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The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on epidemiology, screening & testing, classification, signs & symptoms, diagnosis, staging, treatment and follow-up of non-melanoma skin cancers is provided.By the end of the tutorial, the following objectives should be addressed:
Non-melanoma skin cancer is the most common type of cancer in the world. The two most common types of non-melanoma skin cancers are basal cell carcinoma (~80%) and cutaneous squamous cell carcinoma (~20%) [1,2].
It is difficult to know the true incidence of non-melanoma skin cancers as very few cancer registries worldwide maintain statistics on these cancers [1,2]. According to the Canadian Cancer agency, it was estimated that there would be 76,100 new cases of non-melanoma skin cancer in Canada in 2014, with 440 deaths [3]. Despite the low rate of mortality from these cancers, they demand treatment. Australian statistics indicate that the incidence of treated non-melanoma skin cancers is more than 5 times the incidence of all other skin cancers combined [4].
Epidemiologic studies have revealed patterns common to both basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Both BCC and cSCC have higher rates of incidence in populations located closer to the equator. Incidence also increases exponentially with age, although cases of BCC before age 40 are becoming more frequent. Additionally, both BCC and cSCC are significantly more frequent in light skinned populations than darker skinned individuals [1,2,4,5,6].
By far the biggest risk factor for both BCC and cSCC is UV light exposure [1,2,7,8]. UV light is divided by wavelength into three subtypes: UVA (320-400nm), UVB (290-320nm) and UVC (200-290nm). It is estimated that 95% of UV rays that reach the earth are UVA, with the vast majority remaining being UVB rays. UVC rays do not reach the earth’s surface in appreciable amounts, as they cannot pass through the ozone layer [7].
The depth of UV light penetration through the skin is proportional to its wavelength. It is estimated that 20-30% of UVA rays penetrate to the deep dermis. Conversely, only 10% of UVB rays penetrate to the superficial dermis (see image) [7].
UVB is absorbed directly by DNA, ultimately leading to mutations that result in cancer such as those in the tumor suppressor gene p53. There is increasing evidence that UVA also contributes to carcinogenesis. It is hypothesized that UVA indirectly alters DNA through the creation of reactive oxygen species [7,8].
Although UV light exposure is a major risk factor for development of both BCC and cSCC, there is a difference in the type of exposure that increases risk. BCC is associated with intermittent sun exposure, history of sun burns and excessive childhood sun exposure, whereas cSCC is associated with chronic sun exposure throughout life [5,6,7, 9].
People who produce less melanin are at higher risk for damage from UV radiation and as a result are at higher risk for NMSC. Differences in melanin production are due to differences in the melanocortin-1 receptor [10]. People with fair or light coloured skin, blond or red hair and blue, green or grey eyes are at an elevated risk for skin cancers. People with a complete lack of melanin as is seen in albinism are at further increased risk of skin cancers.
Those who have previously been diagnosed with skin cancer are at increased risk of developing NMSC again. A family history of NMSC also increases risk, even beyond lifestyle similarities and effects of pigmentation within families.
PUVA is a treatment for skin conditions such as psoriasis which involves application of psoralen which makes the skin more sensitive to UV radiation followed by exposure to UVA [9]. Long term PUVA treatment results in increased risk for cSCC.
Chronic arsenic exposure has been shown to lead to both cSCC and BCC [1,2]. Arsenic exposure can be as a result of occupational exposure or environmental exposure, such as drinking contaminated water or eating contaminated food. Evidence suggests that BCC occurs 30-40 years after exposure [2]. Working with certain products such as coal, shale, paraffin, chimney soot, tar and pitch can also increase the risk of developing NMSC [9].
Studies have demonstrated that ionizing radiation also increases the incidence of both BCC and cSCC, with a higher risk of BCC development [1,2]. Ionizing radiation is used for a variety of therapeutic purposes, including the treatment of acne in the past and cancer. The risk of developing a NMSC increases with increasing dose of radiation and when it is delivered over sun exposed areas of skin [4].
