Case Studies in Advanced Skin Cancer Management: An Osce Viva Resource

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CASE 1

Male aged 84 years, Diagnosis Melanoma Breslow 1.6 mm non ulcerated location chest. In this case the diagnosis has already been made, the object of this case is to assess your management strategy and depth of knowledge of primary care melanoma management.

Questions. Discuss Excision margins, Staging, Sentinel Lymph Node Biopsy (SLNBx) relevance and rates of positivity, follow up and include in your initial discussion the Dermoscopic features required to establish a diagnosis of melanoma and the histological features required to make a diagnosis of Melanoma .

Excision margins in this case are 1-2 cm and down to fascia. Ever increasing evidence is emerging that 1 cm margins are adequate for Melanomas of this Breslow depth with no evidence of increasing local recurrence or systemic metastatic spread. In a small study featured in the journal, Dermatologic Surgery October 2015 Volume 41 Issue 10 by Koskivuo et al studying 1 cm vs 2 cm margins for patients with intermediate thickness melanoma with 80 matched patients in each group showed that a 1 cm margin may be sufficient in melanomas 1.1 to 2 .0mm in Breslow as there were no differences in melanoma specific survival between the study groups (41 months follow-up). In this same vein, quoting from an article in Annals of Surgery Volume 241, number 2, February 2005 by McKinnon, Starritt, Scolyer, McCarthy and Thompson there is no apparent effect of any width of surgical margin on survival and assessment of LR (local recurrence) and survival data of 2681 patients seen at the Sydney Melanoma Unit with Melanomas less than 2 mm Breslow with a median follow-up of 81 months showed that their data supported the safety of 1 cm margins for melanomas that are 1-2 mm in thickness. The authors also state even with histopathologic margins less than 0.8cm, the LR rate as still low, 6.7% at 180 months If a clinical margin of 1cm is obtained then there is no difference in LR rates between the patients with a 1 cm margin vs a 2 cm margin in melanomas 1-2 mm thick.

It is worth noting, (not that it applies to this case), that with respect to depth of excision for melanomas on the EAR, if the Breslow is less than 1mm then the perichondrium and cartilage can be spared, which obviates the need for a wedge resection , an excision and flap or graft repair is adequate, (http://www.ncbi.nlm.nih.gov/pubmed/22081097.) See also (http://www.ncbi.nlm.nih.gov/pubmed/25971418).

Staging this lesion, the Breslow is 1.6 mm so that makes it a T2 lesion that is, T 1 <1 mm, T2 1-2 mm, T3 2-4 mm and T4 > 4 mm Breslow thickness. So this lesion is T2a, that is, Breslow 1-2 mm and non-ulcerated. T2a is STAGE 1B with a 90% 5 year survival. It is worth remembering the TNM and AJCC Staging.

Breslow thickness is measured from the stratum Granulosum or the base of the ulcer if ulcerated to the deepest melanoma cell. (Skin layers are from inferior to superior Stratum Basale, Stratum Spinosum , stratum Granulosum and Stratum Corneum of course in Acral Skin there is an extra layer called the Stratum Lucidum between Stratum Granulosum and Corneum)

SLNBx (Sentinel Lymph Node Biopsy)

The chance of a positive SLNBx is approximately 15% (This handy web based tool allows quick calculation of SLNBx positivity: mskcc.org and click on the melanoma sentinel lymph node nomogram, this is from the Memorial Sloan Kettering Cancer Center), 80% will only have 1 node involved, that is, the sentinel node. In 30% of patients with a positive sentinel node metastatic disease already exists, this will be micro-metastases. The false negative rate is 4 %.The MSLT1 trial found that a SLNBx procedure is valuable in prognosticating the chance of 10 year survival for intermediate thickness Melanomas (1.2 mm to 3.5 mm Breslow) in that a Positive SLNBx predicts a 10 year survival of only 62% whereas a negative SLNBx predicts a 10 year survival of 85%.This information must be put into perspective after the presentation in 2015 at the ASCO meeting of a study conducted in Germany by DR Claus Garbe for the German Dermatologic Cooperative Oncology Group (DeCOG) that was a 3 year prospectively randomised study of Patients with a Melanoma Breslow thickness greater than 1 mm all of whom had biopsy proven positive SLNBx who were randomised for immediate ELND or observation. The conclusion was patients who did and did not undergo complete lymph node dissection were statistically indistinguishable with respect to distant metastases-free survival, recurrence free survival, and melanoma-specific survival This was a phase 3 randomised trial of 483 patients with stage 3 melanoma and micro-metastases in their sentinel nodes. (Oncology Practice Digital Network, May 31s, 2015) So it is very unlikely that this patient would be offered or benefit from a SLNBx. Certainly ELND or CLND improves loco-regional control as any lymph nodes that contain micro-metastases (which could progress to macroscopic lymph node disease, or may not) would have been removed, but this is not eventuating into better overall survival.

