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Classification of Melanoma,
Simulants and Precursors, and
Pathway Concept
DE Elder
Hospital of the University of Pennsylvania
Philadelphia, PA
Hanoi, July 2023
WHO Classification of Skin Tumours
4e, 2018
• Edited by
• David E Elder
• Daniela Massi
• Richard A Scolyer
• Rein Willemze

• And > 100 contributors

• 2023 – 5th Edition in

Final Preparation
 The “New” (2018)
Classification builds on
previous work …
 CSD/Site-Related Classification
• Seminal work by Clark, McGovern, Reed, Spitz and
others … Previous WHO “Blue Books”
• Bastian’s CSD/Site-Related Classification (Taxonomy)
of Melanoma Boris Bastian MD, PhD

“The guiding principles for distinguishing taxa are genetic alterations that arise
early during progression; clinical or histologic features of the primary tumor;
characteristics of the host, such as age of onset, ethnicity, and skin type; and
the role of environmental factors such as UV radiation.”
 Fourth Edition WHO “Pathway”
Classification

• 4e WHO Classification “Blue Book” (2018), defines 9 “Pathways” to

melanoma.

• The “Pathway” concept is based on epidemiologic, clinical, histological,

and genomic attributes and includes the mode of evolution of
melanomas from precursors (i.e., tumor progression).
 Tumor Progression in Melanoma
• Precursor Nevus………………….
• Radial Growth Phase (RGP)/MIS
• Good Prognosis
• Vertical Growth Phase (VGP)…...
• Worse Prognosis

• Characteristics of Precursors:
• Not obligate
• Steps can be skipped
 4 step progression scheme of
melanocytic tumors
Nevus
Single driver anomaly

Low grade dysplasia

Two or More «melanocytoma»
Genomic
Abnormalities High grade dysplasia
«melanocytoma»
Melanoma Arnaud de la Fouchardiere,
Lyon, France

Multiple genomic alterations

 Fifth Edition WHO “Pathway”
Classification (2023)

• Printed/PDF Book is in Final Preparation

• Mainly Incremental Changes based on 4e

• Updated Genomic Classification

• Few if any changes relevant to diagnostic pathology/dermatopathology

• High Grade Low Grade emphasized over “Mild, Moderate, Severe”

 Melanocytic Tumour Classification and the Pathway Concept of Melanoma Pathogenesis
Elder DE, Barnhill RL, Bastian BC, Cook MG, de la Fouchardière A, Gerami P, Lazar AJ, Massi D, Mihm MC Jr, Nagore E, Scolyer RA, Yun SJ, WHO 2018.

• Epidemiology
“CSD” Melanoma is more Common in Sun-Susceptible Populations:
• Pathway I. Low CSD Melanoma/Superficial Spreading Melanoma (SSM)
• Pathway II. High CSD Melanoma/Lentigo Maligna Melanoma (LMM)
• Pathway III. Desmoplastic Melanoma

• Incidence about the same world-wide (?)

• Pathway IV. Malignant Spitz Tumor (?)
• Pathway V. Acral Melanoma
• Pathway VI. Mucosal Melanoma
• Pathway VII. Melanoma in Congenital Nevus (MCN)
• Pathway VIII. Melanoma in Blue Nevus (MBN)
• Pathway IX. Uveal Melanoma
Lv, Jiaojie, et al
(Shanghai, 2016)
• Variable Pathways: Nodular Melanoma
 Classification includes

• Pathway
• End Point of Pathway
(Melanomas)
• Low Grade Precursors
• Intermediate / High
Grade Precursors
• Melanomas

• Based on:
• Epidemiology
• CSD and non CSD
• Topography
• Histopathology
• Genomics
CSD = Cumulative Solar Damage • Bastian BC, et al WGHO Classification of Skin
Tumours, In Preparation, 2023
 Melanocytic Tumour Classification and the Pathway Concept of Melanoma Pathogenesis
Elder DE, Barnhill RL, Bastian BC, Cook MG, de la Fouchardière A, Gerami P, Lazar AJ, Massi D, Mihm MC Jr, Nagore E, Scolyer RA, Yun SJ, WHO 2018.

