Mckee Melanoma Cap 26

Chapter 26
Melanoma
26
CHAPTER
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Jeffrey P. North, Boris C. Bastian and Alexander J. Lazar
MELANOMA 1310 Prognostic indicators 1320 Angiotropic and angiomatoid (pseudovascular)

Clinical features 1310 Differential diagnosis 1327 melanoma 1341
Lentigo maligna and lentigo maligna Metaplastic melanoma (melanoma with
Immunohistochemistry of melanoma 1328 heterologous differentiation) 1341
melanoma 1311
Superficial spreading melanoma 1312 Histologic variants of melanoma 1330 Pigmented epithelioid melanocytoma (pigment
Nested melanoma 1330 synthesizing melanoma; animal-type
Acral lentiginous melanoma 1312
Minimal deviation melanoma 1330 melanoma) 1342
Nodular melanoma 1313
Nevoid melanoma 1331 Epidermotropic metastatic melanoma 1343
Melanoma arising at noncutaneous (primarily
Small cell melanoma 1334 Blue nevus-like metastatic melanoma 1344
mucosal) sites 1313
Spitzoid melanoma 1334 Desmoplastic and neurotropic
Histologic features 1313 Signet ring cell melanoma 1336
Lentigo maligna and lentigo maligna melanoma 1344
Rhabdoid melanoma 1336
melanoma 1315 Balloon and clear cell melanoma 1337 Melanoma in children 1350
Superficial spreading melanoma (pagetoid Myxoid melanoma 1338 Dermal squamomelanocytic tumor 1351
melanoma) 1317 Melanoma with neuroendocrine
Acral lentiginous melanoma 1318 Basomelanocytic tumor 1351
differentiation 1338
Nodular melanoma 1319 Adenoid and pseudopapillary melanoma 1339 Lentiginous melanoma 1353
Cell types 1319 Blue nevus-like melanoma (malignant blue Primary dermal melanoma 1354
Epithelioid cells 1319 nevus) 1339 Molecular classification of melanoma 1355
Spindled cells 1319
MELANOMA
adults, especially in patients less than 10 years of age; however, metastasis
Clinical features
rates of 36–39% and overall mortality of 10–29% after 5 years or more
Over the last several decades, the conspicuous increasing incidence of this follow-up have been documented.20,27,28 Transplacental spread with resultant
malignant neoplasm has made this disease more prominent, linked to some congenital melanoma has been documented exceptionally rarely.29
rise in morbidity and mortality.1–7 While roughly half of the major cancers Melanoma may:
in the United States showed decreasing incidence trends from 2009 to 2013, • develop within a pre-existent benign (congenital or acquired)
melanoma incidence continued to significantly increase over this period melanocytic nevus,30–36
just as it had done previously in both men and women.8,9 At present it • complicate a dysplastic nevus,
accounts for approximately 4% and 6% of all new malignancies in females • arise de novo,
and males, respectively.5 This has made melanoma the fifth and sixth most • very rarely, evolve within a cellular blue nevus or other dermal
common cancers in the United States in terms of estimated new cases in dendrocytosis (see malignant blue nevus).
2017.10 However, the number of deaths from this disease places it well Precise figures are not available, but considering that the average adult has
outside the top 10 causes of cancer-related deaths for both sexes at 9730 approximately 15–40 acquired melanocytic nevi and that the incidence of
annually.10 Mortality for this disease is still increasing in males, but has melanoma in the United States is roughly 30 per 100,000 of the population
leveled off and appears to be decreasing in females, according to present per annum, then the likelihood of any one benign acquired melanocytic
data.6 Currently, the average rate of increasing incidence is of the order of nevus undergoing malignant transformation is markedly remote.2,37 On
4–6% per year.7,11–13 The estimated number of new cases of melanoma per the other hand, at least 35% of nodular and superficial spreading melano-
year is in excess of 87,000 in the United States.6,10,14 Current projections for mas arise within a background of melanocytic nevi (congenital, acquired
non-Hispanic white individuals in the United States estimate that 1 person or dysplastic).3,30,36,38–42 Only very rarely do the more typical (small) con-
in 28 males and 1 in 44 females will ultimately develop melanoma.10,15 Men genital nevi develop melanomatous features. Giant ‘bathing-trunk’ vari-
are 1.6 times more likely to suffer from melanoma, but 2.4 times more ants, however, are a greater cause for concern, with approximately 3–18%
likely to die of the disease.10 undergoing malignant transformation.22,43–45 Lentigo maligna melanoma is
Although melanoma is seen predominantly in adults, it occasionally pre- not associated with pre-existent benign or dysplastic nevi.
sents in children.10,16–23 The latter often have an associated risk factor, such While the etiology is multifactorial, including genetic and racial factors,
as xeroderma pigmentosum, congenital bathing-trunk nevus, familial dys- by far the most important known predisposing environmental agent in the
plastic nevus syndrome or familial melanoma, and possibly immunosuppres- majority of tumors (with the exception of acral lentiginous and mucosal
sion. Pediatric melanoma accounts for 1–3% of all childhood malignancies, variants) is excessive exposure to ultraviolet (UV) light.46–49 Surprisingly, the
amounting to less than 500 cases per year in the United States.24–26 Its bio- contribution of the UV is modest, with an estimated 1.7-fold increase in
logical behavior is more variable and difficult to predict than melanoma in risk.50 Although traditionally UVB has been regarded as the causative agent,
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Clinical features 1311
more recent evidence implicates UVA, at least in some patients.51–55 This • a size of 6.0 mm diameter or greater,
association is complex and recent compelling work also stresses the impor- • irregularity of the border of the lesion, usually with scalloping,
tance of moderate, non-burning sun exposure for overall human health • irregular and variable pigmentation,
including vitamin D production and other benefits—including prevention of • asymmetry,
skin cancer.56–58 Melanin pigment protects against the effects of solar irra- • recent and rapid change in a pre-existing lesion.
diation and therefore cutaneous melanoma is rare in dark-skinned races, Irritation and bleeding are also a source of concern. The development of
except for albinos and at those sites where pigment is absent (e.g., nail beds, ulceration, which often relates to a rapidly evolving tumor, is important and
palms, soles, and mucous membranes). UV irradiation, possibly by inducing is regarded as an indication of a potentially poor prognosis. Clinical evi-
free-radical formation, results in the development of dimers between adja- dence of nodule formation by definition implies that the tumor has entered
cent pyrimidine molecules. Patients who lack the necessary endonucleases the vertical growth phase. In contrast to benign melanocytic nevi, the skin
for repairing such damage, such as those with xeroderma pigmentosum, lines are usually absent over the surface of a melanoma.
have a greatly increased risk of developing cutaneous neoplasms, including Lesions on the integument have traditionally been classified into four
melanoma.59 major clinicopathological subtypes although in the more recent literature
Melanoma is particularly common in those individuals who are the validity of such subdivision has been questioned, and classification into
most susceptible to the effects of excessive sunlight (e.g., Celts with red more genetically oriented groups may offer advantages.101–103 Gene profiling
hair, blue eyes, and fair complexions who tan poorly and tend towards and the results of other high-throughput technologies will also likely aid
sunburn and excessive freckling, i.e., skin types I and II). It is notewor- in revising our traditional classification scheme so that clinically and ther-
thy that the incidence of superficial spreading melanoma is more closely apeutically relevant subsets can be identified.104,105 An evolving molecular
related to sporadic intensive exposure to sunlight, particularly isolated classification is presented in the final section of this chapter. The currently
episodes of severe sunburn in childhood, rather than to chronic lifelong accepted subdivision is particularly based on perceived differences in prog-
exposure as with lentigo maligna melanoma.47,53,60–62 It is more common nosis and etiology and the genomic features of these groups largely bear this
in those who sporadically sunbathe than in long-term outdoor workers. out. Although any variation in biological behavior relates more to tumor
The relationship between melanoma and sunlight is further highlighted by thickness than histogenetic subtype, there are certainly histologic differences
the increasing incidence towards the equator where UV radiation is most that make the distinction possible in the majority of cases. Contrariwise, in
intense.49,63 some melanomas, it is not possible to effect a precise classification and, in
Patients who already have one melanoma have an increased risk of devel- such instances, an unqualified diagnosis of melanoma is quite sufficient. For
oping a second independent primary tumor. The reported incidence varies the moment, however, subtyping melanoma is firmly entrenched in both the
from 1% to 8% of cases, with the upper end of this range being seen in the literature and pathology dogma.106 Four major subtypes of cutaneous mela-
setting of familial melanoma.64–67 It should be noted, however, that much of noma are currently recognized:29,107–113
the literature referring to multiple melanomas does not take epidermotropic • lentigo maligna melanoma (melanoma arising within a pre-existent
metastatic disease into account and therefore the true incidence is likely to lentigo maligna),
be towards the lower figure. The incidence of other cancers is increased in • superficial spreading melanoma,
melanoma survivors as well.68 • acral lentiginous melanoma,
There is a lack of convincing evidence that pregnancy strongly influ- • nodular melanoma.
ences the outcome and prognosis of melanoma.69–71 Although earlier studies The majority of melanomas have a radial (in situ) growth phase before the
indicated that the mean thickness of pregnancy-associated tumors was sig- development of invasive tumor.114 The radial growth phase is greatest in
nificantly greater than that of nonpregnancy-associated melanomas, later lentigo maligna, of shorter duration in superficial spreading melanoma and
studies have not, and the clinical outcome parallels that of nonpregnant acral lentiginous melanoma, and, by definition, absent in nodular melanoma.
female patients of the same age and tumor characteristics, though dissenting Our understanding of melanoma has been radically transformed through
meta-analyses remain.72–84 Similarly, there is no clearly acceptable proof that research of the genomics and tumor biology of this disease. These topics
the use of oral contraceptives by females increases the risk of developing are discussed in the final section of this chapter, under the molecular clas-
melanoma.69,74,85 sification of melanoma. A number of efficacious targeted treatments are
Familial melanoma accounts for between 8% and 14% of affected available for melanoma such as those inhibiting the constitutively activated
patients.86,87 Genes that have been implicated include CDKN2A (9p21) signaling proteins produced by mutated BRAF and KIT genes. In addition,
(the majority), and very occasionally CDK4 (12q14). The former encodes the current ability to unleash the patient’s own immune system through the
p16, which normally functions to inhibit CDK4 activity.88,89 Approximately application of immune checkpoint inhibitor therapy is providing treatment
20–30% of patients with familial melanoma have germline mutations in for many patients for whom there was little to offer in the past. Such ther-
CDKN2A.86,90,91 Genetic variants in MC1R encoding the melanocortin 1 apies are transforming the treatment landscape for patients with metastatic
receptor and associated with red hair appears to increase the penetrance of disease and much research is ongoing to test such approaches in lower stage
melanoma in CDKN2A and CDK4 germline families.92,93 BAP1 germline disease with adjuvant approaches. Much research is ongoing to identify
deficits are associated with familial ocular melanoma.94–96 Researchers are which subsets of patients will benefit from immuno-oncological approaches
focusing on other predisposition genes as well, such as EBF3, though addi- and why some patients respond while others do not. Many factors includ-
tional work is needed.97 Familial melanoma patients are often younger than ing tumoral mutational load, tumor-infiltrating lymphocytes, serum lactate
those who develop sporadic melanoma and tumors are frequently multiple. dehydrogenase (LDH) levels, oncogenic signaling pathways, gut micro-
Dysplastic nevi can be present.98 biome, and immune checkpoint protein expression, to name a few, have
Melanoma shows a male preponderance (3 : 2) and males have a higher been correlated with responses. However, a full understanding of exactly
mortality.6,10,37 This probably relates at least in part to later presentation. how and why these agents work in some patients and not others has yet
Females generally have thinner tumors than males at first examination. The to emerge and our ability to predict is currently limited. Discoveries are
leg (particularly the calf) is the site of predilection in females, whereas the proceeding at an incredible rate in this area and thus are not addressed in
back is most often affected in males.37 Melanoma arising on the head and greater detail in this chapter.
neck is also more common in males than in females.37
The prognosis of melanoma is to some extent site dependent. Tumors
Lentigo maligna and lentigo maligna melanoma
arising on the BANS sites (upper back, posterior arm, posterior neck, and
posterior scalp) behave less favorably than those on the extremities.37,99 Lentigo maligna (Hutchinson melanotic freckle) is a relatively uncommon
The majority of melanomas arise de novo and as such, at least in their variant of melanoma and typically develops on chronic sun-damaged skin of
radial (in situ) growth phase, they clinically present as flat lesions. The most the elderly.115–117 In the United States, it is estimated to account for 4% of all
important signs for newly acquired potentially early melanoma include100: cases of cutaneous melanoma.118 It is characterized by a positive correlation
1312 Melanoma
Fig. 26.1 Fig. 26.3

Lentigo maligna: this variably pigmented lesion was present for many years. Lentigo maligna melanoma: this is a very advanced lesion with a multinodular
There is no invasive component. From the collection of the late N.P. Smith MD, invasive component. By courtesy of J.C. Pascual, MD, Alicante, Spain.
the Institute of Dermatology, London, UK.
Fig. 26.2 Fig. 26.4

Lentigo maligna: a dark black nodule of invasive tumor is surrounded by typical Lentigo maligna: the sun-damaged skin of the bald scalp is at risk for developing
lentigo maligna. From the collection of the late N.P. Smith MD, the Institute of this tumor. A concomitant ulcerated basal cell carcinoma is also evident above
Dermatology, London, UK. the melanoma. From the collection of the late N.P. Smith MD, the Institute of
Dermatology, London, UK.
with increasing age.119,120 Sites of predilection are the malar region, nose,
temple, and forehead; much less frequently acral sites, such as the dorsum border of the lesion is characteristic, and hypopigmented areas of regres-
of the hands, may be involved (Figs 26.1–26.5). The tumor presents most sion are also a frequent finding. Ulceration is an important diagnostic (and
often in the sixth and seventh decades as a variably pigmented, gradually prognostic) clue.
enlarging, irregular, flat macule. It may be brown or black and usually
shows areas of hypopigmentation representing areas of regression. The in
Acral lentiginous melanoma
situ lesion is often present for 10–15 years before invasive tumor develops.
Lentigo maligna melanoma is a term used to denote to lentigo maligna that Acral lentiginous melanoma accounts for approximately 8–10% of all mel-
has progressed to dermal invasion.121 anomas in Caucasians.123,124 It is, however, the predominant subtype affect-
ing Afro-Caribbeans and Asians.125–127 The tumor is particularly found on
the digits (especially beneath the nails) and on weight-bearing sites; plantar
Superficial spreading melanoma
tumors are the most common, with the heel being the most frequently
Superficial spreading melanoma is the most common variant and shows an affected region (Figs 26.7 and 26.8).128,129 Subungual variants, which most
equal sex incidence.122 The sites most frequently affected are the leg (espe- commonly affect the great toe and the thumb, are rare tumors, accounting
cially in females) and the back (particularly in males). The lesion initially for only 2% of all cutaneous melanomas. They show a female preponder-
presents as a flat scaly macule or plaque, which after a variable period of ance and present most often in the elderly.123 In addition to acral lentiginous
time develops a blue or blue-black nodule of invasive melanoma (Fig. 26.6). lesions, subungual melanoma can also present as superficial spreading and
Hypopigmented or amelanotic variants are erythematous or flesh colored. nodular histologic variants.130–132
The initial plaque is irregular, often 1–2 cm in diameter, and shows much Acral lentiginous tumors usually present as irregular, gradually enlarging,
greater variation in color than a banal or dysplastic nevus. Scalloping of the and variably pigmented macules. With progression to vertical growth phase,
Histologic features 1313
Fig. 26.5 Fig. 26.7

Lentigo maligna: close-up view. From the collection of the late N.P. Smith MD, Acral lentiginous melanoma: this variant arises on the non–sun-damaged skin of
the Institute of Dermatology, London, UK. the palms, soles, and under the nails. From the collection of the late N.P. Smith
MD, the Institute of Dermatology, London, UK.
Fig. 26.6 Fig. 26.8

Superficial spreading melanoma: there is a large nodule of invasive melanoma Acral lentiginous melanoma: this ulcerated tumor had extended deeply into the
with a surrounding macular component. From the collection of the late N.P. Smith underlying tissues. From the collection of the late N.P. Smith MD, the Institute of
MD, the Institute of Dermatology, London, UK. Dermatology, London, UK.
frequently ulcerated, blue or black nodular lesions are encountered. In Cau- for a vascular tumor, such as lobular capillary hemangioma (pyogenic gran-
casians, acral lentiginous melanoma presents most often in the seventh uloma) (Figs 26.9 and 26.10).
decade, has an equal incidence in both sexes, and is generally associated
with a poor prognosis since tumors are generally thick by the time of diag-
Melanoma arising at noncutaneous
nosis. Mucosal melanomas are often classified within the acral lentiginous
(primarily mucosal) sites
spectrum, given certain partial morphological overlap. These two types of
melanoma are distinct clinically, although genomic characterization does Melanoma may arise at a diverse range of sites other than the skin, including
indicate shared features.103,133,134 the orbit, the oral cavity and nasal cavities, the external genitalia, vagina,
urethra, and anus.137–139 In general, mucosal tumors are associated with
aggressive behavior and a poor prognosis.138,140–143 This relates particularly
Nodular melanoma
to delayed presentation. Rare sites for primary melanoma also include the
Nodular melanoma (3–4%) has no radial growth phase and therefore may meninges, esophagus, stomach, uterus, cervix, breast, biliary system, bron-
be distinguished clinically from nodules of invasive tumor that have arisen chus, and adrenal gland.
in lesions associated with a pre-existent radial growth phase.135 It has a poor
prognosis (the majority being thick tumors by the time of excision), affects
Histologic features
more males than females (2 : 1), and generally arises in the fifth or sixth
decade.136 The trunk and limbs are most commonly involved. The tumor, Central to our understanding of the histologic classification of cutaneous
which may be nodular or polypoid (polypoid melanoma), is often ulcerated melanoma is the concept of radial (horizontal) growth phase and verti-
and, when lacking pigment (amelanotic melanoma), is frequently mistaken cal (invasive) growth phase.33,108,114,144,145 By current definition, the radial
1314 Melanoma
Fig. 26.9 Fig. 26.11

Nodular melanoma: this heavily pigmented, dome-shaped nodule has no adjacent Melanoma: radial growth phase. The tumor is wholly intraepidermal (in situ
macular component. From the collection of the late N.P. Smith MD, the Institute melanoma). Intraepidermal tumor cells at all levels are present (pagetoid spread).
of Dermatology, London, UK.
Fig. 26.10 Fig. 26.12

Nodular melanoma: amelanotic tumors as shown here are often a source of Melanoma: microinvasive
clinical (and histological) diagnostic difficulty. From the collection of the late N.P. radial growth phase. In
Smith MD, the Institute of Dermatology, London, UK. addition to in situ tumor,
small numbers of single
tumor cells are present in
growth phase may include (in addition to a wholly in situ, intraepidermal the papillary dermis.
component) evidence of microinvasion into the papillary dermis (microinva-
sive radial growth phase), often accompanied by features of regression (Figs phase (Fig. 26.14).33,145,151 Mitotic figures are common.33 Features of regres-
26.11 and 26.12). The microinvasive stage of melanoma is believed to lack sion may be seen but are usually absent at the base of the tumor. The tumor
significant metastatic potential and as a consequence is associated with an cells in the vertical growth phase are pleomorphic and apoptosis is often
excellent prognosis.146–149 Indeed, in a large series of patients discussed by present. Vertical growth phase implies an alteration in biological potential
Clark and coworkers, no tumors in the radial growth phase were associated with a capacity for lymphovascular invasion and metastatic spread.33,145,146
with metastatic spread.109 A subset of melanocytic tumors can be challenging to definitively assess
Histologically, the microinvasive radial growth phase tumor is charac- as either benign or malignant and are described under various names to
terized by single cells or small aggregates of melanoma cells, histologically indicate their uncertain malignant potential. Such cases often have some,
similar to their intraepidermal counterparts and invariably forming tumor but not all or fully developed features of the malignant phenotype histo-
nests smaller than those present within the overlying epidermis.33 A lym- logically. Experts often disagree on the designation of malignancy in this
phohistiocytic infiltrate is usually present. Mitotic figures are absent by defi- group of exceedingly challenging lesions.152–155 Multi-probe fluorescence in
nition. The last feature is of particular importance; multiple levels should situ hybridization (FISH) and genomic hybridization can assist diagnosti-
therefore be carefully examined before making a diagnosis of microinvasive cally, but in some cases the biological potential of these equivocal lesions
radial growth phase melanoma (Fig. 26.13).150 remains uncertain.156 Proposals have suggested that in such cases, group-
Vertical growth phase melanoma is composed of cohesive nests, nodules, ing the lesions into classes linked to the type or extent of excision needed
or plaques larger than those present within the epidermis and consisting of increases agreement and aids in communication of the clinical care needed
tumor cells that are cytologically different from those in the radial growth despite the uncertainty in the diagnosis.157
Fig. 26.13
(A, B) Melanoma: lentigo maligna melanoma. This tumor was incorrectly
diagnosed as a microinvasive radial growth phase lesion on the grounds
that only single cells were present in the dermis and there were no nests.
A Dermal mitoses were, however, present (B). The patient developed cerebral
metastases.
Fig. 26.14 Fig. 26.15

Melanoma: vertical Lentigo maligna: the epidermis is atrophic and flattened. Atypical melanocytes are
growth phase. In addition basally located and the superficial dermis shows marked solar elastosis.
to in situ (radial growth
phase) tumor, there are
multiple nests in the tumor thickness, particularly if obliquely cut sections are examined, when
dermis. These are larger the relationship of the tumor cells to the adnexal epithelium may not be
than the epidermal ones.
clear. In more advanced lesions, junctional nests are apparent and multinu-
cleate tumor giant cells are commonly seen (Figs 26.18–26.20). Pigmentation
is variable, but is often abundant, sometimes involving the full thickness of
Lentigo maligna and lentigo maligna melanoma
the epidermis, including the stratum corneum. The very occasional presence
Lentigo maligna is characterized by proliferation of atypical melanocytes of marked intraepidermal (pagetoid) spread may result in histologic overlap
predominantly located along the dermal–epidermal junction (Figs 26.15 with superficial spreading melanoma, though junctional nesting is usually
and 26.16).158 Chronic sun damage evidenced as extensive solar elastosis is less prominent in lentigo maligna. Assessing excision margins for residual
often prominent, particularly in cases from the head and neck region.159 The atypical melanocytes in this variant is often fraught with difficulty. To avoid
tumor cells often show a conspicuous cytoplasmic fixation retraction arti- unnecessary surgery it is important not to confuse actinically damaged nuclei
fact and contain pleomorphic irregular hyperchromatic, sometimes angular, from residual lentigo maligna (Fig. 26.21), though molecular studies suggest
nuclei. The cells are frequently orientated perpendicular to the surface, and that this may not be possible on strictly morphological grounds given the
involvement of hair follicles and sweat duct epithelium is a characteristic field effect of genomic aberration present in even morphologically normal
finding (Fig. 26.17). This may sometimes result in difficulties in assessing melanocytes.160 This likely underlies the elevated risk of local recurrence in
1316 Melanoma
A B
Fig. 26.16
Lentigo maligna: (A) viewed with higher power, the melanocytes demonstrate a prominent fixation artifact. The nuclei are irregular, angular, and hyperchromatic; (B) in
this example, the tumor cells have abundant eosinophilic cytoplasm and there is early pagetoid spread.
Fig. 26.17 Fig. 26.18

