114 Melanoma
Frank O Nestle
Helmut Kerl
Key features
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Melanoma is a malignant tumor arising from melanocytes
Melanoma has been increasing in incidence and mortality in recent
decades
Many deaths will occur at a younger age than for other solid tumors
Early detection is an important factor in melanoma management
Appropriate surgical treatment of low-risk melanoma (<1 mm Breslow
depth) with 1 cm margins will cure patients in nine cut of ten cases
INTRODUCTION
Melanoma is a tumor arising from melanocytes. Its incidence and patient mortality rates has been
rising in recent decades. Melanoma is among the most common types of cancer in young adults 1.
It therefore represents a substantial public health problem. Up to one-fifth of patients develop
metastatic disease, which usually is associated with death. However, early detection and
appropriate excision of the tumor leads to a cure rate of over 90% in low-risk (<1 mm Breslow
depth) melanoma patients. Innovative early detection programs in combination with improved
diagnostic tools and new immunological treatments in advanced stages of the disease will likely
have an impact on the outcome of the disease in the future.
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Figure 114.1 Molecular pathogenesis of melanoma development. CDKN2A (INK4a/ARF)
encodes two separate gene products p16 and p14ARF, which are both negative regulators of
cell cycle progression. The p16 protein executes its effects by competitive inhibition of cyclindependent kinase 4 (CDK4). CDK4 interacts with cyclin D and phosphorylates the master
gatekeeper retinoblastoma protein (Rb). Phosphorylation of Rb will lead to S phase
progression and ultimately cellular division and proliferation. An intact p16 protein is essential
for cell cycle arrest. The net effect of CDKN2A mutation with loss of p16 function will increase
the likelihood that mutagenic DNA escapes repair before cell division. The second gene
product p14ARF binds to MDM2 and regulates melanocyte growth through effects on the p53
'guardian of the genome' pathway. MDM2 accelerates the destruction of p53. The net effect of
CDKN2A mutation with loss of p14ARF function is p53 loss with enhanced growth/survival of
altered cells.
MOLECULAR PATHOGENESIS
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Epidemiologic studies have demonstrated a role for genetic predisposition and sun exposure in
melanoma development. Substantial information has been added to the body of evidence
suggesting that inherited and somatic genetic events contribute to the pathogenesis of
melanoma. In particular, aberration of cell cycle control and transcriptional control mechanisms
are implicated in the disease pathogenesis2. The major gene involved in melanoma development
resides on chromosome 9p21. This gene (also known as CDKN2A or INK4a/ARF) encodes two
separate gene products p16 and p14ARF (alternative reading frame) that are both negative
regulators of cell cycle progression (Fig. 114.1). The p16 protein itself executes its effects by
competitive inhibition of cyclin-dependent kinase 4 (CDK4). CDK4 interacts with cyclin D and
phosphorylates the master gatekeeper retinoblastoma protein (Rb). Phosphorylation of Rb will
lead to S phase progression and ultimately cellular division and proliferation. An intact p16 protein
is essential for cell cycle arrest. The net effect of CDKN2A mutation with loss of p16 function will
increase the likelihood that mutagenic DNA escapes repair before cell division. The second gene
product p14ARF (p19ARF in mice) binds MDM2 and regulates melanocyte growth through
independent effects on the p53 pathway3,4. The net effect of CDKN2A mutation with loss of
p14ARF function is increased p53 destruction with enhanced growth/survival of altered cells. p16
is abnormal in about 30-50% of familial melanoma cases and 25-40% of sporadic melanoma.
Less frequent genetic alterations may also involve the CDK4 gene, the protooncogene Ras, the
phosphatase and tensin homologue/mutated in multiple advanced cancers PTEN/MMAC1 gene
(which is also mutated in Cowden's disease) as well as the tumor suppressor gene p53 (also
responsible for the Li Fraumeni cancer syndrome)5. The recently described inactivation of the
apoptosis effector Apaf-1 also contributes to inhibition of p53-mediated apoptosis and melanoma
development6.
The impact of these genetic alterations are best studied using in vivo models. These include (1)
human skin grafted to immunodeficient mice to provide an orthotopic environment for both
melanoma growth and for induction by irradiation with UV light; (2) nongenetic animal model for
UV-induced melanoma genesis such as the xiphophorus hybrid fish; and (3) genetically modified
mice, e.g. mice with deletions in the INK4A locus crossed with animals expressing the Ras
oncogene under a tyrosinase promoter7,8. The value of such models has been recently shown by
demonstrating that neonatal sunburn induces melanoma in hepatocyte growth factor/scatter
factor transgenic mice9. Although germline mutations in CDKN2A are present in many large multicase melanoma families, they are much rarer in the smaller melanoma families that make up
most individuals reporting a family history of this disease. In addition, only three families
worldwide have been reported with germline mutations in a gene other than CDKN2A (i.e. CDK4).
Accordingly, current genome-wide scans using high density microarrays are underway with the
hope of revealing linkage to one or more chromosomal regions, and ultimately leading to the
identification of novel genes involved in melanoma predisposition.
A combination of cytogenetic, molecular, and functional studies suggests that additional genes
involved in melanoma development are located to chromosomal regions 1p, 6q, 7p, 11q, and
possibly also 9p and 10q. With the completion of the human genome sequencing effort, combined
with the advent of high throughput mutation analyses and new techniques including cDNA and
tissue microarrays, the identification and characterization of additional genes involved in
melanoma pathogenesis and subsequent molecular classification of melanoma seem likely in the
near future10. The first report of the discovery of gene clusters in a subset of melanomas identified
by such techniques supports this notion11.
HOST IMMUNE RESPONSE TO MELANOMA
Clinical observations such as incomplete or complete regression of melanoma, occurrence of
vitiligo-like depigmentation and halo nevi as well as a higher rate of melanoma in
immunosuppressed patients point to the fact that melanoma is an immunogenic tumor 12. Studies
of melanoma have played a central role in understanding recognition and rejection of tumors by
the host immune system. The molecular characterization of melanoma antigens recognized by
autologous T cells or antibodies was a scientific breakthrough13,14.
Major melanoma antigens recognized include (1) mutated antigens (e.g. mutated p16 (CDKN2A);
(2) shared tumor-specific antigens of the cancer/testis family (e.g. Mage-1,-3, NY-ESO-1); and (3)
differentiation antigens (e.g. tyrosinase, gp100, MelanA/MART-1). The expression pattern of the
majority of these antigens may be followed in situ at the protein level using monoclonal
antibodies. In an extensive immunohistochemical study, 44% of primary melanomas expressed
MAGE-3, while 88% and 94% expressed MelanA/MART-1 and tyrosinase, respectively15. These
proteins are processed inside the cell and presented on the melanoma cell surface as
MHC/peptide complexes. CD8+ cytotoxic T cells recognize these antigenic structures and, if
appropriately activated, are able to kill such tumor cells in an MHC-dependent manner through
release of cytotoxic granules (e.g. perforin and granzyme B) or activation of FAS/TNF pathways.
CD8 cells are believed to be the major effector cells for an anti-melanoma-specific immune
response, but CD4 helper T cells as well as antibodies also play a critical role. Activation of
melanoma-specific CD8 T cells is dependent on the migration of tumor antigen-loaded
professional antigen presenting cells (dendritic cells) from the tumor site to a draining lymph node
(Fig. 114.2). Here, melanoma antigens are presented to CD8 T cells in the presence of costimulatory molecules, which is the decisive step of CD8 T cell activation. This alert system often
fails in melanoma patients, but may be activated or substituted by specific immunotherapies (see
below).
Since melanoma is an immunogenic tumor a variety of immune escape mechanisms may be
found in advanced tumors. These include loss of tumor-specific antigens, loss of MHC class I
molecules as well as secretion of immuno-inhibitory cytokines such as IL-10 and transforming
growth factor (TGF)-beta16. New insights into mechanisms of host immune response against
melanoma antigens has set the stage for innovative approaches to melanoma immunotherapy
(see below).
EPIDEMIOLOGY
The incidence and mortality rate of melanoma has been increasing in recent decades in all parts
of the world from which reliable cancer registration data can be obtained, and represents a
substantial public health problem. The annual incidence rates have increased in the order of 37% in fair-skinned populations in recent decades. The mortality rates have increased at a lower
rate. This has been attributed to educational programs designed to improve the early detection of
melanoma, as the treatment of melanoma has not changed substantially in recent decades.
There has been a decrease in the thickness of melanoma with an increasing proportion of thin
melanomas at diagnosis.
The incidence rates in Australia continues to be the highest worldwide approaching 35 per 100
000 individuals in 2000. Yet, cohort analysis of both the incidence and mortality rates for
melanoma in Australia reveal that the overall rise is not reflected in all age groups. In the younger
cohorts which might have been influenced by public health campaigns in the last 20 years, both
incidence and mortality are falling17. In Europe the rate of increase began in the 1950s in the
more affluent European countries and has been in part attributed to greater opportunity for travel
to southern European countries for sunbathing. Hope for the end to the melanoma epidemic is
seen in the UK where melanoma mortality is falling in young women in spite of a general increase
in mortality18. It has been suggested that the epidemic of lethal melanoma has been arrested by
earlier recognition and surgery of thin tumors19.
In the US more than 40 000 new cases of melanoma were diagnosed in 1997, and it was
estimated that in the year 2000, 7700 Americans will die from malignant melanoma20 indicating
that nearly every hour an American will die from melanoma. The incidence has increased from 1
per 100 000 to 15 per 1 000 000 in the last 40 years (Fig. 114.3). This 15-fold increase is more
rapid than in any other malignancy. In contrast to women, mortality is still increasing in men (Fig.
114.4). Importantly, deaths from melanoma occur at a younger age than most other cancers, and
melanoma is among the most common types of cancer in young adults 21. Moreover, US cancer
statistics demonstrate that melanoma had the second highest mortality rate increase among
Americans 65 years of age and older (from 1973-1997) especially for men22.
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Figure 114.2 Anti-melanoma immune response involves migration of dendritic cells into
secondary lymphoid organs. Activation of melanoma-specific CD8 T cells is dependent on
the migration of tumor antigen loaded professional antigen presenting cells (dendritic cells)
from the tumor site to a draining lymph node. Here, melanoma antigens are presented to CD8
T cells in the presence of co-stimulatory molecules as well as CD4 helper T cells which is the
decisive step of CD8 T cell activation. Activated T cells upregulate chemokine receptors and
adhesion molecules that enables them to enter tissue sites where metastases are located.
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Figure 114.3 Age-adjusted incidence of melanoma in the US from 1969-1998. The
incidence has increased for both the male and female population, while an early indication of a
plateau or regression may be observed in recent years. This might be related to the effects of
public health campaigns. Data from the Surveillance, Epidemiology, and End Results (SEER)
program of the National Cancer Institute, 2001.
In conclusion, it seems that public health campaigns in the last 20 years might have had an
impact on melanoma incidence and mortality. Future assessments should also include other
outcomes such as behavior modification and the stage and thickness at which melanoma are
being removed23. The future will likely emphasize molecular epidemiology which will allow the
understanding of the molecular background of phenotypic variations of melanoma including
congenital melanoma and correlation of epidemiological data with molecular alterations in
melanoma.
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Figure 114.4 Age-adjusted mortality of melanoma in the US from 1969-1998. Mortality has
increased especially for male population in contrast to the female population. Data from the
Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute,
2001.
RISK FACTORS
Definition of major risk factors for development of melanoma are essential to optimize primary
and secondary (early recognition) prevention strategies. Risk factors may be subdivided into
genetic and environmental categories (Table 114.1).
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Table 114-1. Risk factors for the development of melanoma.
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RISK FACTORS FOR THE DEVELOPMENT OF MELANOMA
Genetic markers (e.g. CDKN2A mutations)
Family history of dysplastic nevi or melanoma
Ultraviolet irradiation
Sunburns during childhood
Intermittent burning exposure in unacclimatized fair skin
Number (>50) and size (>5 mm) of melanocytic nevi
Congenital nevi
Number of atypical nevi (>5)
Atypical/dysplastic nevus syndrome
Personal history of melanoma
High socioeconomic status
Skin type I, II
Equatorial latitudes
DNA repair defects (e.g. xeroderma pigmentosum)
Immunosuppression
Genetic markers of individuals at increased risk for melanoma are the subject of intensive
research. Three major genes have been identified which influence melanoma risk (see previous
section): (1) the CDKN2A gene on chromosome 9; (2) the CDK4 gene on chromosome 12; and
(3) a gene on chromosome 13. There is correlation between CDKN2A mutations in family
members with the atypical/dysplastic nevus syndromes. Germline mutations of CDKN2A have
been described in about 20% of melanoma prone families and CDK4 mutations have been
described in three families.