• Epidemiology
“CSD” Melanoma is more Common in Sun-Susceptible Populations:
• Pathway I. Low CSD Melanoma/Superficial Spreading Melanoma (SSM)
• Pathway II. High CSD Melanoma/Lentigo Maligna Melanoma (LMM)
• Pathway III. Desmoplastic Melanoma

• Incidence about the same world-wide (?)

• Pathway IV. Malignant Spitz Tumor (?)
• Pathway V. Acral Melanoma
• Pathway VI. Mucosal Melanoma
• Pathway VII. Melanoma in Congenital Nevus (MCN)
• Pathway VIII. Melanoma in Blue Nevus (MBN)
• Pathway IX. Uveal Melanoma
Lv, Jiaojie, et al
(Shanghai, 2016)
• Variable Pathways: Nodular Melanoma
• Intermediate Lesions of
Class I, Low CSD
Melanoma

• Biologically benign
• Simulants of melanoma
• May be precursors of
melanoma (low risk but
greater than in “wholly
benign” nevi).
• Have more than a single
genomic aberration
• Bastian BC, et al WHO Classification of Skin
Tumours, In Preparation, 2023
Intermediate Lesions of Tumor Progression

• Term defined by Wallace H Clark Jr.

• Lesions that are intermediate between benign and malignant tumors
• Includes MIS

• Biologically benign
• May be precursors of malignant tumors – however the rate of individual lesion
progression is very low
• Morphologically intermediate – clinically atypical and histologically dysplastic –
SIMULANTS OF MELANOMA
• Genomic profile is also intermediate
• DIFFICULT TO REPRODUCIBLY DIAGNOSE – UNCERTAINTY (MPATH PROJECT)

Clark WH. Tumour progression and the nature of cancer. Br J Cancer. 1991;64:631-44
The Genetic Evolution of Melanoma from Precursor Lesions.
Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The Genetic Evolution of Melanoma from
Precursor Lesions. N Engl J Med. 2015;373(20):1926-36.

• Dissected parts of lesions and did next generation sequencing

• Parts (regions) were classified as “Benign”, “Intermediate, Probably Benign”,

“Intermediate probably Malignant”, “Melanoma in situ”, and “Invasive
Melanoma”
The Genetic Evolution of Melanoma from
Precursor Lesions. Shain, NEJM 2015.

• Unequivocally benign precursors had only

BRAF V600E mutations

• “Intermediate” lesions (e.g., dysplastic

nevi) had NRAS and additional driver
mutations.

• TERT promoter mutations were present in

intermediate lesions and melanomas in
situ.

• Biallelic inactivation of CDKN2A

exclusively found in invasive melanomas.

“Intermediate” category has more than one

genetic alteration and distinctive
histopathologic features.
Reconceptualizing the current classification
Genetic anomalies can be pooled into pathways.

Arnaud de la Fouchardiere,
Lyon, France
 Reconceptualizing the current classification
Genetic anomalies can be pooled into pathways
• MAPK pathway : H/N/KRAS – A/B/CRAF – MEK1/2 – ERK
• PKC pathway activation of MAPK pathway: CYSLTR2, GNAQ, GNA11, PLCB4, PKC gene fusion
• RTK activation of MAPK and MTOR “survival” pathway : KIT, ALK , ROS, NTRK1/2/3, MET, RET
• RAS modulators: NF1 or SPRED1 mutations; RASGRF1 and RASGRF2 fusions
• RAF modulators by PKA activation: PRKAR1A inactivation by mutation / fusions
• MEK modulators: MAP3K8 mutations/ fusions
• ERK modulators: MAP3K3 by p38 pathway
• MTOR “survival” pathway regulator: PTEN
• Cell-cycle modulator: CDKN2A via p14/MDM2/TP53 and p16/CDK4/CCND1/RB
• WNT-activation: CTNNB1 and APC mutations
• Chromatin remodeling: BAP1 inactivation, ARID1A/B; ARID2…
• Epigenetic / DNA methylation : TET2; IDH1 mutation…
• Telomerase modulator: H-TERT mutation, shelterin complex
• Spliceosoma : SF3B1
• Pigmentation genes: MiTF, OCA1/2, TYR, TYRP
Melanoma in Asia
 British Journal of Dermatology
(2020) 182, pp1205–1213

