Melanoma Clinic: Lunch, Lesions and Lessions: Part 2

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 14th, 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.

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

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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.

Cutaneous Oncology: Clinical Pearls

George Martin, MD

How are you managing your cutaneous oncology patients? Dr Martin provides us with his clinical pearls…

  • Remember that AK patients are not just Medicare patients, we see patients 30-40 years old as well. Also remind older patients that actinic damage is chronic disease and no one therapy will result in a long lasting or permanent cure.
  • When treating AKs, expect side effects based on the MOA of the active ingredient.
  • Treating AKs on the chest? Therapeutic considerations include:  Topical 5-FU cream 0.5/1.5%; Ingenol Mebutate gel 0.5%; and Diclofenac gel 3%., Expect a significant skin reaction to ingenol mebutate 0.05% (not .5%) within 24 hrs that will include blistering and discomfort requiring analgesia when large areas are covered.. 5-FU can be “titrated” and can be used for 7-10  days, discontinued for a month and re-started in a month and used for 2-3 weeks with less of a reaction. DO NOT USE IMIQUIMOD on the chest as it is not FDA approved for the chest and  an result in permanent depigmentation.
  • Managing reactions is key! Utilize analgesia as needed; sunscreen to reduce potential for dyschromia; moisturizers; topical antibiotics as needed; and weekly follow-up.
  • Imiquimod can trigger flu-like symptoms including myalgias and fever before a significant skin reaction such as erosions and ulceration may occur.
  • Ingenol Mebutate has two mechanisms of action: an immediate cytotoxic effect initiated via the PKC pathway which causes swelling  and edema even blistering and weeping and a second MOA involving IL-8 production by rapidly proliferating ketatinocytes and endothelial cells which recruits neutrophils and in vigorous responses can result in sterile pustules.
  •  Counsel patients on anticipated responses and set expectations.
  • Have patients fill prescriptions between Monday to Thursday—less likely to be switched than Fridays or weekends.
  • Have patients start treatments on Sundays, for ingenol mebutate during Mon-Thurs as the immediate reaction to ingenol mebutate may trigger a phone call within 24 hours; this way, reactions occur mid week rather than on weekends.
  • Make sure that surgical sites are well healed and that cryotherapy sites have had a week or two after healing before initiating therapy.
  • Use every adjunct possible except steroids as the immune system plays a role in each modality used.

Melanoma Clinic: Lunch, Lesions, and Lessions

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.

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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.

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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.

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Pigmented Lesions: Clinical Pearls

Ashfaq Marghoob, MD

Dr Marghoob provides us with his clinical pearls on pigmented lesions….

  1. The larger the congenital nevus the greater is the risk for developing melanoma.
  2. The risk of a melanoma developing in a small congenital nevi is small enough that prophylactic excision is not required.
  3. Presence of many nevi and dysplastic nevi are strong risk factors for melanoma.
  4. Analytical, Differential and comparative recognition are all helpful in differentiating nevi from melanoma.
  5. Total body photography assists clinicians in finding concerning lesions.
  6. Dermoscopy assists clinicians in deciding which lesions require a biopsy.
  7. Unna’s theory of nevogenesis is not supported by recent cross sectional and longitudinal studies.
  8. Nevi with a peripheral globular pattern or a starburst pattern are growing nevi (not yet in senescence).
  9. Most halo nevi have a globular pattern.
  10. Patient driven healthcare with the use of Apps is likely to help in finding early melanomas.

Dermoscopy: Clinical Pearls

Ashfaq Marghoob, MD

Are you performing dermsocopy in your clinical practice? Dr Marghoob provides us with his clinical pearls…

  1. Dermoscopy helps in differentiating benign lesions from skin cancer.
  2. The presence of network (reticular network, negative network, polygonal lines), streaks (radial streaming, pseudopods), aggregated globules/peripheral globules, homogeneous blue pigmentation is most often seen in melanocytic lesions.
  3. Melanocytic lesions that deviate from the 10 benign patterns and has at least one of the 10 melanoma-specific structures needs to be biopsied to rule out melanoma.
  4. The presence of spoke wheel structures and/or leaf like areas is 100% specific for BCC.
  5. Comedo like openings and milia cyst are often seen in SK but can also be seen in other lesions including melanoma.
  6. Polarized light makes blood vessels and crystalline structures more conspicious, and makes milia cyst less conspicuous.
  7.  A polymorphous vascular pattern in an amelanotic lesion should raise concern for melanoma.
  8. Dermoscopy improves the clinician’s diagnostic accuracy.
  9. All structureless or featureless or not-otherwise-diagnosable lesions should be viewed with suspicion.
  10. Raised lesions should never be monitored for change.

