Primary

Cutaneous

Melanoma:

A Report from the QueenslandMelanomaProject Neville C. Davis, F.R.A.C.S., G. Roderick McLeod, F.R.A.C.S., Graeme L. Beardmore, F.A.C.D., John H. Little, F.R.C.P.A., Redmond L. Quinn, F.R.C.P.A. and John Holt, Ph.D.

Malignant melanoma of the skin is generally regarded as a particularly viru lent and usually fatal disease, a reputa tion no longer deserved. If individuals are instructed to report any change in a mole, and if physicians are alert to the possibility of melanoma,* the diag nosis can be made at an early biologi cal and potentially curable stage. In Queensland, Australia, there are few major cancers that have as hopeful a prognosis. From 1963 through 1968, all cases of malignant melanoma occurring in Queensland were registered at the Re search Unit of the Princess Alexandra Hospital in Brisbane as part of the Queensland Melanoma Project.' Mi croscopic diagnoses were reviewed by a panel of pathologists, whose agree ment was required before the case was considered proven. More than 1,500 patients with malignant melanoma have been recorded, and form the basis of this article. In Queensland, the average annual incidence rate per 100,000 population was 14 for males and 17 for females, an average annual rate of 16 new pa tients per 100,000 population.2 This is the highest reported incidence in the world. * The

terms

malignant

used synonymously 80

melanoma

in this paper.

and

melanoma

are

No aborigines have been treated for melanoma in Queensland since the study began. No marked predilection was found in persons with a fair com plexion, blue eyes, blond or red hair.2 Unlike squamous cell carcinoma, no particular concentration of melanoma on exposed sites was noted.2 An environmental factor is probably responsible for the high incidence of malignant melanoma in Queensland; sunlight is the most likely etiologic agent, and possibly exerts both a direct and an indirect effect on the develop ment of this skin cancer.3 Dr. Davis is Visting Surgeon, Princess Alexandra Hospital and Coordinator, Queensland Melanoma Project, Brisbane, Q. 4102 Australia. Dr. McLeod is Visiting Surgeon, Princess Alexandra Hospital and Senior Research Fellow, Queensland Melanoma Project, Brisbane. Dr. Beardmore is Visiting Dermatologist, Royal Brisbane Hospital and Honorary Research Fellow, Queensland Melanoma Project, Brisbane. Dr. Little is Director of Pathology, Princess Alexan dra Hospital, Brisbane. Dr. Quinn is Anatomical Pathologist, Princess Alex andra Hospital, Brisbane. Dr. Holt is Lecturer in Numerical Analysis, Depart ment of Mathematics, University of Queensland and Research Fellow, Queensland Melanoma Project, Brisbane. The Queensland Melanoma Project is financially sup ported by the Queensland Cancer Fund and the Clive and Vera Ramaciotti Foundations. We thank Mr. D. Crowley and Mr. R. Fox of the Princess Alexandra Hospital for photographic services and the Queens land Health Education Council for help in preparing the illustrations.

CA—A CANCERJOURNALFORCLINICIANS

Fig. 1.

size.

Malignant melanoma—change

in

Fig. 2. Malignant elevation.

The diagnosis of malignant melanoma is based on the history and clinical appear ance of the lesion, and must be con firmed by microscopic examination after surgical excision. History

I

Change

in

elevation:

A

VOL 26, NO. 2 MARCH/APRIL 1976

I

Change

in

surface

characteris

tics: A previously smooth surface has become rough and scaly. (Fig. 8.) Serous discharge (Fig. 9.) or bleeding after trivial trauma is highly suspi cious of melanoma. (Fig. 10.) Bleed ing is usually relatively minor, com pared to the more profuse hemorrhage that may occur from a hemangioma or pyogenic granuloma.

previously

flat lesion has become elevated or thickened, or a nodule has developed within the tumor. (Fig. 2.) •¿ Change in color: A brown mole has become darker or black. (Fig. 3.) Change in pigmentation may not be uniform, producing all shades of brown, blue, grey, black and pink. (Fig. 4.) Sometimes, a dark mole has

in

developed into a pink or amelanotic tumor (Fig. 5.) that, to an inexper ienced observer, may resemble a granuloma or an infected lesion. The development of pale areas of depig mentation within the pigmented tumor is characteristic, (Fig. 6.) and may be seen under the microscope as areas of local tumor regression. An intensity of pigmentation may also develop at the periphery (Fig. 7.): the descriptive terms “¿halo― or “¿flare― are, however, best avoided as they may connote different images to dif ferent observers.

CLINICALDIAGNOSIS

A history of change, often extending over a period of weeks or months, in a pre-existing mole or the development of a new mole in an adult is of great impor tance in the diagnosis. Malignant mela noma should be suspected if any of the following changes occur: •¿ Change in size: A lesion has spread to a larger area. (Fig. 1.)

melanoma—change

I

Change

in

surroundings:

Pig

mented or amelanotic satellite tumors have developed in the immediate vi 81

@1@

.,@--

4

@

•¿

,—

I—

Fig. 3. Malignant color.

in

melanoma-change

Fig. 4. Malignant melanoma—varietyof colors.

.\@.