• Comprehensive genomic profiling of 409 cancer-

associated genes in 66 primary melanoma, 45 Acral
Melanomas (AM), and 21 Non-acral Melanomas
(NAM)

• Results: Most of the AMs (60% but only 24% of the

NAMs) were triple wild type tumors
• Triple WT lacks well-characterized “driver mutations”
in three of the major known driver genes in
melanoma - BRAF, NRAS, and NF1

• Compared with AMs NAMs had a higher frequency of

BRAF mutations (47%)
• Most NAMs on skin without chronic sun damage had
mutations in BRAF V600E, whereas NAMs on
chronically sun-damaged areas had BRAF non-V600E
or NRAS mutations
• Results: Most of the AMs (60% but only 24% of the NAMs) were “triple wild
type” (triple WT) tumors
• Triple WT lacks well-characterized “driver mutations” in three of the major known
driver genes in melanoma - BRAF, NRAS, and NF1
• Compared with AMs NAMs had a higher frequency of BRAF mutations (47%)
• Most NAMs on skin without chronic sun damage had mutations in BRAF V600E,
whereas NAMs on chronically sun-damaged areas had BRAF non-V600E or NRAS
mutations
Figure 1 presents the distribution of incident melanoma
cases and deaths in 2020 across world regions. With
150 672 cases, close to half the global melanoma cases
occurred in Europe (46.4%), followed by North America
(32.4%). Most melanoma deaths were observed in Central
and Eastern Europe (16.3%), followed by North America
(14.7%) and Western Europe (13.0%). Although 5.9% of all
melanoma cases occurred in Oceania, the continent’s share
of melanoma deaths was about half that (ie, 3.4% of global
deaths). This is in contrast to Asia, where 7.3% of all cases
but 21.0% of all deaths occurred, and to Africa, which
contributed 2.1% of cases yet had 4.7% of global melanoma
deaths
 Melanoma in Asia
• Acral melanoma is the most common subtype in Asian
Populations
• Also mucosal and other “Non-CSD” subtypes

• Absolute incidence of acral melanoma is similar in all

ethnic groups
• Vastly higher incidence of CSD melanoma in Western/Caucasian
populations skews the statistics

• Although the incidence of melanoma is low in Asia, the

mortality is disproportionately high
 “Intermediate” category has more
than one genetic alteration and
distinctive histopathologic features.

Term “Melanocytoma” has been

applied to these lesions
• Intermediate Lesions of
Class I, Low SD
Melanoma

• Biologically benign
• Simulants of melanoma
• May be precursors of
melanoma (low risk but
greater than in “wholly
benign” nevi).
• Have more than a single
genomic aberration
• Bastian BC, et al WHO Classification of Skin
Tumours, In Preparation, 2023
 Lentiginous
Low UV junctional nevus
Pathway I
Low-CSD Melanoma
Superficial Spreading Melanoma
Precursors:
Banal Acquired Nevus (junctional, compound, dermal)

Dysplastic Nevus with Low Grade Dysplasia Pigmented

Deep penetrating
Bap-1 Deficiency
nevus (DPN)/
Epithelioid Compound
Melanocytoma Melanocytoma
Melanocytoma
(PEM) dysplastic nevus
Dysplastic Nevus with High Grade Dysplasia

Superficial Spreading Melanoma (SSM)

- In Situ Melanoma in Melanoma in Melanoma in PEM
- RGP (nontumorigenic), BPDM (rare) DPN (rare) (rare)
- VGP (tumorigenic)

BRAF V600E OR NRAS (Gain of function, (BRAF or (BRAF, MEK1, or BRAF + PRKAR1A
activated oncogenes, mutually exclusive) NRAS)+BAP1 NRAS) + (CBNN1 or PRKCA Superficial
or APC)
spreading or
“pagetoid”
melanoma
TERT (promoter mutation)
CDKN2A, TP53, PTEN (loss of function/
suppressor)
SAM Q1.
Best diagnosis for this lesion?

