Melanoma Destacado

Current Problems in Surgery 50 (2013) 351382
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Current Problems in Surgery
journal homepage: www.elsevier.com/locate/cpsurg
Current management of melanoma
Current state of melanoma in the United States
Melanoma is now the fth most common cancer in the United States. It is estimated that 76,250
men and women were diagnosed with melanoma in 2012 alone.1 Although melanoma accounts for
less than 5% of all skin cancers, it is responsible for the majority of skin cancer-related mortality.2
According to Surveillance, Epidemiology and End Results data, there were an estimated 9180 deaths
attributed to melanoma in 2012,1 and the incidence of melanoma continues to rise. During the 1970s
and 1980s, the incidence of melanoma was increasing at an annual percent change of approximately
6%.1 Currently, the incidence of melanoma is still increasing at a rate of approximately 3% per year.1
This remains the largest annual percent change for any malignancy in the United States. Fortunately,
the overall death rate attributed to melanoma has remained relatively stable since 1990.1
Melanoma is predominantly a disease of Caucasians, with an incidence of 29 per 100,000
Caucasians in 2009, compared with approximately 1 per 100,000 non-Caucasians that same
year.1 The median age of diagnosis is 61; however, melanoma occurs over a wide distribution of
ages, affecting patients in nearly all stages of life.1 Although the incidence of melanoma
increases signicantly with age, it is also one of the most frequent cancers found in adolescents
and young adults.1 This is particularly true in young women, as melanoma is the most common
malignancy in women ages 20-30.1
Tumorigenesis
Melanocytes are naturally occurring cells found within the epidermis of the skin and are
responsible for the production of melanin. Melanin is an endogenous pigment that protects the skin
from harmful ultraviolet (UV) radiation. Most melanomas occur as a result of sporadic
tumorigenesis rather than hereditary genetic mutations.3 Multiple mechanisms of tumorigenesis
may exist, including inactivation of tumor suppressor genes, activation of proto-oncogenes, and
defects in housekeeping genes such as mismatch repair genes.3 These mutations result in
proliferation of malignant melanocytes as well as their evasion of the host's natural immune system.
Although considered a solid tumor, melanoma has been observed by pathologists to have a
heterogenous morphology. This has led some to hypothesize that melanoma may exist as multiple
subpopulations of cells according to the cancer stem cell (CSC) theory.4 In the CSC model, a
heterogenous tumor contains a hierarchy of cells ranging from stem cells to progenitor cells to
transient amplifying cells.4 A fundamental principle of this theory is that chemoresistance and
tumor recurrence are a result of the inability to eliminate the CSCs. Although this is certainly true of
melanoma, the CSC theory is an unproven hypothesis at this time.
0011-3840/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
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352 E.M. Dunki-Jacobs et al. / Current Problems in Surgery 50 (2013) 351382
Risk factors
Skin phenotype
Melanoma is primarily a disease of Caucasians, and as a result, phenotype plays a signicant

role in disease prevalence. Fair skin and characteristics that often accompany fair skin, such as
blond or red hair, blue eyes, or freckles, denote patients with an increased risk of developing
melanoma. Alternatively, hyperpigmentation, as seen in black or other dark-complexion
populations, offers a protective effect.
Precursor lesions
Most melanomas arise de novo and therefore are not the result of malignant transformation
from existing skin lesions.5 That being said, melanoma occasionally can develop within certain
precursor lesions, such as dysplastic nevi and congenital nevi. In general, a dysplastic nevus is a
at, pigmented skin lesion with indistinct margins and variable color, although the clinical
distinction between a nevus with or without dysplasia is often difcult. Dysplastic nevi are
described as having mild, moderate, or severe dysplasia. Nevi with moderate or severe dysplasia
should be excised to negative marginswide local excision (WLE) is unnecessary. Nevi with mild
dysplasia do not require excision and can simply be observed.
The risk of a person with congenital nevi developing melanoma is proportional to the size
and number of nevi. Small congenital nevi represent a low risk and are therefore observed
unless they change in appearance. Giant congenital nevi are dened as greater than 20 cm in
diameter and are fairly rare (1 in 20,000 newborns). Giant congenital nevi carry a lifetime risk
for developing melanoma of up to 10% and therefore, when possible, should be completely
excised.6
Spitz nevi (also known as juvenile melanoma, spindle cell melanoma, or epitheloid cell
melanoma) are rapidly growing, pink or brown, benign skin lesions arising most often in
children, although adult skin lesions may also have spitzoid features. Spitz nevi may be difcult
to distinguish histologically from melanoma. Consultation with an expert dermatopathologist is
recommended; however, even the most experienced pathologists may have difculty in
determining the malignant potential of spitzoid tumors. Complete excision with negative
margins is adequate for an unequivocal Spitz nevus; however, the diagnosis often is not so
obvious. If there is any question that the lesion may be melanoma, WLE with melanoma-
appropriate margins should be performed. Sentinel lymph node (SLN) biopsy has been
suggested as a mechanism to clarify the malignant potential in indeterminate cases, although
this is controversial.7
UV radiation
Although the mechanism of malignant transformation is not completely dened, it is clear

that exposure to UV radiation is the most signicant environmental factor contributing to
melanoma.8 UV radiation is classied as UVA or UVB based on radiation wavelength. UVA
radiation has a longer wavelength of 320-400 nanometers (nm), whereas UVB radiation ranges
from a wavelength of 280-320 nm.9 Natural sunlight exists as a variety of wavelengths ltered
by the atmosphere; however, it is largely UVB radiation that is responsible for the development
of sunburns. Cumulative sunlight exposure and frequency of sunburn events both have a
causative relationship in the development of melanoma.5
Longer wavelength, UVA radiation, is the primary light utilized by tanning beds. UVA
radiation is known to penetrate more deeply into the dermis than the shorter wavelength, UVB
radiation. UVA radiation, therefore, was historically felt to be less likely to cause damaging
supercial sunburns.5 Multiple studies now clearly demonstrate a signicant correlation
between tanning bed use and melanoma.10-13 The risk of melanoma increases measurably with
E.M. Dunki-Jacobs et al. / Current Problems in Surgery 50 (2013) 351382 353
each use, and the risk increases inversely with age.5 Women under the age of 35 are particularly
vulnerable. This population is 50% more likely to develop melanoma having ever used a tanning
bed and is 8 times more likely to develop melanoma with regular tanning bed use.12,13 Based on
these data, the International Agency for Research on Cancer has classied UV exposure from
tanning beds into the highest category for carcinogenic risk.14 Likewise, the National Institutes of
Health have also concluded that sunbeds and sunlamps are known human carcinogens. In
Australia, the country with the highest incidence of melanoma worldwide, legislation has been
passed to ban tanning beds by the year 2014.
Family history and genetics
A family history of melanoma increases an individual's personal risk of melanoma by a factor

