SubungualSubungual MelanomaMelanoma

Paul K. Shitabata, M.D.Paul K. Shitabata, M.D.DermatopathologistDermatopathologist

Pathology Inc.Pathology Inc.

4 4 y.oy.o. boy. boyJapanese, Korean, ChineseJapanese, Korean, ChineseAsthma, mild CPAsthma, mild CP

8 mo8 mo--Thin black line on nail, 2Thin black line on nail, 2ndnd

fingerfinger13 mo13 mo--Widened to include half nailWidened to include half nail23 mo23 mo--Entire nail involvedEntire nail involved24 mo24 mo--Biopsy read as negativeBiopsy read as negative47 mo47 mo--Nail painful and bleedingNail painful and bleeding

Treatment Options?Treatment Options?

ObservationObservationBiopsyBiopsyAvulse nailAvulse nailThe DoctorThe Doctor’’s Doctors DoctorOtherOther

Clinical PresentationsClinical Presentations

Rapidly spreading darkly Rapidly spreading darkly pigmented patch with pigmented patch with irregular borderirregular borderInvasion associated with Invasion associated with papules, plaques and later papules, plaques and later lesionslesions--ulceration and nail ulceration and nail deformitydeformityInvasion in Invasion in perieccrineperieccrineadventitial dermis may adventitial dermis may remain flatremain flatRegressionRegression--gray whitegray whiteHutchinsonHutchinson’’s signs sign--extension extension of pigmentation around of pigmentation around cuticlecuticle

ABCDE of NABCDE of N

A=Age (5A=Age (5--77thth decades), Africans, Asians, Native decades), Africans, Asians, Native AmericansAmericansB=Brown to black discoloration B=Brown to black discoloration

Breadth of nail pigmentation >3mmBreadth of nail pigmentation >3mmC=Change in nail band or lack of change in nail C=Change in nail band or lack of change in nail morphologymorphologyD=Digit most commonly involvedD=Digit most commonly involvedE=Extension to proximal nail foldE=Extension to proximal nail fold

The ABC rule for clinical detection of subungual melanoma.Levit EK, etal. J Am Acad Dermatol. 2001 May;44(5):875.

MelanonychiaMelanonychia VariantsVariants

LinearLinearTransverseTransverseTotalTotal

EpidemiologyEpidemiology

JapaneseJapaneseAfrican AmericansAfrican AmericansNo clear connection to No clear connection to UV exposure UV exposure Usually increased moles Usually increased moles but less incidence of AK but less incidence of AK and other sunand other sun--related related lesionslesions

Epidemiology and prognosis of subungual melanoma in 34 Japanese patients.Kato T, etal. Br J Dermatol. 1996 Mar;134(3):383-7

Ethnic Ethnic GroupGroup

PercentagePercentage

AfricansAfricans 77%77%JapaneseJapanese 1010--20%20%CaucasiansCaucasians 1%1%

Japanese PatientsJapanese Patients

University Hospital University Hospital StudyStudy34/151 melanoma cases 34/151 melanoma cases over 25 years were over 25 years were subungualsubungualMajority Majority AcralAcrallentiginouslentiginous histologichistologictype followed by SS and type followed by SS and nodularnodular

Epidemiology and prognosis of subungual melanoma in 34 Japanese patients.Kato T, etal. Br J Dermatol. 1996 Mar;134(3):383-7.

SiteSite NumbersNumbersFingernailsFingernails 21 (62%)21 (62%)ToenailsToenails 13 (38%)13 (38%)Thumb or Thumb or great toegreat toe

25 (73%)25 (73%)

Activation Activation vsvs HyperplasiaHyperplasia

Functional Functional melanonychiamelanonychia73% of LM (longitudinal 73% of LM (longitudinal melanonychiamelanonychia) in adults) in adultsPhysiologicPhysiologic--EthnicEthnicTraumaTraumaDermatitidesDermatitidesSystemic diseaseSystemic disease

AddisonAddison’’ssPeutzPeutz--JegherJegher’’ss

Increased matrix Increased matrix melanocytesmelanocytes77.5% of LM in children77.5% of LM in children

PathogenesisPathogenesis

SiteSite BRAF BRAF mutationsmutations

ChromChrom 10 10 lossloss

CCND1 CCND1 gene copiesgene copies

Minimal UV Minimal UV exposureexposure

HighHigh FrequentFrequent LowLow

Increased Increased UV exposureUV exposure

LowLow LowLow IncreasedIncreased

Distinct sets of genetic alterations in melanoma. Curtin JA, etal. N Engl J Med. 2005 Nov 17;353(20):2104-7.

