Melanoma

Melanoma arises from uncontrolled proliferation of melanocytes – the epidermal cells that produce pigment or melanin. Cutaneous melanoma refers to any skin lesion with malignant melanocytes present in the dermis and includes superficial spreading, nodular, acral lentiginous and lentigo maligna melanoma variants (see Figure 1). Melanoma in situ refers to malignant melanocytes that are contained within the epidermis and have not yet invaded the dermis but are at risk of progression to melanoma if left untreated. Lentigo maligna, a subtype of melanoma in situ in chronically sun‐damaged skin, denotes another form of proliferation of abnormal melanocytes. Melanoma in situ and lentigo maligna are both atypical intraepidermal melanocytic variants. All forms of melanoma in situ can progress to invasive melanoma if growth breaches the dermo‐epidermal junction during a vertical growth phase, although malignant transformation is both lower and slower for lentigo maligna than for melanoma in situ (Kasprzak 2015). Melanoma is one of the most dangerous forms of skin cancer, with the potential to metastasise to other parts of the body via the lymphatic system and blood stream. It accounts for only a small percentage of skin cancer cases but is responsible for up to 75% of skin cancer deaths (Boring 1994; Cancer Research UK 2017).

Figure 1

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Sample photographs of superficial spreading melanoma (left), BCC (centre), and cSCC (right). Copyright © 2012 Dr Rubeta Matin: reproduced with permission.

The incidence of melanoma rose to over 200,000 newly diagnosed cases worldwide in 2012 (Erdmann 2013; Ferlay 2015), with an estimated 55,000 deaths (Ferlay 2015). The highest incidence is observed in Australia, with 13,134 new cases of melanoma of the skin in 2014 (ACIM 2017), and in New Zealand with 2341 registered cases in 2010 (HPA and MelNet NZ 2014). In the USA, the predicted incidence in 2014 was 73,870, and the predicted number of deaths 9940 (Siegel 2015). The highest rates in Europe are in north‐western Europe and Scandinavia, with the highest incidence reported in Switzerland at 25.8 per 100,000 in 2012. Rates in England have tripled from 4.6 and 6.0 per 100,000 in men and women, respectively, in 1990, to 18.6 and 19.6 per 100,000 in 2012 (EUCAN 2012). Indeed, in the UK, melanoma has one of the fastest rising incidence rates of any cancer, with the biggest projected increase in incidence between 2007 and 2030 (Mistry 2011). In the decade leading up to 2013, age‐standardised incidence increased by 46%, with 14,500 new cases in 2013 and 2459 deaths in 2014 (Cancer Research UK 2017). Rates are higher in women than in men; however, the rate of incidence in men is increasing faster than in women (Arnold 2014). The rising incidence in melanoma is thought to be primarily related to an increase in recreational sun exposure and tanning bed use and an increasingly ageing population with higher lifetime recreational ultraviolet (UV) exposure, in conjunction with possible earlier detection (Belbasis 2016; Linos 2009). Belbasis 2016 provides a detailed review of putative risk factors, including eye and hair colour, skin type and density of freckles, history of melanoma, sunburn, and presence of particular lesion types.

A database in the USA of over 40,000 patients from 1998 onwards, which assisted in the development of the 8th American Joint Committee on Cancer (AJCC) Staging System, indicated a five‐year survival of 97% to 99% for stage I melanoma, which dropped to 32% to 93% in stage III disease depending on tumour thickness, the presence of ulceration and number of involved nodes (Gershenwald 2017). While these are substantial increases relative to survival in 1975 (Cho 2014), increasing incidence between 1975 and 2010 means that reported mortality rates have remained static. This observation, coupled with increasing incidence of localised disease, suggests that improvements in survival may be due to earlier detection and heightened vigilance (Cho 2014). New targeted therapies for advanced (stage IV), melanoma (e.g. BRAF inhibitors), have improved survival, and immunotherapies are evolving such that long‐term survival is being documented (Pasquali 2018; Rozeman 2017). No new data regarding the survival prospects for patients with stage IV disease were analysed for the AJCC 8 staging guidelines due to lack of contemporary data (Gershenwald 2017).

