8/3/2019 Skin Malignancies
1/20
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.
8/3/2019 Skin Malignancies
2/20
(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
8/3/2019 Skin Malignancies
3/20
(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.
8/3/2019 Skin Malignancies
4/20
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.
8/3/2019 Skin Malignancies
5/20
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.
8/3/2019 Skin Malignancies
6/20
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
8/3/2019 Skin Malignancies
7/20
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.
8/3/2019 Skin Malignancies
8/20
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
8/3/2019 Skin Malignancies
9/20
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
8/3/2019 Skin Malignancies
10/20
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.
8/3/2019 Skin Malignancies
11/20
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
8/3/2019 Skin Malignancies
12/20
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)
8/3/2019 Skin Malignancies
13/20
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.
8/3/2019 Skin Malignancies
14/20
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
8/3/2019 Skin Malignancies
15/20
(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.
8/3/2019 Skin Malignancies
16/20
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.
8/3/2019 Skin Malignancies
17/20
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.
8/3/2019 Skin Malignancies
18/20
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.
8/3/2019 Skin Malignancies
19/20
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.
8/3/2019 Skin Malignancies
20/20
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.