Melanoma

Updated by Anna O. Likhacheva

BACKGROUND

What is the incidence of melanoma in the U.S.?

~75,000 cases/yr of melanoma in the U.S. (and rising)

What are some risk factors for developing melanoma?

UV RT, fair complexion, light hair/eyes, numerous benign nevi or larger atypical nevi (>5 mm, variable pigmentation, asymmetric, indistinct borders), personal Hx of melanoma (900 times), family Hx of melanoma, and polyvinyl chloride exposure

In terms of UV exposure, what is the most important risk factor associated with development of melanoma?

Intermittent intense exposure to UVA and UVB, such as Hx of blistering burns in childhood, is the most important risk factor for developing melanoma.

What are the sex differences in terms of body distribution of melanoma lesions?

Males: lesions predominantly on trunk (e.g., upper back)

Females: lesions predominantly on extremities

What % of melanomas derive from melanocytic nevi?

~15% of melanomas derive from melanocytic nevi.

What % of melanomas are derived from noncutaneous sites?

<10% of melanomas are from noncutaneous sites.

What are the common noncutaneous melanoma sites?

The GI, ocular, and gyn areas are the most common noncutaneous sites.

What % of melanoma pts have LN involvement at Dx, and how does this differ by T stage?

15% of pts have LN involvement at Dx, with 5% being T1 and 25% being ≥T2.

What % of melanoma pts present with DM at Dx?

5% of pts present with DM at Dx.

What proportion of DM pts present with DM from an unknown melanoma primary?

One-third of DM pts or 1%–2% of all pts present with mets from an unknown primary.

What are the 5 subtypes of melanoma?

Superficial spreading, nodular, lentigo maligna, acral lentiginous, and desmoplastic variant

Which of the 5 melanoma subtypes is the most common?

Superficial spreading (70%) is the most common subtype → nodular (25%).

What are typical features of desmoplastic melanoma?

Features of the desmoplastic subtype include older pts (60–70 yo), more infiltrative, higher rate of perineural invasion, higher LF rates, and lower nodal met/DM rates.

Which melanoma subtype has the best prognosis?

Lentigo maligna melanoma has the best prognosis.

What is the LN+ rate and 5-yr OS for lentigo maligna melanoma?

For lentigo maligna melanoma, the LN+ rate is only 10%, with 5-yr OS at 85% after WLE alone.

What subtype commonly presents in dark-skinned populations, and what body locations does it commonly affect?

Acral lentiginous, which commonly affects the palms/soles and subungual areas, is the most common melanoma subtype in dark-skinned populations.

Which subtype of melanoma is most common and has the worst prognosis?

Superficial spreading is the most common subtype. This subtype also has the worst prognosis.

What is the name for lentigo maligna involving only the epidermis (Clark level I)?

Hutchinson freckle is lentigo maligna of the epidermis.

What are 3 commonly used immunohistochemical stains for melanoma?

S100, HNB-45, and Melan-A stains are commonly used for melanoma.

WORKUP/STAGING

A pt presents with a pigmented lesion. What in the Hx can help to determine if this is a suspicious lesion?

Changes in Asymmetry, Borders, Color, Diameter (>6 mm), and Enlargement (Mnemonic: ABCDE)

Per the latest NCCN guidelines, for what melanoma pts should imaging be performed?

Per the NCCN, imaging should be performed for specific signs/Sx or stage ≥III (not recommended for stages IA–II).

What are some common DM sites for melanoma?

The skin, SQ tissues, distant LNs, lung, liver, viscera, and brain are common melanoma DM sites.

What is the preferred method of tissue Dx for a suspected melanoma?

For suspected melanoma, full-thickness or excisional Bx (elliptical/punch) with a 1–3-mm margin is preferred for tissue Dx.

Why should wider margins on excisional Dx be avoided?

Avoid wide margins to permit accurate subsequent lymphatic mapping.

For what locations is full-thickness incisional or punch Bx adequate?

Full-thickness incisional and punch Bx are adequate for the palms/soles, digits, face, and ears or for very large lesions.

When is a shave Bx sufficient?

Shave Bx is sufficient when the index of suspicion for melanoma is low.

How do the Breslow thickness levels correspond to the latest AJCC (7^th edition, 2011) T staging for melanoma?

Into what further categories are T2–T4 broken down?

