37.

Melanomul malign
(epidemiologie, istorie naturală, clasificare TNM și histopatologică, simptomatologie, diagnostic,
evoluție, indicație terapeutică, principalele asocieri de chimioterapie)

Epidemiologie, istorie naturală, evoluție

-2% din cancerele de piele
-80% din mortalitatea cancerelor de piele
-incidență în creștere în ultimii ani
-înainte de 45 ani: risc mai mare la femei
-după 60 ani: risc de două ori mai mare la bărbați decât la femei
-populația caucaziană are un risc pe viață de 2.4%, iar afro-americanii de 0.1%
-riscul pe viață: 1 din 34 la femei și 1 din 53 la bărbați
-vârsta medie de dg 59 ani
-melanoamele mucoaselor apar cel mai frecvent la nivelul cavității bucale, anorectal,
vulvă, vagin, tract gi, tract urogenital
-melanoamele neasociate expunerii cronice la soare au o proporție mai mare de mutații
BRAF
-melanoamele mucoaselor și cele uveale diferă de melanoamele cutanate ca prezentare,
profil genetic, stadializare, răspuns la tratament și tipar de progresie

Factori de risc
-cei mai importanți: istoricul familial, multiplii nevi benigni/atipi, melanom în
antecedente
-factori adiționali: imunosupresia, sensibilitatea la soare, expunerea la radiații UV
-10% din melanoame sunt familiale
-riscul crescut în anumite familii poate fi atât prin susceptibilitate genică cât și prin
factori de mediu
-gene cu penetranță crescută: CDKN2A și CDK4
-mutațiile CDKN2A sunt mai frecvente decât CDK4
-alte gene mai puțin întâlnite: BAP1, TERT, XP (gene asociate cu xeroderma
pigmentosum)
-20% din melanoamele familiale din Australia și 57% din Europa sunt asociate cu
CDKN2A
-gene cu penentranță scăzută: BRCA2, MC1R etc
-sd de melanoame multiple atipice familiale (FAMMM) sau sd familial al nevilor
displazici – familii cu nevi numeroși peste 100, diferiți în dimensiune și culoare, transmitere
autozomal dominantă, vârsta medie de dg 33 ani
-nevii tipici sunt frecvent precursori ai melanomului
-nr crescut de nevi (peste 50) – 27% din cazurile de melanom
-nr de nevi 0-10 – doar 4% din cazurile de melanom
-nevi congenitali sunt benigni și prezenți la naștere, compuși din nevomelanocite
-nevi pigmentați giganți au un risc crescut de transformare malignă
-nevii sebacei sunt asociați cu cc bazocelular
-verucile epidermale și nevi cu păr nu au potențial malign
 -melanom în antecedente – 6-7% risc. Riscul este mai mare la cei care au avut melanom
in situ. Cel mai mare risc: primii 2 ani, dar rămâne crescut pt 20 ani. Risc mai mare: bărbați,
vârstnici, melanomul primar pe față, gât sau trunchi
-incidența unui al treilea melanom primar: 16% după 1 an, 31% după 5 ani
-imunosupresia
-sensibilitatea la razele solare – pielea deschisă la culoare, roșcații, polimorfism al genei
receptorului melanocortin care determină reducerea producției de melanină după expunerea la
radiație UV (crește riscul de melanom)
-expunerea la soare/radiații UV – determină modificări genetice la nivelul pielii,
afectează funcția imună a pielii, crește producția locală de factori de creștere, induce formarea de
specii reactive de oxigen care distrug ADN-ul și afectează keratinocitele și melanocitele
-arsuri solare cutanate frecvente mai ales în copilărie – creșterea riscului de melanom
-saloane de bronzare – risc de melanom
-expunerea ocupațională la gudron de cărbune, creozot, compuși ai arsenicului, radiu
-o rată mai mare de melanoame a fost observată la pacienții cu: boală Parkinson, cancer
de prostată, endometrioză, pacienți tratați cu voriconazol, sildenafil și inhibitori ai TNF

Prevenție
-evitarea expunerii la soare în orele mijlocii ale zilei
-folosirea îmbrăcămintei de protecție
-utilizarea ochelarilor de soare
-utilizarea cremelor de protecție solară SPF 15 sau mai mult
-evitarea arsurilor solare și a saloanelor de bronzare
-persoanele cu istoric familial sau personal de melanom – control periodic, cel puțin
anual la dermatolog

Istorie naturală
-melanomul își are originea în melanocite, celule derivate din creasta neurală care
migrează în timpul embriogenezei în stratul bazal epidermal
-majoritatea melanoamelor apar la nivelul pielii, dar pot exista melanoame și la nivelul
altor localizări (mucoase, uveale)
-situsuri extracutanate posibile: stratul coroidal al ochiului, suprafețe mucosale ale
tractului respirator superior (nas, nazofaringe), tract gastrointestinal (cel mai frecvent anus), tract
urogenital (cel mai frecvent vagin)
-pași în transformarea malignă (modelul Clark):
*proliferare și formarea unui nev benign
*creștere anormală și formarea unui nev displazic
*transformare fie dintr-un nev benign, fie din melanocite împrăștiate prezente
normal în piele
*faza de creștere radială – capacitatea de a crește intraepidermal
*faza de creștere verticală – invazia dermului
*diseminarea la distanță/alte organe/alte zone ale pielii
Nu toate melanoamele trec prin toate aceste faze individuale!
-alterarea semnalelor căilor de transducție:
*mutații punctiforme NRAS (15-20%)
*mutații BRAF (40-50%) – V600E, K, R, D
 *mutații NF1 (14%)
*alterări somatice ale căii PI3K
*pierderea expresiei PTEN
*supraexpresia Akt
*mutație Kit (melanoame ale mucoaselor)
*mutații GNAQ și GNA11 (melanoame uveale)
*mutații BAP1 (melanoame uveale)
-control aberant al ciclului celular: mutații CDKN2A și CDK4
-alte evenimente genetice implicate în patogeneza melanomului: amplificarea MITF,
supraexpresia Bcl-2, inhibarea APAF-1, activarea NF-kappaB
-statusul mutațional se poate schimba de-a lungul progresiei bolii
-mut BRAF și mut Kit se exclud reciproc
-BRAF-V600K și NRAS sunt mai frecvente la vârstnici, BRAF V600E la tineri

-melanoamele pot fi clinic ca subtip: pe leziuni induse de expunerea cronică la soare