Lentigo maligna: note
Lentigo maligna: in this example there are conspicuous junctional nests. The
the presence of atypical
tumor cells have a spindled morphology.
melanocytes within the
outer aspect of a hair
follicle. Shave biopsy
of such lesions is
accompanied by a high
recurrence rate.
these lesions. Evaluation of the extent of epidermal involvement in difficult

cases or small samples can be done by immunohistochemistry ideally with
markers that highlight nuclei including MITF and SOX10.
Lentigo maligna arises at sites showing actinic damage; the epidermis is
therefore typically atrophic and the dermis shows solar elastosis. Usually the
papillary dermis contains melanophages and scattered chronic inflammatory
cells. The finding of the latter, particularly when present in large numbers,
is often associated with invasion and should therefore prompt careful exam-
ination of multiple levels of the specimen. Invasive tumor (lentigo maligna
melanoma) can be multifocal and is usually of the spindled cell type (Figs
26.22–26.24). Due to the extensive involvement of neighboring hair follicles
and cross-sectioning, determining the presence or absence of early invasion
can be very challenging and occasionally, impossible. Desmoplasia, often
with neurotropism, is present in a significant percentage of cases. Very occa- Fig. 26.19
sionally, a storiform growth pattern is evident and if the tumor is amelanotic Lentigo maligna: the tumor cells are pleomorphic and show very marked nuclear
there may be confusion with dermatofibrosarcoma protuberans, particularly hyperchromatism.
Fig. 26.20
Lentigo maligna: multinucleate tumor cells as shown in this example are a
common feature and a useful diagnostic clue. Fig. 26.22
Lentigo maligna
melanoma: in this variant
of melanoma, the invasive
component is often of the
spindle cell type.
Fig. 26.21
Actinic nuclear atypia: sometimes distinguishing between the former and residual
tumor cells as shown in this field can be a real problem. The former, however,
show little nuclear enlargement and nucleoli are absent. In addition, such cells do
not form nuclear palisades as is typical of lentigo maligna.
in small biopsies (Fig. 26.25). More often, the associated melanoma is des-
moplastic with subtle spindle cells and can be mistaken for fibrosis or scar
rather than invasive tumor. Fig. 26.23
Exceptionally, lentigo maligna and lentigo maligna melanoma present Lentigo maligna
as amelanotic lesions (amelanotic lentigo maligna and amelanotic lentigo melanoma: higher-power
maligna melanoma), both clinically and histologically.161–164 Clinically, these view.
appear as erythematous scaly lesions resembling actinic keratoses, squamous
cell carcinoma in situ or eczema.162 Immunocytochemistry may therefore be
necessary to arrive at the correct diagnosis (Fig. 26.26).165 of the epithelium while the cells of Paget disease tend to be superficial
to the basal cell layer. The individual cells are epithelioid with abundant
cytoplasm, often showing fine or dusty melanin pigmentation, and contain
Superficial spreading melanoma (pagetoid melanoma)
pleomorphic vesicular nuclei with prominent eosinophilic nucleoli; scattered
The radial growth phase of superficial spreading melanoma is now encoun- mitotic figures including atypical forms may be evident. Characteristic of
tered more commonly, largely as a consequence of public awareness of mel- this variant is tumor growth in continuity from one rete ridge to another
anoma with the consequent removal of an increasing percentage of thin (a pattern not usually seen in acquired junctional or compound nevi). In
early lesions. It is typified by an asymmetrical proliferation of atypical non- contrast to lentigo maligna, there is often minimal visible evidence of actinic
dendritic melanocytes scattered singly and in clusters throughout all levels damage.159 The epidermis often shows acanthosis with partial or complete
of the epithelium (buckshot scatter), giving an appearance reminiscent of effacement of the ridge pattern. Invasive tumor is mostly of the epithelioid
Paget disease (Figs 26.27 and 26.28). The melanoma cells involve all layers type (Figs 26.29–26.32). Desmoplasia and/or neurotropism are uncommon.
1318 Melanoma
Fig. 26.24 Fig. 26.27

Lentigo maligna melanoma: in this example, mitotic figures are conspicuous. Note Superficial spreading melanoma: there is prominent junctional activity and atypical
the nuclear hyperchromatism. melanocytes are widely scattered throughout the epidermis.
Fig. 26.25
Lentigo maligna melanoma: occasionally the tumor adopts a storiform pattern.
Fig. 26.28
When amelanotic, this may be confused with dermatofibrosarcoma protuberans
Superficial spreading melanoma: the melanocytes have abundant eosinophilic
or spindle cell squamous carcinoma.
cytoplasm and pleomorphic vesicular nuclei. Nucleoli are conspicuous.
Acral lentiginous melanoma

In the early stages of the radial growth phase of acral lentiginous mela-
noma the changes may be quite subtle, consisting of irregular epidermal
hyperplasia and scattered, basally located, atypical melanocytes.166–170 The
established lesion shows acanthosis with marked elongation of the epider-
mal ridges and obvious melanocytic atypia (Figs 26.33 and 26.34). The
lower reaches of the epidermis are infiltrated by large numbers of atypical
melanocytes characterized by nuclear pleomorphism and hyperchromatism,
and showing a cytoplasmic fixation retraction artifact. Nucleoli are con-
spicuous and mitotic figures may be identified. Although spindled forms are
most often encountered, epithelioid and giant cells are sometimes evident.
Scattered foci of junctional nests may also be detected, usually at the tips of
the epidermal ridges (Fig. 26.35). A heavy bandlike chronic inflammatory
cell infiltrate is frequently present. The invasive tumor is often a spindled
cell in type and may elicit a desmoplastic reaction (Fig. 26.36). Deep exten-
sion along the sweat gland epithelium is common and neurotropism may be
Fig. 26.26 evident in a subset of cases. Cross-sectioning of involved sweat glands may
Lentigo maligna: occasionally it is difficult to distinguish between actinic keratosis lead to the erroneous interpretation of invasion. Occasionally, acral tumors
and lentigo maligna. In such cases, immunohistochemistry using a red chromogen may show a superficial spreading in situ component or represent de novo
(in this case alkaline phosphatase) can make the distinction easy. nodular melanoma with absent radial growth phase.
Cell types 1319
Fig. 26.29
Superficial spreading Fig. 26.31
melanoma: invasive Superficial spreading melanoma: diagnosis of amelanotic tumors, particularly when
tumor is usually of the very pleomorphic as in this example, often depends upon immunohistochemistry
epithelioid type as shown if a junctional component is not evident.
in this field. Note the
abundant cytoplasm,
nuclear pleomorphism,
and prominent nucleoli.
Fig. 26.32
Superficial spreading melanoma: this example shows a mitotic figure in the center
of the field.
Fig. 26.30
Superficial spreading melanoma: in this example there is heavy melanin Epithelioid cells
pigmentation.
Epithelioid melanoma cells are large and rounded with abundant, often
eosinophilic, cytoplasm and contain prominent pleomorphic vesicular nuclei
Nodular melanoma
with conspicuous eosinophilic nucleoli. Mitotic figures may be either scant
By definition, nodular melanoma has no evident preceding radial growth or numerous and sometimes abnormal. Pigmentation is variable and can
phase, its growth pattern appearing vertical from inception. Such a tumor, be abundant or minimal. When minimal, Masson-Fontana silver staining is
therefore, does not show an intraepidermal melanocytic proliferation useful to reveal small quantities of pigment not detectable with conventional
beyond three epidermal ridges on either side of the tumor mass (Figs 26.37 hematoxylin and eosin stained sections. Alternatively, immunohistochemis-
and 26.38). This histologic pattern is usually, but not always, seen in the try may be necessary to establish the diagnosis (Fig. 26.39).
same anatomic distribution as superficial spreading melanoma; these have
overlapping genomic features, but some regard them as distinct entities.135
Spindled cells
The spindled cell variant is characterized by cells with elongated, narrow,
Cell types
tapering, cytoplasmic processes, which in nonpigmented variants may be
Although many invasive tumors show a mixed pattern, melanoma cells are confused with cells of mesenchymal derivation and therefore misdiagnosed
typically divided into two major types: epithelioid and spindled cell. Epi- as a variety of soft tissue neoplasms.
thelioid cells most often arise within superficial spreading melanoma and Occasional melanomas are exceedingly pleomorphic, containing tumor
nodular melanoma, while spindled cells are more commonly seen in lentigo giant cells with enlarged nucleoli and conspicuous, frequently abnor-
maligna melanoma and acral lentiginous melanoma. mal, mitotic figures; these variants must sometimes be distinguished from
1320 Melanoma
metastatic tumors, including pleomorphic secondary carcinoma, sarco- resultant death, in the hope that adjuvant chemotherapy, immunotherapy,
mas, and even anaplastic CD30+ anaplastic large cell lymphoma (Figs or other forms of treatment might eventually benefit significant numbers
26.40–26.42). of patients. Prognostic indicators include clinical parameters, morpholog-
ical observations, and measurements in addition to immunohistochemical
markers of cell proliferation, cell regulation, and so on. Many of the mor-
Prognostic indicators
phological observations are tried and tested, but the search for the elusive
While the vast majority of thin melanomas do not metastasize, between immunohistochemical marker of metastatic potential has not yet been fruit-
1% and 2% are known to do so. Conversely, occasional thick melanomas ful. Genomic biomarkers are also being explored, in particular limited gene
fail to disseminate. With this in mind, there has been intensive research expression panels.171–173
in an effort to define those tumors that have the capacity for spread with Clinical prognostic indicators include age, sex, and site of the primary
tumor.174–180 Older patients fare worse than younger ones, and males have a
poorer outlook than females.7,176,177,181–184 The latter is independent of tumor
thickness and site.176 Particularly high-risk sites include the back, upper arm,
neck, and scalp (BANS).185 The acral sites are also thought to be associated
with a poorer prognosis.186
When reporting melanoma, it is generally accepted as essential world-
wide to record and comment on the following variables:176,187–193
• tumor thickness (Breslow method),
• level of invasion (Clark method),
• growth phase (vertical or radial),
• mitotic rate,
• ulceration,
• lymphovascular invasion,
• perineural infiltration,
• regression,
• microsatellitosis,
• tumor infiltrating lymphocytes.
Growth phase is also noted although it should be emphasized that great care
must be taken before allocating a melanoma to the microinvasive category
of radial (horizontal) growth phase. Dermal mitoses automatically place a
Fig. 26.33 tumor in the vertical growth phase (see Fig. 26.14). These elements have
Acral lentiginous melanoma: in this in situ lesion, there is irregular acanthosis, become critical for proper staging and prognostic assignment of patients,
hypergranulosis, and hyperkeratosis. Tumor cells are hyperchromatic and but unfortunately even in countries with a high incidence and acute aware-
distributed in a lentiginous and nested pattern. The dermis is scarred and there ness of cutaneous melanoma, many of the above elements are absent from
are conspicuous melanophages and chronic inflammatory cells. routine reports.194
A B
Fig. 26.34 Fig. 26.35

Acral lentiginous melanoma: there is conspicuous (A, B) Acral lentiginous melanoma: large junctional nests are present at the tips of the rete.
cytoplasmic retraction, hyperchromatism, and
nuclear atypia.
Prognostic indicators 1321
Fig. 26.36 Fig. 26.38

Acral lentiginous melanoma: in this example, the invasive component is mixed Nodular melanoma: by definition, there is no melanocytic proliferative activity in
epithelioid, spindled cell, and desmoplastic. the adjacent epidermis.
Fig. 26.37
Nodular melanoma: this
variant is typically sharply
circumscribed.
Breslow tumor thickness is the single most important single prognos-

tic indicator for primary cutaneous melanoma.195,196 It is measured from
the most superficial aspect of the granular cell layer to the deepest point
of invasion of the tumor. In ulcerated tumors, the measurement should
be from the base of the ulcer. The significance of periadnexal extension is
less clear. If the latter is greater than the conventional Breslow thickness,
the information should also be documented in addition to the traditional
Breslow measurement (Fig. 26.43). Polypoid tumors should be treated no
differently, and should be measured through the thickest region.197 Tumor
B
volume, therefore, is a most important factor influencing outcome in ver-
tical growth phase melanoma. Careful evaluation of the greatest tumor
Fig. 26.39
thickness provides very useful prognostic guidance.198–201 In the latest (8th) Amelanotic melanoma: (A) the tumor cells are very pleomorphic with large
edition of the American Joint Committee on Cancer (AJCC) staging system vesicular nuclei and prominent nucleoli; (B) there is diffuse S100 expression.
(2017, effective in 2018), the thickness thresholds have been maintained as MART-1 was also positive. It is always of value to use at least two markers
in the 7th Edition at 1.0, 2.0, and 4.0 mm, though the T1 group is subdi- for melanoma as very occasionally S100 protein negative variants may be
vided 0.8 mm as well (Table 26.1).196,202–206 The 7th edition staging is still encountered.
1322 Melanoma
Fig. 26.40 Fig. 26.43

Giant cell melanoma: within the dermis is a deposit of metastatic melanoma. Melanoma: periadnexal extension is of uncertain biological significance except
that it is a potential source for recurrence of inadequately excised tumors. In this
example, there is deep involvement of the eccrine sweat glands.
Major changes and clarifications of the 2017 AJCC melanoma

staging system
• Database completely derived from patients of known sentinel lymph

node status thus creating more homogeneous stage groups
• T0 designates no evidence of primary tumor; Tis designates in situ
disease; TX designates tumor thickness that cannot be determined
• T categories maintained, but T1 with new 0.8 mm threshold
• Tumor thickness now reported only to nearest 0.1 mm
• Mitoses in primary tumor are recorded for prognosis, but no longer
used for staging
• Clark level no longer used for staging primary
• For regional lymph node involvement, “microscopic” is now termed
“clinically occult” and “macroscopic” termed “clinically detected” for
clarity
• Sentinel lymph node is disease burden is prognostic and thus to be
recorded, but not currently used for staging
• N category now has 4 subgroups rather than three
• Status of the primary (Breslow thickness and ulceration) extensively
Fig. 26.41 modifies stage III groupings
Giant cell melanoma: the tumor cells are multinucleate and very pleomorphic with • In transit, satellite and microsatellite metastases are now categorized
abundant cytoplasm and large vesicular nuclei containing prominent eosinophilic as N1c, N2c, N3c based on how many other regional nodes are
nucleoli. involved (if any)
• Given the rapidly evolving systemic therapy landscape, Stage IV is no
longer subdivided; metastatic site designation and LDH elevation are
used solely to define clinically relevant patient groupings
provided here for purposes of comparison (Table 26.2). A pleasant feature

of the new staging system is that Breslow thickness is now only reported to
one significant digit after the decimal point, simplifying measurement with
the micrometer. While certainly not perfect, clinical and particularly micro-
pathological staging in melanoma is exceedingly powerful and serves as a
model for other cancers.
The level of tumor invasion when classified according to Clark levels is
as follows:
• Level I: in situ melanoma,
• Level II: invasion of the papillary dermis by single cells or small nests,
• Level III: invasive tumor usually as an expansile nodule abutting on the
reticular dermal interface,
• Level IV: invasion of the reticular dermis,
• Level V: invasion of the subcutaneous fat.
The dermal interface may be identified by the site of the superficial capillary
Fig. 26.42 plexus. It also corresponds to the zone of transformation of the horizontally
Giant cell melanoma: the tumor cells are HMB-45 positive. The patient had a orientated reticular dermis elastic fibers to the vertically aligned ones of the
melanoma excised several years earlier. papillary dermis. The distinction between Clark level II and III and perhaps
Table 26.1
AJCC 2017 (8th Edition) revised melanoma pathological staging system (effective, January 2018)
Disease specific survival1

Stage group Histological features/TNM designation 5 years (%) 10 years (%)
0 Intraepithelial/in situ melanoma2 (TisN0M0) 100 100
IA <0.8 mm primary without ulceration (T1aN0M0)
3
99 98
<0.8 mm primary with ulceration (T1bN0M0) 99 98
0.8-1.0 mm primary without ulceration (T1bN0M0) 99 96
IB > 1.0-2.0 mm primary without ulceration (T2aN0M0) 97 94
IIA > 1.0–2 mm primary without ulceration (T2bN0M0) 94 88
2.0–4.0 mm primary without ulceration (T3aN0M0) 93 88
94 88
IIB 2.0–4.0 mm with ulceration (T3bN0M0) 87 82
> 4 mm without ulceration (T4aN0M0) 86 81
90 83
IIC > 4 mm with ulceration (T4bN0M0) 82 75
IIIA Single regional node, clinically occult4 (T1–2aN1aM0) 93 88
2–3 regional nodes, clinically occult (T1–2aN2aM0)
IIIB Single regional node, clinically detected5 (T1–T3aN1bM0) 83 77
No regional node, in-transit / satellite disease (T1-2aN1cM0)
2–3 regional nodes, at least 1clinically detected (T1–2aN2bM0)
Single regional node, clinically occult (T2b–3aN1aM0)
Single regional node, clinically detected (T2b–T3aN1bM0)
No regional node, in-transit / satellite disease (T2b-3aN1cM0)
2–3 regional nodes, clinically occult (T2b–3aN2aM0)
2–3 regional nodes, at least 1clinically detected (T2b–3aN2bM0)
No evidence of primary tumor (T0N1b-1cM0)
IIIC Single regional node, occult or clinically detected; +/- in-transit / satellite disease (T1a-3aN2cM0) 69 60
4 or more regional nodes, clinically occult (T1a-3aN3aM0)
4 or more regional nodes, at least 1 clinically detected (T1a-3aN3bM0)
2 or more regional nodes clinically occult or detected and/or matted nodes; 2+ regional nodes
+/- in-transit / satellite disease (T1a-3aN3cM0)
Any regional node status greater than N1 (T3b-4aN2a-3cM0)
Any regional node status less than N3 (T4bN1a-2cM0)
No evidence of primary tumor (T0N2b-2c,3b-3cM0)
IIID Any N3 (T4bN3a-3cM0) 32 24
IV Distant metastasis (T1a-4bN1a-3cM1)
M1a = distant metastasis to skin, soft tissue or nonregional node
M1b = distant metastasis to lung +/- M1a site(s)
M1c = distant metastasis to viscera (non-CNS) +/- M1a or M1b site(s)
M1d = distant metastasis to CNS +/- M1a, M1b or M1c site(s)
(0) = LDH normal / not elevated
(1) = LDH elevated
1
Five and 10 year disease specific survival provided for overall stage groups as well as individually definied cohorts that comprise the stage group where available.
2
The underlined portion of the TNM designation is defined by the histologic features for each group.
3
Breslow thickness is defined as the thickness of the lesion using an ocular micrometer to measure the total vertical height of the melanoma from the top of the granular layer
to the area of deepest penetration (and reported to the nearest 0.1 mm). If the entire overlying epithelial surface is ulcerated, measure from the base of the ulcer to the depthest
point of invasion.
4
Clinically occult (previously termed microscopic) metastasis is defined as following pathologic assessment of sentinel lymph node and/or lymphadenectomy specimen. There
is no minimum size lesion for metastasis. Immunohistochemistry can be used to screen for micrometastases, but should include at least one ‘melanoma-specific’ marker (i.e.,
HMB-45, MART1, MelanA).
5
Clinically detected (previously termed macroscopic) metastasis is clinically evident nodal disease known prior to pathologic examination.
Adapted from AJCC Cancer Staging Manual, 8th Edition (2017) Eds: Amin MB, et al. Melanoma of the Skin, pp.563–585. Springer-Verlag, New York. © and Gershenwald, J. E.,
Scolyer, R. A. Hess, K. R., et al. (2017) Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer
J Clin, 67;472–492.
more so between III and IV is somewhat difficult to apply in practice and is defined as ‘the absence of an intact epidermis overlying a major portion of
is observer dependent.207 Clark level was believed to provide independent the primary melanoma based on microscopic examination of the histologic
prognostic information for thin tumors (1.0 mm or less in thickness) but sections’.203 Trauma and artifactual loss of the epidermis must be excluded.
not for thicker melanomas.208,209 The latest data indicate that if mitotic Ulceration is associated with a very significant increased risk of metastasis
rate is assessable in thin melanomas, then Clark level no longer provides and was first included as a second determinant in the T classification in the
additional prognostic information. The 2017 (8th) AJCC staging system no AJCC 6th Edition and retained in the current 8th Edition.196,203,206,208,209,212
longer recommends the use of the Clark level, even for thin melanomas, as Tumor-infiltrating lymphocytes are an important independent prog-
in the previous edition.196,203,204,206 Mitotic rate in the primary melanoma nostic variable and should be recorded as brisk, nonbrisk, or absent (Figs
correlates with sentinel lymph node positivity for metastasis.210 26.44–26.46).145,206,213–215 The brisk category implies lymphocytes present
The presence or absence of ulceration and the width of the ulcer are throughout the whole vertical growth phase or extending across its entire
independent prognostic indicators and should be recorded.175,211 Ulceration base. Nonbrisk tumor infiltrating lymphocytes implies focal infiltration
1324 Melanoma
Table 26.2
AJCC 7th Edition Staging – For historical comparison only, no longer in clinical use
Overall survival
Stage Histological features/TNM classification 1 year (%) 5 years (%) 10 years (%)
0 Intraepithelial/in situ melanoma (TisN0M0) 100 100
IA ≤ 1 mm without ulceration and mitoses <1/mm * (T1aN0M0) 2
97 93
IB ≤ 1 mm with ulceration or level IV/V (T1bN0M0) 94 87
1.01–2 mm without ulceration (T2aN0M0) 91 83
IIA 1.01–2 mm with ulceration (T2bN0M0) 82 67
2.01–4 mm without ulceration (T3aN0M0) 79 66
IIB 2.01–4 mm with ulceration (T3bN0M0) 68 55
> 4 mm without ulceration (T4aN0M0) 71 57
IIC > 4 mm with ulceration (T4bN0M0) 53 39
IIIA Single regional nodal micrometastasis**, nonulcerated primary (T1–4aN1aM0) 78 68
2–3 microscopic regional nodes, nonulcerated primary (T1–4aN2aM0)
IIIB Single regional nodal micrometastasis, ulcerated primary (T1–4bN1aM0) 59 43
2–3 microscopic regional nodes, ulcerated primary (T1–4bN2aM0)
Single regional nodal macrometastasis***, nonulcerated primary (T1–4aN1bM0)
2–3 macroscopic regional nodes, nonulcerated primary (T1–4aN2bM0)
In-transit metastasis(es)/satellite lesion(s) without metastatic lymph nodes (T1–4a/bN2cM0)
IIIC Single microscopic regional node, ulcerated primary (T1–4bN1bM0) 40 24
2–3 macroscopic regional nodes, ulcerated primary (T1–4bN2bM0)
In-transit metastasis(es)/satellite lesion(s) without metastatic lymph nodes, ulcerated
primary(T1–4bN2cM0)
4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit metastasis(es)/
satellite(s) and metastatic nodes (anyTN3M0)
IV Distant skin, subcutaneous, or nodal metastasis with normal LDH (any T any NM1a) 62
Lung metastasis with normal LDH (any T any NM1b) 53
All other visceral metastasis with normal LDH or any distant metastasis with increased LDH(any T any 33
NM1c)
Breslow thickness is defined as the thickness of the lesion using an ocular micrometer to measure the total vertical height of the melanoma from the top of the granular layer to
the area of deepest penetration. The Clark level refers to levels of invasion according to depth of penetration of the dermis.
*Clark level is now only used when mitotic rate is not available in a T1 tumor. Level IV or V invasion would meet criterion for T1b.
**Micrometastases are defined as following pathological assessment of sentinel lymph node and/or lymphadenectomy specimen. There is no longer a minimum size lesion for
metastasis. Immunohistochemistry may be used to screen for micrometastases, but must include at least one ‘melanoma-specific’ marker (i.e., HMB-45, MART1, MelanA).
***Macrometastasis is clinically detectable with pathological confirmation or gross extracapsular extension on pathological examination.Adapted with permission from AJCC
Cancer Staging Manual, 7th Edition (2009) Eds: Edge SB, et al. Melanoma of the Skin, pp.325–344. Springer-Verlag, New York. © and Balch, C. M., Gershenwald, J. E., Soong, S.
J. et al. (2009) Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol, 27; 6199–6206.
A B
Fig. 26.44
(A, B) Melanoma: tumor infiltrating lymphocytes. Category A – Brisk: the lymphocytes infiltrate the tumor and extend along the whole of the base of the lesion.
only. Absent includes two categories: either no lymphocytes at all or lym- 27%, respectively.214 Recently, it has been suggested that tumor-infiltrating
phocytes are present but do not infiltrate the melanoma. Brisk lymphocytic lymphocytes are influenced by sex and sentinel lymph node status only
responses tend to be a feature of thin melanomas whereas absence of a correlated in men and not in women.216 Not surprisingly, the absence of
lymphocytic response is generally seen in thick melanomas.200,214 In a study tumor-infiltrating lymphocytes also correlated with metastasis to senti-
of 285 vertical growth phase tumors, the 10-year survival rates for brisk, nel lymph nodes as a surrogate marker of melanoma risk in a cohort of
nonbrisk, and absent tumor-infiltrating lymphocytes were 55%, 45%, and 887 patients with full multivariate analysis.215 Image analysis and feature
A A
B B
Fig. 26.45 Fig. 26.47