• Clinical Information.
• A 3 mm macular slightly variegated lesion from the back of a 37-year-old
woman.
• Reason for Consultation.
• Is this a dysplastic nevus?
• Small
• Poorly circumscribed
• Nest predominate, discrete
• Patchy lymphocytes, scant fibroplasia, numerous melanophages (clinically atypical)
• Slight/absent
cytologic atypia
• No mitoses
Best Diagnosis?

1. Superficial spreading melanoma

2. Junctional nevus

3. Dysplastic nevus
Answer to SAM Q1
Junctional nevus (formerly often called mild dysplasia)
- “mild dysplasia” has been over-diagnosed, has no significance as a risk
marker or as a precursor of melanoma

• In the 2018 (and 2023) WHO classification, the following are all required for a
diagnosis of a dysplastic nevus
• Size 4 mm or greater
• Architectural disorder (lentiginous proliferation, bridging nests, fibroplasia)
• Cytologic atypia, with nuclear size compared to resting basal keratinocyte
• 1-1.5x Low Grade Dysplasia
• > 1.5x High Grade Dysplasia
• Also chromatin changes and prominent nucleoli

• Elder DE, Barnhill RL, Bastian BC, Duncan LM, Massi D, Mihm MC Jr, Piepkorn M, Rabkin M, Scolyer RA. Dysplastic naevus. In Elder DE, Massi
D, Scolyer RA, Willemze R. WHO Classification of Skin Tumours. 4th ed. Lyon: IARC; 2018
Severe Dysplasia

Nests near tips and sides of rete, bridging nests

Nuclei > 1.5 x the size of a resting basal keratinocyte
(>5/hpf)
Chromatin clumping and hyperchromasia
Significance of Dysplastic Nevi

• Simulants of Melanoma
• clinical, histological
• Potential Precursors of Melanoma
• But very low risk of progression for individual lesions
• No need to re-excise for low grade dysplasia even if on the margin
• High grade dysplasia – consider re-excision if only because diff dx may include MIS
• Risk Markers for future development of Melanoma
• Very low risk for a single lesion
• Increased risk with increasing risk factors – FH and PH of melanoma, sunburns,
freckles, Total Number of Nevi, Large Nevi, Atypical (dysplastic nevi)
“Dysplastic nevi are a subset of melanocytic nevi that are clinically atypical and
characterized histologically by architectural disorder and cytological atypia, always
involving their junctional component.” WHO, 2018.
• Intermediate Lesions of
Class I, Low SD
Melanoma

• Biologically benign
• Simulants of melanoma
• May be precursors of
melanoma (low risk but
greater than in “wholly
benign” nevi).
• Have more than a single
genomic aberration
• Bastian BC, et al WHO Classification of Skin
Tumours, In Preparation, 2023
 Low UV
Pathway I Bap-1 Inactivated
Melanocytoma
Low-CSD Melanoma
Superficial Spreading Melanoma & Melanocytomas
Precursors:
Banal Acquired Nevus (junctional, compound, dermal)

Low Grade Dysplasia Deep penetrating

Bap-1 Deficient Deep penetrating nevus Pigmented Epithelioid
Melanocytoma (DPN)/ Melanocytoma Melanocytoma (PEM) nevus (DPN)/
High Grade Dysplasia Melanocytoma

Superficial Spreading Melanoma in BPDM

Melanoma in DPN (rare) Melanoma in PEM (rare)
Melanoma (rare)