ImplicationsImplications

GroupGroup InterventionIntervention

BRAF mutations frequentBRAF mutations frequent Target RASTarget RAS--RAFRAF--ERKERKand PI3K pathwaysand PI3K pathways

BRAF mutations infrequent BRAF mutations infrequent Increased copies of CCND1 Increased copies of CCND1 or CDK4or CDK4

Less likely to respond to Less likely to respond to therapeutic interventions therapeutic interventions that target upstream that target upstream components of the components of the mitogenmitogen--activated protein activated protein kinasekinasepathway including BRAF pathway including BRAF ((sorafenibsorafenib))

HistopathologyHistopathology

ExpansileExpansile nests of nests of pleomorphicpleomorphicmelanocytesmelanocytesSuperficalSuperfical spreading to spreading to lentiginouslentiginous growth growth patternpatternIrregular pigment Irregular pigment incontinenceincontinence

HistopathologicHistopathologic VariantsVariants

Two cases of regressed Two cases of regressed subungualsubungual melanomamelanomaLymphoscintigraphyLymphoscintigraphy and and sentinel lymph node sentinel lymph node (SLN) biopsies(SLN) biopsies--1 1 positive and 1 negativepositive and 1 negative

Dermatol Surg. 2006 Apr;32(4):577-80

Clinical Differential DiagnosisClinical Differential Diagnosis

MelanonychiaMelanonychia StriataStriata

Frictional Frictional MelanonychiaMelanonychia

CoumadinCoumadin--Associated Associated MelanonychiaMelanonychia

Longitudinal Longitudinal ChromonychiaChromonychia((MelanonychiaMelanonychia) )

Secondary to TraumaSecondary to TraumaPseudoPseudo--Hutchinson's sign due to Hutchinson's sign due to

periungualperiungual tissue transparencytissue transparency

TineaTinea NigraNigra(T. (T. rubrumrubrum varvar nigricansnigricans))

Rule out Candida Rule out Candida paronychiaparonychia))

PsuedoPsuedo--Hutchinson SignsHutchinson Signs

RacialRacialLauzierLauzier--HunzikerHunziker and and PeutzPeutz--JeghersJeghers syndromessyndromesRadiation therapyRadiation therapyMalnutritionMalnutritionMinocyclineMinocyclineAIDSAIDSCongenital nevusCongenital nevusTraumaTraumaPseudomonas and Proteus Pseudomonas and Proteus infectionsinfectionsBowenBowen’’s diseases disease

PrognosisPrognosis

Worse than conventional Worse than conventional melanomas?melanomas?SubungualSubungual worse than other worse than other acralacral melanomas?melanomas?VariablesVariables

Delayed diagnosisDelayed diagnosisPoorer prognosis:Poorer prognosis:

BreslowBreslow thicknessthicknessMale Male AmelanosisAmelanosis

Mets to CNS, liver lungs, Mets to CNS, liver lungs, bone, and LNbone, and LN

Acral lentiginous melanoma: a clinicoprognostic study of 126 cases.Phan A, etal. Br J Dermatol. 2006 Sep;155(3):561-9

Delay in DiagnosisDelay in Diagnosis5YS 5YS

88% <2.5mm88% <2.5mm40% >2.5mm40% >2.5mm

Nail apparatus melanoma. Thai KE, etal Australas J Dermatol 2001;42:71-81The incidence and prognosis of nail apparatus melanoma. A retrospective study of 105 patients in four English regions. Banfield CC, etal. Br J Dermatol 1998;139:276-279.