(A, B) Melanoma: tumor infiltrating lymphocytes. Category B – Nonbrisk: the (A, B) Regression: no residual epidermal component is present. Note the
lymphocytes infiltrate only part of the tumor. lymphocytic infiltrate, plasma cells, abundant melanin-containing macrophages,
scarring, and conspicuous vasculature.
extraction have been used to assess tumor-infiltrating lymphocytes with

salutary results.217 Assessing tumor-infiltrating lymphocytes in lymph node
metastases also has predictive value.218,219
In thin melanoma it is important to recognize the features of regression,
which may be particularly evident in the dermal component (Figs 26.47 and
26.48).145,220 These include absence or reduced numbers of malignant mela-
nocytes, degenerate (apoptotic) forms, and a chronic inflammatory cell infil-
trate (Fig. 26.49).221–223 Melanophages, horizontal scarring, isolated tumor
islands, and telangiectatic vessels are also commonly present in the later
stage. Clinically, regression presents as macular gray, white, or pink areas.
Although the importance of regression as a determinant of biological
behavior has been the subject of considerable argument in the literature,
a number of authors believe that, in thin tumors, it correlates with an
impaired prognosis, though this contribution may be minor relative to other
factors in many cases.223–232 Complete regression of an undiagnosed primary
melanoma may be the explanation for patients presenting with metastatic
tumor of unknown primary (Fig. 26.50).233 Some authors recommend senti-
nel node biopsy for thin melanomas if there is evidence of extensive (> 50%)
Fig. 26.46 regression, while other series do not show an association between regression
Melanoma: tumor and nodal status.176,234
infiltrating lymphocytes.
Mitotic rate is determined by the number of mitotic figures/1 mm2 of
Category C – Absent:
lymphocytes are present
tumor in the most mitotically active area. It has become clear that tumors
but they do not invade displaying a high mitotic rate are associated with a poorer prognosis and
the tumor. The category that mitoses are a more robust predictor of outcome than ulceration and thus
also includes complete mitotic rate was incorporated into the 7th AJCC staging system.145,204,235–240
absence of lymphocytes. While mitoses are still recognized as a prognostic factor, the current 8th
1326 Melanoma
AJCC staging system relies on ulceration rather than mitoses due to stage number of studies.215,248–253 The use of immunohistochemistry for D2-40 sig-
group stability.196,206 Despite earlier contrary evidence and the complex nificantly increases the sensitivity for detection of lymphatic invasion and
interrelations of tumor thickness, ulceration, and mitotic rate, mitotic rate also correlates with lymph node metastasis and survival.254–257 More study
appears to carry prognostic information independent of both of the other and a prospective trial is needed to validate the application and interpreta-
factors.176,241,242 tion of the technique. Contrariwise, absence of vascular involvement in thick
The presence of a microscopic satellite is defined by a distinct tumor melanomas correlates with increased survival in a number of studies.258,259
nodule of any size at any distance discontinuous from the main primary Perineural and intraneural infiltration are most often encountered in desmo-
tumor mass separated by normal tissue (no scarring, fibrosis or extensive plastic variants, thereby accounting, in part, for the increased risk of local
inflammation).206 It is found in thicker tumors and is associated with an recurrence (Fig. 26.52). In this context, CD57 immunohistochemistry can
increased risk of local recurrence, regional lymph node metastases, and be helpful in identifying residual nerve (Fig. 26.53).
diminished survival.243–246 The presence of microsatellites results in upstag- Angiogenesis, which is defined as the increasing development of new
ing to N1c if there is no regional lymph node involvement, and upstaging to blood vessels at the base of the melanoma, parallels increases in tumor
N2c or N3c with one or more than one lymph nodes involved, respectively,
in the 2017 AJCC melanoma staging system.206
The presence of lymphatic invasion correlates with the development
of in-transit metastases (Fig. 26.51).247 Lymphovascular invasion has been
shown to represent a predictor of diminished survival in melanoma in a
Fig. 26.49
Regression: in this
example, there is
Fig. 26.48 conspicuous apoptosis.
Partial regression: in this variant, the junctional component is still present. Its Note the eosinophilic
significance is less certain. bodies.
Fig. 26.50
(A, B) Regression: in this example, there is no residual tumor. The dermis is
scarred and there is abundant melanin pigment. The patient presented with an
A unknown primary. By courtesy of M. Forder, MD, St Anne’s Medical Center,
Pietermaritzburg, South Africa.
Differential diagnosis 1327
Fig. 26.53
Melanoma: CD57 immunohistochemistry may be particularly valuable when tumor
growth has largely destroyed the nerve.
thickness.260–265 Increasing angiogenesis therefore correlates with thick

tumors, ulceration, relapse, and tumor-associated death.263,266 Perhaps related
to the likelihood of lymphovascular invasion, increased intratumoral and
peritumoral lymphangiogenesis as measured by D2-40 or VEGF-C also cor-
relates with metastasis to sentinel lymph nodes and reduced disease-specific
survival.267,268
Sentinel node biopsy also adds extremely valuable prognostic informa-
tion.269–273 It has been shown to represent the most important factor in
determining likelihood of tumor recurrence and patient survival in stage I
and stage II disease.270 Completion lymph node dissection for positive sen-
tinel lymph nodes is expected to become less common with the MSLT-II
trial failing to show a survival benefit of the completion procedure.274,275
B The latest AJCC staging system requires incorporation of sentinel lymph
node data in cases where it would inform management, as this procedure
Fig. 26.51 significantly increases the accuracy and discriminatory power of the stage
Melanoma: vascular invasion: (A) pleomorphic tumor cells are adherent to the groups.204,206 Lymph nodes are bivalved or serially sectioned along their long
endothelium; (B) tumor cells are growing into the lumen. axis and in addition to the examination of hematoxylin and eosin stained
sections, immunohistochemistry – such as S100 protein, HMB-45, and/or
MART-1 (melanoma antigen recognized by T cells 1) – should invariably be
performed in those cases where the initial sections are negative. Detection of
single or tiny groups of cells using an antibody against a ‘melanoma-specific’
antigen such as HMB-45 or MART1 is now incorporated into the AJCC
staging system. More recently, molecular techniques including reverse tran-
scriptase polymerase chain reaction for tyrosinase messenger RNA have
been proposed.276,277 A major disadvantage of such procedures is the likeli-
hood of false-positive results due to the common presence of banal capsular
nevi, though the use of markers more specific to melanoma over nevus cells
could potentially alleviate this problem.278
Sentinel node biopsy is currently recommended for all tumors measur-
ing 1.00 mm or more in thickness. Other possible indications include ulcer-
ated tumors, tumors with 50% or more regression, tumors having achieved
the vertical growth phase, and those lesions which have been biopsied and
involve the deep margin.176,272,279,280 The procedure should also be consid-
ered for tumors that are less than 1.00 mm thick but display conspicuous
mitotic activity.281
Differential diagnosis
Amelanotic spindled cell melanoma may be histologically indistinguishable
from other cutaneous spindled cell tumors including leiomyosarcoma, spin-
dled cell squamous carcinoma, atypical fibroxanthoma, and even dermato-
Fig. 26.52 fibrosarcoma protuberans. In such cases, the use of an appropriate panel
Melanoma: intraneural invasion. Note the pleomorphic tumor nuclei within this of immunohistochemical reagents, including antibodies to S100 protein,
nerve trunk. SOX10, HMB-45 or MART-1, pan-cytokeratin, AE1/AE3, smooth muscle
1328 Melanoma
actin (SMA), and CD34, is often essential. Similarly, highly pleomorphic,

amelanotic epithelioid melanoma sometimes has to be distinguished from
anaplastic carcinoma and occasionally anaplastic lymphoma. The use of
antibodies to keratins, epithelial membrane antigen (EMA), carcinoembry-
onic antigen (CEA), leukocyte common antigen (LCA), T- and B-cell anti-
gens, and CD30 may be necessary to achieve a definitive diagnosis.
Immunohistochemistry of melanoma
Immunohistochemistry is a valuable adjunct to histology in the diagnosis
of melanoma, particularly in amelanotic, epithelioid, and spindled cell vari-
ants and their distinction from undifferentiated carcinomas and mesenchy-
mal tumors.1–3 Owing to problems of specificity and sensitivity, it is prudent
to use two or even three ‘melanoma markers’ in such problematical cases.
Using these markers as part of a panel looking at multiple lines of differ-
entiation is also of practical use, such as inclusion of keratins to exclude
epithelial tumors. In morphologically challenging cases, a panel of stains
that supports the ultimate diagnosis by their pattern of reactivity or nonre- A
activity is very helpful. The role of immunohistochemistry is to provide sup-
portive data. It should rarely if ever be used as the sole criterion by which a
diagnosis of melanoma is achieved.
S100 protein remains the yardstick in the immunohistochemical diag-
nosis of melanoma.4–6 Although there are now substantial numbers of new
markers available, none as yet, in isolation, measures up to S100 protein.
However, S100 protein lacks specificity and there are very exceptional
S100 protein-negative melanomas, virtually all metastatic.7,8 In cases where
the diagnosis remains in doubt, use of a battery of immunohistochemical
markers may be of great value.1
S100 protein is a calcium binding F-band protein, isolated from brain.
It is variably positive in 94–100% of primary and metastatic melanomas.1,2
In addition to melanocytes, Schwann cells, myoepithelial cells, adipocytes,
chondrocytes, macrophages, Langerhans cells, and tumors derived thereof,
express S100 protein. Staining of Langerhans cells can sometimes be a
problem, particularly when assessing the extent of intraepidermal melano-
cyte spread. In such instances, the addition of MITF, SOX10, HMB-45, or
MART-1 may be helpful. S100 protein may also be expressed in a number of B
breast carcinomas and undifferentiated carcinomas.5,6 The most commonly
employed antibody against S100 is a purified rabbit polyclonal antibody Fig. 26.54
against S100 protein purified from bovine brain. More than 20 members of Melanoma: this tumor has arisen in a background of a banal nevus. (A) Compare
this family exist and monoclonal antibodies are available for many of them. the eosinophilic, pleomorphic tumor cells with the small basophilic nevus cells;
While not well established in large series, there may be some selectivity of (B) the melanoma cells are HMB-45 positive; the nevus cells are negative.
the isoforms between melanoma and other traditionally S100 protein reac-
tive neoplasms in the differential diagnosis.9 Sertoli cell, and granulosa cell tumors, and tumors in the PEComa group of
HMB-45 reacts with the cytoplasmic premelanosome glycoprotein gp100 lesions including angiomyolipoma, lymphangiomyomatosis, and clear cell
and is less sensitive than S100 protein.9 It is expressed by 80–86% of met- sugar tumors of the lung in addition to melanoma.18,19 It has a similar sensi-
astatic melanomas and between 90% and 100% of primary tumors.1,4,9 tivity to S100 protein in epithelioid melanomas but is less sensitive in spin-
However, expression is often more focal than with S100. Sensitivity dimin- dled cell tumors and is not usually expressed in the desmoplastic variant.
ishes in spindled cell variants and it is usually negative in desmoplastic mel- A study has shown evidence that diminished MART-1 expression correlates
anoma (see below).10,11 The junctional and superficial dermal components with increasing tumor thickness, reduced disease-free interval, and increased
of banal nevi also react with HMB-45 but the deeper dermal nevus cells are patient mortality.18 MART-1 expression has also been demonstrated in
generally negative. This differential staining pattern may be of value in con- compound, dermal nevi and Spitz nevi with the exception of neurotized
firmation of pre-existent banal nevus cells associated with a melanoma and variants.15–17
in particular their distinction from small cell and nevoid melanoma, which Antityrosinase antibody (e.g., T311) appears to be less sensitive than
are typically positive in a patchy fashion in the deepest nests of cells (Fig. either S100 protein, HMB-45, or Melan-A (A103).21–26 It does not appear
26.54). It is very important to remember that this pattern is lost in cases to label desmoplastic melanoma. Cocktails of HMB-45, MART-1, and
where melanocytes are pigmented as the latter are positive for HMB-45. antityrosinase antibodies are used by some to increase sensitivity for detec-
Dysplastic nevi are similarly labeled. Blue nevi and deep penetrating nevi tion of melanocytic differentiation.27
are also HMB-45 positive.1 Spitz nevi are often HMB-45 positive in the Microphthalmia transcription factor (MITF) is a transcriptional regula-
superficial aspect of the lesion and this is usually, but by no means always, tor important for tyrosinase expression.28 It is strongly positive in nevi and
lost with depth. This finding may be of value in its distinction from spit- epithelioid melanoma.29–31 Sensitivity is reduced in spindled cell and des-
zoid melanoma in which staining is typically present throughout the tumor. moplastic variants.32 Spitz nevi and neurotized banal nevi show diminished
Although it is more specific than S100 protein, HMB-45 also reacts with the expression. The specificity of MITF is low and this limits its use in the
group of perivascular epithelioid cell tumors (PEComas) including angiomy- differential diagnosis of mimickers of melanocytic lesions. Its main use is
olipoma, lymphangiomyomatosis, and clear cell sugar tumor of the lung.12,13 in the evaluation of intraepidermal melanocytes as the staining is nuclear
MART-1 (Melan-A) is a melanosomal differentiation antigen recognized and other cells that reside in the epidermis are not positive for this marker.
by autologous cytotoxic T cells.14–20 Some antibodies raised to this protein The monoclonal antibody, SM5-1, was created by a subtractive immu-
(e.g., A103) label a variety of lesions including adrenocortical, Leydig cell, nization protocol using human melanoma samples and binds a variant of
Immunohistochemistry of melanoma 1329
fibronectin.33,34 Initial reports indicated that its sensitivity is similar to S100

protein with improved specificity for other traditionally S100 protein reac-
tive, but the antibody also reacts with hepatocellular carcinoma and breast
cancer cells.26,35 This antibody is not widely used for clinical diagnosis.
SOX10 is a transcription factor that is a critical regulator of
melanocytes.36–38 Antibodies raised against it represent another marker of
melanocytic and Schwann cells and tumors derived from the neural crest.39
While it lacks specificity and stains other cells it is equally sensitive and
more specific than S100 protein in relevant differential diagnoses with soft
tissue neoplasms.40,41 It is also useful in desmoplastic melanoma, though
expression has also been noted in scars.42–44 It has gained widespread use
as a sensitive marker for melanoma, often used in combination with other
melanocytic markers.45 It has been suggested to be more specific than other
melanocytic markers in the setting of determining melanocytic density in
chronically sun-damaged skin where misleading false-positive rates are
noted with other markers.46 A role has also been suggested in evaluation of
sentinel lymph nodes.47
The bar is high for inclusion of new markers as standards for melanoma
in clinical practice. All antibodies have a natural history of decreasing speci-
ficity with study of additional tumor types and new antibodies are not as far Fig. 26.55
down this curve as older antibodies, creating potential for misinterpretation Melanoma: this tumor (right side of field) has arisen in a background of a
congenital nevus (left side of field).
if the new reagents are used alone.
Melanoma cells can express epithelial markers including keratins, EMA,
and CEA.2,48–50 Keratin, particularly those of low molecular weight, may
be identified in as many as 10% of melanomas, both on frozen and on
paraffin-embedded sections.2 CEA is commonly encountered if polyclonal
antibodies are utilized.49,50 Metastatic disease more often shows such aber-
rant staining patterns than primary tumors. Diagnostic difficulties are
unlikely to be encountered provided S100 protein and/or other melanoma
markers have been included in the antibody panel. SMA and desmin are
very rarely expressed in melanoma with the exception of the desmoplas-
tic variant where, as in most spindle cell tumors, SMA can be detected to
varying degrees.51 One study with dual labeling for S100 protein and SMA
in desmoplastic melanoma indicates that the SMA reactivity may be in
accompanying stromal myofibroblasts.52
Melanoma cells can express histiocytic markers such as CD68 (KP1) in
80% or more of tumors.53,54 Mac 387 and α1-antitrypsin may also be pos-
itive. This is of particular significance since the distinction between tumor
cells and histiocytes, particularly in sentinel lymph node specimens, can
sometimes be problematical. In addition, distinguishing between balloon
cell melanocytic lesions and xanthomatous infiltrates may require immu-
nohistochemical confirmation, particularly if no residual recognizable mela-
nocytic component is visible. In such circumstances, positive melanocytic
markers are obviously of major diagnostic importance.
There is an ever-expanding range of reputed immunohistochemical A
prognostic markers.55–57 Most of these lack appropriately powered full
multivariate analysis linking the marker with specific outcome such as
melanoma-specific mortality supplemented by hazard ratios and do not fully
describe the methods utilized as recommended by the REMARK (Report-
ing recommendation for tumor MARKer prognostic studies) guidelines of
the NCI-EORTC or AJCC precision medicine reporting recommendations
for tumor marker prognostic studies.58–62 The more useful of these are very
briefly discussed below. Few of these are validated to the level necessary
for routine application to clinical samples; virtually all are reported in ret-
rospective cohorts with referral and other biases. Use of multiple markers
and application of rigorous methods of quantification have efficacy, distin-
guishing different prognostic groups.63 The markers discussed below are
primarily used to help support a diagnosis of melanoma or nevus in the
relatively small subset of cases where this determination is challenging on
purely histologic grounds.
Ki-67 (MIB-1) is a particularly valuable adjunct in the distinction
between benign melanocytic nevi (including Spitz nevi) and melanoma.64,65
In nevi, less than 5% of nuclei are positive (and these are usually located B
in the most superficial aspect of the dermal component) whereas in mel-
anoma 25% or more of cells are labeled (Figs 26.55 and 26.56). Its role Fig. 26.56
in predicting biological behavior is controversial; thus although in earlier (A, B) Melanoma: the melanoma shows very brisk MIB-1 expression, and the
studies increased expression in thick tumors was thought to correlate with nevus is completely negative.
1330 Melanoma
poor survival, more recently it has been claimed that increased expression including some that are U.S. FDA-approved companion diagnostics, but
in thin tumors (< 1.5 mm) is of greater significance.66–69 A further study indi- such testing is not currently required to use immune checkpoint inhibitor
cates that increased MIB-1 reactivity is a poor prognostic factor in terms of therapy in melanoma.123 Indeed, melanomas can respond to PD-1 (CD247/
disease-specific survival independent of tumor thickness.70 Obviously, there programmed cell death protein 1) inhibitors even if they completely lack
is a proportional, though not exact, relationship between degree of nuclear membranous PD-L1 expression.124 Most PD-L1 antibodies have very similar
MIB-1 reactivity and mitotic rate. Mitotic rate is an important determinate staining profiles in melanoma and other tumors as well.125,126 Specific scoring
of melanoma outcome, though it no longer drives groupings in the 8th approaches have been suggested and used for clinical trials and in routine
Edition of the AJCC staging system.71 How to correlate Ki-67 reactivity practice. Staining for CD8-positive T-cells in melanoma can also be per-
with mitotic rates is evolving. Increased Ki-67 expression also correlates formed and higher levels are associated with increased likelihood of response
with overexpression of p53 protein and loss of p16 (see below).68,70 to immuno-oncological therapy. Approaches for scoring these infiltrates have
Phosphohistone H3 (PHH3) recognizes mitotic figures directly rather been suggested, but are not widely employed in routine clinical practice.127–130
than cell cycle like MIB-1 and can assist in more objectively determining These biomarker approaches are used primarily in metastatic disease and
mitotic rates which do correlate with outcome.72–79 Care must be taken their correlation with response is not perfect.131,132 This is an active area
when increasing the sensitivity of mitotic rate detection since the majority of research and a number of genomic and other patient factors have also
of the data is derived using the less sensitive, but currently gold standard been associated with patient response. Companion immunohistochemical
microscopic detection on H&E stains, as inappropriate inflation of progno- approaches are not currently used in clinical practice for CTLA-4 (CD152)
sis can occur. inhibitors in melanoma. Anti-CTLA-4 therapy is sometimes used in combi-
Bcl-2 is strongly expressed in normal melanocytes and in a variety of nation with PD-1 inhibitors. PD-L1 expression can inform whether PD-1
nevi including banal, congenital, Spitz, blue, and dysplastic variants.80–83 monotherapy or combination approaches are employed in melanoma.124
Although there is some variability of results in the literature, diminished Additional work in this area is likely to produce more associated biomarkers
expression has been said to correlate with melanoma, particularly meta- as immuno-oncology expands to a number of emerging novel agents such
static lesions. Similarly, in problematical spitzoid lesions, strong expression as inhibitors of IDO1, LAG-3, and others where expression of the protein
may favor a diagnosis of benignancy.84 Bcl-2 downregulation has been cor- targets might be associated with treatment efficacy.133,134
related with melanoma progression.85–87 High bcl-2 was associated with
improved disease-specific outcome when assessed in either primary or met-
Histologic variants of melanoma
astatic lesions using automated assessment of immunofluorescent immu-
nohistochemistry.88 From our own experience, however, bcl-2 is as often Quite a range of histologic variants have been described.1–3 With the excep-
positive in melanoma as it is in banal nevi and it is therefore of little value tion of desmoplastic melanoma, these are of limited prognostic significance
in difficult cases. but are of importance because they may easily be mistaken for other tumors,
Cyclin D1 may be of help in differentiating between a banal nevus and a with potentially serious consequences. In addition, some of the types are
nevoid melanoma or a nevic component within a melanoma. Its expression more or less likely to have mutations such as BRAF V600E that represent a
throughout the full thickness of a melanoma has been reported in up to therapeutic target, though the genotype histology correlation is not enough
60% of cases, whereas staining may be absent or limited to only occasional for treatment in most cases and direct molecular testing is required.4,5
cells in the superficial aspect of a nevus.89,90 Increased cyclin D1 reactiv-
ity may correlate with amplification of its encoding genetic locus.91–93 High
Nested melanoma
levels of cyclin D3 in superficial melanoma have been found to correlate
with early relapse and decreased survival.94 This finding regarding cyclin This is a rare, recently described distinctive type of melanoma described as
D3 needs further confirmation.90 Interestingly, cyclin D1 may interact more a variant of superficial spreading melanoma.1,2 It presents in middle-aged to
with CDK4 while cyclin D3 interacts more readily with CDK6, suggesting elderly adults with the same sex incidence. Although the clinical features are
different functions for these two cyclin D isoforms.95 usually suspicious of melanoma, the histologic appearances are misleading.
Loss of p16 protein expression correlates with invasive and metastatic Tumors are in-situ or invasive and the junctional component is distinctively
melanoma.96–99 It has also been shown to correlate with increased Ki-67 nested with little or no proliferation of melanocytes between the nests. The
immunolabeling and independently to predict a poor prognosis.70,98 P16 latter may be confluent and are located at the tips or less commonly, the
may also be helpful in differentiating capsular nevus from metastatic mela- slopes of the rete-ridges. Mitotic activity tends to be low within the nests
noma in sentinel lymph nodes.100,101 and cytologic atypia varies from moderate to severe. Multiple chromosomal
Although mutation of the TP53 gene is relatively uncommon in mela- abnormalities are demonstrated by cytogenetic analysis.
noma at around 20%, overexpression of p53 protein may be identified in
up to 40% of cases of invasive and metastatic melanoma, perhaps indicat-
Minimal deviation melanoma
ing disruption of this pathway.102–107 It may therefore be of value in distin-
guishing between nevi (banal and Spitz) and melanoma. The former show The concept of minimal deviation melanoma was introduced to define a
virtually no positive cells whereas in the nodular and to a lesser extent subset of invasive melanoma that showed minimal histologic deviation from
superficial spreading melanoma they may be conspicuous. Expression of banal nevi and therefore lacked the pleomorphism seen in classic melanoma.
p53 also appears to be an independent predictor of poor prognosis.68,106,108 It was further postulated that such tumors appeared to have a better prog-
Immunohistochemistry for the BRAF V600E mutation using the VE1 nosis than classic melanoma.1–8 Over the last decade, use of this nomen-
clone is a highly sensitive and specific means of determining the mutational clature has precipitously declined and it is now presented primarily for
status of melanoma, usually applied in the metastatic setting.109–111 It does historical interest.
not reliably detect common alternative BRAF V600 variants such as V600K As defined, two subtypes were recognized6:
that constitute 15–20% of BRAF mutations in some series.112,113 This can • borderline minimal deviation melanoma where the dermal component is
be helpful in the rapid assessment for eligibility for BRAF inhibitor therapy, confined to the papillary dermis (Clark level 3),
but DNA sequencing is still the gold standard for determining BRAF muta- • minimal deviation melanoma where there is infiltration into the
tional status. A similar approach can detect a subset of the common NRAS reticular dermis or beyond (Clark level 4 or 5).
mutant proteins Q61R and Q61L in melanoma with two separate antibody Minimal deviation melanoma is characterized by the presence of an expan-
clones, but is not widely adopted.110,114–118 sile nodule showing only mild to moderate cytological atypia. It lacks the
In the setting of immunotherapy, membranous expression of PD-L1 (pro- disorderly, more marked pleomorphism of conventional epithelioid or spin-
grammed death-ligand 1) can influence the choice of immuno-oncological dled cell melanoma. The spectrum includes epithelioid variants composed
agents, but is not required to use such approaches.119–122 A number of antibodies of cells resembling those of a compound melanocytic nevus, spitzoid forms,
are available against PD-L1 for use in routine clinical immunohistochemistry, spindled cell variants, and halo nevus-like lesions.1
Histologic variants of melanoma 1331
Fig. 26.57 Fig. 26.58

