Skin Cancer

Cutaneous Melanoma

• The BRAF V600 mutation is a frequent somatic/acquired driver mutation in cutaneous melanoma.

• Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the most frequently mutated high-risk gene associated with familial cutaneous melanoma.

Staging:

• Any N+ disease is Stage IIIA and up

• Memorize staging:

Stage	Thickness	Ulceration
T1a	< 0.8 mm	No
T1b	< 0.8 mm	Yes
T1b	0.8–1 mm	with or without
T2a	1–2 mm	No
T2b	1–2 mm	Yes
T3a	2–4 mm	No
T3b	2–4 mm	Yes
T4a	> 4 mm	No
T4b	> 4 mm	Yes

Stage	T	N	M
Stage 0	Tis	N0	M0
Stage IA	T1a	N0	M0
Stage IB	T1b, T2a	N0	M0
Stage IIA	T2b, T3a	N0	M0
Stage IIB	T3b, T4a	N0	M0
Stage IIC	T4b	N0	M0
Stage III	Any T, Tis	≥N1	M0
Stage IV	Any T	Any N	M1

Localized Melanoma: 

• Surgical Margins are based on the Breslow thickness:

Thickness: Surgical margin:

In situ 0.5-1 cm

≤ 1 mm 1 cm

> 1 mm - 2 mm 1-2 cm

>2 mm 2 cm

• Adjuvant radiation:

  • Consider for desmoplastic melanoma with risk factors for local recurrence:

    • Location on the head and neck

    • Extensive neurotropism

    • Pure desmoplastic melanoma subtype

    • Close margins where re-resection in not feasible, or locally recurrent disease

    • Extracapsular extension of melanoma in clinically (macroscopic) involved lymph node

      • ≥1 involved parotid node

      • ≥ 2 involved cervical or axillary nodes

      • ≥ 3 involved inguinofemoral nodes

      • ≥3 cm cervical or axillary node

      • ≥ 4 cm inguinofemoral node

• Routine imaging:

  • NOT recommended for stage IA-IIA melanoma with no evidence of disease (only if concerning sign/symptom).

• Routine SLN biopsy:

  • NOT recommended for patients with Stage IA (T1a N0 M0)

  • Consider SLN biopsy for Stage IB (T1b/T2a N0 M0)

  • If clinically negative node but SLN+ → complete LN dissection + ultrasounds q3 months

• For in-transit metastasis (Stage III):

  • If resectable:

    • Resection followed by adjuvant therapy

  • If unresectable:

    • Systemic therapy

    • Local treatment options (TVEC, IL2, imiquimod, RT)

• Adjuvant therapies:

  • For stage IIB/C:

    • Adjuvant Nivolumab (Checkmate-76K)

    • Adjuvant Pembro x1 year (Keynote-716)

  • For stage IIIA:

    • Better outcomes than Stage IIB/C, consider against adjuvant therapies (great prognosis)

  • For stage IIIB/C/D:

    • Adjuvant Nivolumab x1 year (Checkmate-238)

    • Adjuvant Pembro x1 year (Keynote-054: did not include stage IIIA with SNL+ and <1 mm tumor burden)

    • Perioperative pembro (3 doses prior and 15 doses after) for stage IIIB-IVC (SWOG 1801)

    • Adjuvant Dabrafenib/Trametinib

      • if actionable BRAF mutation: only BRAF/MEK combination approved (COMBI-AD)

  
  

Metastatic Melanoma:

• First line treatment

  • Ipilimumab + Nivolumab

    • Checkmate-067 (Nivo 1 + ipi 3) - combo more side effects

    • Checkmate-511: flip dosing (Nivo 3 + Ipi 1) - improved AE’s

  • Nivolumab/relatlimab-rmbw (Opdualag)- preferred in metastatic disease

  • Nivolumab

  • Pembrolizumab 

• If BRAF V600E or V600K: 

  • Still use IO in 1L setting

    • DREAMSeq Trial: Ipi + Nivo followed by Dabrafenib+Trametinib (BRAF/MEK inhibitor) after PD showed OS benefit in patients with BRAF V600E (compared to the opposite)

  • BRAF/MEK inhibitor provides a rapid response rate compared to immune-based therapy. However, responses can sometimes be short-lived.

