Clinical Review - Malignant melanoma

Diagnosis and management of melanoma skin cancer. By consultant dermatologist and dermatological surgeon Dr James Langtry.

Irregularly pigmented mole on the back: excision biopsy showed an MM with Breslow thickness of 0.7mm (Author image)
Irregularly pigmented mole on the back: excision biopsy showed an MM with Breslow thickness of 0.7mm (Author image)

Section 1: Epidemiology and aetiology

Primary cutaneous malignant melanoma is often referred to as malignant melanoma (MM).

Incidence of MM has risen in the past few decades. A Danish population-based study showed that age-standardised rates per 100,000 rose from 6.5 to 14.4 for men and from 8.6 to 18.9 for women between 1978 and 2007.1

The increase has been greater than for other cancers. It is predicted that the trend of increasing skin cancer incidence, including MM, will continue for several decades.2

The cause of the rising incidence is uncertain but may include an increase in risk-prone behaviour, better detection and the possibility of overdiagnosis due to diagnostic drift (lesions previously diagnosed as biologically benign being diagnosed as early stage MM).

Predisposing factors
MM is predominantly a disease of fair-skinned individuals.

Environmental and genetic factors form the basis of the complex aetiology of MM, which remains poorly understood.

Environmental factors relate predominantly to UV radiation exposure, where a history of sunburn and intermittent sun exposure are established risks. In addition, there is increasing evidence that indoor tanning devices are associated with an increased risk of MM.3

Phenotypic risks are largely heritable and include pigmentation (fair skin, blond or red hair, blue or green eyes), an inability to tan, sun sensitivity, high number of melanocytic naevi (moles) or the presence of clinically atypical naevi (moles of variable shape and pigmentation).

Genetic studies of familial melanoma kindreds have identified two high-penetrance melanoma genes (CDKN2A and CDK4) which account for a minority of genetic risk in melanoma families. It is clear that MM shows significant genetic heterogeneity.

Candidate-gene studies and genome-wide association studies have resulted in an emerging molecular subclassification of MM (see table below).4

MM incidence increases with age. It is rare below the age of puberty and when it occurs is usually associated with genetic and congenital predisposition.5

A common belief is that skin cancer only affects UV-exposed sites. Any skin site may be affected by MM, but the most common site for MM in a man is the back and for a woman, the legs and back.

Incidence is higher in females than males, but females have better survival rates.

Section 2: Making the diagnosis

Advanced disease has a universally poor prognosis, therefore early diagnosis is crucial. The principal factor impeding this is delayed recognition.

The ABCD signs (Asymmetry of the lesion, Border irregularity, Colour variability, Diameter >6mm) are an aid to early detection.

Diagnosis is based on the history, clinical examination and histopathology. All patients who present with a suspected MM or have atypical pigmented lesion(s) should have a full skin examination. All suspected MM should be referred urgently through the two-week rule to local screening services (see box, below).6

Suspected MM6

Suspect MM in the presence of

  • A new mole appearing after onset of puberty, which is changing in shape, colour or size.
  • A long-standing mole which is changing in shape, colour or size.
  • Any mole which has three or more colours or has lost its symmetry.
  • A mole which is itching or bleeding.
  • Any new persistent skin lesion especially if growing, pigmented or vascular in appearance, and if the diagnosis is not clear.
  • A new pigmented line in a nail, especially where there is associated damage to the nail.
  • A lesion growing under a nail.

Recording clinical features in the notes is important and should include details of the history (duration of the lesion, change in size, colour or shape, and symptoms such as itching and bleeding) and examination (site, size, elevation, description including irregular margins, irregular pigmentation and if ulceration is present).

Examination
Dermoscopy is no substitute for clinical history and examination but may be of value in those with expertise and experience in MM diagnosis. Biopsy and histopathological examination is the definitive diagnostic step. Wherever possible this should be an excision biopsy with a 2mm margin including the full thickness of the dermis.

Excisional biopsy is important for accurate diagnosis and staging, which informs subsequent treatment and prognosis. The standard of care following a histological or uncertain diagnosis of MM is review of slides in a melanoma consensus group.

Histopathology reporting of MM must include a standard set of information for the purposes of staging, including Breslow thickness and histological subtype.6 The clinician who has taken the biopsy is responsible for interpreting the histopathology report and taking necessary action.

It is recommended that all diagnoses or suspected diagnoses of MM should be referred to the skin cancer multidisciplinary team (MDT) for review and to signpost further involvement of appropriate specialists and the skin cancer nurse specialist.