—¿

Fig. 5. Amelanotic malignant melanoma.

cinity of an advanced (Fig. 11.) I

Change

in

sensation:

Fig. 6. Pale areas in malignant melanoma.

melanoma. A

mole

has

begun to itch or tingle. In a small proportion of patients, no primary tumor can be found and the first 82

sign of a melanoma is the development of metastases, usually in lymph nodes but occasionally elsewhere.

Gross Morphology The tumor should be examined carefully CA—ACANCER JOURNAL FOR CLINICIANS

C. @: :.. Fig. 7. Malignant pigmentation

melanoma—intensity of

at periphery.

Fig. 9. Ulcerated serous discharge.

malignant

melanoma

with a magnifying lens in a good light. The clinical appearance is often diag nostic even when the patient reports no obvious change in the lesion.4 The size, height, color, surface, outline and the VOL. 26, NO. 2 MARCH/APRIL 1976

Fig. 8. Malignant melanoma—surfacescaly and rough.

presence or absence of hairs should be noted. Clark,5 McGovern6 and their co workers believe that primary cutaneous melanomas, with or without a pre-exist 83

Fig. 11. Satellites from malignant melanoma.

ing nevus, fall into three histogenetic types, which may be recognized both clinically and histologically: 1. malig nant melanoma, invasive, with adjacent intraepidermal component of superficial spreading type (superficial spreading melanoma); 2. malignant melanoma, in vasive, with adjacent intraepidermal component of Hutchinson' s melanotic freckle (lentigo maligna melanoma): 3. malignant melanoma, invasive, without adjacent intraepidermal component (nodular melanoma). Superficial Spreading Melanoma (Fig. 12.) This is the most common type and can occur on any part of the body. It is usually more than 0.5 cm. in diameter and may be several centimeters in size. Superficial spreading melanoma tends to grow more rapidly than a melanoma arising in Hutchinson's melanotic freckle, but usually does not grow as large. Discrete, rounded black, grey or pink nodules can develop within the primary tumor; close inspection re veals a variety of color combinations —¿shades of brown, black, grey, blue, 84

pink and even white. A translucent, dark grey color or pale areas of depig mentation in an overall black mole is particularly suggestive of melanoma. (Fig. 6.) The surface may be scaly, with a crusted, opaque and silvery ap pearance, or ulcerated, causing serous or blood-stained discharge. The skin furrows are usually lost. A few lesions have a verrucous appearance. The out line of the tumor is usually irregular with indentations and protrusions. A surrounding red rim of inflammation can sometimes be seen. It is unusual for coarse hairs to grow from an inva sive melanoma, unless it is situated on the scalp. Lentigo Maligna Melanoma (Fig. 13.)

Hutchinson's melanotic freckle is found most frequently on the malar regions or the temples of persons in their seventies. It may also occur on other parts of the body, habitually exposed to the sun. A Hutchinson's melanotic freckle begins as an irregularly pigmented brown patch that is always flat and CA—ACANCER JOURNAL FOR CLINICIANS

‘¿. 14.

impalpable. It grows very slowly over a period of 10 to 15 years, advancing and regressing in no fixed manner. There is usually a great variation in color from brown to tan to black, in uniform or irregular patches. Malig nant melanoma developing in Hut chinson's melanotic freckle is charac terized by thickening and later by discrete black or amelanotic tumor nodules, developing within the macu lar part. By this time, the lesion is four to six cm. in size. A very irreg ular outline is characteristic of this tumor. Nodular Melanoma (Fig. 14.)

This type of malignant melanoma may occur anywhere on the skin, exposed or unexposed. It has no antecedent spread ing of pigmentation and even when it arises in association with a pre-existent junctional nevus, there is no warning en largement of the nevus prior to invasion of the dermis. When first noted clini cally, this lesion is always palpable and usually convex in shape. The majority of polypoidal melanomas fall into this VOL. 26, NO. 2 MARCH/APRIL 1976

Typical

nodular

malignant

group. Rarely, a plateau-shaped lesion may be encountered. Nodular mela noma has a relatively uniform color ation, including shades of blue-black, blue-grey and reddish-blue, but an amel anotic lesion is occasionally observed. It rapidly increases in size and, ne glected, may grow to several centime ters in diameter. Ulceration occurs early in the course of the disease. With experience, the degree of der mal invasion of a melanoma can be pre dicted. When tumor cells are intraepi dermal (i.e., melanoma in situ) the le sion is flat or only just palpable. With commencing invasion of the papillary dermis, there is greater thickening de tectable by the examining finger. Deeper invasion results in tumor nodules.

DIFFERENTIALDIAGNOSIS Benign Melanocytic Tumors No two lesions are so alike in appear ance as moles and melanomas, but so different in subsequent behavior. Yet, careful examination can often differen Text continued on page 97. 85

BENIGN PIGMENTED NEVI

Junctional

Nevus (Fig. 15.)

Clinical History The lesion may have altered in size or color but the change has been gradual, often with the growth of the child.

Life History I

Appearance I

Size:

Varies

from

a few

millimeters

to two cm. •¿ Color: Light to dark brown or black. May be speckled. •¿ Surface: Usually flat and smooth, but may be palpable. I

Edge:

Arises

I

Usually May

remain

I

May

regress.

May

develop

I

Differential Features

I

Regular

age of most pattern

I

Visible

I

No

I

Melanomas

in the

junc

into compound

nevus

nevus. inactive. into

melanoma,

but

very

rarely before puberty.

Note

Young

evolves

I

Histology Single or clusters of five or more nevus cells in the lower epidermis.

