As clinicians, awareness of malignant wounds and their management is important to ensure that patients are treated in a timely fashion. Malignant ulcers are fortunately uncommon, accounting for 2-4% of lower limb wounds, but they often present in insidious ways, with features overlapping with other pathologies (eg venous changes) that can potentially delay diagnosis (Lautenschlager and Eichmann, 1999). That said, over the past 30 years skin cancer incidence rates have risen dramatically in England, with a projected cost to the NHS in 2020 likely to be in the region of £180 million (Vallejo-Torres et al, 2014).
A high index of suspicion for wounds that ‘just don't seem right’ or fail to heal in a typical fashion with standard treatments should raise suspicion for malignancy. A correct, early diagnosis is essential to avoid inappropriate investigations or treatment.
When faced with a clinical conundrum, it is always useful to take a back-to-basics approach. Revisiting the history of a chronic wound can identify important information that may have been overlooked in differentiating its aetiology. A thorough history may, for example, elicit a history of deep venous thrombosis (eg following surgery or pregnancy) or venous symptoms (aching, throbbing and swelling of the leg(s), that is particularly worse at the end of the day or exacerbated by prolonged periods of standing/dependency and relieved by elevation). There may be a history of intermittent claudication (muscle discomfort, fatigue, aching or cramping most commonly localised to the calf, but which may also affect the thigh or buttocks, that is reproducible by exercise and relieved by rest within 10 minutes (Norgren et al, 2007)), suggestive of arterial insufficiency as the underlying problem.
For malignant ulcers, a thorough history of causative risk factors is essential, and should include whether there is a history of ultraviolet (UV) sunlight exposure, use of tanning beds or a positive family history of skin cancers (Sham et al, 2016). Given the overlap of clinical presentations and features, a thorough understanding of malignant tumours is necessary to ensure prompt recognition and improve patient outcomes.
Clinical features of malignant wounds
The wide variation in malignant ulcers adds to the complexity of establishing a clinical diagnosis. As such, a methodological approach to skin ulcers can provide clues suggestive of a malignant wound.
As a minimum, ulcer examination should include the basics, for example the location, size and shape of the wound, colour of the base, shape of the border, depth of the ulcer and composition of the discharge (Lautenschlager and Eichmann, 1999). The ‘BBEDDS’ framework for examining an ulcer can provide structure to a basic, stepwise approach (Box 1).
On examination, the following characteristics should raise suspicion of malignant ulcers:
Atypical location
Ulcers of non-malignant aetiology, namely venous stasis, arterial or neuropathic ulcers, are well-described and familiarity with common anatomical sites of development of these wounds is paramount to identifying irregularities. Venous ulcers are commonly found in the gaiter region of the lower leg (malleoli to the mid-calf); ischaemic or neuropathic ulcers typically occur over bony prominences that experience pressure (Figure 1); while ulcers on the calf are not commonly associated with vascular pathology and should raise suspicion for vasculitic, infective or malignant aetiology (Hayes and Dodds, 2003; Spentzouris and Labropoulos, 2009). Chronic venous stasis ulcers in the gaiter region that are refractory to standard treatments, however, should undergo evaluation for malignancy, due to their potential for malignant transformation (Labropoulos et al, 2007).
Atypical appearance
Further to its location, the appearance of an ulcer provides invaluable clinical clues to its aetiology. Long-standing ulcers with features of excessive granulation tissue in the ulcer base with, or without, extension beyond the ulcer margins, raised or rolled wound edges and changes in shape or size are atypical and suggestive of malignancy (Hayes and Dodds, 2003; Isoherranen et al, 2019).
Other, less specific, clues for malignant ulcers include irregular wound borders, malodour, increasing pain severity and associated bleeding (Isoherranen et al, 2019). Despite the overlap in signs and symptoms with other aetiologies, one cardinal feature of malignant wounds is their poor tendency to heal despite standard treatment such as compression therapy for venous stasis ulcers (Lautenschlager and Eichmann, 1999). Consequently, interval examination is highly recommended, with a delay in wound healing or changes in ulcer morphology alerting the clinician to the possibility of a malignant wound.
