skin malignancies

8/3/2019 Skin Malignancies

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SKIN MALIGNANCIESREF:(SCHWARTZ 9/E)

Key Points

1. The epidermis consists of five layers. The two most superficial layers (the stratum corneum and lucidum)

contain nonviable keratinocytes.2.Collagen IIIprovides tensile strength to the dermis and epidermis.

3. Adult dermis contains a 4:1 ratio of type I:type III collagen.

4. Of the congenital skin disorders, onlypseudoxanthoma elasticum andcutis laxia are responsive to

surgical rejuvenation.

5. Hemangioma is the most common cutaneous lesion of infancy and a large majority spontaneously involute

(resolve) past the first year of patient age.

6. Basal cell carcinoma (BCC) is the most common form of skin cancer and nodular BCC is the most frequent

form of this tumor.

7.Breslow thickness is the most important prognostic variable predicting survival in those with cutaneo

melanoma.

Although malignancies arising from cells of the dermis or adnexal structures are relatively uncommon, the skin i

frequently subject to epidermal tumors, such as basal cell carcinoma (BCC), SCC, and melanoma.Perhaps of gresignificance is that increased exposure to UV radiation is associated with an increased development of all skin

cancer.

In addition, albino individuals of dark-skinned races are prone to develop cutaneous neoplasms that are typicall

rare in nonalbino members of the same group. This observation suggests thatmelanin, and its ability to limit U

radiation tissue penetration, plays a large role in carcinogenesis protection.

RISK FACTORS

y Chemical carcinogens such as tar, arsenic, and nitrogen mustard.y Radiation therapy directed at skin lesions increases the risk for local BCC and SCC.6972y HPVhave been linked toSCC.y Chronically irritated or nonhealing areas such as burn scars, sites of repeated bullous skin sloughing, an

decubitus ulcers present an elevated risk of developingSCC.6972

y Immunosuppressedpatients receiving chemotherapy, those with advanced HIV/AIDS, andimmunosuppressed transplant recipients have an increased incidence of BCC, SCC, and melanoma.

(OXFORD 2/E)

Benign acquired pigmented lesions of the skinBenign acquired pigmented lesions are important for three reasons. First, these lesions must be distinguished fro

cutaneous melanoma, which occasionally may be a diagnostic problem.Second, some benign acquired pigmentelesions are potential precursors (e.g. dysplastic nevi) for melanoma and are markers of increased risk for cutane

melanoma People with greatly increased numbers of benign acquired nevi (even non-dysplastic) are also at incr

risk of melanoma developing. Third, the presence of lentigines and caf-au-lait macules may indicate the presencertain neurocutaneous syndromes, some of which have surgical implications.

Distinguishing benign pigmented lesions from melanoma

Most benign acquired pigmented lesions are not difficult to distinguish from cutaneous melanoma since they lack

irregularity of border, surface, and pigment pattern found in radial growth phase melanoma. Lesions that may

difficulty include some dysplastic nevi, irritated seborrheic keratoses, traumatized hemangiomas, pyogenic

granulomas, pigmented basal cell carcinomas, and blue nevi. The last, with its melanin pigment located in the m

dermis, may resemble the nodular form of cutaneous melanoma.


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(OXFORD 2/E)

Table 1 Benign acquired pigmented lesions

Lentigo

Flat, uniformly medium, or dark brown lesion with sharp borders. Solar lentigines are acquired

lesions on sites of chronic solar exposure (backs of hands/face). Lesions are 2 mm to 1 cm Solar

lentigines have reticulate pigmentation when examined by magnification

Nevus, junctionalFlat to barely raised brown lesion. Sharp border. Fine pigmentary stippling noted especially upon

magnification

Nevus, compound

Round or oval shape, well demarcated, smooth bordered. May be dome shaped or papillomatous;

colors range from flesh-colored to very dark brown, individual nevi being relatively homogeneous in

color

Blue nevus

Gun metal or cerulean blue, blue-gray. Stable over time. One-half occur on dorsa of hands and feet.

Lesions are usually single, small (3 mm to < 1 cm) Must be distinguishedfrom nodular

melanoma

Seborrheic keratosisRough, stuck on, waxy feeling with sharp borders ranging in color from flesh to tan, to dark brown.

Presence of keratin plugs in surface help in discriminating dark lesions from melanoma.

Pigment

dermatofibroma

Lesion is not well demarcated visually, is firm, and dimples downward when compressed laterally.

Usually on extremities. Usually < 6 mm in diameter

HemangiomaDome-shaped reddish, purple, or blue nodule. Compression with a glass microscope slide may result

in blanching. Must be distinguished from nodular melanoma

Subungual

hematomaMaroon (red-brown) coloration. As lesions grows out from nailfold, a curving clear area seen

Tattoos, medical ortraumatic

Medical tattoo lesions are made up of small pigmentary dots, often blue or green, which make aregular pattern (rectangle). Traumatic tattoos are irregular, and pigmentation may appear black

Pigmented basal cell

carcinoma

Dark blue-black papule or plaque on sun-exposed skin, most commonly on the head and neck. May

have a translucent, rolled border

Benign acquired nevi as markers of increased melanoma risk

Melanocytic nevi can be either precursors or markers of increased risk for melanoma. As precursors, it is

recognized that approximately one-third to one-half of all melanomas arise within previously benign

melanocytic nevi (usually dysplastic nevi). The development of a change in color or size in a previously stable

pigmented skin lesion may be one of the earliest changes in the development of melanoma. Signs such as

ulceration and bleeding are less common in early melanoma and more frequently occur in advanced disease.

The presence ofincreased numbers of benign acquired nevi greatly increased the risk for cutaneous melanom

Clinically atypical nevi or dysplastic nevi (a.k.aClark's nevi, B-K mole, atypical nevus, FAMMM

mole) are recognized markers for cutaneous melanoma, and are potentialprecursor lesions. The dysplastic

nevus was first described in patients with familial melanoma by Clark and namedB-K moles after the index

families studied, and by Lynch who termed this thefamilial atypical multiple mole melanoma (FAMMM)

syndrome.In melanoma-prone families, the risk for cutaneous melanoma appears to be transmitted as a

dominant trait.