Verrucous nevoid melanoma: verrucous nevoid lesions in the elderly should be Nodular nevoid melanoma: the diagnosis of nodular nevoid melanoma depends
viewed with suspicion. upon careful scrutiny of all ‘nevi.’ Inspection at scanning magnification will ensure
misdiagnosis as a banal nevus!
Although widely publicized, the concept has not gained general accep-
tance.1 This relates particularly to a lack of precise definitions combined
with the well-known unpredictable behavior of many melanomas. Patients
with apparently high-grade and thick tumors sometimes survive for many
years, or even decades, while the converse may also be true. The postu-
lated good behavior of these lesions has been challenged on the basis that
those that neither recurred nor metastasized may have been benign nevi and
those that metastasized and/or proved fatal were obviously malignant at the
outset.
In our view, although there are histologic variants of melanoma that
show only limited morphological deviation from banal nevi, the evidence
relating to biological behavior suggests that these tumors fare no better than
classical melanoma and should be treated in exactly the same way. Sub-
types that could be included within this category of ‘minimal deviation’ are
nevoid melanoma, small cell melanoma, and spitzoid melanoma. We prefer
these categories for histologic classification and these three are dealt with
below.
Nevoid melanoma Fig. 26.59

Nevoid melanoma:
Nevoid melanoma is a rare histologic subtype of vertical growth phase expansion of the papillary
melanoma, which on low-power inspection may be (and often is) confused dermis by a diffuse
with a banal melanocytic nevus.1–5 It can be equally challenging to recognize nevoid population with
stretching and thinning of
clinically on patient skin examinations as well.6 Diagnosis depends on a
the associated epidermis
high index of suspicion and careful attention to cytological detail includ-
may be a clue to the
ing a thorough search for dermal mitotic activity. A practical or functional diagnosis.
definition of nevoid melanoma is the ‘diagnosis of a nevus which one later
regrets’.
Because nevoid melanoma is commonly misdiagnosed as a banal nevus, with hyperkeratosis and marked papillomatosis. The epidermis frequently
subsequent delay in appropriate treatment is common, with potentially dev- appears attenuated with loss of the rete-ridge pattern. In nodular tumors, the
astating consequences.1,2,7–12 Confusion with a banal nevus is most probably epidermis is similarly thin and stretched directly over the surface of a dense
a reflection of too cursory an inspection of a ‘nevus,’ frequently at scan- dome-shaped tumor cell population. Junctional activity in either variant is
ning magnification. Grossly, there are no particular distinguishing features, often minimal and limited to atypical cells distributed predominantly along
most lesions being clinically described as verrucous to dome-shaped variably the basal layer of the epidermis. Very occasionally, more obvious in situ
pigmented nevi or non-specific papules or nodules. Follow-up information melanoma may be seen.
indicates a recurrence rate of 50%, a metastasis rate of 25–50%, and a At medium-power examination, diffuse and, less often, nested growth
mortality rate of at least 25%.12 patterns may be encountered (Figs 26.59 and 26.60). In the latter there is
Histologically, on low-power examination nevoid melanoma may present often considerable variation in nest size accompanied by little tendency for
as a warty/verrucous or dome-shaped lesion (the former pattern in an elderly diminution in nest size with depth.
patient is itself a clue to the diagnosis, as nevi in the elderly are more often The infiltrating tumor cells are small, epithelioid melanocytes (reminis-
dome-shaped papulonodules) (Figs 26.57 and 26.58). cent of type-A nevus cells) with pale staining or eosinophilic cytoplasm and
The verrucous variant has a rather characteristic histologic appearance round to oval vesicular nuclei with small eosinophilic nucleoli. Although the
presenting as an often asymmetrical, poorly circumscribed, warty lesion low-power impression may suggest maturation with depth, closer inspection
1332 Melanoma
A
Fig. 26.60
Nevoid melanoma: the
tumor cells are very
uniform. Nuclei are
vesicular and nucleoli
prominent. A small
number of tumor cells are
evident in the overlying
epidermis.
Fig. 26.62
(A, B) Nevoid melanoma: this lesion at low power is suggestive of a congenital
nevus. At high-power magnification, multiple mitoses were present.
Fig. 26.61
Nevoid melanoma: there
may sometimes be a
suggestion of maturation
with depth. Note the
mitosis. This field is taken
from the deep aspect
of the lesion shown in
Figure 26.58.
invariably shows this to be false (Fig. 26.61).13 Pleomorphism, while subtle,

is typically present and mitoses (frequently multiple) can invariably be iden-
tified, often within the deeper aspect of the tumor. Pigmentation, although
variable, is sometimes seen in the deeper reaches of the dermal component
and in a minority of cases, tumor-infiltrating lymphocytes are present. Occa-
sionally, perineural infiltration is present (Figs 26.62 and 26.63). A single
report describes a case with Homer-Wright type rosettes.14
Verrucous variants must be distinguished from keratotic melanocytic
nevi, the most important histologic discriminants being the lack of mat- Fig. 26.63
uration, subtle pleomorphism, and mitotic activity.15 Others have termed Nevoid melanoma: note the perineural infiltration (same tumor as Fig. 26.64).
Fig. 26.64
Nevoid melanoma: MIB-1 expression is usually brisk and
positively staining nuclei are commonly seen at all levels
of the tumor compared with banal nevi in which only very
A B rare positive cells are seen. (A) Nevoid melanoma; (B) banal
dermal nevus.
Fig. 26.65
Nevoid melanoma: nuclear cyclin D1 expression is typically
brisk and present throughout the depth of the tumor
A B compared to a banal nevus where only scattered cells are
positive. (A) Nevoid melanoma; (B) banal nevus.
very similar lesions ‘papillomatous nevoid’ melanoma.16 Very occasionally, with melanoma cells when viewing MIB-1 stained sections. Double or dual
melanoma metastatic to the skin from another cutaneous site can present staining with MIB-1 and a melanocytic marker such as MART-1 can be
with a nevoid appearance.17 particularly valuable. Correlation with the hematoxylin and eosin stained
Immunohistochemistry may be of help in distinguishing between nevoid section is always advised. HMB-45 can also sometimes be useful. Dermal
melanoma and a banal nevus.18 In our experience, demonstration of ele- nevi are only positive in the most superficial part of the nevus as a counter-
vated proliferative activity using MIB-1 and sometimes cyclin D1 can be part to morphological maturation, whereas in melanoma positive cells may
particularly valuable (Figs 26.64 and 26.65). Banal nevi show only very be identified throughout the depth of the tumor.
scattered positive cells in the superficial part of the dermal component, FISH and comparative genomic hybridization (CGH) studies will often
whereas in melanoma they may be numerous and present throughout the show findings similar to conventional melanoma and thus are frequently
thickness of the lesion. It is important not to confuse positive lymphocytes helpful in the diagnosis of nevoid melanoma.5,19
1334 Melanoma
Fig. 26.66 Fig. 26.67

Small cell melanoma: this variant of melanoma simulates type-B nevus cells at Small cell melanoma: high-power view. The tumor is commonly mistaken for a
low-power magnification, the tumor cells being small and deeply basophilic. lymphoma or neuroendocrine carcinoma if melanin pigment or junctional activity
is absent.
While one must always be wary of missing nevoid melanoma, it is also

important not to overdiagnose melanoma in nevi. This diagnostic reversal in the literature. This being said, age is a revealing variable with most
can also have untoward clinical and medicolegal consequences.20 Spitz-like features in young children being benign, but the same features in
adults, particularly older adults, are much more likely to be associated with
malignancy.5,6 There have thus been a number of papers describing melano-
Small cell melanoma
mas with features reminiscent of Spitz nevus (spitzoid melanoma, malignant
The term ‘small cell melanoma’ is often a source of confusion.1–3 In the lit- Spitz nevus) and diagnostic criteria to afford their distinction have been pro-
erature it has been applied to a variety of different lesions. It has been used posed and extensively discussed.7–20 Agreement between expert dermatopa-
as a synonym for nevoid melanoma as defined above.4,5 It has also been thologists in assessing malignancy in atypical spitzoid melanocytic tumors is
utilized in the context of a high-grade variant of childhood melanoma. Such quite poor.21 Agreement on what should be considered spitzoid or Spitz-like
tumors, which present on the scalp or developing in a congenital nevus, is also suboptimal.22 Given this uncertainty, treatment recommendations
are highly aggressive.6,7 Other authors have employed the term to describe from pathologists can show considerable variance.22
a tumor occurring in adults, which mimics lymphoma, cutaneous neuroen- Features that may favor a diagnosis of spitzoid melanoma include large
docrine carcinoma, or metastatic undifferentiated carcinoma.8–11 It has been size, deep dermal penetration, parakeratosis, epidermal atrophy (as opposed
used in the Australian and UK literature to describe a low-grade variant to the marked hyperplasia typical of Spitz nevus), asymmetry and lack of
of melanoma arising on the sun-damaged skin of middle-aged males.12,13 A circumscription, pagetoid spread at the edge of the lesion (pagetoid spread
recent study indicates that a small cell component in cutaneous melanoma in the center of the nevus is quite common in a Spitz nevus), absence of
is a independent poor prognostic indicator.14 Kamino (eosinophilic) bodies, dusty pigmentation, dermal nests larger than
In our view, small cell melanoma should be distinguished from nevoid the junctional ones, a diffuse (non-nested) dermal component, an expan-
melanoma. We reserve the term for a high-grade melanoma, presenting as sile rather than infiltrating lower border, lack of maturation, nuclear pleo-
a small blue cell tumor reminiscent of type-B nevus cells. It is characterized morphism and hyperchromatism, conspicuous mitoses, deep mitoses, and
by a monotonous population of cells with minimal cytoplasm and round atypical mitoses (Figs 26.68–26.70).7,9,15,23 In a meta-analysis, Walsh and
to oval hyperchromatic nuclei, often containing prominent nucleoli (Figs coworkers15 found the following to be the most useful and consistently
26.66 and 26.67). Mitoses are frequently conspicuous and karyorrhexis is applied criteria:
common. The tumor cells are sometimes aggregated into elongated expan- • symmetry,
sile nests but may also present as a diffusely sheeted infiltrate.15 Maturation • uniformity of nests from side to side,
with depth is not apparent. A pseudorosette pattern has been documented.15 • Kamino bodies,
In recurrent tumors where junctional activity is no longer apparent, and • brisk mitotic rate,
in metastatic disease, small cell melanoma can be easily confused with a • mitoses close to the base of the lesion,
poorly differentiated carcinoma, a lymphomatous infiltrate, and neuroen- • abnormal mitoses.
docrine carcinoma.8–10,16 Appropriate immunocytochemistry should readily A recent study by 13 experts of 75 cases confirmed the usefulness of all these
solve the problem. factors excepting Kamino bodies and adding ulceration as a feature favoring
malignancy.21 Thus the presence of the first three and absence of the second
three argue for a diagnosis of Spitz nevus and vice versa. Spatz and cowork-
Spitzoid melanoma
ers16 have devised a grading system for dividing atypical Spitz nevi into low-,
The diagnosis of Spitz nevus, and in particular its distinction from mela- medium-, and high-risk categories (of being frankly malignant). This is based
noma, is one of the most difficult areas in dermatopathology.1–3 Spitz nevus on age, diameter, involvement of subcutaneous fat, presence or absence of
is predominantly a lesion of children and young adults, whereas melanoma ulceration, and mitotic rate. The category of atypical Spitz with uncertain
occurs most often in the middle aged and elderly. There is therefore a ten- biological (or malignant) potential has also been much discussed.24,25 This
dency when encountering a spitzoid lesion in a child to automatically try to concept is often applied to spitzoid lesions as many diagnosticians find these
categorize it in the benign group merely on the basis of the age.4 Overreli- tumors challenging to definitively categorize as wholly benign or malignant
ance on age is a dangerous practice, since although rare, melanoma occur- in a subset of cases. Cases in this category may not represent neoplasms with
ring in childhood and showing spitzoid features has been well documented the full biological potential of standard melanoma; however, this category
Fig. 26.68
Spitzoid melanoma: (A) low-power view showing deep extension into the
A subcutaneous fat; (B) the presence of ectatic vessels in the superficial dermis is
reminiscent of Spitz nevus.
Fig. 26.69
A Spitzoid melanoma: (A) multiple Kamino bodies may also mislead the unwary;
(B) multiple mitoses, however, should raise a high index of suspicion.
may be tainted with Spitz nevi containing unusual features. The descriptions feature pointing to melanoma as opposed to Spitz nevus when present,
in the literature and use of these categories highlight the diagnostic difficul- though some question its usefulness.21,26,27 It is important to emphasize that
ties presented by Spitz nevi and spitzoid melanoma. this feature is useful when the thinning of the epidermis is continuous but
Mones and Ackerman20 have emphasized involvement of the deep dermis usually not when it is focal.
or subcutaneous fat by a vertically orientated tumor showing only mild Immunohistochemistry may be of value. Thus 50% or more of tumor
asymmetry on scanning magnification. Other clues include uneven melanin cells in spitzoid melanoma may express proliferating cell nuclear antigen
distribution, often at the base of the tumor, variability in size and shape (PCNA) whereas in Spitz nevus, usually less than 5% of cells are posi-
of the dermal nests and fascicles, confluence of nests and fascicles to form tive.28 A similar staining pattern is noted with MIB-1 where less than 2%
diffuse sheets of tumor cells, and diminution or loss of adnexae. They also strongly favors nevus and greater than 10% strongly favors melanoma with
make the point that the superficial features can be virtually indistinguish- others factors impinging more strongly between these two thresholds.29,30
able from Spitz nevus. Consumption of the overlying epidermis is a helpful HMB-45 expression in the deep dermal component would favor a diagnosis
1336 Melanoma
Fig. 26.70
Spitzoid melanoma:
deep or abnormal Fig. 26.71
forms are important Signet ring cell melanoma: very occasional signet ring melanoma cells are not
diagnostic features and uncommonly seen in epithelioid melanomas; exceptionally, however, they can
are absolute indicators of constitute the majority of the tumor.
an unequivocal diagnosis
of melanoma. Note that
there is no evidence of
maturation. change in recurrent and primary disease. The phenomenon does not have
prognostic significance.1–15
Signet ring cell change is characterized by a large pale or eosinophilic
cytoplasmic globular inclusion or vacuole, which compresses the nucleus to
of spitzoid melanoma.29,31 Amplification of the p-arm of chromosome 11 the edge of the cell (Fig. 26.71). This appearance may affect a melanoma
where the HRAS oncogene resides is seen in a subset of Spitz nevi; this in part or constitute the whole of the lesion. The periodic acid-Schiff (PAS)
change is not encountered in melanoma and thus this finding may be helpful stain is variably weakly positive (diastase resistant) but an Alcian blue reac-
in distinguishing Spitz nevi and melanoma.32–35 Comparative genomic tion is consistently negative.1,2,11 The nature of the PAS-positive material is
hybridization and FISH assays can be used to make this determination. The unknown. The signet ring appearance is due to excess intermediate filament
distinction between Spitz tumor and atypical Spitz tumor is not always well presenting as an intracytoplasmic ‘mass’ or vacuole.
informed by such assays, but can be helpful when characteristic melanoma The signet ring cells contain vimentin and may express S100 protein and
deficits are present.36,37 As for spitzoid melanoma, 6p25 and/or 11q13 gains HMB-45 although the latter two can be patchily distributed and occasion-
or 9p21 deletions on FISH favor malignancy while no FISH abnormality or ally absent altogether.2,4,16 Diagnosis in such a case is then dependent upon
6q23 deletions are associated with less aggressive behavior or benignancy.38 finding more typical melanoma cells with appropriate immunocytochemistry
Spitzoid melanomas generally lack mutations in genes such as BRAF and elsewhere in the specimen. Signet ring cell melanoma must be distinguished
NRAS common in some other melanoma subtypes in some studies, but not from other signet ring cell tumors, particularly mucin-containing adenocar-
others.39,40 This may illustrate the difficulty in histologically defining what cinoma and lymphoma. To this end, antibodies to LCA, keratin, EMA, and
amounts to a spitzoid melanoma versus a standard melanoma. Spitz lesions CEA should invariably be included in the immunocytochemistry panel.
can also show inactivation of the tumor suppressor BAP1 (BRAF V600 Cytological diagnosis of signet ring cell melanoma (by fine needle aspira-
mutations can also be seen with BAP1 loss) as well as rearrangements in tion and from a peritoneal effusion) has been documented.8,10
ALK, RET, ROS, BRAF, NTRK1, and RET. These features can be seen in Signet ring cells have also exceptionally been described in banal and
both benign and malignant Spitz tumors.38,41–48 Spitz melanocytic nevi.6,17,18
Although Smith and coworkers10 suggested that malignant Spitz nevus
might represent a tumor that rarely spread beyond the draining lymph
Rhabdoid melanoma
nodes, subsequent papers have suggested that the tumor is often no differ-
ent from any other melanoma and therefore has the same risk of systemic Rhabdoid melanoma shows considerable overlap with signet ring cell
spread and an identical mortality.15,28,49 Spitz-like lesions that metastasize melanoma.1
to lymph nodes in children do appear to be less aggressive than traditional The term ‘rhabdoid tumor’ was originally coined to describe an aggres-
melanoma in children and adults. Metastasis of Spitzoid lesions in adults sive childhood renal tumor, which was thought to represent a rhabdo-
appears to bear the same prognosis as that of other metastasizing mela- myosarcomatous variant of nephroblastoma.2 It was characterized by the
noma. Some authors recommend sentinel lymph node biopsy in problemati- presence of eosinophilic hyaline intracytoplasmic inclusions, later identified
cal spitzoid lesions to help establish a diagnosis of melanoma in addition to ultrastructurally as whorls of intermediate filaments. Extrarenal rhabdoid
adding prognostic information, though this approach is not without contro- tumors have been identified at a wide range of sites including soft tissues,
versy.19,50–56 Patients younger than 11 years of age with spitzoid melanoma skin, brain, orbit, uterus, bladder, prostate, and liver. A rhabdoid phenotype
may have a better prognosis than older adolescents and adults, but this was first described in metastatic melanoma.3–10 More recently, small numbers
finding has not been universal.49,56 of primary tumors showing rhabdoid features have been documented.11–17
At present, there are too few cases documented to determine whether the
rhabdoid phenotype in melanoma has any prognostic significance.
Signet ring cell melanoma
The rhabdoid phenotype is characterized by the presence of large epithe-
Signet ring cell melanoma is a very rare histologic variant, which shows lioid cells with abundant cytoplasm containing a large round eosinophilic
considerable overlap with rhabdoid variants (see below). It has been mostly hyaline inclusion (Fig. 26.72). The nuclei are typically vesicular and nucleoli
described in metastatic tumors. There are also reports of signet ring cell are eosinophilic and conspicuous. Extrarenal rhabdoid tumors are not a
Fig. 26.72 Fig. 26.74

Rhabdoid melanoma: this variant often causes diagnostic difficulty since lesions Balloon cell melanoma: the tumor cells have clear or faintly granular cytoplasm.
are commonly amelanotic. Note the vesicular nuclei, prominent nucleoli, and large This example is amelanotic and could easily be mistaken for a xanthomatous
eosinophilic cytoplasmic inclusions. lesion.
Fig. 26.73 Fig. 26.75

Rhabdoid melanoma: in the absence of a known history of melanoma, the Balloon cell melanoma: high-power view.
diagnosis commonly depends upon immunohistochemistry (S100 protein).
homogeneous entity; most often rhabdoid features are seen focally in an is more commonly seen than in classic melanoma.2 Prognosis is usually poor
otherwise recognizable and classifiable lesion, i.e., rhabdoid change rep- but this relates to the tumor thickness at presentation rather than any feature
resents a morphological endpoint in dedifferentiation. specific to this unusual melanoma variant. Balloon cell change appears to be
The results of immunocytochemistry are variable. Some tumors are more common in nevi than melanoma.6
characterized by S100 protein, SOX10, and HMB-45 expression (Fig. Balloon cells have abundant eosinophilic or clear cytoplasm showing fine
26.73).11,12 Mart-1 is also often expressed by tumor cells. In a number of granularity or vacuolation (Figs 26.74 and 26.75). The tumor cells are typ-
tumors, however, the rhabdoid cells fail to show any of the above and the ically S100 protein, Mart-1, SOX10, and HMB-45 positive. They contain
inclusions contain keratin, smooth muscle actin, or desmin.3,12 Rare exam- PAS-positive, diastase-resistant granules. These are also iron hematoxylin
ples of melanoma with rhabdoid morphology display rhabdomyosarcoma- positive, hyaluronidase resistant. Sensitivity to ribonuclease indicates that
tous differentiation with expression of desmin, myogenin, and MYOD1. the granules are composed of ribonucleoprotein.2 The cause of the vacuo-
Ultrastructurally, the inclusions have usually been found to consist of lation is uncertain but is believed to represent either abnormal melanosome
aggregates of intermediate filaments. In one series of metastatic melanoma, metabolism or else a melanosome degenerative phenomenon.
the rhabdoid inclusions were composed of tubular inclusions within dilated Balloon cell melanoma can be distinguished from balloon cell nevus
rough endoplasmic reticulum and mitochondria.5 by the absence of nuclear pleomorphism and mitotic activity in the latter.7
Balloon cell melanoma may also be confused with sebaceous and xantho-
matous tumors. Sebaceous lesions have a characteristic ‘bubbly’ cytoplasm
Balloon and clear cell melanoma
and often the nucleus is crenated. In addition, sebaceous tumors express
Balloon cell melanoma is a very rare vertical growth phase variant with less epithelial membrane antigen as well as adipophylin and are S100 protein
than 20 cases well documented in the medical literature.1–5 There are no par- and HMB-45 negative. Xanthomatous lesions contain lipid, express CD68,
ticular distinguishing clinical features except that a polypoid configuration and are S100 protein negative.7–10
1338 Melanoma
Fig. 26.76 Fig. 26.77

Clear cell melanoma: this is an exceedingly rare variant of melanoma. In the Myxoid melanoma: this rare variant can be a source of considerable diagnostic
absence of a known history of melanoma or visible melanin pigment, the difficulty. Note the ‘undifferentiated’ irregular cells associated with an abundant
diagnosis depends upon immunohistochemistry. myxoid stroma.
Pure clear cell variants due to intracytoplasmic glycogen deposition are

very rare and may be encountered in primary tumors or metastatic deposits
(Fig. 26.76).5,11–16 They may be confused with clear cell carcinomas, includ-
ing clear cell squamous carcinoma, clear cell hidradenocarcinoma, and clear
cell metastases such as from clear cell carcinoma of the kidney. In cases
where there is real diagnostic difficulty, the use of immunocytochemistry for
melanocytic and keratin expression will resolve the issue.
Exceptionally, multiple small intracytoplasmic vacuoles can give rise to a
pseudolipoblast appearance with conspicuous nuclear scalloping.
Myxoid melanoma
Myxoid stromal change in melanoma is very rare and may be seen in primary,
recurrent, and metastatic disease.1–11 It is of no prognostic significance.4,8
Myxoid change is a feature of vertical growth phase melanoma. It may
be evident as a minor component of the tumor or be present throughout.
Tumors showing the latter can be a source of considerable diagnostic dif-
ficulty with epithelioid cases suggesting carcinoma and spindle cell cases
mimicking sarcoma. It has been described as a reactive change after pho-
Fig. 26.78
totherapy.12,13 Typically, the tumor cells are smaller than those present in
Adenoid (pseudoglandular) melanoma: this variant also associated with excess
nonmyxoid areas and may be epithelioid, spindled, or stellate in appearance mucin deposition may easily be misdiagnosed as an acantholytic squamous
(Fig. 26.77). Melanin pigmentation is variable. The mucin, which presents carcinoma or adenocarcinoma if a junctional component or pigment is absent.
as basophilic ‘stringy’ material, is usually PAS negative, colloidal iron and Diagnosis often depends upon immunohistochemistry. By courtesy of R.
Alcian blue positive, and sensitive to hyaluronidase (consistent with stromal Margolis, MD, St Elizabeth’s Medical Center, Boston, USA.
mucin).8 Often the melanoma cells are present as discohesive clumps, cords,
and strands such that a pseudoglandular or ‘acantholytic’ appearance may
sometimes result (Figs 26.78 and 26.79). Occasionally, pseudoacinar dif-
Melanoma with neuroendocrine differentiation
ferentiation and intercellular molding reminiscent of adenocarcinoma are
features.8 Neuroendocrine differentiation has been rarely described in melanoma
Immunohistochemistry is typical for melanoma, the tumor cells being cases and sometimes in non-cutaneous cases.1–4 Mixed melanocytic and
invariably positive for S100 protein and usually positive for HMB-45.8 neuroendocrine tumors have also been described in the lung, thymus, and
HMB-45 negativity has, however, been documented.5 thyroid and challenge current classification schemes.5 Immunohistochem-
Myxoid change may sometimes be seen in the stroma of desmoplastic ical expression of chromogranin and synaptophysin, along with neurofil-
melanoma, but other areas more typical of conventional desmoplastic mel- ament protein, has been noted as has expression of CD56.3 Less specific
anoma are usually present. markers of neuroendocrine differentiation such as neuron-specific enolase
Myxoid melanoma may be confused with mucus-secreting adenocar- and perhaps CD56 expressed in isolation should be interpreted with caution
cinoma and myxoid malignant peripheral nerve sheath tumor (MPNST) when seen in melanoma as they may not imply such differentiation. Char-
or other sarcomas. The former may be excluded on the basis of negative acteristic melanocytic markers remain intact. While not clearly associated
keratin immunocytochemistry and absence of PAS-positive mucin. Myxoid with any difference in natural history, neuroendocrine differentiation can
malignant peripheral nerve sheath tumor usually shows much less strong be associated with diagnostic confusion, especially with presentation at sites
and only focal S100 protein expression, and HMB-45 is negative. In addi- where other neuroendocrine tumors can be seen such as in the sinonasal
tion, MPNST limited to the dermis is exceedingly rare. region.6 Further complicating the distinction is that melanoma exhibiting
Fig. 26.79 Fig. 26.80

Adenoid (pseudoglandular) melanoma: high-power view showing undifferentiated Malignant blue nevus: note the heavily pigmented primary tumor associated with
tumor cells dispersed within abundant mucin. By courtesy of R. Margolis, MD, St multiple satellite lesions on this elderly patient’s forehead. By courtesy of the
Elizabeth’s Medical Center, Boston, USA. Institute of Dermatology, London, UK.
neuroendocrine differentiation appears to show small cell morphology.