Dermoscopic image: irregularly shaped, pigmented naevus (Author image)

Subtypes
The four most common clinical subtypes of MM differ in their clinical presentation, epidemiology and growth characteristics. Superficial spreading MM (62% of cases) exhibits predominantly horizontal growth; nodular MM (22%) exhibits predominantly vertical growth; lentigo maligna (12%) occurs in sun-exposed sites and in older age; acral lentiginous MM (2%) involves the nail apparatus, palms or soles.

The colour variability of MM depends on the amount and depth of melanin present, and is more likely to be seen in tumours with a horizontal growth pattern.

Amelanotic melanoma can occur if melanocytes lose the ability to produce melanin. It may arise in any of the clinical subtypes of MM (for example, amelanotic lentigo maligna, amelanotic nodular MM) and has a similar prognosis to equivalent Breslow thickness MM.

The concern with these tumours is the increased likelihood of diagnostic delay, given the lack of pigmentation.

Section 3: Managing the condition

Prevention is an important part of the management strategy for MM. It should include primary prevention - reducing risk through public education on the risks of sun exposure - and secondary prevention through early detection, which may be achieved by teaching high-risk patients to self-examine and the ABCD signs. It is likely that regular sunscreen may reduce the risk of MM.7

All MM should be discussed in the local or specialist skin cancer MDT. All skin cancer of stage 1B and above should be discussed in the specialist skin cancer MDT (SSMDT) and managed by members of the SSMDT.

Excision
The only known cure for MM is complete excision of the tumour. This is not possible once the tumour has spread (spread is strongly correlated with Breslow thickness), underlining the importance of the diagnosis being made as early as possible.

Following complete excision, re-excision with a wide margin is recommended. Excision width is based on the Breslow thickness (see table, below).

Excision margins for primary cutaneous MM6
 MM Breslow thickness  Width of excision
 In situ  5mm
 <1mm  1cm
 1.01–2mm  1–2cm
 2.1–4mm  2–3cm
 >4mm  3cm

Wide excision reduces the risk of loco-regional recurrence but has not been shown to have any effect on disease-specific survival.

There is no role for elective lymph node dissection in patients who have no clinical evidence of lymphadenopathy. Sentinel lymph node biopsy (SLNB) may be considered in patients with stage 1B or greater; however, it has no proven therapeutic value, has associated surgical risks and the possibility of false negative results.

In the presence of lymphadenopathy or symptoms that might indicate metastatic disease, further investigation is needed (lymph node biopsy, CT, MRI or PET scans) with lymphadenectomy where lymph nodes are involved.

The use of staging CT scans, MRI and PET scans, ultrasound-guided lymph node biopsy and SLNB where appropriate is discussed by the SSMDT. It may be necessary to consider various modalities for disease control, including isolated limb perfusion, radiotherapy, and surgery of oligometastatic disease.

The standard chemotherapy treatment is dacarbazine. However, along with the evolving molecular classification of MM, we are entering the dawn of targeted molecular treatments, including BRAF inhibitors, perhaps changing the grim outlook of metastatic MM.

Section 4: Prognosis

MM patients with advanced disease have a universally poor prognosis with median survival rates measured in months and leading to the notoriety of MM as an aggressive form of (skin) cancer.

Assessment of prognosis is dependent on accurate staging. It is recommended that the stage of the lesion, following the American Joint Committee on Cancer (AJCC) staging system,8 should be recorded when the MM is reviewed in the skin cancer MDT meeting.

Purpose of follow-up
The purpose of follow-up is to detect any disease recurrence and appropriately treat this, as well as the detection of second primaries, provision of support, information and education.

All patients should be taught how to examine themselves, including the examination of lymph nodes.

At follow-up, the scar of the MM excision and the area around the scar are inspected and palpated, and a full skin examination is undertaken for possible second primary MM. The risk of a second primary is approximately 2% in patients with AJCC stage I-II.

The most common second primary MM subtype is superficial spreading MM, with 75% having a Breslow thickness ≤1mm. Patients developing a second primary MM do not appear to have a decreased overall survival.

Further primaries
In the 2% of patients with primary cutaneous MM who develop further primary cutaneous MM, one fifth will be synchronous (presenting at the same time) and four fifths will be metachronous (presenting at a later date).9

This underlines the importance of complete skin examination at the initial visit and at follow-up.

Any subsequent primary cutaneous MM is treated in the same way as any other primary cutaneous MM.