of 3-8.15-18 This risk increases with the number of family members who are affected.18
In 1820, a British surgeon named William Norris published a report of what is likely the rst
described case of familial melanoma.19 In the 1960s and 1970s, Lynch and Clark described
families with the familial atypical multiple mole melanoma syndrome, characterized by patients
with rst-degree relatives with melanoma, large numbers of nevi (50-100), and especially
dysplastic nevi.20,21 Another syndrome, the atypical mole syndrome (also known as the
dysplastic nevus syndrome), has also been described (patients have 50-100 nevi, at least one of
which is 8 mm, at least one of which is atypical, with no personal or family history of
melanoma).22
More recently, several genes have been implicated in the development of melanoma.
Mutations in the cyclin-dependent kinase (CDK) gene CDKN2A are thought to account for 20%-
40% of cases of familial melanoma.23 Other genes that have been linked to familial melanoma
include CDK4, the xeroderma pigmentosum genes, the melanocortin-1 receptor gene (MC1R),
and the BRAF oncogene.24-29
Demographic risk factors
Age and gender are also risk factors for the development of melanoma. Although melanoma
is one of the most common malignancies of young adults, the incidence of melanoma continues
to steadily increase throughout the life, with its highest incidence in people who are older than
50 years.30 Likewise, the incidence of melanoma is higher in men than in women: the risk of a
man developing a melanoma during his lifetime is 1.6 times the risk of a woman developing
melanoma.30
Personal history of melanoma
A person who has already developed one melanoma has a 3%-7% chance of developing a
second primary melanoma. This risk is 900 times higher than the risk of melanoma in a person
without a previous personal history of melanoma.31-34
Diagnosis
History and physical examination
Melanoma usually presents as an irregularly pigmented skin lesion with a history of growth
or change over time. Melanomas most commonly arise de novo, but can occasionally arise
within a congenital or acquired nevus. The distinction between a benign nevus and an early
melanoma can be quite difcult. Pigmented lesions are sometimes so prevalent that it is difcult
to detect an early melanoma among the many benign lesions. The most common pigmented skin
lesions are seborrheic keratoses. These benign lesions are also known as the barnacles of life
because of the propensity for patients to acquire them with increasing age. These are typically
scaly, waxy, raised lesions with a stuck-on appearance that seem as if they could be easily
scraped off. Their characteristic appearance is usually completely diagnostic. These lesions do
not need to be removed; however, even experienced clinicians have been fooled by a lesion that
appeared to be an irritated seborrheic keratosis, but ultimately was a melanoma.
The majority of melanomas can be diagnosed by history and physical examination. The
history should include assessment of the risk factors described previously, paying particular
attention to sun or UV radiation exposure, and personal or family history of melanoma.
Additionally, history regarding the lesion itself should be ascertained. This includes any itching,
bleeding, or subjective change associated with the lesion. The physical examination is simple but
requires full exposure of the patient, and therefore is often omitted or incomplete. A complete
head-to-toe skin examination involves surveying all of the body's surfaces, including the
interdigital and mucosal regions. Palpation of lymph node basins (cervical, axillary, epitrochlear,
inguinal, and popliteal) should be a routine part of any physical examination for melanoma.
Early detection of a melanoma by performing a thorough physical examination can have a
signicant effect on survival.
The ABCDEs of melanoma are used to guide the decision of which lesions to biopsy:
Asymmetry, irregular Borders, variable shades of Color, Diameter greater than 6 mm (roughly the
size of a pencil eraser), and Evolution, or change over time. Although these features are
characteristic, not all melanomas follow these rules. Primary cutaneous melanomas can also be
amelanotic, or nonpigmented. These melanomas may manifest as a raised pink or esh-colored
skin lesion. A high index of suspicion is needed, and particular attention should be paid to any
history of change regarding the lesion. In general, if a patient presents with a skin lesion that has
changed in size, color, or shape, or if the lesion itches or has a history of bleeding, a biopsy
should be performed.
Biopsy
There are 3 basic types of skin biopsy: excisional, incisional, or shave biopsy. An excisional
biopsy completely removes the lesion in question and is the most prudent method of obtaining a
diagnosis for small, pigmented skin lesions. After injecting local anesthesia, a grossly negative,
narrow-margin excision is performed. The depth of the biopsy should extend completely
through the dermis and should include some subcutaneous fat. This would classify as a full-
thickness biopsy. The defect is then closed primarily with sutures. Attention should be paid to
the orientation of the excision. An elliptical excision should be oriented in such a way as to
prepare for the possibility that, if the lesion is a melanoma, WLE would be performed. For
extremity lesions, a longitudinal orientation is best, and for other locations, consideration should
be given to an orientation that would allow for closure with the least tension and best cosmetic
outcome in the event WLE is needed.
An incisional biopsy is a full-thickness biopsy that does not remove the entire lesion, but
merely removes enough tissue to obtain a diagnosis. This is most appropriate for large lesions or
lesions highly suspicious for melanoma, which would ultimately require WLE. The simplest form
of incisional biopsy is a punch biopsy. Punch biopsy is performed with a disposable instrument,
usually measuring 2-8 mm in diameter. By twisting the instrument into the anesthetized skin, a
cylinder of dermis and subcutaneous tissue is removed. The biopsy defect is then closed
primarily with a simple interrupted suture. Punch biopsies of at least 4 mm should be
performed, as smaller punches often do not provide adequate tissue for accurate pathologic
evaluation. A punch biopsy should be performed through the thickest area of the lesion, and
multiple punch biopsies can be performed for larger lesions.
Shave biopsy is a method of skin biopsy that usually results in a partial-thickness specimen.
When used for nonpigmented skin lesions, such as squamous cell carcinoma and basal cell
carcinoma, this can be an effective method of diagnosis. When used to diagnose cutaneous
melanoma, one runs the risk of inadequate assessment of lesion depth. This is a distinction
worth noting, as lesion depth plays a signicant role in the clinical management and pathologic
staging of melanoma. Shave biopsy is performed by elevating the skin lesion with forceps and
then shaving underneath the lesion with a razor blade or scalpel. Hemostasis is achieved using
topical agents, and the wound is allowed to heal by secondary intention. Shave biopsy is very
popular because it is quick, simple to perform, and does not require sutures for closure.
Much debate exists regarding the role of shave biopsy in the diagnosis of melanoma. Stell and
colleagues reviewed their experience with primary cutaneous melanoma in 2006.35 They found
that 57% of melanoma diagnoses were made using the shave biopsy technique instead of
incisional or excisional biopsy.35 Additionally, 22% of all shave biopsies had a positive deep
margin compared with only 7% of incisional biopsies and 2% of excisional biopsies.35 Most
signicant is the nding that 17% of thin melanomas (1 mm) had positive deep margins,
compared to no positive deep margins for thin melanomas diagnosed by either incisional or
excisional biopsy.35 Although lesion depth greater than 1 mm is not the only indication for SLN
biopsy, it does play an important role in the decision-making process. Lowe and colleagues
reviewed thin melanomas diagnosed by shave biopsy that ended up having SLN biopsy as part of
their management.36 They found that, of the 99 patients who had positive deep margins, 70
patients had other criteria (ie, ulceration or Clark's level) that were used as an indication for SLN
biopsy.36 This still left approximately 30% of patients who underwent unnecessary SLN biopsy,
which was performed only because of the inability to accurately assess the depth of the lesion as
a result of a positive deep margin on shave biopsy. Despite the difculties that shave biopsy can
present in clinical decision making, overall survival does not appear to be affected.36
Both the National Comprehensive Cancer Network (NCCN) and the American Academy
of Dermatology recommend excisional biopsy with narrow margins as the preferred method of
biopsy for the diagnosis and evaluation of primary cutaneous melanoma.35,37,38 Regardless
of biopsy technique, all pigmented lesions should be sent for pathologic evaluation.39 Ablation of
pigmented skin lesions using cryotherapy, cautery, or lasers is specically discouraged.
Pathologic description
Melanocytic degeneration to malignant melanoma exists along a spectrum that ranges from
mild, moderate, or severe dysplasia to atypical melanocytic proliferation, to melanoma in situ, to
early invasive melanoma. As mentioned previously, the incidence of melanoma continues to rise
in the United States. Some of this rise almost certainly results from a lower threshold on the part
of pathologists to diagnose equivocal lesions as melanoma, largely because of the potential
consequences of a missed diagnosis of melanoma. Misdiagnosis of melanoma recently overtook
breast cancer as the most frequent reason for malpractice litigation against pathologists.40 In
situations in which a pathologist reports a borderline or equivocal lesion, the prudent
management strategy is to treat the lesion as an early invasive melanoma and widely excise with
a 1-cm margin.
Melanoma in situ is considered a premalignant lesion with a signicant risk of progression to
invasive melanoma. By denition, melanoma in situ has not invaded beyond the basement
membrane. As a result, it does not have access to blood vessels or lymphatics, and therefore, it
does not in general have metastatic potential.
Invasive melanoma arises as a proliferation of melanocytes in the basal layer of the skin. As
the cells multiply, they expand radially in the epidermis and supercial dermal layer. This is
termed the radial growth phase. With time, the growth also begins in a vertical direction. This
is called the vertical growth phase and is responsible for palpable lesions.
Histologically, invasive cutaneous melanomas are divided into 4 major subtypes. These
subtypes are based on growth pattern and location, and are categorized as supercial spreading,
nodular, lentigo maligna, or acral lentiginous. A fth subtype is also dened: desmoplastic
melanoma (DM). In general, the histologic subtype of melanoma is not a major factor in
determining prognosis. That being said, some histologic subtypes are more likely to be detected
at an advanced stage, thus indirectly affecting prognosis.
The most common histologic subtype of melanoma is supercial spreading. This subtype
accounts for 60%-70% of all melanomas.41 Supercial spreading melanoma is not necessarily
specically associated with sun-exposed skin, but can occur in any dermal tissue. As the name
suggests, supercial spreading melanoma begins as a at, pigmented lesion growing in the
radial dimension. Given enough time, these melanomas would develop a vertical growth phase
and invade more deeply into the dermis.
Nodular melanoma accounts for 15%-30% of all melanomas.41 Nodular melanomas are an
exception to the usual growth pattern: the vertical growth phase is present early in tumor
development. The vertical growth phase allows invasion into the deeper layers of the skin where
the tumor may achieve metastatic potential by invasion of blood and lymphatic vessels.42
Nodular melanomas are raised, papular lesions that often carry a poor prognosis because of
above-average tumor thickness and frequent ulceration.
Lentigo maligna melanoma accounts for only approximately 5% of all melanomas.41 This
subtype occurs most commonly on the face of older individuals with sun-damaged skin and
presents as a at, dark, variably pigmented lesion with irregular borders and a history of slow
development. It is not uncommon for lentigo maligna melanoma to become quite large prior to
diagnosis, as the lesion's slow progression may go unnoticed by the patient. Overall, the prognosis
of lentigo maligna melanomas is better than that of the other histopathologic subtypes because
the lesion is often supercial, but a delay in diagnosis can thwart this lesion's favorable histology.
Acral lentiginous melanoma is classied as such based on its anatomical site of origin. This
subtype of melanoma develops on the palms of the hand, on the soles of the feet, or in the
subungual areas (beneath the ngernails and toenails). This is the most uncommon type of
melanoma overall, but it accounts for approximately 45% of melanoma arising in Asians, and 70% of
melanoma arising in blacks.41 The histologic appearance of acral lentiginous melanoma is similar
to melanomas arising from the mucous membranes. Because this subtype typically occurs in
populations presumed to be low risk and in locations that are inconspicuous, the diagnosis is often
made when the tumor is at an advanced stage. This contributes to a poor prognosis associated with
these tumors in general. The delay in diagnosis associated with subungual acral lentiginous
melanomas occurs because these lesions are often mistaken for subungual hematomas. One key
distinction between a subungual melanoma and a subungual hematoma is that, with a subungual
hematoma, the pigment should migrate distally as the nail grows. Biopsy of lesions concerning for
subungual melanoma can be accomplished by performing a digital nerve block with local
anesthesia, and then either removing the nail, or performing punch biopsy through the nail itself.
DM is a specic subtype of cutaneous melanoma that was rst described by Conley and
colleagues in 1971.43 DM is rare and only accounts for approximately 1.7%-4% of all
melanomas.41,44 Clinically, DM is present as an amelanotic lesion, most commonly of the head
and neck region. DM is associated with male gender and a history of extensive sun exposure.45
DM is known to exhibit different behavioral patterns than other subtypes of cutaneous
melanoma. These lesions often exhibit neurotropism and have a greater propensity for local
recurrence with a decreased risk of nodal metastasis. Local recurrence rates for DM have been
reported to be as high as 50%, with pooled analysis reporting a local recurrence rate of 27.2%.44
Likewise, rates of nodal metastasis have frequently been reported as less than 10%, leading some
clinicians to question the need for SLN biopsy.46,47 However, our group recently reported that
the rate of positive SLN biopsy in patients with DM enrolled in the Sunbelt Melanoma Trial was
17%. (Egger ME, Huber KM, Dunki-Jacobs EM, et al. Is sentinel lymph node biopsy necessary for
desmoplastic melanoma? J Am Coll Surg. 2013, submitted for publication.)
There is a growing body of evidence that DM can be further categorized into mixed and
pure subclassications. The pure subclassication is comprised of at least 90% histologically
typical DM, whereas the mixed subclassication is more than 10% DM and more than 10%
conventional melanoma.48 Distinction between the pure and mixed subclassications appears to
have prognostic signicance. Mixed DM tends to behave more like conventional melanoma, with
SLN-positive rates of 8.5%-22%.48-50 Conversely, pure DM has a more favorable prognosis, with
SLN-positive rates of 2.2%-4.9%.49,50 Behavioral and genetic differences between mixed and pure
DM continue to be investigated and will likely lead to variations in clinical management in the
future.51 At the present time, however, we recommend that patients with DM be managed with
routine SLN biopsy. (Egger ME, Huber KM, Dunki-Jacobs EM, et al. Is sentinel lymph node biopsy
necessary for desmoplastic melanoma? J Am Coll Surg. 2013, submitted for publication.)
Prognostic factors
Many patients with newly diagnosed melanoma are quite anxious, with concern that they
may die of their disease. It must be recognized that approximately 87% of all patients with
melanoma are ultimately cured of their cancer, a number that is even higher with early
detection.52 The prognosis of an individual patient can vary widely and depends largely on the
stage of the melanoma at the time of diagnosis. It is therefore extremely important to stratify
patient risk and predict prognosis in order to guide individual patient management decisions.
The status of the regional lymph nodes is the single most important prognostic factor for
overall survival.53,54 Metastasis to regional lymph nodes increases the chance of mortality from
melanoma substantially. Other prognostic factors, in order of importance, are Breslow thickness,
ulceration, mitotic rate, age, anatomical location of the primary tumor, and gender.55-74
In 1969, Wallace Clark described a classication system for melanoma based on the level of
invasion into the anatomical layers of the skin. This classication system, thereafter known as
the Clark level of invasion, correlated signicantly with overall survival.73 Clark level I tumors
represent melanoma in situ and are limited to the epidermis. Level I lesions, therefore, have no
metastatic potential. Clark level II melanomas extend into the papillary dermis. Clark level III
melanomas ll the papillary dermis. Clark level IV melanomas extend to the reticular dermis.
Clark level V melanomas invade the subcutaneous fat.
In 1970, Alexander Breslow described a similar system of stratication, but in a simpler form.
Breslow measured the depth of invasion as vertical thickness of the melanoma in millimeters.
This is now known as the Breslow thickness.75 As one would predict, the prognosis worsens as
the thickness of the melanoma increases. Using Breslow thickness, melanomas are commonly
considered to be thin (1 mm), of intermediate thickness (41-4 mm), or thick (4 4 mm). Over
time, Breslow thickness has become the classication system of choice, as it has been shown to
be a more accurate method of predicting prognosis. The Clark level continues to be reported
routinely, even though it is an inferior prognostic factor.
Ulceration has also emerged as a very robust predictor of prognosis.58-68 Ulceration is dened
pathologically as the absence of an intact epithelium overlying the melanoma. Patients with
ulcerated melanomas have a worse prognosis than those with nonulcerated melanomaseven
among patients with regional nodal metastasis. Why patients with ulcerated melanomas have a
worse prognosis is not clear, but ulceration appears to be a phenotypic marker for worse tumor
biology and greater propensity for invasion and metastasis.
Mitotic rate is the most recently validated prognostic factor and is very important to consider.
Among patients with thin melanomas, mitotic rate 1 may be the only indication for evaluation
of the regional lymph nodes by SLN biopsy.68,69
Several other factors have minor effects on prognosis. Age affects prognosis: older patients
have a greater risk of melanoma mortality than do younger patients.74 This is true despite the
fact that younger patients are more likely to have nodal metastasis.74 Patients with axial (trunk,
head, and neck) melanomas have a worse prognosis than patients with extremity tumors.70
Women have a better prognosis than men, for reasons that are not clear.71 Tumor regression has
been evaluated as a prognostic factor but has not been shown to be statistically signicant in
predicting nodal metastasis or survival.72
Staging
In an ongoing effort, the American Joint Committee on Cancer (AJCC) Melanoma Staging
Committee, led by Charles Balch, has analyzed multi-institutional data from North America,
Europe, and Australia and has developed an evidence-based staging system that predicts
prognosis with good accuracy.
Staging for cutaneous melanoma follows the tumor-node-metastasis system of classication
as dened by the AJCC (Tables 1 and 2).67 The seventh edition (2009) of the staging system is
based on analysis of a database of more than 30,000 patients.68 The important prognostic factors
in the staging system include Breslow thickness, ulceration, mitotic rate, nodal status, and the
presence of other manifestations of lymphatic spread (satellite lesions, in-transit disease), as
well as the presence of distant metastatic disease. The principal deviation from the sixth edition
is that mitotic rate is now used instead of the Clark level to discriminate T1a from T1b tumors,
based on the nding that mitotic rate is a more powerful predictor of prognosis.
The AJCC staging system provides good discrimination of survival among various stages of
disease (Fig 1). Based on the work of Balch, Seng-jaw Soon, and other collaborators from the
AJCC staging committee, an online tool is available to assess prognosis based on individual
patient and tumor characteristics. This is available at www.melanomaprognosis.org.
Our group has recently created an independent, validated model that was shown to predict
prognosis in patients with melanoma staged by SLN biopsy more accurately than the AJCC
model, especially in patients with stage III disease.76 This model is available online at www.
melanomacalculator.com or as the melanoma calculator application for mobile devices.
Table 1
TNM staging categories for cutaneous melanoma67
T category Thickness (mm) Ulceration status or mitoses
Tis NA NA
T1 1.00 a: Without ulceration and mitosis o1/mm2
b: With ulceration or mitoses 1/mm2
T2 1.01-2.00 a: Without ulceration
b: With ulceration
T3 2.01-4.00 a: Without ulceration
b: With ulceration
T4 4 4.00 a: Without ulceration
b: With ulceration
N category Number of metastatic nodes Nodal metastatic mass
N0 0 NA
N1 1 a: Micrometastasis*
b: Macrometastasis
N2 2-3 a: Micrometastasis*
b: Macrometastasis
c: In-transit metastasis or satellite(s)
without metastatic nodes
N3 4 metastatic nodes, or matted nodes, or
in-transit metastases or satellites
with metastatic nodes
M category Site Serum LDH
M0 No distant metastases NA
M1a Distant skin, subcutaneous, or nodal metastases Normal
M1b Lung metastases Normal
M1c All other visceral metastases Normal
Any distant metastasis Elevated
NA, not applicable; LDH, lactate dehydrogenase.

Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this
material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Medical
LLC, www.springer.com.
n
Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).

Macrometastases are dened as clinically detectable nodal metastases conrmed by therapeutic lymphadenectomy or
when nodal metastasis exhibits gross extracapsular extension.
Table 2
Anatomical stage or prognostic groups for cutaneous melanoma67
Clinical staging* Pathologic staging
T N M T N M
0 Tis N0 M0 0 Tis N0 M0
IA T1a N0 M0 IA T1a N0 M0
IB T1b N0 M0 IB T1b N0 M0
T2a N0 M0 T2a N0 M0
IIA T2b N0 M0 IIA T2b N0 M0
T3a N0 M0 T3a N0 M0
IIB T3b N0 M0 IIB T3b N0 M0
T4a N0 M0 T4a N0 M0
IIC T4b N0 M0 IIC T4b N0 M0
III Any T N 4 N0 M0 IIIA T1-4a N1a M0
T1-4a N2a M0
IIIB T1-4b N1a M0
T1-4b N2a M0
T1-4a N1b M0
T1-4a N2b M0
T1-4a N2c M0
IIIC T1-4b N1b M0
T1-4b N2b M0
T1-4b N2c M0
Any T N3 M0
IV Any T Any N M1 IV Any T Any N M1
Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this
material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Medical
LLC, www.springer.com.
n
Clinical staging includes microstaging of the primary melanoma and clinical or radiologic evaluation for
metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment
for regional and distant metastases.

Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional
lymph nodes after partial (ie, sentinel node biopsy) or complete lymphadenectomy. Pathologic stage 0 or stage IA
patients are the exception; they do not require pathologic evaluation of their lymph nodes.
Overall, the use of such computer models represents a powerful new strategy to rene
prognosis for an individual patient, instead of for a group of patients. The principal purpose of a
cancer staging system is to assess risk in order to determine appropriate treatment. In the case of
high-risk stage II and stage III melanoma, current adjuvant therapies (as described below) are
toxic and of limited benet; therefore, accurate prognostic information is essential in order to
determine which subgroups of patients stand to benet the most from treatment and merit
being subjected to the involved risk. Ultimately, as prognostic models for melanoma become
more sophisticated, they would likely incorporate anatomical, nonanatomical, and molecular
markers, similar to the Adjuvant! Online and Oncotype DX models for breast cancer.77-79
Treatment of the primary lesion
WLE
In 1857, William Norris, noting the aggressive nature of melanoma, recommended surgery not
only to remove the disease, but to cut away some of the healthy parts.80 This concept became known
as WLE, and it remains the standard for surgical management of melanoma today. Although WLE
was universally accepted as necessary, the appropriate margin required for appropriate WLE
was unknown. Multiple studies identied atypical melanocytes as far as 5 cm away from a
primary lesion.81 As a result, 5-cm margins were historically the goal, and morbidity from WLE was
substantial.
Fig. 1. Survival curves from the AJCC Melanoma Staging Database (2008) based on (A) different T categories, (B) stage
groupings for stages I and II melanoma, (C) different N categories of stage III melanoma, and (D) stage groupings for stage
III melanoma. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original
source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and
Business Medical LLC, www.springer.com.
Beginning in the 1990s, multiple prospective, randomized, controlled trials began to challenge
the necessary margins needed for adequate surgical resection. In a trial conducted by the World
Health Organization, 612 patients with melanomas less than 2 mm thick were randomized to WLE
using a 1-cm or 3-cm margin.82 Local recurrence as the site of rst recurrence was observed in
4 patients, all with melanomas 1-2 mm thick who were in the 1-cm margin group; however, this
did not signicantly affect overall survival.82,83 In the Intergroup Melanoma Trial, 462 patients with
melanomas of the trunk or proximal extremity between 1 and 4 mm Breslow thickness were
randomized to receive WLE with either a 2-cm or 4-cm margin.84 At a median follow-up of
10 years, the incidence of local recurrence was the same for patients undergoing 2-cm or 4-cm
margin excision (2.1% vs 2.6%, respectively); there was no statistically signicant difference in
overall survival.84 Factors were found to be signicantly associated with local recurrence were
ulceration, thickness, and anatomical location of the primary melanoma (head and neck
melanomas had a much greater risk of local recurrence).84 The Swedish Melanoma Trial and the
French Melanoma Trial both compared WLE with 2-cm or 5-cm margins in patients with
melanomas less than 2 mm Breslow thickness.85,86 Neither trial showed a 5-cm margin of excision
to be advantageous in terms of local recurrence, disease-free survival, or overall survival. The British
Collaborative Trial randomized 900 patients with melanomas greater than 2-mm thick to WLE with
either a 1-cm or 3-cm margin; elective lymph node dissection (LND) and SLN biopsy were not
permitted.87 There were no statistically signicant differences in local or in-transit recurrence,
disease-free survival, or overall survival.87 There was, however, a marginally signicant increase in
locoregional recurrence in the group that underwent a 1-cm WLE when local, in-transit, and
regional nodal recurrence were considered together.87 As a result, for patients with melanomas
greater than 2 mm thick, a 1-cm margin is considered inadequate.
Taken together in a meta-analysis performed by Haigh and colleagues in 2003, these studies
suggest that a 1-cm margin is sufcient for melanomas less than 1 mm thick.88 For melanomas
1-2 mm thick, a 1-cm margin is acceptable, but a 2-cm margin may reduce the risk of local
recurrence slightly, and is preferred when feasible. For patients with melanomas greater than 2 mm
thick, a 2-cm margin is adequate, as a wider margin has not shown to improve outcomes. Appro-
priate margins of excision for thick melanomas (44-mm thick) have not been studied in the context
of randomized trials; however, retrospective analysis suggests that there is no advantage for margins
wider than 2 cm. Nonetheless, it may be appropriate to perform wider margin excision for locally
advanced melanomas when clinical assessment considers the risk of recurrence to be high.89,90
Melanoma in situ is generally adequately treated by a 0.5-cm margin excision; this
recommendation is not based on randomized data, but on clinical experience with this disease.
Given that there is a signicant interobserver variability among pathologists when making the
diagnosis of melanoma in situ and that invasive melanoma may be diagnosed after WLE if the
entire lesion was not removed during the initial biopsy, it may be prudent to perform a 1-cm
WLE for melanoma in situ when anatomically feasible.91
WLE can be performed under local anesthesia in most cases, although general anesthesia is
preferred for patients undergoing concomitant SLN biopsy or lymphadenectomy. The
appropriate margin of excision is measured radially from the edge of the lesion or from the
previous biopsy scar. WLE should involve removal of the skin and subcutaneous tissue down to
the muscular fascia. Excision of the fascia is not necessary, but may be performed for patients
with thick primary tumors. The specimen is submitted for permanent section pathology, as
frozen section analysis of margins is not generally possible.
The majority of incisions required for WLE can be closed primarily if planned properly. For
fusiform incisions, the long axis of the incision should be approximately 3 times the length of the
short axis to allow for a tension-free closure. If needed, the skin and subcutaneous tissue can be
mobilized off of the underlying fascia to facilitate closure. Skin grafts or complex tissue aps may be
necessary for melanomas located in areas with especially cosmetically important or immobile skin,
such as the head and neck or distal extremities. Subungual melanomas are treated with
amputation of the distal digit to provide, at a minimum, a 1-cm gross margin from the tumor.
In all cases, resection should achieve histologically negative margins on nal pathologic
evaluation. It should be noted that the recommended margins of excision are measured grossly
from the edge of the lesion at the time of surgery. It is not necessary to re-excise the melanoma
if, on nal pathology, the measured distance from the melanoma to the edge of the excised skin
is less than the recommended margin of excision. Re-excision should only be performed if the
margin is involved or is very nearly involved by tumor.
Mohs micrographic surgery (MMS) involves sequential tangential excision of skin malig-
nancies with immediate intraoperative pathologic margin assessment in an attempt to minimize
the overall area of excision while still providing negative histologic margins. MMS is used most
commonly for skin cancers, such as squamous cell and basal cell carcinomas, and has resulted in
favorable outcomes. Unlike these other skin malignancies, in which the primary lesion is in
continuity and would rarely metastasize, invasive melanoma is known to have discontiguous
nests of malignant cells that lie away from the gross primary lesion. In theory, despite negative
histologic margins, Mohs resection of the gross primary lesion could miss excision of these
peripheral nest cells, resulting in a higher rate of local recurrence. Some centers have advocated
MMS for the management of melanoma in situ, with a reported local recurrence rate of 1%.92
Regardless, MMS for invasive melanoma should be discouraged, as there are no randomized
prospective trials to compare it to conventional WLE, and MMS would not address nests of tumor
cells that lie away from the primary tumor, which is the founding principle of WLE.90
Management of the regional lymph nodes
It is essential for clinicians to understand the proper terminology regarding operations

