells,and the frequent adnexal involvementby melanoma. The invasive dermalcomponent is frequently composed ofspindle cells. They occur singly or inbundles with varying stromal desmopla-sia and invasion of nerve twigs (seedesmoplastic melanoma). However, theinvasive component may contain anycell type. Invasion of the dermis mayoriginate from appendageal-associatedmelanoma cells or nests. In the latterinstances, depth of invasion (Breslowthickness) should not be measured fromthe granular layer of the epidermis since

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� FIGURE 11-11 Solar melanoma in situ. There is a striking basilar proliferation of variably atyp-

ical melanocytes in the epidermis.

� FIGURE 11-12 Solar lentiginous melanoma. Higher magnification shows atypia of basilar

melanocytes.

this value would overestimate tumordepth. The measurement of tumorthickness instead should ideally betaken from the granular layer of the hairfollicle or sweat gland.


BOX 11-9 Summary

• Solar lentigo

• Solar melanocytic hyperplasia (photoacti-

vation)• de novo

• Occurrence with nevi, fibrous papule,

basal cell carcinoma, actinic keratosis,

etc.

• Atypical intraepidermal melanocytic prolif-

eration, not otherwise specified

• Solar lentiginous junctional or compound

melanocytic nevi with or without atypia

(may overlap atypical (dysplastic) nevi)

• Pigmented spindle cell tumor

• Pigmented actinic keratosis

• Squamous cell carcinoma, spindle cell

type

• Atypical fibroxanthoma

• Cellular neurothekeoma

• Malignant peripheral nerve sheath

tumor

• Angiosarcoma

• Kaposi’s sarcoma

• Leiomyosarcoma

Solar melanocytic proliferations withatypia (SIMP) and lentiginous melanomasfrom markedly sun-damaged skin mustbe distinguished from solar lentigo,AMN, and pigmented spindle cell tumor(see previous discussions32,33). The for-mer lesions may in fact develop fromsome varieties of solar lentigo. Well-dif-ferentiated forms of SIMPS and solarmelanoma in situ with spindle cells maycause confusion with pigmented spindlecell tumor (PSCT). Typical PSCT usuallyinvolves covered skin and commonlyoccurs in children and young adults;whereas SIMP and solar melanomain situ invariably develops in sun-ex-posed skin and usually in older persons.An effaced epidermis, cellular nests withdiminished cohesion and a prominentbasilar single cell proliferation of markedlyatypical spindle cells argue in favor ofSIMP and solar melanoma in situ. Pigment-ed spindle cell tumors are usually well cir-cumscribed with well-formed, orderly,and regular fascicles of pigmented spindlecells. Epidermal hyperplasia usuallyencountered in PSCT contrasts with theatrophy of SIMP and solar melanomain situ. Cytologically, PSCT is usually com-posed of monotonous fusiform cells withnuclei containing delicate chromatin.

ACRAL (AND MUCOSAL)

MELANOMAS

BOX 11-10 Summary

• Clinical Features• Age 60–70 years• Men � women• Equal incidence in all racial groups


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Acral and mucosal melanomas (alsoknown often as melanomas (but notnecessarily) with adjacent predomi-nately lentiginous intraepithelial com-ponent of acral skin, the nail apparatus,and mucosal surfaces) are usuallyadvanced, often ulcerated, and charac-

• Most prevalent form of melanoma in

Africans, Asians, Native Americans, other

peoples of color• Glabrous (volar) skin and nail unit

➤ Palms, soles, digits 85% of AM

➤ Nail unit 15%• Feet 90% of cases

➤ Soles 68 to 71%

➤ Toes 11%

➤ Nail units 16 to 20%

➤ Palms 4 to 10%

➤ Fingers 2%• 0.3–12 cm

➤ Often 0.7cm or larger

➤ �0.7 cm with irregular borders, color, or

“parallel ridge” pattern on epilumines-

cence microscopy• Often jet-black macule early but also tan,

brown, gray, blue, pink, white• Pigmented or amelanotic papule or nodule

(advanced) with ulceration, bleeding, eschar• Irregular borders, notching

• Histopathologic Criteria• Prominent acanthosis with elongated epi-

dermal rete common• Thickened stratum corneum• Contiguous or near contiguous lentiginous

melanocytic proliferation in almost all lesions• Intraepidermal melanocytes appear to lie in

lacunae (clear spaces)• Variable cytologic atypia with minimal

atypia in early lesions• Pagetoid spread (particularly in more

advanced lesions)• Intraepidermal nesting (particularly in more

advanced lesions)• Proliferation of melanocytes downward

along eccrine ducts (even into deep dermis

and subcutis)• Pronounced pagetoid spread, large

intraepidermal nests, significant numbers

of melanocytes in stratum corneum in

advanced lesions• Polygonal to spindled melanocytes often

with prominent dendrites• Nuclear enlargement, hyperchromatism,

pleomorphism prominent• Invasive component

➤ Cohesive nests, sheets of cells, or

loosely aggregated files of cells

➤ Spindle cells common but also polygo-

nal, small, and highly pleomorphic cells

are noted

➤ Nevoid and sarcomatoid variants occur• Desmoplasia, neurotropism, angiotropism

common

� FIGURE 11-13 Acral melanoma. The epidermal is hyperplastic and exhibits characteristic

lentiginous proliferation of pleomorphic melanoma cells.

BOX 11-11 Summary

• Melanotic macule

• Lentigo

• Atypical intraepidermal melanocytic prolif-

eration, not otherwise specified

• Acral melanocytic nevus with or without

atypia (may overlap atypical (dysplastic)

nevus)

terized by a tumor nodule frequentlyextending deeply into the stroma.1–12,21–25

Scanning magnification will usuallyreveal a hyperplastic epidermis and fre-quent lentiginous proliferation of atypicalmelanocytic cells (Figs. 11-13 to 11-15).These cells are commonly contiguouswith occasional clustering, appear to liewithin lacunae, and display prominentdendrites that extend through the epider-mis. Pagetoid patterns are also observedfrequently, either alone or associatedwith lentiginous proliferation. The nucleiare enlarged, hyperchromatic, and oftenhighly pleomorphic (Fig. 11-14). Withtumor progression, there is a tendencyfor greater pagetoid melanocytosis anddermal invasion. Variable degrees ofmelanization are present.

� FIGURE 11-14 Acral melanoma. Higher magnification shows striking pleomorphism of

melanoma cells.

The dermal component is most oftencomposed of spindle cells but epithe-lioid cells, small nevus-like cells, andhighly pleomorphic cell types are occa-sionally noted.1–12 A small proportionexhibit desmoplasia and neurotropism(see the next section).



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The differential diagnosis for acralmelanoma primarily includes lentiginesand lentiginous melanocytic nevi of acralskin. Lentigines of acral skin usually donot exhibit the frequency of melanocyticproliferation or cytologic atypia that istypical of acral melanoma.9 Occasionalacral nevi may have alarming featuressuch as upward migration of cellsthroughout the epidermis, prominentlentiginous melanocytic proliferation,and some degree of cytologic atypia.Although upward migration may benoted in acral nevi, particularly in chil-dren, the constituent cells seldom revealmore than low-grade cytologic atypiaand the pattern of pagetoid spread isusually orderly and confined to the low-ermost epidermis. Other characteristicsof acral nevi include regular size, spac-ing, and cohesive qualities of the junc-tional nesting. One particular note ofcaution is that well-differentiated acralmelanoma may exhibit dermal compo-nents with little or no inflammatoryresponse. In such cases, careful evalua-tion for cytologic atypia, necrotic cells,and mitotic activity are helpful in recog-nizing melanoma.

“NODULAR” MELANOMA

Scanning magnification discloses a raised,dome-shaped, or polypoid tumor oftenbut not always exhibiting some asym-metry (Fig. 11-16).1–9,13 The epidermisover the tumor is usually thin, effaced,and may be ulcerated. Variable upwardmigration of melanoma cells in the epi-dermis may be present but intraepider-mal spread should not extend beyondthe margins of the tumor. The dermalcomponent is typified by a cohesivenodule or smaller nests of tumor cellshaving a pushing or expansile pattern ofgrowth (Fig. 11-16). The tumor cells

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� FIGURE 11-15 Acral melanoma. Hyperplastic epidermis exhibits irregular and confluent

nesting of melanoma cells.

� FIGURE 11-16 “Nodular” melanoma. The tumor has an asymmetrical dome-shaped

configuration.


• Squamous cell carcinoma, spindle cell

type



• Malignant peripheral nerve sheath tumor

• Angiosarcoma


• Leiomyosarcoma

• Ulceration, bleeding• Asymmetry but symmetry may be present• Often well-defined borders

• Histopathologic Criteria• Dome-shaped polypoid or sessile tumor

often• May be pedunculated• Asymmetry• Epidermis commonly thinned, effaced,

ulcerated • Overlying intraepidermal component may

or may not be present and usually does

not extend peripherally beyond dermal

invasive tumor• Pagetoid spread, lentiginous melanocytic

proliferation, intraepithelial nesting may be

present• Cohesive aggregate or aggregates of tumor

cells fill subjacent dermis, subcutis• Usually no maturation• Host response at base and/or tumor-infil-

trating lymphocytes common• Epithelioid cells often comprise invasive

component but spindle cells, small

cuboidal cells common and often hetero-

geneity is present• Partial regression relatively uncommon• Precursor nevus present ~6% of cases

BOX 11-12 Summary

• Clinical Features• Age 30–70 years (often 40–50 but any

age)• Men � women• Any site especially trunk dorsal surfaces

of hands• 0.4 to 5 cm• Often rapid evolution, e.g., 4 month to 2

years• Papule or nodule, pigmented or amelan-

otic (advanced)

➤ Often protuberant, polypoid

➤ Black, blue-black, pink


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most frequently are epithelioid.However, other cell types including spin-dle cells and small epithelioid cellsresembling nevus cells may predominateor be admixed with other cell types.1–9


“Nodular” melanoma (NM) may be con-fused with metastatic melanoma, Spitztumor, and atypical varieties of cellularblue nevus, squamous cell carcinoma,atypical fibroxanthoma, fibrous histiocy-toma, leiomyosarcoma, myoid fibroma,cellular capillary hemangioma, andKaposi’s sarcoma. Epidermotropic meta-static melanoma involving the papillarydermis may prove difficult to distinguishfrom NM.38 Metastatic melanoma is oftenfairly monomorphous with little stromalresponse while NM are often polymor-phous and exhibit greater stromalresponse. However, distinction may beimpossible in certain cases and discrimina-tion must rely on clinical information andclinical course.