Both the number and type of nevi have been identified as elevating the risk of melanoma


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(OXFORD 2/E)

Table 2 Clinical features distinguishing dysplastic nevi from benign acquired nevi

Clinical

eature Dysplastic nevi Benign acquired nevi

Color

Variable mixture of tan brown, black, or red/pink

within a single nevus; nevi may look very different from

each other

Uniformly tan or brown

Shape

Irregular borders; pigment may fade off into

surrounding skin; macular portion at the edge of the

nevus

Round; sharp, clear-cut borders between the

nevus and the surrounding skin; may be flat or

elevated

SizeUsually more than 6 mm; may be more than 10 mm;

occasionally smaller than 6 mmUsually less than 6 mm in diameter

NumberOften very many (more than 100), but occasionally

may be only one

In a typical adult:10 to 40 are scattered over the

body; perhaps 15 per cent of patients have no nevi

Location

Sun-exposed areas; the back is the most common

site, but dysplastic nevi may also be seen on the scalp,

the breasts, and buttocks

Generally on the sun-exposed surfaces on the skin

above the waist; the scalp, breasts, and

buttocks are rarely involved

Spitz nevi (spindle and epithelioid cell nevi,juvenile melanoma)

The Spitz nevus, also termed benign juvenile melanoma, described by Sophie Spitz in 1948, deserves special

comment since the diagnosis and appropriate management of these lesions may be difficult. Also termed spindle

and epithelioid cell nevi, from the histopathologic appearance, the Spitz nevus does not only occur in children

and adolescents, but also in adults. The typical history is the sudden appearance of a flesh-colored to pink or red

dome-shaped papule or nodule (although in individuals with a dark complexion the lesion may be deeply

pigmented). Mitoses and cells with an atypical appearance may be present, and the pathologist may be tempted

to regard these as melanoma.

Diagnostic biopsy should ideally be excisional and should extend to the full depth of the lesion.

It is usually treatedwith complete excision to prevent local recurrence.

Local recurrence has been reported to be infrequent in incompletely removed Spitz nevi.

Follow-up

These patients should undergo regular cutaneous examination to exclude the unlikely possibility that the lesion

was actually a melanoma masquerading as a Spitz nevus.

(OXFORD 2/E)

Neurocutaneous syndromes

The presence of benign lentigines and caf-au-lait macules are helpful in the recognition of certain

neurocutaneous syndromes Several of these syndromes may present with signs and symptoms requiring

surgical therapy for alleviation. An example would be the development of acoustic neuroma in patients with

neurofibromatosis or gastrointestinal polyps in PeutzJegher's syndrome.


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Table 3 Syndrome characterized by lentiginosis

Syndrome Synonym Inheritance*Cutaneous findings Associated features

Multiple

lentigines

syndrome

LEOPARD

syndrome

AD Multiple, hyperpigmentedLlentigines, EECG

abnormalities

macules, especially on the torso Oocularhypertelorism

Mucosal surface spared Ppulmonary stenosis

Aabnormal genitalia

(infantilism, cryptorchidism)

Rretardation of growth

Ddeafness (sensorineural)

LAMB and

NAME

syndromes

Syndrome

myxoma?

Multiple lentigines ephelides, blue

nevi,Llentigines, Aatrial myxoma

mucocutaneous myxoma Mmucocutaneous myxoma

Bblue nevi

Nnevi

Aatrial myxoma

Mmucocutaneous myxoma

Eephelides

PeutzJegher's

syndrome

Periorificial

lentiginosisAD (SM ) Brown to black macules

Gastrointestinal polyp especially

at jejunum

Characteristically around the mouth,

on lips and buccal mucosa. May also

occur on the hands and feet

Greater risk of gastrointestinal

and non- gastrointestinal

malignancies

Cronkhite-Canada

syndrome

?Brown macules commonly on faceand extremities. Alopecia and

dystrophic nail changes

Multiple gastrointestinal polyps

* AD, autosomal dominant; SM, spontaneous mutation.


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Table 4 Cutaneous manifestations of neurofibromatosis

Pigmentary

Axillary freckling

Caf-au-lait spots

General hyperpigmentation

Hypopigmented macules (rare)

Large pigmented macules overlying plexiform neurofibroma

Lisch nodules (iris)

Non-pigmentary

Angiomas

Atrophic hypoplastic macules (rare)

Blue-red macules

Malignant Melanoma

Melanoma may arise from transformed melanocytes anywhere that these cells have migrated during normal

embryogenesis. Although nevi (freckles) are benign melanocytic neoplasms found on the skin of many people,

dysplastic nevi contain a histologically identifiable focus of atypical melanocytes. These lesions are thought to

represent an intermediate stage between benign nevus and true malignant melanoma.

Once the melanocyte has transformed into the malignant phenotype, tumor growth occurs radially in theepidermal plane.7376 Even though microinvasion of the dermis may have occurred, metastases do not occur

until these melanocytes form dermal nests. During the subsequent vertical growth phase, cells develop

different cell-surface antigens and their malignant behavior becomes much more aggressive.

Although the eye and anus are notable sites, over 90% of melanomas are found on the skin76 In addition, 4% of

tumors are discovered as metastases without any identifiable primary site. Suspicious features suggestive of

melanoma include any pigmented lesion with an irregular border, darkening coloration, ulceration, and raised

surface.In addition, approximately 5 to 10% of melanomas are nonpigmented.In order of decreasing frequency, thefour types of melanoma are superficial spreading, nodular, lentigo ma

and acral lentiginous.7376 The most common type, superficial spreading, accounts for up to 70% of melanoma

These lesions occur anywhere on the skin except the hands and feet. They are typically flat and measure 1 to

in diameter at diagnosis.7376 Before vertical extension, aprolonged radial growth phase is characteristic of

lesions.