Interestingly, carcinoid-like trabecular and pseudorosette patterns have
been noted in melanoma as well, but these cases lacked neuroendocrine
markers.7,8
Adenoid and pseudopapillary melanoma

This rare variant shows considerable overlap with myxoid melanoma.
Primary or metastatic deposits show extreme discohesion such that
pseudoglandular spaces sometimes with papillary architecture are formed
and sometimes these can be filled with mucin.1,2 Occasionally ‘intralumi-
nal’ papillary processes and ‘mucin’-filled lakes are formed, heightening the
resemblance to adenocarcinoma.3 A possibly related form has been described
as discohesive melanoma.4,5 In the latter, melanomas showed striking disco-
hesion of cells both in the intraepidermal and invasive component closely
mimicking an acantholytic disease.
Blue nevus-like melanoma (malignant blue nevus)

This term covers a variety of lesions including melanoma arising in a back-
ground of cellular blue nevus and to a lesser extent common blue nevus Fig. 26.81
or showing morphological overlap with blue nevus.1–5 Variants have also Malignant blue nevus:
been documented complicating nevi of Ito and Ota and pilar neurocris- this tumor arose on the
tic hamartoma.6–8 It also includes cases of melanoma that show histologic scalp. There is a dense
overlap with cellular blue nevi but which are devoid of a precursor lesion expansile tumor nodule
(de novo variants).9–13 Pigmented epithelioid melanocytoma (previously which has extended into
termed animal-type or pigment-synthesizing melanoma; see below) can the subcutaneous fat.
have a highly similar morphological spectrum but are distinct from blue
nevus-like melanoma at the genomic level.14
epithelioid or spindled melanocytes showing a diffuse growth pattern and
Clinical features obvious cytological features of malignancy (Figs 26.83 and 26.84).
Malignant blue nevi are often very slowly growing lesions that commonly Tumors that mimic cellular blue nevus, but in which no precursor lesion
present as a consequence of a sudden onset of growth and show a predilec- can be identified, commonly show an expansile growth pattern with usually
tion for the scalp (Fig. 26.80). Males are affected more often than females. pushing borders extending into the subcutaneous fat (Fig. 26.85). Occasion-
No age group is immune and exceptionally children are affected. This is a ally a dumbbell scanning morphology may be evident and rarely an alveolar
high-grade lesion with outcome similar to stage-matched cases of traditional growth pattern is seen.11 Typically, at low-power magnification, a diagnosis
melanoma cases.15,16 The lung, liver, and lymph nodes are most commonly of benign cellular nevus is anticipated. The tumor cells most often have
affected by metastatic disease. spindled cell morphology but epithelioid and mixed variants are sometimes
encountered. High-power detail, however, shows an increased nuclear-to-cy-
Histologic features toplasmic ratio, mild to moderate nuclear pleomorphism, hyperchromatism,
Tumors that arise in a background of pre-existent blue nevus typically show nucleolar prominence, and increased mitotic activity (Figs 26.86 and 26.87).
an abrupt transition from a benign precursor lesion to obvious melanoma Necrosis, sometimes exhibiting a geographic pattern, may also be present
(Figs 26.81 and 26.82). The latter presents as one or more nodules of and perineural infiltration is an occasional feature.
1340 Melanoma
Fig. 26.82
Malignant blue nevus:
a pilar blue nevus was
evident in the adjacent
skin.
Fig. 26.84
Malignant blue nevus: (A) there are multiple dendritic cells; (B) note the two
mitoses.
Fig. 26.83
Malignant blue nevus: the tumor cells have vesicular nuclei with prominent
nucleoli.
Scattered dendritic cells are often present in this second variant. Whether
this represents a residual benign precursor lesion or indicates malignant
dendritic cells is problematical. In favor of the latter possibility is the pres-
ence of dendritic cells in metastases (Fig. 26.88).
A subset of melanocytic proliferations is difficult to classify definitively
as benign or malignant. These have been referred to as atypical cellular blue
nevi or cellular blue melanocytic proliferation of uncertain malignant poten-
tial.1,17 There appears to be a lack of consensus regarding diagnostic criteria
for malignancy across the blue nevus spectrum.18
Both blue nevus and blue nevus-like melanoma are associated with muta-
tion in GNAQ or less commonly GNA11, encoding the alpha subunit of
a heterotrimeric G-protein.14,19 Similar to ocular melanoma, mutations in Fig. 26.85
BAP1, SF3B1, and EIF1AX are commonly encountered in blue nevus-like Malignant blue nevus: a
melanoma and their presence may help to establish malignancy.14,20 The precursor lesion was not
standard multi-probe FISH assay can be helpful in distinguishing blue identified in this case.
Fig. 26.86
Malignant blue nevus: note the central mitotic figure.
Fig. 26.88
(A, B) Malignant blue nevus: the sentinel node contained metastatic melanoma. A
small number of dendritic cells are present. This is the same case as illustrated in
Figures 26.81–26.84.
Fig. 26.87
Malignant blue nevus: dendritic cells are conspicuous in this field.
cases.14,15 Angiotropism can also be seen in nevi, particularly congenital
melanocytic nevi.16
nevus-like melanoma from atypical forms of cellular blue nevus, but limited Exceptionally, melanoma may show blood-filled dilated spaces lined
data are available.21,22 by endothelium-like tumor cells reminiscent of angiosarcoma (angioma-
toid melanoma).17–22 Intraluminal tufting may result in pseudoglomeruloid
structures.18
Angiotropic and angiomatoid
(pseudovascular) melanoma
Metaplastic melanoma (melanoma with
Angiotropism has been described in only a few cases of vertical growth
heterologous differentiation)
phase melanoma.1–5
Histologically, this rare manifestation of melanoma is characterized by Exceptionally, melanoma is associated with heterologous metaplastic ele-
the growth of melanoma cells within or along the walls of vessels, prin- ments, including bone and cartilage.1–6 Mostly, these have complicated acral
cipally veins, but usually without showing evidence of intravascular inva- lentiginous lesions (particularly arising in a subungual location) although
sion.1,6 While a relatively rare occurrence, interobserver concordance is high examples have also been described in primary desmoplastic melanoma,
when standardized diagnostic criteria are applied.7 More recently, this phe- mucosal melanoma, and melanoma arising in a congenital nevus.6,7 It can
nomenon has been suggested as a type of vascular invasion and shown to also be seen in metastatic melanoma, both with or without being present
be associated with a poor prognosis, perhaps even brain metastases in some in the cognate primary lesion.8,9 From the limited available literature, these
cases.8,9 It is also independently correlated with the presence of microsat- tumors are high grade (due to thickness at presentation) with frequent
ellites in primary cutaneous melanoma.10 Some contend that this pericytic metastases and considerable mortality. Histologically, they usually present
association may represent an extravascular mechanism for local or regional as sarcomatoid lesions with osteoid and to a lesser extent chondroblastic
metastasis.11,12 Angiotropism has also been described in epidermotropic differentiation (Figs 26.89 and 26.90). A number of these cases represent
and other metastatic melanomas.13 A recent mouse model study indicated osteosarcomatous differentiation, i.e., osteoid deposition in association with
that inflammation induced by UV exposure can promote angiotropism and malignant cells, and/or chondrosarcomatous differentiation.10,11 Too few
proposed this as a means of metastasis also relevant to humans in some cases have been reported to be certain whether heterologous differentiation
1342 Melanoma
Fig. 26.89 Fig. 26.91

Metaplastic melanoma: multiple deposits of osteoid are present in association Metaplastic melanoma: this melanoma was associated with an intense osteoclast-
with malignant cells in this amelanotic melanoma. like giant cell infiltrate.
under the name of pigmented epithelioid melanocytoma. There is certainly

morphological overlap with malignant blue nevus, but genomically these
two entities are distinct and we believe that they represent independent his-
tologic entities based on this and differences in their natural history. The
original term of animal-type melanoma was coined to reflect the similarity
of these tumors to melanocytic lesions occurring in horses and a variety of
experimental animal models – so-called equine melanotic disease.1,2 This is
a condition in which aging gray horses lose their pigmentation and develop
melanocytic tumors particularly around the external genitalia, undersurface
of tail, breast, and lip mucosa. Subsequent development of melanoma in
these animals is an important complication.
Clinical features
Around 200 cases of this seemingly rare tumor have been documented,
mostly as single case reports.3 Although the age range is quite wide, the
majority of lesions have arisen in patients in the second to fourth decades.4–7
There is no recognized sex or site predilection. Most present as 1.0 cm or
more diameter, brown, blue-black or black nodules or plaques clinically
thought to represent melanoma.8 These tumors can occur sporadically or
Fig. 26.90 as part of the autosomal dominant Carney complex where these tumors
Metaplastic melanoma: high-power view. have traditionally been termed epithelioid blue nevus.9 Carney complex
consists of spotty skin pigmentation, and a variety of unusual endocrine
and non-endocrine tumors such as myxomas, pigmented nodular adreno-
influences prognosis. Certain properties of mesenchymal stem or precursor cortical disease, calcifying Sertoli cell tumor and psammomatous melanotic
cells suggest a pluripotency that includes neural crest, osteogenic, and chon- schwannomas. This complex is associated with germline inactivating muta-
drogenic potential and may help explain the existence of this melanoma tions in the protein kinase A regulatory subunit, PRKAR1A on chromo-
variant.12 Some cases have been shown to express immunohistochemical some 17q.10,11 The unrelated Carney triad is a distinct condition comprised
markers of master regulatory genes for osseous and cartilaginous differenti- of gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal
ation such as SATB2 and SOX9.6,9 paraganglioma driven by succinate dehydrogenase (SDH) definiciency.12,13
Unusually, melanoma may undergo smooth muscle and rhabdomyoblas- Prognosis seems to be better than that of an ordinary melanoma of
tic differentiation.13–16 Case reports of melanoma showing ganglionic and equivalent thickness and it has been proposed that it may be regarded as
ganglioneuroblastic differentiation have been documented.17–19 a low-grade variant of melanoma. A recent meta-analysis of around 190
There are very occasional reports of conventional and desmoplastic mel- cases seems to confirm this notion, but that study was hampered by limited
anoma containing osteoclast-like giant cells (Fig. 26.91).20–25 follow-up for the reported cases and the lack of uniform diagnostic crite-
Rhabdomyosarcoma has been documented in a congenital nevus, includ- ria.3 Nonetheless, this study showed that with a median Breslow thickness
ing a giant form.26–28 of 3.8 mm and 16% ulceration, there were only six patients with distant
metastases and five patient deaths. Sentinel lymph node positivity rates were
notable at 41% of the 78 patients undergoing this procedure, but subse-
Pigmented epithelioid melanocytoma (pigment
quent progression was uncommon. Thus this tumor has a markedly supe-
synthesizing melanoma; animal-type melanoma)
rior prognosis to conventional melanoma.
An enigmatic lesion with many names, including pigment synthesizing mela-
noma, animal-type melanoma, melanoma with prominent pigment synthesis, Histologic features
equine type melanoma, and low-grade hypermelanotic dermal melanoma, Pigmented epithelioid melanocytoma is characterized histologically by a
this exceedingly rare variant of melanoma is now recognized by the WHO very dense infiltrate of heavily pigmented melanocytes, typically filling the
Fig. 26.92 Fig. 26.94

Pigment synthesizing melanoma: this low-power view shows the intense Pigment synthesizing melanoma: the tumor cells are uniform with large vesicular
pigmentation typical of this variant. nuclei and prominent eosinophilic nucleoli. Abundant pigment-laden macrophages
are present.
tumors previously termed pigment synthesizing melanoma.14–16 While these

lesions appear to have metastatic potential to involve lymph nodes, their
outcome is favorable compared to stage-matched cases of traditional mela-
noma.3 More and longer-term study of this entity and the above-mentioned
spectrum will be insightful.
Loss-of-function mutations in PRKAR1A are common. Gene fusions
with PRKCA encoding protein kinase Cα can also be seen in pure mela-
noma.17 In cases of combined nevi with conventional features and an area
resembling pigmented epithelioid melanoma, BRAF V600 mutations can
be seen with the PRKAR1A mutations. Cases with characteristic activating
GNAQ or GNA11 mutations would be better regarded as blue nevus or
blue nevus-like melanoma rather than pigmented epithelioid melanocytoma.
Use of the standard multi-color FISH assay to assess for malignancy in
pigmented epithelioid melanocytoma has been reported as helpful in a few
cases, but should be interpreted with caution given the alternative genetics
of this tumor.18,19
Fig. 26.93 Epidermotropic metastatic melanoma

Pigment synthesizing melanoma: scattered tumor cells are present in the lower
Metastatic melanoma is common and, in the majority of cases, causes
epidermis.
little diagnostic difficulty. Rarely, however, cutaneous deposits are accom-
panied by epidermal involvement such that distinction from a second or
papillary and reticular dermis and often spilling over into the subcutaneous third primary tumor can be extremely difficult, if not impossible, particu-
fat (Fig. 26.92). The epidermis may be atrophic or hyperplastic. A small larly if clinical information is not available (Figs 26.95 and 26.96).1–9 Tra-
number of cases are not purely intradermal but display a junctional com- ditionally, the features in favor of epidermotropic metastatic disease have
ponent (Fig. 26.93). In cases with a junctional component, tumor cells are included a well-circumscribed dermal nodule, widespread lymphovascular
plump and dendritic and do not tend to exhibit pagetoid spread. Tumor invasion, and filling of the papillary dermis by melanoma cells with atrophy
cells are spindled, polygonal, or rounded and are distributed in a fascicular of the overlying epidermis.1,10 Typically, the epidermal component is equal
or nodular growth pattern, sometimes displaying a focal storiform appear- in width to, or is less than, the dermal component. A lateral epidermal
ance.6 Dendritic processes may be identified. The tumor cell cytoplasm typ- collarette may sometimes be present. Exceptionally, patients have presented
ically contains abundant fine to coarse melanin granules, which commonly with showers of metastases which, due to extensive lateral spread of the epi-
obscure the nuclear morphology. Examination of bleached sections can be dermal component beyond the dermal mass or even wholly intraepidermal
helpful. The cytoplasm of tumor cells is pale, and nuclei appear enlarged and disease, have histologically been indistinguishable from a primary tumor. In
sometimes hyperchromatic. A single prominent basophilic nucleolus is often such instances, clinicopathological correlation is essential in establishing a
seen. Although there is cytological atypia, tumor cells display little variation diagnosis of metastatic disease.2,3 A recent study with molecular testing sug-
throughout the tumor (Fig. 26.94).6 Mitoses are typically sparse. The latter gests that the genetic relationship of primary melanomas and their potential
and the uniformity of tumor cells allow distinction from malignant blue epidermotropic metastases is complex, with certain cases showing divergent
nevus. Perineural infiltration may be present but lymphovascular invasion loss of heterozygosity and X-chromosome inactivation patterns consistent
has not been described. with either complex divergent clones or possibly new primaries.11 Addi-
This is an unusual tumor, which shows some histologic overlap with tional study is essential as the distinction has important staging implica-
other dermal dendrocytoses and blue nevus-like melanoma. These lesions tions. Epidermotropic melanoma is a satellite lesion that results in stage III
form part of the spectrum of pigmented epithelioid melanocytoma, which groupings under the 8th edition AJCC, whereas a second primary would be
includes the epithelioid blue nevus associated with the Carney complex and individually staged.12
1344 Melanoma
Fig. 26.95 Fig. 26.96

Epidermotropic metastatic melanoma: numerous tiny blue tumor deposits are Epidermotropic metastatic melanoma: this metastatic deposit is wholly
present in association with the scar from a previously excised melanoma. By intraepidermal and is indistinguishable from in situ superficial spreading
courtesy of J. Gershewald, MD, MD Anderson Cancer Center, Houston, Texas, melanoma. Diagnosis is entirely dependent upon the clinical history.
USA.
Fig. 26.97
Blue nevus-like metastatic melanoma: (A) at low-power examination, the
features could easily be mistaken for a common blue nevus; (B) in addition to
pigment-laden melanophages and dendritic cells, there are scattered melanoma
A cells. Note the multinucleate form with vesicular nuclei and prominent nucleoli.
The patient had a melanoma previously excised at this site.
Cytogenetic studies by FISH may be of help in establishing the distinction.

Blue nevus-like metastatic melanoma
In a study comparing epithelioid blue nevi with blue nevus-like cutaneous
Blue nevus-like metastatic melanoma is rare but represents a very serious metastasis, it was shown that most of the latter had important copy number
source of misdiagnosis.1–3 One or multiple lesions may be seen and they changes in chromosomes 6p25, 11q13, and centromere 6 while the former
usually, but not always, develop at sites close to the primary tumor. Very lacked cytogenetic changes.2 Uveal melanoma can also give rise to blue
rarely, lesions may be distant. They resemble a blue nevus clinically and nevus-like melanoma which can be detected by detection of genetic events
histologically. They are often small and microscopically are characterized such as monosomy for chromosome 3 resulting in loss of BAP1.4 Detection
by dendritic, deeply pigmented melanocytes. Cytological atypia can be of the GNAS or GNA11 mutation of uveal melanoma is not helpful alone
very subtle and this is further compounded by the prominent pigmentation in this context since these mutations can also be seen in blue nevi.
(Fig. 26.97). Bleaching can therefore be useful. Resemblance to ordinary
blue nevus or epithelioid blue nevus may be seen. Clues to the diagnosis
Desmoplastic and neurotropic melanoma
of malignancy reside in the presence of cytological atypia, mitotic figures,
and inflammation mainly at the periphery of the lesion. Histologic diagno- Desmoplastic and neurotropic variants of spindled cell melanoma are
sis is extremely difficult and close clinicopathological correlation is crucial. inter-related high-grade tumors that are commonly associated with histologic
Desmoplastic and neurotropic melanoma 1345
Fig. 26.98 Fig. 26.99

Desmoplastic melanoma: these tumors are frequently amelanotic, as seen in this Desmoplastic melanoma: this tumor was initially thought to represent a cyst. By
patient. By courtesy E. Wilson Jones, MD, Institute of Dermatology, London, UK. courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK.
diagnostic difficulty.1–7 A history of a mistaken diagnosis of reactive fibro- disease.3,24–30 Others have not observed this phenomenon as starkly, but this
blastic proliferative lesion is common and relates particularly to the usual could be due to differences in diagnostic criteria.31–34 In this regard it is
absence of melanin pigment and the relative infrequency of obvious epider- important to define desmoplastic melanoma carefully with the pure desmo-
mal melanocytic involvement, particularly in recurrent lesions. Desmoplastic plastic pattern being the predominant one, as cases showing a significant
melanoma represents an extreme degree of fibroblastic or myofibroblastic component (greater than 10%) of traditional melanoma show the more
metaplasia accompanied by abundant collagen synthesis. In the neurotropic characteristic metastasis to lymph node.35–37 Pure desmoplastic melanoma
variant, the metaplasia may be towards Schwann cell-type differentiation. appears to behave more like a sarcoma in terms of local recurrence and
Although not all desmoplastic melanomas are neurotropic and not all neu- metastatic pattern with the lung being the most common initial site rather
rotropic melanomas are desmoplastic, many authors regard them as vari- than regional lymph nodes. In regard to disease-specific survival, desmoplas-
ations on a theme.8 These tumors are in general associated with a high tic melanoma may behave similarly to classic melanoma, the poor progno-
incidence of recurrence and metastasis and a poor prognosis. sis reflecting an increased thickness of greater than 1.5 mm at presentation
in the vast majority of patients.3,38 Others have found that disease-specific
Clinical features survival for desmoplastic melanoma is superior to conventional mela-
Although the tumor may present at any age, the majority arise in the elderly noma.28 Pure and mixed variants of desmoplastic melanoma are reported
(mean age 61 years) and show a male preponderance (as high as 2.7 : 1), by some to have similar survival.39 There is some debate on this topic, with
which is particularly evident with the frankly neurotropic lesions.3,9–17 The some data that indicate an improved outcome for desmoplastic melanoma
head and neck are most frequently affected, but examples have been doc- patients.28,40–42 Poor prognostic indicators are high mitotic rate, tumor thick-
umented at a wide range of sites, including the trunk and upper or lower ness, ulceration, and inadequate excision margins (< 1.0  cm).3,17,23,43 The
limbs.9,18 The leg is particularly involved in females.3 Although the majority 5-year survival rate is of the order of 70–80%, and the overall mortality
of these neoplasms arise on sun-damaged skin in a background of lentigo varies from 11% to 66%.3,15,23
maligna (melanoma), superficial spreading and acral lentiginous melano-
mas, including subungual variants, have occasionally been documented.12,13 Histologic features
Desmoplastic melanoma has also been described on the palate, gingiva, lip, Desmoplastic melanoma is characterized by a diffusely infiltrative, some-
vulva, anus, and conjunctiva.19 Although a superimposed pigmented lesion times paucicellular, malignant spindle cell tumor with marked interstitial
of lentigo maligna may draw attention to this tumor, more often they present fibrosis and collagenization (Figs 26.100 and 26.101).1,2,9,19,44,45 It is to be
as amelanotic, flesh-colored or erythematous nodules or indurated plaques distinguished from the more common spindled cell melanoma unassociated
(Figs 26.98 and 26.99). These tumors are notoriously deeply infiltrative and with significant desmoplasia.
commonly have extended widely by the time of diagnosis. In addition to The infiltrate often leaves the immediate subepidermal papillary dermis
contributing to the high incidence of recurrence, neurotropism may result in unaffected, but frequently is found to extend into the subcutaneous fat or
peripheral and cranial neuropathy. Spread along the cranial nerves into the beyond at the time of diagnosis. Involvement of skeletal muscle or underly-
base of the skull with eventual meningeal involvement is a rare but import- ing bone is not uncommon. The tumor cytology is variable, the cells resem-
ant complication with an almost 100% mortality.18,20 Although most des- bling fibroblasts, smooth muscle cells, or Schwann cells. They are typically
moplastic melanomas arise in a background of severe sun damage, previous elongated and have eosinophilic or more commonly basophilic cytoplasm
irradiation (therapeutic or otherwise) is occasionally of etiological impor- (Fig. 26.102). Nuclei may be tapered and hyperchromatic or cigar-shaped
tance.9 Rarely, examples have complicated congenital melanocytic nevi and and vesicular with prominent eosinophilic nucleoli (Figs 26.103 and
even chronic burns scarring.21,22 26.104). Mitoses are scanty but may be conspicuous, and sometimes abnor-
Recurrence is common (range 22–77%, mean 46%) and metastasis mal forms are present (Fig. 26.105). Most commonly, the tumor has a dis-
(particularly to the lungs) frequently supervenes (range 11–56%, mean of tinctly fascicular arrangement, but focal storiform areas are occasionally
approximately 30%).10,15 Local control in the head and neck region, where evident, which can result in a mistaken diagnosis of dermatofibroma or der-
many of these tumors arise, is particularly problematic.23 Careful evalua- matofibrosarcoma protuberans. Foci of myxoid change, giving the tumor a
tion of surgical margins is critical for local control.17 Surprisingly, nodal feathery appearance, are sometimes seen. Recurrent tumors are frequently
spread has been documented very infrequently such that sentinel lymph paucicellular and are easily taken for scar tissue (Figs 26.106 and 26.107).
node biopsy is not regarded by some as an effective staging tool in this Tumor giant cells are an infrequent manifestation. Lymphocytic infiltrates,
1346 Melanoma
Fig. 26.100
Desmoplastic melanoma: Fig. 26.102
low-power view showing Desmoplastic melanoma: the tumor cells have basophilic cytoplasm and are
a spindle cell tumor dispersed in a densely collagenous stroma.
extending throughout
the full thickness of the
dermis and associated
with superficial lymphoid
infiltrates.
Fig. 26.103
Desmoplastic melanoma: nuclei are vesicular and nucleoli are prominent.
Fig. 26.101
Desmoplastic melanoma: the overlying epidermis shows an atypical lentiginous
melanocytic proliferation.
often evident as nodular aggregates, are a characteristic (but not diagnostic)

feature (Fig. 26.108). They are, however, a useful histologic pointer in early
lesions.46,47 Vascular invasion is sometimes present.
Careful scrutiny of the overlying epidermis not uncommonly shows fea-
tures of atypical melanocytic hyperplasia, most often of the lentigo maligna
pattern.9 Very occasionally, the changes of superficial spreading melanoma
are present. In a significant proportion of cases no such in situ change is
detected (the so-called de novo variant) (Fig. 26.109). Whether this rep-
resents regression, inadequate sampling, a de novo dermal tumor, or a previ-
ously treated in situ component is uncertain. In most examples, the invasive
tumor cell population is amelanotic.9
Vascular changes including hemangiopericytomatous features and glo-
meruloid vascular lesions may rarely be encountered.48 Fig. 26.104
The neurotropic variant of melanoma may show a range of manifesta- Desmoplastic melanoma: the tumor cells are compressed by the adjacent
tions.2,9,19,48 Microscopic perineural or endoneural involvement is common sclerotic fibrous stroma.
Fig. 26.105
Desmoplastic melanoma: note the central mitotic figure.
Fig. 26.106 Fig. 26.107