Basal cell carcinoma

BCC can arise from multiple stem cell populations, including from the follicular bulge and interfollicular epidermis (Grachtchouk 2011). BCC growth is usually localised, but it can infiltrate and damage surrounding tissue, sometimes causing considerable destruction and disfigurement, particularly when located on the face (Figure 1). The four main subtypes of BCC are superficial, nodular, morphoeic or infiltrative, and pigmented. BCCs typically present as slow‐growing, asymptomatic papules, plaques or nodules that may subsequently bleed or form ulcers that do not heal (Firnhaber 2012). People with a BCC often present to healthcare professionals with a non‐healing lesion rather than specific symptoms such as pain. Many lesions are diagnosed incidentally (Gordon 2013).

BCC most commonly occurs on sun‐exposed sites on the head and neck (McCormack 1997), and they are more common in men and in people over the age of 40. Different authors have attributed a rising incidence of BCC in younger people to increased recreational sun exposure (Bath‐Hextall 2007; Gordon 2013; Musah 2013). Other risk factors include Fitzpatrick skin phototypes I and II (Fitzpatrick 1975; Lear 1997; Maia 1995), a history of skin cancer, immunosuppression, arsenic exposure, and genetic predisposition such as in basal cell naevus (Gorlin) syndrome (Gorlin 2004; Zak‐Prelich 2004). Annual incidence is rising worldwide; Europe has experienced an average increase of 5.5% per year over the last four decades, and the USA of 2% per year, while estimates for the UK show that incidence appears to be increasing more steeply at a rate of an additional 6 per 100,000 persons per year (Lomas 2012). The rising incidence has been explained by an ageing population, changes in the distribution of known risk factors, particularly ultraviolet radiation, and improved detection due to the increased awareness amongst both practitioners and the general population (Verkouteren 2017). Hoorens 2016 points to evidence for a gradual increase in the size of BCCs over time, with delays in diagnosis ranging from 19 to 25 months.

According to National Institute for Health and Care Excellence (NICE) guidance (NICE 2010), low‐risk BCCs are nodular lesions occurring in patients older than 24 years old who are not immunosuppressed and do not have Gorlin syndrome. Furthermore, they should be located below the clavicle, should be small (diameter of less than 1 cm) with well‐defined margins, not recurrent following incomplete excision and not in awkward or highly visible locations (NICE 2010). Superficial BCCs are also typically low risk and may be amenable to medical treatments such as photodynamic therapy or topical chemotherapy (Kelleners‐Smeets 2017). Assigning BCCs a low or high risk influences the management options (Batra 2002; Randle 1996).

Advanced locally destructive or aggressive BCC can be found on 'high‐risk' anatomical areas such as the eyebrow, eyelid, nose, ear and temple (these are at higher risk of invisible spread and therefore are more at risk of being incompletely excised (Baxter 2012; Lear 2014)), and they can arise from long‐standing untreated lesions or from a recurrence of aggressive basal cell carcinoma after primary treatment (Lear 2012). Very rarely, BCC metastasises to regional and distant sites, resulting in death, especially cases of large neglected lesions in those who are immunosuppressed or those with Gorlin syndrome (McCusker 2014). Rates of metastasis are reported at 0.0028% to 0.55% (Lo 1991), with very poor survival rates. It is recognised that basosquamous carcinoma (more like a high‐risk SCC in behaviour and not considered a true BCC) is likely to have accounted for many cases of apparent metastases of BCC, hence the spuriously high reported incidence in some studies of up to 0.55%, which is not seen in clinical practice (Garcia 2009).

Squamous cell carcinoma of the skin

Primary cSCC arises from the keratinising cells of the epidermis or its appendages. People with cSCC often present with an ulcer or firm (indurated) papule, plaque or nodule (Griffin 2016), often with an adherent crust and poorly defined margins (Madan 2010). This type of carcinoma can arise in the absence of a precursor lesion or can develop from pre‐existing actinic keratosis or Bowen's disease (considered by some to be cSCC in situ); the estimated annual risk of progression being less than 1% to 20% for newly arising lesions (Alam 2001), and 5% for pre‐existing lesions (Kao 1986). It remains locally invasive for a variable length of time, but it has the potential to spread to the regional lymph nodes or via the bloodstream to distant sites, especially in immunosuppressed individuals (Lansbury 2010). High‐risk lesions are those arising on the lip or ear, recurrent cSCC, lesions arising on non‐exposed sites, scars or chronic ulcers, tumours more than 20 mm in diameter, depth of invasion greater than 4 mm and poor differentiation on pathological examination (Motley 2009). Perineural invasion of nerves at least 0.1 mm in diameter is a further documented risk factor for high‐risk cSCC (Carter 2013).