Primary skin tumours
Malignant ulcers can be subclassified as primary or secondary skin tumours.
Basal cell carcinoma
BCC is the most common type of skin cancer, accounting for about 75% of all NMSC (Chintamani and Tandon, 2016). About 8% of BCC arise in the lower extremity (Labropoulos et al, 2007). These tumours are slow growing, locally destructive, painless and arise from a subset of basal cells within the epidermis. Their typical clinical course involves superficial dome-shaped nodules that progress to central areas of ulceration (Figure 2). Despite the low rate of metastasis, BCCs can invade local tissue, causing destruction. Fair skin and red hair (Fitzpatrick skin type 1 or 2), exposure to ionising radiation, immunosuppression and genetic predisposition are all important associated risk factors.
Squamous cell carcinoma
SCC of the lower extremity has a spectrum of presentations and is the second most common skin cancer after BCC, with an increasing incidence (Alam et al, 2018). This rise is thought to be due to an increase in cumulative exposure to UV light, which is the greatest environmental risk factor for development (Xiang et al, 2014). This relationship is evident by SCCs of the lower limb being more prevalent in women than men, with higher rates over the anterior surface of the leg, and is likely to be due to lifestyle and clothing choices (Kim et al, 2014). Other risk factors for SCC are similar to those for BCC.
SCCs are characterised by indurated, nodular, keratinising or crusted tumours that ulcerate or ulcers without keratinisation (Motley et al, 2020) (Figure 3). Among the African American population SCC is the most common type of skin cancer (Labropoulos et al, 2007), classically affecting non-chronically sun exposed areas. SCCs can grow rapidly, with a higher incidence of metastasis compared with BCC.
Malignant melanoma
Malignant melanomas (MMs) are cancerous tumours arising from the melanocytes (pigment-producing cells) of the skin (Figure 4). They comprise a small proportion of cutaneous tumours, yet are the most lethal, accounting for the majority of skin cancer deaths. Lower-extremity MMs are more common in women (Ganguly and Sarkar, 2016).
Secondary skin tumours
Marjolin's ulcers
In the 19th century, French surgeon Jean Nicolas Marjolin described the phenomenon of chronic ulcers undergoing malignant transformation, hence their collective name. Marjolin's ulcers describe rare, malignant cancers originating from chronic non-healing wounds.
The malignant transformation is most commonly associated with burn wounds, however other non-healing ulcers, such as pressure sores, venous stasis ulcers, traumatic wounds and osteomyelitis, have been reported to undergo malignant transformation. Marjolin's ulcers develop slowly, with an average latency period of 25 years.
Most commonly, Marjolin's ulcers are histopathologically SCCs followed by BCC. They tend to be more aggressive with higher rates of metastases and mortality, highlighting the importance of periodic surveillance for chronic non-healing wounds (Pavlovic et al, 2011).
Diagnosis
Wounds that generate a high index of suspicion should undergo biopsy for histological analysis. Although an objectively defined ‘observation period’ for chronic wounds before referral for biopsy does not exist, much of the literature suggests a period of 12-17 weeks (Hayes and Dodds, 2003; Labropoulos et al, 2007).
Biopsies can either be in the form of a punch biopsy (3-4 mm), shave biopsy or deep wedge-shaped incisional biopsy. A minimum of two biopsies, taken from different areas of the wound, ideally the wound edge and wound bed, should be performed. Overall, biopsies are safe procedures, commonly performed under local anaesthesia with good wound healing.
With regards to BCCs and SCCs, a ‘single-best-biopsy’ technique has not been published in the literature and choice of biopsy therefore remains dependent on factors such as clinical characteristics, suspected malignancy, tumour morphology and patient-specific factors (eg patient preference and bleeding diathesis) (Alam et al, 2018). Contrastingly, the recommended biopsy modality for a suspected MM is an excisional biopsy with inclusion of the whole tumour and an additional 2 mm margin of normal epithelium. Shave biopsies are not recommended for MM and may lead to misdiagnosis (Marsden et al, 2010). On certain occasions punch biopsies are acceptable, such as in cases of suspected lentigo maligna melanoma on the face.