    • Consider using first in patients with visceral crisis who have BRAF V600E/V600K mutation

    • Associated with increased risk of hemorrhage, cardiomyopathy, and ocular toxicities

    • Treatment options with BRAF/MEK inhibitors:

      • Dabrafenib/Trametinib

        • Best CNS penetration- Associated with fevers

      • Cobimetinib/Vemurafenib

        • Vemurafenib causes more SCC and rash/photosensitivity

      • Encorafenib/Binimetinib

• If progression with above options:

  • Consider tumor-infiltrating lymphocyte therapy (TILs) with Lifileucel

• If oligometastatic disease:

  • Can do resection followed by “peri-adjuvant” therapy

Uveal Melanoma

• Associated with BAP1 (familial uveal melanoma) or GNAQ/GNA11 mutation

• They like to metastasize to liver (Buzz word)

• Treatments for advanced disease:

  • Pembrolizumab

  • Nivolumab

  • Ipi/Nivo

  • Tebentafusp (ImmTAC) T cell receptor targeting gp100  MHC-A/class 1 molecule

    • Preferred over immunotherapy in patients with HLA-A*01:01-positive disease

  • Ipilimumab

  • Chemotherapy

  • Trametinib

  • HEPZATO KIT (melphalan for injection/hepatic delivery system)

Acral/Mucosal Melanoma

• Acral melanoma: Distinct type of melanoma found on palms of hands or feet

• Mucosal Melanoma: Markers are S-100 and HMB-45 and Melan-A

• If KIT mutation is present:

  • Can treat with imatinib, dasatinib, nilotinib, ripretinib

Basal Cell Carcinoma (BCC)

• Associated with abnormalities in the sonic hedgehog pathway

• Rarely Metastasizes 

Local Disease:

• Low risk disease:

  • Location in trunk/extremity <2cm in size

  • Well defined borders

  • Primary disease

  • No sites of prior RT

  • No immunosuppression

  • Nodular and superficial subtypes

  • No perineurial invasion

• High risk disease:

  • Poorly defined borders

  • Larger than 2cm on trunk/extremities

  • Any lesions located on head, neck, hands, feet, anogenital area

  • Recurrent disease

  • Site of prior RT

  • With perineural invasion

  • Aggressive growth pattern

• Treatment:

  • If low-risk disease: Resection

  • If high-risk disease: Mohs, standard excision with wider margins, radiation (avoid in patients with predisposition to develop neoplasm), systemic therapy

Metastatic/Locally Advanced:

• First line:

  • Sonidegib

    • For patients with recurrence following surgery or radiation therapy

    • For patients who are not candidate for surgery or radiation therapy

    • Not approved for metastatic disease

  • Vismodegib

    • For metastatic disease (SHH pathway)

• Subsequent lines:

  • Cemiplimab upon progression

Squamous Cell Carcinoma (SCC)

• Risk factors: 

  • Sun exposure, advanced age, sensitivity to UV radiation, immunosuppression use.

Local disease:

• Treatment:

  • Surgical resection

  • Consider neoadjuvant cemiplimab if:

    • Locally advanced disease/surgery would be too morbid

    • Very rapid growth

    • Positive lymphovascular invasion)

  • For high-risk localized disease (same criteria as BCC):

    • Consider adjuvant radiation, standard excision with wider margins, Mohs, PDEMA

Metastatic disease:

• First line:

  • Cemiplimab

  • Pembrolizumab

• Second line:

  • Carboplatin/paclitaxel/cetuximab (also consider if contraindication to immunotherapy)

Merkel Cell Carcinoma

• Background:

  • Cutaneous neuroendocrine cancers

  • Highly aggressive

  • Associated with polyomavirus

  • CK20 is highly positive marker

• Local disease:

  • Surgery with SLNB

    • +/- radiation in high risk patients (HIV, CLL, Head and Neck Primary site, +LVI, >1cm)

• Metastatic disease:

  • First line:

    • Pembrolizumab (Keynote-017)

    • Avelumab (JAVELIN Merkel 200)

    • Nivolumab

    • Ipi + Nivo

    • Retifanlimab

  • Subsequent lines:

    • platinum/etoposide, topoitecan, cyclophosphamide, doxorubicin, and vincristine, TVEC, Ipi/nivo, pazopanib, somatostatin analogues (if positive)

Kaposi Sarcoma

• Typically associated with HIV

Limited disease:

• If asymptomatic: Consider observation or treating HIV

• If symptomatic: Consider local therapies, RT, or systemic therapies

Advanced disease:

• In patients with untreated HIV → start HAART

• In patients with treated HIV:

  • First line:

    • Doxil (preferred), Paclitaxel

  • Subsequent lines:

    • Nivolumab, Pembro, Pomalidomide, Abraxane (if paclitaxel intolerant), Bortezomib, Etoposide, Gemcitabine, Imatinib, Ipi/Nivo, Lenalidomide, Sirolimus (for transplant associated KS), Thalidomide (for patients with IRIS), Vinorelbine