BRAF V600E, NRAS (Gain (BRAF or NRAS) + BAP1 (BRAF, MEK1, or NRAS) BRAF + PRKAR1A
of function, activated loss +(CBNN1 or APC or PRKCA loss
oncogenes, mutually activating mutation) Pigmented
exclusive) Epithelioid
Melanocytoma
(PEM)
Progression to Melanoma:
CDKN2A, TP53, PTEN (loss of function/ suppressor)
TERT (promoter mutation)
Melanocytomas
• Melanocytic tumors with intermediate architectural and cytologic features
• Increased cellularity, atypia, may be a few mitoses, insufficient for melanoma
diagnosis
• Genomically, have two mutations
• e.g., BRAF Driver + BAP-1 loss OR Beta catenin activation OR PRKAR1a loss
• May appear as a component of a combined nevus
• Increased risk of progression to malignant variants, though still low
• Should be completely excised.
• Classification as Benign or Malignant depends on traditional
clinicopathologic attributes:
• History of change, Morphology, Atypia, Mitoses, Ulceration, Necrosis, etc.
Diagnosis of malignancy (if present) is based primarily on
traditional histopathologic attributes
• Ulceration, High cellularity with sheet-like growth of cells,
Severe uniform cytologic atypia, High mitotic rate, etc.
• Clinical behavior / follow-up!
• PRAME, GEP, or FISH could be useful, also possibly CGH
DPN (combined)
 New Case
27 y.o. woman with a 3-month history of a
tumor of the mandible, invading bone and
displacing teeth
Absent staining for
p16
 Mitotic Rate of
6 per sq. mm

Diagnosis of malignancy is based primarily on traditional

histopathologic attributes:
• Ulceration, High cellularity with sheet-like growth of cells,
Severe uniform cytologic atypia, High mitotic rate, etc.
• Clinical behavior / follow-up!
• PRAME, GEP, or FISH could be useful, also possibly CGH
 PEM-Like Melanoma
• (Pigment-Synthesizing Melanoma, PSM)

• Diagnosis of malignancy was based on traditional

histopathologic attributes
• Ulceration, High cellularity with sheet-like growth of cells, Severe
uniform cytologic atypia, High mitotic rate, etc.

• Diagnosis of malignancy also based on clinical behavior.

• Lesion grew rapidly and was locally destructive
• Patient was dead of disease within 4 months of diagnosis, no
response to immune therapy
 Lentiginous
Low UV junctional nevus
Pathway I
Low-CSD Melanoma
Superficial Spreading Melanoma
Precursors:
Banal Acquired Nevus (junctional, compound, dermal)

Low Grade Dysplasia

Compound
dysplastic nevus
High Grade Dysplasia

Superficial Spreading
Melanoma

BRAF V600E, NRAS (Gain

of function, activated
oncogenes, mutually Superficial
exclusive) spreading or
“pagetoid”
melanoma
TERT (promoter
mutation)
CDKN2A, TP53, PTEN (loss
of function/ suppressor)
Superficial
Spreading
Melanoma SSM

RGP:-
• Asymmetry

• Border irregularity

• Color variegation

• Diameter > 4 mm

• Discrete border VGP – (bottom middle and right) - more symmetrical, color may be
uniform, border may be sharply defined
Viros A, et al. Improving melanoma
classification by integrating genetic and
morphologic features. Plos Med.
2008;5(6):e120

SSM v LMM
• High pigment
• High scatter
• High nesting
• Good circumscription
• Thickened epidermis
• Larger cell size
• Similar nuclear size
• Epithelioid > spindle
cells
• Lower CSD
 High UV Viros A, et al. Improving melanoma
classification by integrating genetic and
Pathway II morphologic features. Plos Med.
2008;5(6):e120
High-CSD Melanoma (LMM)
SSM v LMM
Severe CSD (exposed skin, outdoor work) • Low pigment
• Low scatter
High Tumor Mutation Burden (TMB) • Low nesting
UV signature mutations • Poor circumscription
• Thinned epidermis
Lentigo maligna melanoma in situ before
invasive melanoma, may progress to vertical • Smaller cell size
growth phase • Similar nuclear size
Lentigo Maligna Melanoma: Continuous basal • Spindle > epithelioid
“lentiginous” proliferation of uniformly cells
atypical melanocytes. • HIGH CSD
non-V600E
NRAS, BRAF , KIT, (gain of function,
activated oncogenes, mutually exclusive)
NF1 (Loss of function)

