Part 2

Hensin Tsao, MD, PhD

Keith Flaherty, MD

Ilona Frieden

Philip LeBoit, MD

Case 2

In early August of 2007, a 47 year-old patient presented to her PCP with concerns of an atypical appearing lesion on the left lower leg. She was referred to a dermatologist. On August 14^th, the biopsy showed 0.97 mm, Level IV, SSM, four mitoses, and non-ulcerated. A wide excision was performed and there was no residual melanoma and no further surgery was recommended. ‎In April of 2009, the patient noted a small cutaneous mass in scar line on the lower left leg.  In June, the patient underwent wide local excision and sentinel lymph node biopsy. The results showed two out of three positive sentinel nodes, the largest metastasis was 4mm; and (+) extracapsular extension.  On July 29, 2009, she underwent (L) inguinal LND and sartorius muscle transposition flap.  Zero out of seven nodes (including Cloquet’s node) were negative.   There were a total of two out of ten positive nodes. She received adjuvant interferon. Unfortunately, two years later, a PET-CT showed an increase in the number of FDG avid lesions in the leg and inguinal and pelvic adenopathy. She’s now considering systemic treatment.

What specimen should be used for determining the patient’s BRAF status?

1. Primary melanoma FFPE
2. Primary melanoma FFPE and blood DNA for comparison
3. Sentinel lymph node metastasis
4. Soft tissue metastasis from leg

The general guidelines are to take the most recent evidence of advanced disease. Concordance is very important. Do you know that the lesion in the lung is identical to the lesion that presented five years ago according to its genotype?

SNaPshot panel reveals BRAF WT, NRAS and Q61R mutation. On March 21, 2011, she received high-dose IL-2 therapy. In June of 2011, the PET/CT revealed increased FDG uptake in pre-existing left leg subcutaneous nodules and an increase in size as well as FDG uptake in bilateral inguinal lymph nodes. In August, she enrolled in a clinical trial of bevacizumab and ipilimumab. A CT C/A/P performed in April of 2012 revealed an increase in the size of the largest lung mestastasis (15mm to 20mm) and a new 1.6cm liver metastasis. MRI of the brain was negative. June 8, 2012 was her first day on 10-017, a phase 1 study of a CDK4/6 dual inhibitor. By the end of the July, CT C/A/P revealed disease progression in the lung and a new, solitary brain metastatsis measuring 4mm; the disease burden was otherwise relatively stable. In August, she underwent stereotactic radiation to the solitary, 4mm brain mestastasis. October 23, 2012 was cycle one/day one of BKM120/MEK162 trial # 11-308. She remained stable for four months.

One of our greatest challenges is that NRAS is not something that we can target with a drug. Indirect strategies; however, may work.

MEK inhibitors in NRAS-mutant melanoma have some efficacy. It’s not comparable to what a MEK inhibitor or BRAF inhibitor can do in BRAF-mutant cancer, but it is certainly a suggestion that may perturb these tumors.

Part 1

Hensin Tsao, MD, PhD

Keith Flaherty, MD

Ilona Frieden

Philip LeBoit, MD

Dr Hensin Tsao, of Harvard Medical School, discusses several challenging cases with regards to the management of melanoma and pigmented lesions…Remember that melanoma, as an area, is not always easy.

Case 1

A ten year-old girl presents with a pink plaque on the left shoulder. The lesion has been present for four months and she has no other medical problems.

As a clinician, what would you do next?

1. Photo and follow up in 6 months
2. Reassure and continue careful surveillance at home
3. Perform an excisional biopsy with local anesthesia
4. Biopsy under general anesthesia

Why not photograph and follow or reassure and continue surveillance. Because of the shape of this lesion, it’s a little bit bigger than normal spitz nevus. Because of her age, she can probably tolerate anesthesia so it would be worth obtaining a good specimen. The biopsy showed 1.5mm thick, Clark level IV, it was non-ulcerated and 2 mits/mm².

Managing Pediatric Melanoma

A study by Cordoro and colleagues demonstrated that pediatric melanoma does not follow the ABCDs. What do we look for? Most teenagers who get melanomas get adult-type melanoma. Up until age 13, melanoma is diagnosed at a relatively low level. Amelanotic or bleeding is also more frequent presentations of melanoma in younger kids.

ABCDE Modified for Children

• Amelanotic
• Bleeding; bumps
• Color uniformity
• De Novo; Diameter; any
• Evolution

Make sure that you have a dermatopathologist with whom you are very confident!

Risk stratification, rather than black and white diagnosis, is the way things are going now with regards to tumors and general pathology. There are lesions where we cannot always make a precise diagnosis, even after molecular testing. In many of these cases, all we can say is that it is a Spitzoid neoplasm with very low or high malignant potential. Spitzoid neoplasms can be stratified into four categories. These are Spitz nevus, Spitz nevus with atypical features, atypical Spitz tumor and Spitzoid melanoma.  Bastian and his colleagues have developed Spitzoid taxons:

• H-ras mutated
• Bap-1 mutated
• Braf fusion
• Alk fusion
• Ntrak1 and ntrak3 fusion
• Ros-1 fusion

One very interesting concept is that many of these genes, if you take them and translocate them in cells other than melanocytes, they are extremely potent in terms of oncogenic effect. ROS-1 and Alk, for example, are important players in lung cancer. Mutations or fusion partners do not define benign versus malignant, but only lineage. So, doing a test for Alk will not tell us if the lesion is benign or malignant; however, if the lesion does metastasize these are very important venues for therapy. For instance, BRAF, even though there’s no Braf mutation in these lesions, it is over-expressed and anti-BRAF therapies may be effective in Spitzoid melanomas that have a BRAF fusion. You don’t have to have the mutation for BRAF inhibition to work, if it’s a tumor where other things are turning it on.