SiteSite Mean Mean ThicknessThickness

NonNon--acralacral <1.0 mm<1.0 mm

AcralAcral 3.05 mm3.05 mm

SubungualSubungual vs. vs. AcralAcral

67 Japanese cases of 67 Japanese cases of acralacral malignant melanomasmalignant melanomas>40% >40% palmoplantarpalmoplantar and and subungualsubungual80% 80% acralacral lentiginouslentiginous typetype15% nodular malignant melanoma15% nodular malignant melanoma3% superficial spreading 3% superficial spreading No difference in prognosis of No difference in prognosis of acralacral malignant melanomas malignant melanomas vsvs otherotherbody sitesbody sitesPalmoplantarPalmoplantar and and subungualsubungual malignant melanoma malignant melanoma

Women younger, better survival ratesWomen younger, better survival ratesNo significant difference with thickness No significant difference with thickness

Biological behavior and natural course of acral malignant melanoma. Clinical and histologic features and prognosis of palmoplantar, subungual, and other acral malignant melanomas. Jimbow K, etal. Am J Dermatopathol 1984;6:43-53.

AcralAcral Melanomas vs. Other SitesMelanomas vs. Other Sites

84, 836 cases84, 836 casesNational Cancer Data Base (1985National Cancer Data Base (1985--1994)1994)Nodular MM and Nodular MM and AcralAcral MM decreased survivalMM decreased survivalIndependent prognostic variableIndependent prognostic variable

The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. Chang AE, etal. Cancer 1998;83:1664-1678.

Nail BiopsyNail Biopsy

TechniqueTechnique

Must biopsy proximal Must biopsy proximal nail fold, location where nail fold, location where tumor usually arisetumor usually ariseIncisionalIncisional bxbx of nail plate of nail plate or proximal foldor proximal foldPunch Punch bxbx of proximal of proximal foldfold

4 4 y.oy.o. boy. boyJapanese, Korean, ChineseJapanese, Korean, ChineseAsthma, mild CPAsthma, mild CP

8 mo8 mo--Thin black line on nail, 2Thin black line on nail, 2ndnd

fingerfinger13 mo13 mo--Widened to include half nailWidened to include half nail23 mo23 mo--Entire nail involvedEntire nail involved24 mo24 mo--Biopsy read as negativeBiopsy read as negative47 mo47 mo--Nail painful and bleedingNail painful and bleeding

Treatment OptionsTreatment Options

ObservationObservationBiopsyBiopsyAvulse nailAvulse nailThe DoctorThe Doctor’’s Doctors DoctorOtherOther

PatientPatient’’s Mothers Mother’’s Solutionss Solutions

1) Do Nothing & Monitor? = DISAGREE - Delay in treatment increases severity if Melanoma is found/treatment more invasive

2) Do Another Biopsy? = DOESN'T MAKE SENSE - b/canesthesia will still have to be used

3) REMOVE NAIL NOW? = LOGICAL - Eliminates Melanoma risk BUT Increases Anesthesia risk (If nail is benign - future risk remains)

4) Transplantation with Toenail? = Derm knew about recent success & wanted to investigate - DON'T LIKE -creates 2 trauma sites

Remove Now!Remove Now!

A = Age (Low - child); Race (High - Japanese/Asian)B = Band (High - visible bands); Pigment (High -

brown/black), Breadth (High - 9 mm size); Border (? - ?)C = Change (High - rapid/esp 1st yr); Dystrophy (High -

Mostly biopsy caused but is brittle, weak, & rough edgesD = Digit (High - single digit); Dominant Hand (Low - is not

dominant hand)E = Extension/Hutchinson's sign (High - visible pigment in

fold)

Family history is unknown.Parallels most cases in literature - starting with 1 line, widening

rapidly, completely covering nail

Literature SupportLiterature Support

Childhood subungual melanoma in situ in diffuse nail melanosis beginning as expanding longitudinal melanonychia. Antonovich DD, etal. Pediatr Dermatol 2005:22;210-212.

A rapidly growing pigmented nail streak resulting in diffuse melanosis of the nail. A possible sign of subungual melanoma in situ. Kato T, etal. Cancer. 1989 Nov 15;64(10):2191-7.

SolutionsSolutions

Dr. Beth Rubin, Dr. Beth Rubin, DermatopathologistDermatopathologist UCSFUCSFDr. Dr. ScherScher and Dr. and Dr. TostiTosti

Dr. Stefani TakahashiDr. Stefani Takahashi--UCLAUCLA