SLNBx positivity rates by Breslow and ulceration status.

SLNBx positivity rates are also influenced by number of mitoses per mm2 and degree of TILs that is Tumour infiltrating lymphocytes, also Melanomas exhibiting significant regression also exhibit less SLNBx positivity. With respect to TILs and SLNBx positivity TILs are graded 0-3, with grade 3 being marked presence of Tumour Infiltrating Lymphocytes (which is a good prognostic sign), the TIL grade and its corresponding degree of SLNBx positivity were Grade 0: 28% Grade 1: 20% Grade 2: 18% Grade 3: 5.6% so more TILs less SLNBx positivity. Further information regarding staging.

Recurrence by stage

These recurrence figures are divided into 1/ Local recurrence 10% 2/ In-transit 10% 3/ Regional Lymph nodes 35% and 4/ Systemic Mets 45%. Note 80% of recurrences occur in the first 3 years, 95% by 5 years and rarely after 11 years. The Sydney Melanoma Group published that the recurrence of Melanoma after 10 years in their series was 0.65%. The published data for local recurrence figures for Melanomas 1-2 mm thick are 1% for trunk and proximal limb sites and 3.8% for Head and neck and Distal extremity sites at 10 years.

What are the dermoscopic features of a PSL (Pigmented Skin Lesion) indicating that Melanoma is the likely diagnosis?

Dermoscopy or dermatoscopy allows much more rigorous examination of a pigmented lesion and is proven to more accurately diagnose the Melanoma and avoid unnecessary excisions. Any Dermoscopic algorithm can be used but Associate-Professor Cliff Rosendahl’s and Harold Kittler’s Chaos and Clues algorithm is extremely useful and accurate (Dermatoscopy An Algorithmic method based on pattern analysis by Harald Kittler, Cliff Rosendahl, Alan Cameron and Philip Tschandl; ISBN 978-3-7089-0717-8). Chaos: the presence of asymmetry of colour or structure is the first pre-requisite. Clues there are eight. 1/ eccentric structure-less zone of any colour except skin colour. 2/ grey circles lines and dots. 3/ Black dots or clods at the periphery. 4/ Pseudopods or radial streaming. 5/ thickened atypical network. 6/Polymorphous vessels. 7/Parallel ridge pattern. 8/ PSWLs Polarising Specific White Lines. Remember PSWLs are found in the big 4 plus 1, the big 4 being Melanoma, Spitz, BCC and Dermatofibroma and the plus 1 being Pyogenic Granuloma, note all these are raised lesions. In flat lesions PSWLs are found in Melanoma, BCC, LPLK and Scars. Only 1/875 clinical DN showed PSWLs (traumatised) 0/26Common naevi showed PSWLs.

As an aside should this person be tested for a familial melanoma gene? What are the common Melanoma genes? (CDKN2A, MC1R, CDK4, POT1)The answer of course is NO, the most common melanoma gene is CDKN2A occurring on the short arm of chromosome 9 (9p21). This gene encodes for two proteins p16 and p 14 arf, loss of p16 expression is observed during tumour progression. 1/200 Melanomas diagnosed occur in individuals carrying this gene, that is 1% of all Melanomas diagnosed, and only 2% of the population are carriers of this gene. In families with multiple members with Melanoma only 30% exhibit positive CDKN2A (occurring when 3 or family members have had a Melanoma). Of note 85% of familial melanoma clusters only affects two family members usually 1 parent and 1 child (Philadelphia study). Other genes to consider are MC1R, CDK4 and the POT1 gene discovered at the QIMR Berghofer institute in Brisbane (co-author Professor Nick Hayward) which has at its core the regulation of the Shelterin protein complex which regulates telomere length.