I

melanocytes

or intradermal

Regular.

I

from

tional zone of the epidermis. It is theorized that melanocytes migrate to the epidermis from the neural crest of the embryo and therefore are derived from the neuroectoderm.

skin

patients.

•¿ Usually appears in the first few years of life, but may occur at any age. Often

occurs

in

crops

in

adolescent

patients.

of color.

furrows.

indentations

of outline.

are usually

readily

palpable.

86

CA—ACANCER JOURNAL FOR CLINICIANS

ill11111 111111 IIiltI. 111111 Compound

Nevus (Fig. 16.)

Clinical History The lesion may have altered in diameter, height or color but the change has been slow. Size:

Color:

I

Surface:

I

Usually

less

than

one

cm.

but

Brown

I

into

intradermal

May

acquire

a

depigmented

halo

Elevated

may

May

rarely

develop

into

malignant

melanoma. I

and

finely

nodular

Giant

nevus

may

become

malignant.

Note I

Most

I

Comprises

ring around periphery. Hairs

develops

to black.

or smooth. •¿ Edge: May have light brown macular I

Commonly

nevus. (halo nevus).

may be huge, as in a giant nevus (e.g., bathing trunk nevus). I

•¿ Develops from junctional nevus.

I

Appearance I

Life History

be

present.

common

in adolescents. the

great

I

May

be

clinically

from intradermal

Histology Nevus cells in both the lower epidermis and the dermis.

majority

of

pig

mented nevi in children.

I

May

bear

indistinguishable

nevus.

a superficial

malignant melanoma raised center.

resemblance

to

by virtue of its

Differential Features I

Young

age

of patients.

•¿ Orderly color and pattern.

VOL. 26, NO. 2 MARCH/APRIL1976

87

@

@@—¿â€˜i@ir'—'@'--@-@—--@l1uuuI1huhl1huulhI11 --.I@r'--'--@-------@

‘¿-‘-‘i@1f@

Intradermal

Nevus (Fig.17.)liiiI

Clinical History The lesion may have altered in diameter, elevation or color but the change has been slow. Size:

Usually

less

than

one

cm.

in size

but may be huge, as in a giant nevus (e.g., bathing trunk nevus). •¿ Color: Skin tone to light or dark brown. I

Surface:

Usually

raised

but

may

Hairs

may

General

inactivity.

be present

and

I

Develops

from

I

Usually

benign.

I

Giant

nevus

may

compound

nevus.

become

malignant.

Note •¿ This is the common mole on face and

scalp of adults.

be

warty, flat and smooth, sessile, pe dunculated or papillary. •¿ Edge: Regular. I

I

Life History

Appearance I

DifferentialFeatures •¿ Presence of hair.

I

Infection

(e.g.,

from

hair

plucking)

may cause a painful lump beneath the nevus and confuse the diagnosis.

coarse.

Histology Nevus cells predominantly or entirely within the dermis.

88

CA—ACANCER JOURNAL FOR CLINICIANS

Spitz Nevus (Fig. 18.) Appearance I I

Size: Color:

Usually

less

Generally

than pink

one or red

Life History Almost always remains benign but ma

cm. but

may

be brown or black. I

Surface:

Usually

dome-shaped

but

sometimes sessile or pedunculated. May be soft or hard. •¿ Edge: Regular. I

lignant change has been reported.

Note I I

Occurs

particularly

in children

uncommon

in adults.

May

anywhere

occur

on

but

not

body.

Hairless.

Histology Predominantly a compound lesion com posed of plump epithelioid spindle cells with large nuclei and nucleoli. Mononu clear and multinucleated giant cells common. Extension into dermis tends to be sinuous and permeating rather than destructive. Histological distinction re

quires an experienced pathologist.

___________________ —¿@—.——. . VOL.26,NO.2 MARCH/APRIL 1976

89

@

@-

-...

-

-:

Halo Nevus (Fig. 19.) Synonyms:

Leukoderma

acquisitum

Clinical History White ring develops around a brown nevus. Size:

I

Color:

Less

than

Central

two

papule,

sur

depigmentation. Surface:

I

Edge:

I

Hairless.

Flat

or barely

palpable.

Well-circumscribed.

Histology A compound nevus with a heavy disruptive infiltration of lymphocytes, histiocytes and a few plasma cells surrounded by a margin of melanin free epidermis.

90

and benign-looking

nevus in center dis

Life History

cm.

brown

rounded by a pale white circle of I

Differential Features Regularity of circle of depigmentation tinguishes it from regressing melanoma.

Appearance I

centrifu gum, Sutton ‘¿s nevus.

With time, the central brown nevus dis appears leaving a small depigmented patch, probably the result of some im munological process. Note I

Totally

benign.

I

Occurs

especially

on

backs

of

chil

dren and adolescents. I

May

cause

attention

when

it becomes

sunburned.

CA—ACANCER JOURNAL FOR CLINICIANS

@

@‘¿ @r

C

@

4

@

‘¿.;.@-

@. -.

@..-

... .@ s—-'-'

.

‘¿[email protected].*_

1.1I 11111 I I 111111111111111111 Blue Nevus (Fig. 20.) Clinical History

DifferentialFeatures

There is often no history of change.

I

Characteristic

I

Raised

I

Regular

outline.

I

Slight

induration.