The main environmental risk factor is excessive exposure of fair-skinned individuals to UV
irradiation, mainly in the form of natural sunlight. However the exact wavelengths and pattern of
exposure are not yet well established. It has been suggested that intermittent high intensity
exposure of unacclimatized fair skin is a greater risk factor for melanoma than chronic lifetime sun
exposure24.
Overwhelming evidence indicates that patients with increased numbers of benign melanocytic
nevi have increased risk for the development of melanoma. A suggested number of nevi over
which patients are at an increased risk for the development of melanoma is 5025. Atypical
(dysplastic) nevi that are larger than 5 mm in diameter, darkly and/or irregularly pigmented with
irregular, ill-defined borders are also risk factors for melanoma, especially if they occur in families
as manifestation of the so-called atypical/dysplastic nevus syndrome (see Chapter 113). The risk
for developing melanoma in such families has been estimated to be 10% (close to 100% if a
history of previous melanoma is present)26. Large congenital nevi (>20 cm) have an estimated life
time risk between 5 and 20% for malignant transformation (Chapter 113). Patients with a history
of previous melanoma in the absence of atypical nevi are at a 3-5% risk of developing a second
melanoma.
Studies have established that melanoma is found more frequently in more affluent persons, but
this most likely serves as a surrogate for recreational sporadic sun exposure. Further risk factors
include skin type I/II (pale skin, poor tanning ability, light hair and eyes, presence of freckles,
burns easily), latitude (inverse relationship of melanoma incidence noted with latitude),
immunosuppression (threefold risk, e.g. after solid organ transplantation or inherited
immunodeficiencies), and the presence of defective DNA repair mechanisms (e.g. xeroderma
pigmentosum). There are conflicting data regarding the impact of sunscreen use on melanoma
development. The same is true for commercial sun bed use, where several case/control studies
found an association with increase of melanoma risk. There is no clear evidence that pregnancy
or estrogen use increases the risk of melanoma. There is also no evidence that pregnancy
occurring after the diagnosis of melanoma worsens prognosis.
ULTRAVIOLET RADIATION AND PHOTOPROTECTION
Exposure to sunlight is a major factor in the induction of cutaneous malignant melanoma27. In
particular, recreational, intermittent exposure to the ultraviolet (UV) component of sunlight
associated with sunburns may play an important role in melanoma formation. The link of
sunburn(s) in childhood to melanoma development later in human life is consistent with recent
findings in an experimental model with genetically engineered mice, in which a single dose of
burning UV radiation to neonates, but not adults, is sufficient to induce tumors with high
penetrance that are reminiscent of human melanoma9. However, in contrast to non-melanoma
skin cancers, in which there are distinctive UVB-induced mutations (i.e. C to T and CC to TT
transitions) in the p53 gene, the exact mechanisms and wavelengths by which sunlight induces,
promotes or contributes to the development of melanoma have not been identified.
Experimental work in the Xiphophorus fish model indicates that wavelengths other than those in
the UVB range of the sunlight spectrum are also important in melanoma formation27. It was
reported that in addition to the induction of melanoma in the UVB wavelength range, there was
also induction in the UVA and short visible wavelength range, suggesting that wavelengths not
directly absorbed by DNA can still induce melanoma. If the action spectra that cause melanomas
in humans and fish are similar, the use of common sunscreens that protect better against UVB
than UVA radiation would be sub-optimal. The hypothesis that UVA is important in the etiology of
melanoma is also supported by epidemiologic studies, in which exposure to UVA-emitting sun
beds was related to an increased melanoma risk 27. Moreover, the fact that in Norway a higher
melanoma to non-melanoma skin cancer ratio parallels a higher UVA to UVB ratio, implicates
UVA radiation in the etiopathogenesis of melanoma. UVB is still a critical factor. Experimental
animal work in the South American opossum (Monodelphus domestica) and in different mouse
strains has suggested that exposure to UVB is significant in the initiation of melanoma. Atillasoy
et al.28 reported that treatment with 7,12-dimethyl(a)benzanthracene and UVB radiation induced
atypical melanocytic lesions and melanoma in human skin grafted onto RAG-1 mice.
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Table 114-2. Table 114.2 Different types of malignant melanoma.
Type of
melanoma
Superficial
spreading
melanoma
Nodular
melanoma
DIFFERENT TYPES OF MALIGNANT MELANOMA
Frequency Site
Radial Special features
(%)
growth
60-70
Any site, preference for Yes
More pagetoid, less
lower extremities
solar elastosis
(female), trunk (male)
15-30
Any site, preference for No
Nodule with vertical
trunk, head, neck
growth
Lentigo maligna 5-15
melanoma
Face, especially nose
and cheeks
Yes
Acral
lentiginous
melanoma
Palms, soles,
subungual
Yes
5-10
Slower growth over
years on sundamaged skin
Most common
melanoma in patients
with darker skin types
Several retrospective epidemiologic studies have assessed the risk of melanoma in relation to
sunscreen use29. In some of those studies the use of sunscreens offered no protection against
melanoma, but instead was associated with an increased melanoma risk. The interpretation of
these studies must be done with great caution, because retrospective data collection is not
optimal. For example, persons with a history of sunburn and increased sun exposure are more
likely to use sunscreens more frequently, thus sunscreen use may erroneously appear as a risk
factor. There is also controversial evidence as to whether chemical sunscreens have the capacity
to protect humans against UV-induced formation of melanocytic nevi, which are potential
precursors of melanoma30,31. One mechanism by which sunscreens may lead to an increased
melanoma risk is that their use may allow prolonged intensive sun exposures, which may
increase the melanoma risk31. Also, UV radiation-induced immune suppression may be an
important factor in the pathogenesis of melanoma and there is conflicting evidence from animal
and human studies as to whether chemical sunscreens offer sufficient immunoprotection32. A
recent study32 has indicated that UVA sunscreen protection may be particularly important in
preventing the suppression of the efferent immune response that may be a crucial factor in the
protection against the formation of skin cancer, including malignant melanoma (see Chapter 154).
TYPES OF PRIMARY MELANOMAS
Four major subtypes (growth patterns) of primary cutaneous melanoma have been historically
differentiated. These include (1) superficial spreading melanoma; (2) nodular melanoma; (3)
lentigo maligna melanoma; and (4) acral lentiginous melanoma (Table 114.2)33. It should be
noted that these clinical subtypes do not predict prognosis independently of other factors such as
the measured depth of the lesion (Breslow's thickness) or ulceration, and the argument has been
made that such categorization has limited value.
Superficial Spreading Melanoma
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Figure 114.5 Melanoma in situ. Note the macular character, indistinct defined borders and
variations in color.
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Figure 114.6 Melanoma in situ. Tan to dark-brown macule with irregular outline.
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Figure 114.7 Melanoma. This small lesion is only 5 mm at its greatest diameter.
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Figure 114.8 Melanoma - superficial spreading type. This neoplasm is characterized by
asymmetry, scalloped borders, a combination of various colors and an ulcerated nodule.
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Figure 114.9 Melanoma with regression. Note asymmetry, variegation in color and uneven
surface. The lighter zones are evidence of regression.
Superficial spreading melanoma (SSM) is the most common type of cutaneous melanoma in the
fair skinned individuals and is diagnosed most frequently between the ages of 30 to 50 years. It
accounts for approximately 70% of all melanomas and occurs at any site, but is most frequently
seen on the trunk of men and the legs of women. It begins as an asymptomatic brown to black
macule with color variations and irregular, notched borders. Melanoma in situ is usually a macule
with an irregular outline and variable size (Figs 114.5 & 114.6), including diameters ≤5 mm (Fig.
114.7). After a typically slow horizontal (radial) growth phase limited to the epidermis or focally in
the papillary dermis, a rapid vertically oriented growth phase which presents clinically with
development of a papular nodule can be frequently observed (Fig. 114.8). In up to two-thirds of
cases regression (visible as hypo- or depigmentation) of part of the lesion is observed (Fig.
114.9), potentially reflecting the interaction of the host immune system with the progressing
tumor. About one-third of these melanomas arise in a pre-existing nevus. In this instance, a
previously stable melanocytic nevus is generally observed to change, becoming asymmetric with
an irregular border, color variation and an enlarging diameter (ABCD mnemonic). Melanomas
lacking clinically evident pigment are termed 'amelanotic' (Fig. 114.10).
Nodular Melanoma
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Figure 114.10 Amelanotic melanoma. Hypopigmented erythematous patch with focally
pigmented margin.
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Figure 114.11 Melanoma - nodular type. A Black nodule on the nose. Courtesy Ron Rapini
M.D. B This lesion is technically classified as a nodular component of superficial spreading
melanoma because of the adjacent flat tanbrown intraepidermal component (radial growth
phase) extending beyond the nodule.
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Nodular melanoma (NM) is the second most common type of cutaneous melanoma in the fairskinned population and is diagnosed most frequently in patients in their sixth decade of life. It
accounts for approximately 15 to 30% of all melanomas and occurs at any body site, but is most
frequently seen on the trunk, head and neck. It is observed more frequently in men than in
women. It usually presents as a blue to black sometimes red to skin-colored nodule which might
be ulcerated or bleeding and has rapidly developed over months (Fig. 114.11). Nodular
melanoma lacks significant surrounding macular hyperpigmentation and thus should not be
confused with nodules occurring in superficial spreading melanoma.
Lentigo Maligna Melanoma
Lentigo maligna melanoma (LMM) represents a minority of cutaneous melanoma (up to 15%) and
is diagnosed most frequently in the seventh decade of life. It occurs on chronically sun-damaged
skin, most commonly on the face, with a preference for the nose and cheek. It usually develops
as a slowly growing asymmetric brown to black macule with color variations and irregular,
indented borders (Fig. 114.12). The term lentigo maligna is used to mean melanoma in situ of
sun-damaged skin (radial growth only) and lentigo maligna melanoma is used for those with
dermal invasion (vertical growth). Lentigo maligna has a slow evolution over years and may
develop a papule or nodule, generally indicating invasion.
Acral Lentiginous Melanoma
Acral lentiginous melanoma (ALM) is a relatively uncommon type of cutaneous melanoma and is
diagnosed most frequently in the seventh decade of life. It typically occurs on the palms and soles
or in and around the nail apparatus. It accounts for approximately 5 to 10% of all melanomas but
represents up to 70% of melanomas in darkly complected individuals and up to 45% in Asians.
ALM is cumulatively more common in fair-skinned patients, but is the most common type found in
pigmented races.
It presents as an asymmetric brown to black macule with color variation and irregular borders
(Fig. 114.13). It is believed that the progression of this type of melanoma tends to be faster than
for LMM or SSM. Amelanotic tumors are diagnostically challenging and may be mistaken for
warts or squamous cell carcinoma. Subungual melanoma accounts for 1 to 3% of all melanomas
and is typically classified as a variant of ALM. They present as longitudinal nail pigmentation or
ulcerated nodules (Figs 114.14 & 114.15). Persistence of a pigmented band in the nail bed,
particularly in an elderly patient, should raise suspicion of melanoma and prompt a biopsy. That
said, any persistent pigmentation of the nail apparatus should raise concern for melanoma,
realizing that benign causes are common (see Chapters 71 & 113). Correct biopsy of the nail
matrix is important (see Chapter 149). Extension of pigment into the proximal or lateral nail fold is
known as a Hutchinson sign and generally indicates the presence of ALM.
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Figure 114.12 Melanoma - lentigo maligna type on sun-damaged skin. The neoplasm is
broad and flat, asymmetrical, poorly circumscribed and shows various shades of tan-brown to
black.
OTHER MELANOMA VARIANTS
Malignant melanoma may present with unusual manifestations. Some of these are defined by
clinical features, others by histologic findings.
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Figure 114.13 Acral lentiginous melanoma. A Extensive centrifugal spread, illustrating the
macular character, irregular shape, poor circumscription, variations in color, reticulation, and
whitish area of regression. B This lesion on the toe could be mistaken for a traumaticallyinduced injury. Courtesy Ron Rapini, M.D.
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Figure 114.14 Melanoma in situ of the nail. Darkly pigmented band in the nail bed and matrix.
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Figure 114.15 Subungual melanoma. Ulcerated nodule with destruction of the nail.
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Figure 114.16 Nevoid melanoma. The patient developed metastases from this red-brown
plaque.
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Figure 114.17 Histopathology of melanoma mimicking Spitz nevus. This neoplasm could
be misdiagnosed as a Spitz nevus because the lesion is symmetrical and well-circumscribed.
This is a melanoma because: nests of melanocytes have become confluent with formation of
sheets; there is no distinct maturation of melanocytes; nuclei of melanocytes are atypical; and
melanocytes are in mitosis, also at the base of the neoplasm.
Nevoid Melanomas
These melanomas do not display clinically distinct features, creating diagnostic difficulty (Fig.
114.16) because they may resemble a Spitz nevus or an acquired or congenital type of a
melanocytic nevus34. Two histologic types of nevoid melanoma are be recognized and are
described below.