TERT (promoter mutation),

CDKN2A, TP53, PTEN (Loss of function)
RAC1
CSD Melanomas
(Pathways 1-III)

Bastian BC, de la Fouchardiere, A,

Elder, DE, Gerami P, Lazar AJ, Massi
D, Nagore E, Scolyer RA, Yun SJ.
Genomic Landscape of Melanoma.
In Elder DE, Massi D, Scolyer RA,
Willemze R: WHO Classification of
Skin Tumours, Lyon, 2018
CSD Melanomas
(Pathways 1-III)

Bastian BC, de la Fouchardiere, A,

Elder, DE, Gerami P, Lazar AJ, Massi
D, Nagore E, Scolyer RA, Yun SJ.
Genomic Landscape of Melanoma.
In Elder DE, Massi D, Scolyer RA,
Willemze R: WHO Classification of
Skin Tumours, Lyon, 2018
 High UV
Pathway III
Desmoplastic Melanoma

Skin with Severe CSD

High Tumor Mutation Burden

Melanoma in situ, or may be no in situ lesion

Infiltrative spindle cells separated by

“desmoplastic” collagen

NF1 (loss of function)

ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET
(amplifications)

TERT, NFKBIE, NRAS PIK3CA PTPN11

 Eroglu Z, Zaretsky JM, Hu-Lieskovan S,
Kim DW, Algazi A, Johnson DB, et al. High
response rate to PD-1 blockade in
desmoplastic melanomas.
Nature. 2018;553(7688):347-50.

“ … patients with advanced

desmoplastic melanoma
derive substantial clinical
benefit from PD-1 or PD-L1
immune checkpoint
blockade therapy, even
though desmoplastic
melanoma is defined by its
dense desmoplastic fibrous
stroma. The benefit is likely
to result from the high
mutational burden and a
frequent pre-existing
adaptive immune response
Desmoplastic Melanoma
limited by PD-L1
NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET, expression”

TERT, NFKBIE, NRAS PIK3CA PTPN11

HIGH TUMOR MUTATION BURDEN (Potential checkpoint

therapy)
No CSD Melanomas
(Pathways IV-IX)

Bastian BC, de la Fouchardiere, A,

Elder, DE, Gerami P, Lazar AJ, Massi
D, Nagore E, Scolyer RA, Yun SJ.
Genomic Landscape of Melanoma.
In Elder DE, Massi D, Scolyer RA,
Willemze R: WHO Classification of
Skin Tumours, Lyon, 2018
 Pathway IV
No UV Fatal Malignant Spitzoid
Malignant Spitz Tumor tumor (vs Spitz melanoma)
Spitz Nevus in a 12 y.o. girl
Atypical Spitz nevus
STUMP
Malignant Spitz Tumor
(vs. Malignant Spitzoid
Tumor, vs. “Melanoma with Typical Spitz Nevus
Spitzoid Features”)
• Younger patients/
HRAS (GOF), ALK, ROS1,
RET, NTRK1, NTRK3, BRAF, children
MET (Fusions), • Fusion genes
• Closely related
CDKN2A (LOF) pigmented spindle cell
nevus of Reed

Wiesner
LesionsT,that
He J, may
Yelensky R, Esteve-Puig
look R, Botton
like a Spitz T, Yeh I,but
Melanoma et al.
Kinase fusions are frequent in Spitz tumours and spitzoid
lack the defining genomic variations (and may
melanomas. Nature communications. 2014;5:3116
have BRAFV600E or NRAS mutations or be WT) are
termed “Spitzoid
VandenBoom Melanoma”
T, Quan VL, and EM,
Zhang B, Garfield likely have
Kong a
BY, Isales
MC, et al.prognosis
worse Genomic Fusions
than intrue
Pigmented Spindle Cell Nevus of
Spitz melanomas,
Reed. The American journal of surgical pathology.
which are very rare …
2018;42(8):1042-51
Atypical Spitz Tumor