(CSD – chronic sun damage) și pe piele fără leziuni induse de expunerea cronică la soare (non-
CSD)
-diseminarea primară este la nivelul ggl limfatici prin apariția leziunilor satelite și a
metastazelor în tranzit, apoi implicarea ggl regionali
-leziunile micro-satelite sunt leziuni cutanate sau subcutanate până în 2cm de la
tumora primară și reprezintă extensie intralimfatică
-metastazele în tranzit sunt leziuni la distanță de mai mult de 2cm de tumora
primară, dar FĂRĂ depășirea bazinului ggl regionali
-diseminarea poate fi și hematogenă, uneori după implicarea limfatică, alteori sărind
peste implicarea limfatică
-metatazele la distanță pot fi: cutanate, subcutanate, plămân, ficat, creier, alte organe
-metastazele cerebrale ale melanoamelor sunt bine vascularizate și sunt mai predispuse la
sângerare față de alte metastaze
-meta cerebrale apar adesea târziu în decursul bolii și apar modificări de comportament,
cefalee, grețuri, deficite neurologice
-evoluția melanomului depinde de stadiul la diagnostic
-prognosticul este excelent pt tumori 1mm sau mai puțin în grosime, localizate
-probabilitatea ca ggl regionali să fie implicați crește cu grosimea tumorii
-impactul tratamentelor sistemice asupra supraviețuirii melanomului în st IV fie la
prezentare fie la recurență a crescut posibilitatea remisiunilor pe termen lung la un număr mare
de pacienți
-SN+ doar celule neoplazice reduce supraviețuirea la 5 ani de la 80%-95% la 35%-75%.
Detecția macrometastazelor în SN o reduce și mai mult

-2-6% pot fi melanoame cu tumoră inaparentă

-se presupune că în aceste cazuri tumora primară a regresat spontan
-metastazele cel mai frecvente sunt cutanate, subcutanate și ggl limfatici
-supraviețuirea este similară cu cei la care se cunoaște tumora primară

-melanomul cu creștere superficială = 70% din melanoame, cel mai frecvent vârstă
mijlocie, torace posterior superior ambele sexe sau pe mb inferioare la femei, doar 25% se
asociază cu un nev preexistent, tipar de creștere radială pt o perioadă, apoi devine invaziv,
progresia se corelează cu evoluția a diferite culori: roșu inflamație, gri zonă de regresie, negru
melanocite neoplazice
-melanomul nodular = 15-20%, mai frecvent la vârstnici, de 2 ori mai frecvent la
bărbați, creștere rapidă și verticală încă de la început
-melanomul malign lentigular = 4-15%, mai frecvent la vârstnici (decada 6-7), apare pe
zone expuse la soare, mai ales pe față, creștere lentă, creșterea radială poate dura 5-50 ani până
ce crește vertical, frecvent regresie parțială
-melanomul lentiginos acral = cea mai puțin întâlnită variantă 2-8% la caucazieni,
dar 30-75% la negri, hispanici, asiatici, apare pe plante, palme, falangă terminală
-melanomul nevoid = seamnănă cu nevii benigni, poate metastaza
-melanomul desmoplastic = seamănă cu o cicatrice/fibrom, apare pe zone expuse la soare,
tinde la recurență locală sau metastaze izolate

-la bărbați melanomul apare mai frecvent la nivelul trunchiului, capului și gâtului
-la femei: trunchi posterior și picioare
-deși adesea sunt leziuni pigmentat, pot fi și nepigmentate, roșii sau ca noduli subcutanați

Factori prognostici
-grosimea leziunii (indicele Breslow), ulcerația (absența epiteliului intact deasupra
tumorii+reacția țes subiacent) – cei mai importanți predictori ai supraviețuirii
-rata mitotică
-nivelul Clark (profunzimea anatomică a invaziei) nu mai este utilizat în stadializare
-nr ggl implicați/prezența leziunilor în tranzit/sateliți
-nivelul LDH
-prezența metastazelor viscerale

-supraviețuirea la 5 ani: localizat: 98%, regional: 62%, metastatic: 16%

Follow-up
St 0 (in situ): examen fizic și anamneză cel puțin anual, nu se recomandă analize de
rutină și nici imagistică
St IA-IIA: examen fizic și anamneză la 6-12 luni pt 5 ani, apoi anual după indicație
clinică, fără analize de rutină, fără imagistică de rutină, imagistică pt semne și simptome
specifice
St IIB-IV: examen fizic și anamneză la 3-6 luni primii 2 ani, 3-12 luni următorii 3 ani,
apoi anual după indicație clinică, fără analize de rutină, imagistică pt semne/simptome specifice,
+/- imagistică la 3-12 luni pt 2 ani, apoi la 6-12 luni pt încă 3 ani pt screeningul recurenței/bolii
metastatice (2B), după 3-5 ani, nu se mai recomandă screening de rutină pt pacienți
asimptomatici, în funcție de riscul de recurență

Clasificare TNM
(caiet roz)

Clasificare histopatologică
-melanom cu tipar de creștere superficială
-melanom nodular
 -melanom lentigular
-melanom acral lentiginos
-melanom nevoid
-melanom desmoplastic

Simptomatologie
Melanomul superficial – leziuni tip placă/maculă variat pigmentată cu formă bizară și
margini neregulate
Melanomul nodular – leziune tip dom închisă la culoare sau tip nodul polipoid care poate
să se ulcereze sau să sângereze, ocazional amelanotic
Melanomul lentigular – leziune de culoarea bronzului, adesea mare în dimensiune 3-6cm
Melanomul acral lentiginos – leziune maro închis/negru cu petice colorate neregulat
Melanomul nevoid – leziune tip verucă sau dom
Melanomul desmoplastic – leziune tip cicatrice sau fibrom adesea amelanotică

Ulcerația/sângerarea apare când leziunea este profundă.

Schimbarea unor nevi preexistenți sau apariția unui nou nev cu aceste caracteristici este
înalt suspect pt malignitate
Apariția de leziuni în tranzit sau metastaze cutanate – noduli eritematoși, pot să fie
nepigmentați, pot conglomera și ulcera
Simptome ale bolii metastatice în funcție de situsul afectat: insuf resp, dispnee, disfuncție
hepatică, icter, fatigabilitate, tulburări neurologice
The clinical picture of ITM can vary – from single, small nodules to neoplastic
infiltration covering large areas of the skin. The latter can be combined with serious
complications such as bleeding, infections and necrosis with loss of a significant mass of tissue.
This can be a life-threatening situation and is usually connected with a significant decrease in
quality of life.