Typically of darker coloration and often raised, the nodular type accounts for 15 to 30% of melanomas.7376 Th

lesions are noted for their lack of radial growth; hence, all nodular melanomas are in the vertical growth pha

diagnosis. Although considered a more aggressive lesion, the prognosis for patients with nodular-type melanom

similar to that for a patient with a superficial spreading lesion of the same depth.

Lentigo maligna accounts for 4 to 15% of melanomas, and occurs most frequently on the neck, face, and hands

the elderly.7376 Although they tend to be quite large at diagnosis, these lesions have the bestprognosis because

invasive growth occurs late.


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Acral lentiginous melanoma is the least common subtype, and is rare in white populations. Although acra

lentiginous melanoma among dark-skinned people is relatively rare, this type accounts for 29 to 72% of all

melanomas in dark-skinned people (African Americans, Asians, and Hispanics).74,75Acral lentiginous melanoma

frequently is encountered on the palms, soles, and subungual regions. Most common on the great toe or thumb,

subungual lesions appear as blue-black discolorations of the posterior nail fold. The additional presence of

pigmentation in the proximal or lateral nail folds (Hutchinson's sign) is diagnostic of subungual melanoma.

Prognostic indicators

y Those with lesions of the extremities have a better prognosis than patients with melanomas of the head, or trunk.

y Lesion ulceration carries a worse prognosis.y Gender:Numerous studies demonstrate thatfemales have an improved survival compared to males.y Lentigo maligna types, however, have a better prognosis even after correcting for thickness, anda

lentiginous lesions have a worse prognosis.

(OXFORD 2/E)

Primary tumor thickness remains the most critical prognostic indicator in this malignancy. While early

diagnosis and surgical excision of in situ, or early invasive melanomas, is curative in most patients, the efficacy

treatment of advanced melanoma remains limited.Risk profiles

Increase in size and change in color are the two most common characteristics of early cutaneous melanoma. Th

increased risk associated with increasing numbers of nevi and with sporadic and familial dysplastic nevi is

reviewed elsewhere.

MacKie has proposed an algorithm that can be used in screening to distinguish between high- and low-risk

people. Those who freckle, have three or more dysplastic nevi, three or more severe sunburns, or 20 or more nev

have an increased risk of about 600-fold (men) or 200-fold (women) over people with none of these factors

Table 2 Risk factors for cutaneous melanoma(OXFORD 2/E)

Greatly elevated (>40-fold increase)

Mole exhibiting persistent changesDysplastic nevus in a patient who has two family members with

melanoma

Adult versus child

>50 nevi 2 mm in diameter

Moderately elevated (approximately five- to

10-fold)

Family history of melanoma

Personal history of melanoma

Dysplastic nevi, non-familial

Caucasian vs. Oriental or black subjectsCongenital nevi (?)

Slightly elevated (two- to fourfold)

Immunocompromised individuals

Excess solar exposure or sun sensitivity


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Risk Factors(M.D.ANDERSON 4/E)

1. Skin type: People with a white racial background have at least ten times the melanoma incidence ofAfrican Americans and seven times the melanoma incidence of American Hispanics. In addition, white

patients who are fair or who have red hair, light skin, or blue eyes have a particular propensity to be at

increased risk for melanoma.

2. Age: The incidence of melanoma increases with age3. Gender: In general, the incidence of melanoma is higher in men than in women. Specifically, a man's

risk of melanoma development over his lifetime is 1.7 times a woman's risk.

4. Tanning bed use5.Previous melanoma:6.Sunlight exposure: There is a correlation between the number of severe and painful sunburn episodes

and the risk of melanoma; patients who have a history of ten or more severe sunburns are more than

twice as likely to develop a melanoma compared with patients who have no history of sunburns.. The

effects of sunlight have been attributed to exposure to UV-B radiation, which, according to

hypothetical mechanisms of melanoma induction, may account for approximately two-thirds of

melanomas.

7.Benign nevi: Although a benign nevus is mostlikely not a precursorof melanoma, the presence oflarge numbers of nevi has been consistently associated with an increased risk of melanoma.

Persons wimore than 50 nevi, all of which are greater than 2 mm in diameter, have 5 to 17 times the melanoma ris

of persons with fewer nevi.

8.Family history:9.Genetic predisposition: Another genetic alteration that may play a role is mutation in the B-RAF gen

RAF proteins are a family of serine/threonine-specific protein kinases that form part of a signaling

module that regulates cell proliferation, differentiation, and survival. Most studies have concluded that

B-RAF is not a melanoma predisposition gene. Rather, some investigators have proposed a model in

whichB-RAF plays a key role in protecting against progression in the early stages of the

disease. One mutation, a glutamic-acid-for-valine substitution at position 600 (V600E), accounts for

more than 90% of theB-RAF mutations in melanoma. This mutation causes activation of downstream

effectors of the mitogen-activated protein kinase-signaling cascade, leading to melanoma tumor

progression by an unknown mechanism.10.Atypical mole and melanoma syndrome: Previously known as dysplastic nevus syndrome,

atypical mole and melanoma syndrome(FAMM) is characterized by the presence of large numbers of

atypical moles (dysplastic nevi) that represent a distinct clinicopathological type of melanocytic lesion.

They can be precursors of melanoma and/or markers of increased melanoma risk.

(M.D.ANDERSON 4/E)

Amelanotic melanomas are melanomas that occur without pigmentation changes. These lesions are

uncommon and are more difficult to diagnose because of their lack of pigmentation. Factors such as change in

size, asymmetry, and irregular borders suggest malignancy and should prompt a biopsy.

Fingers andToes

More than three-fourths of subungual melanomas involve either the great toe or the thumb. A melanoma locatedon the skin of a digit or beneath the nail should be removed by a digital .In general, amputations are performedat the middle interphalangeal jointof the fingers or proximal to the distal joint of the thumb. More proxima

amputations are not associated with improved survival. For a melanoma located on a toe, an amputation of the

entire digit at the metatarsal-phalangeal joint is indicated; for melanomas of the great toe, the amputation can b

performed proximal to the interphalangeal joint. Lesions arising between two toes may require amputation of

both toes.