Melanoma with features of a Spitz nevus ('spitzoid' melanoma)
This variant shows histologic features suggestive of Spitz nevus (Fig. 114.17) with overall
symmetry and a dermal nodule of epithelioid melanocytes that do not mature with progressively
deeper dermal extension. Other important histological clues for the diagnosis of a melanoma are
sheets of atypical melanocytes in the dermis and mitotic figures at the base of the lesion (see
Chapter 113).
Melanoma with small nevus-like cells (small cell melanoma)
This tumor contains large variably sized nests of small melanocytes with hyperchromatic nuclei
and prominent nucleoli. Mitoses are generally found throughout the dermal tumor.
Malignant Blue Nevus: Malignant Melanoma in Association with Blue Nevus
Malignant blue nevus is a rare dermal tumor of melanocytes most commonly located on the head
and particularly the scalp (Fig. 114.18). It appears as a blue-black, deeply situated nodule,
generally >1 cm in diameter. Histologically, elements of a classic benign blue nevus are
associated with nodular areas of atypical spindle-shaped and bipolar dendritic melanocytes,
mitotic figures, necrosis, and melanophages35. The clinical course is characterized by a high rate
of recurrence and metastasis.
Desmoplastic/Spindled/Neurotropic melanoma
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Figure 114.18 Melanoma in association with blue nevus (malignant blue nevus). Satellite
metastases at the periphery.
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Figure 114.19 Histopathology of desmoplastic malignant melanoma. A Loosely textured
spindle cells in focally fibroblastic stroma. In the epidermis there are changes of melanoma in
situ with proliferation of atypical melanocytes. Note lymphoid infiltrates. B Positive S-100
spindle cells within the dermis.
While this type of melanoma is histologically defined, the typical clinical lesion consists of a skincolored, red to hyperpigmented nodule or plaque, mostly on sun-exposed skin. It may arise de
novo, but is also the most common melanoma arising in lentigo maligna, ALM and mucosal
melanoma. Metastasis is uncommon, but the tumor is highly infiltrative and thus, locally
aggressive with recurrence after incomplete excision. Deep tissue samples are necessary to
establish the diagnosis (Fig. 114.19) as superficial portions of the tumor show subtle or
nondiagnostic findings which may be mistaken for fibrosis of a scar or other spindle cell
neoplasms.
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Figure 114.20 Ciliary body melanoma.
Clear Cell Sarcoma: Melanoma of Soft Parts
Clear cell sarcoma most often presents on the distal extremities of adolescents and young adults.
Several features point to melanocytic derivation (expression of HMB45, S-100 protein and
melanosomes on electron microscopy), but clear cell sarcoma and cutaneous melanoma may be
two distinct clinicopathological entities36. The tumors usually arise in association with tendons and
aponeuroses. The tumor is composed of nests and fascicles of oval to spindled cells with
vesicular nuclei, basophilic nucleoli, and eosinophilic to clear cytoplasm. Multinucleated giant
cells and melanin can be frequently demonstrated. Upon incomplete excision, local recurrence
and metastasis may ensue.
Animal-type Melanoma
Animal type melanoma is characterized by nodules and fascicles of epithelioid melanocytes with
pleomorphic nuclei and striking hyperpigmentation, dendritic cells, numerous melanophages and
sometimes an inflammatory infiltrate of lymphocytes37. Clinically, blue to jet black plaques or
nodules have been described. The prognostic features are not well known; metastases have
been observed in several patients. It is so named because it resembles melanocytic neoplasms
with similar morphological features seen in gray horses and laboratory animals.
Ocular Melanoma
Primary ocular melanomas, which are very rare (5% of all melanomas), can be divided into
conjunctival melanomas and uveal melanomas (iris-, choroidal- and ciliary-body melanomas)
(Fig. 114.20). Little is known about the pathogenesis of these tumors. Patients with dysplastic
nevus syndrome have an increased number of conjunctival and uveal nevi. Although the true
association between dysplastic nevus syndrome and ocular melanoma is controversial, it has
been suggested that patients with ocular melanoma have an increased risk for cutaneous
melanoma. Patients with type I neurofibromatosis and melanosis oculi (nevus of Ota) may also be
at higher risk for uveal melanoma. The prognostic features and the treatment of ocular melanoma
differ from cutaneous tumors38.
Mucosal Melanoma
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Table 114-3. Melanocytic lesions that simulate melanomas clinically and/or
histopathologically39.
MELANOCYTIC LESIONS THAT SIMULATE MELANOMAS CLINICALLY AND/OR
HISTOPATHOLOGICALLY39
 Acral nevi
 Ancient nevi
 Black (hypermelanotic) nevi
 Blue nevi and variants
 Combined nevi
 Congenital nevi biopsied shortly after birth
 Deep penetrating nevus
 Dysplastic (Clark's) nevi
 Halo nevi
 Hyperplasia of melanocytes in sun-damaged skin or in the epidermis
 Melanocytic proliferation over some benign neoplasms*
 Longitudinal melanonychia
 Melanosis of mucosal regions*
 Nevi exposed to UV radiation
 Nevi in genital regions (including milk-line nevi and flexural nevi)
 'Nevus sur nevus' (Nevus on nevus)
 Pigmented streaks in melanoma scars*
 Proliferating nodules in giant congenital nevi in newborns
 Recurrent (persistent) nevi
 Reticulated (ink-spot) lentigo*
 Spitz nevi and variants
*These are not melanocytic diseases strictu sensu.
Melanomas may occur in the mouth, nasopharynx, larynx, vagina and anus. These are rare, but
tumors tend to be advanced, perhaps because early detection is difficult.
DIFFERENTIAL DIAGNOSIS: MELANOMA SIMULATORS
A variety of conditions may simulate malignant melanoma either clinically, histopathologically or
both. Awareness of these simulators is of great practical importance to avoid over-diagnosis of
melanoma39. Tables 114.3 and 114.4 list several melanocytic and non-melanocytic lesions that
can mimic malignant melanomas and which should be included in the differential diagnosis.
MELANOMA AND PREGNANCY
During pregnancy levels of melanocyte-stimulating hormones are elevated. Increased
pigmentation occurs in some patients. More than 10% of women experience darkening of
melanocytic nevi in the first 3 months of pregnancy40. However, an association between hormonal
changes during pregnancy and development of melanoma or worsening of the prognosis of an
existing melanoma has not been demonstrated41. Transplacental metastases may arise in
pregnant women with melanoma. Surgery with local anesthesia is the treatment of choice in
stage I or II melanoma patients (see Table 114.8). In more advanced stages discussions with the
patient of the advantages and disadvantages of possible termination of the pregnancy is
recommended. There have been no studies demonstrating an adverse effect of hormonal
contraception on melanoma development42. Due to the presence of estrogen receptors on a
certain percentage of melanomas, alternative forms of contraception are recommended in women
after excision of thick tumors (>1.5 mm) with increased risk of recurrence 41. In women with a
history of high risk melanoma it may be reasonable to wait 2 years after diagnosis before
becoming pregnant, because two-thirds of recurrences occur within this time period.
CHILDHOOD MELANOMA
Table 114-4. Non-melanocytic simulators of melanoma39.
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NON-MELANOCYTIC SIMULATORS OF MELANOMA39
Paget's disease
Extramammary Paget's disease
Pigmented epidermotropic metastasis of breast carcinoma
Epidermotropic neuroendocrine carcinoma
Bowen's disease (pagetoid or pigmented)
Pagetoid reticulosis
'Clear-cell' artefacts around keratinocytes
Complete regression of skin tumors other than malignant melanoma (e.g.,
lichen planus-like keratosis, basal cell carcinoma)
Pigmented basal cell carcinoma
Pigmented actinic keratosis
Dermatofibroma
Seborrheic keratosis
Pigmented poroma and pigmented porocarcinoma
Pigmented pilomatrixoma
Subungual hematoma
Black heel (hemorrhage in stratum corneum caused by trauma) (Fig. 114.21)
Pyogenic granuloma
Tinea nigra
Thrombosed hemangioma
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Figure 114.21 Black heel. Traumatically induced subcorneal hematoma simulating acral
melanoma.
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Table 114-5. Dermatoscopic criteria and their corresponding
histopathological features.
DERMATOSCOPIC CRITERIA AND THEIR CORRESPONDING
Criterion
Pigment
network
Typical
network
Atypical
network
HISTOPATHOLOGICAL FEATURES
Morphological definition Associated
histopathological
changes
Network of brownish lines Pigmented rete ridges
over a diffuse tan
background
Brown pigmented,
Regular and elongated rete
regularly meshed and
ridges
narrowly spaced network
Black, brown, or gray
Irregular and broadened
network with irregular
rete ridges
meshes and thick lines
Dots/globules Black, brown, and/or gray
round to oval, variously
sized structures regularly
or irregularly distributed
within the lesion
Pigment aggregates within
stratum corneum,
epidermis, dermoepidermal junction, or
papillary dermis
Streaks
Confluent junctional nests
of melanocytes
Blue-whitish
veil
Blotches
Regression
structures
Milia-like
cysts
Comedo-like
openings
Leaf-like
areas
Red-blue
lacunas
Irregular, linear structures
not clearly combined with
pigment network lines at
the margins
Irregular, confluent, grayblue to whitish-blue diffuse
pigmentation
Acanthotic epidermis with
focal hypergranulosis
above sheets of heavily
pigmented melanocytes in
the dermis
Black, brown, and/or gray Hyperpigmentation
pigmented areas with
throughout the epidermis
regular or irregular
and/or upper dermis
shape/distribution
Diagnosis
Melanocytic
lesion
Benign
melanocytic
lesion
Melanoma
If regular:
benign
melanocytic
lesion; If
irregular:
melanoma
Melanoma
Melanoma
If regular:
benign
melanocytic
lesion; if
irregular:
melanoma
White (scar-like) areas,
Thickened papillary dermis Melanoma
blue (pepper-like) areas, with fibrosis and/or variable
or combinations of both
amounts of melanophages
White-yellowish, roundish Intraepidermal horn
Seborrheic
dots
globules, also called horn keratosis
pseudocysts
Brown-yellowish, round to Keratin plugs situated
Seborrheic
oval or even irregularly
within dilated follicular
keratosis
shaped, sharply
openings
circumscribed structures
Brown-gray to gray-black Pigmented, solid
Basal cell
patches revealing a
aggregations of basaloid
carcinoma
leaflike configuration
cells in the papillary dermis
Sharply demarcated,
Dilated vascular spaces
Vascular lesion
roundish to oval areas with situated in the upper
a reddish, red-bluish, or
dermis
red-black coloration
Vascular
structures
Comma-like vessels
Arborizing vessels
Hairpin vessels
Dotted or irregular vessels
Benign
melanocytic
lesion
Basal cell
carcinoma
Seborrheic
keratosis
Melanoma
With permission from Argenziano & Soyer46, Lancet Oncology 2:443-9. © 2001 Elsevier.
Childhood melanomas are extremely rare. Between 1 and 4% of melanoma cases occur in
patients younger than 20 years of age, and 0.3% are younger than 14 years 43. Tumors may arise
de novo or in association with congenital melanocytic nevi. Children with xeroderma
pigmentosum, inherited or acquired immunodeficiencies or a family history of melanoma have an
increased risk of melanoma development. Histologically, these tumors may resemble those of
adults, but small cell melanomas and melanomas with features of Spitz tumor are reported 44. The
diagnosis is difficult because the clinical and histological distinction is often subtle. Of special
importance is the differentiation of melanoma from Spitz nevi with atypical features. Overall
survival and prognosis seems to be stage dependent and similar to adults45. Treatment follows
the same rationale as in adults with the aim of early detection and appropriate resection of
primary melanoma.
DERMATOSCOPY
Most melanocytic lesions of the skin can be correctly diagnosed based on unaided clinical
observation. That said, certain melanocytic and non-melanocytic tumors may prove to be
diagnostically challenging.
Dermatoscopy, also known as skin surface microscopy or epiluminescence microscopy (ELM), is
a helpful noninvasive tool in this setting46. For dermatoscopic examination the skin lesion is
covered with mineral oil, alcohol or even water, and a hand-held lens, stereomicroscope, camera
or digital imaging system is used to inspect it. The magnifications of these instruments range from
sixfold to 100-fold. The most widely used dermatoscope provides a tenfold magnification and is
sufficient for routine assessment of pigmented skin lesions. The fluid placed on the lesion
eliminates surface reflection and renders the cornified layer translucent, so that morphologic
structures within the epidermis, the dermo-epidermal junction, and the superficial dermis can be
better visualized. The most important practical application for dermatoscopy is differentiation of
the early stages of melanoma in situ and melanoma from benign lesions. Differentiation of
melanocytic tumors in general from non-melanocytic pigmented skin lesions such as seborrheic
keratosis, pigmented basal cell carcinoma and vascular proliferations is also possible.