The Breslow thickness levels are identical to and define the AJCC T staging of malignant melanoma:

T1: ≤1 mm

T1a: no ulceration and mitosis <1/mm²

T1b: ulceration or mitosis ≥1/mm²

T2: 1.01–2 mm

T3: 2.01–4 mm

T4: >4 mm

a: no ulceration

b: with ulceration

What is considered N1, N2, and N3 in melanoma staging?

All regional LN mets:

N1: 1

N2: 2–3

N3: ≥4, or matted, or in-transit mets with mets to regional node(s)

For melanoma nodal groups, into what further categories are N1–N2 stages broken?

N1a: micromets

N1b: macromets

N2a: micromets

N2b: macromets

N2c: satellite or in-transit mets without nodal mets

How do M1a, M1b, and M1c differ in a pt with metastatic melanoma?

M1a: skin, SQ, distant LNs

M1b: lung only

M1c: viscera or other sites with ↑ LDH

Describe the overall stage groupings per the latest AJCC classification.

Stage 0: Tis

Stage IA: T1aN0

Stage IB: T2aN0 or T1bN0

Stage IIA: T3aN0 or T2bN0

Stage IIB: T4aN0 or T3bN0

Stage IIC: T4bN0

Stage III: any N+

Stage IV: any M1

With regard to the pathologic staging of melanoma, how does regional nodal involvement figure into stages IIIA, IIIB, and IIIC Dz?

Stage IIIA: nonulcerative primary with LN micromets

Stage IIIB: ulcerative primary + LN micromets or nonulcerative primary + LN macromets/in-transit mets

Stage IIIC: ulcerative primary + LN macromets/in-transit mets or N3 Dz

What are the Clark levels? Under what circumstance does the Clark level need to be known on the pathology report for a pt with melanoma?

Clark levels:

Level I: epidermis only

Level II: invasion of papillary dermis

Level III: filling papillary dermis, compressing reticular dermis

Level IV: invading reticular dermis

Level V: SQ tissue

The Clark level should be provided on the pathology report for lesions ≤1 mm.

What are the similarities and differences between clinical and pathologic staging for melanomatous lesions?

Both require microstaging of the primary after resection:

Clinical staging: clinical exam + radiology allowed (after complete resection)

Pathologic staging: pathology assessment of LN after dissection

What should the pathology report reveal about the primary tumor in a pt with a newly diagnosed melanoma after surgical resection?

The pathology report should list the Breslow thickness, ulceration status, mitotic rate, deep/peripheral margins, evidence of satellitosis, and Clark level (only for lesions ≤1 mm).

What are some adverse features on pathology after surgical resection for a melanoma?

Adverse pathology features after surgical resection include +margins (+ deep margin), LVSI, and a mitotic rate >1/mm².

For clinical staging purposes, what stage designates regional nodal involvement?

Stage III designates nodal involvement in melanoma staging.

What is the most powerful prognostic factor for recurrence and survival for pts with melanoma?

Sentinel LN status is the most powerful prognostic factor.

What are 3 favorable clinical factors at presentation for pts with a newly diagnosed melanoma?

Female sex, young age, and extremity location are all favorable prognostic factors.

What are 5 poor prognostic factors on pathology in melanoma?

Increasing thickness, # of nodes involved, ulceration, Clark level (if <1 mm), and satellitosis are 5 poor prognostic factors in melanoma.

What are microsatellites as seen with melanoma?

With melanoma, microsatellites are discrete nest of cells >0.05 mm that are separated from the body of the primary lesion by collagen or fat.

What are satellite metastases as seen with melanoma?

Gross cutaneous or subcutaneous intralymphatic mets, observed £2 cm from primary Dz.

What are the in-transit mets seen with melanoma?

Gross cutaneous or subcutaneous intralymphatic mets, observed >2 cm from primary Dz, but before reaching the 1^st echelon nodes.

In order of frequency, which melanoma sites have the highest LR rates after surgery?

Melanoma sites with the highest LR rates after surgery (in descending order of frequency): H&N (9.4%) > distal extremities (5%) > trunk (3%) > proximal extremities (1%) (Balch CM et al., Ann Surg Oncol 2001)

What are the comparative OS rates of melanoma pts by stage at presentation?

