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Prognostic Factors in Melanoma

Progress in understanding melanomas

There has been significant progress in our understanding of melanomas, both from a pathological and clinical point of view. Several studies have increased our understanding of prognostic factors, including microscopic features of biopsies and sentinel lymph node biopsy. Advances in genetic changes have led to new therapies for melanoma. This article highlights some of these advances and explains their relevance to the way melanomas are reported.

Biopsy and histological analysis remain the standard for the diagnosis of melanoma, although this analysis has been refined.

From a histological point of view the main prognostic factors are:
1. Breslow thickness.
2. Mitotic rate.
3. Ulceration.
4. Other.

BRESLOW THICKNESS

Breslow thickness, which measures the depth of invasion of melanoma from the top of the granular layer of the epidermis, or the top of an ulcer if present, is the most important prognostic factor, and is the basis of recommendations for width of excision.(1)

Breslow thickness melanoma in situ: margin 5mm.
Breslow thickness <1.0mm margin 1cm.
Breslow thickness 1.0-2.0mm margin 1-2cm.
Breslow thickness 2.0-4.0mm: margin 1-2cm.
Breslow thickness >4.0mm: margin 2cm.

These margins are clinically measured margins. Margins measured microscopically and provided in pathology reports are usually smaller than clinical margins due to tissue retraction on removal from the body. The degree of tissue retraction depends on the elasticity of the skin, which reduces with increasing age of the patient and with solar elastosis.(2)

MITOTIC RATE

This is given as mitoses per square millimetre. The method of counting mitotic figures has changed to the “hot-spot” method, in which an area with the highest concentration of mitotic figures is chosen.(3)

ULCERATION

The presence of tumour ulceration is an adverse prognostic factor. The ulceration has to be due to “consumption of the epidermis”, that is the thinning and ulceration of the epidermis directly due to the growth of the melanoma.(4)

OTHER FACTORS

There are other important factors which are less common, such as vascular or perineural invasion and satellite lesions.(1)

 

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CLARK’S LEVEL

You will note that Clark’s level has not been mentioned. Taking all melanomas together, as a marker of depth of invasion Clark’s level has been shown to be less accurate as a prognostic factor than Breslow thickness, demonstrated by Cox model analysis of melanoma. Cox model is a statistical technique for exploring the relationship between the survival of a patient and several explanatory variables.(5)
From the analysis a Chi-square value is derived. In brief, the greater the value of the Chi square value the more significant the variable is as a prognostic factor. The Chi-square values are(1):

Breslow thickness: Chi square value 84.6.
Clark’s level: Chi-square value 8.2.

For this reason Clark’s level is considered to be less significant in the pathology report.

SENTINAL LYMPH NODE BIOPSY

Consensus has not been reached as to whether perform sentinel lymph node biopsies, with some specialists advocating against it and others advocating for it. Analysis of the largest long term trial completed may be summarised as follows: a sentinel lymph node biopsy is confirmed as a prognostic test but does not influence melanoma-specific survival at 10 years.(6)

AJCC MELANOMA STAGE

The American Joint Committee on Cancer publishes the Cancer Staging Manual, which is combines the pathology of the tumour (T) together with lymph node status (N) and metastatic spread (M) to arrive at a tumour stage. This provides survival data for patients and aids in determining treatment. The staging for melanoma is shown in the following two tables.(7)

    

GENETICS

Genetic research in the last few years has provided us with a much better understanding of the mechanisms of the development and subsequent evolution of melanoma. This has been useful in the development of specific drug treatment for melanoma, however at present has not provided utility in the diagnosis of melanoma, as there is a large number of point mutations in melanoma.(8)

BIOPSY

From a dermatopathologist’s point of view, many factors are taken into account in the diagnosis of melanocytic lesions and a decision is made on the various factors. No single factor is used to determine malignancy in melanocytic lesions, as there is overlap in benign and malignant lesions. One important factor though is the biological symmetry of a melanocytic lesion. This cannot be determined in a partial biopsy of a lesion. For this reason, it is recommended that melanocytic lesions be excised in toto whenever possible.(9)
Also remember to include the patient’s age and the site of the lesion, as well as information of any change in the lesion and any previous history of dysplastic naevi or melanoma. If possible, the provision of clinical and or dermoscopic images are also very useful.

FURTHER QUESTIONS

Please feel free to contact me with any further questions.
Dr Alex Nirenberg
MBBS BSc FRCPath FRCPA FIAC Diploma in Dermatopathology
Alex.Nirenberg@clinicallabs.com.au
Phone: 0405 651 025

 

REFERENCES

1. Australian Cancer Network, Clinical practice guidelines for the management of melanoma in Australia and New Zealand, 2008.
2. Dauendorffer et al, Shrinkage of skin excision specimens: formalin fixation is not the culprit, Br J Dermatol, 2009, 160, 810-814.
3. Balch et al, Multi¬variate analysis of prognostic factors among 2313 patients with stage III melanoma, J Clin Oncol, 2010, 28, 2452-2459.
4. Ohata et al, Consumption of the epidermis in acral lentiginous melanoma, J Cutan Pathol, 2012, 39, 577-581.
5. Walters, What is a Cox Model, www.whatisseries.co.uk.
6. Dixon et al, Sentinel lymph node biopsy now has a limited role in melanoma management, Australian Family Physician, 2014, 43, 479-480.
7. American Joint Commity on Cancer Staging Manual, 7th Edition 2010
8. Bastian, The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia, Annu Rev Pathol. 2014, 9, 239-271.
9. Ng et al, The impact of partial biopsy on histopathologic diagnosis of cutaneous melanoma: experience of an Australian tertiary referral service. Arch Dermatol, 2010, 146, 234–239.