A crucial aspect of dermatoscopy is the observation of the pigment-network in melanocytic
tumors, which histologically corresponds to elongated and pigmented rete ridges with an
increased number of melanocytes in the basal layer. Other structures that can be seen are brown
globules, black dots, irregular streaks and the blue-whitish veil. Table 114.5 lists the
dermatoscopic criteria and their corresponding histopathological features.
The clinical application of dermatoscopy requires training and experience. Various steps can be
used. The approach of pattern analysis (Table 114.5) correlates individual criteria with each other
and puts them into the context of a pattern that is typical for the specific pathology of a lesion
(Fig. 114.22). Other diagnostic approaches, including the ABCD rule47, Menzies method48 and the
seven-point checklist49, represent advances in dermatoscopic diagnosis in terms of sensitivity and
specificity. Clinical examination allows a correct diagnosis in 65 to 80% of melanomas, based on
physician experience, whereas the proportion of correct diagnoses based on dermatoscopic
observation ranges from 70 to 95% and depends on training 50.
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Figure 114.22 Dermatoscopy. This pair of images from an invasive malignant melanoma
illustrates the clinical pictures (A) and the same lesion viewed with dermatoscopy (B). Note the
multicomponent pattern with an atypical pigment network, black dots, irregular streaks, focally
a blue-whitish veiland a white regression zone with hairpin vessels. All these dermatoscopic
criteria are suggestive of a melanoma.
Dermoscopy is also useful in follow-up examinations of pigmented skin tumors to document
morphological changes including growth and/or alterations in color. This approach is especially
important for monitoring patients, who have many atypical melanocytic nevi or the familial
dysplastic nevus syndrome. Teledermatoscopy, the combined use of dermatoscopy and
telemedicine technologies, enables general practitioners and specialists to exchange digital
image information. It has been shown that excellent diagnostic results can be achieved in this
manner.
Computer-assisted diagnosis based on systems analyzing symmetry and color are available.
Dermatoscopy has opened a new dimension in determining clinical morphology. The method is a
useful addition to the clinical evaluation of pigmented skin tumors by improving the diagnostic
accuracy and allowing a more reliable preoperative assessment of malignant melanoma.
PATHOLOGY
Since the basic histologic criteria for melanoma are the same at all anatomic sites, it has been
proposed that the classification of malignant melanoma into distinct histopathologic subtypes
should be omitted51. The criteria listed in Table 114.6 overlap variably in individual tumors but
generally enable distinction of melanoma from melanocytic nevi.
It has been proposed that tumor progression in melanoma exhibits two patterns, which are
correlated with prognosis52. The first is the horizontal (radial) growth pattern, characterized by
intraepidermal centrifugal spread of neoplastic melanocytes and infiltration of the papillary dermis
as single cells or small nests. In the vertical growth phase, large dermal nodules with
melanocytes that differ cytologically from the intraepidermal cells are found. It has been further
postulated, that the horizontal growth phase lacks metastatic potential even in the presence of
dermal invasion, whereas the vertical growth phase correlates with the capacity for metastasis.
Table 114-6. Criteria for histopathologic diagnosis of malignant melanoma.
CRITERIA FOR HISTOPATHOLOGIC DIAGNOSIS OF MALIGNANT MELANOMA
Architectural pattern
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Asymmetry
Poor circumscription of intraepidermal melanocytic component
Silhouette of tumor base uneven (except in nevoid melanoma)
No maturation of melanocytes with progressive descent into the dermis
Nests of melanocytes within the epidermis not equidistant from one another
Nests of melanocytes vary in size and shape
Some nests of melanocytes become confluent
Scatter of melanocytes above the dermo-epidermal junction
Melanocytes arranged as solitary units predominate over nests within the
epidermis
Melanocytes in some nests are not cohesive
Melanocytes extend down adnexal epithelium
Sheets of melanocytes within the dermis
Nests at base of lesions occasionally large
Cytomorphology
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Atypical melanocytes (with pleomorphic nuclei)
Mitotic figures
Necrotic melanocytes
Other features
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Signs of regression
Actinic elastosis
Melanin is not distributed in uniform fashion
Plasma cells at base of the lesion
Adapted from Ackerman et al51.
Early diagnosis and accurate identification of malignant melanoma is crucial in order to remove
lesions at a stage when complete cure can still be achieved. The majority of melanomas evolve in
a similar way. The earliest histological changes ('melanoma in situ') are characterized by
increased numbers of individually disposed atypical melanocytes in the basal layer (Fig. 114.23).
Some melanocytes, singly or in nests, are scattered higher in the epidermis and often reach the
granular layer (pagetoid spread)53. After a variable period of time, neoplastic melanocytes invade
the papillary dermis, either as coalescent nests or as multiple single cells.
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Figure 114.23 Pathology of melanoma in situ. Increased number of melanocytes with
atypical nuclei not only in the basal zone, but also at the upper levels of the epidermis.
Add to lightbox
Figure 114.24 Pathology of melanoma. Pagetoid melanocytes organized as solitary units and
nests varying in size and shape are present throughout the entire epidermis. Neoplastic
melanocytes extend into the dermis. Absence of maturation at deeper levels of the dermis.
A classic melanoma (Fig. 114.24)51,54 is asymmetrical, poorly circumscribed and characterized by
nests of melanocytes within the epidermis that are not equidistant from one another, vary in size
and shape, and have become confluent in foci. Melanocytes disposed as solitary units within the
epidermis predominate over nests. Some solitary melanocytes and nests of melanocytes are
present well above the dermo-epidermal junction, at times extending into the upper epidermis,
even the cornified layer. One element of this histologic asymmetry is the observation of these
intraepidermal changes away from the invasive intradermal component. Similar findings are
present in the adnexal epithelium of pilosebaceous units and eccrine ducts. Within the dermis,
nests of melanocytes do not become smaller with progressive descent (absence of maturation).
In parallel, nuclei of melanocytes do not become smaller.
Nests of melanocytes within the dermis also vary in size and shape and become confluent,
sometimes forming sheets of cells. The base of the neoplasm is uneven. Melanin is sometimes
more plentiful at the base than at the surface of the neoplasm. Frequently, an infiltrate of
lymphocytes can be observed. The neoplastic melanocytes show a wide spectrum of
cytomorphological features including spindled, pagetoid, small and large round-shaped,
polygonal, multinucleate and dendritic characteristics. Certain cytological features of the
melanocytes are more common in particular anatomical sites than in others. For example, the
finding of increased numbers of intraepidermal atypical melanocytes with elongated branching
dendritic processes are a very helpful diagnostic sign of early melanomas on palms and soles.
Add to lightbox
Figure 114.25 Pathology of melanoma in situ on sun-exposed surfaces. Atypical
melanocytes both singly and in small nests within the epidermis and along the follicular
epithelium.
Identifying atypia of melanocytes may be quite subjective. Generally, atypia is defined by nuclear
features including variable nuclear size, shape and basophilia. Even in highly anaplastic tumors,
the intranuclear pseudoinclusions typical of benign melanocytic tumors, may be identified. Mitotic
figures in the dermal component of benign melanocytic tumors are distinctly uncommon. In
melanoma, atypical mitotic forms may be observed in addition to more typical ones with tripolar
and other bizarre configurations. The absence of mitotic figures in the dermal component of a
melanocytic tumor does not exclude the diagnosis of melanoma.
LMM differs from the stereotypical melanoma by its presence on sun-damaged skin of older
patients, and the tendency to have little pagetoid spread within the epidermis. The atypical
melanocytes are commonly present along the epithelium of adnexal structures especially along
the external root sheath of hair follicles (Fig. 114.25). The invasive component is more often
composed of spindle cells. Desmoplastic stromal change and neurotropism of tumor cells are
common findings. Epidermal atrophy and signs of solar elastosis can be observed in the upper
dermis.
ALM often shows a proliferation of atypical melanocytes within the basal layer of a hyperplastic
epidermis. Atypical melanocytes are arranged singly and in irregularly shaped nests, at all levels
of the epidermis ('pagetoid scatter') with predominance of single cells. In the cornified layer
numerous melanocytes and melanin granules are usually found in a diffusely scattered
distribution. Notably, melanomas in volar and subungual sites display strikingly dendritic
melanocytes (Fig. 114.26).
Microstaging
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Figure 114.26 Melanoma in situ on the plantar surface of a foot. Atypical melanocytes are
scattered throughout the hyperplastic epidermis including the horny layer. Note dendritic
melanocytes.
The Breslow tumor thickness (depth of invasion) is measured in millimeters from the top of the
granular cell layer of the epidermis (or base of an ulcer) to the deepest point of tumor penetration
using an ocular micrometer (Fig. 114.27). Clark's levels of invasion utilize a stair-step
determination: level 1 is confined to the epidermis (in situ); level 2 invades the papillary dermis;
level 3 fills the papillary dermis to the junction of the superficial reticular dermis; level 4 invades
the reticular dermis; and level 5 invades the fat. In addition to tumor thickness, a number of other
histological features including ulceration, Clark's level of invasion 54, presence of tumor infiltrating
lymphocytes, mitoses/mm 2, regression, vascular invasion and microscopic satellites may be
associated with an unfavorable prognosis. Several studies of interobserver agreement that
compared a variety of microstaging criteria, revealed that tumor thickness and ulceration were
more reliable than Clark's level of invasion, growth pattern (radial/vertical growth phase) and
mitotic index55. Table 114.7 shows a recommendation of the features that should be included in
the histopathological report of a malignant melanoma56.
Immunohistology
A wide range of monoclonal antibodies reactive with melanoma-associated antigens is available.
Special stains are not used in routine cases and are mainly employed to confirm derivation of a
tumor from melanocytes when this is unclear with H&E stains. Most frequently used and
particularly helpful are antisera to S-100 protein and HMB45, which recognizes a premelanosomal glycoprotein. The most useful marker in terms of identifying spindled forms of
melanoma is S-100, since HMB45 and MART-1 are often negative in spindled melanocytes.
Immunohistological markers are not reliable in the differential diagnosis of melanoma from benign
melanocytic tumors.
STAGING
Table 114-7. Histopathological reporting of cutaneous melanoma.
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HISTOPATHOLOGICAL REPORTING OF CUTANEOUS MELANOMA
Diagnosis
Thickness (Breslow depth)
Mitoses/mm2
Level of invasion (Clark)
Regression, tumor infiltrating lymphocytes, presence of plasma cells
Ulceration
Vascular invasion
Microscopic satellites
Associated nevus
Margins
The World Health Organization has recommended notation of radial or vertical growth phase.
Add to lightbox
Figure 114.27 Microstaging of malignant melanoma. Breslow's method: measure from the
granular layer of the epidermis to the deepest part of the tumor.
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Table 114-8. Proposed stage groupings for cutaneous melanoma.
0
IA
IB
IIA
IIB
PROPOSED STAGE GROUPINGS FOR CUTANEOUS MELANOMA
Survival (%)*
Clinical staging†
Pathologic staging‡
T
N
M
T
N
M
Tis
N0
M0
Tis
N0
M0
95
T1a
N0
M0
T1a
N0
M0
90
T1b
N0
M0
T1b
N0
M0
T2a
T2a
78
T2b
N0
M0
T2b
N0
M0
T3a
T3a
65
T3b
N0
M0
T3b
N0
M0
T4a
IIC
III#
45
IIIA
T4b
Any T
T4a
T4b
N0
M0
M0
66
T1-4a
T1-4a
N1a
N2a
M0
IIIB
52
26
IV
7.5-11
N1a
N2a
N1b
N2b
N2c
N1b
N2b
N3
Any N
M0
IIIC
T1-4b
T1-4b
T1-4a
T1-4a
T1-4a/b
T1-4b
T1-4b
Any T
Any T
Any T
N0
N1
N2
N3
M0
M0
Any N
Any M1
M0
Any M1
*Approximate five-year survival in percent, modified from Balch et al57.
†Clinical staging includes microstaging of the primary melanoma and clinical/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 or complete lymphadenectomy. Pathologic stage 0
or stage IA patients are the exception.
#There are no stage III subgroups for clinical staging.
Modified from Balch et al63.
Add to lightbox
Figure 114.28 Fifteen-year survival curves comparing different melanoma stages. Survival
of localized melanoma (stage I and II), regional metastases (stage III) and distant metastases
(stage IV) are compared. The numbers in parentheses are patients from the AJCC melanoma
staging database used to calculate the survival rates. The differences between the curves are
significant (p <0.05). Reproduced from Balch et al. Journal of Clinical Oncology 19:3635-3648.