Diagnostic
Anamneză (istoric personal și familial)
Examinare fizică:
Regula ABCDE pentru semne de suspiciune de melanom:
A – asimetrie, B – borders (margini neregulate), C – color (schimbări ale culorii,
pigmentare neuniformă), D – diametru (peste 6mm), E – evoluție (creștere/evoluție)
Schimbarea unor nevi preexistenți sau apariția unui nou nev cu aceste caracteristici este
înalt suspect pt malignitate
Examinarea întregului corp, inclusiv scalp, axilă, regiune genitală, interdigitală, cavitate
bucală.
Observarea leziunilor tip ”rățușca cea urâtă”: care arată diferit de alte leziuni ale pielii,
chiar dacă nu se încadrează în regula ABCDE
Dermatoscopia – x10, foarte important mai ales pt examinarea leziunilor plane sau ușor
elevate
Biopsia leziunilor suspecte și EHP – excizie cuprinzând întreaga grosime a leziunii cu
margini de 1-3mm dacă se suspicionează melanom, TRU-CUT sau tangențială poate fi folosită
pentru leziuni foarte mari care necesită dg EHP. EHP trebuie să menționeze: regresie, TILS, faza
de creștere (verticală/radială), invazia angiolimfatică, neurotropismul, subtipul histologic.
(Ulceration is defined as a complete absence of the epidermis above the primary melanoma,
accompanied by adjacent tissue reaction. In lack of adjacent tissue reaction, the loss of epidermis
above the primary tumour is likely artificial and should not be reported as ulceration.)
Pt stadializare necesar: Breslow (grosimea tumorii), ulcerație/nu, nivel Clark, rată
mitotică, statusul marginilor, prezența/nu leziuni satelite
Biologic: LDH, HLG, biochimie cu transaminaze, S100
CT/RMN TAP + cap (important la pacienții high risk st IIIC)
PET-CT poate fi util pt evaluarea posibilei boli osoase/meta intestinale
Evaluarea ggl santinelă (SLNB should generally be discussed and offered for patients
with higherrisk stage IB (>1 mm thick or 0.76–1.0 mm thick with ulceration or mitotic rate ≥1
per mm2) or stage II melanoma.)

Diagnostic diferențial
Nev compus, nev cu halo, nev dermal, cc bazocelular, keratoză seboreică, angioame,
dermatofibroame

Indicație terapeutică și principalele asocieri de chimioterapie

(caiet roz, keep)
-Pt pacienții cu volum tumoral mai mic, meta puține și LDH normal, cu mutație BRAF se
poate alege ca primă linie fie antiBRAF fie imunoT
-în cazurile în care se dorește un răspuns rapid se alege terapia țintită
-atezo+vemurafenib+cobimetinib a fost aprobat în 2020 de FDA pt tratam melanom
metastatic cu mutație BRAF v600
- surgical excision margins of at least 1 cm and no more than 2 cm are adequate.
- Topical imiquimod has emerged as a treatment option, especially for lentigo maligna.
- Radiotherapy has also been used selectively for lentigo maligna.
- For in situ melanoma, a measured margin of 0.5 to 1 cm around the visible lesion
should be obtained. For large in situ lentigo maligna melanoma, surgical margins greater than 0.5
cm may be necessary to achieve histologically negative margins.
- For selected patients with positive margins after optimal surgery, topical imiquimod or
RT can be considered as non-standard options (category 2B).
-margini: in situ 0.5cm, 1mm sau mai mic: 1cm, 1-2mm: 2cm, peste 2mm: peste 2cm
- Adjuvant treatment outside of a clinical trial is not recommended for patients with stage
I/II disease
In low-risk melanomas (pT1a), after complete excision, no additional investigations are
necessary and patients enter follow-up
Sequential nodal observation by ultrasound is indicated for SN+ disease rather than
CLND
In selected cases with disease progression on subsequent IO/chemotherapy, it is possible
to rechallenge with BRAF/MEK inhibitors

-risk is higher among patients who initially presented with melanoma in situ than in those
with invasive melanoma
-nev benign - nev displazic - melanom - fază de creștere radiară (intraepidermală) - faza de
creștere verticală (invazia dermului) - metastazare
-alterarea semnalelor de transmitere intracelulară: mutații NRAS și BRAF, mutația NF1,
alterări somatice ale căii PI3K, pierderea expresiei PTEN și supraexpresia Akt, mutațiile
Kit, GNAQ, GNA11, BAP1
-alterarea ciclului celular: mutații CDK4, CDKN2A
-alte modificări genetice implicate: amplificarea MITF, supraexpresia Bcl-2, inhibiția
APAF-1, activarea NF-kB

Melanomul cu creștere superficială:

-cel mai frecvent subtip
-mai ales pe torace la ambele sexe, pe picioare la femei
-pattern de creștere radiară
-formă bizară cu margini neregulate
-evoluție cu trecere prin nuanțe de roșu (inflamație), gri (arii de regresie) până la negru
(melanocite neoplazice).

Melanomul nodular:
-mai frecvent la bătrâni
-de două ori mai frecvent la bărbați decât la femei
-leziuni închis pigmentate în formă de dom sau nodul polipoid care se ulcerează și
sângerează ușor
-uneori poate fi amelanotic
-pattern de creștere verticală și rapidă

Melanom lentigular:
-cel mai frecvent la bătrâni
-mai ales pe față, zone expuse la soare
-leziune maculară maro de tip bronz, mare în dimensiuni (3-6cm)
-creștere lentă, cu faza radiară între 5-50 ani până la creșterea verticală

Melanom acral lentiginos:

-cea mai puțin frecventă formă
-apare pe palme, tălpi, falange terminale
-leziune sub formă de zonă maro închis spre negru neuniform colorată

Melanom - forme rare:

*melanom nevoid - seamănă cu nevii benigni, formă de verucă sau dom
*melanom desmoplastic - seamănă cu o cicatrice sau fibrom, apare pe zone expuse la soare,
frecvent amenalotic