Spitz tumors, particularly those withatypia, enter into the differential diagno-sis of NM. Clinical information is perti-nent to the diagnosis since melanoma isuncommon in the young, whereas atyp-ical lesions are more suspicious formelanoma in adults.

On occasion, nonmelanocytic lesionsare considered in the differential diagno-sis of melanoma. The principal condi-tions include Paget’s disease, either mam-mary or extramammary, squamous cellcarcinoma in situ, sebaceous carcinoma,epidermotropic eccrine carcinoma, cuta-neous T cell lymphoma, and other epi-dermotropic carcinomas. In mostinstances, the dilemma can be resolved

simply by careful attention to histologicdetails in routinely stained sections.39

UNUSUAL VARIANTS

OF MELANOMA

These rare variants of melanoma exhibita continuum of histologic features corre-sponding to the neuroectodermal originof the melanocyte.7–9,40–56 The phenotypeof the tumor may thus include any com-bination of the following:

1. Desmoplasia—fibroblast-like spindlecells usually in fascicles (predominantpattern);

2. Neurotropism (perineurial invasion)—invasion of nerve structures by tumorcells;

3. Neural differentiation (both Schwannian andperineurial)—formation of nerve-likestructures recapitulating perineuriumand endoneurium or delicate sheets ofspindle cells reminiscent of neurofi-broma, and less commonly myofibro-cytic or neuroendocrine differentia-tion, as in Merkel cell carcinoma.

Desmoplastic Melanoma (DM)

DM most frequently arises in associa-tion with lentiginous melanomas,9,46,47

however, de novo variants of desmoplas-tic melanoma also occur.47

The pathogenesis of desmoplasia andthe true nature of the spindle cells indesmoplastic melanoma remain a sub-ject of controversy.41,42 Some authorsmaintain that the fibroplasia resultsfrom the induction of collagen synthesisby benign fibroblasts while othersbelieve that melanoma cells function asadaptive fibroblasts to promote collage-nization in these tumors. The latter con-clusion is based on ultrastructural andimmunohistochemical studies, andbecause melanocytes are capable of col-lagen production as well as melanin syn-thesis and schwannian differentiation.

CLINICAL FEATURES The usual presenta-tion is as a raised, firm nodule that isskin-colored or associated with variablepigmentation (Fig. 11-17).20,40,43–47 The

BOX 11-13 Summary

• Metastatic melanoma

• Spitz tumor


• Atypical halo-like nevus

• Cellular blue nevus with atypia

• Squamous cell carcinoma

• Adnexal carcinomas


• Fibrous histiocytoma

• Adult xanthogranuloma

• Lymphoma, particulary large cell anaplas-

tic variants


• Malignant peripheral nerve sheath tumor

• Capillary hemangioma

• Malignant glomus tumor or with atypia

• Angiosarcoma


• Leiomyosarcoma

• Clinical Features • Age 60–65 years• Men � women• Sun-exposed skin, head and neck, but

also acral, mucosal sites• Firm nodule• Flesh-colored or with pigmented lesion

(29 to 43%)• 1–3 cm

BOX 11-14 Summary

� FIGURE 11-17 Desmoplastic melanoma involving vertex of scalp. The lesion is seen as

a firm pink nodule.

• Occasional dysesthesias, nerve palsies

• Histopathologic Features• Intraepidermal melanocytic proliferation in

�75%• Solar melanoma in situ, most common• Fibrous nodule in dermis and possibly sub-

cutis• Often absence of pigment• Fascicles of atypical spindle cells• Schwannian, perineurial differentiation• Neurotropism common (perineurial and

endoneurial invasion)• Patchy lymphoid infiltrates common• Variable myxoid stroma• Occasional mitoses in dermis


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Neurotropic Melanoma

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� FIGURE 11-18 Desmoplastic melanoma. Fibrotic nodule occupies dermis.

� FIGURE 11-19 Desmoplastic melanoma showing intersecting fascicles of spindle cells

with dense fibrous stroma.

BOX 11-15 Summary

• Neurotropic melanomas involve the per-

ineurium and/or endoneurium of cuta-

neous nerves.

• Histologic clues to nerve involvement include

the presence of hyperchromatic spindle cells

in the perineurium or endoneurium and

mucinous alteration of the nerve.

• Melanoma spindle cells involving cutaneous

nerves usually show nuclear enlargement,

hyperchromatism, and pleomorphism.

irregular and variegated features of anassociated intraepithelial componentsuch as melanoma in situ may be themost visible feature of desmoplasticmelanoma. Difficulty in recognizingdesmoplastic melanoma, clinically andhistologically, usually causes a delay inrecognition and appropriate surgery.

HISTOPATHOLOGIC FEATURES Scanningmagnification usually discloses a fibrousnodule displacing the normal dermal colla-gen or lamina propria and often extendinginto subcutaneous fat (Fig. 11-18).40–47

Intraepidermal melanocytic proliferation isusually observed in the majority of cases.47

The most common histologic patternof DM is a predominantly desmoplasticpresentation.47 Interspersed among densecollagenous fibers are individual spindlecells and variably sized fascicles of cells(Figs. 11-19 and 11-20). The nuclei mayshow minimal to pronounced pleomor-phism and wavy or serpiginous nuclearmorphology (Fig. 11-20), though mostnuclei are enlarged with tapering con-tours. However, some nuclei are plumpand occasional bizarre multinucleategiant cell forms are noted. Most desmo-plastic melanomas lack pigment butoccasional cells may contain fine melaningranules within cellular processes. Thetumor stroma is usually fibrous, but myx-oid alteration is occasionally encounteredand uncommonly may be prominent. Afinding typical of desmoplastic melanomaand useful in its recognition is variablydense perivascular lymphocytic infil-trates usually scattered throughout thetumor.47 The tumor cells in desmoplasticmelanoma are also notable for infiltratingwalls of blood vessels (angiotropism).Mitotic figures are often scant, less thanone or two per square millimeter, but canusually be found even in the most pauci-cellular forms of this tumor.46,47

Desmoplastic melanoma is usuallydiagnosed at an advanced stage, e.g., usu-ally at least 4 or 5 mm in thickness andlevel IV or V.43–48 Because of misdiagno-sis, they are commonly first recognizedas recurrent or metastatic tumors.Desmoplastic melanomas frequentlyrecur (range 25 to 82%).43–45 Based on aseries of 45 cases, local recurrence wasassociated with the following factors:failure to diagnose the tumor correctly,inadequate surgery (resection marginsless than 1 cm), location on the head andneck, anatomic level V, and thicknessgreater than 4 mm.45 Failure to com-pletely extirpate desmoplastic melanomais related to the difficulty of assessingmargins, infiltration of nerves, and thefact that they are usually amelanotic.

The term neurotropism refers to theinvolvement of perineurium and/orendoneurium of cutaneous nerves bymelanoma cells (Fig. 11-21).45,49–51

There may be considerable thickeningof the perineurium and expansion ofthe endoneurial space by the tumorinvolvement. Extension of tumor alongthe cutaneous nerves may, however, beextensive and subtle. Histologic cluesto nerve involvement include the pres-ence of hyperchromatic spindle cells inthe perineurium or endoneurium andmucinous alteration of the nerve.


The spectrum of tumors potentially con-fused with desmoplastic and neurotropicmelanoma is varied and includes spindlecell proliferations and tumors with afibrous appearance.40,43–48 The principallesions to be considered include sclerosingblue nevus,46,47 desmoplastic Spitz tumor,9

neurothekeoma,57 malignant peripheralnerve sheath tumor,dermatofibroma,atypical fibroxanthoma, malignant fibroushistiocytoma, scar, fibromatosis, myx-oma, spindle cell squamous cell carcinoma,and leiomyosarcoma.46,47 The epidermallentiginous melanocytic proliferation com-monly found in desmoplastic melanoma isusually absent in the other conditions.

Sclerosing blue nevus and desmoplasticSpitz tumor both are characterized by anorderly infiltration of the fibrotic stromaand an overall benign cytologic appear-ance. Mitotic figures, usually encounteredin desmoplastic melanoma, are exceed-ingly rare or absent in sclerosing bluenevus, but early forms of desmoplasticmelanoma may be extremely difficult todistinguish from sclerosing blue nevus andit is vital to weigh all clinical and histologicfeatures. For example, desmoplasticmelanoma in a young individual on ananatomic site besides the head and neck oracral areas would be highly unusual andsuch circumstances would argue against adiagnosis of desmoplastic melanoma.

The desmoplastic Spitz tumor is char-acterized by symmetry, a wedge-shapedconfiguration, and infiltration of the der-mis by relatively monotonous epithelioidor spindle cells, allowing its distinctionfrom desmoplastic melanoma in mostinstances. Desmoplastic melanoma mayalso show a fascicular arrangement ofcells that is generally lacking in desmo-plastic Spitz tumor.

Relatively cellular variants of neu-rothekeoma (nerve sheath myxoma)may suggest desmoplastic melanoma.57

Neurothekeoma commonly arises in thehead and neck region, as does desmoplas-tic melanoma. Neurothekeoma generally152

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Careful examination of cutaneousnerves at the surgical margins is manda-tory to assess adequate excision.Melanoma spindle cells involving cuta-neous nerves usually show nuclearenlargement, hyperchromatism, andpleomorphism.

The term neurotropic (or neurogenic)melanoma also describes neural orSchwannian differentiation in a patternresembling peripheral nerve sheathtumors such as neurofibromas or neuro-mas and the recapitulation of per-ineurium and endoneurium.45–47,49–51 Thetumor cells in such areas are character-ized by serpiginous or wavy nuclear con-figurations and filamentous cytoplasmic

� FIGURE 11-20 Desmoplastic melanoma. Spindled melanoma cells display nuclear

pleomorphism and hyperchromatism.