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Table 4 Clinical features of malignant melanoma(OXFORD 2/E)

Type Site

Average age

of diagnosis

(years)

Duration of

known

existence

(years)

Color

Lentigo

maligna

melanoma

Sun-exposed surface

particularly malar

region of cheek and

temple

70 520a or large

In flat portions, shades of brown and tan

predominant, but whitish gray occasionally

present; in nodules, shades of reddish brown

bluish gray, bluish black

Superficial

spreading

melanoma

Any site (more

common on upper

back and in women

lower legs)

4050 17

Shades of brown mixed with bluish red

(violaceous), bluish black, reddish brown an

often whitish pink, and the border of lesion i

at least in part visibly and/or palpably

elevated

Nodular

melanoma Any site 4050

Months to


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papillary/reticular dermal junction; IV, reticular dermis; and V, subcutaneous fat],Breslow modified the appr

to obtain a more reproducible measure of invasion by the use of an ocular micrometer. The lesions were measur

from the granular layer of the epidermis or the base of the ulcer to the greatest depth of the tumor(I, 0.7

or less; II, 0.76 to 1.5 mm; III, 1.51 to 4.0 mm; IV, 4.0 mm or more).

Diagnosis&Investigation

Diagnosis of melanoma typically requires excisional biopsy. A 1-mm margin of normal skin is taken if the woundbe closed primarily. If removal of the entire lesion creates too large a defect, then an incisional biopsy of a

representative part is recommended. Biopsy incisions should be made with the expectation that a subsequent wi

excision of the biopsy site may be done.

(OXFORD 2/E)

Total excisional biopsy with narrow margins is the procedure of choice for the diagnosis of cutaneous melanoma

Either punch (trephine) or incisional biopsy can be used when total excisional biopsy is not easily accomplished.biopsies are not appropriate if a melanoma is suspected, as this procedure disrupts the tumor and precludes acc

microstaging.When partial biopsies are performed, biopsy of the most raised portion will usually be sufficient fodiagnosis. In flat or plaque-type lesions biopsy of the darkest portion most frequently produces a representative

specimen.Final determination of melanoma type and thickness (important for prognosis) must await complete

excision, however.

Table 30-2 -- American JointCommittee on CancerTNM MelanomaClassification2002

PrimaryTumor(T)

Tis Melanoma in situ

T1 Melanoma 1.0 mm in thickness, with or without ulceration

T1a Melanoma 1.0 mm in thickness and level II or III, no ulceration

T1b Melanoma 1.0 mm in thickness and level IV or V or with ulceration

T2 Melanoma 1.01-2.0 mm in thickness, with or without ulceration

T2a Melanoma 1.01-2.0 mm in thickness, no ulceration

T2b Melanoma 1.01-2.0 mm in thickness, with ulceration

T3 Melanoma 2.01-4.0 mm in thickness, with or without ulceration

T3a Melanoma 2.01-4.0 mm in thickness, no ulceration

T3b Melanoma 2.01-4.0 mm in thickness, with ulceration

T4 Melanoma >4.0 mm in thickness, with or without ulceration

T4a Melanoma >4.0 mm in thickness, no ulceration

T4b Melanoma >4.0 mm in thickness, with ulceration

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in one lymph node

N1a Clinically occult (microscopic) metastasis

N1b Clinically apparent (macroscopic) metastasis

N2 Metastasis in two or three regional nodes or intralymphatic regional metastasis without nodal metastases


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N2 Clinically occult (microscopic) metastasis

N2 Clinically apparent (macroscopic) metastasis

N2c Satellite or in-transit metastasis without nodal metastasis

N3 Metastasis in four or more regional nodes, matted metastatic nodes, in-transit metastasis, or satellites with metastasis i

regional node(s)

Distant Metastasis (M)

MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

M1 Metastasis to skin, subcutaneous tissue, or distant lymph nodes

M1 Metastasis to lung

M1c Metastasis to all other visceral sites or distant metastasis at any site associated with elevated serum LDH

Table 7 Prognostic variables for clinical stage I/II melanoma

Effects on prognosis

Primarytumour

variables

Tumor thickness Increasing thickness worsens prognosis

Clark level Deeper level of invasion worsens prognosis

Mitotic rate High mitotic activity worsens prognosis

Prognostic index Higher index; poorer prognosis (PI is a

(thickness mitoses) purported better indicator than thickness alone)

Tumor volume Increased volume worsens prognosis; better indicator than thickness but difficult to quantify

Ulceration (gross ormicroscopic)

Presence worsens prognosis

Microscopic satellitosiPresence worsens prognosis; correlates with higher frequency of local recurrence, regional nodal meta

and disseminated disease

Regression Controversial, may be adverse when present in vertical growth phase melanoma

Host factors

Anatomic subsite Scalp, acral lesions, possibly poorer prognosis; forearm, leg (except feet) possibly better prognosis

Age Prognosis worsens with increasing age

Sex Women survive longer than men

Treatment

Regardless of tumor depth or extension, surgical excision is the management of choice. Lesions 1 mm or less in

thickness can be treated with a 1-cm margin.7376 For lesions 1 mm to 4 mm thick, a 2-cm margin is recommende

Lesions ofgreater than 4 mm may be treated with3-cm margins.7376 The surrounding tissue should be remdown to the fascia to remove all lymphatic channels. If the deep fascia is not involved by the tumor, removing it

not affect recurrence or survival rates, so the fascia is left intact.

Treatment of regional LNs

In patients with thin lesions (less than 1 mm), the tumor cells are still localized in the surrounding tissue, and t

cure rate is excellent with wide excision of the primary lesion; therefore treatment of regional LNs is not

beneficial.


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With lesions deeper than 4 mm, it is highly likely that the tumor cells already have spread to the regional LNs

distant sites. Removal of the melanomatous LNs has no effect on survival. Most of these patients die of metastati

disease before developing problems in regional nodes.

In patients with intermediate-thickness tumors (T2 andT3, 1 to 4.0 mm) and no clinical evidence of nod

metastatic disease, the use of prophylactic dissection (elective LN dissection on clinically negative nodes) is

controversial.

