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Acral Melanoma
D Elder, Maui, HI 2020
Subtlety and Uncertainty
• 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
• Variable Pathways: Nodular Melanoma Lv, Jiaojie, et al (Shanghai, 2016)
Role of UV: Low UV High UV Low to No (or Variable) CSD
Pathway: I II III IV V VI VII VIII IX
Low-CSD MelanomaSuperficial Spreading Melanoma
High-CSD Melanoma
(LMM)
Desmoplastic Melanoma
Spitz Melanoma Acral Melanoma Mucosal
Melanoma
Melanoma in Congenital
Nevus
MelanomaIn Blue Nevus Uveal Melanoma
Benign Nevus ? IAMP ? IAMP Spitz Nevus ?IAMP Melanosis Congenital Nevus (CN) Blue Nevus ?
Borderline Low
Low Grade Dysplasia Bap-1 Deficiency
Melanocytoma /MELTUMP
DPN Melanocytoma
/MELTUMP
PEM Melanocytoma
/MELTUMP
? IAMP ? IAMP Atypical Spitz nevus
Atypical melanocytic proliferation
Atypical melanosis
Nodular proliferation in CN
Cellular Blue Nevus Uveal nevus
Borderline High
High Grade Dysplasia Lentigo maligna Melanoma in situ STUMP Melanoma in situ IAMPUS/
SAMPUS ? MIS in CN Atypical CBN ?
MalignantSuperficial Spreading Melanoma
Melanoma in BPDM (rare)
Melanoma in DPN (rare)
Melanoma in PEM (rare)
Lentigo Maligna Melanoma Desmoplastic Melanoma Malignant Spitz
TumorAcral lentiginous melanoma
Mucosal lentiginous melanoma
Melanoma in CN Melanoma ex Blue Nevus Uveal melanoma
Common mutations
BRAF V600E, NRAS
(BRAF or NRAS)+BAP1
(BRAF, MEK1, or NRAS) +(CTNNB1 or APC)
(BRAF +PRKAR1A) or PRKCA
NRAS, BRAFnon-V600E, KIT, NF1
NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET,
HRAS, ALK, ROS1, RET, NTRK1, NTRK3, BRAF,MET
KIT, NRAS, BRAF, HRAS, KRAS, NTRK3, ALK, NF1
KIT, NRAS, KRAS, or BRAF
NRAS, BRAF V600E (small lesions), BRAF
GNAQ, GNA11, or CYSLTR2
GNAQ, GNA11,CYSLTR2, or PLCB4
TERT, CDKN2A, TP53, PTEN
TERT, CDKN2A, TP53, PTEN, RAC1
TERT, NFKBIE, NRAS, PIK3CA , PTPN11
CDKN2A CDKN2A, TERT CCND1, GAB2
NF1, CDKN2A SF3B1, CCND1, CDK4, MDM2
BAP1, EIF1AX, SF3B1
BAP1SF3B1, EIF1AX,
Table 1. Classification of Melanocytic Tumors by Epidemiologic, Clinical, Histopathologic & Genomic Attributes
Notes: Progression is not obligate and steps can be skipped
Color Code: Mutations: Red; gain of function; Blue, loss of function; Green, change of function, Black, promoter mutation. Orange, amplifications. Purple: Rearrangements.
Role of UV: Low UV High UV Low to No (or Variable) CSD
Pathway: I II III IV V VI VII VIII IX
Low-CSD MelanomaSuperficial Spreading Melanoma
High-CSD Melanoma
(LMM)
Desmoplastic Melanoma
Spitz Melanoma Acral Melanoma Mucosal
Melanoma
Melanoma in Congenital
Nevus
MelanomaIn Blue Nevus Uveal Melanoma
Benign Nevus ? IAMP ? IAMP Spitz Nevus ?IAMP Melanosis Congenital Nevus (CN) Blue Nevus ?
Borderline Low
Low Grade Dysplasia Bap-1 Deficiency
Melanocytoma /MELTUMP
DPN Melanocytoma
/MELTUMP
PEM Melanocytoma
/MELTUMP
? IAMP ? IAMP Atypical Spitz nevus
Atypical melanocytic proliferation
Atypical melanosis
Nodular proliferation in CN
Cellular Blue Nevus Uveal nevus
Borderline High
High Grade Dysplasia Lentigo maligna Melanoma in situ STUMP Melanoma in situ IAMPUS/
SAMPUS ? MIS in CN Atypical CBN ?