(A, B) Desmoplastic Desmoplastic melanoma:
melanoma: this example (A) high-power view
represents recurrent of tumor shown in
tumor following a previous Figure 26.106; (B)
excision. Melanoma can immunohistochemistry for
easily be mistaken for S100 protein highlights
scar tissue, particularly if B the considerable tumor
the clinical history is not cell population.
available. The lymphoid
aggregates should
A raise the suspicion of
desmoplastic melanoma.
Fig. 26.108
B Desmoplastic melanoma: nodular aggregates of lymphocytes are a useful
diagnostic clue.
1348 Melanoma
Fig. 26.109
Desmoplastic melanoma: Fig. 26.111
in this example, the Desmoplastic melanoma: epithelioid cells are sometimes encountered within the
overlying epidermis tumor. This example shows extensive peri- and intraneural spread.
shows no evidence of
a pre-existent atypical
melanocytic proliferative
lesion (the so-called de
novo variant).
Fig. 26.112
Desmoplastic melanoma (neural transformation): low-power view of a tumor
which has infiltrated through the full thickness of the dermis.
Fig. 26.110
Desmoplastic melanoma: perineural infiltration is very commonly present,
accounting in part for the high recurrence rate of this tumor.
in many desmoplastic melanomas (Figs 26.110 and 26.111). The term neu-
rotropic, however, is often reserved for lesions where nerve involvement
is very marked or more particularly when it results in clinical evidence of
nerve irregularity and thickening. In rare examples, the tumor appears to be
limited to a nerve trunk with no discernible spread to the adjacent tissues.9
Occasionally, the spindled cell population displays histologic features rem-
iniscent of neurofibroma, schwannoma, or malignant nerve sheath tumor
(sometimes known as neural transformation) (Figs 26.112–26.114).18,49
These latter features often comprise smaller cells, with pale eosinophilic
cytoplasm and irregular wavy nuclei separated by variable amounts of
collagen and ground substance and sometimes giving the tumor a loose
myxoid appearance. Mitotic activity is variable and therefore these vari- Fig. 26.113
ants can sometimes be very deceptive, resulting in a mistaken diagnosis Desmoplastic melanoma (neural transformation): the tumor cells have small,
of benign nerve sheath tumor. Recently, neurotropic melanoma associated twisted, and comma-shaped nuclei with ill-defined eosinophilic cytoplasm
with profound vascular infiltration (so-called angiotropic melanoma) has reminiscent of peripheral nerve sheath tumor. Note the nuclear hyperchromatism.
positivity was documented in the earlier literature, more recent studies have
not confirmed this observation.70,71 Loss of p16 reactivity can be useful in
distinguishing desmoplastic melanoma from desmoplastic nevus when this
differential diagnosis arises in small biopsies, but not all desmoplastic cases
show loss.72,73 P75 nerve growth factor receptor,WT1, and nestin immuno-
histochemical markers have also been suggested to have clinical utility.74–76
Desmoplastic melanoma has been described to MPNST. Loss of H3K27
nuclear staining characteristic of MPNST is not helpful for distinguishing
MPNST from melanoma, desmoplastic, or otherwise, as a subset of melano-
mas also show nuclear loss of this histone trimethylation marker.77
Evaluation of scar versus desmoplastic melanoma can be difficult as
the degree of fibrosis in desmoplastic melanoma can be extensive with
only scattered melanoma cells. This same problem complicates the assess-
ment of margins. Use of polyclonal S100 protein immunohistochemistry in
the setting of re-excision can be complex given the focal S100 reactivity
present in many scars due to scattered macrophages and other cells showing
Schwannian differentiation.78 Careful assessment of the degree of nuclear
hyperchromasia in these spindled cells is paramount in evaluating these
situations.79
Fig. 26.114 Metastases may be desmoplastic, neuroid, or more obviously melano-
Desmoplastic melanoma: the adjacent epidermis shows atypical melanocytic cytic. Although some authors have suggested that the desmoplasia is a
lentiginous hyperplasia.
consequence of reactive stromal fibroblast hyperplasia, it is now generally
accepted that these features are of melanocytic derivation.
Ultrastructural studies have shown that the tumor spindled cells may
rarely contain premelanosomes and melanosomes.1,2 Fibroblastic, myofibro-
blastic, and Schwann cell differentiation, particularly in neurotropic variants
(including elongated and interdigitating cellular processes sometimes encir-
cling collagen fibers reminiscent of mesaxon formation, discontinuous basal
lamina, and intercellular junctions) have also been documented.19,71,80–83
The genome of desmoplastic melanoma harbors approximately an order
of magnitude more mutations than that seen in conventional cutaneous mel-
anoma.84 Most of these are UV-linked. Exome sequencing revealed recur-
rent NFKBIE promoter mutations, and activation of the MAP kinase and
PI-3 kinase pathways through mutations in genes such as NF1, MAP2K1,
MAP3K1, EGFR, MET, RAC1, and PIK3CA.84–88 Mutations in BRAF V600
and NRAS G61 were not seen. TERT promoter mutations are common as
well.89 Standard multi-probe FISH can be useful to demonstrate desmoplas-
tic melanoma over other mimics.90
Differential diagnosis
The diagnosis of desmoplastic melanoma is frequently missed, particularly
if only superficial biopsies are available for study. The lesion is commonly
misdiagnosed as a reactive process, such as scarring and superficial nodular
Fig. 26.115
fasciitis, and deeper lesions may be mistaken for a fibromatosis or even
Desmoplastic melanoma: the tumor cells are strongly S100 protein positive.
fibrosarcoma. Examples showing storiform morphology have sometimes
been confused with atypical fibrous histiocytoma and dermatofibrosarcoma
protuberans. Scar tissue may be a particular problem, especially in recurrent
been documented.50 Metaplastic bone formation has been described albeit lesions.91,92 Pointers towards the latter include horizontal orientation of the
rarely.51 Sarcomatoid dedifferentiation is also rarely noted.49 fibroblast population, absence of adnexae, loss of the rete-ridge pattern, and
Immunohistochemically, desmoplastic melanoma expresses S100 protein vertically orientated dermal blood vessels. Immature scar tissue, however,
(94–100%), neuron-specific enolase, and vimentin (Fig. 26.115).3,36–38,40,41 can be much more problematical and, in the case of re-excision specimens
HMB-45 (gp100) may be positive in the superficial papillary dermal tumor or recurrences, the features may represent an admixture of both.92 Recur-
cells but more often is totally negative.52–57 The results with MART-1 rent lesions following surgery may sometimes be associated with marked
(melan-A) are variable (24–60% positive), and tyrosinase does not appear nerve proliferation in addition to scar tissue. SOX10 and S100 may display
to be present in desmoplastic melanoma.58–60 Microphthalmia transcription positivity in scars and although this positivity can be strong it is usually
factor (D5) is of limited value, expression having been documented in from restricted to a small number of cells.93
only 35% to 55% of cases.61,62 A relatively new marker, SOX10, is reactive Diagnosis is dependent upon an awareness of the condition and often
in melanoma, desmoplastic melanoma, and peripheral nerve sheath tumors requires the inclusion of a battery of immunohistochemical markers to
and can be a very useful marker.63–66 Members of the S100 protein family establish the histogenesis of the tumor infiltrate. In many instances, however,
such as S100A6 may have efficacy in distinguishing desmoplastic melanoma careful scrutiny of the epidermis to detect atypical melanocytic hyperplasia
from malignant peripheral nerve sheath tumors, but the diffuse pattern of combined with the use of antibodies to S100 protein and pankeratin (to
traditional polyclonal S100 protein expression in melanoma is usually suffi- exclude desmoplastic spindled cell squamous carcinoma) will be sufficient
cient in this regard.67 Melanoma cell adhesion molecule may be more useful, to establish the correct diagnosis. Occasionally, in recurrent disease, pro-
82% of tumors in a series of 17 tumors having shown strong expression.68 liferating neural elements may be admixed with scar and residual tumor
EMA may be present in up to 43% of tumors but keratin, leu 7, CD31, and with resultant increased diagnostic difficulty. Neurofilament protein, which
CD34 are uniformly negative.48,55,56,68 Smooth muscle actin is often positive, is expressed by the neural elements but not the melanomatous component,
reflecting the myofibroblastic population.55,56,69 Although occasional desmin can often be of discriminatory value.
1350 Melanoma
Melanoma in children
Clinical features
Melanoma is extremely rare in children; less than 1% of all melanomas
present in childhood.1–20 Historically, many so-called examples have likely
represented misdiagnosed Spitz nevi.13 As a consequence, pathologists and
clinicians are extremely reluctant to make the diagnosis, with resultant delay
in treatment and potentially devastating consequences. Although excep-
tionally the tumor may develop in utero (complicating a large congenital
nevus or arising de novo) or be acquired transplacentally (from a maternal
melanoma), the majority are acquired and may be related to sun exposure
during childhood.4,14,21 Predisposing conditions include xeroderma pigmen-
tosum, dysplastic nevi, familial melanoma, melanoma-pancreatic cancer
syndrome, giant congenital nevi, neurocutaneous melanosis (leptomeningeal
melanoma), prior irradiation, Li-Fraumeni syndrome, and immunodefi-
ciency.3,4,14,22–27 Melanoma arises in up to 12% of giant congenital nevi (i.e.,
those that measure 20 cm or more in diameter) and this can occur during
childhood or later adult life.28–30 It has been suggested that childhood mel-
anoma can be segregated into three distinct categories based on the age of
diagnosis: congenital melanoma which occurs in utero up to birth; infan-
tile melanoma that presents after birth up to 1 year of age; and childhood
melanoma that occurs after 1 year of age to puberty.31 Some include in the Fig. 26.116
Childhood melanoma:
childhood melanoma category patients up to the age of 18, but such upper
example of melanoma
age ranges are clearly arbitrary.32 which has arisen in a
The sexes are affected equally and tumors are more common in the giant congenital nevus.
second than the first decade.9 The majority of childhood melanomas have
developed in Caucasians.7 Lesions arise on the trunk and extremities, with
only 20% affecting the head and neck.5 Many childhood melanomas are not
easily recognized clinically.13,33 Sometimes, however, clinical features similar
to those described in adults – including increase in size, change in color, and
onset of bleeding – may be encountered.14,17
Some earlier reports suggested that the prognosis of melanoma in chil-
dren might be favorable.34 In our experience, however, childhood tumors
behave no differently from adult ones with the possible exception of spit-
zoid melanomas in very young patients as discussed further below. This is
also generally borne out in the more recent literature.4–6,13,18,35–37 Overall,
childhood melanoma should therefore be treated in much the same way
as adult tumors and, when appropriate, sentinel lymph node mapping and
biopsy are recommended.4,6,13,38–40 The majority of children present with
stage 1 disease with a 5-year disease-free survival rate of 77%.4,7 Crude
survival figures for the largest series reported to date are 71% overall, 64%
males, 81% females.9 Some, but clearly not all or even most in some series,
melanomas of childhood exhibit Spitz-like histology.41 These cases may have
a more favorable outcome than in adults, particularly in patients aged 11 or
less, but this finding is not universal.41–44 This could be due to inappropriate
assignment of Spitz nevi, albeit atypical, to the melanoma group; however,
even such tumors metastatic to lymph nodes appear to have a better prog-
nosis.45,46 Clearly, more study is required. Nonetheless, mortality is encoun-
tered within this age group. Spitzoid melanoma is discussed in more detail Fig. 26.117
in the section above. Childhood melanoma: in this view, pleomorphic tumor cells are seen on the left;
nevus is present on the right.
Histologic features
Melanoma in children may arise within the context of a precursor lesion
such as a banal, congenital, or dysplastic nevus or it may present de novo.
Melanoma arising within a giant congenital nevus presents most often as a TERT promoter mutations are common, excepting the cases arising in con-
dermal, sharply delineated nodule composed of tumor cells showing obvious genital nevi.49
cytological features of malignancy (Figs 26.116–26.118).30 Although all the As with adult melanoma, the most important prognostic indicators are
common subtypes may be encountered, superficial spreading and nodular Breslow thickness and presence of ulceration. Melanoma in children should
melanoma variants are most frequently seen (Figs 26.119–26.123). Partic- be reported in exactly the same way as adult melanoma.51
ular subtypes that often cause diagnostic difficulty include small cell mel-
anoma, spitzoid melanoma, and malignant blue nevus.7,11,47 These are all Differential diagnosis
described under variants of melanoma (see above). Clinicopathological correlation is of great importance when considering a
Cytogenetic features detected by FISH are similar to those seen in adult diagnosis of melanoma in a child, particularly in the first few years of life.
superficial spreading melanoma.48 BRAF mutations can be seen in free- Significant cytological atypia affecting junctional and dermal components
standing cases while NRAS mutations are seen in the cases associated with accompanied by pagetoid spread and mitotic activity is not uncommon in
congenital nevi.49,50 UV damage signatures are commonly encountered and congenital nevi, especially those affecting neonates.
Basomelanocytic tumor 1351
Fig. 26.118
Childhood melanoma: in the center of the field is an atypical mitotic figure. Fig. 26.120
Childhood melanoma:
there is surface
ulceration. By courtesy of
M. Little, MD, University
College Hospital, Galway,
Ireland.
Fig. 26.119
Childhood melanoma: this tumor, which presented as a nodular lesion, arose in
a girl aged 13 years. By courtesy of M. Little, MD, University College Hospital,
Galway, Ireland.
Fig. 26.121
Dermal squamomelanocytic tumor Childhood melanoma:
there is no maturation
Clinical features with depth. Note the
sharply delineated lower
Reports of this tumor are exceedingly rare in the pathology literature.1–6
border. By courtesy of
Patients present with brown or purple-black facial nodules measuring up M. Little, MD, University
to 1.0 cm in diameter. The age range documented is 32–94 years and there College Hospital, Galway,
have been less than 15 cases reported with equal sex distribution.5 A pre- Ireland.
cursor lentigo maligna has been documented in one case.1 The relatively
short follow-up information (mean 2.7 years) has shown no evidence of
recurrence or metastasis.2 A recently reported ‘metastatic’ case purportedly 26.126).2 Matrical differentiation has also been described.5 The two popu-
showing micrometastasis to a sentinel lymph node has an appearance much lations are distinctive morphologically, but the distinction is highlighted by
more characteristic of a capsular nevus.6,7 S100 protein or other melanocytic markers and cytokeratin immunohisto-
chemistry (Fig. 26.127).2
Histologic features
Although a precursor lesion or origin from the epidermis may be identifi-
able, the tumor may present as an upper dermal nodule independent of any Basomelanocytic tumor
epidermal connection (Fig. 26.124).2 A case limited to the epidermis has
also been described.3 It consists of a sharply delineated, lobular tumor com- Clinical features
posed of intimately admixed malignant squamous epithelium and a usually Basomelanocytic tumor is a very rare biphasic neoplasm similar, or
less prominent population of malignant melanocytes (Figs 26.125 and perhaps related, to the dermal squamomelanocytic tumor described above.1
1352 Melanoma
Fig. 26.122 Fig. 26.125

Childhood melanoma: the presence of expansile nodules is an important Dermal squamoproliferative tumor: in this field, the tumor is composed of variably
diagnostic clue. By courtesy of M. Little, MD, University College Hospital, Galway, pigmented cells with irregular hyperchromatic nuclei. By courtesy of S. Poole,
Ireland. MD, Beth Israel Deaconess Medical Center, Boston, USA.
Fig. 26.123
Childhood melanoma: multiple dermal mitoses are present in this field. By
courtesy of M. Little, MD, University College Hospital, Galway, Ireland. Fig. 26.126
Dermal squamoproliferative tumor: focal squamous differentiation is evident. By
courtesy of S. Poole, MD, Beth Israel Deaconess Medical Center, Boston, USA.
However, basomelanocytic tumor is a combination of basaloid carcinoma

and melanoma.2–4 As would be expected, the melanocytic component of the
tumor appears to be the more aggressive component and has been reported
to metastasize with fatal outcome.3
Histologic features
In this combined tumor, the basaloid component in the few described cases
can take the appearance of a basaloid squamous cell carcinoma or be more
basal cell carcinoma-like (Fig. 26.128). Unlike so-called collision tumors,
biphasic tumors show an intimate association of the epithelial and mela-
nocytic components. An intraepidermal component is not always present.
Cases of melanoma metastatic to a basal cell carcinoma or colonization
by melanoma in situ have been described as mimics of basomelanocytic
tumor.5,6
The melanoma component stains with traditional melanocytic markers
such as S100 protein, MART-1, and HMB-45 (Fig. 26.129). Cytokeratins,
Fig. 26.124 including AE1/AE3, mark the basaloid component, and Ber-EP4 can also be
Dermal squamomelanocytic tumor: low-power view of a facial tumor. By courtesy positive (Fig. 26.130).3,4 Characteristic copy number alterations can be seen
of S. Poole, MD, Beth Israel Deaconess Medical Center, Boston, USA. in the melanoma component.1
Lentiginous melanoma 1353
Fig. 26.129
Basomelanocytic tumor: the inner cells express HMB-45. Mart-1 was also
positive. By courtesy of L. Erickson, MD, Mayo Clinic, Rochester, Minnesota.
Fig. 26.127
Dermal squamoproliferative tumor: (A) the squamous component is highlighted
with keratin immunohistochemistry; (B) S100 protein. By courtesy of S. Poole,
MD, Beth Israel Deaconess Medical Center, Boston, USA.
Fig. 26.130
Basomelanocytic tumor: the background population of basaloid cells expresses
keratin. By courtesy of L. Erickson, MD, Mayo Clinic, Rochester, Minnesota.
Lentiginous melanoma
Clinical features
This type of melanoma should be distinguished from acral lentiginous mela-
noma. These tumors have a propensity for the shoulders and upper back in
elderly patients while the lower legs, particularly in younger female patients,
may also be affected.1–6 Similar to lentigo maligna, this form of melanoma
may be associated with an extended in situ phase of many years, and in an
important number of cases there is a precursor lesion. The latter have been
described as atypical lentiginous melanocytic nevus and dysplastic atypical
nevus of the elderly with some questioning whether these lesions are truly
malignant.7–9 Additional study is required to further define and characterize
this seemingly distinct lesion.
Histologic features
Lentiginous melanoma, as the name implies, consists of a primarily single
Fig. 26.128 cell array of melanocytes achieving confluence at least focally with limited
Basomelanocytic tumor: surrounding undifferentiated tumor cells is a striking associated junctional nests (Figs 26.131–26.133). Pagetoid intraepidermal
palisade of basophilic cells typical of basal cell carcinoma. By courtesy of L. ascent can be noted but it tends to be very focal when present. Epidermal
Erickson, MD, Mayo Clinic, Rochester, Minnesota. atrophy is not present and there is preservation of normal rete architecture
1354 Melanoma
at the dermal–epidermal junction. Cytological atypia varies and may not be