- Based on data from 2009 to 2011, the lifetime risk of developing cutaneous melanoma is 1
in 34 for women and 1 in 53 for men.
- The median age at diagnosis is 59 years.
- Risk factors for melanoma include skin type, personal history of prior melanoma,
multiple clinically atypical moles or dysplastic nevi, a positive family history of melanoma,
and rarely, inherited genetic mutations.
- environmental factors including excess sun exposure and UV-based artificial tanning
contribute to the development of melanoma.
- the outcome of melanoma depends on the stage at presentation
- prognosis is excellent for patients who present with localized disease and primary tumors
1.0 mm or less in thickness, with 5-year survival achieved in more than 90% of patients
- For patients with localized melanomas more than 1.0 mm in thickness, survival rates
range from 50% to 90%, depending on tumor thickness, ulceration, and mitotic rate
- The likelihood of regional nodal involvement increases with increasing tumor thickness,
as well as the presence of ulceration and mitotic rate
- within stage III, 5-year survival rates range from 20% to 70%, depending primarily on
the nodal tumor burden.
- the impact of emerging effective systemic therapies on the survival of patients with stage
IV melanoma, either at presentation or recurrence, has made long-term remission possible
for a larger proportion of patients
- clinical subtypes of cutaneous melanoma are: non-chronic sun damage (non-CSD):
melanomas on skin without chronic sun-induced damage; CSD: melanomas on skin with
chronic sun-induced damage signified by the presence of marked solar elastosis; and acral:
melanomas on the soles, palms, or sub-ungual sites.
- Melanocytes exist outside of the skin as well, and can give rise to non-cutaneous
melanomas on mucosal membranes, the uveal tract of the eye, or leptomeninges. Mucosal
melanomas most often occur in the head and neck sinuses and oral cavity, anorectum,
vulva, and vagina, but can arise in any of the mucosal membranes lining the
gastrointestinal and urogenital tracts
- non-CSD subtype was found to have the highest proportion of BRAF mutations
- NRAS mutations were found in 5% to 20% of the subtypes.
- Mucosal and uveal melanomas differ significantly from cutaneous melanoma in
presentation, genetic profile, staging, response to treatment, and patterns of progression.
- Patients presenting with a suspicious pigmented lesion optimally should undergo an
excisional biopsy (elliptical, punch or saucerization), preferably with 1- to 3-mm negative
margins.
- Excisional biopsy may be inappropriate for certain sites (including the face, palmar
surface of the hand, sole of the foot, ear, distal digit, or subungual lesions) or for very large
lesions. In these instances, a full-thickness incisional or punch biopsy of the clinically
thickest portion of the lesion is an acceptable option.
- If the initial biopsy is inadequate to make a diagnosis or to accurately microstage the
tumor (based on evaluation by a dermatopathologist) for treatment planning, re-biopsy
with narrow margin excision should be considered. Shave biopsy may compromise
pathologic diagnosis and complete assessment of Breslow thickness. However, it is
acceptable in a low suspicion setting.
- a broad shave biopsy may help to optimize accurate diagnosis of lentigo maligna.
- in addition to patient-specific factors of age and gender, tumorspecific factors of Breslow
tumor thickness, ulceration, and mitotic rate were found to be the three most important
characteristics independently predictive of outcome
- Mitotic rate is an indicator of tumor proliferation and is measured as the number of
mitoses per mm2
- Reporting detection of microscopic satellites in the initial biopsy or wide excision
specimen is also important for AJCC staging, as this defines at least N2c, stage IIIB disease.
- a microsatellite = the presence of tumor nests greater than 0.05 mm in diameter, in the
reticular dermis, panniculus, or vessels beneath the principal invasive tumor but separated
from it by at least 0.3 mm of normal tissue on the section in which the Breslow
measurement was taken.
- The American Academy of Dermatology (AAD) Task Force recommends the inclusion of
additional factors such as vertical growth phase (VGP), tumor-infiltrating lymphocytes
(TIL), and regression in the report.
- mitotic rate has replaced Clark level as a criterion for upstaging patients with melanomas
less than or equal to 1.0 mm in thickness from IA to IB
- pathologists should note cases of pure desmoplastic melanoma (as opposed to the presence
of desmoplasia admixed with spindle cell and/or epithelioid cells) as this may impact
decisions about further diagnostics and treatment
- Some melanocytic proliferations can be diagnostically challenging. Examples include
atypical melanocytic proliferation, melanocytic tumor of uncertain malignant potential,
superficial melanocytic tumor of uncertain significance, atypical Spitz tumor, and atypical
cellular blue nevus. These lesions are more frequently seen in younger patients, and when
suspected, referral to a pathologist with expertise in atypical melanocytic lesions is
recommended. In cases where melanoma is included in the differential diagnosis, the
pathology report should include prognostic elements as for melanoma.
- Among patients with nodal metastases (stage III), the clinical nodal status (nonpalpable
vs. palpable) and the number of metastatic nodes are the most important predictors of
survival
- For patients with a positive SLN, prognostic factors include number of positive nodes,
tumor burden in the sentinel node, primary tumor thickness, mitotic rate and ulceration,
and patient age.
- For patients with clinically positive nodes, prognostic factors include number of positive
nodes, extranodal extension, primary tumor ulceration, and patient age
- In-transit metastasis is defined as intralymphatic tumor in skin or subcutaneous tissue
more than 2 cm from the primary tumor but not beyond the nearest regional lymph node
basin
- The presence of microsatellites, clinically evident satellites, and/or regional intransit
disease is all part of the biologic continuum of regional lymphatic involvement, and these
are all associated with a prognosis similar to that of patients with clinically positive nodes.
This is recognized in the staging system with the designation of stage IIIC.
- Among patients with distant metastatic melanoma (stage IV), the site of metastases is the
most significant predictor of outcome
- LDH crescut - factor prognostic inclus în stadializare
- The prognosis for patients with metastatic melanoma has dramatically improved with the
emergence of several effective systemic therapies associated with improved overall survival
(OS) and long-term survival in some patients
- mutation status can change during disease progression, such that recurrences or
metastases may have mutations not present in the primary tumor
- For the pathology report, the NCCN Melanoma Panel recommends at a minimum the
inclusion of Breslow thickness, ulceration status, mitotic rate (#/mm2), deep and peripheral
margin status (positive or negative), presence or absence of microsatellites, pure
desmoplasia if present, and Clark level for nonulcerated lesions 1.0 mm or less where
mitotic rate is not determined.
- BRAF and c-KIT mutational analyses are clinically useful only for patients with advanced
disease
- In the absence of metastatic disease, testing of the primary cutaneous melanoma for
BRAF mutation is not recommended.
- After the diagnosis of cutaneous melanoma has been confirmed, detailed personal and
family history, including any personal history of prior melanoma or dysplastic nevi, should
be obtained.
- Patients with in-situ melanoma are stage 0.
- Patients with invasive (not insitu) melanoma and clinically negative nodes are stage I-II.
- Patients with palpable regional nodes, as well as those with in-transit disease or
microsatellites are clinical stage III.
- Patients with distant metastases are clinical stage IV, and should be further assigned to a
substage by recording all sites of metastatic disease and the serum LDH (within normal
limits or elevated).
- Based on preliminary workup and clinical staging patients are stratified into one of six
groups for further workup and treatment:
• Stage 0 (melanoma in situ); or stage IA or IB with thickness 0.75 mm or less, regardless of
other features (eg, ulceration, mitotic rate)
• Stage IA with thickness 0.76 to 1.0 mm, with no ulceration, and mitotic rate 0 per mm2
• Stage IB with thickness 0.76 to 1.0 mm with ulceration or mitotic rate greater than or
equal to 1 per mm2; or stage IB or II with thickness 1.0 mm thick, any feature (eg, with or
without ulceration, any mitotic rate), and clinically negative nodes
• Stage III with clinically detected (palpable) positive nodes, microscopic satellitosis (from
assessment of the primary lesion), and/or in-transit disease
• Stage IV (distant metastatic disease)
- The yield of routine blood work and imaging studies in screening patients with clinical
stage I-II melanoma for asymptomatic distant metastatic disease is very low.
- Pt pacienții cu volum tumoral mai mic, meta puține și LDH normal, cu mutație BRAF se
poate alege ca primă linie fie antiBRAF fie imunoT
- în cazurile în care se dorește un răspuns rapid se alege terapia țintită
- atezo+vemurafenib+cobimetinib a fost aprobat în 2020 de FDA pt tratam melanom
metastatic cu mutație BRAF v600
- The technique for SLNB consists of preoperative dynamic lymphoscintigraphy,
intraoperative identification using isosulfan blue or methylene blue dye, and a gamma
probe to detect radiolabeled lymph nodes