The staging of melanoma is categorized into local, regional or distant disease and strongly
correlates with survival (Table 114.8 & Fig. 114.28). Microstaging of localized disease is
performed using the Breslow depth (see above)58. A distinction between low-risk stage I patients
with a Breslow depth of ≤1 mm and high-risk stage II patients with a Breslow depth of >1 mm is
usually made. Involvement of regional lymph nodes (stage III) or distant metastases (stage IV) is
associated with increasingly worse prognosis. This difference in prognosis is reflected in current
staging classifications of melanoma. The American Joint Committee on Cancer (AJCC) staging
classification distinguishes localized disease (T1-T4), regional lymph nodes metastases (N1-N3)
and distant metastases (M1a-M1c) (Tables 114.8 & 114.9). There has been considerable
investigation of clinical and pathological features of melanoma that predict the risk of metastases
and survival. A major advance in the ability to stage patients more accurately is provided by a
minimally invasive microscopic staging technique: the so-called sentinel node biopsy. This
technique has changed our understanding of the natural history of melanoma59,60. Increased
ability to detect micrometastasis has caused a significant upward stage migration that has
necessitated a revision of older staging classifications. A new tumor-node-metastases (TNM)
staging system was introduced by the AJCC in 2000, critically evaluated by the European Union
for Research and Treatment of Melanoma group61, and revised in 2001 based on a 17 600
melanoma patient database derived from 13 cancer centers and melanoma cooperative groups
(Tables 114.8 & 114.9)57. With the publication of the sixth edition of the AJCC Cancer Staging
Manual in 2002 this classification is now in use.
The most important modifications are: (1) the noted gradations for tumor thickness are ≤1 mm, 1
to 2 mm, 2 to 4 mm, and >4 mm; (2) the primary determinant of tumor (T) staging is tumor
thickness as measured in millimeters. The Clark level of invasion is used only for further defining
T1 melanomas; (3) microscopic ulceration has been added as a major prognostic factor of the
primary tumor; (4) local recurrence, satellite disease, and in-transit metastases are now all
classified together as regional stage III disease because of similar prognosis; (5) size of lymph
node as a prognostic factor has been eliminated and replaced with the number of positive nodes;
(6) the presence of an elevated serum lactate dehydrogenase (LDH) level is used in the
metastasis (M) category; and (7) the site of distant metastases is of importance for prognosis.
Furthermore, the intent of the surgical procedure that led to the detection of nodal metastases
should be reported, i.e. therapeutic lymphadenectomy, lymphadenectomy for clinically detectable
metastatic lymph nodes or either sentinel or elective lymphadenectomy that detected clinically
occult metastases. Stage grouping includes clinical and pathologic parameters. Clinical staging
requires histological microstaging of the primary melanoma as well as clinical/radiological
evaluation for metastases. Pathologic staging includes microstaging of the primary melanoma
and pathologic information about regional lymph nodes after selective or complete
lymphadenectomy. The revised AJCC staging system includes new prognostic markers and
hopefully improves the stratification of patients in future clinical trials. This staging system may
not accurately reflect variants of melanoma such as desmoplastic, childhood, mucosal or ocular
melanoma.
PROGNOSIS
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Table 114-9. Melanoma TNM classification.
MELANOMA TNM CLASSIFICATION
T
Thickness
Ulceration status
classification
T1
≤1.0 mm
a: Without ulceration and
level II/III
b: With ulceration or level
IV/V
T2
1.01-2.0 mm
T3
2.01-4.0 mm
T4
> 4.0 mm
N
Number of metastatic nodes
classification
N1
1 node
a: Without ulceration
b: With ulceration
a: Without ulceration
b: With ulceration
a: Without ulceration
b: With ulceration
Nodal metastatic mass
a: Micrometastasis*
b: Macrometastasis
N2
2-3 nodes
a: Micrometastasis*
b: Macrometastasis†
c: In transit met(s)/satellite(s)
without metastatic node(s)
N3
4 or more metastatic nodes, or matted
nodes, or in transit met(s)/satellite(s) with
metastatic node(s)
M
Site
Serum lactate
classification
dehydrogenase
M1a
Distant skin, subcutaneous, or nodal
mets
Lung metastases
All other visceral metastases
Any distant metastasis
M1b
M1c
Normal
Normal
Normal
Elevated
*Micrometastasis are diagnosed after sentinel or elective lymphadenectomy.
†Macrometastases are defined as clinically detectable nodal metastases confirmed by
therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular
extension.
Adapted from Balch et al57.
The prognosis of a patient with melanoma is dependent on its stage at diagnosis (Fig. 114.28).
Prognosis for patients with localized melanoma and no nodal or distant metastases is generally
good. An overall 5 year survival rate of over 79% for stage I/II disease has been reported 62.
Clinical variables with prognostic significance in stage I/II disease include tumor thickness,
ulceration, sex, age and anatomic site63-65 (Table 114.10). Ulceration is defined as the absence of
an intact epidermis overlying a major portion of the primary tumor based on microscopic
examination. Women with stage I/II disease tend to have better survival than men. Location of the
primary melanoma on the trunk, head or neck portends a poorer prognosis than a location on the
extremities. Tumor regression, which can occur in up to 20% of melanomas, has been proposed
by some researchers to be of prognostic significance but has not been confirmed by others 66.
There is evidence that Clark's level, growth phase, tumor-infiltrating lymphocytes and mitotic rate
also have prognostic value. However, the applied accuracy of these measurements and the
definition of these attributes among pathologists has been questioned in the recent American
Academy of Dermatology melanoma guidelines67.
UPDATE
Date Added: 25 October 2004
Dr John A. Fisher
Metallothionein-overexpression as a prognostic factor in melanoma
Although metallothioneins (MTs) are ubiquitous and are known to play a role in the metabolism of
heavy metal ions such as copper, cadmium, and zinc, their precise function is yet to be defined.
They are small, intracellular proteins that are rich in cysteine, which protect cells against ionizing
and ultraviolet radiation, as well as (controversially) conferring resistance to anticancer drugs.
Their synthesis is induced by glucorticosteroids, interleukins, interferon-γ, tumor necrosis factor-α
and vitamin D3. MT overexpression has been reported to be a useful prognostic sign in certain
malignancies, including melanoma and nonmelanoma skin cancers.
The authors of this prospective study investigated the role of MT overexpression in melanoma
patients in comparison to other factors, as a prognostic factor for progression and survival.
Five hundred twenty patients from an original cohort of 760 were evaluated. Measurement end
points were the time of detection of lymph node and/or distant metastases, and death due to
widespread disease. The 240 patients who dropped out were either lost to follow up or died from
other diseases. Of the 520 who were evaluated, men and women were evenly balanced and the
median age was 57.5 years (mean 56.3). The median observation time was 25 months. Breslow
thickness (which varied from in situ to1.9 mm), Clark level, ulceration, site of primary tumor, age
and gender were all noted for statistical analysis.
The primary monoclonal MT mouse IgG1 antibody E9 was used on routinely fixed and paraffinembedded tissues. The immunoreactive MT expression in tumor specimens was analyzed
visually by two independent observers. The immunohistochemical overexpression of MT was
defined as MT reactivity in more than10% of tumor cells.
During the 5 years of the study, 45 patients (8.7%) showed disease progression with a median
time of 24.0 months (mean 28.7). Thirty of these patients (5.8% of the total group) died due to
metastatic disease. None of the patients with a tumor thickness less than 0.75 mm developed
metastasis.
MT overexpression in the primary melanoma (P<0.001) was demonstrated by 73% of patients
with progression, and by 80% of those who died due to metastasis. Even in patients with thin
melanomas (<1.5 mm), the majority of those who died, i.e. five of six, or showed progression, i.e.
six of nine, had statistically significant MT overexpression in their primary melanoma (P<0.005
and P<0.01, respectively).
Over a period of 72 months, 21.2% of the MT-positive group developed metastasis compared
with only 3.3% of the MT-negative group (P< 0.0001), MT overexpression proved to be a highly
significant and independent factor for prognosis in a univariate analysis with Breslow thickness,
and in multivariate analysis with other prognostic markers.
The authors conclude that MT overexpression is a potent and significant factor in determining the
risk for melanoma progression, independent of Breslow thickness. It is easy to assess in most
laboratories and helps to distinguish thin melanomas which are at increased risk of progression.
Weinlich G, Bitterlich W, Mayr V, Fritsch PO, Zelger B. Metallothionein-overexpression as a prognostic factor for
progression and survival in melanoma. A prospective study on 520 patients. British Journal of Dermatology 2003;149:53541.
Table 114-10. Major independent prognostic factors of survival in
multivariate analyses63.
MAJOR INDEPENDENT PROGNOSTIC FACTORS OF SURVIVAL IN
MULTIVARIATE ANALYSES63
Prognostic factor
Commentary
Tumor thickness
≤ mm low risk, >1 mm higher risk melanoma
Ulceration
Worse prognosis with ulceration
Age
Higher age with worse prognosis
Sex
Only for localized disease, males with poorer prognosis
Anatomic Site
Trunk, head and neck with poorer prognosis than extremities
Number of involved
lymph nodes
Cut off points: 1, 2-3, 4 or more lymph nodes
Regional lymph node
tumor burden
Macroscopic (palpable) nodal metastases with poorer
prognosis than microscopic (non-palpable) nodal metastases
Site of distant
metastases
Visceral metastases with poorer prognosis than non-visceral
(skin, subcutaneous, distant lymph nodes)
Stage III melanoma patients are a heterogeneous group with respect to their risk for distant
metastases and melanoma specific mortality. The 5-year survival rates range from 69% for
patients with non-ulcerated melanomas who had a single clinically occult nodal metastasis to a
low of 13% for patients with ulcerated primary melanomas and four or more clinically apparent
metastases63. Major prognostic factors in this group are the number of metastatic lymph nodes
and the tumor burden. Tumor burden is reflected by whether the nodal metastases are clinically
occult (as detected by sentinel or elective lymph node dissection) or clinically palpable.
In stage IV patients the major prognostic factor is the site of distant metastases with a poorer
prognosis for visceral than non-visceral (e.g. skin, subcutaneous, and distant lymph nodes)
metastases. The median survival time of stage IV patients in a recent study was 7.5 months; the
estimated 5-year survival rate was 6%68. The main variables that predicted survival were initial
site of metastases, disease-free interval before distant metastases and stage of disease
preceding distant metastases. Patients with cutaneous, nodal or gastrointestinal metastases had
a median survival of 12.5 months (estimated 5-year survival rate 14%); with pulmonary
metastases the median survival is 8.3 months (estimated 5-year survival rate 4%); and patients
with metastases to the liver, brain or bone had a median survival of 4.4 months (estimated 5-year
survival rate 3%). Up to 9% of metastatic melanoma patients present with an unidentified primary
tumor. This finding is not in itself a negative prognostic indicator.
There has been a long-standing search for melanoma-specific tumor markers that determine the
prognosis. Reverse transcription (RT) of tyrosinase mRNA and specific cDNA amplification to
facilitate the early detection of circulating tumor cells in melanoma patients has been reported as
a promising tool. However, recent results indicate that a low amount of tyrosinase-specific
transcripts is detected only in a small subset of stage IV patients and suggest that the analysis of
tyrosinase mRNA in peripheral blood samples is therefore not helpful as a prognostic marker or
monitoring tool in these melanoma patients69.
Serum levels of S-100-beta and melanoma-inhibiting activity (MIA), 5-S-cysteinyldopa as well as
conventional variables, such as LDH levels have been proposed as monitors in advanced
melanoma patients70. In a recent study the highest sensitivities for determining metastasis were
found for S-100-beta and MIA (91% and 88%, respectively). LDH had the highest specificity
(92%). However, LDH was identified to be the only statistically significant marker for progressive
disease71.
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EVALUATION OF A PATIENT WITH SUSPECTED MELANOMA
Medical History
A thorough medical history should be taken, focusing especially on risk factors for the
development of melanoma (see above), such as a personal or family history of melanoma, skin
type I/II (see Chapter 134), extensive sun bed use, childhood history of sunburns, large number
of melanocytic nevi, presence of atypical melanocytic nevi, presence of large congenital
melanocytic nevi, genetic syndromes with skin cancer predisposition (e.g. xeroderma
pigmentosum), iatrogenic (immunosuppressive drugs used in transplant medicine or extended
PUVA therapy) or acquired (e.g. HIV) immunosuppression. A detailed history of the specific
lesion in question should be obtained. Was the lesion present at birth? Did the lesion develop in a
preexisting mole? Did it change in size or shape? Did it change in color or ulcerate? Was there
itching or bleeding? What is the time course of change? Are there systemic symptoms such as
weight loss, fatigue, night sweats, headache or cough72. Other family members should be
screened if either melanoma or atypical melanocytic nevi are present. This patient should be
educated about the clinical features of melanoma and about sun protection measures (see
Chapter 154). Suggested follow-up intervals are considered in Chapter 113.