prominent, and solar elastosis is not a feature. These features help separate
this entity from other forms of lentiginous melanoma. Melanocytic stains
may be helpful to better visualize the increased density of atypical mela-
nocytes. These lesions may be more readily recognized in larger excision
specimens as the features may be difficult to discern in smaller biopsies.2 As
stated before, in many lesions there is evidence of a lentiginous nevus with
variable atypia, suggesting a precursor lesion. This is the reason the diagno-
sis can be missed in small biopsies.
Primary dermal melanoma
Clinical features
The described cases of this apparently rare presentation of melanoma show
a dermal nodule lacking an identifiable in situ component or association
with a pre-existing nevus.1–4 Published series indicate that this presentation
of melanoma represents less than 1% of all melanomas.5–7 A wide ana-
tomic distribution is reported, but the head and neck region and extremities
Fig. 26.131 are the most common sites. In one study, in a cohort of 13 patients, the
Lentiginous melanoma: in this field, there is a lentiginous and focally nested average Breslow depth was 9.6 mm with 92% survival at a mean of about
atypical melanocytic proliferation. Note the upper dermal lymphocytic infiltrate.
4 years.8,9 Subsequent studies have documented a somewhat less impressive
but still relatively favorable 88% 5-year survival in a cohort of nine cases
with a median Breslow thickness of 3.4 mm.6 A series of 49 cases with
mean Breslow depth of 3.0 mm and mean mitotic rate of 4.3 per mm2 is
also reported.7 A caveat of this latter series is that 14 cases showed associa-
tion with a pre-existing intradermal nevus and average follow-up was only
26 months. Nineteen percent of patients developed locoregional recurrence
and 6% showed distant metastases; only one patient died of disease. Tra-
ditional AJCC parameters did not correlate with outcome. These studies
suggest that this tumor behaves much less aggressively than comparable
traditional nodular melanoma. Others examining a larger series of 101
cases defined as a solitary dermal melanoma (as distinct from melanoma of
unknown primary which usually presents as an isolated lymph node metas-
tasis) within larger well-characterized cohort of 12,817 patients found no
difference in outcome compared to stage-matched traditional melanomas.5
Other studies show various results, but most include melanoma of unknown
primary which could skew the results.10–14 Indeed, in all of these papers, it
is unclear whether the authors are describing the same tumor. Much more
study is needed to refine our definitions and understanding of this possible
entity and delineate its natural history. At the present time, this presenta-
tion is probably best assessed and reported as a standard melanoma with
Fig. 26.132
Lentiginous melanoma: the tumor cells are predominantly basally located. There is
risk proportional to the assessed Breslow depth, though a note suggesting
no evidence of solar elastosis. that such cases have been described to have more indolent behavior would
certainly be appropriate.
Histologic features
The lesion is characterized by a nodular deposit of melanoma composed
of epithelioid to spindled cells in the dermis and/or subcutis. Spitzoid and
blue nevus-like features have been noted in some cases, but many have
the appearance of traditional melanoma.7 Some cases have conspicuous
mitoses, but overall a Ki-67 index may be lower than that seen in com-
parable cases of nodular melanoma or metastatic melanoma.8 It would be
extremely important to distinguish these cases from metastatic melanoma
or melanoma of unknown primary, both of which have vastly different
staging implications.15 This can be challenging and indeed such cases have
now been described to have BRAF and NF1 mutations as well as P16/
CDKN2A loss and other copy number aberrations similar to traditional
cutaneous melanoma.7,16 Explanations for this entity include an origin in
association with follicular melanocytes and complete regression of a prior
intraepidermal component. More recently, de la Fouchadiere and colleagues
have described five cases of non-pigmented dermal melanoma each with
a CRTC1-TRIM11 fusion that are dermal based and nodular in outline.17
Cytology ranges from epithelioid to spindled sometimes with scattered mul-
Fig. 26.133 tinucleate cells. In some ways the appearance is similar to that of clear cell
Lentiginous melanoma: junctional nests showing moderate to severe cytological sarcoma which can also sometimes be confined to the dermis.18 Behavior is
atypia are evident. low grade. This lesion would appear to fall within the spectrum of primary
Molecular classification of melanoma 1355
dermal melanoma though where it falls in the end in the spectrum between indicate such a signature.5,6 For example, the most common mutation at
melanoma and dermal clear cell sarcoma remains to be seen. BRAF codon 600 is a T to A transition and thus does not match the clas-
sical UV signature.7 The fact that these mutations lack a UV signature does
not exclude a role for UV radiation in their formation, as they can form as
Molecular classification of melanoma
the result of indirect consequences of UV radiation such as the formation
Over the last decade significant molecular data have shed new light on dif- of reactive oxygen species. Furthermore, activating an oncogene requires
ferences between melanoma subtypes. This continues to inform an emerging mutations to change very specific amino acid sequences in the protein,
classification, which integrates epidemiology, clinical and histopathological whereas abrogating a tumor suppressor protein’s function can occur
features with patterns of somatic mutations and mutational mechanisms. through numerous possible mutations (missense, nonsense, and frameshift
This final portion of the melanoma chapter focuses on conceptual infor- mutations). Therefore, mutations that activate oncogenes tend to cluster in
mation regarding the molecular classification of melanoma and its cor- a few critical hotspots, whereas mutations in tumor suppressor genes are
relation to UV damage, as well as the progression from melanoma in situ more widespread and enriched for damaging mutations that truncate or
to invasive and metastatic melanoma. Molecular data continue to inform scramble the DNA sequence. The need for specific growth promoting muta-
our traditional classification schemes, validating them in some instances tions in oncogenes such as BRAF and NRAS therefore significantly skews
and expanding them in others. While traditional classification categories the mutations observed in these genes. The causative role for UV radiation
of melanoma are still employed, the molecular characterization of mela- in mutagenesis of melanomas on sun-exposed skin is clearly demonstrated
nocytic neoplasia continues to progress and will have to be continually by the high burden of UV signature mutations in the tens to hundreds of
integrated with the traditional features to establish a classification system thousand mutations found in the genomes of cutaneous melanomas and
that correctly describes distinctive phenotypes but is firmly based in the by the observation that mutations in critical genes such as the TERT pro-
underlying mechanistic alterations that are in large part caused by genetic moter, CDKN2A, P53, and PTEN are indeed enriched for UV signature
alterations. mutations.8,9
However, not all melanoma subtypes harbor genomic damage attrib-
Melanoma epidemiology utable to UV radiation. Melanomas arising on the palms and soles, nail
Melanomas are most common in Caucasians, where they typically arise on beds, and mucosal sites, as well as uveal melanoma, typically lack the high
sun-exposed skin. In patients under the age of 50, the highest density is mutation burden with a UV signature found in cutaneous melanomas. This
found on the trunk and extremities. In patients older than 50, the highest indicates that while UV radiation plays a critical role in the pathogenesis of
density of melanomas is found on the head and neck. The high frequency of some melanoma subtypes, it does not in others. This could also explain why
melanoma and non-melanoma skin cancers in Caucasians is considered to acral and mucosal melanomas affect all world populations independent of
be the result of light skin pigmentation with the consequence of increased skin complexion.10
UV-induced mutagenesis. Some aspects of skin color variation are likely due
to selective advantage during human evolution that optimizes benefits from Melanoma is composed of distinct subtypes
solar radiation (e.g., lighter skin pigmentation to enhance vitamin D syn- There is considerable variation in the clinical and histopathological presen-
thesis) in less sunny climates. Association studies have revealed common tation of melanomas that partially depends on the anatomic site in which
polymorphisms in pigmentation genes are genetic factors controlling skin the tumor arises and how much ultraviolet radiation exposure has occurred.
color, tanning ability, and freckling, with some variants increasing mela- As outlined previously in this chapter, these differences formed the tradi-
noma risk. These pigmentation genes include the melanocortin receptor tional ‘histogenetic’ classification of melanoma as initially proposed in the
one (MC1R), its antagonist the agouti signaling protein (ASIP), tyrosinase Sydney Classification.11 There has been considerable controversy on the jus-
(TYR), tyrosinase-related protein (TYPR), the P-gene mutated in oculocuta- tification of this classification and opponents have long posited that mel-
neous albinism type II (OCA2), ion exchange proteins of the solute carrier anoma is a single disease, with the variation in clinical and pathological
family SLC24A5, SLC24A4, and SLC45A2 (MATP), and the interferon reg- features representing secondary phenomena. This belief stemmed both from
ulatory factor IRF4 or MUM1.1 the lack of difference with regards to prognosis of advanced disease and the
Decreased pigmentation in Caucasian skin leads to decreased protection inability in the past to predict a different response to therapy between sub-
from UV radiation and results in increased somatic mutations in skin cells, types.12 In addition, there was significant overlap in the defining phenotypic
including melanocytes. However, increased melanoma susceptibility in Cau- features that hindered unequivocal classification of a considerable portion
casians may not be entirely attributed to differences in skin pigmentation, of primary tumors.13
because albinos of African descent do not share the increased incidence of Considerable progress has now been made in the identification of genetic
melanomas, while they do suffer more frequently from cutaneous squamous alterations in melanoma and has provided strong support for the concept of
cell carcinoma.2 Melanin, which is present in Caucasian skin and absent biologically distinct melanoma types. This is consistent with work leading
in albinos who lack functional tyrosinase, appears to have both protec- to the discovery and validation of clinically relevant genetic subtypes that
tive and deleterious effects for DNA. Mutations from UV radiation con- have emerged in other malignancies such as lung and colon cancer. This is
tinue to accumulate in the skin for hours after removal from UV light.3 a decisive trend in oncology that is critical for the implementation of pre-
These ‘dark’ mutations do not occur in albino mice lacking melanin. In cision cancer medicine. Mutations in specific genes, mutational signatures,
mice with intact melanin production, these mutations were twice as fre- and other genetic alterations such as genome-wide chromosomal aberra-
quent in those with increased pheomelanin (due to MC1R mutation) versus tions correlate with specific clinical and histopathological features of mel-
those with high eumelanin, implicating melanin, particularly pheomelanin, anoma, providing genetic support for the original concept that melanomas
as a critical factor in these ‘dark’ mutations. Further evidence is found in fall into different categories of diseases. New genetic data offer an oppor-
transgenic mouse models in which melanoma development after UVA radi- tunity to integrate causal genetic alterations with clinical or histopatholog-
ation only occurs in black mice with intact melanin production and not in ical disease attributes, as well as predisposing and environmental factors.
albino mice.4 The emerging melanoma subtypes that integrate clinicopathological features
overlap considerably with the original ‘histogenetic’ melanoma types, but
Melanoma and UV radiation offer a more nuanced picture of the categories. This continuity is satisfying
The establishment of a causal link between UV radiation and melanoma and underscores the enduring importance of thoughtful clinicopathologi-
formation requires several considerations. UV radiation causes a wide spec- cal characterization as a basis for initial classification. The extent of UV
trum of mutations. Among these UV signature mutations, pyrimidine dimers radiation damage can serve as an initial branch point in the classification
resulting in C > T or CC > TT transitions are the most common and are due of melanoma: melanomas found in skin with high cumulative sun damage
to a direct photochemical reaction with the DNA. However, mutations in (high-CSD), low cumulative sun damage (low-CSD), and melanomas on
common melanoma oncogenes such as BRAF and NRAS typically do not sites with negligible (e.g., acral) or no sun exposure (e.g., mucosal).
1356 Melanoma
%\0XWDWLRQ6WDWXV
Melanoma on sun-exposed skin
0XWDWLRQ %5$) 15$6 1(,7+(5
Epidemiological data alone suggest differences between melanomas from
sun-exposed skin and melanomas on acral or mucosal sites, the latter of :+27\SH
which do not show variation in incidence between races. Additionally, the 3LJPHQW
anatomic site of origin and the cumulative dose of UV radiation are two 6FDWWHU
intricately linked features that are strongly associated with distinctive clin-
1HVWLQJ
ical and histopathological presentations of melanoma. Melanomas on the
head and neck tend to occur in older individuals with a peak incidence of &LUFXPVFULSWLRQ
about 72 years of age.14 The skin surrounding these melanomas typically (SLG&RQWRXU
shows signs of chronic sun damage, as evidenced by pronounced solar elas- 6RODU(ODVWRVLV
tosis and other signs of chronic sun-induced damage such as solar lentigi-
&HOO6KDSH
nes and actinic keratoses.15 Total cumulative UV dose appears to represent
a major risk factor for these melanomas. The traditional lentigo maligna &HOO6L]H
variant of melanoma falls into the high-CSD category.
$JH
By contrast, melanomas involving the trunk arise earlier in life, with a
peak incidence at around age 54, and signs of chronic sun damage (severe Fig. 26.134
solar elastosis) are typically absent.14 The drop in incidence of melanomas Morphological and clinical features of 302 primary melanomas by mutation
on the trunk after age 54 suggests that it is not the cumulative dose of status: the heat map shows the features that are significantly associated with
UV radiation but timing of UV exposure that plays a decisive role in these mutation status for three groups of melanomas: BRAF mutant, NRAS mutant,
or neither mutation. The scores for the features in the following rows range
melanomas, with a particular window of vulnerability present earlier in
from shades of blue (low score) to gray (intermediate scores) to yellow (high
life. Epidemiological studies demonstrate that exposure to UV irradiation
scores): pigmentation of neoplastic melanocytes, upward scatter of intraepidermal
in childhood plays an important role in the pathogenesis of melanoma in melanocytes, nesting of melanocytes, degree of solar elastosis, cell size, and
general.16 Patients with melanomas on the trunk, but not with melanomas patient age. For circumscription, yellow indicates an abrupt transition from
on chronically sun-exposed sites such as the face, have more melanocytic involved to adjacent uninvolved skin, gray scores represent a continuous
nevi, suggesting a common pathogenesis between low-CSD melanomas and transition, and blue scores a discontinuous transition. Epidermal contour ranges
nevi.17 This is supported by the fact that low-CSD melanomas more fre- from yellow (acanthotic) to blue (atrophic) of the epidermis involved by the
quently have adjacent precursor nevi than CSD melanomas and that nevi melanoma. Cell shapes range from blue (round) to yellow (spindled). Samples
and low-CSD melanomas share a high frequency of BRAF V600E muta- are listed in columns and are ordered within each category using agglomerative
tions. A functional scale for assessing sun damage has been proposed to hierarchical clustering. The color codes for WHO types are superficial spreading
melanoma (SSM) green, lentigo maligna melanoma (LMM) yellow, nodular
grade the degree of solar elastosis involving the dermis.18,19 Recent studies
melanoma (NM) red, and acral lentiginous melanoma (ALM) orange. Unclassifiable
have demonstrated how melanomas progress from such nevi through the
samples are in black.
acquisition of additional UV-associated mutations.20 The fact that most nevi
arise during childhood and adolescence furthers highlights the possibility
of a window of vulnerability towards UV radiation early in life for these
types of melanocytic neoplasms.21 Genetic data also support the concept of loss.20 The latter mutations reflect the importance of replicative senescence
distinct melanoma types based on sun-exposure as discussed below.22 and maintaining G1/S checkpoint control in preventing nevi from progress-
ing to melanoma. UV signature mutation profiles implicate UV radiation as
Melanoma with low cumulative sun damage (low-CSD) the driving factor in this transformation of nevi to melanoma.20
Low-CSD melanomas occur most frequently in patients under 50 on the Progression from in situ to invasive melanoma involves additional genetic
trunk or extremities and show a low to moderate degree of solar elastosis alterations required for unrestrained growth outside the confines of the epi-
histopathologically. BRAFV600E mutations are very common (approximately dermis. Ability to grow and survive in the dermis alone is not indicative of
70%) in low-CSD melanomas, representing the main driver mutation, fol- malignant transformation, as the cells of melanocytic nevi already have this
lowed by NRAS mutations (approximately 20%).19,23 BRAF mutant mel- property. Loss of cell cycle checkpoint regulation is critical in unleashing or
anomas frequently exhibit specific histomorphological features such as increasing the proliferative capacity associated with invasive melanoma as
increased upward scatter of intraepidermal melanocytes (pagetoid scatter), evidenced by frequent homozygous loss of the CDKN2A gene encoding both
a predominance of nests over single cells, thickening of the involved epider- p16 and p14ARF in the transition from in situ to invasive melanoma. Addi-
mis, a sharper demarcation toward the adjacent uninvolved epidermis, and tional mutations in genes encoding critical tumor suppressor proteins such
constituent tumor cells that are larger, rounder, and more heavily pigmented as TP53 and PTEN occur later in the progression to more advanced stage
(Fig. 26.134).24 Simple combinations of these independently associated fea- disease.20 Additionally, invasive melanomas must evade antitumor immune
tures predicted BRAF mutation status with 90% accuracy in one study.24 surveillance through mechanisms such as induction of immune tolerance.
These histomorphological criteria also performed better in predicting muta- The vast majority of melanomas exhibit some degree of genomic insta-
tion status than the traditional WHO melanoma classification, indicating bility in the form of chromosomal gains and losses. This instability seems to
the potential for developing improved classification schemes that define coincide with the transition from benign melanocytic nevi to melanoma in
more biologically homogeneous subsets. This is increasingly relevant with situ, as nevi tend to not have chromosomal copy number changes, whereas
the increased use of targeted therapies to specific genetic alterations includ- they can be detected in melanoma in situ.20 The instability may be related to
ing BRAF inhibitors25 and KIT inhibitors.26–28 telomere shortening and end-to-end fusion of sister chromatids with eroded
The shared high incidence of BRAFV600E mutations in melanocytic nevi telomeres that result in dicentric chromosomes that can rupture during
and low-CSD melanomas supports a common etiology with regard to UV mitosis. The selective advantage of TERT promoter mutations early during
radiation and timing of exposure. Approximately one-fourth to one-third of melanoma progression suggests that replicative senescence becomes an early
melanomas arise within histopathologically identifiable precursor nevi, with barrier to transformation. TERT promoter mutations only lead to marginal
low-CSD melanomas representing the main melanoma type in which precur- telomerase expression, which manages to preserve critically short telomeres
sor nevi can be identified.29 Frequently only melanoma in situ is present with but cannot fully suppress telomere fusions resulting in instability that gen-
the associated nevus, the latter of which remains identifiable in the under- erates DNA copy number changes.30 This explains why the telomeres of
lying dermis. The melanoma in situ harbors the same initiating mutation melanomas with TERT promoter mutations remain short.30,31
as the precursor nevus (typically BRAF or NRAS), with additional genetic While there are some similarities in the patterns of the chromosomal
aberrations such as TERT promoter mutation or heterozygous CDKN2A gains and losses across melanoma subtypes, significant differences exist with
0.6 Gains Fig. 26.137

0.2 .,7 .,7DQG .,7DQG 15$6 %5$) Frequency distribution of
-0.2
Non-CSD
Losses 15$6 %5$) genetic alterations in BRAF,

-0.6 NRAS, and KIT among four
0.2 Amplifications groups of melanoma: non-
0.0

Homozygous deletions CSD, melanomas on skin
-0.2
without chronic sun-induced
1 3 5 7 9 11 13 15 17 19 21 damage; CSD, melanomas
on skin with chronic sun-
induced as evidenced by the
3HUFHQW$EHUUDQW
0.6 Gains presence of marked solar
0.2
elastosis; acral, melanomas
-0.2
Losses on the soles, palms, or
CSD
-0.6
0.2
subungual sites; mucosal,
Amplifications
0.0 melanomas on mucosal
-0.2 Homozygous deletions membranes. One CSD
melanoma had a KIT and
1 3 5 7 9 11 13 15 17 19 21
an NRAS mutation, and one
Fig. 26.135 acral melanoma had a KIT
1RQ&6' &6' $FUDO 0XFRVDO
Frequencies of DNA copy number changes in non-CSD and CSD melanomas: and a BRAF mutation.
the upper histogram for each melanoma type shows the frequencies of gains
(green) and losses (red), and the lower histogram shows amplifications (green)
and homozygous deletions (red). The x axis represents the genomic position By contrast, activating mutations in NRAS activate both the MAP kinase
from chromosome 1 to 22. Vertical solid blue lines mark the boundaries between and the PI3 kinase pathway, therefore obviating the need for a loss of PTEN
chromosomes, and the vertical dashed gray lines mark the position of the in tumors with NRAS mutations.32 Point mutations in the catalytic subunit
centromeres. of PI3 kinase have also been found in a small minority of melanomas.33
Gains of chromosome 7 are more common in low-CSD melanomas.19
BRAF resides at 7q34 and the copy number increase reflects duplication of
Receptor Tyrosine Kinase the mutant BRAF allele, which provides a proliferative advantage.34,35 Copy
(e.g., KIT) number increases of CCND1 encoding cyclin D1 at chromosome 11q13
represent an additional distinguishing feature as they occur infrequently
in low-CSD melanomas, while present in up to 50% of high-CSD mela-
noma.19,36 These genetic changes demonstrate how both the major prolif-
PTEN erative and survival pathways are activated during melanoma progression.
NRAS
BRAF PI3K
This can be accomplished through different combinations of mutations and
chromosomal aberrations such as activating mutations in upstream tyrosine
kinase receptors such as KIT or NRAS which activate both the MAP kinase
MEK AKT
pathway and PI3K pathway, or through combinations of activating muta-
tions in BRAF combined with loss of PTEN (Fig. 26.136).
ERK Survival Melanoma with high cumulative sun damage (high-CSD)