Chronic ultraviolet light exposure through recreation or occupation is strongly linked to cSCC occurrence (Alam 2001). It is particularly common in people with fair skin and in less common genetic disorders of pigmentation, such as albinism, xeroderma pigmentosum, and recessive dystrophic epidermolysis bullosa (RDEB) (Alam 2001). Other recognised risk factors include immunosuppression; chronic wounds; arsenic or radiation exposure; certain drug treatments, such as voriconazole and BRAF mutation inhibitors; and previous skin cancer history (Baldursson 1993; Chowdri 1996; Dabski 1986; Fasching 1989; Lister 1997; Maloney 1996; O'Gorman 2014). In solid organ transplant recipients, cSCC is the most common form of skin cancer; the risk of developing cSCC has been estimated at 65 to 253 times that of the general population (Hartevelt 1990; Jensen 1999; Lansbury 2010). Overall, local and metastatic recurrence of cSCC at five years is estimated at 8% and 5%, respectively. The five‐year survival rate of metastatic cSCC of the head and neck is around 60% (Moeckelmann 2018).

Treatment

For primary melanoma, the mainstay of definitive treatment is wide local surgical excision of the lesion, to remove both the tumour and any malignant cells that might have spread into the surrounding skin (Garbe 2016; Marsden 2010; NICE 2015a; SIGN 2017; Sladden 2009). Recommended lateral surgical margins vary according to tumour thickness, as described in Garbe 2016, and to stage of disease at presentation, as recommended in NICE 2015a.

Treatment options for BCC and cSCC include surgery, other destructive techniques such as cryotherapy or electrodessication, and topical chemotherapy. A Cochrane Review of 27 randomised controlled trials (RCTs) of interventions for BCC found very little good‐quality evidence for any of the interventions used (Bath‐Hextall 2007a). Complete surgical excision of primary BCC has a reported five‐year recurrence rate of less than 2% (Griffiths 2005; Walker 2006), leading to significantly fewer recurrences than treatment with radiotherapy (Bath‐Hextall 2007a). With apparently clear histopathological margins (serial vertical sections) following standard excision biopsy with 4 mm surgical peripheral margins, there is a reported recurrence rate of around 4% at five years (Drucker 2017). Mohs micrographic surgery, whereby surgeons microscopically examine horizontal sections of the tumour intraoperatively, undertaking re‐excision until the margins are tumour‐free, are options for high‐risk lesions on the face where standard wider excision margins might lead to incomplete excision or considerable functional impairment (Bath‐Hextall 2007a; Lansbury 2010; Motley 2009; Stratigos 2015). Bath‐Hextall 2007a found a single trial comparing Mohs micrographic surgery with a 3 mm surgical margin excision in BCC (Smeets 2004); the update of this study showed non‐significantly lower recurrence at 10 years with Mohs micrographic surgery (4.4% compared to 12.2% after surgical excision, P = 0.10) (van Loo 2014).

The main treatments for high‐risk BCC are standard surgical excision, Mohs micrographic surgery or radiotherapy. For low‐risk or superficial subtypes of BCC, or for small and or multiple BCCs at low‐risk sites (Marsden 2010), destructive techniques other than excisional surgery may be used (e.g. electrodessication and curettage or cryotherapy (Alam 2001; Bath‐Hextall 2007a)). Alternatively, non‐surgical (or non‐destructive) treatments may be considered (Bath‐Hextall 2007a; Drew 2017; Kim 2014), including topical chemotherapy imiquimod (Williams 2017), 5‐fluorouracil (5‐FU) (Arits 2013), ingenol mebutate (Nart 2015), and photodynamic therapy (PDT) (Roozeboom 2016). Non‐surgical treatments are most frequently used for superficial forms of BCC, with one head‐to‐head trial suggesting topical imiquimod is superior to PDT and 5‐FU (Jansen 2018). Although use of non‐surgical techniques is increasing, these do not allow histological confirmation of tumour clearance, and their use depends on accurate characterisation of the histological subtype and depth of tumour. The 2007 Cochrane Review of BCC interventions found limited evidence from very small RCTs for these approaches (Bath‐Hextall 2007a), which have only partially been addressed by subsequent studies (Bath‐Hextall 2014; Kim 2014; Roozeboom 2012). Most BCC trials have compared interventions within the same treatment class, and few have compared medical versus surgical treatments (Kim 2014).