Sentinel lymphadenectomy for malignant melanoma is gaining acceptance. The sentinel node may bepreoperatively located with the use of a gamma camera, which identifies the radioisotope injected into the prima

lesion.7781 Whereas preoperative identification may provide the surgeon greater reliability in localizing the LN,

intraoperative mapping with 1% isosulfan blue dye injection may be equally effective.7781 Both techniques identif

lymphatic drainage from the primary lesion, and determine the first (sentinel) LN draining the tumor area.7781

micrometastasis is identified in the removed node by frozen-section examination, a complete LN dissection is

performed.7781 This method may be used to identify patients who would benefit from LN dissection, while sparin

others an unnecessary operation.

All microscopically or clinically positive LNs should be removed by regional nodal dissection. When groin LNs

removed, the deep (iliac) nodes must be removed along with the superficial (inguinal) nodes, or disease will rec

that region. For axillary dissections, the nodes medial to the pectoralis minor muscle also must be resected.77

lesions on theface, anterior scalp, and ear, a superficial parotidectomy to removeparotid nodes and

modified neck dissection is recommended.

Metastatic lesions

Solitary lesions in the brain, GI tract, or skin that are symptomatic should be excised when possible. As the treat

choice for patients with symptomatic multiple brain metastases, radiation therapy producedmeasurable improLocally recurrent, lymphatic-invading, or tumors unamenable to surgical excision present a significant manage

challenge. In-transit disease (local disease in lymphatics) develops in patients with a high-risk primary melanom(>1.5mm).Hyperthermic regional perfusion with a chemotherapeutic agent (e.g., melphalan) is presen

treatment of choice. The goal of regional perfusion therapy is to increase the dosage of the chemotherapeutic

maximize tumor response while limiting systemic toxic effects. Melphalan generally is heated to an elevated

temperature [up to 41.5C, (106.7F)] and perfused for 60 to 90 minutes. Although difficult to perform and assoc

with complications (neutropenia, amputation, death), it does produce a high response rate (greater than 50%).74

The introduction of tumor necrosis factor alpha or interferon-2alfa with melphalan results in improved respons

more toxicity


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IMMUNOTHERAPY

Interferon alfa-2b is the only Food and Drug Administrationapproved adjuvant treatment for AJCC stages

IIB/III melanoma.80,81 In these patients, both the relapse-free interval and overall survival were improved with u

of INF-2alfa.

Melanoma cells contain a number of distinctly different cell-surface antigens, and monoclonal antibodies have braised against these antigens.One defined-antigen vaccine has entered clinical testing; the ganglioside GM2.Gangliosides are carbohydrate antigens found on the surface of melanomas as well as many other tumors.

(OXFORD 2/E)

In summary, there is now strong evidence that1-cm margins are safe and efficacious for melanomas less tha

1 mm in thickness. For melanomas greater than 1 mm in thickness there remains controversy regarding optimal

excision margins.

The optimal excision margin for in situ or thick melanomas(>4 mm) has not been rigorously studied to dat

a controlled, randomized surgical trial. The most recent National Institutes of Health consensus conference in 19

recommended0.5-cm margins for melanomas in situ. For thick primary melanomas (>4 mm), many surgeon

prefer to take margins greater than 2.0 cm.

Sole of the Foot(M.D.ANDERSON 4/E)

Excision of a melanoma on the plantar surface of the foot often produces a sizable defect in a weight-bearing are

possible, a portion of the heel or ball of the plantar surface should be retained to bear the greatest burden of

pressure. Where possible, deep fascia over the extensor tendons should be preserved as a base for skin coverage.

plantar flap, which can be raised either laterally or medially, can provide well-vascularized local tissue for weig

bearing areas, while also providing some sensation. More recently, staged closure of some plantar melanomas,

particularly of the heel, have been performed with initial use of a vacuum-assisted closure device to stimulate

granulation tissue followed by staged skin graft application.

Management of In-TransitDisease(M.D.ANDERSON 4/E)


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Traditionally, in-transit disease has been described as recurrent locoregional disease found in the dermis or

subcutaneous tissue between the primary melanoma and the regional lymph node basin. This pattern of recurre

is unique to melanoma and is reported to occur in 5% to 10% of melanoma cases.

For patients with in-transit metastases confined to a limb that are not amenable to standard surgical measures

(e.g., patients with recurrent and/or multiple in-transit metastases and patients with large-burden in-transit

disease), regional chemotherapy techniques such as isolated limb perfusion or, more recently, isolated limb infus

may be considered. Amputation is rarely indicated.

(OXFORD 2/E)

Elective lymph node dissection

The role of elective lymph node dissection (ELND) in patients with American Joint Commission on Cancer stage

melanoma has been one of the most controversial aspects in the surgical management of melanoma. The debate

focused primarily on the role of ELND in intermediate thickness melanomas(1-4mm), as thin melanomas

rarely have nodal metastases making the value of ELND in this group low. Similarly, most patients with melano

thicker than 4 mm fail from systemic metastases and ELND does not appear to improve their prognoses.

Sentinel lymph node biopsy has been recently developed and is a minimally invasive staging procedure whi

may obviate the need for performing an ELND. This technique involves using lymphoscintigraphy to map precis

the nodal basin draining the primary melanoma, and thus identify the initial lymph node that drains from the

primary tumor to determine if melanoma is present in that basin. One per cent Lymphazurin Blue dye is injected

around the lesion to permit intraoperative localization of the first node draining the lymphatic basin, the sentine

node, that the primary melanoma drains to. This allows subsequent histopathologic examination to determine th

presence or absence of tumor in the blue sentinel node. The sentinel lymph node biopsy facilitates identification o

those patients who have subclinical micrometastases in a minimally invasive way and target these patients for n

dissection. Selective lymph node biopsies therefore can identify only those with nodal involvement without

subjecting the vast majority who lack metastases to the morbidity of ELND.To improve the intraoperativelocalization of the sentinel node a radioactive tracer, technetium-99, has been utilized with intraoperative

localization with a hand-held gamma probe.