performed for regional lymph nodes in the context of melanoma. LND, or lymphadenectomy, is
dened as removal of all, or a majority of the lymph nodes in a particular nodal basin. A LND is
described as elective or early when it is performed for patients without clinical evidence of
nodal metastasis (ie, those without palpable nodes or imaging studies to suggest regional nodal
disease). Therapeutic LND is used to describe a lymphadenectomy when it is performed for
palpable or clinically evident nodal disease. The term delayed LND exists in the setting of
historical clinical trials, when patients were randomized to clinical observation of the nodal
basin. Delayed LND describes lymphadenectomy performed for interval development of
palpable or clinically evident disease. Completion LND refers to the operation performed after
nding nodal metastasis by SLN biopsy.
Elective LND
In 1892, Herbert Snow reported the propensity for melanoma to metastasize to the regional
lymph nodes. As a result, he advocated that treatment of melanoma with curative intent should
include elective LND.93 Snow's manuscript created a controversy regarding elective LND that
lasted for a full century. Snow explained that melanoma commonly metastasizes to the regional
lymph nodes rst, before progressing to distant disease. The rationale for elective LND stemmed
from Snow's concept that regional nodal metastases might metastasize to distant sites and that
the greater the tumor burden in the regional nodes, the greater the likelihood of distant
metastasis. Early removal of microscopic nodal metastases, he believed, would lead to improved
survival. Opponents to Snow's concept of elective LND argued that no survival advantage can be
seen with elective LND and there is signicant morbidity associated with the procedure that, for
a majority of patients, would not even demonstrate occult disease.
The controversy over elective LND led to several randomized prospective trials, none of
which have demonstrated an overall survival benet for elective LND.90,94-100 Despite the
negative results overall, there are 2 studies worth noting. The rst is the Intergroup Melanoma
Trial, which randomized 740 patients with melanomas 1-4 mm thick to elective LND or nodal
observation.96 Although overall there was no survival difference between the 2 arms, subgroup
analysis suggested that some patients may benet from elective LND: specically, patients
younger than 60 years of age, those without ulcerated melanomas, those with melanomas
1-2 mm in Breslow thickness, and those with extremity melanomas.96 Similarly, a trial
conducted by the WHO and reported in 1998 evaluated 240 patients with truncal melanomas
greater than 1.5 mm thick and randomized them to elective LND or nodal observation followed
by delayed LND for development of clinically palpable nodal disease. Again, there was no
survival advantage for elective LND, but on subgroup analysis there was a statistically signicant
improvement in 5-year survival when patients with occult nodal metastatic disease detected at
elective LND were compared to patients in the observation arm who ultimately developed nodal
metastasis and underwent therapeutic LND (48% vs 27%, respectively, P 0.04).97 These
randomized trials provided some support for the theory that early removal of nodal metastasis is
better than waiting for patients to develop large palpable nodes.
The difculty in demonstrating a survival advantage for elective LND over delayed LND
occurs because only approximately 20% of patients with melanomas greater than 1 mm thick
have nodal metastases at the time of presentation.101 By simple math, this means that 80% of
these patients do not have nodal metastases at the time of presentation and therefore cannot
possibly benet from early LND. Considering the substantial morbidity of LND, including wound
complications, chronic pain, and lymphedema, there is understandably little enthusiasm for
elective LND in the absence of a demonstrable survival benet. Despite the lack of resolution, the
controversy surrounding elective LND disappeared with the advent of SLN biopsy.
SLN biopsy
During early surgical treatment of melanoma, truncal melanomas posed a particular