High-CSD melanomas typically occur in Caucasians over age 50 mostly on
p16
the head and neck and display marked solar elastosis histopathologically.
CCND1 In contrast to low-CSD melanomas, high-CSD melanomas typically have
CDK4 no associated precursor nevus, arising ‘de novo’ in the epidermis. These
CDK6 melanomas are often characterized by an extended in situ stage, in which
Proliferation the neoplasm can grow to the size of several centimeters over many years
prior to becoming invasive. Genomic data on the in situ stage of high-CSD
melanoma are limited. Approximately 20% of such in situ melanomas have
Fig. 26.136 BRAF mutations, although BRAFnon-V600E mutations (e.g., BRAFV600K) are
Simplified schematic of pathways important in melanoma: downstream from more frequent than BRAFV600E mutations in this group.37 In addition to the
certain receptor tyrosine kinases lies Ras which bifurcates to the BRAF/ERK and striking difference in BRAF mutations between high-CSD and low-CSD
PI3K/AKT pathways leasing to proliferation and survival. It appears that activation melanomas (15% vs 70%),34,38 additional genetic differences have also been
of both of these pathways (and others) is required for melanoma development found. For instance, some studies report up to 30% of high-CSD melano-
and these are grouped in a rational fashion. For instance, activating mutations
mas harbor mutations or DNA copy number increases of KIT, whereas KIT
in KIT, NRAS, and BRAF are mutually exclusive since they activate the same
pathways and loss of PTEN is seen with BRAF, but not NRAS mutation, because
mutations are rare in low-CSD melanomas (Fig. 26.137).39 Differences in
NRAS activates the PI3K pathway while BRAF does not. These combinations will the mutation frequency of NRAS have been reported by some, but do not
likely have therapeutic relevance as more specific inhibitors are developed. appear to be a consistent finding.19,40
Desmoplastic melanoma represents a specific variant of melanoma that
occurs in chronically sun-damaged skin and has a high mutation burden
respect to tumors based on the degree of UV exposure.19 Gain of chromo- that typically exceeds that of all other melanomas (median 62 mutations/
some 6p and loss of 6q are common in both low-CSD and high-CSD mel- Mb compared to approximately 15/Mb in low-CSD melanoma).41 The
anomas, but chromosome 10 loss occurs in 40% of low-CSD melanomas mutational profile of desmoplastic melanoma has a strong UV radiation
and fewer than 10% of CSD melanomas (Fig. 26.135). The region com- profile and is notable for the complete absence of BRAF and NRAS hotspot
monly lost on chromosome 10 contains the tumor suppressor PTEN, which mutations and a high prevalence of inactivating NF1 mutations, which can
encodes a negative regulator of the PI3 kinase pathway and is considered also be detected in the overlying in situ component.41,42 In addition, there are
to represent the major selective force for chromosome 10 loss. BRAF muta- recurrent mutations in the promoter of NFKBIE, which encodes an inhibi-
tions only activate the MAP kinase pathway, which explains the advantage tor of nuclear factor NF-κB signaling, and inactivating mutations in TP53,
of concurrent PTEN loss to activate the PI3 kinase pathway (Fig. 26.136).32 CDKN2A, ARID1A, ARID2, and RB1. TERT promoter mutations are also
1358 Melanoma
Table 26.3
Genes implicated in melanoma development
Gene Function Associated with melanoma susceptibility
ACD/POT1/TERF2IP Nuclear proteins that bind telomeres and prevent inappropriate recombination events Yes
ARID1/ARID2 Chromatin remodeling
BAP1 Deubiquitinase that binds to BRCA1 and is involved with chromatin dynamics Yes
BRAF Protein kinase in the MAP kinase pathway
CDKN2A Encodes p16, an inhibitor of cyclin-dependent kinases, and p14, an inhibitor of MDM2 Yes
CDK4 Cyclin-dependent kinase that phosphorylates Rb Yes
CTNNB1 Encodes beta-catenin, an adherens junction protein that signals in the WNT pathway
ERBB4 EGFR family of tyrosine kinase receptors involved in differentiation and proliferation
GNAQ/GNA11 G-protein coupled receptor that activates phospholipase C-beta
KIT Tyrosine kinase receptor activating multiple pathways in cell survival and proliferation
MC1R Encodes the melanocortin 1 receptor that binds melanocyte stimulatory hormone Yes
MGMT DNA repair protein Yes
MITF Transcription factor in melanocyte development Yes
NF1 Encodes neurofibromin that negatively regulates RAS signaling
NRAS Tyrosine kinase receptor that activates the MAP kinase and PI3K pathways
POLE DNA polymerase subunit involved in DNA repair Yes
PTEN Lipid phosphatase antagonist of PI3K pathway Yes
RAC1 GTPase involved in cell growth
SLC45A2 Transporter protein in melanin synthesis Yes
TERT Encodes telomerase which maintains telomere length; can be amplified or have Yes
promoter mutation
TP53 Encodes tumor suppressor p53
XP genes Xeroderma pigmentosum genes encode nucleotide excision repair proteins Yes
common in desmoplastic melanomas.41 Desmoplastic melanomas have fewer corneum providing additional UV protection. The nail matrix is protected
chromosomal copy number alterations than most other melanomas, though by the proximal nail fold and the nail plate. With the exception of the lips
focal amplifications of oncogenes such as EGFR, CDK4, CCND1, MDM2, and the bulbar conjunctiva, mucosal sites in which melanoma arise are not
TERT, and MAP3K1 and focal deletions in tumor suppressor genes such as exposed to sunlight. Genomic analyses with CGH and DNA sequencing in
CDKN2A occur.41 melanomas from these UV-protected sites show a high degree of genomic
Numerous other recurrent genetic alterations have been discovered in instability reflected by frequent chromosomal aberrations, with focused gene
melanomas on sun-exposed skin including amplifications or mutation of amplifications in particular and a low mutation burden (Fig. 26.138).19,50–53
MITF and activating mutations in CTNNB1, encoding β-catenin. MITF is a The mucosal example in Fig. 26.138 in particular shows copy number
basic helix-loop-helix (hHLH)-leucine zipper protein that plays a role in the changes affecting virtually every chromosome. Although mucosal melano-
development of melanocytes.43 β-catenin is a critical signaling component of mas are typically detected with considerable latency and therefore tend to
the WNT pathway where it acts as an adherens junction protein that can be thicker than the primaries of the other melanoma categories, this high
also function as a transcription factor and is mutated in a small subset of degree of genomic instability can already be demonstrated in thinner lesions.
melanomas.44,45 It is also increasingly clear that telomere-related proteins In other cancers, gene amplifications usually arise late during progression
are critical factors in melanoma development. Germline mutations in com- and often are a sign of adverse prognosis.54 By contrast, in acral melanoma
ponents of the telomere shelterin complex (e.g., POT1, ACD, TERF2IP), these amplifications arise very early during progression and can already be
which is responsible for capping telomere ends and preventing recombina- detected at the in situ stage.50
tion events, have been linked with familial melanoma.46 Mutations in the Gene amplifications typically arise through repeated cycles of
promoter of TERT, a gene encoding the protein component of telomer- double-stranded DNA breaks and subsequent end-to-end fusions of chro-
ase, have also been described in familial melanoma and in 35% to 70% of matids and thus indicate a loss of control over genomic integrity. The cause
sporadic melanomas.47,48 TERT promoter mutations are the most common of this loss of control and subsequent genetic instability is currently unclear
mutations in melanoma and have a UV signature C > T pattern. The predis- since TP53 and other known instability-inducing mutations are uncommon
posing mutations in TERT and other telomere-related factors are thought in these melanomas. While it is evident that UV radiation does not play
to contribute to increasing melanoma risk by increasing telomere length and a significant role in these melanomas, it is currently unresolved whether
extending the replicative lifespan of neoplastic cells, thereby increasing the or not there are specific carcinogens involved in the pathogenesis of acral
likelihood of acquiring the additional mutations required for transforma- and mucosal melanomas or whether they arise as a consequence of sto-
tion.49 Numerous additional genes have been implicated in melanoma, many chastic alterations without external influence. The marked differences in the
of which are listed in Table 26.3. degree of genomic instability and mutation burden between melanomas on
sun-protected sites and those on sun-exposed skin indicates that the types
Melanomas on UV-protected sites of genetic insults are fundamentally different between these melanoma sub-
Acral and mucosal melanoma types. In sun-exposed melanomas UV photoproducts and oxidative damage
The volar surfaces of the hands and feet are minimally exposed to UV radi- are the predominating drivers of tumorigenesis, whereas double-stranded
ation, and glabrous skin has a thicker epidermis with a very thick stratum DNA breaks as part of breakage-fusion-bridge cycles and/or other yet to be
2 4 6 8 10 12 14 16 18 20 22 Y 10 mm
2.0
A B
1.5
1.0 C
Non-CSD
0.5
Log2Ratio
0.0
-1.0
-2.0
1 3 5 7 9 11 13 15 17 19 21 X
1.0292
D
2 4 6 8 10 12 14 16 18 20 22 Y
3
2
Log2Ratio
1
CSD
-1
-2
1 3 5 7 9 11 13 15 17 19 21 X Cyclin D1
1.0292
hTERT
65 0.24 sample AM108 acral
2 4 6 8 10 12 14 16 18 20 22 Y Fig. 26.139
2.0 Field cells in acral melanoma: the top panel shows an acral melanoma with
1.5
close-ups of four particular areas underneath. Area A shows superficially invasive
1.0
melanoma that by FISH shows amplification of CCND1 (cyclin D1) and TERT
0.5
Log2Ratio
telomerase reverse transcriptase (clusters of red and green signals in blue stained
Acral
0.0
nuclei, respectively). Area B shows melanoma in situ with amplification of CCND1
-1.0 and normal copy number of hTERT. Areas C and D show histopathologically
uninvolved epidermis which by FISH harbors single basal melanocytes with
-2.0 amplification of CCND1 (clusters of red signals within blue stained nuclei). In the
1.0292 1 3 5 7 9 11 13 15 17 19 21 X
second FISH panel for area D a melanocyte with CCND1 amplification is situated
72 0.37 sample AM124 amucosal in an eccrine duct.
2 4 6 8 10 12 14 16 18 20 22 Y
2.0
1.5
1.0 that they reflect an early progression phase of disease.55 Once their clini-
Mucosal
0.5 cal relevance has been defined, the determination of field effect may offer
Log2Ratio
0.0
a more objective guidance for the size of surgical margins for removal of
-1.0 primary melanomas than the current empirically derived recommendations.
Although acral and mucosal melanomas share a high incidence of chro-
-2.0 mosomal aberrations, including frequent gene amplifications, the genomic
1.0292 1 3 5 7 9 11 13 15 17 19 21 X
regions affected by these copy number alterations differ significantly
Fig. 26.138 between the two.19 The most commonly amplified site in acral melanomas
Differences in the degree of genomic instability among melanoma types: is the CCND1 locus encoding cyclin D1 on chromosome 11q13. Another
representative examples of array CGH profiles of non-CSD, CSD, acral, and commonly amplified site includes the TERT telomerase locus on chro-
mucosal melanoma. The y axis represents the copy number for each array mosome 5p15. However, while approximately 50% of acral melanomas
element (average value of a triplicate measurement) expressed as the log2 of amplify CCND1, mucosal melanomas typically do not. Instead, a subset of
the ratio of the tumor to reference fluorescence intensities. Values between mucosal melanomas amplifies cyclin dependent kinase 4 (CDK4) on chro-
+0.25 and –0.25 would be considered normal; values above that range are mosome 12q14, encoding the binding partner of cyclin D1.19 CDK4 is nor-
gains and below that range are losses. Values above 0.9 would be considered mally inhibited by p16 function, which functions as the gatekeeper of the
amplifications. In practice, a more complex assessment that takes into account
G1/S transition point. In mucosal melanomas, the amplification of CDK4
the signal-to-noise ratio for each individual case is used.33 The x axis represents
the genomic position from chromosome 1p to 22.
is mutually exclusive with deletions at the p16 locus, indicating that these
genomic aberrations may be functionally equivalent. Mucosal melanomas
also have recurrent mutations in SF3B1, a gene commonly mutated in uveal
discovered mechanism(s) appear critical for acral and mucosal melanoma melanoma, which is typically not found in acral melanoma.56
formation. In contrast to the high number of chromosomal copy number changes
This chromosomal instability in acral and mucosal melanoma occurs and amplifications in acral and mucosal melanomas, their mutational
early in disease progression and has even been detected in histopathologi- burden is much lower than sun exposed melanomas. Many of the mutations
cally normal appearing melanocytes around acral melanoma in situ, so-called show a pattern of mutagenesis seen with aging in which there is sponta-
field cells or field effect (Fig. 26.139).55 Field cells harbor some, but not all neous deamination of 5-methylcytosine at CpG dinucleotides.31 UV signa-
of the gene amplifications found in the adjacent melanoma, indicating that ture mutations are absent for the most part. Most genetic studies of acral
they are precursors of the histopathologically manifest form of melanoma and mucosal melanoma focus on invasive melanoma, with very little pub-
in situ (Fig. 26.140). These cells represent clonal expansions of melanocytes lished on the in situ stage. BRAFV600E mutation in acral melanoma in situ
with severe genetic alterations stemming from loss of control over mainte- has been reported,57 but the incidence of BRAF mutation in acral melanoma
nance of genomic integrity. Such genetic changes are qualitatively different (approximately 15–20%) is significantly lower than in low-CSD melanomas
from point mutations in oncogenes such as BRAF, as they indicate loss (approximately 70%) and even lower in mucosal melanoma (approximately
of protective factors that preserve genomic integrity. Field cells are there- 5%), suggesting BRAF mutation initiates a comparatively small percentage
fore best interpreted as an early form or precursor of melanoma in situ. of these melanomas.34,58–63 NRAS mutation and KIT mutation or amplifi-
These fields of neoplastic melanocytes can be extensive, present up to > 1  cm cation are more frequently found in acral and mucosal melanoma.58,64,65
beyond the histopathologically detectable in situ portion, and the size of the These two mutations activate the MAP kinase pathway and drive prolifera-
field is completely independent of tumor thickness, further demonstrating tion, so it is logical to assume they occur in the early proliferative phase of
1360 Melanoma
toward the uninvolved epidermis. These growth characteristics may be

related to biological effects of KIT activation. KIT is essential for mela-
noblast migration from the neural crest into the skin and for homing into
epithelial structures during development. If constitutively active KIT is
introduced into human melanocytes in vitro, it induces a migratory phe-
notype resembling a lentiginous pattern.78 Aberrant KIT signaling in mela-
noma may therefore help explain the field effect described for melanomas
on acral skin (Figs 26.139 and 26.140).50
Melanocytic tumors arising without associations to

epithelial structures
Most melanocytic neoplasms, benign melanocytic nevi as well as mela-
nomas, originate from melanocytes situated within epithelial structures
throughout the body and have mutations in genes such as BRAF, NRAS,
NF1, and KIT. However, a subset of melanocytic neoplasms arises without
an apparent connection to epithelial structures and does not show these
mutations.38,79 One category, uveal melanoma, arises from melanocytes
within the choroidal plexus, the ciliary body, and the iris of the eye and is
biologically distinct from cutaneous melanoma by a very strong propensity
to metastasize to the liver.80 It also differs in the presence of certain chro-
mosomal aberrations such as frequent loss of chromosome 3, which serves
as a negative prognostic indicator in uveal melanoma.81 In the skin, intra-
dermal melanocytic proliferations, which can be congenital or acquired,
present in diverse ways ranging from discrete blue papules (blue nevi) to
large blue-gray patches affecting the conjunctiva and periorbital skin (nevus
of Ota), shoulders (nevus of Ito), and the lower back (Mongolian spot).82 A
potential connection between intradermal melanocytic neoplasms and uveal
melanoma is suggested by the fact that nevus of Ota represents a risk factor
for uveal melanoma in Caucasians. In addition, blue nevi can show cytolog-
ical similarities to uveal melanoma.80 Interestingly, while uveal melanomas
strongly express KIT on immunohistochemistry, they lack mutations in the
KIT gene.79
A forward genetic screen in mice identified germline mutations in the
Fig. 26.140 heterotrimeric G-protein subunits GNAQ and GNA11 that cause skin
Field cells in acral melanoma: bottom panel: clinical picture with (1) melanoma in hyperpigmentation by inducing a subtle intradermal proliferation of mela-
situ; (2) clinically, dermoscopically, and microscopically normal skin; (3) invasive nocytes.83 GNAQ and GNA11 are members of the q class of G-protein
melanoma of 3.0-mm thickness. Black line, surgical margin; white line, field cell alpha subunits and are involved in mediating signals between G-protein
margin identified by amplification of 11q13. Middle and upper panels, respectively: coupled receptors (GPCRs) and downstream effectors.84 Somatic mutations
H&E and FISH for areas 1–3. FISH images represent one focal plane, so not all in GNAQ are found in 83% of blue nevi, 50% of blue nevus-like melanoma
signals are visible. A green immunofluorescent labeled Melan-A antibody was (‘malignant blue nevi’), and 46% of uveal melanomas.85 The mutations in
used to aid in identifying basal melanocytes. Cells with amplification of 11q13 are human tumors differed from the genetic variants discovered in the mouse
highlighted by arrowheads for areas 1 and 2 (upper panels). screen. In human melanocytic tumors, all mutations occurred exclusively at
codon 209, which is homologous to codon 61 of NRAS family members
and leads to constitutive activation. GNAQ activates protein kinase C
melanoma in situ on acral and mucosal sites. Future studies are necessary (PKC) family members PKCδ and ε via the release of diacylglycerol (DAG)
to confirm this supposition. TERT promoter mutations are less common in by phospholipase Cβ.86 In vitro studies show that the GNAQQ209L muta-
acral melanoma (approximately 10%),58 but TERT gene amplification is tion transforms melanocytes with efficiencies comparable to NRAS muta-
frequently seen and has been documented in acral melanoma in situ.66 tions and leads to activation of the MAP kinase pathway. This MAP kinase
While mutations in the receptor tyrosine kinase KIT often occur in acral activation occurs specifically through recruitment of RasGRP3 to the cell
and mucosal melanomas, similar to high-CSD melanomas, their incidence membrane by DAG and its phosphorylation and activation by PKC δ and
varies by anatomic site.34,56,58,67–69 Anorectal and vulvovaginal have the ɛ. RasGRP3 then activates RAS to initiate MAP kinase pathway signaling.86
highest number of KIT mutations (approximately 35%).56,68–70 Anorectal When introduced into murine melanocytes, mutant GNAQ induces heavily
melanomas also have frequent NF1 and SF3B1 mutations (20% each), the pigmented tumors that morphologically resemble the spectrum of human
latter of which is often present in uveal melanomas.56 Twenty percent of blue nevi and pigmented epithelioid melanocytomas, confirming its role in
acral and penile melanomas have KIT mutations58,68 while oral melanomas driving these tumor types.85
have approximately 10% KIT mutation prevalance.62,63 While early clini- While GNAQ or GNA11 mutations are sufficient to initiate growth of
cal trials of unselected melanoma patients failed to show any efficacy with these melanocytic neoplasms (Fig. 26.141), additional genomic aberrations
KIT inhibitors,71 subsequent case reports and follow-up studies indicate that are required for transformation into melanoma (e.g., uveal melanoma, blue
when melanoma patients with confirmed KIT mutations are selected for, nevus-like melanoma). Additional mutation or loss of the tumor suppressor
dramatic responses to KIT inhibitors such as imatinib and other agents do BRCA1-associated protein 1 (BAP1) gene in uveal melanoma is associated
occur.26–28,72–74 Although the majority of melanomas with genetic alterations with a poor prognosis and has also been found in the transformation of blue
in KIT overexpressed the protein as determined by CD117 immunohisto- nevi to melanoma.87,88 Recurrent SF3B1 and EIF1AX mutations have also
chemistry, increased immunoreactivity does not reliably predict responding been found. They typically occur in mutually exclusive fashion from BAP1
patients.39,75–77 Patients with KIT amplification without mutation do not loss and are associated with a more indolent disease course.89,90 Array CGH
appear to significantly benefit from the KIT inhibitor therapy.72–74 profiling of cellular blue nevi, atypical cellular blue nevi, and blue nevus-like
The melanoma categories in which genetic alterations of KIT are found melanoma shows increasing genomic instability during progression through
frequently show a lentiginous growth pattern and poor circumscription these stages, with most nevi having no chromosomal aberrations and a
features, appears to be a heterogeneous category with the majority of cases

representing BRAF and NRAS mutant melanoma98 rather than melanomas
that evolved from bona fide Spitz nevi or atypical Spitz tumors with HRAS
mutations or various kinase fusions. The genetic features of bona fide
Spitzoid melanomas, i.e., melanomas that originate from Spitz nevi or are
closely related to them molecularly, are currently poorly characterized. Both
homozygous loss of CDKN2A99 and TERT promoter mutation100 appear to
occur in some lethal Spitzoid melanomas, though the small number of cases
reported with these aberrations limits the generalizability of these findings.
Emerging concepts in metastatic melanoma

The traditional concept of melanoma progression to metastasis starting
from primary invasive melanoma and spreading through lymphatics to
regional lymph nodes, and then from regional lymph nodes to distant sites
is inadequate in explaining the observed biological behavior of metastatic
melanoma. Phylogenetic analysis of separate metastatic foci in melanoma
patients shows genetically distinct populations within the same patient,
indicating that parallel seeding of metastatic sites occurs from the primary
tumor followed by subsequent separate genetic evolution at the sites of
metastasis.101–103 Metastatic ‘reseeding’, in which cells from a distant met-
astatic site travel to other sites of metastasis and proliferate,104 may also
occur and could explain the emergence of multifocal treatment resistance
Fig. 26.141 to targeted therapies in some patients.105 Some evidence supporting WNT
An animal model pathway activation in the progression to metastatic melanoma has been
of GNAQ mutant reported,101,106 and MITF amplification has been found to be more preva-
melanocytes: mouse lent in metastatic disease.107 However, multiple genetic analyses of primary
melanocytes stably tumors and metastases have not identified a distinct set of genetic changes
transduced with mutant that reproducibly predict progression to metastasis.108–110
GNAQ, but not with
wild-type GNAQ, induce The Cancer Genome Atlas
highly pigmented tumors
The Cancer Genome Atlas (TCGA) is a National Institute of Health
of spindled and epithelioid
melanocytes after 10 (NIH)-sponsored cooperative effort to comprehensively analyze various
weeks cancer types. The TCGA published results on a collaborative, multi-platform
analysis of 333 melanomas with a high percentage of metastatic melano-
mas (80%, mostly regional lymph node metastases) representing the largest
study of melanoma to date.111 This study categorized melanoma by DNA
minority of atypical cellular blue nevi showing one to two chromosomal mutations, copy number alterations, gene expression (RNA), non-coding
aberrations.88,91 Blue nevus-like melanomas exhibit multiple chromosomal RNA, methylation, protein expression, and histologic images linked to a
aberrations (typically ≥ 3) including recurrent deletions of chromosomes 1p, database with clinical annotation and follow-up. In this analysis, melano-
3p, 4q, 6q, 8p, 9, 16, and 17q and recurrent gains of chromosomes 6p, 8q, mas were classified into four types: BRAF, RAS, NF1, and triple-wild type
20, and 21q.88,91 (WT). The first three types had > 90% UV signature mutation profile with
Another signaling pathway implicated in the pathogenesis in tumors high-frequency TERT promoter mutations corresponding to the low-CSD
that share phenotypic features with blue nevi is the protein kinase A and high-CSD melanoma classes. The triple WT melanoma mutation profile
(PKA) pathway. Loss-of-function mutations in a regulatory subunit of PKA was only 30% UV signature with < 10% TERT promoter mutation and
(encoded by PRKAR1A) are found in epithelioid blue nevi associated with had more copy number changes and fusion driver events, corresponding
Carney complex and result in hyperactivation of PKA with subsequent to the category of acral and mucosal melanomas. RNA expression analy-
activation of the MITF transcription factor.92 Such mutations have also sis identified three clusters with significantly different survival rates, with
been detected in a subset of tumors designated as pigmented epithelioid the ‘immune’ signature subgroup having the most favorable survival rates
melanocytomas.93 and the ‘keratin’ signature subgroup showing an adverse prognosis.111 This
and additional studies demonstrating prognostic value from histologic doc-
Spitzoid melanoma umentation of lymphocytic infiltrates as well as expression profiling of the
Spitzoid melanocytic neoplasms represent a class of neoplasia with a range immune response in these tumors have been reported as well.112 A separate
of malignant potential from Spitz nevi at the benign end to spitzoid mel- TCGA study of primary uveal melanoma cases (n = approximately 80%)
anoma at the malignant end, and atypical Spitz tumors as a biologically demonstrated the near universal detection of GNAQ and GNA11 muta-
intermediate category. Spitz nevi are defined by distinct histopathological tions as well as poor prognosis associated with chromosome 3 monosomy
features and an age distribution skewed towards children. They have a dis- (loss of the tumor suppressor BAP1) on chromosome 3p.90 In addition,
tinctive mutational landscape that distinguishes them from common nevi, EIF1AX and SF3B1 mutations were associated with distinct copy number
which include activating mutations in HRAS and kinase fusions of ROS1, alteration and methylation patterns within the chromosome 3 disomy group
NTRK1, NTRK3, ALK, BRAF, RET, or MET.94–97 Spitz nevi tend to have that corresponded to better prognosis.
no chromosomal aberrations with the exception of lesions with isolated
chromosome 11p gain, which is typically associated with an oncogenic Summary
HRAS mutation on the duplicated chromosomal arm.94 Some Spitz nevi can Genetic analyses have revealed that deregulation of a few key signaling
also have isolated copy number increase of distal chromosome 7q, which pathways is critical in melanoma formation. Common key events include
indicates fusions of BRAF or MET mapping in this area.96,97 activating mutations in the MAP kinase (proliferation) and PI3 kinase (sur-
Atypical Spitz tumors have similar oncogenic alterations as Spitz nevi, vival) pathways and inactivating mutations in the RB1 pathway (cell cycle
but have some additional chromosomal aberrations, often with loss of control). Kinase activation can occur at the receptor level (KIT mutations
chromosome 9. Spitzoid melanoma, when defined by solely by histologic and fusions of receptor tyrosine kinases such as MET, RET, ALK, ROS1,
1362 Melanoma
NTRK1, NTRK3) often activating both the MAP kinase and PI3 kinase melanoma, blue nevi, and related tumors have highlighted additional signal-
pathways or further downstream (NRAS, PTEN, BRAF, PI3KCA) acti- ing pathways of relevance in subsets of melanocytic neoplasia. The advent
vation of a pathway. The mutation patterns often correlate with the ana- of high-throughput genomic tools has initiated the construction of sets of
tomic site of the primary tumor and clinical and histologic features. These critical genetic alterations in melanoma which will in time complete the
driver mutations initiate proliferation in early stages of melanocytic neo- foundation for comprehensive classification of melanoma that will continue
plasia and are followed by loss of cell cycle checkpoint inhibition (e.g., to integrate genomic alterations with established phenotypes and is expected
p16, Rb), dysregulation of chromatin remodeling proteins (e.g., ARID1/2), to significantly improve prognostication and treatment stratification.
and protection from replicative senescence through TERT gene amplifica-
tion or TERT promoter mutation. Mutations in GNAQ/GNA11 in uveal Access ExpertConsult.com for the complete list of references
References 1362.e1
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Chapter 26

MELANOMA 1310 Prognostic indicators 1320 Angiotropic and angiomatoid (pseudovascular)

Fig. 26.1 Fig. 26.3

Fig. 26.2 Fig. 26.4

Fig. 26.5 Fig. 26.7

Fig. 26.6 Fig. 26.8

Fig. 26.9 Fig. 26.11

Fig. 26.10 Fig. 26.12

Fig. 26.14 Fig. 26.15

Fig. 26.17 Fig. 26.18

these lesions. Evaluation of the extent of epidermal involvement in difficult

Fig. 26.24 Fig. 26.27

Acral lentiginous melanoma

Fig. 26.34 Fig. 26.35

Fig. 26.36 Fig. 26.38

Breslow tumor thickness is the single most important single prognos-

Fig. 26.40 Fig. 26.43

Major changes and clarifications of the 2017 AJCC melanoma

• Database completely derived from patients of known sentinel lymph

provided here for purposes of comparison (Table 26.2). A pleasant feature

Disease specific survival1

Fig. 26.45 Fig. 26.47

extraction have been used to assess tumor-infiltrating lymphocytes with

thickness.260–265 Increasing angiogenesis therefore correlates with thick

actin (SMA), and CD34, is often essential. Similarly, highly pleomorphic,

fibronectin.33,34 Initial reports indicated that its sensitivity is similar to S100

Fig. 26.57 Fig. 26.58

Nevoid melanoma Fig. 26.59

invariably shows this to be false (Fig. 26.61).13 Pleomorphism, while subtle,

Fig. 26.66 Fig. 26.67

While one must always be wary of missing nevoid melanoma, it is also

Fig. 26.72 Fig. 26.74

Fig. 26.73 Fig. 26.75

Fig. 26.76 Fig. 26.77

Pure clear cell variants due to intracytoplasmic glycogen deposition are

Fig. 26.79 Fig. 26.80

neuroendocrine differentiation appears to show small cell morphology.

Adenoid and pseudopapillary melanoma

Blue nevus-like melanoma (malignant blue nevus)

Fig. 26.89 Fig. 26.91

under the name of pigmented epithelioid melanocytoma. There is certainly

Fig. 26.92 Fig. 26.94

tumors previously termed pigment synthesizing melanoma.14–16 While these

Fig. 26.93 Epidermotropic metastatic melanoma

Fig. 26.95 Fig. 26.96

Cytogenetic studies by FISH may be of help in establishing the distinction.

Fig. 26.98 Fig. 26.99

often evident as nodular aggregates, are a characteristic (but not diagnostic)

Fig. 26.106 Fig. 26.107

Fig. 26.122 Fig. 26.125

However, basomelanocytic tumor is a combination of basaloid carcinoma

at the dermal–epidermal junction. Cytological atypia varies and may not be

Primary dermal melanoma

0.6 Gains Fig. 26.137

Losses 15$6 %5$) genetic alterations in BRAF,

ERK Survival Melanoma with high cumulative sun damage (high-CSD)

toward the uninvolved epidermis. These growth characteristics may be

Melanocytic tumors arising without associations to

features, appears to be a heterogeneous category with the majority of cases

Emerging concepts in metastatic melanoma

Myxoid melanoma Blue nevus-like melanoma (balignant blue nevus)

66. Tacha D, Qi W, Ra S, et al. A newly developed mouse monoclonal SOX10

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66. Tacha D, Qi W, Ra S, et al. A newly developed mouse monoclonal SOX10