Other recent refinements of the sentinel node procedure have involved attempts by pathologists to improve th

detection of micrometastases in the sentinel node after removal. Conventional routine histopathology and

immunohistochemistry may yield false-negative results on pathologic examination of the sentinel node, promptithe use ofreverse transcriptase assays for messenger RNA for the tyrosinase gene.The significance of'metastases' detected solely bypolymerase chain reaction remains to be determined.

Adjuvant therapy

Until recently, there has been no standard therapy for patients with resected melanoma who are at high risk for

recurrence (adjuvant therapy). Interferon-a2b (20 MU/m2/day, given intravenously, 5 days/week for 4 week

this was followed by maintenance therapy of 10 MU/m2/day, given subcutaneously, three times a week for 4

weeks) in treated node-positive resected patients.

(MANUAL OFCLINICAL ONCOLOGY6/E)

Patients who present with involvement of regional lymph nodes (high-risk group) and patients with localized thitumors (i.e., thickness >4 mm, or between 2 and 4 mm with ulceration, or thickness >4 mm with ulceration

[intermediate-risk group]), may benefit from adjuvant therapy.

ECOGTrial 1648. Patients enrolled in the large, randomized ECOG 1648 trial were treated with high doses ofI

2b. The schedule consisted of IV therapy at maximal-tolerated doses of 20 MU/m2 5 days/week for 4 weeks

followed by 10 MU/m2 subcutaneously three times a week for additional 48 weeks.

When patients were followed for a longer time, and when the pooled analysis of three high dose IFN-2b clinical

trials was performed, the difference in overall survivalwas not statistically significant.


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Side effects of INF therapy

fatigue, nausea, fever, depression, neutropenia, and reversible elevation of liver enzymes.

Autoimmunity as a complication of therapy with IFN- can result in the development of clinical AI syndrome

(hyperthyroidism, hypothyroidism, hypopituitarism, vitiligo, antiphospholipid syndrome) or of autoantibodies

(antithyroid microsomal, antithyroglobulin, antinuclear, anti-DNA, antiplatelet, or antiislet-cell antibodies).

Recommendations/ Indications

After discussion of side effects, adjuvant treatment with IFN- should be offered to patients with completely reseskin melanoma of stages IIB, IIC, and III, who are


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(M.D.ANDERSON 4/E)- Limb perfusion/Hyperthermic Isolated Limb Perfusion..)

Hyperthermic isolated limb perfusion with melphalan has been used to treat in-transit metastases of the extremi

since the mid-1950s. Melphalan is currently the most active single agent for use in hyperthermic isolated limb

perfusion.

The routine use of hyperthermic isolated limb perfusion in the adjuvant setting has marginal, if any, benefit.

Although hyperthermic isolated limb perfusion may be effective as primary treatment for in-transit metastases, isolated limb perfusion technique involves a complex and invasive operative procedure entailing expensive

equipment, long operating times, and considerable ancillary staff. In an attempt to achieve similar results using

complex techniques, a new regional chemotherapy technique, isolated limb infusion, has recently been

developed for the management of in-transit metastases.

Isolated Limb Infusion

Isolated limb infusion is essentially a low-flow isolated limb perfusion performed via percutaneously inserted

catheters, butwithoutoxygenation of the circuit.

In general, using standard radiologic techniques, catheters are inserted percutaneously into the main artery and

vein of the unaffected limb and delivered intravascularly to the contralateral tumor-bearing extremity. Under

general anesthesia, after a pneumatic tourniquet is inflated proximally, cytotoxic agents (generally melphalan a

actinomycin-D) are infused through the arterial catheter and hand-circulated with a syringe technique

20 to 30 minutes. Progressive hypoxia occurs because, in contrast to isolated limb perfusion, no oxygenator is us

The hypoxia and acidosis associated with isolated limb infusion are therapeutically attractive because numerous

cytotoxic agents, including melphalan, appear to damage tumor cells more effectively under hypoxic conditions.

fact, hypoxia and acidosis have been reported to increase the cytotoxic effects of melphalan.

At the completion of the drug exposure, the limb vasculature is flushed with a crystalloid solution via the arteria

catheter, and the effluent is discarded. Although the limb tissues are exposed to the cytotoxic agent for only a sho

period (up to 30 minutes), there appears to be adequate cellular uptake for tumor cell killing. Isolated limb infus

has been shown to yield response rates similar to those observed after conventional hyperthermic isolated limb

perfusion

Because of the simplicity of the isolated infusion technique, it may be a more attractive option for patients with

comorbidities or the elderly.

Toxicity and MorbidityHyperthermic isolated limb perfusion and isolated limb infusion can be associated with potentially significant

regionaladverse effects,

y myonecrosis,y nerve injury,y compartment syndrome,y arterial thrombosis( sometimes necessitating fasciotomy or even major amputation.)y Systemic toxic effects- hypotension and adult respiratory distress syndrome

Following isolated limb infusion, regional adverse effects appear to be similar to those reported after convention

hyperthermic isolated limb perfusion.

Because limb perfusion or infusion requires a high degree of technical expertise and is associated with a significa

risk of complications, the procedure should be performed only in centers that have experience with the technique

At present, there is little evidence to justify the use of prophylactic perfusion or infusion, except as part of a clinic

trial.


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Figure 3.1. Schematic drawing depicting an isolated limb infusion. The catheters are typically placed percutaneously by an

interventional radiologist via the contralateral extremity, with the catheter tips positioned in the tumor-bearing extremity ju

below the inguinal ligament in the superficial femoral artery and vein. After inflation of the tourniquet, chemotherapy is man

infused for 20 to 30 minutes, after which the limb is washed out with 1 liter of normal saline.

(M.D.ANDERSON 4/E)

Desmoplastic Melanoma

Desmoplastic melanomas resemble a scar or fibroma and appear mainly on sun-exposed areas. Very often they amelanotic.Desmoplastic melanoma is an uncommon histologic variant of melanoma that is characterized b

unusualspindle-cell morphology and the presence of fusiform melanocytes dispersed in a prominent collage

stroma. Classically presenting as a thick primary tumor, desmoplastic melanoma is associated with a higher

incidence oflocal recurrence than nondesmoplastic melanoma.