- The most common complications associated with SLNB are wound dehiscence and
infection, seroma/hematoma, and lymphedema; other associated complications are nerve
injury and thrombophlebitis, deep vein thrombosis, and hemorrhage
- SLNB did improve DFS by 7% and 10% for patients with intermediate thickness (1.2–3.5
mm) or thick (>3.5 mm) primary lesions, respectively.
- In patients with thin melanoma (≤1 mm) the prognostic value of SLNB results is unclear.
- SLNB should generally be discussed and offered for patients with higherrisk stage IB (>1
mm thick or 0.76–1.0 mm thick with ulceration or mitotic rate ≥1 per mm2) or stage II
melanoma.
- Since patients with stage IIIC have an appreciable risk of symptomatic CNS recurrence,
and symptomatic CNS metastasis are associated with significant morbidity and poor
survival, baseline CNS imaging should be considered in these high-risk patients.
- Genetic analyses (eg, BRAF or KIT mutation status) are appropriate for patients being
considered for treatment with targeted therapy, or if mutational status is relevant to
eligibility for participation in a clinical trial.
- To ensure that adequate metastatic material is available for mutational analysis, biopsy
(core, excisional, or incisional) is preferred if initial therapy is to be systemic and archival
tissue is not available.
- Panelists encourage baseline chest/abdominal/pelvic CT with or without PET/CT in
patients with stage IV melanoma. Because patients with metastatic melanoma have a high
incidence of brain metastases, brain MRI or CT scan with contrast should be performed at
presentation with stage IV disease.
- Although LDH is not a sensitive marker for detecting metastatic disease, the panel
recognizes its prognostic value. It is recommended that serum LDH be obtained at
diagnosis of stage IV disease.
- surgical excision margins of at least 1 cm and no more than 2 cm are adequate.
- Topical imiquimod has emerged as a treatment option, especially for lentigo maligna.
- Radiotherapy has also been used selectively for lentigo maligna.
- For in situ melanoma, a measured margin of 0.5 to 1 cm around the visible lesion should
be obtained. For large in situ lentigo maligna melanoma, surgical margins greater than 0.5
cm may be necessary to achieve histologically negative margins.
- For selected patients with positive margins after optimal surgery, topical imiquimod or
RT can be considered as non-standard options (category 2B).
- For melanomas 1.0 mm or less, wide excision with a 1-cm margin is recommended
(category 1). Wide excision with a 1- to 2-cm margin is recommended for melanomas
measuring 1.01 to 2 mm in thickness (category 1). For melanomas measuring more than 2
mm in thickness, wide excision with 2-cm margins is recommended (category 1).
- the probability of clinically occult positive pelvic nodes is increased when there are
clinically positive inguinofemoral nodes, three or more inguinofemoral nodes involved, or
when Cloquet’s node is positive, but the impact of elective pelvic lymphadenectomy on
survival in this specific patient cohort is unknown
- Potential complications associated with CLND include wound dehiscence or infection,
hematoma/seroma, neuropathy, lymphocele formation, and lymphedema.
- The risk and severity of complications may depend on the location of the nodal basin
undergoing lymph node dissection, with the groin being the highest risk location, especially
for lymphedema.
- there is no uniform agreement on the number of lymph nodes needed to define an optimal
CLND in a given lymph node basin
- Adjuvant radiation therapy (RT) is rarely necessary following adequate excision of a
primary melanoma. One exception may be desmoplastic neurotropic melanoma (DNM),
which tends to be locally aggressive.
- adjuvant RT is suggested that it improves local control in patients with desmoplastic
melanoma
- Adjuvant treatment outside of a clinical trial is not recommended for patients with stage
I/II disease
- In patients with resected stage III disease at low risk of recurrence (eg, AJCC 8th Edition
stage IIIA and/or those with SLN metastasis <1 mm), the toxicity of adjuvant therapy may
outweigh the benefit and should be discussed with the patient.
- Ipilimumab, a monoclonal antibody that binds and blocks the function of the immune
checkpoint receptor CTLA-4, has been shown to significantly improve progression-free
survival (PFS) and OS in patients with unresectable or metastatic melanoma,403,404 and
originally received FDA approval in 2011 for treatment of patients with metastatic
melanoma.
- high-dose ipilimumab as adjuvant treatment in melanoma: the FDA-approved indication
includes all patient groups included in the trial, patients with stage III in-transit disease
(provided they also have at least one nodal metastasis >1 mm diameter), and those who had
received prior systemic therapy for melanoma
- Adjuvant ipilimumab was tested and FDA approved with a prolonged highdose regimen:
10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years
or until documented disease recurrence or unacceptable toxicity.
- An ongoing phase III randomized trial (ECOG 1609, NCT01274338) is testing whether
adjuvant ipilimumab using the 3 mg/kg dosing will reduce toxicity without reducing
clinical benefit.
- In contrast, for treatment of unresectable or metastatic disease, the recommended
ipilimumab dose is lower (3 mg/kg) and the treatment duration is shorter (every three
weeks for a total of 4 doses)
- Ipilimumab is associated with a variety of irAEs, and the frequency and severity of these
toxicities have been shown to increase with dose
- The programmed cell death protein 1 (anti-PD-1) antibodies interfere with ligand binding
by the T-cell surface receptor PD-1, resulting in enhanced T-cell activation.
- For patients with a nodal recurrence after previous exposure to an antiPD-1 agent, repeat
exposure to adjuvant nivolumab or pembrolizumab may be less effective.
- Based on results from COMBI-AD, dabrafenib/trametinib combination therapy was FDA
approved as adjuvant therapy for patients with BRAF V600E/K mutations resected stage
III or recurrent disease. Dabrafenib/trametinib is an adjuvant treatment option for all
patients with stage III disease. adjuvant dabrafenib/trametinib is a category 2A option for
patients with satellite/in-transit disease (if completely excised to clear margins).
- dabrafenib/trametinib is not a recommended adjuvant treatment option for resected stage
IV disease.
- vemurafenib was associated with an increase in hyperproliferative cutaneous AEs. Given
the improved efficacy/safety profile of BRAF/MEK inhibitor combination therapy
compared to BRAF inhibitor monotherapy, vemurafenib monotherapy is not FDA
approved for adjuvant treatment of melanoma
- Currently there are insufficient data to recommend any specific agent as neoadjuvant
therapy for melanoma, but given the promising results in initial trials and the number of
trials currently available, the NCCN Panel recommends considering enrollment into a
clinical trial of neoadjuvant systemic therapy in patients with borderline resectable
lymphadenopathy or for those at very high risk of recurrence after lymphadenectomy.
- The tumor burden, time course of appearance, and duration of in-transit disease is
variable. In some patients, in-transit lesions remain confined to a region of the body for
many years. This may occur in isolation or in combination with other sites of metastatic
disease. A major concern in patients in which in-transit disease occurs in isolation is the
high probability of subsequent development of visceral metastasis
- Many different treatment options, mostly locoregional, are available to patients
presenting with stage III in-transit metastases. The choice of therapy depends on the
patient’s health status and tumor burden, defined by the size, location, and number of
tumor deposits. Since the tempo of spread of in-transit disease is not always known at
presentation, it may be reasonable to start with conservative local therapies and move to
regional/systemic therapy if response to local therapy is short-lived
- Excision to clear margins is the mainstay of treatment for limited resectable in-transit
metastasis
- in-transit disease has a high probability of clinically occult regional nodal involvement
- For patients for whom resection is not feasible, prior resections have been unsuccessful, or
who refuse surgery, non-surgical local approaches for treating stage III in-transit
melanoma include intralesional injections, local ablation therapy, topical imiquimod, and
RT.
- talimogene laherparepvec (T-VEC), an agent that uses a modified herpes simplex virus to
induce tumor cell lysis and to deliver localized expression of GM-CSF to injected lesions
- Exploratory subset analyses showed that the effect of T-VEC on response was greater for
patients with less advanced disease.
- For T-VEC, common toxicities (treatment-emergent in ≥20%, any grade) were fatigue,
chills, pyrexia, nausea, flu-like illness, injection-site pain, and vomiting. Treatment-related
toxicities of grade 3–4 occurred in 11% of patients, and included injection-site reactions
(eg, cellulitis, pain, peripheral edema) and systemic toxicities (fatigue, vomiting, and other
flulike symptoms).
- Intralesional injection of IL-2 is far less toxic than high-dose IV IL-2. Grade 1-2 adverse
effects are common but manageable, and grade 3–4 toxicities are extremely rare. E.A.:
injection site inflammatory reaction with local swelling, erythema, pain, and sometimes
necrosis. Common systemic effects include fever and other flu-like symptoms (chills,
fatigue, nausea, and emesis, and sometimes stomach pain, diarrhea, and headache) that are
usually mild and often respond to analgesics

