Melanoma

Dr. Amy Hughes

11/4/16

Subtypes of melanoma

• Four major subtypes of invasive cutaneous melanoma: – Superficial spreading

–Nodular melanoma

– Lentigo maligna

–Acral lentiginous

Subtypes melanoma

– Superficial spreading • 75% of melanomas; 25% preexisting nevus • Grows radially before vertically; color

change noted

–Nodular • 2nd most common; 15-30% • Darkly pigmented although amelanotic

(nonpigmented) variants. • Most difficult to diagnose at an early stage.

At least half are >2 mm. >50% of melanoma lesions >2 mm in thickness are nodular.

Subtypes melanoma

• Lentigo maligna

• sun-damaged areas; begins as a freckle-like macule which gradually enlarges and develops darker, asymmetric foci .

• Transformation slow, possibly 10 to 50 years before vertical

• Acral lentiginous

• <5 percent of all melanomas. Most common type among dark-skinned individuals, who are at lower risk for more sun-related melanoma subtypes.

• Palmar, plantar, and subungual surfaces. Dark brown to black, irregularly pigmented macules or patches.

• Subungual melanoma nail matrix longitudinal brown or black band, +/- nail dystrophy. Sometimes subungual mass with various degrees of ulceration and nail plate destruction.

Lentigo maligna melanoma on the left cheek with characteristic nodule signifying dermal invasion in the precursor surrounding in situ lesion (lentigo maligna).

Lentigo maligna melanoma

TNM Staging

Hi

• 2

Early Detection

• The probability of metastases with invasive, vertical growth-phase melanoma is most strongly predicted by measuring the thickness of the tumor (ie, Breslow depth), in millimeters, from the epidermis to the deepest malignant cell in the dermis or subcutaneous fat .

• Other factors including ulceration of the tumor, mitotic rate, presence of lymphovascular invasion, microsatellites, regression, perineural invasion, and the presence of lymphocytes infiltrating the tumor, can also affect metastatic potential of the tumor.

Clinical Diagnosis: Cutaneous

• Asymmetry (if a lesion is bisected, one half is not identical to the other half)

• Border irregularities

• Color variegation (brown, red, black or blue/gray, and white)

• Diameter ≥6 mm

• Evolving: a lesion that is changing in size, shape, or color, or a new lesion

Clinical Diagnosis: Subungual

• The ABCDE rule may not be applicable. • Subungual melanoma arising from the nail matrix

longitudinal brown or black band, with or without nail dystrophy.

• Biopsy of the nail matrix may be warranted for any of the following characteristics: – patient age >50 years – dark color – Solitary – width >3 mm – dyshomogeneous pigmentation – change in shape or pigmentation – irregular margins

Treatment: Local disease

Taken from NCCN.org version 2.2016

When Should Sentinel Lymph Node Evaluation Be Performed?

Taken from NCCN.org version 2.2016

Stage III

***Interferon alfa improved DFS but not OS ***Ipilimumab improves recurrence free survival but OS not yet reported

Radiation Therapy

Advanced Disease: Treatment

• Surgical metastatectomy

• Immunotherapy

– Ipilimumab (CTL4 antibody)

– Pembrolizumab, Nivolumab (PD-1 inhibitors)

• Targeted therapy

– Vemurafenib, dabrafenib (BRAF inhibitors)

– Trametinib, cometinib (MEK inhibitors)

Advanced Disease: Treatment

• Patients with good performance status immunotherapy (PD-1) +/- ipilimumab

• Patients with poor performance status if targeted therapy mutation present, this is preferred (works faster)

• No role for traditional chemo unless out of options

Systemic Therapy in Advanced Disease

** Nivolumab/ipilimumab Combination has improved recurrence free survival over single agent but toxicity is significant with combination. OS has not been established over single agent

Immunotherapy: Anti-PD1 agents

• Anti-PD1 agents (Pembrolizumab and nivolumab):

• Immune mediated reactions

• Grade 3-4 less common than with ipilimumab

• Most common (>20%): fatigue, rash, itching, cough, diarrhea, constipation, arthralgia.

• For moderate to severe immune mediated “itis,”

• DC drug and use steroids.

• Infliximab 5mg/kg is preferred tx of severe immune related colitis that doesn’t respond within 1 week to high dose steroids.

Immunotherapy: PD-1 inhibitors

Immunotherapy: CTLA-4

• Ipilimumab – 52% quit therapy d/t side effects – 1% mortality – Moderate to severe should be discontinued and

steroids started – Immune mediated dermatitis sometimes responds to

topical steroids – Infliximab severe immune mediated colitis – For severe hepatitis mycophenolate preferred over

infliximab for 2nd line after failure of steroids – Use with extreme caution in patients with underlying

autoimmune disorders

CTLA-4 inhibitor

Targeted Therapy

• BRAF inhibitors: – Vemurafenib

– Dabrafenib

• MEK inhibitors: – Trametinib

– Cometinib

• Combination therapy: – Vemurafebib/cometinib: improved PFS and

response rate vs single agent vemurafenib

BRAF mutation

Targeted therapy: BRAF/MEK

• BRAF: assoc with cutaneous squamous cell carcinoma, extreme photosensitivity which is less common than MEK inhibitors.

• Pyrexia is common side effect (55%) of combination BRAF/MEK and occurs less commonly with BRAF monotherapy (20%). – Episodic, onset 2-4 weeks from start of tx with median

duration 9 days – Pyrexia can be assoc with chills, night sweats, rash,

dehydration, electrolyte abnormality and hypotension. – Stopping or holding dabrafenib and trametinib at onset of

pyrexia will interrupt episode and tx can resume with full dose once symptoms subside.

Local Therapy in Advanced Disease

***TVEC: RR >6 months for 16% highly selected patients ***TVEC is genetically modified attenuated herpes simplex 1 oncolytic virus which selectively replicates in and lyses tumor cells.

Follow up recommendations

Summary

• Features of primary melanoma are important – Tumor thickness (duration of growth) – Mitotic rate (rate of growth) – Tumor ulceration (marker of de-differentiation) – Lymph node involvement

• Sentinel node evaluation is essential part of staging for clinical T1b to T4N0M0 patients

• For Stage III, the number of nodal mets are significant; Yervoy now used in stage III

• For Stage IV, site of mets and elevated LDH are significant • No role for traditional chemo. • Advanced melanoma treated with immunotherapy +/- targeted

therapy.