Appearance I I

Size:

Usually

less

Royal

blue,

Color:

than

one

cm.

blue-black

Surface:

Smooth

and

flat

or

slightly

Edge:

Usually

well-defined

cytes

Hairless.

are believed

to have

into melanoma.

Histology Noncircumscribed collections of elon gated hyperpigmented melanocytes and shorter, thicker melanophages in the

dermis. More cellular variants termed cellular blue nevi.

which

failed to complete their migration from the neural crest to the epi dermis. •¿ A cellular blue nevus rarely changes

and

regular. I

color.

Life History •¿ Develops in the dermis from melano

elevated. The skin seems to be tightly stretched. I

blue

surface.

or gun

metal blue. I

regular

smooth

Note I

Occurs

especially

on

the

face,

but

tocks and dorsum of the hands and feet.

are I

The

blue

color

is

due

to

the

refraction

of light by the collagen fibers superfi cial to the pigment cells. I

VOL. 26, NO. 2 MARCH/APRIL1976

The

pigment

is melanin.

91

NON-MELANOCYTIC

TUMORS

.@,

Seborrheic Synonym:

Keratosis

Senile wart, acanthotic

Usually

remains

unchanged

or

the

rate of change is slow. I

Small

pieces

of

off with minor slight bleeding diagnosis.

the

lesion

may

flake

trauma, leading to and confusing the

I

Seems

I

Friable,

I

A

few

millimeters

to

several

Color:

Yellow,

light

brown,

grey

Surface:

Usually

raised,

warty

and

greasy, but may be smooth and sessile or dry and rough-pitted. I

Edge:

I

Hairless.

Regular.

I

92

basal

cells

skin. off.

Arises

from

of

the

epi

Almost

always

benign;

malignant

is rare.

The

most

common

tumor

of

the

skin

in persons of middle age or older. I

Usually

occurs

in adults

with

greasy

skin. I

Common

I

Often

I

Melanocytes

on the

trunk,

face

and

neck.

multiple. incorporated

in

the

pro

liferating basal cell clumps produce pigmentation.

Histology Proliferation of basal cells with epithe hal cyst formation and hyperkeratosis. Melanocytes and melanin pigment may

be present.

be picked

Note or

black. I

the

can

transformation

centimeters. I

parts

dermis. I

Size:

as if “¿stuck― on

Life History

Appearance I

basal cell papilloma.

DifferentialFeatures

Clinical History I

(Fig. 21.)

nevus, pigmented

I

Only

a small

percentage

mimic

mela

noma. I

Bleeding

and

infection

may

confuse

the diagnosis.

CA—ACANCERJOURNALFORCLINICIANS

Senile Hemangioma Synonym: Appearance I

Size:

I

Color:

I

Surface:

I

Edge:

I

Palpation:

(Fig. 22.)

Venous lake. Differential Features

Usually

less

than

five

mm.

I

Smooth,

Easily

compressible

producing

Bluish-red.

Compressible.

Histology Greatly dilated capillaries.

a glass

slide

tensity of color and size.

raised.

Well-defined.

with

significant reduction in in

I

Reddish-blue

color,

compared

with

the blue-black of melanoma. Throm bosis can produce a blue-black color and firmness, which may confuse the diagnosis. Life History

Usually seen on face and upper trunk in patients over 50 years old.

VOL. 26. NO. 2 MARCH/APRIL 1976

93

.@,

@

1@1@1 st@i@1 @j I Sclerosing Synonym:

Hemangioma

Clinical History Lesion may have grown but the rate of change is very slow. Size:

I

Color:

Usually Generally

Surface:

I

Edge:

Smooth Easily

I

Superficial.

•¿ Hard and non-tender on palpation. Attached

to epidermis,

freely

mobile

over deeper tissues. less

than

one

pink

cm.

but

may

be

dark brown. I

histiocytoma.

DifferentialFeatures

I

Appearance I

(Fig. 23.)

Dermatofibroma,

UféHistory I

and defined,

well-circum

Reaches

a maximum

size

and

then

re

mains static; rarely regresses.

featureless. I

Never

becomes

malignant.

scribed, slightly raised. I

Usually

hairless.

Histology A dermal collection of histiocytes, fi brous tissue, blood vessels and iron pig ment, varying in proportion from lesion to lesion.

94

Note I

Described

as feeling

like

“¿lead-shot―

in the skin. I

Usually

I

Most

I

Pigment

occurs common

in adults. on

legs.

is hemosiderin.

CA—A CANCERJOURNALFORCLINICIANS

Granuloma

Telangiectatum

Synonym:

Clinical History Often develops rapidly after a minor in jury or infection. Appearance I

Size:

I

Color:

Usually Dull

less red,

than like

two an

Surface:

May

be ulcerated

often pedunculated. I

Edge:

I

Hairless.

Histology

A pedunculated proliferation of capil laries in edematous and inflamed stroma, with frequent ulceration of the overlying epidermis.

cm. amelanotic

melanoma, but may be pigmented. I

(Fig. 24.)

Pyogenic granuloma.

DifferentialFeatures I

Growth

usually

more

rapid

than

in

melanoma.

or crusted, I

More

persistent

bleeding

with

minor

traumathan in melanoma.

Regular. I

Compressible.

Life History

VOL. 26, NO. 2 MARCH/APRIL 1976

I

Spontaneous

I

No

malignant

resolution

rare.

change.