- IFN has been used as an intralesional injection agent for treating in-transit melanoma,
although there is very little published evidence to support this approach (case reports and
one small retrospective study).
- Intralesional Bacillus Calmette-Guérin (BCG) has been shown to provide at least
transient complete or partial responses in most injected lesions, with much higher response
rates in cutaneous versus subcutaneous metastases (Table 8). Although initial response
rates are high for injected lesions, intralesional BCG is associated with a number of
significant local and occasional systemic adverse effects. BCG injection has been largely
supplanted by other local injection options and is rarely used in clinical practice.
- Rose Bengal, a photosensitizing dye, is an investigational agent in development as another
method for chemoablation of melanoma metastases by intralesional injection (using PV-10,
a 10% w/v Rose Bengal saline solution). It has similar activity to other intralesional agents,
but is not currently available outside of the clinical trial setting
- Topical Therapy for patients with in-transit/locally metastatic disease, case reports
suggest: imiquimod monotherapy and (DPCP), also known as diphenylcyclopropenone
- For patients with regionally recurrent melanoma not suitable for local or topical therapy,
regional administration of cytotoxic chemotherapy with either isolated limb perfusion
(ILP) or isolated limb infusion (ILI) is designed to administer high doses to an affected
extremity while avoiding toxicities associated with systemic drug exposure. These
approaches are limited to patients with regional metastases confined to an extremity.
- for ILP melphalan (L-phenylalanine mustard) is the cytotoxic agent most commonly used,
often in combination with either actinomycin D or TNF-alfa.
- Disadvantages to ILP include the technical complexity and invasiveness of the procedure,
which make it challenging (or contraindicated) in elderly and frail patients, and difficult to
use again in the same patient in the event of recurrence or progression. This approach
should only be performed in centers with the expertise to manage both the procedure and
the potential complications.
- ILI was developed as a simpler and less invasive approach, amenable to repeated
applications, and safe for use in elderly patients. Melphalan is commonly used for ILI,
often with actinomycin D. Addition of papaverine for cutaneous vasodilation has been
shown to increase response rate but also the risk of regional toxicity. ILI is associated with
lower rates of toxicity and morbidity compared with ILP, but retrospective comparisons of
response and survival with ILP versus ILI have shown varying results.
- Treatment in the context of a clinical trial is the preferred option for intransit disease. For
those with a single or a small number of resectable intransit metastases, complete surgical
excision with histologically negative margins is preferred, if feasible.
- If a complete surgical excision to clear margins is not feasible, treatment in the context of
a clinical trial is generally the preferred option. Other local, regional, or systemic therapies
can be considered. If the patient has a limited number of in-transit metastases, particularly
dermal lesions, which are not amenable to complete surgical excision, intralesional local
injections should be considered. Patients with least one cutaneous, subcutaneous, or nodal
lesion or aggregation of lesions >10 mm in diameter, may be appropriate candidates for
intralesional injection with TVEC.
- If T-VEC is not available, intralesional injection with IL-2 is another option, as is
injection with BCG or IFN. All of these options are category 2B recommendations.
- Based on non-comparative studies, laser ablation, topical imiquimod, or RT are category
2B options that may help for palliation or to establish regional control for selected patients
with unresectable in-transit disease. Topical imiquimod can be considered as an option in
very low-volume cutaneous metastases.
- Five-year overall survival (OS) in stage I-II disease is 65%-100%, dropping to 41%-71%
in patients with local metastases (stage III) and 9%-28% in patients with distant metastases
(stage IV).
- The risk of metastatic disease increases with the thickness of the primary tumour
- In low-risk melanomas (pT1a), after complete excision, no additional investigations are
necessary and patients enter follow-up
- Immunohistochemical staining with melanocytic markers, such as S100, is usually used
for more accurate measurement.
- Along with the tumour thickness, ulceration is a T-category criterion. It is designated as
T-‘a’ or ‘b’, according to its presence or absence.
- Ulceration is defined as a complete absence of the epidermis above the primary
melanoma, accompanied by adjacent tissue reaction. In lack of adjacent tissue reaction, the
loss of epidermis above the primary tumour is likely artificial and should not be reported
as ulceration.
- Mitotic rate is defined as the number of mitoses per square millimetre in the invasive part
of the primary tumour and was previously used in the TNM staging. This should be noted
even if it's not part of the staging anymore. Other factors, recommended to be assessed, are
(Clark’s) level of invasion, tumour-infiltrating lymphocytes (TILs) and lymphovascular
and neural invasion.
- Distant lymph node or soft tissue metastases are staged as M1a, lung metastases as M1b,
other visceral metastases as M1c and central nervous system (CNS) metastases as M1d.
- Even though lactate dehydrogenase (LDH) level remains an important prognostic factor,
it is not considered a category criterion in the most recent staging manual.
- At initial staging, various imaging techniques can be used. However, brain MRI and PET-
CT/CT should be applied only for very high-risk (>pT3b) patients
- The number of organs affected by metastatic disease is reported to be prognostic.
However, it is not an M-category criterion. Clinical and pathological staging occur at the
initial diagnosis. In the case of recurrent melanoma, it is suggested that recurrent TNM
(rTNM) classification is used.
- Primary tumour thickness is an independent prognostic factor, which directly correlates
with melanoma-specific survival.
- Increased mitotic rate (>1 mitosis/mm2) and tumour ulceration are associated with poor
disease-free survival (DFS) and OS.
- TILs have been reported to be associated with negative sentinel lymph node and better
prognosis. A positive effect of TILs is also seen in metastases.