� FIGURE 11-21 Desmoplastic-neurotropic melanoma. A cutaneous nerve shows pro-

nounced nodular perineurial and endoneurial infiltration by melanoma cells (neurotropism).

processes. The cells are embedded in avariably mucinous and fibrous stroma. Insome instances, the stromal may be sosufficiently myxoid to suggest a myx-oma. However, the tumor cells demon-strate loose fascicular arrangements,cytologic atypia, and occasional mitoticfigures.


BOX 11-16 Summary

• Sclerosing blue nevi including variants

with hypercellularity

• Desmoplastic (sclerosing) Spitz nevus

• Neurothekeoma, particularly cellular vari-

ants

• Malignant peripheral nerve sheath tumors

• Myxoma

• Dermatofibroma

• Dermatofibrosarcoma protuberans


• Malignant fibrous histiocytoma

• Scar

• Fibromatosis

• Spindle cell squamous cell carcinoma

• Leiomyosarcoma


153

occurs in young individuals (averageage 20 years), does not demonstrate anintraepidermal melanocytic proliferationand is typified by a lobular architecturein the dermis. Concentric and fasciculararrangements of cells are often noted inneurothekeoma, the constituent cellsmay be epithelioid, or bipolar and stel-late and multinucleate forms are seen.Low-grade nuclear pleomorphism andoccasional mitotic figures are occa-sionally encountered. Distinction fromdesmoplastic melanoma is based on aregular, organized appearance, orderlyinfiltration of the dermis and a lesserdegree of cytologic atypia.

Because of prominent Schwanniandifferentiation, discrimination of desmo-plastic-neurotropic melanoma fromperipheral nerve sheath tumors may bedifficult or impossible. All clinical andhistologic characteristics must be consid-ered. Tumors of the head and neck ofelderly patients associated with lentigi-nous melanomas are usually not a diag-nostic problem. Tumors in other anatomicsites without an intraepidermal compo-nent will cause difficulty and immuno-histochemistry may be of particularvalue in them.47,52,58,59

Lesions demonstrating fibrous orfibrohistiocytic differentiation figureprominently in the differential diagnosisof desmoplastic melanoma and includedermatofibroma (fibrous histiocytoma),juvenile xanthogranuloma, dermatofi-brosarcoma protuberans and atypicalfibroxanthoma, superficial forms ofmalignant fibrous histiocytoma, scar, andfibromatosis. These lesions generally lackintraepidermal melanocytic proliferation,melanin pigment, and neurotropism.Atypical fibroxanthoma and malignantfibrous histiocytoma enter the differentialdiagnosis and often require immunohisto-chemical evaluation, though they maycontain xanthoma cells, not usually seen indesmoplastic melanoma. Fibrohistiocytictumors as a general rule do not displayneurotropism.

Desmoplastic melanomas with exten-sive mucin may raise problems of differ-ential diagnosis, suggesting, e.g., a myx-oma. However, myxomas generally lackthe cytologic atypia and neurotropismof desmoplastic-neurotropic melanomaand the myxomatous variants of desmo-plastic melanoma usually have zones ofprominent cellularity.

Spindle cell squamous carcinoma andcutaneous leiomyosarcoma may be con-fused with desmoplastic melanoma, butneither entity usually shows intraepider-mal melanocytic proliferation or melaninsynthesis. Squamous cell carcinoma may

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show keratinization, dyskeratosis, andintercellular bridges. Leiomyosarcomamay exhibit the cytologic characteristicsof smooth muscle cells, but immunohis-tochemistry may be essential for diagno-sis (desmin and/or actin expression).

Because of the serious consequencesof this tumor, immunohistochemistry isneeded in most desmoplastic melanomasto confirm the diagnosis. Almost 100%of desmoplastic-neurotropic melanomasdemonstrate immunoreactivity withantibodies against vimentin, S-100 pro-tein, and p75 neurotrophin recep-tor47,48,52,56,58,59 but uniquely almost all arenegative for HMB-45, Mart-1, MITF, andtyrosinase. If there is positive immunos-taining for HMB-45 and the latter mark-ers in DM, it involves nondesmoplasticfoci only, i.e., an intraepidermal compo-nent or superficial dermal focus of con-ventional melanoma cells.47 A battery ofmarkers must be utilized to evaluate suchtumors. Other antibodies with variablereactivity with desmoplastic melanomaare neuron specific enolase and NK1/C3.Antibodies against keratin, desmin, actin,and Leu-7 (specific for peripheral nervesheath differentiation but is negative inmelanocytic tumors), in general, are neg-ative in desmoplastic melanoma.47

ANGIOTROPIC MELANOMA

BOX 11-17 Summary

Angiotropic melanoma has been re-ported anecdotally in the literature, moreas a curiosity than as an important bio-logical entity. However, importance ofangiotropism as a biological phenome-non and prognostic factor in localizedmelanoma and as the likely correlate ofextravascular migratory metastasis hasrecently been emphasized.60–63 Angiotro-pism is observed much more frequentlythan vascular invasion, e.g., in a series of650 consecutive invasive melanomas, thefrequency of vascular/lymphatic invasionwas 1.4%.15 In a recently published studyof metastasing melanomas carefullymatched with non-metastasizing mela-nomas for Breslow thickness, age, gender,and site, the presence of angiotropismstrongly correlated with the developmentof metastases whereas vascular invasionwas not observed in any cases.64

Angiotropic melanoma is defined bythe cuffing of (the close opposition to) theexternal surfaces of either blood or lym-phatic channels (in a pericyte-like location),or both, by aggregates of melanoma cellsin at least two or more foci (Fig. 11-22).63

By definition there is no tumor presentwithin vascular lumina. Angiotropic foci

� FIGURE 11-22 Angiotropic melanoma. Melanoma cells cuff microvessel in dermis with-

out intravasation.

• Men � women• Any site• 0.4–5 cm

• Histopathologic Criteria• Any type of melanoma• Melanoma cells cuff microvessels in

pericytic location• Often at least level IV• Increased frequency of neurotropism

• Clinical Features• Age 30–70 years (often 40–50 years,

but any age)


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must be located either at the advancingfront of the tumor or some distance (usu-ally within 1 to 2 mm) from the maintumoral mass. Although angiotropism islikely to be present within the mass of aninvasive tumor, there is no specific meansat present to differentiate simple entrap-ment of vessels by tumor from angiotro-pism. Immunohistochemisty with mark-ers such as S100 protein or Mart-1 mayaid in the identification or confirmation ofangiotropism (Fig. 11-23). Angiotropismis observed with greater frequency inmelanomas also demonstrating desmo-plasia and neurotropism suggestingclosely related mechanisms.

NEVOID MELANOMA

In very broad terms, the term “nevoid”melanoma could connote any form ofmelanoma having some resemblance toor mimicking any type of melanocyticnevus.65–68 An objection to this term isthat a large number of melanomas maymore or less resemble banal nevi andthat the application of the term may berather subjective. A variety of otherterms have been employed to describethis general group of melanomas depend-ing upon how stringent are the criteriafor inclusion, e.g., minimal deviationmelanoma, verrucous and pseudonevoidmelanoma and closely related terms(see below), Spitzoid melanoma, small-diameter melanoma, and small cell mela-noma. Some nevoid melanomas mightalso be characterized as having a smalldiameter or small melanoma cells, i.e.,small cell melanoma. However, the termis used rather restrictively in this chapter(as have most other authors) to describemelanomas that closely resemble ordi-nary compound or dermal nevi; the latterlesions generally fall into four groups: (1)those with a raised, dome-shaped or poly-

poid (nodular nonverrucous) configura-tion and resemble a predominately dermalnevus, (2) those with a distinctly papil-lomatous or verrucous surface, (3) thoseresembling a lentiginous melanocyticnevus arising in sun-exposed skin of olderindividuals, and (4) those with a pre-dominately or exclusively intraepidermalnested appearance mimicking a junc-tional or compound nevus.

The importance of this rare group ofmelanomas cannot be overstated becauseof the profound diagnostic difficulty theypose to pathologists. The latter conclu-sion is simply based on the fact thatmany such lesions are often diagnosedonly in retrospect after the developmentof recurrences or metastases.

The concept that melanomas mayclosely resemble melanocytic nevi prob-ably dates back at least to the introduc-tion of the term minimal deviationmelanoma. Schmoeckel and his col-leagures first coined the term “nevoid”melanoma in their description of 33melanomas with histologic features sug-gesting a melanocytic nevus.65 The latterauthors noted that 15 patients devel-oped metastases, and they concludedthat nevoid melanoma did not seem tohave any better prognosis than conven-tional melanoma. About 70 additionalcases have subsequently been reportedin the literature.66–68

Clinical Features

There are no distinctive clinical featurescompared to conventional melanomas;however, verrucous or papillomatousvariants may suggest a verruca, sebor-rheic keratosis, or warty nevus. Mosttumors reported have been in adults.

Histopathologic Features

The essential histopathologic criteria fordiagnosis are as follows: (1) at scanningmagnification, the lesion has a strikingresemblance to an ordinary compound ordermal nevus (Figs. 11-24 and 11-25), (2)an overall symmetry (some asymmetrymay be present), (3) a rather sharp circum-scription at the peripheries of the lesion,(4) the absence of or often only a limitedintraepidermal component, commonlywith little or no pagetoid spread, (5) amonomorphous population of nevus-likecells in the dermis usually characterizedby a confluent or sheet-like growth pat-tern in some portion of the lesion (Fig.11-26), and (6) dermal mitotic fig-ures.9,65–68 Other features commonly butnot invariably present that may suggest abanal nevus include diameter under 5 to6 mm and changes suggesting maturation.

� FIGURE 11-23 Angiotropic melanoma. Immunostaining of angiotropic melanoma

cells with S100 protein.