MalignantSuperficial Spreading Melanoma
Melanoma in BPDM (rare)
Melanoma in DPN (rare)
Melanoma in PEM (rare)
Lentigo Maligna Melanoma Desmoplastic Melanoma Malignant Spitz
TumorAcral lentiginous melanoma
Mucosal lentiginous melanoma
Melanoma in CN Melanoma ex Blue Nevus Uveal melanoma
Common mutations
BRAF V600E, NRAS
(BRAF or NRAS)+BAP1
(BRAF, MEK1, or NRAS) +(CTNNB1 or APC)
(BRAF +PRKAR1A) or PRKCA
NRAS, BRAFnon-V600E, KIT, NF1
NF1, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, MET,
HRAS, ALK, ROS1, RET, NTRK1, NTRK3, BRAF,MET
KIT, NRAS, BRAF, HRAS, KRAS, NTRK3, ALK, NF1
KIT, NRAS, KRAS, or BRAF
NRAS, BRAF V600E (small lesions), BRAF
GNAQ, GNA11, or CYSLTR2
GNAQ, GNA11,CYSLTR2, or PLCB4
TERT, CDKN2A, TP53, PTEN
TERT, CDKN2A, TP53, PTEN, RAC1
TERT, NFKBIE, NRAS, PIK3CA , PTPN11
CDKN2A CDKN2A, TERT CCND1, GAB2
NF1, CDKN2A SF3B1, CCND1, CDK4, MDM2
BAP1, EIF1AX, SF3B1
BAP1SF3B1, EIF1AX,
Table 1. Classification of Melanocytic Tumors by Epidemiologic, Clinical, Histopathologic & Genomic Attributes
Notes: Progression is not obligate and steps can be skipped
Color Code: Mutations: Red; gain of function; Blue, loss of function; Green, change of function, Black, promoter mutation. Orange, amplifications. Purple: Rearrangements.
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
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 VNo UV
Acral Melanoma
Atypical melanocytic proliferationMelanoma in situ
Acral lentiginous melanomaKIT, NRAS, BRAF, HRAS, KRAS (GOF), NTRK3, ALK (Fusions), NF1CDKN2A (LOF), TERT CCND1, GAB2 (amplifications)
• 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.
Significance of Nevi.
• Nevi are important mainly in relation to melanoma– Precursors – but risk for individual lesions is low– Risk markers – important mainly in high risk situations– Simulants – important in everyday clinical decision-making
• Acral nevi are most important as simulants– Probably not precursors, not clearly risk markers
Puccio FB et al. Arch Pathol Lab Med 2011;135:847-52.
Acral junctional nevus
Acral lentiginous melanoma
Histopathological Differential Diagnosis is not easy!
In Difficult Cases, Clinicopathologic Correlation is Essential!
Histopathology of Acral Nevus
Saida T et al. Am J Dermatopathol2011;33:468-73.Ishihara Y et al. Am J Dermatopathol 2006;28:21-27.
Acral Nevus; Parallel Furrow Pattern Acral Melanoma; Parallel Ridge Pattern
S J Yun, MD, PhD, S. Korea
Dermoscopy for Acral Nevus vs Melanoma
Acral Melanoma; Parallel Ridge PatternAcral Nevus; Parallel Furrow Pattern
Histopathology of Acral Nevus
• Junctional or compound nevi, only slight to moderate atypia• Large, vertically oriented junctional nests, not usually
bridging • Transepidermal elimination• Lentiginous junctional melanocytic proliferation• Limited degree of pagetoid scatter often present (85%)
– Melanocytic acral nevus with intraepidermal ascent of cells (MANIAC, LeBoit)
• Discrete melanin columns in cornified layer
Crease VerticalTissue section: Dermatoglyphics Vertical
Furrow pigment column
S J Yun, MD, PhD, S. Korea
Crease Line : Long axis of nevus parallel to Dermatoglyph
Tissue section: Dermatoglyphics Parallel
Difficult evaluation of Furrow or Ridge pattern
S J Yun, MD, PhD, S. Korea
Acral Nevus vs Acral Melanoma
• Overlapping histopathologic features of acral nevus, special site nevus, dysplastic nevus, and melanoma
• Size : Important criteria for distinction• Excisional biopsy – punch Bx often nondiagnostic• When the case is difficult, clinicopathologic correlation is
essential!• Intraepidermal Atypical Melanocytic Proliferation of
Uncertain Significance (IAMPUS), MELTUMPDescriptive terms, D/D should be expressed.
S J Yun, MD, PhD, S. Korea
Next CaseS J Yun, MD, PhD, S. Korea
Your Diagnosis?
Nevus?
Melanoma?
Acral Junctional nevus
Pagetoid scatter
34F, Lt sole, 3x2mm, 3ms, Lee OO
NEXT CASE - 67 year old female
• 7 Feb 2014: 2 cm x 2 cm brown black, irregularly bordered left heel lesion in a surrounded by an approximately 1-1/2 cm light brown macular fringe.