challenge to proponents of elective LND. Truncal melanomas had the potential to drain to
multiple, and somewhat unpredictable, lymphatic basins: cervical, axillary, or inguinal. This
complicated the decision regarding which nodal basin or basins should undergo elective LND. In
1977, a group of pioneering surgeons, one of whom was Donald Morton, reported the novel
technique of using cutaneous lymphoscintigraphy to identify the lymph node basins draining
truncal melanomas.102 Lymphoscintigraphy involves the use of a radioactive tracer that is
injected into the dermis around the melanoma. The radioactive tracer particles are then taken
up by the lymphatic channels and captured in the draining lymph nodes.
The sentinel node concept developed from the theory that there exists a specic, unique
lymph node that is the rst to receive lymphatic drainage from the site of a primary tumor. As a
result, this sentinel node is also the rst node to receive metastatic tumor cells. Despite the
development of the sentinel node concept, intraoperative identication of the sentinel node was
not possible until Morton presented his work with vital blue dye at the annual Society of
Surgical Oncology meeting in 1990.103 Using this technique, Morton was able to identify and
biopsy the sentinel node with a success rate of 85% and demonstrate that the sentinel node did
indeed accurately determine the presence or absence of microscopic nodal metastasis.103 In
1994, development of the handheld gamma probe made intraoperative lymphatic mapping with
technetium sulfur colloid possible. The combined use of blue dye and radiotracer has increased
the success rate of SLN biopsy to 97%.104
Since its original description by Morton, thousands of articles have been published validating
the SLN hypothesis in a variety of malignancies, and SLN biopsy has become a standard method
of staging the regional lymph nodes in both melanoma and breast cancer.105 Gershenwald and
colleagues at M.D. Anderson Cancer Center demonstrated that SLN biopsy is the single most
important prognostic factor in melanoma patients without clinical evidence of nodal
metastasis.54 Because SLN biopsy is a minimally invasive procedure that usually involves
removal of only 1-3 lymph nodes, it has been shown to result in signicantly fewer
complications than a complete LND.106
Indications for SLN biopsy
SLN biopsy is a staging procedure used to determine the nodal status of patients with
melanoma. Although SLN biopsy is a minimally invasive procedure, it is not without morbidity
or cost and therefore should not be used universally. As mentioned previously, 20% of patients
with intermediate-thickness melanoma (Breslow thickness 1-4 mm) would have microscopic
nodal metastasis.101 Because of the reduced morbidity of SLN biopsy compared with elective
LND, as well as the important prognostic information SLN status provides, there is a general
agreement that SLN biopsy is justied for patients with intermediate-thickness melanoma.
Patients with thin melanomas (1-mm thick) have a low risk of nodal metastasis overall.
Although the risk of microscopic nodal metastasis is less than 5%, this subgroup represents about
65% of all patients with melanoma.45 As a result, a substantial number of node-positive patients
may be missed if SLN biopsy were never performed for thin melanomas. A thorough analysis of
the literature has identied ulceration and mitotic rate as negative prognostic factors that should
be considered when deciding whether or not to perform SLN biopsy for patients with thin
melanomas.107 Although ulceration is infrequently identied in patients with thin melanomas
(4%-9%),45,68,108 the powerful overall prognostic signicance of ulceration suggests that SLN
biopsy should be considered for all ulcerated melanomas, regardless of thickness. Likewise, a
mitotic rate greater than 1/mm2 has been shown to be an important predictor of nodal
metastasis in patients with thin melanomas. Appropriately, ulceration and mitotic rate are now
used in the seventh edition of the AJCC melanoma staging system to discriminate T1a from T1b
melanomas.68 SLN biopsy is therefore recommended for T1b melanomas.
Breslow thickness should also be considered when evaluating patients with thin melanomas.
The incidence of SLN metastasis among patients with melanomas less than 0.75 mm thick is 1%-
4%, and for those patients with melanomas 0.75-1 mm thick it is 6%-8%.45,109,110 Whether or not
all patients with melanomas 0.75-1.0 mm thick should undergo SLN biopsy is controversial;
likely the high-risk patient is better discriminated by considering ulceration and mitotic rate.107
Factors that have not been universally demonstrated to increase the risk of nodal metastasis
include age, gender, the Clark level of invasion, vertical growth phase, tumor inltrating
lymphocytes, and regression.109-111 Kesmodel and colleagues used tumor mitotic rate to develop
a risk classication tree for patients with thin vertical growth phase melanomas (Fig 2).109 This
model provides a useful framework for considering the risk of nodal metastasis as well.
The role of SLN biopsy for patients with thick melanomas (4 4 mm) has also been debated.
Patients with thick melanomas are at increased risk for systemic metastases. This concept
historically led to the dogma that no patients with thick melanomas could ever benet from SLN
biopsy or LND. To contradict this, multiple studies have shown that patients with thick
melanomas and a negative SLN biopsy have a better prognosis than those with tumor-positive
SLNs. As prognosis is determined by more than Breslow thickness alone, some patients with
thick melanomas and nodal metastases can still be cured by resection of nodal metastases.
Therefore, SLN biopsy should be performed in this population as well.112
Technical details of SLN biopsy
The technical details of a correctly performed SLN biopsy are worthy of attention. First, all
patients should undergo preoperative lymphoscintigraphy. Typically, this is performed on the
same day as the operation to perform WLE and SLN biopsy. Technetium-99 sulfur colloid is
injected into the dermis, raising a wheel, in 4 aliquots around the primary melanoma or biopsy
site. It is important to inject the tracer into the normal skin surrounding the melanoma or biopsy
Fig. 2. Risk groups for SLN positivity in thin melanomas. Four risk groups were identied: (1) minimal risk: mitotic rate
(MR) 0 (SLN positivity rate 0.0%); (2) low risk: MR 1 and thickness o 0.76 mm (2.6%); (3) intermediate risk: MR 1,
thickness 0.76 mm and female gender (8.8%); and (4) high risk: MR 1, thickness 0.76 mm, and male gender
(16.1%).109 From Annals of Surgical Oncology, 12(2005):449-458, Kesmodel SB, et al., The Society of Surgical Oncology,
Inc. With kind permission from Springer Science and Business Media.
scar and not directly into the melanoma or biopsy scar itself. Another common mistake is to
inject the radioactive tracer too deep. Injection into the subcutaneous tissue may result in failure
to detect the sentinel node(s). Imaging is then obtained with a gamma camera. Dynamic and
static images allow identication of the lymphatic channels and sentinel nodes. Although
patterns of lymphatic drainage can generally be predicted by the historical anatomical studies of
Sappey,113 lymphoscintigraphy often identies lymph nodes in locations that might not be
anticipated. This is especially true for melanomas in locations with ambiguous lymphatic
drainage, such as the trunk, head, or neck. Anatomical predictions of nodal spread in these areas
are notably unreliable and often it is possible to identify sentinel nodes in more than one nodal
basin. Additionally, it is not uncommon to identify sentinel nodes outside the traditional cervical,
axillary, or inguinal nodal basins. These so-called interval, intercalated, or in-transit nodes
can be found in subcutaneous locations or even between muscle groups. For distal upper or lower
extremity melanomas, the presence of epitrochlear or popliteal sentinel nodes must be evaluated,
respectively. These interval nodes have the same risk of harboring melanoma cells as sentinel
nodes in traditional nodal basins and therefore, should be removed at the time of SLN biopsy.114 In
addition, in 85% of cases in which the SLN is an interval lymph node, the interval node is the only
positive node, even for those patients with other SLNs identied in traditional basins.115
Once in the operating room, a vital blue dye (eg, isosulfan blue or methylene blue) is injected
into the dermis around the melanoma site in a manner similar to injection of the radioactive
tracer (Fig 3). The timing of injection is important, because the dye would not persist within the
sentinel nodes for a prolonged period of time. Up to 5 mL of blue dye can be used, depending on
the size of the melanoma site. Injection of the blue dye within the planned margins of the WLE
should be attempted, as the pigment can persist in the skin for many months. The combined
lymphatic mapping technique of technetium sulfur colloid with vital blue dye would result in
identication of the sentinel node in 99% of patients when performed correctly.116 A handheld
gamma probe is used to guide dissection toward the location of the sentinel node or nodes.
Visible blue lymphatic channels should also be followed toward their draining nodes (Fig 4).
Ideally at least one hot, blue node would be identied. This node is then gently dissected free
from the surrounding tissue and removed.
Fig. 3. Injection of vital blue dye into the dermis surrounding a melanoma lesion. From McMasters KM, Urist MM,
Melanoma and Cutaneous Malignancies, in Townsend: Sabiston Textbook of Surgery, 19th Ed. (2012). Reprinted with
permission of Elsevier.
Fig. 4. Intraoperative image of blue lymphatic channels leading to the sentinel lymph node. From McMasters KM, Urist MM,
Melanoma and Cutaneous Malignancies, in Townsend: Sabiston Textbook of Surgery, 19th Ed. (2012). Reprinted with
permission of Elsevier.
A sentinel node is dened as the most radioactive node in the nodal basin, any node that is
blue (which indicates a direct lymphatic drainage pathway from the primary tumor), any node
that has a radioactive count greater than 10% of the most radioactive node in that basin, or any
node that is palpably suspicious for tumor. On average, 2 sentinel nodes are identied per nodal
basin. Although multiple radioactive lymph nodes may be evident within a nodal basin on
lymphoscintigraphy, many of these represent second echelon nodes and there is often poor
correlation between the number of nodes visualized on the lymphoscintigram and the number
of SLNs identied intraoperatively.117,118 All SLNs should be sent for permanent section
histopathology with immunohistochemical staining for specic melanoma markers (eg, S-100
and HMB-45); immediate frozen section histology should be avoided because even expert
pathologists have difculty diagnosing micrometastatic melanoma in the SLN on frozen sections.
The multicenter selective lymphadenectomy trial (MSLT)
In 1994, the rst MSLT-I was initiated by Donald Morton.101 This study randomized 1347
patients with melanomas 1.2-3.5 mm thick to undergo WLE alone or WLE with SLN biopsy. The
purpose of the study was to determine whether SLN biopsy, with completion LND for those
patients with metastatic disease in the sentinel nodes, improved disease-free or overall survival
compared with nodal observation.101 The 5-year melanoma-specic survival rates were nearly
identical for the 2 arms (87.1% vs 86.6%, respectively, P NS); however, the 5-year disease-free
survival rates did show a small but statistically signicant improvement in the SLN biopsy group
compared with the nodal observation group (78.3% vs 73.1%, respectively, P 0.009).101 In
subgroup analysis, considering only patients with nodal metastasis, there was a statistically
signicant difference in 5-year overall survival when comparing those patients with sentinel
node metastases who then underwent completion LND vs those patients in the observation
group who then developed palpable nodal disease requiring delayed LND (72.3% vs 52.4%,
respectively, P 0.004).101 Additionally, signicantly less disease was present when therapeutic
LND was performed early, as a completion LND following positive SLN biopsy, compared with
delayed, when palpable disease developed in the observation group (1.4 positive nodes vs
3.3 positive nodes, respectively, P o 0.001).101
Interpretation of the MSLT-I has become a topic of debate since its publication in 2006.
Clearly, the study shows that SLN biopsy is a safe and effective technique that can provide
important prognostic information for patients with intermediate-thickness melanoma. More
controversial is the argument that completion LND for patients with micrometastatic disease
improves overall survival, as suggested by the subgroup analysis.
Completion LND
Currently, micrometastatic disease found on SLN biopsy is an indication for completion LND.
Some have questioned the need for completion LND for patients with SLN micrometastasis. This is
largely based on 2 arguments: (1) a lack of clear evidence that completion LND improves overall
survival. (2) Nodal metastasis is often not found beyond the SLN. In support of the latter, 2 large
prospective randomized trials, MSLT-I and the Sunbelt Melanoma Trial, both showed the rate of
tumor-positive nonsentinel nodes among patients who underwent completion LND for tumor-
positive sentinel nodes to be only 16%.101,119 Again, we encounter the dilemma of performing a
potentially morbid procedure on a population in which approximately 80% cannot possibly benet.
With regard to the rst argument that completion LND has not been proven to improve
overall survival, this does have some merit, despite the subgroup analysis of MSLT-I. The
theoretical model used by MSLT-I to justify its subgroup analysis assumes that all positive
sentinel nodes, if given enough time, would progress to palpable disease; therefore, it is
permissible to compare the survival of patients who undergo early LND to those who undergo
delayed LND. In fact, in MSLT-I, the percentage of patients with micrometastatic disease in the
SLN biopsy group was identical to the percentage of patients developing macrometastatic
disease in the observation group (16%). On the surface, this would support the theory that all
microscopic tumor deposits found at SLN biopsy would ultimately become clinically evident
macrometastatic disease if not resected. Unfortunately, if we take a closer look, we nd that this
is not entirely true. In MSLT-I, approximately 3% of patients in the SLN biopsy arm had negative
sentinel nodes but, during follow-up, developed macrometastatic nodal disease. If we assume
that this 3% of patients would have developed macrometastatic disease if randomized to the
observation arm, then only 13% of patients with micrometastatic disease should have had a
positive SLN biopsy. Using this logic, the more likely model is that most, but not all, SLN-positive
patients would progress to palpable disease, and conversely, some SLN-negative patients would
develop palpable disease (false negatives). In MSLT-I, approximately 20% of patients with
positive sentinel nodes would not have gone on to develop macrometastatic disease. This has
been termed by some as prognostic false positivity.120 As a result, the comparison of patients
with micrometastatic disease in the SLN biopsy group to patients who developed macro-
metastatic disease in the observation group is biologically inaccurate. Ultimately, the question of
improved survival with completion LND will be answered by the MSLT-II, which randomizes
patients with positive sentinel nodes to either immediate completion LND or observation, with
completion LND reserved for conrmed, nonsentinel node disease.121
Pathologic evaluation of the SLN
Given the signicant role of the SLN as a prognostic factor and as a tool for decision making with
regard to completion LND, the methods used to determine SLN status must be carefully examined.
The classic technique for pathologic evaluation of the sentinel node is by hematoxylin and eosin
staining, with the addition of immunohistochemical staining for melanoma markers S-100 and HMB-
45 to increase sensitivity. This typically results in detection of nodal metastasis in 15%-20% of patients.
The use of reverse transcriptase-polymerase chain reaction (RT-PCR) has been evaluated
as a method of increasing the rate of detecting micrometastases within the sentinel node.
With RT-PCR, rates of SLN positivity have been reported as high as 70%.55 Although the incidence
of SLN positivity is increased by the utilization of RT-PCR, it was unclear if this information
had prognostic signicance, and if it should therefore be used to make clinical decisions
such as whether to perform completion LND or administer adjuvant therapy. The Sunbelt
Melanoma Trial was designed to answer this question. A total of 1446 patients with
histologically negative SLNs underwent RT-PCR analysis. The SLNs were found to be positive
by RT-PCR in 620 patients and negative in 826 patients. At a median follow-up of 30 months,
there was no statistically signicant difference in disease-free survival or overall survival
between groups.122
SLN tumor burden has also been proposed as a method of pathologic grading used to predict
prognosis and to predict which patients with microscopically positive sentinel nodes are most
likely to have additional nonsentinel node metastases. Examples of tumor burden systems
include the S-classication, which grades depth of micrometastasis within the sentinel node, the
Dewer classication, which straties the microanatomical location of the metastasis within the
node, and the Rotterdam classication, which uses maximum diameter of the largest metastases
within the node to assess prognosis and risk.123-125 In the European Organization for Research
and Treatment of Cancer (EORTC) melanoma database, lymph node tumor burden has been
reported to correlate with overall survival. In this group, estimated overall survival at 5 years
was 91% for metastatic disease measuring less than 0.1 mm, 61% for metastatic disease
measuring 0.1-1 mm, and 51% for metastatic disease measuring greater than 1.0 mm (P 0.001).
The authors reported that the survival rate for patients with a metastatic tumor burden less than
0.1 mm is similar to patients who have negative sentinel nodes, ranging from 90%-94%.125
Although the tumor burden within the SLN appears to correlate with the risk of nonsentinel
node metastasis, there is currently no consensus regarding which sentinel node-positive
patients may safely avoid completion LND.126
In addition to improved overall survival, another goal of completion LND is regional disease
control. In a retrospective multi-institutional study by Wong and colleagues that included 134
patients with SLN metastases who did not undergo completion LND, regional nodal recurrence
was a component of rst recurrence in 15% of patients.127 Therefore, the risk of nodal recurrence
if completion LND is not performed may be estimated as at least 15%. In MSLT-I, the rate of
regional nodal recurrence after completion LND was 4.2%; in the Sunbelt Melanoma Trial it was
4.9%.101,119 Therefore, although it remains unclear whether completion LND cures more patients
or improves overall survival, it does appear to provide excellent regional disease control. Until
the results of MSLT-II are available, it is recommended that patients with metastatic disease in
the SLN undergo completion LND, unless they are candidates for enrollment in the trial
themselves and subsequent randomization to completion LND vs observation.
Therapeutic LND
Patients with nodal metastasis suspected by palpation or imaging studies (clinically positive
lymph nodes) should undergo conrmation with ne-needle aspiration biopsy. If ne-needle
aspiration is nondiagnostic, excisional biopsy may conrm the diagnosis. Occasionally palpable