95

Pigmented

Basal Cell Carcinoma

DifferentialFeatures

Clinical History I

The

lesion

has

slowly

increased

in

size, usually over a-period of months or years. I

May

have

slowly

become

darker.

Size:

Usually

less

than

one

cm.,

I

Different

color

pattern

mela

than

noma. I

Pearly

edge

with

venules.

local

tissue

Life HIstory

Appearance I

(Fig. 25.)

but

I

Progressive

I

Rarely

destruction.

metastasizes.

may be larger. I

Color:

Unevenly

distributed

Note

bluish

black pigmentation, especially toward periphery. Stretching exhibits pearly appearance. I

I

Surface:

Smooth,

nodular

or cystic

I I

on

the

head

and

neck

of

The

pigment

is

of

two

kinds

melanin and hemosiderin. The former

at

first, but may ulcerate producing a central depression.

is due to incorporation of the melano cytes in the collections of tumor cells,

Edge:

and the latter to hemorrhage from small vessels in the tumor.

Raised

and

smooth;

fine

yen

Hairless.

Histology Malignant basal cells arising from the epidermis and invading the dermis.

96

occur

middle-aged persons.

ules may be visible. I

Most

I

Only

a

few

basal

mimic melanoma;

cell

carcinomas

particular

culty occurs with pigmented

diffi

nodular

lesions.

CA—ACANCER JOURNAL FOR CLINICIANS

tiate these lesions clinically. The widely accepted view that ma lignant melanomas commonly arise from pre-existing junctional nevi has recently been challenged by Clark.5 He believes that moles are not pre malignant lesions, and that the in creased frequency of malignant change in these benign lesions can be explained by the increased number of melanocytes at the site of the mole. Whether or not this theory is correct, there is little doubt that at least 30 percent of malignant melanomas arise from the melanocytes of moles. Unlike melanom@s, benign moles typically exhibit an orderly array of color and a regularity of pattern.7 A brown lesion may exhibit fine dots of black pigment that are evenly placed and result in a neat symmetrical stip pling. The outline is usually discrete and regular, but may appear fuzzy when viewed with a hand lens. Nor mal skin marking is usually visible. Hairs often grow in and around a be nign mole. In pregnancy, new moles often appear and pre-existing ones become darker.

WhenThe DiagnosisIs Doubtful

@

If the diagnosis is unclear, a second opinion should be sought before the le sion is excised. An infected wound or hematoma at the site may make clinical assessment of the regional nodes diffi cult and delay definitive surgery. In ad dition, the wound may be situated so that surgery is more difficult and mutilating. The first treatment should be definitive. Several alternatives are available in the treatment of a patient with a sus pected malignant melanoma. One is to excise the tumor under local anesthesia and await rapid paraffin section, which should be available within 48 hours. While it is not our practice, we have no objection to preliminary biopsy exci sion, provided the patient is made fully aware that further surgery in a few days may be necessary. When feasible, we VOL. 26, NO. 2 MARCH/APRIL 1976

believe that the whole tumor, but not the deep fascia, should be excised. Another alternative is to excise the tumor as described above and examine the specimen by the frozen section tech nique. Should the tumor be a malignant melanoma, the depth of invasion and the histogenetic type of tumor can usually

be determined, and guide the extent of subsequent

surgery.

Of the two methods, we prefer frozen section examination of doubtful skin le sions. At the Princess Alexandra Hospi tal, a series of 329 frozen sections from 316 patients have been reviewed with an accuracy rate of 98.8 percent.8'9 If the diagnosis of malignant melanoma is cer tain—and it is possible to be remarkably accurate in the clinical diagnosis—the lesion can often be widely excised without waiting for frozen section exam ination. However, we believe a patient should never be subjected to lympha denectomy without histological proof of cancer.

SURGICALTREATMENT Deciding on Extent of Surgery Not all patients with malignant mela noma should undergo the same treat ment. The clinical and pathological fea tures of the tumor, its anatomical site, as well as the age and sex of the patient influence the prognosis and should be considered before deciding on the extent of excision.1° Prognostic Factors Patients with melanomas on the limbs fare better than those with melanomas on the back. (Fig. 26.) Tumors less than two cm. in size have a better prognosis than larger Flat lesions have a better prognosis than pedunculated or polypoid tumors.'2 Ulceration is asso ciated with poor prognosis.'2 Women, particularly of premenopausal age,'3 always survive longer than men, if other factors are equal. (Fig. 27 and Fig. 28.) 97

0@@

z > > I

90

z 0

H

C I

> H -J

C C 70

0

1

2

7 YEARS

4

0 AFTER

7

8

9

10

@REATMENT

Fig. 26. Age-adjusted survival curves for 1,187 patients with cutaneous melanomas, by site, Queensland, 1963-1967.

However, the depth of tumor invasion and the profile of the tumor cells are probably the most important factors in prognosis. If the tumor cells are con fined to the epidermis (melanoma in situ) or invade only to the papillary layer of the dermis (superficial malignant mela noma), the outlook is excellent. (Fig. 29.) If the melanoma has arisen from a Hutchinson's melanotic freckle (lentigo maligna) the prognosis is usually good,5 probably because the tumor is slow to invade deeply. In contrast, if the mela noma has invaded to the reticular layer of the dermis or beyond, particularly if the dermal lymphatics are involved, the prognosis is poor. (Fig. 29.)