Vismodegib, a first‐in‐class Hedgehog signalling pathway inhibitor, is now available for treating metastatic or locally advanced BCC based on the pivotal study ERIVANCE BCC (Sekulic 2012). It is licensed for use in patients where surgery or radiotherapy is inappropriate, e.g. for treating locally advanced periocular and orbital BCCs with orbital salvage of patients who otherwise would have required exenteration (Wong 2017). However, NICE has recently advised against the use of vismodegib based on cost‐effectiveness and uncertainty of evidence (NICE 2017).

A systematic review of interventions for primary cSCC found only one RCT eligible for inclusion (Lansbury 2010). Current practice therefore relies on evidence from observational studies, as reviewed in Lansbury 2013, for example. Surgical excision with predetermined margins is usually the first‐line treatment (Motley 2009; Stratigos 2015). Estimates of recurrence after Mohs micrographic surgery, surgical excision, or radiotherapy, which are likely to have been evaluated in higher‐risk populations, have shown pooled recurrence rates of 3%, 5.4% and 6.4%, respectively, with overlapping confidence intervals; the review authors advise caution when comparing results across treatments (Lansbury 2013).

Prior test(s)

The diagnosis of skin cancer is based on history‐taking and clinical examination. In the UK, this is typically undertaken at two decision points – first in the GP surgery where a decision is made to refer or not to refer, and then a second time where a dermatologist or other secondary care clinician makes a decision whether or not to biopsy or excise. Visual inspection of the skin is on an iterative basis, using both implicit pattern recognition (non‐analytical reasoning) and more explicit 'rules' based on conscious analytical reasoning (Norman 2009), the balance of which will vary according to experience and familiarity with the diagnostic question. Various attempts have been made to formalise the 'mental rules' involved in analytical pattern recognition for melanoma (Friedman 1985; Grob 1998; MacKie 1985; MacKie 1990; Sober 1979; Thomas 1998); however, visual inspection for keratinocyte skin cancers relies primarily on pattern recognition. Accuracy has been shown to vary according to the expertise of the clinician. Some authors have reported that primary care physicians miss over half of BCC (Offidani 2002), and they misdiagnose a third (Gerbert 2000). In contrast, an Australian study found that trained dermatologists were able to detect 98% of BCC, but with a specificity of only 45% (Green 1988).

A range of technologies have emerged to aid diagnosis to reduce the number of diagnostic biopsies or inappropriate surgical procedures. Dermoscopy using a handheld microscope has become the most widely used tool for clinicians to improve diagnostic accuracy of pigmented lesions, in particular for melanoma (Argenziano 1998; Argenziano 2012; Haenssle 2010; Kittler 2002), although it is less well established for the diagnosis of BCC or cSCC. Three reviews in this series have evaluated the diagnostic and comparative accuracy of visual inspection and dermoscopy (Dinnes 2018a; Dinnes 2018b, Dinnes 2018c).

Role of index test(s)

Used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, in pigmented lesions, HFUS may have a potential role in patient management as an additional test to identify lesions requiring excision. The status of current medical practice and patient benefit for melanoma is particularly suited to improvement by any cost‐effective diagnostic imaging method that might be developed, since early diagnosis that leads to complete excision of primary melanoma before metastatic spread almost always results in a cure. The probability of metastases increases dramatically with increasing depth of tumour invasion of the primary melanoma (known as the Breslow thickness). This is assessed by histological examination after excision but has the potential to be assessed by imaging in vivo. One of the postulated advantages of HFUS is its ability to rule out melanoma as a potential differential diagnosis, for example by identifying pigmented seborrhoeic keratosis (a benign skin lesion).