Skin Investigation and Clinical Diagnosis
The patient should undergo a complete physical examination including a whole body skin
investigation. The entire skin surface, including the scalp and mucous membranes, should be
examined. Bright room illumination is important, and a hand lens is helpful. Clinical criteria for
melanoma include a history of increase in size, an asymmetrical appearance, ill-defined and
irregular borders, variation in colors with shades of brown, black, gray, red, white and blue 73.
There may be focal areas of regression (loss of pigmentation) or newly developing black spots.
The American Cancer Society uses the ABCD mnemonic (see above) to describe these changes.
A specificity of 0.88 and sensitivity of 0.73 has been reported if two out of three of the following
characteristics are noted: irregular outline; diameter greater than 6 mm and color variegation 74.
Addition of an 'E' criterion for enlargement was proposed to optimize sensitivity and specificity of
diagnosis75. A melanotic lesion that is atypical beyond the context of surrounding nevi should
arouse suspicion of melanoma regardless of specific findings. This has been called the 'ugly
duckling' sign76. Even expert clinicians misdiagnose melanoma in up to one-third of cases and
only histologic examination will provide the diagnosis77. Dermatoscopy is a popular diagnostic tool
and increases diagnostic sensitivity when used by dermatologists formally trained in the use of
this technique, but may decrease diagnostic accuracy in dermatologists not formally trained in its
application50 (see above). Any lesion suspicious for the diagnosis of melanoma, but lacking the
full manifestation of all clinical criteria should be recorded by diagram or photography for followup. Alternatively, excisional biopsy is warranted. Examination of lymph node basins and palpation
of the abdomen for hepatosplenomegaly should be routinely performed. Length of scars after
primary or re-excision should be documented and scars palpated at follow up visits for possible
local recurrence.
UPDATE
Date Added: 04 August 2003
John A. Fisher M.D.
Dermoscopy in melanoma screening
The authors describe a study designed to evaluate the impact of dermoscopy (epiluminescence
microscopy, dermatoscopy) on the false-positive rate in routine melanoma screening activity at a
pigmented lesion clinic.
The positive predictive value of melanoma diagnosis by a dermatologist during melanoma
screening is less than 20%1 Koh HK, et al. Evaluation of the American Academy of Dermatology's
national skin cancer early detection and screening program. J Am Acad Dermatol 1996;34:971-8.
i.e. only 2 out of 10 cases of suspected melanoma are confirmed histologically. Surgical excision
has its own attendant morbidity and includes the likelihood of scarring.
In a series of 133 patients consecutively referred to the clinic, 2542 pigmented lesions were
observed through visual examination. Of those, 43 were defined as suspicious or equivocal and
subsequently examined by dermoscopy. Only lesions again defined as suspicious by dermoscopy
(13) were excised. Histopathologic examination revealed three malignant melanomas. Other
lesions were observed through followed up examination.
Compared with visual examination alone, the addition of dermoscopy resulted in an increase in
specificity from 98.4% to 99.6% and in positive predictive value from 6.9% to 23%. The specificity
of a "refer for surgical excision" outcome increased from 69.2% to 92.3%. No false-negative
melanoma diagnoses from dermoscopy were encountered during a follow-up period of 4 years.
The addition of dermoscopy as a second level diagnostic tool in routine examinations led to a
reduction in the number of false-positive diagnoses, with an increase in the specificity and
positive predictive value of melanoma diagnosis.
The authors conclude that confirmatory studies are necessary on larger series of patients, to
provide data about the theoretical risk of false-negative outcomes from dermoscopy.
Carli P, Mannone F, de Giorgi V, Nardini P, Chiarugi A, Giannotti B. The problem of false-positive diagnosis in melanoma
screening: the impact of dermoscopy. Melanoma Research 2003;13:179-182. Medline
Similar articles
Laboratory Investigations and Imaging
Evaluation of a patient with melanoma might include chest radiography, ultrasound investigation
of the abdomen as well as serum markers such as LDH, S100beta or MIA. There is wide variation
in the use of these tests in clinical practice. Evidence is accumulating that routine imaging studies
including chest radiography and blood work have limited, if any value in the initial work-up of
asymptomatic patients with primary cutaneous melanoma 4 mm or less in thickness67. An
American Academy of Dermatology task force recommended that these initial imaging studies
and blood work are optional and most appropriately directed based on findings of a thorough
medical history and physical examination67. In a study involving more than 800 asymptomatic
patients with localized melanomas initially examined with chest radiography, unsuspected
metastasis was demonstrated in only 1 patient78. Unnecessary investigations are costly, may lead
to patient anxiety and are unlikely to impact outcome. Exceptions for obtaining imaging and blood
chemistry studies on asymptomatic patients with primary melanoma include thickness >4 mm and
in the setting of multidisciplinary referral centers conducting prospective studies.
Investigation of stage III/IV melanoma patients includes radiologic investigations such as
magnetic resonance imaging (MRI) of the brain and computed tomography (CT) of the chest,
abdomen and pelvis. The most significant advance in imaging technology for early detection of
metastases is whole body positron emission tomography (PET) using 18F-fluorodeoxyglucose
(FDG)79. It is based on the assumption that melanoma metastases have a higher metabolic rate
than normal tissue and utilize more glucose . The accuracy of nodal staging can be significantly
improved by adding PET to the pre-therapeutic diagnostic procedures80. A meta-analysis of the
existing PET literature determined an overall sensitivity of 92% and an overall specificity of
90%81. However, in a selected patient population, FDG-PET was found to be inferior to CT for
diagnosing lung and liver metastases82.
The combination of FDG-PET with CT or ultrasound guided fine-needle aspiration (FNA) can
increase the sensitivity of both methods83. FNA is used in the cytologic diagnosis of melanoma
metastases often in combination with immunohistochemistry with melanoma-specific antibodies,
but should not be used for the diagnosis of the primary melanoma. In a study in 330 melanoma
patients with metastasis, 739 FNAs were performed with a sensitivity of 97.9% and a specificity of
100%84. FNA is especially useful in combination with ultrasound or CT in melanoma follow-up of
lymph node, lung and liver metastases and has the potential to identify lesions smaller than 1 cm.
MANAGEMENT
Management of melanoma includes prevention, screening, history, physical examination,
histology, laboratory testing, imaging, staging, prognosis, treatment and follow-up.
Management of the Primary Melanoma (Stage I and II)
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Early diagnosis and treatment is essential in the management of primary melanoma, since tumor
thickness remains the most important prognostic indicator in this setting. Secondary prevention
measures such as identification, education and screening of high risk patients complement
management of primary melanoma. A lesion that is clinically suspicious for melanoma should
ideally undergo an excisional biopsy with narrow margins (such as 2 mm). Although there is
evidence that an incisional biopsy does not adversely affect survival 85, this approach should be
an exception and reserved for cases in which the tumor is too large to be excised, or when it is
impractical to perform an excision (e.g. of the nail unit). The biopsy should be interpreted by a
physician experienced in the microscopic diagnosis of melanotic lesions. Fine-needle aspiration
cytology should not be used to assess the primary tumor 67. After excisional biopsy and histologic
diagnosis melanoma should be re-excised with an appropriate margin determined by the Breslow
depth (Table 114.11).
The rationale of excision margin is based on the capacity of melanoma cells to migrate away from
the tumor origin. Melanoma may extend wider or deeper than is visibly apparent. The major goal
is to prevent local recurrence or persistent disease. A WHO randomized trial indicates that 1 cm
excision margins are safe and effective for melanoma with Breslow depth <1 mm 86. A controversy
persists about the effectiveness of 1 cm excision margins for melanomas 1 to 2 mm deep, since
there was a trend to local recurrence in this group in the WHO trial87. Several recent reports,
including the American Academy of Dermatology Guidelines of Care for Primary Melanoma, have
recommended 1 cm margins for melanoma <2 mm depth67,88,89. A randomized trial for
intermediate thickness melanoma (1 to 4 mm deep) demonstrated that 2 cm margins are as
effective as 4 cm margins in preventing local recurrences 90. For this group of melanoma patients,
local recurrence was associated with a high mortality rate. Ulceration of the primary melanoma is
the most significant prognostic factor heralding an increased risk for a local recurrence. There are
no informative randomized trials that determine the optimal margins of excision for melanoma >4
mm thickness or in situ melanoma. Current recommendation are excision margins of 0.5 cm for in
situ melanoma and 2 to 3 cm for melanoma >4 mm depth67,91.
Further investigative efforts will likely alter the standards of care over time. Margins of excision
are also dictated by surgically difficult anatomic areas such as the distal extremities, the mucous
membranes or the face and in many instances an individualized surgical approach must to be
taken92. Some recommendations, such as excision to the underlying fascia, are based on
questionable anatomic concepts25. No randomized trials have compared this approach to excision
to the deep subcutaneous fat25.
Data exist to indicate that definitive surgical treatment may be safely delayed for 3 weeks after an
excisional biopsy without adversely influencing the 5-year survival rate94. Longer time periods
may still be permissible, although the upper limit is unknown.
Follow-up is indicated because of the risk of developing a second melanoma (estimated at 3.44.3%95-97) as well as local relapse and/or metastasis from the original tumor 98. There is little
evidence to support specific follow-up intervals, but the American Academy of Dermatology
melanoma task force recommends follow-up one to four times per year, depending on the
thickness of the lesion and other risk factors such as a melanoma family history for 2 years after
diagnosis and one to two times per year thereafter67. Follow-up interventions usually include
medical history, clinical examination, laboratory/radiologic tests as indicated and may include
patient education.
Local Recurrences
Table 114-11. Surgical treatment of primary melanoma.
SURGICAL TREATMENT OF PRIMARY MELANOMA
Thickness Excision
Comments
In situ
margins (cm)
0.5
<1 mm
1.0
1-4 mm
2.0
>4 mm
2.0-3.0
No randomized studies, lentigo maligna of the face might
be treated with radiotherapy in specialized centers 93
AAD task force suggests 1 cm margin for melanoma <2
mm67
AAD task force suggests 2 cm margin for melanoma ≥2
mm67
No randomized studies
Add to lightbox
Figure 114.29 Recurrent melanoma with metastases.
Local recurrence is defined as any recurrence within 2 cm of the surgical scar of a definitive
excision for primary melanoma57. Recurrence results from extension of the primary tumor or intralymphatic spread. Every effort should be made to identify hematogenous metastases. The overall
risk of recurrence is approximately 3.8%, and is more frequent in thicker or ulcerated tumors as
well as head and neck and distal leg locations (Fig 114.29)99. Ultra late recurrence (>15 years)
may occur in melanoma without identifiable risk factors100. Local recurrence is strongly associated
with the appearance of in transit and regional as well as distant metastases but is not an
independent prognostic indicator of survival in multivariate analysis 99. There is evidence that
patients with local recurrence, satellites and in transit metastases have a similar pathogenesis
and outcome101. There is no evidence that patient survival is adversely affected if local recurrence
results from inadequate excision of the primary melanoma (i.e. persistent disease) provided that
the residual in situ or radial growth-based tumor is promptly re-excised and provided there is no
distant disease at the time25. In a population-based study, local recurrence had no major
detrimental effect on survival102. However in a recent contradictory study local recurrence was
associated with a high mortality rate90. Development of local recurrence in melanomas <4 mm
thick is often due to inadequate surgical treatment103. Patterns of failure after local recurrence
suggest that patients may benefit from aggressive loco-regional therapy104. Surgical resection
with a wide margin (up to 3 cm) depending on the anatomic site is the most common and
effective therapy. In selected patients isolated limb perfusion which has high regional response
rates for the treatment of in-transit metastases may be considered105.
Management of Regional Metastatic Melanoma (Stage III)
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Add to lightbox
Add to lightbox
Figure 114.30 Sentinel lymph node biopsy. Localization of sentinel lymph node by
lymphoscintigraphy: A small incisional biopsy identifies blue sentinel node; B confirmation with
handheld gamma counter. Courtesy of M. Hess and W. Künzi, University Hospital Zürich.
Metastatic spread of melanoma is often regional and confined to the site of the primary
melanoma and its draining lymph nodes. Metastasis may manifest as clinically occult lymph node
(micrometastasis), as a rapidly growing clinically evident macrometastasis, or as in-transit
metastasis.
Elective lymph node dissection
Approximately 20% of patients with intermediate (1 to 4 mm) and high risk (>4 mm) cutaneous
melanoma and no evidence of clinically or radiologically detectable nodal disease at presentation
show microscopic involvement106. On the basis of the primary migration of melanoma cells in an
orderly fashion towards the draining lymph node, surgical resection of regional lymph nodes in all
patients with intermediate and high risk tumors was proposed as 'elective lymph node dissection
(ELND)'. ELND was postulated to be especially beneficial for patients with microscopic disease of
the lymph nodes by preventing spread of tumor cells to internal organs. An opposing view was
that excision of lymph node metastasis might impair the body's immune response to
melanoma107,108. There is significant morbidity associated with ELND, such as postoperative
lymphedema, wound infection, hematoma and lymph fistulas. While on retrospective trial
suggested benefit for ELND in intermediate risk melanoma patients109, four other multicenter
randomized prospective trials in patients with primary melanoma did not show a survival benefit
of patients treated with ELND plus wide re-excision compared to wide re-excision alone110-113. A
further randomized trial did not show a benefit of immediate dissection of regional nodes in
melanoma patients >1.5 mm depth114. Current evidence does not suggest that ELND should be
performed in patients with primary melanoma.