If an ulcer continues to raise suspicion despite previous negative biopsies, repeated interval biopsies may be required to ensure that a malignant diagnosis is not missed (Isoherranen et al, 2019).
Treatment
Over the years, a wide array of non-surgical treatment modalities have entered clinical practice to treat malignant wounds, however surgical excision remains the mainstay for high-risk lesions (Telfer et al, 2008).
Surgical treatment includes standard excision, histologically controlled excision, known as Mohs micrographic surgery (MMS), and curettage and electrodessication (C&E). Standard surgical excision with 4-5 mm margins of normal skin to the depth of the mid-subcutaneous adipose tissue and follow-up histological assessment is a good treatment for primary BCC, and is associated with 95% clearance rates (Bichakjian et al, 2018). Slightly wider margins (4–6 mm) are recommended with standard excision for low-risk primary SCCs (Alam et al, 2018).
MMS, a technique pioneered by Dr Frederic Mohs in the 1940s, was developed on the principles of maximal tissue conservation with complete tumour excision through the use of real-time micrographic analysis. MMS is the recommended modality for high-risk BCC and SCCs, with superior curative rates over traditional excisions. However, MMS is superseded by wide excisions, with or without flap reconstruction, in the lower limbs, due to the ease of access and typically concomitant presence of chronic inflammation limiting microscopic analysis (Sham et al, 2016).
C&E is an effective, easily performed treatment modality that has long been employed for the treatment of low-risk BCCs and SCCs, however, results are highly operator and location dependent (Bichakjian et al, 2018).
Non-surgical therapy remains second line to surgical treatment of BCCs and SCCs. If surgical therapy is not feasible for BCCs, non-surgical methods for their treatment include cryotherapy, topical therapy (eg imiquimod), photodynamic therapy or radiation therapy (Telfer et al, 2008). Topical and photodynamic therapies are not recommended for the treatment of SCCs, largely due to lack of available data (Alam et al, 2018).
Radiotherapy can be considered for some tumour entities or as a palliative therapy, however consideration of the associated poor wound healing and pain when employed for treatment of lower limb malignant wounds must be given, particularly in patients with peripheral vascular disease (Alam et al, 2018; Bachakjian et al 2018).
Referral and follow-up
On encountering a suspected SCC or MM, appropriate referral should be promptly initiated using locally endorsed suspected cancer referral pathways. These ensure patients are seen within the current national target for cancer referrals (within 2 weeks) by a specialist (typically a dermatologist). This is due to their rapidly progressive nature and high risk of metastases (National Institute for Health and Care Excellence (NICE), 2015).
Routine referral is appropriate for patients with suspicion of low-risk BCC, with suspected cancer pathway referrals to the local skin cancer multidisciplinary team reserved for patients with BCC raising suspicion of squamoproliferative processes (NICE, 2010).
The ABCD rule (Box 3) or the 7-point checklist (Box 4) can aid the early identification and referral of suspicious lesions. A score of 3 or more on the 7-point checklist indicates a need for urgent referral under the 2-week rule to local skin cancer services, typically a dermatologist. Lesions suspicious for melanoma should not be removed in the primary care setting (Marsden et al, 2010).
Follow-up is paramount for the effective treatment of lower limb malignant ulcers, to ensure early detection of tumour recurrence or metastases. Some 75% of recurrent SCCs occur within the first 2 years of diagnosis. Therefore, current practices recommend biannual follow-up for low-risk SCCs and more frequent, quarterly, follow-up of high-risk SCCs for the first 2 years (Isoherranen et al, 2019), with consideration of imaging for metastases on clinical suspicion.
Conclusion
In summary, malignant wounds are uncommon yet complex disease processes due to their overlap in aetiology and presentations. Observer familiarity with common lower limb ulcers is crucial for the early detection and prompt referral of malignant wounds, ultimately reducing their associated morbidity and mortality.