They tend to recur locally or as isolated metastasis.

Histologically, desmoplastic melanoma may display morphologic heterogeneity. Specifically, some desmopla

melanomas are characterized by a uniform desmoplasia that is prominent throughout the entire tumor(pure-

desmoplastic melanoma), whereas other desmoplastic melanomas appear to arise in association with other

histologic subtypes (mixed desmoplastic melanoma). Distinguishing the phenotypic heterogeneity of

desmoplastic melanomas has been reported to be important for stratifying patients with regard to rate of lymph

node metastasis and prognosis. Recent data indicate that patients with pure desmoplastic melanoma have a low

incidence of positive sentinel lymph nodes than do patients with mixed desmoplastic melanoma or nondesmopla

melanoma.

Although some authors have reported a worse prognosis for patients with desmoplastic melanoma, the majority

studies have describeda better prognosis for patients with desmoplastic melanoma compared with patients w

have nondesmoplastic melanoma of similar stage. In a few studies in which pure desmoplastic melanoma was

differentiated from mixed desmoplastic melanoma, patients with mixed desmoplastic melanoma had a greater r

death or metastatic disease than patients with the pure form.


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Distant disease

In the presence of disseminated disease, a more systemic approach is usually considered. The response to

chemotherapy is greatest for disease in the skin, lymph nodes, and lung; tumors in bone, brain, and liver rarely

respond. Long-term remission can occasionally be achieved by aggressive surgical removal of an isolated metas

in the brain or other organ, but multiple metastases often appear within months.

Table 9General guidelines for treatment sequences in metastatic melanoma

Metastatic site First option Second option Third option

Skin, subcutaneous (trunk, head,

Neck) Isolated Surgery Radiation System

MultipleRadiation, surgery,

intralesional Systemic

Skin, subcutaneous (extremity)

Isolated Surgery Limb perfusion Radiation or syst

Multiple Limb perfusion ( surgRadiation or systemic

Lung

Isolated Surgery Multiple Systemic

Liver Systemic

Bone Radiation ( surgery) Systemic

Brain

Isolated Surgery ( radiation) Radiation

Multiple Radiation

Gastrointestinal

Isolated Surgery

Multiple Systemic

y Systemic = Chemotherapy or immunotherapy or both.y Surgeryy Radiotherapy

Follow-up

Table 10 Melanoma follow-up schedule at Massachusetts GeneralHospital Melanoma Center

Thickness ( Frequency of follow-up (months) Duration of follow-up (years)b

In situ 3 1 visit then every12 months

4 mm every 3 months 2 years

then every 6 months 3 years

then every 12 monthsb

aTen-year follow-up for all melanoma patient. bIf a patient has clinically atypical moles, the interval may continue every 6 months.


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BasalCellCarcinomaArising from the basal layer of the epidermis, BCC is the most common type of skin cancer. Based on gross and

histologic morphology, BCC has been divided into several subtypes:

y nodular,y superficial spreading,y Cysticy infiltrative,y pigmented,y morpheaform.

Nodulocystic or noduloulcerative type accounts for 70% of BCC tumors. Waxy and frequently cream colo

these lesions present with rolled, pearly borders surrounding a central ulcer.Although superficial basal cell tumcommonly occur on the trunk and form a red, scaling lesion, pigmented BCC lesions are tan to black in color.

Morpheaform BCCoften appears as a flat, plaque-like lesion.This particular variant is considered relativelyaggressive and should prompt early excision.

A rare form of BCC is the basosquamous type, which contains elements of both basal cell and squamous cell c

These lesions may metastasize similar to SCC, and should be treated aggressively.

BCCs are slow growing, and metastasis is extremely rare.6972 Due to this slow developmental progression, exten

local tissue destruction is common. The majority of small (less than 2 mm), nodular lesions may be treated via

curettage, electrodesiccation, or CO2 laser vaporization.Although effective, these techniques destroy any potentitissue sample for confirmatory pathology diagnosis and tumor margin analysis.

Surgical excision may be used to both effect complete tumor removal as well as allow proper laboratory evaluati

Basal cell tumors located at areas of great aesthetic value, such as the cheek, nose, or lip, may be best approache

Mohs' surgery.Typically completed by specialized dermatology surgeons, Mohs' surgery uses minimal tissueresection and immediate microscopic analysis to confirm appropriate resection.

Large tumors, those that invade surrounding structures, and aggressive histologic types (morpheaform, infilt

and basosquamous) are best treated by surgical excision with 0.5-cm to 1-cm margins.

Squamous CellCarcinomaSCCs arise from epidermal keratinocytes .While less common than BCC, SCC is more devastating due to an incre

invasiveness and tendency to metastasize.

Before local invasion, in situ SCClesions are termedBowen's disease. In situ SCC tumors specific to the peni

referred to as erythroplasia of Queyrat.67,68

Following tissue invasion, tumor thickness correlates well with malignant behavior. Tumor recurrence is more

prevalent once SCC tumors grow more than 4 mm in thickness, and lesions that metastasize are typically at le

mm in diameter.6972 Tumor location is also of great prognostic importance.

Although SCC tumors in areas with cumulative solar damage are less aggressive, and respond well to local excis

lesions arising in burn scars (Marjolin's ulcer), areas of chronic osteomyelitis, and areas of previous injury

metastasize early.

Treatment

Although small lesions can be treated with curettage and electrodesiccation, most surgeons recommend surgical

excision.

Lesions should be excised with a 1-cm margin, and histologic confirmation of tumor-free borders is mandat

Tumors within areas of great aesthetic value, such as the cheek, nose, or lip, may be best approached withMohs

surgery. This precise, specialized surgical technique uses minimal tissue resection and immediate microscopic

analysis to confirm appropriate resection yet limit removal of valuable anatomy.


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Lymph node (LN) dissection in the setting of SCC remains a topic of debate. Regional LN excision is indicate

for clinically palpable nodes.6972 However, SCC lesions arising in chronic wounds are more aggressive and regi

lymph node metastases are observed more frequently. In this instance, lymphadenectomy before development of

palpable nodes (prophylactic LN dissection) is indicated.