BOX 11-18 Summary

• Clinical Features• Women � men• All ages, commonly fifth decade• Occurs anywhere, but trunk and lower

extremities most common• No distinctive features, but may have

verrucous appearance• Any size, often relatively small diameter

but up to 2 cm or more

• Histopathologic Features• Striking resemblance to banal com-

pound or dermal nevus at scanning

magnification• Symmetry common• Well-circumscribed lateral margins• Pagetoid spread not common• Often limited intraepidermal component• Relatively small nevus-like cells,

monomorphous appearance

• Some maturation may be present but

often incomplete or absent• Single-cell infiltration at base• Cytologic atypia

➤ Nuclear pleomorphism

➤ Angulated nuclei

➤ Hyperchromatism

➤ Prominent nucleoli may be present• Mitoses in dermal component, particu-

larly deep• Infiltration of adnexal structures• Little or no inflammation


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As mentioned above, there are fourgeneral morphologic variants: (1) thenon-verrucous papular or nodular formsthat present with only limited or no epi-dermal hyperplasia and (2) the verrucousor papillomatous variants that have theconfiguration suggesting a common ver-ruca, seborrheic keratosis or papilloma-tous nevus (Fig. 11-25),68–70 (3) the lentig-inous variants arising in sun-exposedskin of older individuals,71,72 and (4) thestriking intraepidermal nested variantsmimicking a junctional nevus (see earlierdiscussions).

As mentioned above, there may be nointraepidermal melanocytic componentin a large proportion of cases. Theintraepidermal component if presentmay be subtle or limited in nature. Onemay observe melanocytes arranged assingle cells and/or in junctional nestsalong the dermal–epidermal junction.The latter nesting may result in conflu-

ence of nested aggregates of melanocytesreplacing the basilar portion of the epi-dermis. The epidermis is frequentlyeffaced, thinned, and associated withdermal–epidermal separation. Pagetoidspread may be present in a proportion ofcases and is an important finding in con-firming a diagnosis of melanoma; how-ever, it is often not a conspicuous feature.

The principal finding in the dermisincludes a sheet-like or confluent arrange-ment of relatively small cuboidal orpolygonal melanocytes closely mimick-ing nevus cells. Often the dermalemelanocytic population fills the papillarydermis and is closely opposed to the epi-dermis resulting in a strikingly crowdedor hypercellular apprearance. In manycases, the melanocytes extend into thereticular dermis with some diminishedcellular density and also some reductionin cellular and nuclear sizes suggestingsome maturation. In some lesions, one

may observe fairly discreet nesting ofmelanocytes in some areas suggesting anevus; however, other parts of the lesionusually demonstrate the confluence andhypercellulariy that favors melanoma.Furthermore, the heterogeneity of thelesion is another feature consonant withmelanoma. Although the lateral marginsare commonly well demarcated, the baseof the melanoma is often poorly definedand characterized by the presence of sin-gle cells infiltrating collagen. In mostinstances, there is no host inflammatoryresponse.

The melanocytes comprising NM atleast in the superficial part of the lesionand perhaps throughout are generallypolygonal or epithelioid cells (mimickingthe so-called “type A” or epithelioidnevus cells) sufficiently small to suggestnevus cells. They, nonetheless, demon-strate definite but sometimes, subtlenuclear enlargement, pleomorphism,and often hyperchromatism; ratherprominent nucleoli may be present. Asmentioned above, many NM may sug-gest maturation, i.e., diminished cyto-plasmic and nuclear diameters withdepth and a transition to smaller “type B”or lymphocye-like cells and perhaps“type C” or Schwann-like cells. At thesame time, the latter transition may beaocompanied by diminished cellularitywith deph and loss of pigment synthesis.Nonetheless, major clues to diagnosis ofNM are the presence of definite nuclearpleomorphism and in particular irregularnuclear contours, hyperchromatism, andnucleoli and continued pigment synthe-sis in the deepest parts of the dermalcomponent. Generally, one observeswell-defined nests of relatively smallcuboidal cells in the deepest portions ofNM with the latter characteristics.

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� FIGURE 11-25 Verrucous small cell melanoma. The verrucoid epidermal con-

figuration resembles a papillomatous nevus.

� FIGURE 11-24 Nevoid melanoma. The lesion resembles a com-

pound nevus at scanning magnification displaying striking hypercellularity.

� FIGURE 11-26 Verrucous small cell melanoma.The melanoma is comprised of

sheets of small melanoma cells.


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establish the presence of cytologic atypia.In general, the melanocytes may be rela-tively small compared to the usualenlarged epithelioid melanoma cells andthus the resemblance to a nevus.

VERRUCOUS MELANOMA

The most striking feature at scanningmagnification is a fairly symmetricallesion with prominent papillomatous orverrucoid epidermal hyperplasia suggest-ing a seborrheic keratosis, epidermalnevus, verruca, or papillomatous melano-cytic nevus (Fig. 11-25). The intraepider-mal melanocytic component may varyfrom minimal or absent or show promi-nent pagetoid spread. Also common isthe frequent presence of a laterallyextending intraepidermal component.Some of these tumors may show a con-tiguous basilar and suprabasilar prolifera-tion of atypical melanocytes, often invol-ving adnexal epithelium. In commonwith nevoid melanoma, the dermalcomponent in some melanomas mayshow a startling resemblance to a dermalnevus.67–70 The cell type in the latter tu-mors resembles a small nevus cell, butcareful inspection should disclose promi-nent cellular pleomorphism, little or nomaturation, and cells dispersed in conflu-ent nests and sheets without orderly infil-tration of stroma. The presence of mitoticfigures (e.g., greater than two or threeper section) and necrotic cells in the der-mal component also argues against abenign process.


BOX 11-19 Summary

• Papillomatous or cellular melanocytic nevi


BOX 11-20 Summary

• Clinical Features• Women � men• All ages, commonly fifth decade• Occurs anywhere, but trunk and lower

extremities most common• Verrucous appearance• Any size, often relatively small diameter


• Histopathologic Features• Papillomatous epidermal hyperplasia• Common resemblance to banal com-

pound or dermal nevus at scanning

magnification• Symmetry common• Well-circumscribed lateral margins• Pagetoid spread not common• Often limited intraepidermal component• Relatively small nevus-like cells,

monomorphous appearance• Some maturation may be present but

often incomplete or absent• Single-cell infiltration at base• Cytologic atypia



➤ Hyperchromatism

➤ Prominent nucleoli may be present• Mitoses in dermal component, particu-

larly deep• Infiltration of adnexal structures• Little or no inflammation

BOX 11-21 Summary

• Papillomatous or cellular melanocytic nevi

BOX 11-22 Summary

• Clinical Features• High-grade small cell melanoma mimic-

king Merkel cell carcinoma

➤ Extremely rare

➤ Adults (any age)

➤ Any site

➤ Often 0.4–2 cm

➤ Often amelanotic papule or nodule• Small cell melanoma arising in predomi-

nately sun-damaged skin

➤ Often �50 years of age (range 18–91)

One of the most important and some-times the single most important criterionfor diagnosis is the presence of mitoses inthe dermal component.9,68 The latterfinding is often the first clue to consider-ing melanoma in the differential diagno-sis. The presence of one or a small num-ber of dermal mitoses does not constitutesufficient evidence for diagnosis ofmelanoma but it should prompt thehistopathologist to search for additionalcriteria for melanoma and to either con-firm or exclude the diagnosis (if possible).Mitoses are present in virtually all casesand their absence should provoke skepti-cism about melanoma. The mitotic rate iscommonly relatively low, often less thansix per square millimeter. Increasingmitotic rate, deeply situated mitoses, andatypical forms also provide progressivelymore support for NM. The author hasfound that the presence or absence ofmitotic figures in the deepest portion of alesion can be a decisive factor in confirm-ing or ruling out NM.


The principal dilemma is discriminationof such melanomas from melanocyticnevi, especially papillomatous dermalnevi, and metastatic melanoma. One’sconfidence in rendering a diagnosis ofnevoid melanoma directly correlateswith the number of abnormal featurespresent. The following attributes are ofcritical importance in distinguishing NMfrom a nevus: (1) Dermal mitoses, usuallymuliple and scattered throughout thelesion are probably mandatory for thediagnosis. The higher the absolutemitotic rate and the more deeply locatedthe mitoses, the more certain is the diag-nosis. However, the presence of raremitoses particularly in nevi in young orpregnant individuals and in nevi withoutatypia must be interpreted with cautionand are not proof of NM. (2) Dermalaggregates or fascicles of melanocytesshowing high density and confluence,having a sheet-like appearance through-out, or showing both features. The der-mal population often demonstrates amonotonous appearance. (3) Cytologicatypia of melanocytes is mandatory forthe diagnosis. By definition, there arelesser degrees of atypia than in conven-tional melanomas. Careful scrutiny athigher magnifications is necessary to

Although verrucous melanoma was ini-tially described in his classification ofmelanoma in 1967,1 Clark subsequentlydiscarded the term since he believedthat its features could be present in anytype of melanoma.2 Recent reports haveemphasized the prominent clinical andhistologic verrucous features of suchmelanomas and also the difficulty inclassifying many of these lesions.69,70

Some of these melanomas might also bedescribed as nevoid melanoma (see sec-tion titled “Nevoid Melanoma”).

Clinical and Histopathologic Features

Most lesions are well circumscribed, 1 to2 cm in diameter, and characterized by adark-brown, black, or grayish appearanceand hyperkeratotic verrucous surface anddiagnosed clinically as seborrheic kerato-sis or papillomatous nevi.69,70

Verrucous melanoma may suggest non-melanocytic tumors such as seborrheickeratosis, verruca, and epidermal nevus.However, the melanocytic nature of thelesion should become clear with carefulinspection. Of particular concern is thepotential misdiagnosis of verrucousmelanoma as a benign nevus, especiallya papillomatous dermal nevus.9

SMALL CELL MELANOMA


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nevoid melanomas in adults (see the pre-vious section), the following section willdeal only with two entities.

1. Small cell melanoma mimickingMerkel cell (neuroendocrine carci-noma);

2. Exceptionally rare melanomas thatmimic high-grade small round cellmalignancies.

Small cell melanoma mimickingMerkel cell (neuroendocrinecarcinoma)

These variants of melanoma are so rarethat one can only make anecdotalremarks about them.73 Perhaps they havebeen most commonly recognized asmetastases presumably indicating pro-gression or de-differentiation to high-gradeblastlike tumors. Nonetheless, primarytumors occur in adults. The lesions areprimarily defined by a small round cellpopulation arranged in nests, cords, andsheets. Melanin and intrepidermalinvolvement may or may not be present.These tumors feature cells with scantcytoplasm, round to oval nuclei, highmitotic rates, and scattered nectrotic cells.Amelanotic tumors resemble neuroen-docrine carcinoma, primary or metastatic;lymphoma; other small cell carcinomas;and metastatic small cell carcinoma of thelung. Immunohistochemisty is of funda-mental importance for confirming amelanocytic origin versus the other enti-ties mentioned above. In particular, neu-roendocrine carcinoma, metastatic smallcell carcinoma of the lung, and othersmall cell carcinomas may show intraepi-dermal involvement including nestingand pagetoid spread.