Chronic immunosuppression is another risk factor for non-melanoma skin cancer, particularly cSCC [1,2]. Studies from Europe indicated that patients who received heart and kidney transplants were 65-250 times more likely to develop a cSCC than the general population [1,2,4]. The pathogenesis of this risk is complex and likely relates to the inability of the skin to repair the damage caused by UV rays [4]. Approximately 1% of skin cancers occur in chronically inflamed skin, with the vast majority of these being cSCCs [1].
Other potential risk factors for NMSC include HPV infection (particularly for cSCC in the anal and genital regions), taking photosensitizing drugs, and having many freckles or moles. There is increasing evidence that lifestyle factors may play a role in the pathogenesis of NMSCs. It is known that smoking leads to an increased risk of cSCC and it may be contributory to BCC development as well. The potential risks and/or benefits of other dietary and social factors are also currently being investigated [1,2,4].
In addition to environmental risk factors, there are genetic disorders and polymorphisms that increase susceptibility to non-melanoma skin cancers [1,2,4].
Xeroderma pigmentosa (XP) is an autosomal recessive disorder that leads to an increased risk of both cSCC and BCC. The genetic defect associated with XP manifests as a defective DNA repair mechanism to UV radiation leading to increased sun sensitivity [4]. It is estimated that the rate of skin cancers in this population before age 20 is 2000 times the rate of skin cancer in the rest of the population [4].
Epidermolysis bullosa is a group of syndromes that are characterized by blister formation in response to minimal injury. Certain subtypes of this condition increase risk for both BCC and cSCC. The cSCCs that arise in patients with these syndromes are extremely aggressive, with an 80% mortality rate [1].
Basal cell nevus (Gorlin’s) syndrome is an autosomal dominant disorder that arises due to mutations of the human patched gene. It is characterized by developmental anomalies and multiple BCC’s developing at a young age (between age 2 to 35). There are other characteristic clinical features associated with this syndrome [1,2,4].
Other genes have been implicated in the pathogenesis of cSCC and BCC. These include the p53 tumor suppressor gene, and polymorphisms in the glutathione-S-peroxidase enzymes. The role of these genes is the subject of much current research [1,2,4].
The basic principles of UV protection are [8]:
Sunscreen impedes UV radiation from penetrating through the skin’s layers. The use of sunscreen has been proven to decrease the risk of actinic keratoses (the precursor lesion for cSCC) and cSCC. The evidence is inconclusive as to the impact of sunscreen on BCCs [8].
A handout for patients on the proper use of sunscreen can be found by clicking here [8].
There is evidence that certain dietary factors may play a role in preventing non-melanoma skin cancers, including: low dietary fat intake and high antioxidant intake. However, these results have not yet been supported by large studies and thus cannot be used to inform dietary choices [4]. Avoiding exposure to the above mentioned carcinogens that increase risk of skin cancer is also recommended to reduce risk.
To date, Canada has not set out screening guidelines for non-melanoma skin cancer in the general population. Australian practice guidelines suggest that skin cancer screening should be a routine part of the annual check-up. Early detection of non-melanoma skin cancers can reduce morbidity and mortality as well as the costs associated with treatment [1].
The most important part of the clinical assessment for skin cancer is the physical examination.
A suggested approach for a full body skin examination is as follows [2]:
i) With the patient sitting on the examination table:
ii) With the patient lying on his or her back:
iii) With the patient either lying on his or her abdomen or standing:
It is important to ensure complete visualization of any lesion in order to give a thorough description. Every skin lesion should be described noting the following features: location, type, colour, shape, arrangement, distribution, consistency and feel. The two most useful characteristics in terms of forming a differential diagnosis are the type and distribution of lesions. Palpation of the lesion can reveal scale and tenderness. Stretching the skin around the lesion can help expose distinguishing features [3].
Patients may also participate in monitoring their own skin through self-examinations. A useful tool for conducting a self-skin examination is a body map. Patients mark all of their skin lesions on a drawing of a human body. Each time that they examine themselves they mark down new spots and monitor for changes to previously existing spots. There are a number of websites that offer information for patients on how to conduct a proper skin examination [2]:
BCCs are cancers that arise from the non-keratinizing cells of the basal layer of the epidermis. There are three major subtypes of BCC: nodular (~60%), superficial (~30%) and morpheaform/sclerosing (~5-10%) [1]. These subtypes can usually be distinguished from one another based on their appearance (see Signs and Symptoms module).