Patients with in-situ MM do not require follow-up because there is no risk of metastasis.

The current recommended follow-up for stage 1A MM (<1mm breslow="" thickness="" no="" ulceration="" mitoses="" is="" every="" three="" months="" for="" one="" year="" p="">

Stage 1B and above should be followed up for five years, at three-month intervals for the first three years and then at six-month intervals for the following two years.10

Patients with familial MM (two or more first-degree relatives with MM) or a genetic syndrome predisposing to MM should be followed up for life.

Irregularly shaped and irregularly pigmented mole on the thigh (Author image)

Section 5: Case study

A 59-year-old woman with Fitzpatrick skin type 2 (burns easily, tans with difficulty) was referred by her GP. She had become aware of a mole on her left thigh that had been changing size and shape, with associated pruritus, over about two months.

She had been an enthusiastic sunbather. She also gave a history of hypertension, osteoarthritis and anxiety disorder. There was no family history of MM.

Examination showed a 12x11mm irregularly shaped and irregularly pigmented brown-black papule of the left anterolateral thigh. There was no inguinal lymphadenopathy. There were no other symptoms of note on systems review.

Investigations
An excision biopsy with a 2mm margin to the fat layer demonstrated an MM in vertical growth phase with a Breslow thickness of 1.9mm, Clark's level 3, a mitotic count of 3/mm2, presence of regression and no ulceration. The AJCC clinical stage was 1B.

A 2cm wide excision to the fascia was undertaken. No further investigations were indicated. Follow-up was planned over five years, starting with every three months for the first three years and then every six months for the next two years, to inspect the scar of wide excision, examine regional lymph nodes and undertake a general skin examination.

Fitzpatrick skin types

 Fitzpatrick skin type

 Characteristics
 1  Always burns, never tans
 2  Burns easily. Tans with difficulty
 3  Tans after initial burn
 4  Tans easily, burns minimally
 5  Rarely burns, tans darkly and easily

Section 6: Evidence base

Clinical trials

  • Green AC, Williams GM, Logan V et al. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin Oncol 2011; 29: 257-63.
  • Lazovich D, Vogel RI, Berwick M et al. Indoor tanning and risk of melanoma. Cancer Epidemiol Biomarkers Prev 2010: 19; 1557-68.

Guidelines

Online

Click here to take a test on this article and claim a certificate on MIMS Learning

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Review the AJCC staging system.
  • Consider if you are confident at teaching high-risk patients how to examine their skin for changes, and revise as appropriate.
  • Play your part in primary prevention. Is there more you could do to promote how to stay safe in the sun? Consider if you could give tips to patients during relevant consultations.

 

References
1. Fuglede NB, Brinck-Claussen UO, Deltour I et al. Incidence of cutaneous malignant melanoma in Denmark, 1978-2007. Br J Dermatol 2011: 165; 349-53.

2. Diffey BL, Langtry JA. Skin cancer incidence and the ageing population. Br J Dermatol 2005: 153; 679-80.

3. Lazovich D, Vogel RI, Berwick M et al. Indoor tanning and risk of melanoma. Cancer Epidemiol Biomarkers Prev 2010: 19; 1557-68.

4. Romano E, Schwartz GK, Chapman PB et al. Treatment implications of the emerging molecular classification system for melanoma. Lancet Oncol 2011: 12; 913-22.

5. Spatz A, Ruiter D, Hardmeier T et al. Melanoma in childhood: an EORTC-MCG multicenter study on the clinicopathological aspects. Int J Cancer 1996: 68; 317-24.

6. Marsden JR, Newton-Bishop JA, Burrows L et al. Revised UK guidelines for the management of cutaneous melanoma. Br J Dermatol 2010: 163; 238-56.

7. Green AC, Williams GM, Logan V et al. Reduced melanoma after regular sunscreen use. J Clin Oncol 2011; 29: 257-63.

8. Balch CM, Gershenwald JE, Soong SJ et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27: 6199-206.

9. Francken AB, Bastiaannet E, Hoekstra HJ. Follow-up in patients with primary cutaneous melanoma. Lancet Oncol 2005; 6: 608-21.

10. Slingluff CL, Vollmer RT, Seigler HF. Multiple primary melanoma: incidence and risk factors in 283 patients. Surgery 1993; 113: 330-9.

Contributed by Dr James Langtry, consultant dermatologist and dermatological surgeon, Royal Victoria Infirmary, Newcastle-upon-Tyne.

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