Small Cell Melanomas ArisingPredominately in Sun-Damaged Skin of Elderly Individuals

Another variant of small cell melanoma,that also might be subsumed under thegeneral category of “nevoid melanoma”,occurring in sun damaged skin of indi-viduals generally over the age of 50years has been proposed by Kossard andWilkinson71,72 and Blessing et al.74 Whileundoubtedly some proportion of ormany these lesions may in fact bemelanoma, the banal appearance of andresemblance of such lesions to lentigi-nous nevi, a negligible mitotic rate, andthe lack of follow-up call into questionthe diagnosis of melanoma. Thus, thelatter group of 131 cases may possiblyinclude an admixtue of atypical nevi,

biologically indeterminate lesions, andmelanomas. Although the author is con-fident that this entity exists, it is certainthat these lesions as a group require fur-ther study.

CLINICAL FEATURES Such lesions gener-ally develop in sun-exposed skin of olderindividuals with about 80% being 50years or older (range 18 to 91 years).72Men outnumber women by a ratio ofabout 2:1. These tumors are most com-mon on the backs of men and the lowerextremities of women.

HISTOPATHOLOGIC FEATURES The lesionsdescribed by Kossard and Wilkinsonsuggest a lentiginous junctional or com-pound nevus at scanning magnification.Features favoring melanoma includelarge diameter, i.e., up to 1 cm or more,asymmetry, poorly defined margins,effacement and atrophy of the epider-mis, host response including partialregression, large junctional and dermalnests of melanocytes that tend to conflu-ence, some pagetoid spread often subtle,and the lack of maturation (Fig. 11-26).


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The term small cell melanoma has beenintroduced into the literature to describea heterogenous assortment of mela-nomas from several settings perhapsrelated only by the common denomina-tor of small melanoma cells. This termhas been used to refer to (1) rare mela-nomas developing in children and adoles-cents on the scalp,9 (2) melanomas devel-oping in congenital melanocytic nevi ofchildren and adolescents,9 (3) melanomasdeveloping in any setting but particularlyadults that resemble small round cellmalignancies such as Merkel cell carci-noma,73 (4) melanomas developing insun-damaged of older individuals in a set-ting of solar melanocytic neoplasia oratypical lentiginous nevi,71,72,74 and (5)melanomas in adults that have the char-acteristics of nevoid melanoma, asdescribed above. Since there is consider-able overlap of small cell melanomas and

BOX 11-23 Summary

• High-grade small cell melanoma mimick-

ing Merkel cell carcinoma• Metastatic melanoma• Primary and metastatic neuroendocrine

carcinoma• Metastatic small cell carcinoma• Lymphoma• Other small round cell malignancies

• Small cell melanoma arising in predomi-

nately sun-damaged skin• Atypical lentiginous nevi of sun-exposed

skin

➤ Men � women (2:1)

➤ Backs of men, legs of women

➤ Usually �1 cm

➤ Variegated color

➤ Often tan, brown, black, gray

• Histopathologic Features• High-grade small cell melanoma mimic-

king Merkel cell carcinoma

➤ Melanin and intraepidermal involve-

ment may or may not be present

➤ Often cohesive nests, cords, sheets of

small round cells

➤ Cells with scant cytoplasm

➤ Round to oval nuclei

➤ Prominent mitotic rate and necrosis• Small cell melanoma arising in predomi-

nately sun-damaged skin

➤ Intraepidermal component often

extensive, lentiginous and nested

➤ Usually some pagetoid spread

➤ Elongated epidermal rete ridges com-

mon

➤ Effacement and thinning of epidermis

also common

➤ Small cuboidal melanocytes with

scant cytoplasm

➤ Melanocytes larger that those in nevi


➤ Irregular nuclear contours

➤ Dense chromatin

➤ Prominent nucleoli

➤ Dermal nests often large, nodular,

cohesive, anatomosing

➤ Often absence of maturation

➤ Continued pigment synthesis with

depth

➤ Mitotic figures rare

➤ Solar elastosis

➤ Host response with fibroplasia, partial

regression common

Distinguishing such lesions from atypi-cal lentiginous compound nevi is themajor challenge; some lesions prove sodifficult that they can only be catego-rized as biologically indeterminate.Unfortunately, since dermal mitoses aregenerally rare or absent, a major aid todiagnosis is lacking. Of particular utilityis the recognition of melanoma in situ andcontiguity of the latter with the dermalcomponent. Effacement and thinningof the epidermis, confluent nesting ofmelanocytes along the dermal–epider-mal junction, some pagetoid spread,and sufficient atypia of the melanocytesallow for a diagnosis of intraepidermalmelanoma.


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SPITZOID MELANOMA

The term Spitzoid melanoma if used atall should be reserved for melanomasthat truly have a striking morphologicresemblance to Spitz tumors.9,75 Theterm probably best describes a raregroup of tumors often developing inyoung individuals that are only diag-nosed as melanoma in retrospect, i.e.,after the development of metastases andan aggressive course.


The authors recommend such melano-cytic proliferations be categorized if at allpossible into one of the following groups:(1) Spitz tumor, (2) Spitz-like melanocytictumor with atypical features (atypicalSpitz tumor) and possibly indeterminatebiological potential (describing theabnormal features present such as largesize, deep involvement, ulceration, lackof maturation, mitotic rate, presence ofdeep mitoses), and (3) melanoma.

MELANOMA ARISING IN

COMPOUND OR DERMAL NEVI

atypical cells. The latter cells are mostcommonly enlarged with abundantcytoplasm and pleomorphic nuclei.Mitotic figures are found usually withinthe cellular nodule.


BOX 11-24 Summary

• Clinical Features• Women � men• Any age• Occurs anywhere• Any appearance• Any size, often relatively small diameter


• Histopathologic Features• Plaque-type, dome-shaped, or polypoid

configuration• Epidermal hyperplasia common• Striking resemblance to Spitz tumor at

scanning magnification• Asymmetry common• Size often �1 cm• Usually enlarged epithelioid to spindled

melanocytes• Diminished or absent maturation• Mitotic rate �2–6 mm2

• Cytologic atypia



➤ Hyperchromatism

➤ Prominent nucleoli may be present• Mitoses deep

BOX 11-25 Summary

• Atypical Spitz tumor

BOX 11-26 Summary

• Clinical Features• Women � men• All ages, commonly 40–60 years• Occurs anywhere, but head and neck

most common• Any size, often larger that ordinary nevi• Often history of recent change or

enlargement

• Histopathologic Features• Often eccentric and/or asymmetrical

nodule in melanocytic nevus• Nodule shows confluence and hypercel-

lularity• Often abrupt interface with surrounding

nevus• Lack of maturation• Cytologic atypia



➤ Hyperchromatism

➤ Prominent nucleoli may be present• Mitoses in dermal component

�2–3/mm2

BOX 11-27 Summary

• Cellular nodules (typical or atypical) pre-

sent in melanocytic nevi

BOX 11-28 Summary

• Clinical Features• Two-thirds men• All ages, mean age about 46 years

Given the profound difficulty of distin-guishing some Spitz or Spitz-like tumorsfrom melanoma, the author discouragesthe use of term Spitzoid melanoma sinceit may result in the indiscriminate label-ing of a heterogeneous group of lesionsincluding benign Spitz tumors, lesionsthat are biologically indeterminant, con-ventional melanomas, and also a rarecontroversial group of tumors previouslytermed “metastasizing Spitz nevus/tumor.” The latter group of lesions in-cludes some that have given rise to singlelymph node metastases without subse-quent recurrence of melanoma on long-term follow-up.

The development of melanoma in thedermal component of an acquired nevusis an uncommon or rare event.76–78 Someof these melanomas may originate fromadnexal-associated nevus elements.

Clinical and HistopathologicFeatures

Most patients are approximately 40 to 60years of age and the most common site isthe head and neck area.77 The lesions areoften larger than ordinary dermal nevi,e.g., 1 to 2 cm, and there is usually a his-tory of recent change or enlargement.

Usually within an otherwise ordinarydermal nevus, one encounters a distinctnodule of cytologically atypical melano-cytes.77 There is usually an abrupt transi-tion from the ordinary dermal nevuscomponent to the nodular aggregate of

The most obvious dilemma is the differ-entiation of a focus of melanoma fromdermal nevus, especially a nevus withcytologically bizarre nevus cells as inancient schwannoma or a distinct focusof epithelioid or fusiform cells, i.e.,MNPH or the so-called “combined”nevus, “inverted type A” nevus, or mel-anocytic nevus with focal dermal epithe-lioid cell component or dermal nodules.9

The nodular area in question shoulddemonstrate a cohesive or expansileaggregate of cells with unequivocal cyto-logic atypia. Although these melanocyticcells will usually have a monomorphousor clonal appearance, inspection of indi-vidual cells should disclose substantialnuclear pleomorphism and often-promi-nent nucleoli and hyperchromatism.Mitotic figures should also be present inthis focus. A dermal nevus with bizarreor ancient cytologic features usually doesnot show mitoses. One should also con-sider clinical factors such as the age of thepatient (melanoma usually in personsgreater than 40 years of age), size (suchlesions are often �1 cm in diameter), andhistory of recent change or enlargement.On the other hand, MNPH are often pre-sent in younger individuals, are charac-terized by a small dark nodule or papulein a relatively small symmetric nevus,and are characterized usually by low-grade or no cytologic atypia of theepithelioid/fusiform cells. Often the lat-ter cells display prominent melaniniza-tion of melanocytes and are accompaniedby melanophages.