Pathologic evaluation confirms the diagnosis and subtype of BCC. BCCs appear histologically as nests of basaloid cells with hyperchromatic nuclei and scanty cytoplasm within the dermis. Most BCCs have peripheral nuclear palisading. Pigmented BCCs contain melanin [1].
cSCCs are cancers of the keratinocyte, which is the major cell type of the epidermis [2]. cSCC’s can arise spontaneously, however at least 60% of them arise from actinic keratoses (AK). It should be noted, however, that <1% of AKs become cSCCs [3]. cSCC’s can be subdivided into cutaneous squamous cell carcinomas in situ (bowen’s disease) and invasive squamous cell carcinomas [2].
These lesions do have characteristic clinical features (see Signs and Symptoms section), however they can only be definitively distinguished histologically. All three of these lesions show nuclear atypia of the keratinocyte [2]. Additionally all may show hyperkeratosis, which produces the rough scales seen clinically. Actinic keratoses and cSCC in situ are distinct from invasive cSCC in that only invasive cSCC penetrates from the epidermis into the dermis [2,3].
Non-melanoma skin cancers vary in their appearances and presentations. Clinical examination plays a key role in determining management of skin lesions, thus it is essential to be able to recognize and distinguish between benign skin lesions and non-melanoma skin cancers. It is beyond the scope of this module to describe the features of benign skin lesions; however, students should familiarize themselves with these.
Basal cell carcinomas can be divided into 3 subtypes: nodular, superficial and morpheaform [1]. Any of these subtypes can present in a pigmented form. In this case they must be distinguished from malignant melanoma [2]. The common presentation of each of these subtypes will be described below.
cSCC has a spectrum of disease. 60% of invasive SCCs originate from actinic keratoses [5]. Bowen’s disease is cSCC in situ, where the disease has not penetrated into the dermis through the basement membrane. Invasive cSCC involves both the epidermis and dermis [2,3,6,7]. The spectrum of cSCC can often be distinguished clinically. The characteristic clinical features are described below:
The first step in establishing a diagnosis of skin cancer is to gather a history. Below is a suggested approach to gathering a comprehensive history for a suspected skin cancer [1,2,3]:
Prescription, over the counter, supplements
Previous cutaneous reactions
The most important part of the clinical assessment for skin cancer is the physical examination. Students should review the approach outlined in the screening module.
It is important to note that cSCCs metastasize in 1-5% of cases [2,4]. The most common locations for metastasis are to the local lymph nodes. As such, the regional lymph nodes should be examined any time that a lesion is suspicion for cSCC [4,5].
A full body skin examination should be performed anytime an examination of a single skin lesion is done. This aids not only in characterizing the distribution of lesions, but it provides the opportunity to screen for other skin lesions [4].
A biopsy is needed in order to definitively establish the diagnosis of BCC or cSCC. All of the following techniques may be used [6]:
The choice of which biopsy technique to use is dependent on the clinical situation and the judgment of the treating physician [4,6]. Consideration should be given to choosing a technique that will provide the maximal information regarding the skin cancer and its prognosis, and insight into the optimal treatment modality. For instance, an excisional biopsy may be preferable with small lesions where the clinician suspects that excision may be curative. For lesions that are suspected to be malignant it is preferable to use either an excisional or punch biopsy in order to determine the depth of the lesion [4].
In the case of a suspected BCC a shave biopsy that includes the full depth of the lesion is preferred as it results in a good cosmetic result and accurate diagnosis [4]. If it is a characteristic BCC and there are no cosmetic concerns about removal of the lesion excisional biopsy is also appropriate. Punch biopsies are a less favourable option as there is evidence of significant misdiagnosis, particularly in the case of mixed aggressive tumours.
There are no laboratory tests that play a role in the diagnosis of non-melanoma skin cancers [2,3,5].
Imaging is seldom used in the diagnosis of non-melanoma skin cancers. Ultrasound may be used in the assessment of regional lymph nodes. In rare cases when the lesions are large and it is difficult to determine the lesion’s depth an ultrasound, CT or MRI can be ordered [4,5]. Imaging may also be used to determine the stage of disease (see Staging).