Sentinel lymph node biopsy
Since in 80% of patients with ELND there is significant morbidity in the absence of microscopic
disease. A less traumatic procedure to identify regional metastatic disease was devised based on
similar concepts, namely progression of metastatic disease through the lymphatic system before
widespread dissemination115. This so-called sentinel lymph node biopsy (SLNB) is based on the
concept that the skin involved with melanoma drains to one or more lymph node basins and
particularly to one (rarely more) lymph node, the sentinel node, which is the first site of deposition
of metastatic cells. The concept and its utility are also based on the ability to accurately identify
this node. The sentinel node is identified by intraoperative lymphatic mapping using
lymphoscintigraphy and dye injection. Lymphoscintigraphy is performed by injection of 99
mTechnetium sulfur colloids around the tumor site or scar of primary excision. The isotope is
transported through the draining lymphatics and phagocytosed by macrophages and
concentrated within the sentinel lymph node before draining to other regional lymph nodes. The
position of the sentinel node is marked on the skin by a hand-held gamma counter. Additionally, a
blue dye is injected around the primary tumor or scar which is also transported through the
lymphatics to the sentinel node. The blue dye is helpful in giving visual conformation
intraoperatively (Fig 114.30). The 'hot, blue' sentinel node(s) is selectively biopsied through a
small incision and examined by serial sectioning using H&E stains combined with
immunohistochemistry (S-100, HMB45). If metastatic melanoma is identified, then complete
regional lymph node dissection is undertaken. Draining patterns are sometimes difficult to predict,
especially on the head, neck and trunk. For example, two sentinel lymph nodes may be identified
or the skin may drain into the contralateral site of the original tumor. It is recommended to remove
all radioactive nodes116. Since the application of lymphoscintigraphy for SLNB it has been
realized that ELND based on classic draining patterns might have led to resection of
inappropriate lymphatic basins117. A recent trial comparing SLNB followed by node dissection to
ELND showed no difference in survival.
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Training and experience are important in SLNB. SLNB performed with blue dye plus a
radiocolloid is more accurate (99.1%) than SLNB performed with blue dye alone (95.2%).
Evidence exists that at least 30 SLNBs are required to gain the appropriate skill level118.
Numerous studies have documented the accuracy of this procedure for identifying nodal
metastases. A randomized trial provided further evidence that lymphatic mapping and SLND
biopsy accurately reflect the status of the regional nodal basin 119. This study also reported a low
rate of tumor recurrence (11%) in sentinel node negative patients. In 80% of these cases occult
micrometastases were later identified by serial sectioning and appropriate immunohistochemistry
using S-100 and HMB45 monoclonal antibodies. The use of RT-PCR to examine sentinel nodes
for mRNA of melanoma associated proteins such as tyrosinase or MelanA might increase
sensitivity of detection. In one study tyrosinase transcripts were detected in 36-52% of stage I and
II melanoma patients with negative sentinel nodes by histopathology alone. Importantly, the
recurrence rate was significantly higher in patients with histologically negative sentinel nodes who
were found to be positive by RT-PCR than in patients with negative results by both techniques120.
Unanswered questions such as the clinical importance of RT-PCR positive sentinel nodes as well
as the effect of adjuvant therapy in patients with negative sentinel nodes will hopefully be
answered on-going prospective trials121.
Based on current data, there are four major reasons to perform SLNB. First, SLNB provides
information on subclinical lymph node status with minimal morbidity. As such it is not only a
staging tool but provides valuable prognostic information for patients and physicians to guide
subsequent treatment decisions. Second, SLNB identifies patients with metastatic lymph nodes
for early therapeutic lymph node dissection (see below). Third, SLNB identifies patients who
might be candidates for adjuvant therapy with interferon alpha. Fourth, results of SLNB are a
stratification criterion to enter more homogeneous patients into adjuvant clinical trials 122.
From the perspective of staging, SLNB has caused stage migration. This means that detection of
microscopic metastases in patients leads to an upgrading to stage III disease. This is recognized
in the recent revision of the AJCC TNM classification system (Tables 114.8 & 114.9). The marked
diversity in the natural history of stage III melanoma is demonstrated by fivefold differences in 5year survival rates for defined substages that range from 69% for patients with non-ulcerated
melanoma who had a single clinically occult metastases to 13% for patients with an ulcerated
melanoma with four or more clinically apparent nodal metastases as detected by therapeutic
lymphadenectomy63. These differences are so great that the AJCC recommends that all patients
with a primary melanoma >1.0 mm in tumor thickness have nodal staging with sentinel
lymphadenectomy before entry into melanoma clinical trials 63.
The above mentioned reasons have led some investigators to propose SLNB as standard of
care121 which is disputed by others67,123,124. Certainly, the use of SLNB in specialized centers in
the context of controlled studies may answer important issues relating to melanoma treatment.
Whether SLNB represents a clinical standard of care is debatable67,121,123,124.
From a therapeutic perspective there is little evidence that early dissection in sentinel node
positive patients affords improved survival compared to dissection performed when clinically
detectable nodes develop. However, a recent study suggested that further node dissection in
patients with positive lymph nodes might be beneficial114.
In conclusion, intraoperative lymphatic mapping and SLNB followed by selective complete
lymphadenectomy has revolutionized the management of the regional lymph node basin in
patients with melanoma. The sentinel node hypothesis has been validated by a multicenter
clinical trial showing that SLNB in melanoma can be accurately performed in a uniform manner by
multidisciplinary teams. Although the diagnostic and prognostic accuracy of SLNB has been
established, demonstration of the therapeutic use of this procedure awaits analysis of survival
data from multicenter randomized trials of wide excision alone versus wide excision plus
SLNB/complete lymphadenectomy115, as well as trials linking SLNB to adjuvant therapies.
Adjuvant therapy
The goal of adjuvant therapy is the active suppression of growth of clinically inapparent
micrometastases. A major emphasis in adjuvant therapy are patients with resected high risk
stage II and III melanoma. Trials have also targeted resected stage IV patients. A number of
postsurgical adjuvant approaches have been tested including systemic chemotherapy,
immunotherapy using microbial agents such as Bacillus Calmette-Guerin (BCG) or
Corynebacterium parvum125-127. None of these approaches were successful in randomized
controlled trials117.
The current recommendation is to include appropriate patients in well controlled clinical studies to
obtain valid data leading to recommendations about future adjuvant therapy. One of the most
promising candidates for adjuvant therapy of patients with malignant melanoma are recombinant
biological response modifiers, in particular the intensively studied interferon alpha (IFN-α). IFN-α
is a type I member of the interferon family of proteins and has pleiotropic functions. These include
complex immunoregulatory functions such as induction of MHC class I expression as well as
impact on immune effector cells such as the activation of natural killer (NK) cells and the
maturation of dendritic cells. Some of its activities may have direct or indirect anti-tumor
effects128. Little anti-tumor activity has been demonstrated in metastatic stage IV melanoma, with
overall response rates of 10-15%. However, IFN-α has been most widely studied in the adjuvant
setting for stage II and III disease. It is important to distinguish high-dose IFN therapy with the aim
to reach maximally tolerated dosage (20 MU/m 2 intravenously during the induction phase
followed by 10 MU/m2 subcutaneously three times per week) from low-dose IFN therapy which is
much better tolerated in terms of side effects (typically 3 MU three times per week) (Table
114.12).
High-dose IFN has demonstrated an improvement in relapse-free and overall survival compared
to controls in two studies (ECOG 1684 as well as ECOG 1694) (Table 114.12). However, a
beneficial effect on overall survival was not seen in another high-dose IFN study (ECOG 1690).
Toxicity in high-dose IFN include constitutional (flu-like) symptoms, neuropsychiatric (depression,
suicidal intention), hematologic, and hepatic effects as well as cases of fatal
rhabdomyolysis129,130. These toxicities have a major impact on the patient's quality of life, and on
the physician's ability to optimally treat the patient and led to dose modifications in two-thirds of
the patients in the first month of high-dose IFN. The application of high-dose IFN was questioned
especially in Europe due to the inconsistent impact on overall survival and the considerable dosedependent toxicity131,132. It is possible that recurrence of metastases might have a worse effect on
patient's quality of life than high-dose IFN therapy133. The relative importance of the induction
component of this treatment regimen is being addressed in an ongoing Intergroup trial for
intermediate-risk melanoma134. For low-dose IFN, randomized studies have consistently reported
a benefit with regard to relapse free but not overall survival for patients treated with IFN-α
compared to untreated controls135,136. The impact on extension of overall survival remains
unclear. Currently, the most important question is the efficacy of very toxic high dose therapy
compared to lower dose long-term treatment. This will hopefully be answered by the data from
the large US-Intergroup high-dose and EORTC intermediate-dose and long-term maintenance
therapy trials.
Recently, a meta-analysis has been performed of all available IFN-α trial results, largely based on
published reports. The endpoints evaluated were disease-free survival and overall survival in
approximately 3700 patients included in ten trials137. For disease-free survival, there was clear
benefit for IFN-α, but the advantage was less clear for overall survival. There was no statistically
significant evidence that the benefit of IFN-α is greater in higher than in lower dose trials. The
authors conclude that 'decisions on the use of IFN-α for melanoma will need to be based on
considerations such as the relative importance of benefits on disease-free survival compared to
overall survival, patient quality of life and financial costs'.
Management of Distant Metastases (Stage IV)
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Table 114-12. Completed trials for adjuvant interferon- α2 therapy in
melanoma.
COMPLETED TRIALS FOR ADJUVANT INTERFERON-α2 THERAPY IN
MELANOMA
Trial
TNM n Agent Treatment
RFS OS
Low-dose
EORTC
T3-4, 800 IFN- IFN-α2b 1MU sc, qod, 52wk
18871
N1
α2b
versus
IFN-γ 0.2 mg sc, qod, 52wk
IFN-γ versus
Iscador
versus
Observation
138
WHO 16
N1-2 444 IFN- 3MU sc, t.i.w, 36mo
α2a
versus
Observation
Austrian
T3-4, 311 IFN- 3MU sc, daily, 3 wk, followed by +
trial135
N0
α2a
3MU, t.i.w., 48wk
versus
Observation
French
trial136
T3,
N0
NCCTG
837052139
ECOG
1684140
T3-4, 262 IFNN1
α2a
T4, 287 IFNN1
α2b
High-dose
versus lowdose
ECOG
1690141
T4,
N1
High-dose
versus
ganglioside
ECOG
1694142
T4;
N1
High-dose
499 IFNα2a
3MU sc, t.i.w., 18mo
versus
Observation
20MU/m2 IM, t.i.w. 12wk
+
-
-
-
20MU/m2 IV daily×5/7d/wk,
+
4weeks followed by 10MU/m 2 sc
t.i.w., 48wk
642 IFN- 20MU/m2 IV
+
α2b
daily×5/7d/wk,4weeks followed
by 10MU/m2 sc t.i.w., 48wk
(HDI)
versus
3MU sc t.i.w, 24mo (LDI)
880 IFN- 20MU/m2 IV daily×5/7d/wk,
+
α2b
4weeks followed by 10MU/m 2 sc
versus t.i.w., 48wk (HDI)
GMK versus
GMK sc 1/wk, 3mo
+
-
+
RFS, relapse-free survival; +, statistically significant; -, statistically insignificant; wk, weeks;
t.i.w., three times per week; MU, million units; IM, intramuscular; IV, intravenous; SC,
subcutaneous; ECOG, Eastern Cooperative Oncology Group; NCCTG, North Central Cancer
Treatment Group; mo, months; HDI, high-dose interferon; LDI, low-dose interferon; GMK, GM2
ganglioside, keyhole limpet hemocyanin plus OS21 adjuvant; OS, overall survival.
Despite new treatment options, the prognosis of patients with metastatic melanoma has not
changed significantly over the last 22 years; with survival rates of 6% and median survival of 7.5
months68. The initial site of metastasis determines prognosis. Nodal or gastrointestinal
metastases (median survival of 12.5 months; estimated 5-year survival rate 14%) have a better
prognosis than pulmonary metastases (median survival of 8.3 months; estimated 5-year survival
rate 4%). The worst prognosis is associated with metastases to the liver, brain or bone (median
survival of 4.4 months; estimated 5-year survival rate 3%)68. Thus the focus is on palliative
therapy with special emphasis on the quality of life of the patient. To enable progress towards
new therapeutic approaches in stage IV patients inclusion in controlled clinical trials should be
considered and discussed with every patient. There is evidence that patients included in clinical
trials have better outcome143. Recent developments with a favorable benefit/side effect profile
include oral chemotherapeutic agents and innovative approaches to therapeutic cancer
vaccination. It should be also noted that surgery has its place in management of stage IV patients
since randomized trials have demonstrated that the value of surgery for local metastatic disease
is probably underestimated while the value of extensive surgery and prophylactic surgical
procedures is overestimated132.