Although the primary aim in diagnosing potentially life‐threatening conditions such as melanoma is to minimise false negative diagnoses (to avoid delay to diagnosis and even death), a test that can reduce false positive clinical diagnoses without missing true cases of disease has clear patient and resource benefits. False‐positive diagnoses not only cause unnecessary scarring from a biopsy or excision procedure, but they also increase patient anxiety whilst they await the definitive histological results and increase healthcare costs as the number needed to remove to yield one melanoma diagnosis increases. Pigmented lesions are common, so the resource implication for even a small increase in the threshold to excise lesions in populations where melanoma rates are increasing, will avoid a considerable healthcare burden to both patient and healthcare provider, as long as lesions that are not excised turn out to be harmless.

Delay in diagnosis of a BCC as a result of a false‐negative test is not as serious as for melanoma because BCCs are usually slow‐growing and very unlikely to metastasise. However, delayed diagnosis can result in larger and more complex surgical procedures with consequently greater morbidity. Very sensitive diagnostic tests for BCC, on the other hand, may compromise on lower specificity leading to a higher false‐positive rate and an enormous burden of skin surgery, so a balance between sensitivity and specificity is necessary. As with melanoma, the consequences of falsely reassuring a person with cSCC that they do not have skin cancer can be serious and potentially fatal. Thus, a good diagnostic test for cSCC should demonstrate high sensitivity and a corresponding high negative predictive value. A test that can reduce false positive clinical diagnoses without missing true cases of disease has patient and resource benefits. False‐positive clinical diagnoses not only cause unnecessary morbidity from the biopsy but could lead to initiation of inappropriate therapies and also increase patient anxiety.

Studies have also evaluated HFUS as a method for non‐invasive measurement of melanoma thickness in vivo so that melanomas can be excised with the appropriate margin in a single surgical procedure as opposed to two separate procedures (Jasaitiene 2011; Machet 2009; Meyer 2014). In addition to its optical B‐mode imaging cousin, Wang 2013 evaluated optical coherence tomography, while Crisan 2013 studied its role in appropriate treatment planning for BCC. There is potential for refining surgical procedures, as well as increasing the use and efficacy of non‐surgical methods of treating BCC, if non‐invasive imaging can be developed that allows confirmation of tumour clearance. However, this review does not consider any of these uses.

Alternative test(s)

Doppler ultrasound, unlike B‐mode ultrasound, measures moving structures such as blood cells, as opposed to stationary tissues (Kleinerman 2012), and it shows the relative speed of blood flow as well as relative vessel size and density. In skin cancer, it can be used in combination with B‐mode HFUS and may have value for staging or assessing the aggressiveness of malignancy due to increased vascular proliferation. Doppler ultrasound may be useful in preoperative staging due to correlation between the extent of vascularisation and blood flow with Breslow thickness. As a stand‐alone technique, Doppler ultrasound is not useful to differentiate skin cancers from benign lesions (Kleinerman 2012), so we do not include it as an index test; however, its use in combination with high‐frequency ultrasound may be able to improve lesion discrimination.

Cochrane DTA Reviews have assessed a number of other tests that may have a role in the diagnosis of skin cancer as part of this series, for example, visual inspection and dermoscopy (Dinnes 2018a; Dinnes 2018b; Dinnes 2018c); reflectance confocal microscopy (RCM) (Dinnes 2018d; Dinnes 2018e); optical coherence tomography (OCT) (Ferrante di Ruffano 2018a); and computer‐assisted diagnosis (CAD) techniques applied to various types of images, including those generated by dermoscopy, diffuse reflectance spectrophotometry (DRS) and electrical impedance spectroscopy (EIS) (Ferrante di Ruffano 2018b).

RCM and OCT are two alternative ways to achieve depth‐resolved optical reflectance imaging. To attain axial resolution, RCM uses a very low numerical aperture with out‐of‐focus data suppression, while OCT uses interferometry to isolate optical reflections at a defined echo time (conceptually similar to HFUS). They are emerging as non‐invasive adjuncts to dermoscopy in a specialist setting, and RCM can potentially serve as an alternative to dermoscopy for skin cancer diagnosis (Edwards 2016).