The current standard for staging non-melanoma skin cancers is the TNM classification system. This classification is only applicable to malignant disease and cannot be applied to precursor lesions. The American Joint Committee on Cancer (AJCC) staging system lacks prognostic accuracy for NMSCs and as a result the use of high risk features is often preferred. There have also been efforts to develop alternative staging systems with better prognostic value. The 8th edition staging system was published in 2017 and was designed for use only with NMSC of the head and neck [8]. The 2017 AJCC guidelines are as follows [8]:
ENE = extranodal extension
In the aforementioned TNM system, imaging is necessary to establish the “N” and “M” stages. However, imaging is not performed on the majority of patients with BCCs or cSCCs because only 1-5% of cSCCs and <0.1% of BCCs metastasize [2,3]. That being said, it is important to note that despite the low rate of mortality incurred by these cancers, there can be significant morbidity. BCCs can be extremely locally destructive to tissues and bones despite being low grade [4].
There is no definitive consensus as to how to determine which patients should be imaged. Experts agree that the TNM system is inadequate, as the vast majority of patients have T1 or T2 N0M0 disease and they do not all have the same prognosis [2,5,6]. As such, most guidelines suggest that tumours should be classified as either “high risk” or “low risk” according to their potential for metastasis [2,5,6]. These defining features are not standardized, however, the high-risk features typically increase the 5-year recurrence rate and/or metastatic rate over 15% [3].
The Brigham and Women’s Hospital Tumour Staging system has been designed to improve prognostic value in assessment of tumours [12]. In this staging system tumours are risk stratified based on the presence of risk factors: T1 tumours have zero high risk factors, T2a tumours have one high risk factor, T2b tumours have two to three high risk factors and T3 tumours have over four high risk factors or bone invasion. Risk factors are defined as the following: tumour diameter >/= 2cm, poorly differentiated histology, perineural invasion >/= 0.1mm, or tumour invasion beyond fat (excluding bone).
As it is exceedingly rare for BCCs to metastasize, there is no standardized approach for imaging high risk BCCs. BCCs that do metastasize most commonly spread to the local lymph nodes, lung and bone [3].
The protocol for imaging cSCCs is much more established than that for BCCs because of their higher rate of nodal spread and metastasis. cSCCs most commonly spread to regional lymph nodes, however they can also metastasize to the lung, liver, bone and brain [3].
A suggested approach for investigating invasive cSCC is depicted in the image below [modified from reference 3]:
All cSCC patients should have a regional lymph node examination to detect clinical lymphadenopathy [10]. Patients with palpable lymphadenopathy must undergo a lymph node biopsy to establish whether there is evidence of disease in the palpable node. The biopsy is typically conducted using a fine needle aspiration technique. If the cytology confirms that the node is positive for disease, the patient should undergo imaging tests to characterize the extent of nodal involvement along with complete nodal dissection. If the cytology does not indicate that there is disease in the palpable lymph node, the physician should consider whether the tumour is “high-risk”. Physicians may decide to send patients with sufficient high-risk features, with or without palpable lymphadenopathy, for imaging of the regional lymph nodes. Ultrasound of lymph nodes may also be considered for high risk cSCCs. In large infiltrating tumours with signs of involvement of underlying structures imaging such as CT or MRI may be required to assess the extent or tumour spread. The most common imaging modality used for staging nodal involvement is CT. Other imaging techniques that may be considered are MRI, PET and ultrasound [2,3].
Patients with confirmed nodal involvement and/or extremely high-risk disease may undergo full-body imaging for distant metastases. The options for full-body imaging include CT, PET and PET-CT. The gold standard is currently unknown [3].
The prognosis for NMSCs is extremely good in most cases with a greater than 95% disease free survival at 5 years for low stage disease [2]. However, this prognosis changes considerably for high-risk lesions with rates dropping down below 50% for T4 lesions [3]. This underscores the importance of properly staging NMSCs.
The most commonly used therapy for both BCCs and cSCCs is surgical excision. Radiation therapy is the second most common therapy. The following flow chart outlines an approach for what therapies are appropriate in which cases:
1 - E&D, cryotherapy and topical therapy are used in select cases when lesions are of low risk (including low metastatic potential) and slow growing. These treatments typically slow disease progression but may not be fully curative and lesions may recur.