MALIGNANT MELANOMA

ORIGINATING FROM OR

RESEMBLING A BLUE NEVUS

(MALIGNANT BLUE NEVUS)


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Malignant blue nevus (MBN) is anextremely rare form of melanoma origi-nating from or associated with a preexist-ing blue nevus and characterized by adense proliferation of variably pigmentedspindle cells without involvement of theepidermis. Approximately 80 cases ofMBN have thus far been reported.9,79–82

Clinical Features

The average age at diagnosis is 46 years,two-thirds of the patients are men, andthe commonest site is the scalp. MBNmost frequently present as blue or blue-black plaques or nodules ranging from 1to 4 cm (mean 2.9 cm),79–82 that are oftenmultinodular. There is usually a history ofrecent enlargement or change in a previ-ously stable blue nevus. MBN are highlyaggressive with metastasis to lymphnodes and a variety of visceral sites.

Histopathologic Features

MBN usually presents in one of threepatterns: (1) a lesion with an overtlymalignant component (Fig. 11-27) jutx-taposed to a benign blue nevus compo-nent, usually a CBN, (2) a more subtlesarcoma-like presentation (withoutflorid benign and malignant compo-nents) initially suggesting CBN butexhibiting large densely cellular fasciclesor nodules of spindle cells that on closerinspection have sufficient atypicality formalignancy and are distinctly moreabnormal that the usual small fascicular

or alveolar patterns in CBN, and (3) alesion suggesting a benign CBN withadditional atypical features such as largediameter, asymmetry, prominent cellu-lar density, nuclear pleomorphism, andsome mitotic activity at least focallybut not obviously malignant that subse-quently results in malignant behavior(the author terms such lesions biolo-gically indeterminate). In the mostcommon presentation MBN are char-acterized by nodular or multinodularaggregations of spindle cells in tightlypacked fascicles in the dermis and oftenthe subcutis (Figs. 11-27). By definition,there is sparing of the epidermis.Occasional epithelioid cells and multin-ucleate giant cells are encountered.Melanin pigment and cytoplasmic vac-uolization are noted in approximatelytwo-thirds of cases.81 Necrosis, a featurepreviously thought characteristic ofMBN, is observed in only about one-third of cases.82 In general, there is strik-ing cytologic atypia, prominent nuclearpleomorphism, infrequent mitotic fig-ures (approximately one to two mitosesper square millimeter) and uncommonlyatypical mitoses. Most MBN have acomponent of cellular blue nevus (CBN),but elements of common blue nevus(pigmented dendritic melanocytes,fibrosis, and melanophages) and rarelynevus of Ota or Ito may be observed.


MBN must be distinguished from CBNand its atypical variants (see differentialdiagnosis for CBN)9,81,82 and primary ormetastatic melanoma, and clear cell sar-coma. Because there are no histologicfeatures specific for MBN, a contiguousremnant of blue nevus should be identifiedor a history of an antecedent blue nevusdocumented to distinguish MBN fromeither nodular or metastatic melanoma.

BALLOON CELL MELANOMA

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� FIGURE 11-27 Malignant blue nevus (melanoma arising in association with a cellular

blue nevus). Fascicular arrangements of atypical spindle cells, many of which contain

melanin, can be observed in this field.

BOX 11-29 Summary

• Cellular blue nevus and atypical variants


• Clear cell sarcoma

BOX 11-30 Summary

• No distinctive clinical features

• At least 50% of melanoma cells have

abundant vacuolated cytoplasms

• Balloon cells are large round or polyhedral

cells with clear or eosinophilic cytoplasms

• The nuclei are irregularly placed and

exhibit only slight to moderate atypia

• All ages, mean age about 46 years• Scalp most common site• Usually �1–2 cm• Blue-black multinodular appearance

• Histopathologic Features• Often overtly malignant component jux-

taposed to benign usually cellular blue

nevus• Nodule shows confluence and hypercel-

lularity• Often abrupt interface with surrounding

nevus• Lack of maturation• Cytologic atypia



➤ Hyperchromatism

➤ Prominent nucleoli may be present• Sarcoma-like presentation without dis-

tinct benign and malignant components

➤ Hypercellular fascicles or nodules• Cellular blue nevus-like lesion with addi-

tional atypical features

➤ Mitoses in dermal component

�2–3/mm2

Balloon cell melanoma (BCM) exhibitsballooning in at least 50% of themelanoma cells.83,84 The individual “bal-loon cells’ have abundant vacuolatedcytoplasms that impart a clear cellappearance. Knowledge of BCM isimportant so that it is distinguishedfrom the much more common ballooncell nevus and from other clear celltumors of the skin. BCM is reported tohave a particular propensity for multipleskin and subcutaneous metastases.83

Clinical and HistopathologicFeatures

There were no distinctive clinical fea-tures of BCM. The balloon cells are


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large, round, or polygonal cells withclear or eosinophilic, slightly granularcytoplasm.83,84 The nuclei are irregularlyplaced and exhibit only slight to moder-ate atypia. Mitotic activity is also gener-ally low. Melanin has been noted inabout a quarter of cases.84 Metastasesfrom BCM often show balloon cellchange but maybe difficult to diagnosisbecause of they are amelanotic and failto exhibit nesting. Virtually all BCMstudied thus far show positive immuno-staining with S-100 protein and HMB-45.84 A small number may be positivefor carcinoembryonic antigen.


Melanoma is notable for its frequency ofspontaneous regression.9,85–92 The preva-lence of histologic regression variesaccording to the definition of regressionused and the thickness range of themelanomas reported.85–87 In a study of563 cases of primary melanoma, histo-logic regression was noted in 46% of thin(�1.5 mm), 32% of intermediate (1.5–3.0mm), and 9% of thick (�3.0 mm)melanomas.86 McGovern has alsorecorded regression in 58% ofmelanomas �0.70 mm in thickness.87

Complete regression of melanoma isuncommon and has been reported to

occur with a frequency of 2.4 to 8.7%(Fig. 11-28 ).88,89 Many cases of metastaticmelanoma with unknown primary arethought to be explained by spontaneousregression of the primary melanoma.89,90

Spontaneous regression is consideredto be immunologically mediated becauseof mononuclear cell infiltrates contain-ing T lymphocytes, and monocyte/macrophages at the site of regression.91

Regression is seen most often inmicroinvasive or thin melanoma and ispresent as focal, partial, and rarely com-plete regression of the tumor. Thechanges of regression form a continuum,but may be arbitrarily categorized intothree stages (see earlier discusions).92

METASTATIC MELANOMA

BOX 11-31 Summary

• Balloon cell nevus

• Xanthoma

• Hibernoma

• Granular cell tumor

• Primary and metastatic clear cell carcino-

mas, such as renal cell carcinoma

• Liposarcoma

• Clear cell cutaneous appendageal tumors


BOX 11-32 Summary

• Early (or active): Zone of papillary dermis

and epidermis within a recognizable

melanoma, characterized by dense infil-

trates of lymphocytes disrupting/replacing

nests of melanoma cells within the papil-

lary dermis and possibly the epidermis, as

compared to adjoining zones of tumor;

degenerating melanoma cells should be

recognizable. There is no obvious fibrosis.

• Intermediate: Zone of papillary dermis and

epidermis within a recognizable

� FIGURE 11-28 Tumoral melanosis. There is complete regression of melanoma

with residual aggregates of melanophages.

BOX 11-33 Summary

• Melanoma metastasizes through lymphatic

channels, vascular channels, and along the

surfaces of vessels (angiotropism)

• Lymph nodes are the most common sites

of metastases

• Cutaneous metastases are common and

include local satellite, in transit (between

primary lesion and regional lymph nodes),

and epidermotropic metastases

BCM may be confused with balloon cellnevus, xanthoma, hibernoma, granularcell tumor, metastatic clear cell carcino-mas such as renal cell or adenocarcinoma,liposarcoma, and clear cell appendagetumors.83,84 Perhaps, the greatest problemis distinction of BCM from balloon cellnevus. In general, balloon cell nevi occurin young individuals (under age 30 years),show “maturation” of nevus cells(decreased size of cells and nuclei withdepth), the presence of multinucleategiant cells, in contrast to BCM that tendsto develop in older patients, to lack “mat-uration” of melanoma cells, and to havecellular atypia and mitotic activity.

REGRESSION

melanoma, characterized by reduction

(loss) in the amount of tumor (a disruption

in the continuity of the tumor) or absence

of tumor in papillary dermis and possibly

within the epidermis, compared to adja-

cent zones of tumor, and replaced by

varying admixtures of lymphoid cells and

increased fibrous tissue (as compared to

normal papillary dermis) in this zone.

Variable telangiectasia (and new blood

vessel formation), and melanophages may

also be present.

• Late: Zone of papillary dermis and epider-

mis within a recognizable melanoma,

characterized by marked reduction in the

amount of tumor compared to adjacent

areas of tumor, or absence of tumor in

this zone, and replacement and expansion

of the papillary dermis in this zone by

extensive fibrosis (usually dense fibrous

tissue, horizontally disposed) and variable

telangiectasia (and new blood vessel for-

mation), melanophages, sparse or no lym-

phoid infiltrates, and effacement of the

epidermis (other than fibrosis, the latter

features are frequently present but not

essential for recognizing regression).

Melanoma can spread hematogenously,through lymphatic channels, by migra-tion along vascular channels (angiotro-pism) or by direct local invasion andthus may occur in any site of the body.Metastases are more frequent to lymphnodes, skin, and subcutaneous tissue(nonvisceral sites) than to visceralorgans.9,93–101 Lymph nodes are the mostcommon site of metastases and 60 to80% of patients with metastatic


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melanoma develop lymph node metas-tases.96,97 The lymph node groups mostcommonly involved are ilioinguinal,axillary, intraparotid and cervical lymphnodes. The metastatic tumor may beclinically apparent (macroscopic metas-tasis) or detected only by histologicexamination (microscopic metastasis).