Cutaneous Oncology: Talking Points

Marc Brown, MD

Here are some of the key points from Dr Brown’s presentation at MauiDerm NP+PA Summer 2014….

  1. High risk parameters for BCC include location on the central face, larger size, recurrence, prior radiation and aggressive histology.

 

  1.  High risk histology for BCC includes the following:  infiltrating, morpheaform, micronodular, basosquamous, sclerosing, desmoplastic, and perineural invasion.

 

  1. Risk factors for the development of SCC include:  UV light exposure, X ray exposure, HVP infection, immunosuppression, chronic non-healing or inflammatory wounds, an rare genetic syndromes.

 

  1. High risk locations for SCC are ear, lip, genitalia and scalp.

 

  1. Other risk factors for aggressive SCC include:  poorly differentiated histology, depth of invasion, perineural invasion, size (greater than 2 cm.).

 

Actinic Keratoses: Clinical Pearls

George Martin, MD

Are you using 5-FU to treat AKs?

  • To minimize the duration of side effects, compliance issues and phone calls when prescribing 5-FU prescribe 0.5% 5-FU therapy for 1 week.  Phase 3 FDA data on 0.5% 5-FU used for 1 week demonstrate over 70% individual lesion clearance. Is it worth continuing an extra 3 weeks to achieve a > 90% clearance?  No.
  • What does Dr. George Martin do? He cycles 5-FU therapy: 1st cycle—Face: 7 days 5-FU/Non-facial areas: 10 days 5-FU; Rest period for at least one month; 2nd cycle— 5-FU for at least 2 weeks.  Data suggest that 0.5% 5-FU QD is at least as effective as 5% 5-FU BID in percent reduction of AK lesions. The short treatment cycles result in great compliance and minimal downtime.

Treating AKs on the chest?

  • Avoid 3.75% imiquimod. It is likely to result in permanent depigmentation at the AKs treated sites on the chest in the majority of patients. It is not yet FDA approved for the trunk…and with good reason.
  • Try: ingenol mebutate 0.05% x 2 nights. Instead of spot treating, cover the entire sun-damaged AK area of the chest with the entire amount in the tube. Best used on moistened skin post shower because it spreads better. Because of its direct cytotoxic effect, in addition to up-regulation of IL-8 induced neutrophil chemotaxis, it produces discomfort within 4 hours requiring analgesia. Be sure to set patient expectations and prescribe analgesia.  Patients describe it’s use on large areas on the upper chest as feeling like a “really bad sunburn.” Although not FDA approved to treat areas >25 cm2 and there is no efficacy data, Dr. Martin has found it to produce excellent AK clearance and a great cosmetic result.

Cutaneous Oncology: Part 2

Actinic Keratoses

George Martin, MD

Unfortunately, field therapy for the treatment of AKs continues to remain underutilized in clinical practice even though we have a number of therapies available. Recent studies on dermatologist treatment practices demonstrate that 92% of patients treated for actinic damage are treated with cryotherapy alone; 7% with cryotherapy plus a prescription for a field therapy; and 1% of patients leave the office with a prescription for a field therapy alone. Why is field therapy underutilized? This is, in part, due to prolonged downtime, patient compliance issues, the costs of medication, and patient discomfort during therapy. Therapies such as ingenol mebutate and short duration 0.5% 5-FU and combination therapies have been developed to address the above noted issues.

Our expert panel (George Martin, Eggert Stockfleth, Ted Rosen, Neal Bhatia, Neil Swanson, and Marc Brown) reviewed various challenging clinical cases with AKs. Some of the recommendations and comments are as follows:

How does a dermatologist optimally treat AKs? For facial AKs, 5-FU remains the basis of field therapy in most clinical practices.  During phase III clinical trials, clearance rates in excess of 70% were measured 30 days following daily treatment for 1 week using 0.5% 5-FU.  Lengthening the therapy to 4 weeks results in better efficacy but is in Dr. Martin’s opinion not worth the additional downtime and patient local skin reactions. Dr. Martin protocol involves treating daily for seven days, then the patient has a rest period of 1 month, then he treats again for 2 weeks or longer depending on the desired clinical result.  What about 3.75 imiquimod?  The 2 week on-off-on for facial AKs results in significant downtime.  Investigator initiated studies are looking at using 3.75% imiquimod daily for 7 days followed by a 2 weeks rest and then instituting once weekly applications. Ingenol Mebutate has also proven to be efficacious as a full-face field therapy using a single tube application to cover the entire face.  Complete healing with excellent clinical responses have been observed in larger area therapies. Large controlled studies quantitating efficacy on full face and scalp, large surface areas on the trunk and extremities have not been completed. Be sure to have your patients refrigerate their ingenol mebutate as soon as possible after picking it up.

Actinic damage on the chest of women poses a great challenge to the practitioner. Because of permanent depigmentation when used on chest areas, imiquimod 3.75% should be avoided. While PDT has shown to be effective, it is off-label for use on the chest and does not have any well-controlled studies to support its use. Both ingenol mebutate and 5-FU are viable options for treatment of AKs on the chest. Ingenol mebutate 0.05% QD x 2 days results in a “chemical peel” like reaction but produces excellent AK clearance and cosmesis.

What about the management of a patient with significant AK damage on the dorsal hands and forearms? Combined use of 5-FU QD in the morning for seven days with 5% imiquimod QD in the evening for six days followed by three to four weeks of “rest” and repeating the cycle for a total of three cycles has proven effective. Using 0.5% 5-FU QD for ten days followed by ALA PDT (3 hour incubation) is also effective but painful. Ingenol mebutate .05% applied QD for two days, while approved by the FDA for treatment of the hands/forearms, lacks significant efficacy and might benefit from future clinical studies examining the efficacy and safety of a three to four day regimen. It is important to remember actinic damage is a chronic disease that requires vigilance and therapeutic intervention.

Cutaneous Oncology: Part 1

Viral Skin Carcinogenesis

Eggert Stockfleth, MD

Dr Stockfleth reviewed the latest data and the role of the human papillomavirus (HPV) in skin cancer.   HPV is a very stable, host-specific virus, which it is why it is referred to as “human” papillomaviruses.  HPV is a frequent virus in most everyone.  The most known strains of HPV are 16 and 18. HPV also has a very special DNA from the oncogenic type (E6 and E7). Currently, there are two prophylactic quadrivalent vaccines available, which harbor HPV 6, 11, 16 and 18.

It’s important to know that the target cell for HPV is the keratinocyte. HPV types can infect skin tumors and mucosa tumors.

Currently, there are over 150 human papillomavirus types. These types can be distinguished by either alpha type, the wart-associated types, or cutaneous types, which are mainly the beta- or gamma-PV types.

Genital HPV, as we know, is one of the most frequently transmitted diseases; however, don’t forget that most of us already have these viruses for life.

Cutaneous HPV

Transmission of cutaneous HPV is through skin contact. Yet, the virus is very stable so can remain for several days. Probably, the best known oncogenic HPV types for cutaneous HPV are types 5 and 8.

Cutaneous Squamous Cell Carcinoma

SCC is prevalent on 80% of sun-exposed areas in cutaneous HPV and the main risk factor is UV radiation (UVA and UVB).  Dr Stockfleth and colleagues found that 118 genes were identified as differentially expressed in skin cancer.

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There are multiple risk factors during skin carcinogenesis. With a functional immune system, your body can repair DNA image or lead to programmed cell death, i.e, apoptosis. Chronic UV exposure leads to a local down-regulation of immune response; therefore, leading to an increased risk of developing skin cancer. HPV blocks apoptosis and the repair mechanism which can lead to SCC.

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What are the criteria to define a causal role in disease by infectious agents?

Biology of HPV

  • Presence of HPV in (pre)cancer cells
  • Expression of  viral genes in (pre)cancer cells
  • Transforming properties (in vitro and in vivo models)

Epidemiology

  • Relative Risk (RR) and Odds Ratio (OR)
What about cellular networks?

Research on cellular networks over the years has led researchers to look for the “guardian” genes.

A 2011 publication by Dr Stockfleth and colleagues, looked at the interaction of cutaneous HPV 23. Of note, HPV 23 and 38 are the most prevalent types of virus and play a role in development of skin cancer. These HPV subtypes (23 and 38) induced anti-apoptotic effects in UV-damaged cells through the expression of two oncogenic proteins E6 and E7 that lead to persistence and accumulation of further mutations.  Data from this paper suggest that cutaneous HPV23 E6 protein directly targets HIPK2 function; therefore, HIPK2 was identified as the guardian gene.