Now for some Histology. Describe the features likely to be found in this superficial spreading Melanoma. The features to note are Loss of L to R symmetry, Buckshot scatter and spread that is, Pagetoid spread, Single Melanocytes outnumber nests, the nests vary in size and shape and are no longer just confined to the tips and shoulders of the rete ridges, dermal nets are present and are the same size or larger than nests at the DEJ (Dermo-epidermal junction), there is loss of Maturation and dispersion of Melanocytes at the base of the lesion, there is deep staining to the base with HMB45 (Human Melanoma Black), there is marked cytological atypia present and often deep mitoses, there may be consumption or ablation of the epidermis by the melanomas cells.

It is worth remembering which other skin lesions can exhibit Pagetoid Spread? The list is, Melanoma, Bowen`s disease, Paget`s disease (DCIS of the Breast) Extra-mammary Pagets, Intra-epidermal Porocarcinoma, Sebaceous Carcinoma, T cell lymphoma (Mycosis Fungoides) and MCC Merkel cell carcinoma which exhibits epidermo-tropism. And of course many benign Melanocytic lesions exhibit limited centrally placed Pagetoid scatter. These entities being: Acral naevi, Irritated naevi, congenital naevi, Spitz naevi, and Childhood naevi.

Follow-up Schedules: Every institution and every country has a different follow-up regime. Firstly one must ascertain why you are following up the patient, is it to detect recurrences either local or metastatic? Or is it to detect earlier the appearance of a new primary? Patients who have had a melanoma are 10 times more likely to get a 2nd melanoma than a person getting their first melanoma. Surprisingly Patients whose first melanoma was an insitu melanoma have a greater risk of a 2nd melanoma than those patients whose first melanoma was an invasive melanoma.

A review of the literature by Pomeranz H et al, J Am Acad Dermatol 2015 Mar 12 showed that in a cohort of 168,274 melanoma patients 6.5% developed at least one subsequent melanoma, and the MIS group had a higher incidence of a subsequent melanoma than the invasive cohort. Cumulative risk at 5 years was 2.8% in the MIS group and 2% in the invasive melanoma group. Interestingly and more worryingly was the finding that the MIS group was significantly more likely to develop subsequent invasive melanoma after 10 years and subsequent MIS at every time point. Professor John Thompson from the Sydney Melanoma Unit suggests that patients be seen yearly if there melanoma had a Breslow less than 1 mm and more often if thicker but did not specify how often.

The Clinical practice guidelines for the Management of melanoma 2008 suggest the following non evidence based guidelines (www.nhmrc.gov.au/_files_nhmrc/publications/.../cp111.pdf)

Stage 1………Q6/12 for 5 years then yearly noting that Stage 1 is 1A which is T1a & 1B which is T1b & T2a.

Stage2………..Q3-4/12 for 5 years then yearly noting that 2A is T2b & T3a and 2B is T3b & T4a & 2C is T4b

Stage 3……….Q3-4/12 for 5 years then yearly noting Stage 3 is Lymph node Mets, In transit Mets and Satellitosis.

Quoting Dr Jeff Keir a Fellow of the SCCA he has a very simple follow-up routine

Insitu………….Q6/12 for 5 years then yearly

Invasive……….Q3/12 for 2 years then Q6/12 for 3 years then yearly.

So this concludes this relatively straight forward case where an atypical Melanocytic lesion dermoscopically suggestive of Melanoma was originally excised with a 2mm margin for diagnostic purposes the result of which is a Superficial spreading Melanoma with a Breslow of 1.6mm, wider excision ensued with 1 cm margins and deep to fascia and the patient entered into a follow-up routine of 3