- 4 y.o. child, large size

- Mitotic rate 4 per sq mm
- Lack of good maturation

HRAS (GOF, Activated oncogene),

ALK, ROS1, RET, NTRK1, NTRK3, BRAF, MET
(fusions),

CDKN2A (loss of function, suppressor gene)

Diagnosis of malignancy is based on traditional histopathologic
attributes
• Ulceration, High cellularity with sheet-like growth of cells,
Severe uniform cytologic atypia, High mitotic rate, etc.
• TERT promoter activation can also be helpful
• BRAFV600E or NRAS mutation rules out a Spitz lesion
Table from: Barnhill R.L. Bahrami A.
Bastian B.C. Busam K.J. Cerroni L. de la
Fouchardière A., Elder DE, et al.
Malignant Spitz tumour (Spitz
melanoma). In Elder DE, Massi D, Scolyer
RA, Willemze R. WHO Classification of
Melanoma, Lyon, IARC, p132, 2018
 Pathway V
No UV
Acral Melanoma

Atypical melanocytic
proliferation
Melanoma in situ

Acral lentiginous melanoma

KIT, NRAS, BRAF, HRAS, KRAS,

NTRK3, ALK, NF1

CDKN2A, TERT CCND1, GAB2

• RELATIVELY COMMON IN ASIA, ALSO AFRICA, POLYNESIA

• ABSOLUTE INCIDENCE ABOUT THE SAME IN ALL ETHNICITIES

• Moon KR, Choi YD, Kim JM, Jin S, Shin MH, Shim HJ, et al. Genetic Alterations in Primary
Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show
Distinct Cytomorphological Features. J Invest Dermatol. 2018;138(4):933-45.
• Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-
genome landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-80.
 Pathway VI
No UV
Mucosal Melanoma
Melanosis
Atypical melanosis
IAMPUS/ SAMPUS
Mucosal lentiginous
melanoma
KIT, NRAS, KRAS, or BRAF

NF1, CDKN2A SF3B1,

CCND1, CDK4, MDM2

Substitutions, insertions,
deletions and structural
variants

Probably about the

same incidence in
all ethnicities
 Mucosal Melanoma
• Anal Mucosa
• Elderly woman
• Two VGP nodules,
RGP between them

KIT, NRAS, KRAS, or BRAF (activated

oncogenes, mutually exclusive)

NF1, CDKN2A SF3B1 (suppressors,

loss of function)

CCND1, CDK4, MDM2

(amplifications)

Substitutions, insertions, deletions

and structural variants

Hayward NK, Wilmott JS, Waddell N, Johansson PA, Field MA, Nones K, et al. Whole-genome
landscapes of major melanoma subtypes. Nature. 2017;545(7653):175-80.
Diagnosis of malignancy is based on traditional histopathologic
attributes
• Asymmetry, Invasion, Tissue Destruction, Ulceration,
Necrosis, Pleomorphism, High cellularity with sheet-like
growth of cells, Severe uniform cytologic atypia, High
mitotic rate, etc.
 Pathway VII
No/Variable UV

Melanoma in Congenital Nevus (MCN)

Congenital Nevus (CN)

Nodular proliferation in CN

? MIS in CN

Melanoma in CN

NRAS, BRAF V600E (small nevi)

BRAF fusions

Probably about the same incidence in all ethnicities

“ …increased expression of 22 genes in GHN compared

with nearby normal skin. Decreased expression was
noted in 73 genes …
Dasu MR, Barrow RE, Hawkins HK, McCauley RL. Gene expression profiles
of giant hairy naevi. J Clin Pathol. 2004;57(8):849-55.
Nodular intradermal and
subcutaneous proliferation of
atypical epithelioid
melanocytes, of uncertain
malignant potential, arising
secondarily in a giant
congenital melanocytic nevus

Array CGH done in another

institution demonstrated gain
and chromosomes 1Q, 2, 4, 6,
8, 10, 13, 19, 20 and 21, as
well as loss of chromosome
14. With the exception of gain
in 1q, the copy number
change consists of whole
chromosome gain or loss as is
common to proliferative
nodules.