2 - Watchful waiting may be suitable for lesions which are slowly growing or in cases where patients have multiple comorbidities exceeding the risk of their cancer.
The preferred treatment for invasive cSCC is surgical removal [5]. If an SCC is growing among many actinic keratoses and in situ tumours destructive but blind modalities such as cryotherapy, electrodessication and curettage, photodynamic therapy or topical agents such as imiquimod or 5- fluorouracil may be used. Excisional surgery is generally first line and results in 95% local cure rates. Mohs surgery is another option, particularly when preservation of tissue for cosmetic or functional reasons and cure are important factors. Radiation therapy may be the primary treatment in cases where the lesion is inoperable, or may be used as adjuvant therapy where there is significant perineural involvement, positive margins or nodal involvement. Radiation therapy is also an effective palliative treatment to stop extension, pain and hemorrhage. Electrochemotherapy may be used to control locally advanced lesions with bleomycin and cisplatin.
There is no standard chemotherapy regimen for stage IV cSCC with no controlled prospective trial evidence available. Multiple agents including platin derivatives, 5 fluorouracil, bleomycin, methotrexate, adriamycin, taxanes, gemcitabine and ifosfomide have all been used. Palliative chemotherapy is indicated for those with distant metastases.
The preferred treatment for BCC depends on the risk and the location of the lesion [6]. For lesions with a low risk of recurrence electrodessication and curettage or surgical excision and less commonly 5-fluorouracil, imiquimid, cryosurgery, intralesional injection and photodynamic therapy are options. Electrodessication and curettage is an option for superficial and nodular primary BCC on extremities and the trunk but may result in a hypopigmented scar and may cause more destruction if the lesion recurs. Excision is the most effective method when conservation of tissue is not a priority such as for lesions on the trunk or extremities. Mohs microscopically staged surgery provides the highest cure rate with maximal tissue preservation and is indicated for lesions at increased risk of recurrence. Radiation therapy results in low recurrence rates and is the primary choice when surgery is not possible; however, negative cosmetic outcomes are common.
Vismodegib is a targeted therapy that acts on the hedgehog pathway which is frequently mutated in BCC [13]. It is used in advanced and metastatic BCC which cannot be treated surgically. Metastatic BCC is rare and includes involvement of lymph nodes, or distant sites such as the liver, lung or bone. Though it is rare, metastatic BCC is important as it carries a poor prognosis with a median overall survival of 8 months. In trials 48.5% of patients with metastatic disease showed response to Vismodegib while 60.3% with locally advanced disease responded. Median duration of response was 14.8 months in metastatic disease and 26.2 months in those with locally advanced disease.
Follow-up of non-melanoma skin cancers is essential in order to monitor for disease recurrence, metastasis and the presence of new skin cancers. The protocol for follow-up, as laid out by the BC Cancer Agency, differs according to the type of cancer [1]. Any patient with disease recurrence should be referred to a dermatologist or to the cancer agency for further treatment.
It is very common for patients with one BCC to develop a second BCC. As such, careful follow-up is critical. The following is a suggested approach:
1st Follow-up Visit – 6-8 weeks after treatment
1st Year – Follow-up every 6 months
After 1st Year – Annual follow up, this should be more frequent if the patient develops new BCCs
The follow-up for patients with a cSCC depends on whether the tumour was high or low risk. There is a 30-50% chance of developing a second cSCC within 5 years and patients should be encouraged to perform self skin and nodal exams. For low-risk disease it is suggested that patients undergo a full body skin examination and a regional lymph node assessment annually for at least 5 years. It is suggested that this approach is continued past the first 5 years as well. The presence of multiple cSCCs puts patients at increased risk for local recurrence and metastases and as a result these patients need more frequent follow up [2].
Patients with high-risk disease should be examined more frequently. The following is a suggested approach:
1st Year – Follow-up every 2-3 months with careful examination of the treatment site and regional lymph nodes as well as a full body skin examination
Year 2-5 – Decrease frequency of follow-up in stages
Year 5+ – Annual follow-up
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