RCM and OCT differ from each other in that RCM tends to use a shorter wavelength (830 nm as opposed to 1305 nm for OCT) and has considerably less penetration (RCM < 300 µm; OCT < 2 mm), poorer depth of focus (RCM 3 µm to 5 µm; OCT 1 mm), and a more limited basic field of view (RCM basic 500 µm × 500 µm in the horizontal plane; OCT basic 6 mm × 6 mm) than OCT, but it has better lateral resolution (RCM 1 µm, cellular; OCT 7.5 µm, near cellular). They have similar axial resolution, however (RCM 3 µm to 5 µm; OCT 5 µm), and both have fields of view that are extendible by mechanical scanning and image mosaicking, although for equivalent fields of view 3D imaging is much faster with OCT (RCM for mosaicked field of view and stack > 10 min; OCT 6 cross‐sectional frames per second, < 2 min for 6 mm × 6 mm × 2 mm volume). With RCM, the contrast for the monochrome images produced is achieved by the variation of the optical scattering properties within the skin when illuminated by a near‐infrared light. At a wavelength of 830 nm, the greatest contrast is achieved from melanin, so that RCM is recommended as particularly useful for assessing pigmented lesions (Dinnes 2018d). Similar to Doppler ultrasound but with higher resolution, vascular flow information can be extracted from OCT images, allowing the visualisation of neovascularisation, potentially enabling earlier diagnosis of melanoma (Kokolakis 2012; Themstrup 2015).

CAD or artificial intelligence‐based techniques use predefined algorithms to process and manipulate acquired data to identify the features that discriminate malignant from benign lesions. The use of CAD‐based techniques has potential for both reducing the subjectivity of, and de‐skilling, the diagnosis of skin lesions. Although such techniques have most commonly been applied to digital dermoscopy images (Esteva 2017; Rajpara 2009), they may be applied to several types of images or spectra (e.g. Wallace 2000).

For example, SIAscopy and MelaFind are based on diffuse reflectance spectrophotometry. DRS also uses optical reflectance, albeit not depth‐resolved, but it distinguishes between lesion types based on the lesion‐average spectral shape and calibrated level of reflected light for wavelengths continuously varying from the ultraviolet (320 nm) to the near infrared (1100 nm) with a high spectral resolution (4 nm) (e.g. Marchesini 1992; Wallace 2000a). The extension to imaging spectrophotometry (DRSi) to allow spatial (dermoscopic) as well as spectral information to contribute to the diagnosis, as described in Haddock 2003, has resulted in the development of handheld DRSi units (Bish 2014). Researchers have studied two such units with limited spectral capability in both primary and secondary care settings: Moncrieff 2002 and Walter 2012 have evaluated SIAscopy, while Hauschild 2014, Monheit 2011 and Wells 2012 have assessed MelaFind. It is also possible to combine DRSi with HFUS (Bamber 2007). Such approaches remain under development.

The Nevisense system is based on electrical impedance spectroscopy (EIS). EIS measures a combination of resistance and capacitance of the tissue as a function of frequency of an alternating applied voltage. At high frequencies, conduction occurs easily through all tissue components, including cells, but at low frequencies current tends to flow only through the extracellular space. The spectral shape is thus sensitive to cellular components and dimensions, internal structure and cellular arrangements. The Nevisense EIS system measures at multiple depths and at 35 frequencies logarithmically distributed from 1.0 kHz to 2.5 MHz using a 5 mm × 5 mm area electrode covered in tiny pins that penetrate into the stratum corneum. Braun 2017 and Malvehy 2014 have evaluated it, finding high sensitivity but low specificity for melanoma. Although there is concern over a possible increase in needless excision of benign atypical melanocytic lesions (Ceder 2016), this concern is counterpoised against an indication of promise for reducing the need for short‐term sequential digital dermoscopy (Rocha 2017).

DRS and EIS have not been the subject of individual test reviews due to an anticipated lack of data; however, where available, we have included CAD‐based uses of these techniques in our review of CAD for the detection of skin cancer (Ferrante di Ruffano 2018b).

Evidence permitting, we will compare the accuracy of available tests in an overview of reviews, exploiting within‐study comparisons of tests and allowing the analysis and comparison of commonly used diagnostic strategies where tests may be used alone or in combination.