OS rates of melanoma pts by stage:

Stage I: 80%–90%

Stage II: 40%–60%

Stage III: 30%

Stage IV: <10%

TREATMENT/PROGNOSIS

What is the general paradigm for the management of melanoma lesions?

Melanoma lesion management paradigm:

1. WLE → sentinel LN Bx (if >0.6 mm thick or >0 mitotic rate).

2. If sentinel LN Bx is positive, then full LND is required.

When is WLE alone adequate as Tx of melanoma?

WLE alone is adequate for in situ or stage IA lesions without adverse features on Bx.

When should sentinel LN Bx be considered or recommended with WLE for melanoma?

Sentinel LN Bx with WLE for melanoma should be considered/recommended for stage IA with adverse features, stage ≥IB, or Clark level IV–V.

What evidence demonstrates improved survival outcomes for prophylactic LND in the management of melanoma?

For lesions >1.6-mm thick, retrospective data by Milton et al. (Br J Surg 1982) and Urist et al. (Ann Surg 1984) have demonstrated improved survival.

A randomized study by Balch et al. (Ann Surg Oncol 2000) has shown improved survival for pts with nonulcerated lesions, lesions 1–2-mm thick, and limb lesions.

What is the LN recurrence rate for pN+ melanoma pts after LND?

After LND, the LN recurrence rate for pN+ pts is 30% at 10 yrs. (Lee RJ et al., IJROBP 2000: no adj RT; 45% rcvd chemo)

What min surgical margins are required by T stage for the optimal surgical management of melanoma?

Min surgical margins for optical surgical management:

Tis: 5 mm

T1: 1 cm

T2: 1–2 cm

T3–T4: 2 cm

Which randomized trials support the surgical margins currently used in the management of melanoma?

Balch et al. (Ann Surg Oncol 2001): 2 cm vs. 4 cm for >T2; no difference in outcome

Thomas et al. (NEJM 2004): 1 cm vs. 3 cm; 3 cm resulted in better LC for >T2 lesions, but no OS benefit

When is elective iliac or obturator LND necessary after resection of a lower extremity melanoma?

Elective iliac or obturator LND is necessary if there are clinically positive superficial nodes, ≥3 superficial +LNs, or if pelvic CT shows LAD.

When is primary RT ever indicated for Tx of melanoma?

Primary RT is indicated for medically inoperable pts or lentigo maligna of the face (cosmetic outcome better); this is given as 50 Gy/20 fx or 7–9 Gy × 6 biweekly (Farshad A et al., Br J Dermatol 2002), 1.5-cm margin, 100–250 kV photons.

If primary RT is used for medically inoperable pts, what modality can be added to improve the efficacy of RT?

Hyperthermia (Overgaard J et al., Lancet 1995) improves LC (46% vs. 28%) without added toxicity.

How were RT and hyperthermia administered to pts with melanoma in the Overgaard study?

In the Overgaard J et al. study, pts were given 24 or 27 Gy in 3 fx over 8 days ± hyperthermia (43°C × 60 min), which improved LC. (Lancet 1995)

When is adj RT indicated for resected melanoma?

Adj RT indications for resected melanoma:

Primary site: +/close margins, desmoplastic histology

Nodal site: >3 +LNs or matted LNs, >3 cm, +ECE, or incomplete nodal assessment

Note: Per the latest NCCN guidelines, consider RT for stage III pts (category 2b)

What RCT showed that adj RT improves lymph node field control?

ANZMTG 01.02/TROG 02.01. (Burmeister et al., Lancet Oncol 2013) 217 pts at high risk for further LN relapse randomized to adj RT (48 Gy/20 fx) or observation, 40-mo median follow-up. LN field relapse was significantly lower in adj RT arm (HR = 0.56; p = 0.041), but no difference in RFS and OS.

Define what is considered high risk for further lymph node field relapse per TROG 02.01?

≥1 parotid LN, ≥2 cervical or axillary LN, ≥3 inguinal LN; ECE; ≥3 cm cervical LN, or ≥4 cm axillary or inguinal LN.

Which studies suggest that RT can make up for a lack of formal neck dissection in H&N pts?

MDACC data by Ballo et al. (Head Neck 2005): cN+ in neck s/p local excision only with adj RT; 5-yr LC 93%

Ang et al. (IJROBP 1994): high-risk pts ± LND; 5-yr LC 88%

What is the only proven adj systemic therapy that improves DFS and OS in pts with resected high-risk stage III melanoma?