Recommendations After considering all factors, the practi cal problem of how widely and deeply 98

to excise a melanoma in an individual patient should be determined. The extent of surgery advised in the literature varies widely, with a margin of from two to 15 cm.'4'15 For lesions such as a subungual melanoma, amputa tion of a digit or extremity has been ad vocated.16 Olsen favors preserving the deep fascia,'7 while Cade prefers a three-dimensional excision, which in cludes the deep fascia.'8 Pack and col leagues go further and recommend the inclusion of routine, elective regional node dissection with excision of the pri mary skin tumor.'9 A good standard margin for initial consideration is five cm. If the prognosis is thought to be good, the margin may be reduced. For example, a melanoma arising in a Hutchinson's melanotic freckle on the face of an elderly female CA—ACANCERJOURNALFORCLINICIANS

I > > 19

C

U@)

2:

80 > H -J

C C.)

70 0@ @EARS-7FTFR

TREATMENT

Fig. 27. Age-adjustedsurvivalcurves for 664 females with cutaneous melanomas, by site, Queensland,1963-1967. requires excision with a margin of one cm. or even less, depending on anatomi cal considerations. If the prognosis is considered poor, for instance, a mela noma on the back of a male, the width of excision may be increased. However, it has not been proven that this affects the result. All depends on surgical judgement; a two cm. margin may be adequate for a small, slowly growing superficial spreading melanoma on the leg of a female and yet grossly inade quate for a large ulcerating nodular le sion near the axilla of a male, which may be better treated by excision with a mar gin of more than seven to 10 cm. toward the axilla and an in-continuity lymph node dissection. Olsen has shown better results of ex cision when the deep fascia was pre served than when it was removed.'7 We VOL. 26, NO. 2 MARCH/APRIL 1976

have not been able to confirm this find ing, and the issue may not be of vital

importance. We usually include the deep fascia when present, in order to reduce the risk of cutting too close to the deep surface of the tumor. The defect after excision should be covered by a split skin graft rather than a flap, except in special circumstances. Local recur rence is much easier to detect in a split skin graft than under a local flap. One point must be re-emphasized: the initial treatment of a melanoma is the most crucial, as it carries the greatest possibility of cure.

Roleof Lymphadenectomy Therapeutic lymphadenectomy is indi cated if the regional lymph nodes drain ing a primary cutaneous melanoma are clinically involved or suspected. If they 99

C 2: > > I

C (I)

z H I

C w > H -J

C

C

(-)

0

1

2

3

4

YEARS

5 4PTER

6

7

8

9

10

TREAT81ENT

Fig. 28. Age-adjusted survival curves for 523 males with cutaneous melanomas, by site,

Queensland,1963-1967.

are not clinically involved, there is a good deal of controversy on the value of prophylactic (elective) lymph node dis section. We believe there is no place for the routine removal of apparently nor mal nodes. Obviously, the procedure can be beneficial only when apparently normal lymph nodes contain metastases; unfortunately, there is no way of know ing this information before operation. However, a knowledge of the factors which suggest, on statistical grounds, a good or bad prognosis, helps forecast whether the lymph nodes contain metas

tases. For example, we believe that ob servation, rather than elective dissec tion, is indicated when the lesion is con fined to the epidermis or papillary layer of the dermis. These issues have been discussed elsewhere 20 Elective lymph node dissection 100

should rarely be done when: I

the

lesion

is in an

area

with

unpredic

table lymph drainage, for example, the middle of the back; I

the lesion

is at a considerable

in

distance

from the regional nodes, e.g., below a knee or an elbow, and an in-continu ity dissection is not feasible; I

the

lesion

is

small,

flat

and

not

ul

cerated; I

the lesion

has

undergone

no change

or

very little change over a period of a year or more; I

the

lesion

arises

in

a

Hutchinson's

freckle; I

the

patient

is

a female

or

unfit

for

major surgery; I

the

patient

I

the

follow-up

declines; facilitites

are

excellent.

It is not easy to decide on absolute indications for elective dissection, but it CA—ACANCERJOURNALFORCLINICIANS

C

z > > I

C LI)

2:

C H

C C U.)

>

H -J

C C U

YEARS

Fig. 29.

Age-adjusted

AFTER

TREATMENT

survival curves for 1,130 patients with cutaneous melanomas,

by stage,

Queensland,1963-1967. seems reasonable to advocate the proce dure when a deeply invasive melanoma or a pedunculated melanoma overlies or is immediately adjacent to the regional lymph nodes. In patients with a poor prognosis, it may not be significant whether elective dissection is performed or a waiting pol icy is adopted, provided the follow-up is good. However, many surgeons advo cate lymph node dissection for patients with poor prognoses even though some will die of blood-borne metastases. Knowing the statistical frequency of oc cult metastases in different circum stances may make the decision clearer. In summary, elective dissection should be considered when: I

the

primary

tumor

is in the

immediate

vicinity of regional nodes or relatively close to a lymph node area; VOL. 26, NO. 2 MARCH/APRIL 1976

I

the primary

tumor

is in an area

where

it can be expected to have a bad prog nosis; I

there

is microscopic

evidence

of

pe

dunculation or invasion to the reticu lar dermis or beyond; I

the

lesion

is large,

or pedunculated I

the

lesion

ulcerated,

nodular

and rapidly growing;

was

previously

inade

quately excised or treated by cautery; I

the

patient

is a male

or

fit for

major

surgery; I

the

patient

requests

the

procedure

after discussion of its pros and cons; I

the

follow-up

facilities

are

poor.