nodes will be benign and LND for patients who have benign lymphadenopathy should be
avoided. Imaging evaluation to exclude the presence of distant metastatic disease by both brain
magnetic resonance imaging and whole-body positron emission tomography/computed
tomography (PET/CT) scan should be completed for patients with clinically positive nodes prior
to therapeutic LND. In the absence of metastatic disease, therapeutic LND can be performed and
will result in long-term survival and potential cure for a signicant fraction of patients. Prognosis
following therapeutic LND depends on the extent of the nodal disease. The number of involved
lymph nodes appears to have greater prognostic signicance than the size of the nodes, but
there is also a clear range of prognosis depending on whether the nodes have microscopic vs
macroscopic involvement by melanoma. The survival of stage III melanoma patients who
undergo LND ranges from approximately 14%-85% depending on the nodal tumor burden.128
Extent of LND
Considering the lack of effective adjuvant therapy agents, lymphadenectomy for melanoma is
performed with curative intent and therefore should be as complete as possible. This differs
markedly from the role of LND performed for breast cancer. In breast cancer, a level I/II axillary
LND is performed to gain important staging information, but effective chemotherapy, radiation
therapy, and hormonal therapy serve to minimize regional recurrence. In melanoma, a thorough
level I/II/III axillary LND is necessary to reduce the likelihood of nodal recurrence. The
conventional teaching in breast cancer is not to extend the LND cephalad to the axillary vein and
not to remove level III nodes, because of the supposed increased risk of lymphedema. This
conservative approach is appropriate in patients with breast cancer; however, failure to
completely clear these level II and III nodes can frequently be the cause of nodal recurrence in
patients with melanoma after axillary LND. Complete removal of all brofatty tissue around the
axillary vein, the thoracodorsal and medial pectoral neurovascular bundles, and the long
thoracic nerve is essential. If necessary, the pectoralis minor muscle can be divided near its
insertion on the coracoid process in order to clear bulky level II and III nodes. Likewise, the
pectoralis major muscle can be divided to obtain optimal nodal clearance, although this is
usually unnecessary. If the axillary vein is involved by tumor, it can be ligated and divided, often
with less consequence in terms of edema than one might anticipate.
Inguinal LND may include both the supercial inguinal (femoral) nodes and the deep
(internal iliac, external iliac, and obturator) nodes. For most cases of lower extremity melanoma
with inguinal SLN metastasis, a supercial inguinal LND is sufcient. Indications for the addition
of a deep LND vary. Patients with palpable nodal disease should have supercial and deep nodes
dissected in most cases. Metastasis to multiple supercial inguinal nodes or to Cloquet node (the
most proximal femoral lymph node that lies beneath the inguinal ligament, medial to the
common femoral vein) should prompt a deep inguinal node dissection. Imaging suggestive of
deep inguinal node involvement would also indicate the need for a deep nodal dissection.
Finally, deep LND should be considered for patients with buttock or truncal primary melanomas
that metastasize to a supercial inguinal SLN.
For disease metastatic to sentinel nodes in the cervical lymph node basins, a functional lateral
neck dissection, sparing the internal jugular vein and spinal accessory nerve, is recommended.
Epitrochlear or popliteal LND is rarely necessary, but does require careful attention to the
particular anatomy in these regions. In an epitrochlear LND, it is essential to identify and
preserve the brachial artery and vein as well as the median and ulnar nerves. In a popliteal
LND, the critical structures that must be preserved include the popliteal artery and vein,
and the common peroneal and tibial nerves. If necessary, the lateral sural nerve can be divided
without clinical consequence; however, sacrice of the medial sural nerve results in sensory loss
of the lateral ankle and foot. It is very important to perform circumferential dissection of the
vessels during a popliteal LND, because there often exist 1 or 2 lymph nodes located anterior
to the vessels (or deep, from the perspective of the operating surgeon) that are easily
overlooked.129,130
SLN biopsy during pregnancy
Melanoma that manifests during pregnancy poses a difcult clinical scenario. It was once
believed that the growth rate of the tumor was accelerated by hormonal changes during
pregnancy. This idea is currently not generally accepted, as the prognosis for patients treated
during pregnancy is no different from the prognosis for nonpregnant patients of similar stage.
When indicated, SLN biopsy can be considered. Although there exists an obvious desire to limit
radiation exposure to the fetus, data from patients with breast cancer indicate that there is little
risk to the fetus from lymphoscintigraphy. SLN localization with vital blue dye should not be
attempted during pregnancy. Although rare, there is a 1:10,000 risk of anaphylactic reaction
associated with lymphazurin (isosulfan blue), which could threaten the life of both mother and
fetus. The alternative, methylene blue dye, is known to be teratogenic and its use is therefore
contraindicated in pregnancy.
Melanoma of unknown primary (MUP)
Occasionally, melanoma would rst be detected not in a skin lesion, but rather as a
subcutaneous, nodal, or visceral organ deposit. When this occurs, the clinician must rst assume
that this lesion is metastatic disease and a thorough investigation should be carried out in search
of the primary lesion. As always, investigation should begin with a detailed history and physical
examination. History of any prior pigmented skin lesions that may have disappeared
spontaneously or that have been previously excised, cauterized, or treated with lasers should
be elicited. The pathology slides of any lesions that have been excised in the past should be
rereviewed. A complete head-to-toe skin examination should be performed, including the scalp,
external auditory canals, nail beds, external genitalia, and perianal area. Mucosal melanomas
should be searched for by endoscopic examination of the oral cavity and nasopharynx, as well as
the anus and rectum. Ocular melanoma should be investigated by ophthalmologic examination,
and women should undergo pelvic examination. If the primary lesion still cannot be identied
after such a thorough evaluation, whole-body PET/CT may help locate the primary lesion. Only
after all of these methods of localization have failed to reveal a primary lesion, can a
subcutaneous, nodal, or visceral organ tumor deposit be classied as a MUP.131 In a recent meta-
analysis, the incidence of MUP was shown to be approximately 3%.132
Several theories have been proposed to explain the pathophysiology of MUP. One hypothesis
purports that tumor cells arise de novo within lymph nodes or other sites, because ectopic
melanocytes or precursor nevus cells undergo malignant transformation.133,134 An alternative
hypothesis is that an undetected primary melanoma has undergone regression mediated by the
host immune response after it has already metastasized.135 This hypothesis seems consistent
with the behavior of melanoma of known primary (MKP), which is known to regress on
occasion, and which usually metastasizes to regional lymph nodes. MUP is much more likely to
be found in lymph nodes than in visceral organs, much like MKP, and visceral organ presentation
of MUP may be secondary to skip metastases, which can occur in 1% of MKPs.103
When MUP manifests lymph node metastasis, therapeutic LND is performed with the
assumption that it represents stage III disease. Likewise, visceral organ MUP is treated as stage IV
disease, with surgical resection when possible. The overall survival of patients with MUP who
present with lymph node involvement or visceral organ disease is no worse than, and is perhaps
better than, the overall survival of patients with MKP who have stage III or stage IV disease,
respectively.132,135,136
Adjuvant therapy
Systemic therapy
The denition of adjuvant therapy is treatment given in addition to the primary or main
treatment. This denition was never more accurate than in the setting of melanoma, where
surgery is truly the primary treatment. Thus far, the inclusion of additional treatment after
surgical resection of stage IIB or stage III disease has demonstrated modest results at best. There
have been multiple candidates for adjuvant therapies, including systemic chemotherapies,
vaccines, and immunostimulants. Most of these therapies have shown no effect, and some have
even demonstrated a negative effect on overall survival.
Currently, the only adjuvant therapy approved by the US Food and Drug Administration
(FDA) for the treatment of stage IIB/III melanoma is high-dose interferon (HDI) alfa-2b. The
FDA initially approved HDI for stage IIB/III melanoma in 1995 following a clinical trial con-
ducted by the Eastern Cooperative Oncology Group in conjunction with other cooperative
groups: E1684.137 This trial, initiated in 1984, randomized patients with stage IIB/III disease to
either HDI or observation, and results demonstrated a small, but statistically signicant,
disease-free and overall survival benet for treatment with interferon compared with
observation alone.137
HDI alfa-2b is administered as 20 MIU/m2 intravenous infusion, 5 days per week for 1 month,
followed by 10 MIU/m2 subcutaneous injection 3 times per week for 11 months. This dosing
regimen is near to what is maximally tolerated because of the severe toxicity of the drug, making
high performance status a prerequisite for administration. Side effects include severe u-like
symptoms, fatigue, malaise, anorexia, neuropsychiatric side effects, and potential hepatic
toxicity. Owing to the substantial side effects of HDI, a second clinical trial, E1690, was initiated
to verify the results of E1684 and to evaluate the efcacy of an alternative, low-dose interferon
(LDI) alfa-2b regimen.138 This study again demonstrated a marginal improvement in disease-free
survival for HDI, but this time there was no improvement in overall survival. Additionally,
LDI was inferior to HDI and offered no disease-free or overall survival advantage over
observation alone.138 Overall, 7 clinical trials have evaluated LDI; 4 have demonstrated an
improvement in disease-free survival, but only 1 trial has demonstrated an improvement in
overall survival.139
The third study to evaluate HDI, E1694, randomized patients to HDI or a ganglioside vaccine
(GM2).140 This trial was stopped early because of the clear superiority of interferon compared
with the vaccine in terms of disease-free and overall survival. This study was initially interpreted
as evidence of a benecial effect for HDI; however, after yet another randomized prospective
trial conducted by the EORTC demonstrated a signicantly detrimental effect from GM2
compared to a placebo group, the results of E1694 have been questioned.
In another attempt to reduce the toxicity of HDI, pegylated interferon (PEG-IFN) was
developed by Schering-Plough Research International. The pegylated form of interferon allows
the drug to stay active in the body for a longer duration. This is designed to reduce the frequency
of administration and therefore to reduce the toxicity of the drug. The efcacy of PEG-IFN was
evaluated in the EORTC trial 18991, which randomized patients to 5 years of PEG-IFN or
observation.141 In this trial, the PEG-IFN dosing schedule was comparable to that of the HDI
regimen. This study again demonstrated improvement in disease-free survival, but no benet in
terms of distant metastasis-free interval or overall survival.141 Recent long-term follow-up
showed a reduction in the original disease-free survival benet, and again, no distant
metastasis-free interval or overall survival benet.142
Subgroup analyses of many of these studies have been performed in an attempt to identify
patients with the optimal disease burden to benet from treatment with interferon: node-
negative disease, micrometastatic nodal disease, or palpable nodal disease. E1684 had a high
percentage of patients with palpable stage III disease. Conversely, E1690 had more patients with
T4, node-negative disease. The Sunbelt Melanoma Trial randomized patients with a single
positive sentinel node (all of whom underwent completion LND) to observation or HDI.
Although somewhat underpowered to detect small differences in disease-free or overall
survival, this study showed neither statistically signicant differences nor trends to suggest a
benet from HDI in this population.119
Taken together, data from these trials suggest that, without adjuvant treatment, the risk
of recurrence for patients with stage IIB disease is 60%, and the risk of recurrence for patients
with stage III disease is approximately 75%. The addition of adjuvant HDI therapy may provide
a modest 5%-10% improvement in disease-free survival. The effect on overall survival is more
controversial, but is at best quite modest and at worst nonexistent. The 5-year overall survival
rate for SLN-positive patients who do not receive adjuvant interferon, as suggested by the
Sunbelt Melanoma Trial and MSLT-I, is approximately 70%. Overall survival was not improved
by adjuvant interferon. Lower doses of interferon may provide the same disease-free
survival advantage as HDI with a better safety prole. Considering the cost, toxicity, and
marginal efcacy, observation for patients with tumor-positive SLN after completion LND
is considered a reasonable option and is the standard treatment in many centers around
the world.
Radiation therapy
Adjuvant radiation therapy for melanoma is not routinely used, as melanoma is generally
considered to be resistant to irradiation. Radiation therapy has been utilized in some centers in
an attempt to improve locoregional disease control. This is most commonly advocated for high-
risk head and neck melanomas, where the risk of local recurrence and in-transit disease is
substantially greater than for other sites. Retrospective data also suggest that there may be a
small benet when radiation therapy is used for regional disease control in patients with
multiple tumor-involved lymph nodes or extracapsular extension found after LND. The Brisbane
Adjuvant XRT Trial was a prospective multicentered international study that randomized 217
patients with a substantial risk of regional recurrence after LND to adjuvant radiotherapy or
nodal observation.143 Risk factors included the total number of positive lymph nodes (at least
1 for partotid, 2 for neck and axilla, and 3 for the inguinal region), lymph node size (30 mm or
greater for partotid, neck, and axilla, and 40 mm or greater for the inguinal region), or
extracapsular extension of tumor. After a median follow-up of 40 months, there was a
statistically signicant reduction in lymph node eld relapse for the radiation group as
compared with the observation group (18% vs 31%, respectively, P 0.041).143 As with other
forms of adjuvant therapy, there was no difference in overall survival. However, this was the rst
prospective randomized trial to demonstrate a benet for adjuvant radiation therapy in
melanoma patients with nodal metastasis.143
Follow-up after treatment of melanoma
There is no consensus regarding the appropriate way to monitor patients for recurrence after
initial treatment of melanoma; however, some general principles should be considered. Patients
who have been diagnosed with melanoma have a 3%-7% lifetime risk of developing a second
primary melanoma in addition to the risk of local, regional, or systemic recurrence.33 In general,
most recurrences are detected either by the patient, or by a thorough history and physical
examination performed by the clinician. A thorough history should specically inquire about
new cutaneous or subcutaneous lesions, nodal masses, pain, headaches, neurologic changes,
weight loss, and gastrointestinal and pulmonary symptoms. Patients should be educated about
the common signs and symptoms of recurrence so that they can report important changes that
arise between scheduled examinations. Physical examination should include a complete head-
to-toe skin examination, with inspection and palpation to detect local, regional, or in-transit
recurrence. Laboratory and imaging tests such as lactate dehydrogenase levels and PET/CT have
not been proven to lead to earlier detection of metastatic disease and are not routinely obtained
in surveillance of most patients with melanoma. The majority of recurrences ( 475%) would be
detected in the rst 3 years after treatment of the primary melanoma,144 although rarely it is
possible to develop metastatic disease decades after initial treatment. In general, the longer the
disease-free interval, the better the prognosis. Despite advocacy of close clinical surveillance,
there is little evidence that early detection of distant metastatic disease would alter a patient's
overall outcome. We recommend that the follow-up strategy be tailored to the individual
patient's risk of metastasis in compliance with current NCCN guidelines.145
Patients with stage 0 (in situ) disease should undergo at least 1 annual skin examination for
the remainder of their lives. Routine blood tests or radiologic imaging studies are unnecessary;
however, these tests can be useful for investigating specic signs or symptoms concerning for
recurrence.
Likewise, patients with stage I and IIA disease should have at least 1 annual skin examination
for the remainder of their lives. For the rst 5 years following resection, the follow-up schedule
should be individualized to the patients risk of recurrence as inuenced by personal history,
family history, patient or physician concern, and other relevant factors: usually every 3-12
months. Again, routine blood tests or radiologic imaging studies are unnecessary, but can be
obtained if deemed appropriate.
For patients with stage IIB, IIC, and III melanoma, the follow-up schedule recommended by
the NCCN includes a history and physical examination every 3-6 months for the rst 2 years,
every 3-12 months for the next 3 years, and annually thereafter. The use of routine laboratory
tests and imaging tests such as chest x-ray, magnetic resonance imaging, or PET/CT is
controversial, but for patients with stage IIB, IIC, or III melanoma, a surveillance strategy that
includes imaging is not unreasonable. At the very least, interval development of symptoms such
as persistent headaches, bone pain, or weight loss should trigger the clinician to look for
metastatic disease. After 5 years, routine radiologic imaging for asymptomatic patients is
unnecessary.
Patients with stage IV melanoma who are receiving systemic therapy should have regularly
scheduled clinical, laboratory, and radiologic evaluations to monitor their response to
treatment.146
Treatment of recurrent or metastatic disease
Local recurrence
Local recurrence is dened as any melanoma appearing in the skin or subcutaneous tissues
within a 2-cm radius of the scar or skin graft of the WLE site. The risk of local recurrence
increases with increasing tumor thickness and has been reported to be 1%, 2.3%, 4.2%, and 11.7%
for melanomas less than 1 mm, 1-2 mm, 2.01-3 mm, and 3.01-4 mm, respectively.147 Local
recurrence reects aggressive biological behavior and signies a poor prognosis. Approximately
80% of these patients would eventually go on to develop regional or distant metastases and
ultimately die of progressive disease.148 Treatment of local recurrence is surgical resection with
histologically negative margins.
In-transit disease
In-transit recurrence represents endolymphatic disease that manifests as cutaneous or