- Presence of melanoma cells in a sentinel lymph node reduces 5-year OS from 80%-95% to
35%-75%. Detection of macrometastases reduces it even more.
- Extracapsular extension of tumour tissue and involvement of multiple lymph nodes also
correlate with poor DFS.
- In patients with stage IV disease, patients with soft tissue metastases show longer OS,
compared with those with lung and other visceral organ metastases.
- Elevated serological markers, such as serum LDH and S100, are associated with poor
prognosis.
- Low LDH and S100 levels at the baseline are predictive for better response to targeted
and immune therapies.
- Severe (grade 3/4) toxicity from adjuvant BRAF/MEK inhibitors is higher (31%) than
from adjuvant anti-PD-1 (15%). However, toxicity due to BRAF/MEK inhibitors resolves,
but immunotherapy-related toxicity can be
permanent.
- Sequential nodal observation by ultrasound is indicated for SN+ disease rather than
CLND
- Adjuvant systemic therapy should be considered for SN+ disease
- Formal LN dissection is indicated to treat clinical/macroscopic nodal disease (either
palpable or image-detected)
- Neither adjuvant RT nor adjuvant systemic therapy are recommended for stage I/II
melanoma after complete resection.
- High-risk stage III melanoma has been defined as ≥1 parotid, ≥2 cervical/axillary or ≥3
inguinal lymph nodes, ≥3 cm cervical, ≥4 cm axillary/inguinal nodes or extracapsular
extension.
- IFN should only be considered if there is no access to modern adjuvant systemic therapy
and then only for ulcerated and/or sentinel node-positive (SN+) patients. Not for
macroscopic disease.
- The clinical picture of ITM can vary – from single, small nodules to neoplastic infiltration
covering large areas of the skin. The latter can be combined with serious complications
such as bleeding, infections and necrosis with loss of a significant mass of tissue. This can
be a life-threatening situation and is usually connected with a significant decrease in
quality of life.
- The selection of patients for surgical treatment should be cautious, taking into account the
number of lesions, their growth rate and the biological behaviour of the tumours. The risk
of rapid progression after surgery may negatively affect the effectiveness of subsequent
systemic treatment.
- Patients with metastatic melanoma have a poor prognosis which relates to the following
factors: performance status (PS), the site and number of metastases (M), serum lactate
dehydrogenase (LDH), and duration of remission.
- Nowadays IO is a standard of care; it is recommended for no longer than 2 years, until
disease progression or unacceptable toxicity.
- The main relative contraindications for IO are autoimmune diseases and therapy with
steroids: >10 mg or equivalent of prednisolone.
- Nivolumab as monotherapy can be dosed at either 240 mg or 480 mg Q4W, and
pembrolizumab: 200 mg Q3W or 400 mg Q6W, both i.v. (intravenous) infusion.
- Severe immune-related adverse events (irAEs) occur in 10% of patients receiving anti-
PD-1 agents and may be present at any time during therapy. They occur in 38% of patients
on ipilimumab and ~50% of patients on ipilimumab/nivolumab.
- The general guidelines for the treatment of low grade irAEs are: mild symptoms – only
monitoring; moderate – start low-dose corticosteroids, withhold IO temporarily (exception:
pneumonitis, myocarditis). Severe symptoms need a permanent stop of IO. Highdose
corticosteroids should be commenced rapidly. The occurrence of irAEs is often associated
with favourable outcomes.
- Ipilimumab dosing is 3 mg/kg i.v. over 90 minutes Q3W, for a maximum of four doses. In
the event of toxicity, dosing may be delayed, but all treatment must be administered within
16 weeks of the first dose.
- In a randomised phase III trial, the addition of atezolizumab to vemurafenib/cobimetinib
was associated with longer median PFS and longer duration of response than
vemurafenib/cobimetinib alone; however, the triplet induced more toxicity. Same for
pembro+dabra/trame
- In selected cases with metastatic melanoma, the combination of T-VEC and ipilimumab
led to a higher overall response rate (ORR) than ipilimumab alone, which was without
additional safety concerns.
- The most common dabrafenib/trametinib AE is pyrexia (≥38.0° C), which occurs in 71%
of patients, leading to dose delay or reduction in 59% of patients and permanent
discontinuation in 4% of patients. Other dabrafenib-related toxicities are headache,
arthralgia and squamous cell carcinoma (SCC); for trametinib alone: rash, diarrhoea and
peripheral oedema. With dabrafenib/trametinib, rash is rare.
- In selected cases with disease progression on subsequent IO/chemotherapy, it is possible
to rechallenge with BRAF/MEK inhibitors.
- KIT inhibitors are effective in acral or mucosal melanomas: 10%-25% of them harbour
KIT mutation. Response rate (RR) is 15%-30%, with the best responses in KIT mutation
exons 11 and 13.
- The presence of a neurotrophic tyrosine receptor kinase (NTRK) family fusion in
melanoma may provide a therapeutic opportunity for entrectinib or larotrectinib (78%
ORR in NTRK fusion-positive tumours, regardless of histology.
- Pseudoprogression occurs in 7%–10% of patients during treatment with immune
checkpoint inhibitors (ICIs), particularly monotherapy with ipilimumab
- The abscopal effect refers to the rare phenomenon of tumour regression at a site distant
from the primary site of RT. The underlying biological characteristics of the abscopal
effect may be mediated by immunological mechanisms. The combination of ICIs and RT
can be more potent than
either treatment alone.
- Melanoma is one of the solid tumours where brain metastases are relatively common,
being reported in 40%-50% of patients with advanced disease.
- Melanoma brain metastases are vascular and more prone to haemorrhage than other
metastases
- Brain metastases often present late in the disease with fits, headache, nausea or
neurological deficits.
- Without any treatment, median survival for melanoma brain metastases (MBM) is about
1 month, with corticosteroids 2 months.
- WBRT median survival is approximately 3–4 months. Response to corticosteroids may be
a surrogate marker for WBRT response.
- WBRT is associated with reduced neurocognitive function and decreased quality of life.
Morbidity may be reduced by blocking RT to the hippocampus. Neurocognitive morbidity
is more likely in patients aged over 65 years
- WBRT after local treatment, neurosurgery or stereotactic radiosurgery (SRS) for one to
three metastases does not improve survival, intracranial control or preservation of
performance status (PS) compared with observation.