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Research is still ongoing regarding identification of other viruses, vaccination and treatment.

Cutaneous Oncology Part 1

Eggert Stockfleth, MD & George Martin, MD

 

Viral Skin Carcinogenesis – Eggert Stockfleth, MD

Dr Stockfleth reviewed the latest data and the role of the human papillomavirus (HPV) in skin cancer.  SCC is prevalent on 80% of sun-exposed areas in cutaneous SCC and the main risk factor is UV radiation (UVA and UVB).  There are multiple risk factors during skin carcinogenesis. With a functional immune system, your body can repair DNA image or lead to programmed cell death, i.e, apoptosis.

What about cellular networks? Researchers are looking to identify the “guardian genes”.  We have found that HPV 23 and 38 are the most prevalent types of virus and play a role in development of skin cancer. These HPV subtypes (23 and 38)  induced anti-apoptotic effects in UV-damaged cells through the expression of two oncogenic proteins E6 and E7 which lead to persistence and accumulation of further mutations.  Research is still ongoing regarding vaccination and treatment.

Actinic Keratoses – George Martin, MD

Unfortunately, field therapy for the treatment of AKs continues to remain underutilized in clinical practice even though we have a number of therapies available. Recent studies on dermatologist treatment practices demonstrate that 92% of patients treated for actinic damage are treated with cryotherapy alone; 7% with cryotherapy plus a prescription for a field therapy; and 1% of patients leave the office with a prescription for a field therapy alone. Why is field therapy underutilized? This is, in part, due to prolonged downtime, patient compliance issues, the costs of medication, and patient discomfort during therapy. Therapies such as ingenol mebutate and short duration 0.5% 5-FU and combination therapies have been developed to address the above noted issues.

Our expert panel (George Martin, Eggert Stockfleth, Ted Rosen, Neal Bhatia, Neil Swanson, and Marc Brown) reviewed various challenging clinical cases with AKs. Some of the recommendations and comments are as follows:

How does a dermatologist optimally treat AKs? For facial AKs, 5-FU remains the basis of field therapy in most clinical practices.  During phase III clinical trials, clearance rates in excess of 70% were measured 30 days following daily treatment for 1 week using 0.5% 5-FU.  Lengthening the therapy to 4 weeks results in better efficacy but is in Dr. Martin’s opinion not worth the additional downtime and patient local skin reactions. Dr. Martin protocol involves treating daily for seven days, then the patient has a rest period of 1 month, then he treats again for 2 weeks or longer depending on the desired clinical result.  What about 3.75 imiquimod?  The 2 week on-off-on for facial AKs results in significant downtime.  Investigator initiated studies are looking at using 3.75% imiquimod daily for 7 days followed by a 2 weeks rest and then instituting once weekly applications. Ingenol Mebutate has also proven to be efficacious as a full-face field therapy using a single tube application to cover the entire face.  Complete healing with excellent clinical responses have been observed in larger area therapies. Large controlled studies quantitating efficacy have not been completed.

Actinic damage on the chest of women poses a great challenge to the practitioner. Because of permanent depigmentation, imiquimod 3.75% should be avoided. While PDT has shown to be effective, it is off-label for use on the chest and does not have any well-controlled studies to support its use. Both ingenol mebutate and 5-FU are viable options for treatment of AKs on the chest. Ingenol mebutate 0.05% QD x 2 days results in a “chemical peel” like reaction but produces excellent AK clearance and cosmesis.

What about the management of a patient with significant AK damage on the dorsal hands and forearms? Combined use of 5-FU QD in the morning for seven days with 5%  imiquimod QD in the evening for six days followed by three to four weeks of “rest” and repeating the cycle for a total of three cycles has proven effective. Using 0.5% 5-FU QD for ten days followed by ALA PDT (3 hour incubation) is also effective but painful. Ingenol mebutate .05% applied QD for two days, while approved by the FDA for treatment of the hands/forearms, lacks significant efficacy and might benefit from a three to four day regimen. To date there are no published studies looking at a longer treatment regimens for this area.  It is important to remember actinic damage is a chronic disease which requires vigilance and therapeutic intervention.