Mohs' Surgery for Squamous and BasalCellCarcinomasBasal and squamous cell lesions often present on sun-exposed portions of the body such as the head and face.

Unfortunately, these areas are of great aesthetic value and significant tissue loss may significantly alter facial

symmetry, contour, and continuity. This precise, specialized surgical technique uses minimal tissue resection an

immediate microscopic analysis to confirm appropriate resection yet limit removal of valuable anatomy.

Developed in 1936, Mohs' technique uses serial excision in small increments coupled with immediate

microscopic analysis to ensure tumor removal, yet limit resection of aesthetically valuable tissue. One distinct

advantage ofMohs' technique is that all specimen margins are evaluated. In contrast, traditional histologic

examination surveys selected portions on surgical margin.

The major benefitofMohs' technique is the ability to remove a tumor with minimal sacrifice of uninvolved tiss

Recurrence and metastases rates are comparable to those of wide local excision.

Although this procedure is of particular value when managing tumors of the eyelid, nose, or cheek, one majordrawback is procedure length(Long duration).Total lesion excision may require multiple attempts at resectionand many procedures may be carried out over several days.

MerkelCellCarcinoma (Primary NeuroendocrineCarcinoma of the Skin)

y Once thought to be a variant of SCC, Merkel cell carcinomas are actually of neuroepithelialdifferentiation.82,83 These tumors are associated with a synchronous or metasynchronous SCC 25% of the

time.

y Due to their aggressive nature, wide localresection with 3-cm margins is recommended.82,83y Local recurrence rates are high, and distant metastasesoccur commonly.y Prophylactic regional LN dissection andadjuvant radiation therapy are recommended.y Overall, theprognosis is worse than for malignant melanoma.

Dermatofibrosarcoma ProtuberansDermatofibrosarcoma protuberans (DFSP) accounts for 1 to 2% of all soft-tissue sarcomas, occurs most frequen

in persons aged 20 to 50 years, and is more common in males.88,89

The most common presenting location is on the trunk (50 to 60%), although theproximal extremities), as we

as head and neck also are frequently affected .

DFSPoften appears as a pink, nodular lesion that may ulcerate and become infected.

Histologically, the lesions contain atypical spindle cells, probably of fibroblast origin, located around a core of

collagen tissue.

Most authorities seem to advocate a three-dimensional margin of2 to 3 cm with resection of skin, subcutaneou

tissue, and the underlying investing fascia.88,89 The periosteum and a portion of the bone may also need to be

resected to achieve negative deep surgical margins.In addition to achieving wide macroscopic resection,conformation of negative microscopic margins is especially critical.

DFSP is considered to be a radiosensitive tumor, and radiotherapy is given following wide local excisi

Chemotherapy: Imatinib, a selective inhibitor of platelet-derived growth factor (PDGF) beta-chain alph

andPDGF receptor beta protein-tyrosine kinase activity, alters the biologic effects of deregulatedPDGF receptor

signaling. Clinical trials have shown activity against localized and metastatic DFSPcontaining the t(17:22)

translocation, suggesting that targeting the PDGF receptors may become a new therapeutic option for DFSP.

Despite what appears to be complete lesion excision, localrecurrence remains frequentandmorta

associated with metastasis relatively high.


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Syndromic Skin Malignancies

Diseases linked with BCCinclude the basal cell nevus (Gorlin's) syndrome and nevus sebaceus of Jadassohn.

Basal cell nevus syndrome is an autosomal dominant disorder characterized by the growth of hundreds of B

during young adulthood.Palmar and plantar pits are a common physical finding and represent foci of

neoplasms.9092 Treatment is limited to excision of only aggressive and symptomatic lesions.

Nevus sebaceus of Jadassohn is a lesion containing several cutaneous tissue elements that develops during

childhood.

SCC

Skin diseases that cause chronic wounds, such as epidermolysis bullosus and lupus erythematosus, are associate

with a high incidence of SCC.9092

Epidermodysplasia verruciformis is a rare autosomal recessive disease associated with infection with HPV

Large verrucous lesions develop early in life and often progress to invasive SCC in middle age.9092

Xeroderma pigmentosum is an autosomal recessive disease associated with a defect in cellular repair of DNA

damage. The inability of the skin to correct DNA damage from UV radiation leaves these patients prone to

cutaneous malignancies.9092 SCCs are most frequent, but BCCs, melanomas, and even acute leukemias are seen.

MALIGNANTMELANOMA

Familial dysplastic nevus syndrome is an autosomal dominant disorder.9092Patients develop multiple dysplasti

nevi, and longitudinal studies have demonstrated an almost 100% incidence of melanoma.Similarly, thedevelopment of colon cancer can be arrested with total proctocolectomy; unfortunately, a similar solution is not

possible in patients with familial dysplastic nevi

FutureDevelopments in Skin Surgery

y Autologous skin grafts remain the best method to cover skin defects, but donor-site problems and limavailability of autologous skin remain problematic.9598

y Tissue expansion with subcutaneous balloon implants produces new epidermis, and mobilizationachieved via expansion remains a highly effective approach to wound coverage

y Severaldermal replacements based on synthetic materials or cadaveric sources are in clinical use . Abovine-collagen andshark-proteoglycanbased dermis (Integra) has been used primarily in bur

patients. This prosthetic dermis, available in ready-to-use form, can cover large surface areas.

Vascularization of this dermis takes 2 to 3 weeks, and final epidermal coverage of the wound requires a skin graft.

y Cadaveric dermis, with all of the cellular elements removed, is not antigenic and is not rejected by therecipient patient.9598 This human dermal matrix is commercially-available (AlloDerm) and functions

much like Integra, with similar limitations of engraftment and high cost.

y Autologous skin cells for permanent skin replacement.The expansion of epidermis by the growth andmaturation of keratinocytes in culture is readily performed.A small skin biopsy specimen can produceenough autologous epithelium to cover the entire body surface.

skin malignancies

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