- For larger metastases, surgery followed by cavity SRS has a control rate of 80% at 1 year
compared with 40% with surgery alone.
- Initially SRS was used for patients with three or fewer small brain metastases, but as
experience has developed five lesions or more are now treated. The total brain volume
treated, usually below 20 cc, is now considered to be the more important limit. Individual
metastases are not usually larger than 3 cm. The total volume treated is more prognostic of
outcome and overall survival than the number of lesions treated.
- SRS should be offered to patients with up to 10-12 low-volume metastases
- Even with very accurate, focused SRS, there is still a risk of brain necrosis
- The sequencing of RT and immunotherapy may be important, with a benefit if RT is
given first
- After SRS, ‘pseudoprogression’ can occur with increased oedema around the treated
area, which reduces with time and is not disease progression.
- Responses to targeted therapy (TT) are rapid and these treatments are very useful in
patients with symptomatic and rapidly progressing disease. Care needs to be taken about
potential drug-drug interactions in patients requiring antiepileptic medications, which can
increase exposure and toxicity. Adverse events were not increased in patients with brain
metastases
- The most common mutations are the valine substitution at codon 600 (V600) for BRAF,
the glutamine substitution at codon 61 (Q61) for NRAF and, for KIT, the pathogenic
variants at exon 11 (L576P) and at exon 13 (K642E).
All these mutations have been reported as mutually exclusive
- The BRAF-V600E mutation is more common in younger age at diagnosis (primary
melanoma is mostly on the trunk), whereas BRAF-V600K and NRAS mutations are more
common in older age (primary melanoma is on anatomical areas with increased cumulative
sun damage).
- Desmoplastic melanoma (DM) is a variant of spindle cell melanoma (‘neurotropic’
melanoma) typically found on chronically sun-damaged skin of older individuals.
- Regulation of nuclear factor kappa B (NF-κB) activity is a fundamental event in
activating target genes involved in the control of cell cycle, cell growth and survival, and
inflammation. For this reason, NF-κB is persistently activated in many types of human
tumours, protecting the tumour cell from death and thereby contributing to
tumourigenesis and cancer therapy resistance.
- The most frequent site of mucosal melanoma is the head and neck area (up to 60% in the
nasal cavity and paranasal sinuses), followed by the anorectal region (25%) and the vulvo-
vaginal region (20%); about 5% of mucosal
melanoma is in the distal urethra (both male and female).
- Mucosal melanomas generally present at a later stage, are more aggressive and carry a
worse prognosis, regardless of the stage at diagnosis.
- UM (uveal melanoma) is associated with light skin but not, however, with
an ultraviolet (UV)-mutational signature. The pattern of driver mutations is very different
from CM. Presenting symptoms include blurred vision, photopsia, floaters or visual field
loss; however, UM is often asymptomatic, and detected on routine fundoscopy.
- Metastatic UM is hepatotropic. It is unusual to see metastatic disease that does not involve
the liver, although other organs may also be involved.
- UM metastases often remain confined to the liver for some time. Locoregional liver
treatments are therefore frequently used. This includes liver resection and/or ablation of
individual metastases as well as use of locoregional therapies such as chemoembolisation
and percutaneous hepatic perfusion (PHP).
- Immune checkpoint inhibitors (ICIs) have very limited activity in UM, with response
rates of ~3%-8% reported for single agents, and ~10%-18% for combination treatment.
There are no directly druggable mutations in UM (BRAF is not mutated), and key
mutations lead to activation of
multiple downstream pathways.
- Tumour-infiltrating lymphocyte adoptive transfer has shown some efficacy, with a
response rate of 35% and durable benefit in some; however, it is not widely available
- Tebentafusp (IMCgp100) is a novel bispecific agent that redirects T cells against a
glycoprotein 100 (gp100) peptide presented in the context of HLA-A*0201 - improved OS
in uveal melanoma
- Mucosal melanoma constitutes <2% of all melanoma cases. Each individual anatomical
subsite has different characteristics/treatment options.
- Treatment of most mucosal melanoma is primarily surgical, although radiotherapy may
also be used for local control. Recurrence and metastasis are frequent.
- the programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte antigen-4 (CTLA-4)
inhibitor combination fails in ~30% of patients after 3 months. In contrast, 36% of patients
will never progress on PD-1/CTLA-4 combination and a predictive biomarker of sensitivity
would flag these patients for this therapy.
- Similar to immunotherapy, although to a smaller extent, 10% of patients will progress
rapidly within the first 3 months on combined BRAF and MEK inhibitors.
- Although a fraction of patients (20%) will not progress even after 5 years of dual
BRAF/MEK inhibition, 70% of patients will develop adaptive resistance mechanisms.
- An emerging biomarker of response to immunotherapy is the gut microbiome, which is
still difficult to study routinely.
- hepatocyte growth factor (HGF) produced by cancer-associated fibroblasts can rescue
melanoma cells from BRAF inhibition by induction of MET signalling in melanoma cells.
- During adaptation to BRAF inhibitors, increased angiogenesis, increased macrophage
infiltration (M2), reduced T cells and antigen-presenting cells (APCs) can lead to
resistance.
- Tumour mutation burden (TMB), PD-L1, ccfDNA (circulating cell-free DNA) and CTCs
(circulating tumour cells) are emerging markers of BRAF/MEK-inhibitor therapies.
- Only inflamed tumours respond to ICIs. For this reason, there is an unmet need to make
‘cold’ (uninflamed) tumours ‘hot’, and therefore sensitive to immunotherapy.
- The most interesting agents in development are toll-like receptor 9 (TLR9) agonists, anti-
lymphocyte activation gene 3 (LAG-3) antibodies, histone deacetylase inhibitors (HDACis)
and bempegaldesleukin.
- New combinations of immunotherapies with other treatments are now in development, so
the potential of anti-PD-1s in combination with other novel agents is being explored.
- Pathology report: Breslow thickness, ulceration status, dermal mitotic rate, assess deep
and peripheral margin status, microsatellitosis, pure desmoplasia if present,
lymphovascular/angiolymphatic invasion