Pocket Oncology (Pocket Notebook Series), 1st Ed.

MELANOMA

James J. Harding and Paul B. Chapman

Epidemiology

• Incidence: ∼76000 new cases/y & ∼10000 death/y in US

• Only a small % of all skin CA (∼4%) but has the highest morbidity & mortality

• ↑ Incidence, affects younger individuals

• Acquired RFs: Higher number of moles, atypical nevi, hx of prior melanoma, 1st-degree relative w/melanoma, prior nonmelanoma skin CA, freckles, sunburns easily, UVA/UVB exposure (esp before age 15), hx of indoor tanning, red-hair, immunosuppression

• Hereditary RFs: Rarely inherited, some syndrome include: Familial atypical multiple mole melanoma syndrome (CDKN2A, p16), Xeroderma pigmentosum (Mts in NER), LFS (p53), RB1BRCA2, PTEN(Cowden syndrome), WRN(Werner syndrome), BAP1 (syndrome of ocular & cutaneous melanoma & mesothelioma)

Pathology

• Histologic Subtypes

Cutaneous (most common)

Superficial spreading: Most common, radial growth

Nodular: Vertical growth into dermis, worse prognosis

Lentigo maligna: Sun-damaged skin in elderly or middle-aged pts, usu on face

Acral lentiginous: Most common in Asians or African Americans, usu on palms or soles

Desmoplastic/Neurotropic: Locally invasive, less likely to metastasize, CN involvement

Uveal: Arise from melanocytes in iris, ciliary body or choroid

Mucosal: Arise from melanocytes in mucosal surfaces (ie, nasopharynx, anus, vagina)

• Molecular Subtypes

The majority of melanomas are driven by overactivation of the MAPK pathway

BRAF V600 (∼50–60%): V600E > V600K, commonly observed in younger pts w/nodular/superficial spreading melanoma of the trunk. Sensitive to vemurafenib or dabrafenib

NRAS (15–20%): No specific targeted Rx available (MEK inhibition in clinical trials)

KIT: ↑ In mucosal, chronically sun-damaged skin, acral sites (∼20%); similar Mts as in GIST

GNAQ/GNA11: Not observed in cutaneous melanomas, ↑ in uveal melanomas (>80%), activates heterotrimeric G-protein coupled receptors → activates MAPK pathway

Other Mts: PIK3CA/AKT, PTEN loss, NF-1, & BAP1

Clinical Manifestations

• Sx: Cutaneous: Most melanomas found by pt at early stage; adv disease → enlarged LN, skin nodules, sx related to lung, liver, bowel/mesenteric, or brain mets; uveal: Incidental finding or visual complaints; mucosal: Mucosal bleeding

• PEx: Evaluate skin & mucosal surfaces; ABCDEs: Asymmetry, Borders irregular, Color variegated, Diameter >5 mm. Evolution; check for LAN or subcutaneous met, sequela of widespread met disease, melanosis → rare, blackening of the skin & urine due to ↑ melanin production, poor prognosis

• Labs: Microcytic anemia, suspect chronic blood loss from bowel mets; ↑ LDH

Diagnostic Evaluations and Staging

• Punch bx preferred over shave bx; shave bx can transect the tumor & prevent proper depth assessment (T-staging)

• EOD w/CT-CAP or CT-Chest w/PET (especially if 1° lesions is in the distal extremity), if distant disease, FNA or Core bx

• Baseline MRI-brain w/gadolinium for Stage III disease or higher to r/o intracranial met.

• Evaluation/staging/tx of uveal melanoma is different

Treatment of Localized Cutaneous Melanoma (Stages I–III)

• Wide local excision of 1º: Margin of 1 cm if tumor ≤1 mm deep, margin of 2 cm for all other lesions

• Sentinel LN mapping & bx: Lymphoscintigraphy w/Tc99 colloid, usu used for lesions >1 mm, if <1 mm consider if high-risk features

• Completion LND: Performed if sentinel LN positive, whether this procedure improves OS is subject of ongoing phase III study

• Adjuvant Rx & surveillance: IFN-α ↑ RFS; radiotherapy ↑ local regional control, no RFS/OS advantage; clinical trial participation; or observation (serial exam/imaging in IIB–IV NED)

Metastatic Cutaneous Melanoma

• Metastatectomy: In properly selected pts, long-term OS 20–40%

• Immunotherapy:

Ipilimumab (CTLA-4 blocking Ab): ↑ OS in 2 RCT (NEJM 2010;363:711 & NEJM 2011;364:2517), slow acting, monitor for immune-mediated tox (ie, colitis, dermatitis, hepatitis, etc.)

Programmed D-1 receptor: RR ∼30% (NEJM 2012;366:2443)

IL-2: Given in ICU setting, 2–6% pts w/durable disease control/cure

Adoptive cellular Rx/TILs: Experimental, high RR

• Targeted Rx:

RAF inhibitors (vemurafenib, dabrafenib): Rapid RR 50–60%, ↑ PFS compare to DTIC, ↑ OS for Vem (NEJM 2011;364:2507); causes keratoacanthomas & SCC of skin

MEK inhibitor (trametinib): ↑ OS for trametinib (NEJM 2012;367:107); combo BRAFi + MEKi may be superior to BRAFi

c-KIT inhibitors (imatinib/dasatinib/nilotinib): May be particularly effective for exon 11 & exon 13 Mts

• Chemotherapy: Dacarbazine (DTIC)/Temozolomide, RR 7–19%; Combination chemotherapy: Cisplatin, vinblastine, temozolomide (CVT) RR 30–40%, Carboplatin/Taxol RR 20–30%, no OS advantage; Biochemotherapy = chemo + IL-2 + IFN-α, has ↑ RR, no OS advantage over chemo