Bastian BC, Xiong J, Frieden IJ, Williams

ML, Chou P, Busam K, et al. Genetic
changes in neoplasms arising in
congenital melanocytic nevi :
differences between nodular
proliferations and melanomas. Am J
Pathol. 2002;161(4):1163-9.
Diagnosis of malignancy is based on traditional histopathologic
attributes
This young patient died
• Ulceration, High cellularity with sheet-like growth of cells, of his disease about 2
Severe uniform cytologic atypia, High mitotic rate, etc.
• Clinical behavior / follow-up! years after presenting
• PRAME, GEP, or FISH could be useful, also CGH
Diagnosis of malignancy is based mostly on traditional
histopathologic attributes
• Ulceration, High cellularity with sheet-like growth of cells,
Severe uniform cytologic atypia, High mitotic rate, etc.
• PRAME, GEP, or FISH could be useful
 Pathway VIII
No/Variable UV
Melanoma in Blue Nevus (MBN)
Blue Nevus
Cellular Blue Nevus
Atypical CBN

Melanoma in Blue Nevus (MBN)

GNAQ, GNA11, CYSLTR2

BAP1 mutation or loss,

EIF1AX SF3B1, Change of function

Probably
Diagnosisabout the sameisincidence
of malignancy in all
based primarily
ethnicities
on traditional histopathologic attributes:

Genetic• profile
Ulceration, of coexistent GNAQ with
High cellularity or GNA11
mutations with BAP1
sheet-like or SF3B1
growth mutations
of cells, Severe can
aid the histopathological
uniform cytologicdiagnosis atypia, High and
distinguish blue rate,
mitotic nevus-like
etc. melanoma from
conventional epidermal-derived melanomas.”
• PRAME,
Griewank GEP,
KG, Muller H, Jackett or FISH could
LA, Emberger M, Moller I,be
van de Nes
JA, et al (Scolyer, Schadendorf). SF3B1 and BAP1 mutations in blue
useful
nevus-like melanoma. Modern pathology 2017;30:928-39.
Diagnosis of malignancy is based mostly on traditional
histopathologic attributes:
• Ulceration, High cellularity with sheet-like growth of cells,
Severe uniform cytologic atypia, High mitotic rate, etc.
• BAP1 inactivation/loss, Loss of Chromosome 3 by FISH
• PRAME, GEP, or FISH could be useful
 Nodular Melanoma - Clinical Features
• Detectable RGP is absent by definition
• Tumorigenic melanoma without an adjacent non-tumorigenic component
• Short-lived RGP may be obliterated by the developing tumor.
• Likely to occur in all pathways

• ABCD criteria may not apply

• lesions are often symmetrical
nodules/papules with raised
discrete borders, fairly uniform
color, diameter
not always > 6 mm

• Prognosis is similar
to other melanomas
of same microstage
• However small diameter lesions
can be “thick” dangerous melanomas
Nodular melanoma
Dermal nevus adjacent to
nodular melanoma -
indicative of tumor
progression, renders
metastasis unlikely.
New (Revised) Classification of Melanoma
• Integrates Epidemiology, Genomic, Clinical and
Histopathologic Features
• Genomic Attributes are Relevant for Classification and
Therapy for Metastatic Disease
• Of Little Use in Diagnosis of Malignant versus Benign
Neoplasm
• Progression Genes can Assist in this Task:
• Ki-67 – proliferation
• HMB45 – Maturation
• , p16 and other genes
- “progression from bad to worse”
Acknowledgements
Chapter Authors (Melanoma Classification
David Elder
Raymond Barnhill
Boris Bastian
Martin Cook
Arnaud de la Fouchardière
Pedram Gerami
Alexander Lazar
Daniela Massi
Martin Mihm
Eduardo Nagore
Richard Scolyer
Sook Jung Yun
International Melanoma
Pathology Study Group
> 150 Authors (Blue Book 4e)
WHO
Ian Cree
Hiroko Ohgawa
• 1.
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