High-dose IFN-alfa, using the Kirkwood schedule (20 mU/m²/day intravenously, 5–7 days/wk for 4 wks → 10 mU/m²/day SQ, 3 × wk for 48 wks). However, NCCTG 83–7052 did not demonstrate benefit of IFN (costly Tx at $50–$60K/pt).

What RT fractionation scheme is commonly used in the adj setting for melanoma of the H&N?

Biweekly 6 Gy/fx ×5 (30 Gy) based on the Ang et al. study (MDACC data): 5-yr LRC was 88%, OS was 47%, and there was min acute/late toxicity. (IJROBP 1994)

Is there a benefit to hypofractionating RT for melanoma in the adj setting?

No. RTOG 8305 showed no difference between 8 Gy × 4 fx and 2.5 Gy × 20 fx. (Sause WT et al., IJROBP 1991)

What did the University of Florida experience/study (Chang DT et al., IJROBP 2006) demonstrate regarding adj nodal RT in pts with melanoma lesions of the H&N?

The University of Florida study showed excellent 5-yr LC (87%) and no difference between hypofractionation (6 Gy × 5 fx) and standard (60 Gy in 30 fx) dosing. The major cause of mortality was DM.

What is generally recommended for a pt with nodal recurrence after primary management for melanoma?

Recommendations for a pt with nodal recurrence after primary management include restaging, FNA or LN Bx → LND if no previous dissection → consideration for adj RT and/or INF, a clinical trial, or observation.

How is salvage RT delivered in melanoma pts with isolated axillary nodal recurrences?

After axillary LND, RT to the axilla alone is sufficient (the supraclavicular region may be omitted), using 6 Gy × 5 fx (30 Gy) per MDACC data. (Beadle BM et al., IJROBP 2009) The 5-yr LC rate was 88%.

What systemic agents are currently being used or explored for use for met melanoma?

Ipilimumab, a monoclonal antibody to the immune checkpoint receptor CTLA-4. (Hodi FS et al, NEJM 2010; Robert C et al., NEJM 2011; Margolin K et al., Lancet Oncol 2012) Other immune checkpoint inhibitors such as anti-PD1 or PDL1 are being tested in earlier phase clinical trials. In a phase I trial, combining anti-CTLA4 and anti-PD1 monoclonal antibody showed a response rate of 53%, much higher than single agents alone. (Wolchok JD et al., NEJM 2013)

Vemurafenib, a specific inhibitor of V600E mutated BRAF (∼50% of all melanomas). (Chapman PB et al., NEJM 2011; Sosman JA et al., NEJM 2012) In the phase III randomized trial (Chapman et al.) that compared vemurafenib to dacarbazine, vemurafenib had a response rate of 48% (vs. 5%) and an improved OS.

TOXICITY

What is the rate of lymphedema when treating different LN regions with hypofractionated RT?

The rates for lymphedema are 39% for the groin, 30% for the axilla, and 11% for H&N sites. (MDACC data: Ballo MT et al., Head Neck 2005)

What is the a/b ratio of melanoma?

For melanoma, the α/β ratio is 2.5. (Overgaard J et al., Lancet 1995)

When using a hypofractionated regimen (e.g., 6 Gy × 5 [30 Gy]), at what dose does the practitioner come off the spinal cord and small bowel?

24 Gy is the dose tolerance of the spinal cord/small bowel when hypofractionating with 6 Gy/fx.

What are the main toxicities of concurrent IFN and RT in the adj Tx of stage III melanoma?

In stage III melanoma, the use of concurrent IFN and RT in adj Tx can cause acute skin toxicity as well as increased grade 3–4 subacute and late toxicities (fibrosis, SQ necrosis, myelitis, mucositis, pneumonitis, lymphedema). Up to 50% of pts can develop grade 3 toxicities.

What are the latest NCCN follow-up recommendations for melanoma by stage?

NCCN melanoma follow-up recommendations:

1. Annual skin exam for life (all stages)

2. For stages IA–IIA: H&P q3–12mos for 5 yrs, then annually; routine labs/imaging not recommended

3. For stages IIB–IV: H&P q3–6mos for 2 yrs, then q3–12mos for 3 yrs, then annually; routine labs for 1^st 5 yrs; consider imaging (CXR, PET/CT, annual MRI brain)

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