Nearly half of the patients with meta-static melanoma develop skin metas-tases,97 which may occur in the area oflocoregional lymphatic drainage or at aremote location. Two subtypes of re-gional cutaneous metastases are arbi-trarily distinguished by their distancefrom the primary melanoma.97

Cutaneous satellites are discontinuoustumor cell aggregates that are located inthe dermis and/or subcutis within 5 cm ofthe primary tumor, whereas in-transitmetastases are located more than 5 cmaway from the primary melanoma. Thefinding of the latter metastases has poorprognostic implications, since the major-ity of patients with such lesions developdisseminated metastatic disease. Althoughvirtually any organ may be involved, themost common first sites of visceral metas-tases reported in clinical studies are lung(14 to 20%), liver (14 to 20%), brain (12 to20%), bone (11 to 17%), and intestine (1to 7%), while first metastases at othersites are very rare (�1%).97,99

Metastatic melanoma has a tendencyto grow in nests, sheets or fascicles,often with an infiltrative border, pleo-morphism, mitoses and necrosis.9,97

Cytologically, epithelioid and/or spindlecells are commonly found in metastaticmelanoma.9,97 Melanin, which greatlyfacilitates the recognition of metastaticmelanoma, may be apparent, subtle orabsent (amelanotic melanoma).

Diagnostic Problems ConcerningMetastatic Melanoma

distinction between a primary and sec-ondary melanoma.9

MELANOMA SIMULATING OTHER NEO-

PLASMS Metastatic melanoma mayassume a great variety of morphologicappearances and may mimic a numberof nonmelanocytic tumors, such as lym-phoma, undifferentiated carcinoma,adenocarcinoma, a variety of sarcomasand many others.102,103 The differentialdiagnosis is particularly difficult in ame-lanotic melanoma. Often, additionalstudies are needed, such as melaninstains, immunohistochemistry using apanel of antibodies, and electronmicroscopy, to identify conclusively ametastatic tumor as melanocytic.

PRIMARY CUTANEOUS VERSUS CUTANEOUS

METASTATIC MELANOMA

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BOX 11-35 Summary

Primary Melanoma Cutaneous Metastasis

Location of tumor Usually both dermis and Dermis and/or subcutis

epidermis

If epidermal involvement Usually prominent; pagetoid Usually dermal component extends

horizontal and vertical spread laterally beyond epidermal

commonly present; usually component; pagetoid spread

epidermal component extends less common

laterally beyond dermal

component

Size Nearly always �0.4 cm and Often small; may be �1.0 cm

usually �1.0 cm and occasionally �0.3 cm

Epidermal collarette Usually less common More likely present

Cytology Usually pleomorphic Usually monotonous

Reactive fibrosis May be marked Usually mild

Vascular invasion Rarely seen Angiotropism

BOX 11-34 Summary

• May mimic a wide spectrum of neoplastic

lesions

• Amelanotic tumors

• Primary versus metastatic melanoma

• Nodal nevus deposits versus metastatic

melanoma in lymph nodes

• Metastatic melanoma with unknown

primary

• Melanosis in metastatic melanoma

� FIGURE 11-29 Epidermotropic metastatic melanoma. There is involvement of the

epidermis by melanoma cells.

the reticular dermis or subcutis and onlyrarely involve the overlying epidermis,while primary cutaneous melanomas typ-ically have an intraepidermal component.In addition, metastases tend to be smaller(often �4 mm) than primary tumors (usu-ally �4 or 5 mm). In cases of metastaticmelanoma showing epidermotropism,the epidermal component is usually rela-tively limited compared to the dermalcomponent (Fig. 11-29). If the dermalmetastasis is superficial, the overlying epi-dermis may be thinned and the lateralborders may show hyperplastic elongatedrete ridges turned inward forming a col-larette. Tumor cells showing angiotropismwithin vascular lumina are more likely tobe found in and around a metastaticlesion than near a primary tumor.

Primary tumors generally displaymore pleomorphism than metastatic

A common problem is distinguishing anepidermotropic metastasis from a pri-mary melanoma (or possibly a nevus insome instances) (Fig. 11-29).98,100,101

Cutaneous metastases usually lie within

lesions, which often appear as an atypi-cal, but rather monomorphous popula-tion of cells. Primary tumors tend toshow more variation in the overall com-position of the lesion. There is often

Several situations may arise in whichthe diagnosis of metastatic melanoma isnot straightforward. The problem maylie in the identification of a metastatic-appearing lesion as melanocytic or in the


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more fibrosis and more of an inflamma-tory host response. When decidingwhether a melanocytic tumor is ametastasis or a primary lesion, one mustweigh the histologic appearance againsta detailed clinical history to arrive at thecorrect diagnosis. The importance ofhaving precise clinical information ismandatory since there are exceptions toall of the guidelines for diagnosis men-tioned above.101

MELANOCYTIC AGGREGATES VERSUS

MICROMETASTASES Collections of smallmelanocytes are occasionally seenwithin lymph nodes (sentinel or other)draining the skin.104–107 These aggregatesare usually small and inconspicuous butmay occupy as much as a third of alymph node. They are usually located inthe fibrous capsule or trabeculae of thenode rather than the marginal sinus,105

but rarely can be found in the lymphatictissue proper. Their bland appearance,frequent resemblance to nevus cells, andtheir location in the fibrous capsule ofthe lymph node help to distinguishthem from micrometastases. However,especially in frozen sections or in therare situation of intranodal location,such aggregates in lymph nodes maylead to diagnostic confusion. There hasbeen considerable debate as to whetherthese nodal melanocytic lesions derivefrom aberrant migration of melanoblastsfrom the neural crest during embryogen-esis or represent lymphatic spread froma benign cutaneous nevus.

METASTATIC MELANOMA WITH UNKNOWN

PRIMARY SITE Approximately 4 to 12% ofpatients with melanoma develop metas-tases without a clinically detectable pri-mary tumor.108,109 While it is possible thatsome melanomas may arise de novo withina lymph node or visceral site, it is generallybelieved that many of these of these casesare related to complete regression of a pri-mary cutaneous melanoma.110,112 Meta-static melanomas with unknown primarysite are twice as common in men as inwomen, which is in agreement with theobservation that tumor regression is morecommonly observed in men as inwomen.112 The most common site of pre-sentation is in lymph nodes (64%)1120

whereas 21% of the cases present withvisceral metastases.

MELANOSIS IN METASTATIC MELANOMA

Cutaneous or generalized melanosis is arare complication of metastatic mela-noma.113–115 Hyperpigmentation may befocal or diffuse, limited to the skin or gen-eralized, involving internal organs.

Histologic Diagnosis of Malignant Melanoma

to melanoma, is upward migration orpagetoid melanocytosis of melanocyteswith involvement of the superficial epi-dermis. A predominance of single cellsover small aggregates or nests typifiesthis pattern in melanoma. Melanomacells are usually present at all levels of theepidermis including the granular andcornified layers.

Characteristics of the dermal compo-nent suggesting melanoma includeasymmetry, confluent or sheet-like pat-terns of melanocytes without matura-tion, heterogeneity, hypercellularity,mitoses particularly in significant-numbers, deeply located, and atypical,necrosis, and prominent host response.

Cytologic atypia is mandatory for adiagnosis of melanoma. There is a uni-formity or monomorphous quality ofthe atypia in melanoma rather than thediscontinuous pattern of atypia oftenfound in atypical nevi. Melanoma is alsonotable for cellular and nuclear enlarge-ment, nuclear pleomorphism, hyper-chromatic nuclei, high nuclear to cyto-plasmic ratios of melanoma cells, andoften prominent nucleoli. Large polygo-nal melanoma cells often have abundantpink granular cytoplasms, finely divided(“dusty”) melanin granules, or less com-monly opaque cytoplasms. The melaningranules may vary considerably in sizeand shape.

DIAGNOSIS OF THE

BORDERLINE OR

CONTROVERSIAL LESION

SUGGESTING MELANOMA

BOX 11-36 Summary

• Size usually �5–6 mm

• Asymmetry

• Poor circumscription

• Pagetoid melanocytosis

• Diminished or absent maturation

• Confluence and high cellular density

of melanocytes

• Effacement of epidermis

• Dermal mitoses

• Cytologic atypia of melanocytes

BOX 11-37 Summary

• Benign lesion

• Biologically indeterminate lesion

• Malignant melanoma

The histologic diagnosis of melanomaremains subjective and usually dependson the recognition of a constellation ofhistologic features, no single featurebeing diagnostic of melanoma.9 Becausethere are so many exceptions to the con-ventional criteria for melanoma, onemust always utilize as much informa-tion as possible and common sense at alltimes. On the other hand, a large per-centage of melanomas are diagnosedcorrectly by a majority of knowledgeableobservers. It is also true that a small per-centage of melanocytic tumors is histo-logically challenging and will produceno consensus even among experts (seefollowing sections).

In general, melanomas are character-ized by an overall asymmetry and disor-der, whereas benign melanocytic lesionstend to have symmetry and order.Although there is no absolute size crite-rion, the larger the lesion is in breadth(generally over 5 to 6 mm and especiallyover 10 mm), the greater is the likeli-hood that the lesion is melanoma.Melanomas are also often character-ized by poor circumscription of theperipherally extending intraepidermalcomponent and heterogeneity. Otherarchitectural attributes suggestingmelanoma include a contiguous prolifer-ation of single (often basilar) melanocytes,considerable variation in the sizes andshapes of intraepidermal cellular nests,and diminished cohesiveness of thenests of cells. There may be a confluenceof melanoma cells along the dermal–epi-dermal junction. The epidermis is fre-quently significantly altered, e.g., thin-ning, effacement, ulceration, hyperplasia,lack of uniformity from side to side,hyperkeratosis, parakeratosis, and re-placed by melanoma as compared tothat in benign melanocytic lesions.

One of the features most characteristicof melanoma, yet one that is not specific

Not all melanocytic lesions at present canbe classified as benign or malignant. Onemust make use all information availablein order to interpret as precisely as possi-ble a difficult melanocytic lesion and toplace it into one of three categories: (1)benign, (2) biologically indeterminate, or(3) malignant, for the optimal communi-cation to and management of the patient.A biologically indeterminate lesion isdefined as one that has some potential(uncertain) risk for local recurrence andmetastasis but one that cannot also beinterpreted as malignant utilizing all cri-teria currently available. The diagnosticexercise should be comprehensive and


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include information such as age, gender,site, clinical characteristics, presence orabsence of ulceration, diameter, thicknessin mm, mitotic rate per square millimeter,possibly immunostaining for prolifera-tive rate (e.g., with Ki 67) and other mark-ers, etc. in order to quantify as much aspossible the abnormalities present thatfavor or argue against melanoma. Thediagnostic evaluation of such a difficultlesion should probably include obtainingthe opinion of a recognized authority inthe field.