Evaluation of the patient with suspected metastatic disease
Evaluation of the patient with suspected metastatic disease is a demanding task both at the level
of interaction with the patient and family as well as the extensive work up which is often
necessary. It is essential to get an accurate picture of the metastatic burden before considering
therapy. Evaluation and necessary diagnostic tests should be guided by an in depth medical
history and a thorough physical examination including a whole-body skin examination as well as
palpation of the abdomen and the lymph nodes (see above). Possible symptoms related to
metastatic disease are listed in Table 114.13. Further staging investigations include a CT scan of
the thorax and abdomen including the pelvis, as well as an MRI of the brain. Ultrasound
investigation of the abdomen and lymph nodes are optional. At specialized referral centers FDG
PET provides an additional method with high sensitivity for detection of metastases (see above).
Measuring soluble melanoma serum markers such as S-100 and MIA gives an early indication of
progressive disease as well as treatment response in stage IV patients 144,145. Further specialized
diagnostic tests are performed according to individual symptoms of the patient (Table 114.13).
Surgery
page 1809
page 1810
Table 114-13. Symptoms and diagnostic tests for metastatic melanoma.
SYMPTOMS AND DIAGNOSTIC TESTS FOR METASTATIC MELANOMA
Metastatic site (TNM)
Symptoms
Diagnostic tests*
Skin, soft tissue
Skin-colored to
Biopsy + histology
metastasis (TxNxM1), in- blue/brownish
transit metastasis
patches/nodules, ulceration,
(TxN2cM0)
bleeding
Brain metastasis
Headache, nausea,
MRI scan
(TxNxM3)
seizures, depression, visual
Lung metastasis
(TxNxM2)
Gastrointestinal
metastasis (TxNxM3)
Bone metastasis
(TxNxM3)
disturbance, numbness,
paralysis
Chest pain, dyspnea, cough,
hemoptysis
Abdominal pain, anemia
vomiting, constipation,
melena, jaundice
Chest radiograph, CT scan
Liver function tests, fecal
occult blood test,
ultrasonography, CT scan,
radiography, endoscopy
Pain, spontaneous fractures Bone scan
*Always include thorough medical history and physical investigation as well as complete blood
count and blood chemistry including LDH. Special procedures such as FDG-PET investigation
as well as detection of soluble melanoma markers (e.g. S-100, MIA) are performed at selected
melanoma referral centers for increased sensitivity of metastasis detection as part of controlled
studies.
Table 114-14. Treatment options for metastatic melanoma.
TREATMENT OPTIONS FOR METASTATIC MELANOMA
Metastatic site (TNM)
Treatment choice
In-transit metastasis
1st: <5 surgery, >5: extremity perfusion*
(TxN2cM0)
2nd: radiotherapy, CO2 laser ablation, intralesional IL-2
3rd: systemic therapy
Brain metastasis (TxNxM3)
Single
1st: surgery
2nd: stereotactic radiosurgery
Multiple
1st: radiotherapy
2nd: systemic therapy
Lung metastasis (TxNxM2)
Single
1st: surgery
Multiple
1st: systemic therapy
Gastrointestinal metastasis
(TxNxM3)
1st: surgery
Single
1st: systemic therapy
Multiple
Skin, soft tissue metastasis
(TxNxM1)
1st: surgery
Single
1st: systemic therapy
Multiple
Painful bone metastasis
1st: radiotherapy
(TxNxM3)
Disseminated metastasis
1st: systemic therapy +/- surgery, radiotherapy of
(TxNxM3)
symptomatic metastasis
*Should be performed as part of controlled studies.
Despite the well-known behavior of melanoma to disseminate to various organs, resection of
metastases can often provide excellent palliation and in selected patients long-term survival
(Table 114.14). Factors that positively influence prognosis are isolated non-visceral metastasis
and complete resection with free surgical margins. In certain cases median 5-year survival can
even approach up to 35% after surgical treatment. Complete resection of lung metastases can
lead to a median survival of 19 months and a 5-year survival of 25%. Patients rarely survive longterm after brain or gastrointestinal metastases, but surgical resection extends median survival to
about 10 months in this group with a significant improvement in quality of life 146. The combination
of cytoreductive surgery, with the goal of resecting clinically evident disease, and immunotherapy
is a valuable future approach to management of stage IV patients147.
Radiation therapy
Radiotherapy for melanoma never gained acceptance due to unfavorable clinical results
observed in early studies. Recent evidence indicates that melanoma is not only highly variable in
its radiosensitivity but that radioresistance of melanoma might be overcome using large individual
dose fractions148. Radiation therapy has been useful in some extensive lentigo malignas (see
Chapter 139). Radiotherapy provides effective palliation in symptomatic advanced melanoma
(Table 114.14)149. Special indications include pain associated with bone metastases, spinal cord
compression, brain metastases and local control of cutaneous disease. Studies do not support
the recommendation of adjuvant radiotherapy following resection of regional lymph node
metastases in patients with malignant melanoma150.
Whole brain radiotherapy combined with surgical resection have been the mainstay of the
treatment of cerebral metastases. This approach results in a median survival of about 10
months151. A new development producing at least similar results is stereotactic radiosurgery using
either the so-called 'Gamma Knife' or linear accelerator radiosurgical techniques. Radiosurgery
has been shown to be effective in metastatic tumors in surgically inaccessible sites such as the
brainstem. A benefit of radiosurgery is the virtual absence of perioperative complications and the
reduced adverse impact on quality of life compared either to surgery or to whole brain
radiotherapy. Long-term complications of radiosurgery are infrequent and primarily relate to
failure of local tumor control (10%) and radiation-induced edema or necrosis151.
Chemotherapy
Over the past four decades cytotoxic chemotherapy, has had a low but reproducible level of
activity against metastatic melanoma (Table 114.14). Drugs employed include
DTIC/temozolomide, cisplatin , vindesine/vinblastine, BCNU/fotemustine and taxol/taxotere152.
Chemotherapeutic treatment of stage IV melanoma has been disappointing and has not had a
positive impact on melanoma survival during the last 20 years even though several
chemotherapeutic agents have shown activity against melanoma cells in-vitro and in phase I/II
clinical trials68. A promising new development is the selection of melanoma chemotherapy
according to in vitro chemosensitivity assays153. Recent new developments include oral delivery
of the prodrug of a dacarbazine metabolite: temozolomide , combination chemotherapy as well
as combinations of chemotherapy and immunotherapy154. The most widely used single
chemotherapeutic agent is dacarbazine (DTIC). It has shown the greatest effectiveness as a
single agent in most trials and was equally effective when combined with IFN-α or tamoxifen155.
With DTIC as single agent, an approximately 20% response rate can be achieved with median
response duration of 5 to 6 months and complete response rates of 5%156. A novel oral alkylating
agent is temozolomide (a pro-drug of MTIC, the active metabolite of DTIC) with some efficacy in
CNS metastasis and equal efficacy to DTIC157,158. Fotemustine is a member of the nitrosourea
family and has some efficacy in melanoma including brain metastases 159.
page 1810
page 1811
Combination chemotherapy regimens like CVD (cisplatin , vinblastine, DTIC) and BOLD
(bleomycin, vincristine, lomustine , DTIC) have induced responses in metastatic lesions typically
unresponsive to DTIC alone, including the liver, bone and brain, but have failed to improve overall
patient survival. The CBDT (cisplatin , carmustine , DTIC and tamoxifen) or 'Dartmouth regimen'
has achieved high response rates in earlier trials (up to 55%) but a recent phase III trial did not
show a statistical survival benefit compared to DTIC alone160. Therefore DTIC remains the
reference standard of chemotherapy in stage IV melanoma.
Combination chemo-immunotherapy involves the addition of the biological response modifiers
interleukin-2 (IL-2) and IFN-α. These substances have shown modest activity as single agents
with response rates between 15-20% but durable responses have been observed especially after
IL-2 therapy161. Combination chemotherapy with IFN-α or IL-2 has generally resulted in improved
survival but may cause unacceptable levels of myelosuppression162.
Biochemotherapy uses combination chemotherapy plus IL-2 and IFN-α. A widely employed
combination is cisplatin , vinblastine and DTIC (CVD) IFN-α and IL-2. In phase II trials durable
complete remissions have been observed in 10-15% of patients with metastatic melanoma152. In
other trials, the combination of IFN-α and IL-2 with cisplatin 163 or cisplatin/DTIC/tamoxifen164 did
not show significant improvement compared to biochemotherapy.
Another approach is chemohormonal therapy using tamoxifen in addition to chemotherapy.
Addition of tamoxifen has not been shown to improve survival compared to single
agent/combination chemotherapy alone160,165.
In conclusion, a survival benefit from chemotherapy in combination with immunotherapy or
hormonal therapy has not been shown in metastatic melanoma patients. Patients should
therefore be included in randomized controlled trials to hopefully discover new, more effective
protocols. Some long term survivors have been reported with high dose IL-2-based regimens, but
prospective randomized phase III trials are necessary to establish efficacy156.
Immunotherapy
Immunotherapy builds on the concept that the immune system is able to fight cancer 166.
Melanoma is one of the prototypic immunogenic cancers 12. Therapeutic effect might be achieved
passively by infusing effectors of the immune system such as cytokines, killer cells or antibodies.
On the other hand active immunization tries to stimulate the patients own immune effector cells in
response to an injected vaccine (antigen plus adjuvant).
Treatment of advanced melanoma with single cytokines such as IFN-α or IL-2 has been
disappointing, even though high-dose IL-2 might lead to long-term remissions167. Antibody (ab)based therapies, including the use of anti-ganglioside ab or anti-high molecular weight ab, which
might be coupled to a toxin (e.g. ricin) or radioactive isotope (e.g. 131I) has not shown marked
effect in melanoma similar to the activity of anti-CD20 ab in lymphoma168. Adoptive
immunotherapy using in vitro expansion of tumor infiltrating killer cells targeting melanoma
epitopes is an interesting concept but failed to translate into practical use due to low response
rates and technical difficulties. However, it led to the identification of new melanoma antigens 169.
Recently, there has been a marked resurgence of interest in the use of vaccination for the
treatment of advanced melanoma. In the past most vaccines under study were whole cell
preparations or lysates of melanoma in combination with a variety of adjuvants. Examples are (1)
polyvalent allogeneic melanoma cell lines +/- BCG (CancerVax)170; (2) allogeneic melanoma
lysates plus 'detox' (a 'detoxified' bacterial endotoxin) (Melacine) 171; (3) autologous melanoma
cells modified with the hapten dinitrophenol (M-VAX)172; and (4) shed antigen vaccine173. These
have shown effects in phase II trials in advanced melanoma patients but were for the most part
disappointing in randomized controlled trials174. Cellular vaccines are currently tested in four
randomized phase III trials in resected stage II/III/IV melanoma patients 174. A study performed by
the South West Oncology Group in stage IIA melanoma with a vaccine prepared from two
mechanically disrupted allogeneic melanoma patients admixed with 'detox' adjuvant led to a
significant prolongation of disease free survival but not overall survival175. A prospective
randomized study in resected stage III patients with a shed polyvalent vaccine achieved
significant improvement of time to disease progression but not overall survival compared to
placebo173. Gene modified whole cell vaccines are at an early stage of development but have
failed to demonstrate a significant clinical effect176. An antigen based ganglioside vaccine (GM2KLH/QS21)-induced antibody responses was less effective than high-dose IFN-α in a randomized
trial142.
Progress in the field of melanoma immunology has allowed the identification of new melanoma
antigens. Based on this knowledge the new field of antigen specific peptide vaccination is rapidly
expanding. These peptides are defined stretches of amino acids corresponding to a known
melanoma epitope. Peptide epitopes differ depending on HLA class I molecules. An advantage of
the peptide approach is the ability to exactly follow the melanoma specific immune response
during vaccination. Rosenberg et al.177 have demonstrated clinical responses in patients injected
with melanoma peptides, incomplete Freund's adjuvant and IL-2. In other trials tumor regression
as well as immunological responses were observed178,179. An innovative approach is the use of
dendritic cells to boost a melanoma-specific immune response. Early promising clinical trials
using dendritic cells pulsed with melanoma peptides have demonstrated immune responses as
well as clinical responses in selected patients180,181.
The field of melanoma immunotherapy is rapidly expanding and will hopefully provide potent anticancer treatments, especially in the adjuvant/minimal residual disease setting 182.
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