subcutaneous tumor nodules between the primary tumor site and the regional nodal basin
(Fig 5). In-transit lesions may be palpable but may or may not be visible. Frequently, these
lesions are not hyperpigmented, but rather are pink or esh colored. Patients with in-transit
disease should undergo imaging by PET/CT to evaluate for distant metastatic disease. Limited
in-transit disease can be treated adequately with local excision to histologically negative
margins. Although recurrence of in-transit disease after resection is nearly guaranteed, many
patients with limited in-transit disease may be managed for years with sequential excision of
these lesions and a resulting good quality of life. For refractory in-transit disease, local
injection with agents such as the Bacille Calmette-Gurin (BCG) vaccine, interferon, or
interleukin-2 (IL-2) can be effective and, in some cases, laser or other ablative therapies may
be considered.
More extensive or recurrent in-transit disease, when conned to the upper or lower
extremity, may be treated with hyperthermic isolated limb perfusion (HILP), or with the newer
technique of isolated limb infusion (ILI). Both of these therapies are performed with
L-phenylalanine mustard (melphalan).
Creech and colleagues at Tulane University were the rst to perform HILP.149 The concept of
HILP is that, by limiting the circulation of chemotherapy to the affected limb, a higher
concentration of chemotherapeutic agent may be achieved regionally, while minimizing the
overall systemic toxicity of the drug. HILP is performed by open exposure and cannulation of the
major artery and vein of the affected extremity. After proximal vessel occlusion and tourniquet
isolation of the proximal extremity, hyperthermic (401C-421C) perfusion is initiated with the use
of a pump oxygenator. This technique can generate substantial ow rates at approximately 150-
1000 mL/min.150 Several single-institution studies have demonstrated overall response rates to
Fig. 5. Example of cutaneous in-transit melanoma.
HILP as high as 80%, with 40%-60% complete response rates.151,152 Unfortunately, clinical
response to limb perfusion is usually slow and not exceptionally durable. It can take as long
as 6 months to obtain a complete response, and the median limb relapse-free interval is reported
to be anywhere from 9-21 months.151,153,154 Complete response following HILP appears
to predict a better prognosis. In a study by Sanki and colleagues at the Sydney Melanoma
Unit, the 5-year survival for nonresponders and partial responders was only 7%, whereas
the 10-year survival for complete responders was 49%.153 HILP achieved long-term control of
in-transit disease in 57% of complete responders.153 Repeat perfusion can be performed in
patients who recur, but this should only be attempted if the patient responded well to the initial
perfusion.
Based on the favorable response for in-transit disease, HILP has been evaluated in the
adjuvant setting for patients with high-risk melanoma ( 41.5 mm thick) as a method of
prophylaxis against recurrent in-transit disease. In a multicenter, phase III trial, more than 800
patients with high-risk melanomas were randomized to WLE or WLE with HILP.155 After a 6-year
median follow-up, there was no improvement in overall survival, with only a modest reduction
in the number of in-transit recurrences, from 6.6%-3.3%.155 Therefore, because of the substantial
morbidity with little benet in the prophylactic setting, HILP is currently only recommended for
patients with established in-transit metastases.
The addition of tumor necrosis factor (TNF-) to melphalan has been suggested as a strategy
to improve response rates to HILP. Multiple nonrandomized studies initially demonstrated
encouraging results.156-158 To evaluate this question more completely, a study conducted by the
American College of Surgeons Oncology Group randomized 124 patients with extremity in-
transit melanoma to receive HILP with melphalan alone or HILP with melphalan plus TNF-.159
Results of the trial showed equivalent overall response rates of 64% and 69%, with complete
response rates of 25% and 26% in the groups treated with melphalan vs melphalan plus TNF-,
respectively (P NS for both comparisons).159 In addition, limb toxicity was substantially greater
in the group treated with TNF-.159 Results of this study therefore found no benet to the
inclusion of TNF- in the HILP regimen.
The locoregional toxicity of HILP can be substantial, including compartment syndrome,
neuropathy, skin reaction, blistering, and lymphedema; toxicity resulting in amputation may
occur in 1%-3% of patients.154 It is essential that chemotherapeutic dosing be accurately
calculated (Fig 6). Likewise, circulation of the chemotherapeutic agent must be completely
isolated to the affected limb, as systemic toxicity secondary to leakage, is severe and often fatal.
Proper technique is of utmost importance when performing HILP.
Fig. 6. Limb volume calculation for chemotherapy dosing during HILP. Serial cirfumferential measurements can be made
to estimate the limb volume. Melphalan is then dosed at 10 mg/L limb volume.
ILI is a less invasive method of delivering regional chemotherapy, pioneered by John