PROGNOSTIC FACTORS

IN MELANOMA

and thick ones that do not. A number ofother factors also have been reported toinfluence outcome in patients withlocalized melanoma. However, many ofthese various factors largely derive theireffect from a correlation with melanomathickness and generally fail to remainsignificant after multivariate analysis.Five-year survival for all melanomapatients currently approaches 90%.

However, once regional lymph-nodemetastases have developed 5-year sur-vival drops to the range of about 10 to50%, which is largely related to thenumber and extent of lymph nodes in-volved. The median survival for patientswith distant metastases is approximately6 months. The only factors influencing

The pathology report should include thefollowing minimum information: diag-nosis, i.e., malignant melanoma, in situ orinvasive; depth of tumor invasion in mmmeasured vertically from the granularlayer of the epidermis or from the surfaceof an ulcer with an ocular micrometer;and the adequacy of surgical margins.9

The following histologic changes shouldalso be mentioned if present: ulcerationand microscopic satellites because of newstaging guidelines. Other prognostic fac-tors that may be reported are: mitotic rateper square millimeter, angiotropism, truevascular/lymphatic invasion, marked orvirtually complete regression, desmopla-sia, neurotropism, anatomic level, histo-logic type of melanoma, radial or verticalgrowth phase, and tumor-infiltratinglymphocytes. However, some of thelatter factors are highly correlated withtumor thickness. Thus, there may be noadditional significant information beyondthickness.

MANAGEMENT

CONSIDERATIONS

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BOX 11-38 Summary

Prognostic factor Effect on prognosis

Tumor thickness (mm) Worse with increasing thickness

Levels of invasion Worse with deeper levels

Ulceration Worse with ulceration

Mitotic rate Worse with increasing mitotic rate

Tumor-infiltrating lymphocytes (TILs) Better with TILs

Regression Unsettled; some studies have shown an

adverse outcome while others no effect, or a

favorable outcome

Microscopic satellites Worse prognosis

Angiotropism Worse prognosis

Vascular/lymphatic invasion Worse prognosis but rare

Tumor cell type Better prognosis with spindle cells versus other

cell types

Age Worse prognosis with increasing age

Sex Women have better prognosis than men

Anatomic site Extremity lesions have better prognosis than axial

lesions (trunk, head and neck, palms and soles)

BOX 11-39 Summary

• Essential information• Diagnosis: malignant melanoma, in situ

or invasive• Measured depth (in millimeters)• Presence of histologic ulceration• Presence of microscopic satellites • Adequacy of surgical margins

• Other prognostic information reported to

be significant in some databases

BOX 11-40 Summary

• Optimal biopsy for examination of entire

lesion if possible• Elliptical excision or incision for lesions

suspicious for melanoma

• Complete skin and physical examination;

scanning of visceral organs if specifically

indicated

• Sentinel lymph node biopsy may be consid-

ered for melanomas �1.0 mm in thickness

• Surgical margins• Melanoma in situ: 0.5 cm margins• Melanomas �2 mm in thickness: 1 cm

margins• Melanomas �2 mm in thickness: 2 cm

margins

• Follow-up examinations related to Breslow

thickness, stage, etc.• Every 3–6 months for first 5 years• Every 6–12 months for the remaining 5

to 10 years

Over the past 20 to 30 years, there hasbeen extensive investigation of prognosticfactors in melanoma using large databasesand multivariate techniques.2,14,15,116–119

The most powerful predictors of survivalfrom many such studies have been thick-ness of the primary melanoma (measuredin mm from the granular layer of the epi-dermis vertically to the greatest depth oftumor invasion) and stage or extent of dis-ease, i.e., localized tumor, nodal metas-tases, distant metastases.

Although a number of studies havedescribed “breakpoints” for tumor thick-ness and prognosis, e.g., patients withmelanomas �0.76 mm have almost100% 5-year survival,116 there is nowgood evidence that this inverse relation-ship between thickness and survival isessentially linear. While thickness is thebest prognostic factor available for local-ized melanoma, there are occasionalmelanomas that defy this relationship,i.e., thin melanomas that metastasize

the time to death include number ofmetastatic sites, surgical resectability ofthe metastases, duration of remission,and location of metastases, i.e., nonvis-ceral (skin, subcutaneous tissue, and dis-tant lymph nodes) vs. visceral sites (lung,liver, brain, and bone).

HISTOPATHOLOGIC REPORTING

OF MELANOMA

• Mitotic rate (per square millimeter)• Tumor-infiltrating lymphocytes• Anatomic level, i.e, I, II, III, IV, and V• Angiotropism• Vascular/lymphatic invasion• Desmoplasia-neurotropism• Degree of regression, particularly

�50% of lesion• Radial or vertical growth phase• Histologic subtype


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Biopsy

The optimal method of sampling anypigmented lesion suspicious for mela-noma is complete elliptical excision withnarrow surgical margins of approxi-mately 2 mm. Much has been writtenabout the inappropriate use of shaveand even punch biopsy techniques forsuspected melanomas. Examination ofthe entire pigmented lesion allows forthe greatest chance of accurate diagno-sis and also for the measurement ofBreslow thickness and the assessmentof other prognostic factors. However,particular circumstances such as anexcessively large pigmented lesion, acosmetically or anatomically difficultsite may render complete excisionunfeasible and thus necessitate partialbiopsy as with a punch or incisionaltechnique.

Examination and Staging

Patients with newly diagnosed melanomarequire a complete cutaneous and physi-cal examination with particular attentionto lymphadenopathy and hepatomegaly,and a baseline chest radiograph. If thelatter examinations fail to detect anyevidence of metastatic disease and thepatient has no other symptoms or signs,no further laboratory evaluation is indi-cated. However, patients with mela-noma exceeding 1 mm in thickness andwith no other evidence of metastaticdisease are candidates for sentinellymph node biopsy. Selected patientswith melanomas measuring �1 mm inthickness may be considered for SLNbiopsy if the primary melanoma is ulcer-ated, Clark level IV, or shows extensiveregression. Patients with palpable lym-phadenopathy and other signs andsymptoms require additional evaluationwith various scanning techniques andpossible lymph node biopsy, etc.

Sentinel Lymph Node Biopsy

The introduction of sentinel lymphnode (SLN) biopsy has provided themeans to examine regional lymphnodes for evidence of metastasis inlieu of a major surgical intervention. Ifone or more SLNs harbor bona fidedeposits of metastatic melanoma (versusnodal nevi or indeterminate deposits),completion lymphadenectomy is per-formed. Although SLN biopsy is a cur-rently accepted staging procedure, onlylong-term clinical trials will determine ifthe procedure has any significant effecton survival of melanoma patients.

Therapy for Melanoma

Surgery remains the only effective ther-apy for melanoma if it is diagnosed andcompletely excised at a localized andearly stage of development, i.e., �1 to1.5 mm in thickness. There is currentlyno effective treatment for advancedmelanoma, and only a small percentageof patients survive long after (even lim-ited) the documentation of regionalmetastatic disease.

Surgical Margins for Melanoma

The practical and theoretical benefitsaccruing from excising melanoma withsome cuff of normal tissue are: (1)greater assurance that the primarymelanoma is indeed removed with trulyclear margins and (2) the potentialremoval of microscopic metastatic focinear the primary melanoma. Althoughmuch has been published on the subjectof surgical margins for melanoma, nodefinitive data currently exist on thisissue.120 However, it appears that surgi-cal margins may have no real influenceon survival in melanoma, and marginsprobably in excess of 3 cm (and possiblyeven 1 cm) may provide no benefit topatients. Problems clouding the issue ofmargins for melanoma are the lack ofsufficient knowledge about initial mech-anisms of melanoma metastasis at theprimary site, melanoma recurrence ver-sus persistence of the primary melanomaand melanoma metastasis, and other con-siderations such as field effects. Whenthe mechanisms of melanoma metasta-sis, etc. are better understood, the infor-mation needed to address finally thequestion of optimal margins would beavailable.

For the time being, the current (ratherarbitrary) guidelines for the surgicalmanagement of melanoma are completeexcision of the primary lesion with mar-gins of 0.5 cm for melanomas in situ, 1 cmfor melanomas �2 mm in thickness and2 cm margins for melanomas �2 mm. Itis clear that exceptions exist for theseguidelines such as desmoplastic-neu-rotropic melanoma, e.g., wider marginsof at least 3 cm are probably indicated,and anatomic sites necessitating nar-rower margins.

Follow-up Examinations

Follow-up of melanoma patients is relatedto the stage of disease, e.g., patients withdocumented distant or visceral metastasesrequire the most vigilant surveillance, fol-lowed by individuals with regional lymphnode, in transit or satellite metastases; and

finally those with localized primarymelanomas. The frequency of follow-upexaminations is individualized, but usu-ally at least every 3 months initially forregional and distant metastatic disease.Patients with localized primary mela-nomas of thickness �1 to 1.5 mm com-monly undergo physical examination at 3-month intervals for the first 3 years (theperiod of highest risk for the developmentof metastases), every 6 months thereafterfor 2 years, and once annually for an addi-tional 5 years. Patients with low-riskmelanomas (�1 mm) are generally fol-lowed at 6-month intervals for 3 years andannually thereafter.

FINAL THOUGHTS

The importance of malignant melanomaas a potentially fatal skin cancer amongCaucasian populations worldwide hasreceived critical attention in recent years.As compared to other life-threateningmalignancies such as breast or prostatecarcinoma, melanoma may be diag-nosed by simple inspection of the skinsurface with 80 to 90% accuracy. How-ever, there is currently no objective evi-dence that medical intervention of anykind significantly alters the clinicalcourse of melanoma, potentially otherthan the complete excision of localizedmelanoma at an early stage, e.g., gener-ally �1 mm in thickness. Future investi-gations is needed to establish whethereducation and modification of behaviorsuch as reduced sun exposure and variousmethodologies of skin examination havea significant impact in reducing mortalityfrom melanoma. Future research mustalso attempt to identify useful therapeuticinterventions for metastatic melanoma.

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