• Clinical impression: Melanoma.
• Procedure: Punch biopsy.
Bruce Ragsdale MD
Your Diagnosis?
Melanoma in situ?Invasive melanoma?
Our Diagnosis
Malignant melanoma, acral-lentiginous type, in situ, transected at the specimen peripheral margins Note: There may be a few cells in the dermis. The biopsy may not be representative
CASE 2 – Follow up
• No signs of in-transit disease were recorded. • 1 mo. after punch biopsy, a wide excision of the lesion
with reconstruction by rotational flap. • Final thickness = 1.1 mm, margins free.• Sentinel groin lymph node = negative.
• PUNCH BIOPSY WAS NOT REPRESENTATIVE
Acral Melanoma
• Palms, soles, subungual• Great toe region most common• Incidence similar in all races, thus most
common form of melanoma in African, Asian and Indian populations
• May be deceptively thick even in absence of a raised nodule
No UV
Acral Melanoma
The spectrum of acral lentiginous melanoma
Amelanotic melanoma pink plantar lesion in a 92 Y/o M., growing 1.5 years.
Sentinel node – MART 1
Subungual melanoma
• Incidence, distribution and genomic attributes generally similar to ALM
• Differentiation from subungual nevus can be difficult– Lentigo, junctional nevus, compound nevus
• Ridge and furrow patterns do not apply• Confluence, atypia (high grade, uniform), scatter, mitoses• Most lesions in children are benign• WHEN THE CASE IS DIFFICULT,
CLINICOPATHOLOGIC CORRELATION IS ESSENTIAL!
DermNet New Zealand https://creativecommons.org/licenses/by-nc-nd/3.0/nz/legalcode
Hutchinson’s Sign – Extension of Pigment onto the Nail Fold
Lv, Jiaojie, et al (Shanghai, 2016)
Acral Melanomas
Radial Growth Phase (RGP)
Vertical Growth Phase (VGP)
Hutchinson’s sign
Acral-lentiginous Melanoma
• Lentiginous nontumorigenic compartment (RGP)
• Continuous basal proliferation of uniformly atypical melanocytes
• May be very subtle at the periphery
• Often a spindle cell tumori-genic compartment (VGP)
– often desmoplastic and/or neurotropic (local recurrence risk)
• May be deceptively thick even in absence of a raised nodule
Histopathology of Early Acral Melanoma
• Histopathologic features of early acral melanoma are minimal.– only scattered hyperchromatic cells– scattered spindle cells with prominent dendrites
• Excisional biopsy including the deepest area is recommended.
S J Yun, MD, PhD, S. Korea
Punch Biopsy
Scattered small ovoid cells
61M, Lt heel, 3yrs, Lee OOS J Yun, MD, PhD, S. Korea
HMB45 Prominent dendrites61M, Lt heel, 3yrs, Lee OO
HMB4561M, Lt heel, 3yrs, Lee OOMelanoma, Acral Lentiginous Type
Your Diagnosis?
Nevus?Melanoma?
Recurrent melanoma at site of prior biopsy
Field Cells (Bastian)
• Cells at periphery of acral melanomas that have initiating mutations and copy number increase, no morphological abnormalities
• Could account for greater tendency of these melanomas to recur locally– Also perhaps reluctance to perform “wide” excisions
• Follow-up protocols should pay particular attention to risk of local recurrence
Bastian BC, Kashani-Sabet M, Hamm H, Godfrey T, Moore DH 2nd, Bröcker EB, LeBoit PE, Pinkel D. Gene amplifications characterize acral melanoma and permit the detection of occult tumor cells in the surrounding skin. Cancer Res. 2000; 60:1968-73
• Analyzed chromosomal aberrations of 15 AMs and 15 SSMs using comparative genomic hybridization (CGH).
• AMs significantly more amplifications than the SSMs (mean 2 vs. < 1, p < 0.0001).
• Most frequently amplified regions in AMs were at 11q13 (47%, cyclin D).
• Amplifications of 11q13 were found in AM in situ showing that changes arise early in the progression of AM.
• Isolated epidermal melanocytes with amplifications were found up to 3 mm beyond the histologically recognizable extent of the melanomas in 5/15 invasive AMs.
11q amplification (red probe) in acral melanoma. Bastian et al, 2000
Margin Evaluation in Acral Melanoma
• “Field cells” at periphery of acral melanomas have initiating mutations and copy number increase, no morphological abnormalities
• SUBTLETY and UNCERTAINTY• May account for greater tendency of these melanomas to
recur locally• Follow-up protocols should pay particular attention to risk
of local recurrence
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