When possible, the operation should be synchronous with excision of the pri mary tumor and all tissue between the primary growth and nodes removed in continuity with radical dissection of the nodes. 101

.1@i1iEi@t± anhI@I

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@

iii I @41 IllI 111 III@iII1iIi@ -

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.

. ,@:

105'\[SlFN

Fig.30. Age distributionof 1,187patientswith cutaneousmelanomas,Queensland,1963-1967.

SURVIVALDATA Data on survival are presented for all 1,187 patients with cutaneous malignant melanoma treated in Queensland be tween 1963 and 1967, and then sub divided by sex and site, according to the Life Table method.2' The closing date of this study was June 30, 1974, giving all patients a minimum follow-up period of five years. The loss to follow-up in the first five years was less than five per cent. After the fifth year, those patients with incomplete follow-up were termed “¿lost to follow-up― for the purposes of this study. Therefore, the statistical sig nificance of the survival rates after five years decreased. 102

Methods Survival data, except for the age-ad justed cumulative survival rate, were computed using the Biochemical Com puter Programs soft-ware package (pro gram BMDOIS) of the U.C.L.A. Com puter Center,22 and the PDP- 10 digital computer of the University of Queens land Computer Center. The input data for the program BMDOIS were con structed from magnetic tape files con taining patient records updated to in clude follow-up information until June 30, 1974. Survival rates were based on time of first treatment. For the purposes of this paper, all deaths were regarded as the result of the melanoma.

The age-adjusted cumulative survival CA—A CANCERJOURNALFORCLINICIANS

VOL. 26, NO. 2 MARCH/APRIL 1976

103

rate (the fraction of patients alive at a given time, divided by the fraction of controls with the same age distribution expected to be alive at that time) pro vided a base for comparison of survival from one group of patients to another. In calculating age-adjusted survival, the expected survival rates of the control groups were determined by using the Australian Life Tables for 1966, pub lished by the Commonwealth Bureau of Census and Statistics.23 Although the great majority of patients were from Queensland, no published Life Tables were available from this area for any pe nod during 1963-1967. Unpublished 1966 Life Table data for Queensland re vealed no significant difference from the Australian Tables, and the latter were adopted.

Results

nomas and with unknown primary tumors have been excluded. The trunk and the lower extremity were the two most common sites. Sex Distribution

Of the 1,187 patients, 664 (55.9 per cent) were women and 523 (44.1 per cent) were men. The most common sites in women were, in order of frequency, lower leg, upper arm and back and in men, the back, face and lower leg. Age The age distribution of all patients is shown in Fig. 30. The highest incidence for the whole group and for each sex occurred in patients between 35 and 49 years old.

Anatomical Distribution

Age-Adjusted Cumulative Survival

Table 1 shows the anatomical distri bution of cutaneous melanomas by sex. Patients with multiple primary mela

The age-adjusted cumulative survival data for the entire series of 1,187 pa tients is shown in Table 2, and the curves

VOL 26, NO. 2 MARCH/APRIL 1976

105

in Fig. 26. As can be seen, 81.6 percent survived five years.

Of the 1,130 patients whose tumors were staged, 113 (10 percent) had Stage I; 237 (21 percent), Stage II; 715 (63 Survival of Women percent), Stage III; and 65 (six percent), The age-adjusted survival data for the Stage IV. 664 women is shown in Table 3, and the The age-adjusted survival curves for curves, subdivided by site, in Fig. 27. 1,130 patients, subdivided by histo Overall five-year survival for women logical stage, are shown in Fig. 29. At was 87.7 percent. Highest survival rates five years, there were no deaths in pa were found in women with melanomas tients with Stage I melanomas. Five on the limbs; the next highest in those year survival for patients with Stage II with lesions on the head and neck. Sur lesions was 93.1 percent; for those with vival was worst for tumors on the trunk. Stage III lesions, it was 80.6 percent and for those with Stage IV lesions, 37.8 Survival of Men percent. The age-adjusted survival data for the Of 1,187 patients, 79 (6.7 percent) 523 men is shown in Table 4, and the had confirmed metastases either at the curves, subdivided by site, in Fig. 28. beginning of treatment or within one Overall five-year survival for men was month. Of these 79 patients, 60 (five 73.6 percent. Five-year survival was percent) had metastases in the regional highest for lesions on the upper limb, lymph nodes; the remainder had distant rather than the lower limb, followed by metastases. This is a remarkably low head and neck. It was worst for tumors figure when compared with other series. on the trunk. A comparison of our survival data with four major well-documented series Survival Related to Depth of Invasion from the United States,25 England26 and The depth of tumor invasion has been Denmark'7 shows that patients treated subdivided by our pathologists into four for malignant melanoma in Queensland histological stages:24 have better survival rates than patients I. Tumors limited to the epidermis, with the same disease in these other i.e., intraepidermal (melanoma countries. in situ) Why? We believe improved survival II. Invasion of the papillary zone of is due to two factors: public and profes the dermis (superficial malignant sional education. The Queensland pub melanoma) lic is aware of the incidence of skin III. Invasion of the reticular dermis cancer and the potential danger of any IV. Invasion of subcutaneous fat change in a mole, due largely to contin (“Staging― considered in this section is ual publicity from the Queensland Anti histological and does not refer to spread Cancer Council and the Queensland of the tumor beyond its primary site.) Health Education Council. Primary phy The description of the depth of invasion sicians are alert to the possibility of mel in “¿levels,― developed in 1969 by Clark anoma in any pigmented lesion, often and others,5 was accepted by an interna make the diagnosis at an early biological tional meeting of pathologists in Syd stage and immediately refer the patient ney, Australia.6 Our histological stages for appropriate surgery. correspond to Clark's levels as follows: Similar practices in all parts of the world could change the whole spectrum Stage I = Level I Stage II = Levels II or III of the disease and significantly improve Stage III = Level IV the outlook of patients with malignant Stage IV = Level V melanoma. 106