Thompson. The technique of ILI involves placing percutaneous catheters into the major artery
and vein supplying the affected extremity, instead of open operative cannulation of these
vessels.150 Perfusion with ILI is accomplished by manual circulation using a syringe, instead of a
pump oxygenator or perfusion team, and therefore requires less resources and equipment than
HILP. ILI appears to achieve response rates that are comparable to those of HILP, but although
substantially lower ow rates are generated, limb toxicity is not less than with HILP.150 ILI is
especially appealing for the treatment of patients with in-transit disease who do not require
simultaneous regional lymphadenectomy or who have already undergone previous HILP.
Amputation for extensive regional recurrence is rarely indicated. Patients in this situation
have a very high risk of developing other distant metastases, and therefore, long-term disease-
free survival would not be achieved by resection.
Regional nodal recurrence
Regional nodal recurrence is treated by lymphadenectomy as described earlier. Advanced

regional nodal disease can ulcerate through the skin causing pain, bleeding, infection, and
decreased quality of life. Surgical resection for palliation may be indicated in these situations.
Distant metastases
The most common sites of initial distant metastases from melanoma are the brain, lung, and
liver. Less commonly, melanoma metastasizes to the skin, distant lymph nodes, bone, adrenal
glands, or the gastrointestinal tract. The median overall survival of patients with stage IV
melanoma left untreated is approximately 7 months. The pattern of metastasis can vary from a
single focus of distant disease to the more common scenario of widespread, multifocal disease.
Surgical resection should be considered rst-line therapy for patients with stage IV melanoma
whenever complete extirpation of all disease can be accomplished; this includes brain
metastases. Retrospective studies have demonstrated 5-year survival rates of 20%-40% after
resection in selected patients with distant metastases. These survival rates are similar to those of
patients who undergo therapeutic LND for palpable nodal disease. In a recent retrospective
review of patients enrolled in MSLT-I who progressed to stage IV disease, metastasectomy was
possible in 50% of patients and resulted in an improved overall survival compared to medical
management. Among the patients undergoing metastasectomy, there was an even greater
survival advantage for patients with a long disease-free interval (4 12 months) and for patients
with less than 3 visceral organs involved.160 This study supports the creed that one should
never overlook the opportunity to render a melanoma patient surgically free of cancersome
patients at every stage will enjoy long-term survival.161
Patients with unresectable metastatic disease should be considered for either systemic
therapy or palliative care. Melanoma is generally considered to be resistant to conventional
chemotherapy. Prior to 2011, there were only 2 agents approved by the United States. FDA for the
treatment of stage IV melanoma: dacarbazine (DTIC) and high-dose IL-2. DTIC therapy has been
shown to be marginally effective, with response rates of approximately 15%.162-165 However,
DTIC has never been proven to prolong survival for patients with stage IV melanoma, and
median overall survival is approximately 7 months. Likewise, high-dose IL-2 therapy has shown
very marginal response rates, at approximately 6%, and no benet in overall survival. IL-2 is
associated with substantial toxicity, requiring administration in an intensive care unit setting.
Combination therapies have shown improved response rates, but are associated with substantial
toxicity and again, have shown no demonstrable improvement in survival.166
Over the last decade, signicant progress has been made in the systemic treatment of stage IV
melanoma. It has long been suspected that defects in the host immune system play a major role
in the pathway for melanoma tumorigenesis and metastasis. Regulatory pathways that limit the
hosts immune response have become a particularly interesting molecular target for treatment
of metastatic melanoma. Cytotoxic T-lymphocyte-associated antigen (CTLA-4) has been
described as an immune checkpoint molecule that downregulates the pathways of T cell
activation.167,168 Ipilimumab is a monoclonal antibody that blocks CTLA-4 to promote antitumor
immunity.168 In 2004, a randomized, controlled, multicenter phase III trial was initiated for
patients with unresectable stage III or stage IV melanoma whose disease had progressed while
receiving standard systemic therapy.169 A total of 676 patients were randomized to ipilimumab
alone, gp100 vaccine alone, or combination ipilimumab and gp100. Ipilimumab was
administered intravenously once every 3 weeks for a total of 4 treatments at a dose of 3 mg
per kilogram body weight. The results of the trial were published in 2011 and showed that
treatment with ipilimumab (with or without the vaccine) improved overall survival compared to
treatment with the vaccine alone, with a median overall survival of 10.0 and 10.1 months,
respectively, compared to 6.4 months for the vaccine alone.169 This was the rst randomized,
controlled trial to show a signicant improvement in overall survival for patients with
metastatic melanoma treated with systemic therapy.
Another molecular pathway that has been shown to play a role in the progression of
melanoma is the mitogen-activated protein kinase pathway, which is regulated by the protein
BRAF. Mutations in BRAF are found in 40%-60% of cutaneous melanomas and result in
constitutive activation of the mitogen-activated protein kinase pathway.170,171 Approximately
90% of these mutations are BRAF V600E, which is effectively inhibited by the monoclonal
antibody vemurafenib.172 The BRAF Inhibitor in Melanoma Trial 3 was a multicenter clinical trial
that randomized patients with unresectable, previously untreated, stage IIIC or IV melanoma to
either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m2 of body surface area
every 3 weeks).173 At 6-month interim analysis, vemurafenib showed a statistically signicant
improvement in overall survival compared with dacarbazine (84% vs 64%). After review of the
interim analysis by an independent data and safety monitoring board, crossover from
dacarbazine to vemurafenib was recommended. In addition to an improvement in overall
survival, vemurafenib also showed a signicant improvement in tumor response rate. Forty-
eight percent of patients had a conrmed, objective response to vemurafenib compared with
only a 5% response rate for patients treated with dacarbazine.173
In 2012, the FDA approved ipilimumab and vemurafenib for the treatment of stage IV
melanoma, and although these 2 drugs have brought hope and enthusiasm to treat a disease
that has historically been impervious to systemic therapy, there are still many obstacles to
overcome. Even though ipilimumab showed a signicant improvement in overall survival, there
was still only a 10.9% tumor response rate, indicating that the drug effectively slows progression
of the disease but is not as effective at reducing or eliminating the burden of disease.169
Conversely, vemurafenib showed an impressive response rate, but the durability of clinical
responses remains poor, as acquired drug resistance occurs in nearly every patient.174
Identication of new molecular targets for potential immunotherapy as well as development
of new clinical trials to evaluate combination therapies is necessary in order to continue to
advance the treatment of stage IV melanoma.
Palliative treatment of distant metastases
Radiation therapy can sometimes provide useful palliation of painful bone and central
nervous system metastases. Stereotactic radiation therapy can occasionally palliate patients with
brain metastases. However, radiation therapy in general provides little benet for melanoma
metastatic to other sites.
Conclusions
The incidence of cutaneous melanoma continues to rise at a higher rate than any other
malignancy in the United States. An understanding of the risk factors associated with melanoma,
in particular exposure to UV radiation in the form of sunlight and tanning beds, is necessary to
prevent the disease. Surgical resection, when possible, remains the primary treatment for all
stages of disease; however, with the evolving understanding of molecular pathways involved in
tumorigenesis, targeted systemic therapies are playing an increasing role in the treatment of
advanced disease.
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Current Problems in Surgery 50 (2013) 351382

Contents lists available at SciVerse ScienceDirect

Current Problems in Surgery

journal homepage: www.elsevier.com/locate/cpsurg

Current management of melanoma

Current state of melanoma in the United States

Melanoma is primarily a disease of Caucasians, and as a result, phenotype plays a signicant

Although the mechanism of malignant transformation is not completely dened, it is clear

Family history and genetics

A family history of melanoma increases an individual's personal risk of melanoma by a factor

Demographic risk factors

Personal history of melanoma

History and physical examination

T category Thickness (mm) Ulceration status or mitoses

N category Number of metastatic nodes Nodal metastatic mass

M category Site Serum LDH

NA, not applicable; LDH, lactate dehydrogenase.

Clinical staging* Pathologic staging

Treatment of the primary lesion

Management of the regional lymph nodes

It is essential for clinicians to understand the proper terminology regarding operations

During early surgical treatment of melanoma, truncal melanomas posed a particular

Indications for SLN biopsy

Technical details of SLN biopsy

The multicenter selective lymphadenectomy trial (MSLT)

Pathologic evaluation of the SLN

SLN biopsy during pregnancy

Melanoma of unknown primary (MUP)

Follow-up after treatment of melanoma

Treatment of recurrent or metastatic disease

In-transit recurrence represents endolymphatic disease that manifests as cutaneous or

Fig. 5. Example of cutaneous in-transit melanoma.

ILI is a less invasive method of delivering regional chemotherapy, pioneered by John

Regional nodal recurrence

Regional nodal recurrence is treated by lymphadenectomy as described earlier. Advanced

Palliative treatment of distant metastases

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