CA—ACANCERJOURNALFORCLINICIANS

References 1. Davis, NC., and Herron, ii.: Queensland melanoma project: organization and a plea for comparable surveys. Med. J. Aust. 1: 643-644, 1966. 2. Beardmore, G.L.: The epidemiology of malig nant melanoma in Australia. In: McCarthy, W.H. (ed.): Melanoma and Skin Cancer. Sydney: Gov ernment Printer, New South Wales, 1972. 39-64. 3. Davis, NC.: Aetiological factors in melanoma. In: Transactions of Fifth Congress of Plastic and Reconstructive Surgery. Butterworths, Australia, 1971. Pp. 3-8. 4. Davis, NC.; Herron, J.J., and McLeod, G.R.: The macroscopic appearance of malignant mela noma of the skin. Med. J. Aust. 2: 883-886, 1966. 5. Clark, W.H. Jr.; From, L.; Bernardino, E.A., and Mihm, M.C.: The histogenesis and biologic behaviour of primary human malignant melanomas of the skin. Cancer Res. 29: 705-727, 1969. 6. McGovern, V.J. et al.: The classification of malignant melanoma and its histological reporting. Cancer 32: 1446-1457, 1973. 7. Clark, W.H. Jr., and Mihm, MC. Jr.: Moles and malignant melanoma. In: Dermatology in Gen eral Medicine. New York: McGraw Hill, 1971. Pp. 491-5 11. 8. Little, J.H., and Davis, NC.: Frozen section diagnosis of suspected malignant melanoma of the skin. Cancer 34: 1163-1172, 1974. 9. Davis, NC., and Little, J.H.: The role of frozen section in the diagnosis and management of malig nant melanoma. Br. J. Surg. 61: 505-508. 1974. 10. Davis, NC., and McLeod, G.R.: The surgery of primary melanoma: problems and practice. Med. J. Aust. 2: 778-781, 1972. 11. McLeod, G.R.C.: Factors influencing the prognosis in malignant melanoma. In: McCarthy. W.H. (ed): Melanoma and Skin Cancer. Sydney: Government Printer, New South Wales, 1972. Pp. 367-373. 12. Little, J.H.: Histology and prognosis in cutan eous malignant melanoma. In: Melanoma and Skin Cancer, Proceedings of the International Cancer

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Conference. Sydney: Government Printer, New South Wales, 1972. Pp. 107-119. 13. McLeod,G.R.; Beardmore,G.L.; Little,J.H.; Quinn, R.L., and Davis, N.C.: Results of treatment of 361 patients with malignant melanoma in Queensland. Med. J. Aust. 1: 1211-1216, 1971. 14. Southwick, H.W.: Malignant melanoma. How much surgery. Minnesota Med. 47: 1233-1238, 1964. 15. Hiles, R.W. et al.: Malignant melanoma of the skin. In: Taylor, S. (ed): Recent Advances in Surgery: London: Churchill, 1969. 16. Attic, J.N., and Khafif, R.A.: Melanotic Tumors. Springfield, Illinois: C.C. Thomas, 1964. 17. Olsen, G.: The malignant melanoma of the skin. The Finsen Institute and Radium Centre, Copenhagen, 1966. 18. Cade, S.: Malignant melanoma. Ann. Roy. Coil. Surg. Eng. 28: 331-366, 1961. 19. Pack, G.T.; Scharnagel, I., and Morfit, M.: The principle of excision and dissection in continu ity for primary and metastatic melanoma of the skin. Surgery 17: 849, 1945. 20. Davis, NC., and McLeod, G.R.: Elective lymph-node dissection for melanoma. Br. J. Surg. 58: 820-823, 1971. 21. Cutler, S.J., and Ederer, F.: Maximum utiliza tion of the life table method in analyzing survival. J. Chron. Dis. 8: 699-713, 1958. 22. Dixon, W.J. (ed): Biomedical computer pro grams. Los Angeles: University of California Press, 1973. 23. Caffin, SN.: Australian life tables 1965-1967. Commonwealth Bureau of Census and Statistics, Canberra, Australia. 24. McGovern, V.J. et al.: Moles and malignant melanoma: terminology and classification. Med. J. Aust. 1: 123-124, 1967. 25. Knutson. CO.: Hon. J.M., and Spratt, J.S. Jr.: Melanoma. Curr. Probl. Surg. 3-55, 1971. 26. Bodenham, D.C.: A study of 650 observed malignant melanomas in the southwest region. Ann. Roy. Coil. Surg. 43: 218-239, 1968.

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