Chapter 20: Basal Cell Carcinoma, Squamous Cell Carcinoma, And Melanoma

1. Which one of the following statements is correct regarding basal cell carcinoma (BCC)? BCC is a malignant tumor of the skin arising from the basal cells of the epidermis and it represents the most common type of eyelid malignancy. It is the most common type of skin cancer with more than 1.2 million cases reported annually in the US. Its incidence is rapidly rising which is probably due to a combination of increasing population age, increased sun exposure, and better detection. Males are affected more commonly than females. At least 80% of BCCs occur in the head and neck region with the most common sites being the nose, eyelid, and ear. Other sites that are often affected include the cheek, lip, neck, and brow.1–5

2. Shanoff LB, Spira M, Hardy SB. Basal cell carcinoma: a statistical approach to rational management. Plast Reconstr Surg 1967;39(6):619–624 3. Miller S, Alam M, Anderson J, et al. NCCN Guidelines. Clinical practice guidelines in oncology: basal cell and squamous cell skin cancers version 2. 2012. DOI: 10.6004/jnccn.2004.0001 4. American Cancer Society. Medical and editorial content team. www.cancer.org/cancer/melanoma-skin-cancer/about/ key-statistics.html

A common finding in patients with Gorlin’s syndrome is the presence of multiple small red pits on the palm or sole. They appear as small depressions and are caused by partial or complete absence of the stratum corneum. They are typically 2–3 mm diameter with a similar depth. They are present in up to one-third of patients by the start of the second decade, and almost all patients by age 20.1 Although the presence of three or more palmar pits constitutes a major diagnostic criterion in Gorlin’s syndrome, pits may also be seen in patients with other conditions, such as psoriasis.2 Gorlin’s syndrome (nevoid basal cell syndrome) is an autosomal dominant condition affecting chromosome 9 that is characterized by multiple BCCs at an early age. These patients will require lifelong review and multiple procedures for tumor excision. Another common feature associated with Gorlin’s syndrome is development of odontogenic keratocysts, which show as radiolucent areas on panorex. Recurrent dental abscesses are not a specific finding. There are often cranial abnormalities, which include absence of the falx cerebri, hypertelorism, and a broad nasal root. Neither posterior plagiocephaly or recurrent dental abscesses are typical findings. A yellowish plaque on the skin may represent a sebaceous nevus which itself is benign but has the potential for transformation to BCC in around 10% of cases. Coffee-colored patches are more typical of neurofibromatosis.

More than 20 subtypes of BCC have been described. The most common subtype is nodular (50–60%) and other common subtypes are micronodular (15%), superficial spreading (9–15%), infiltrative (7%), and morpheaform (2–3%). Subtypes differ in their behavior and the most aggressive is morpheaform, which has a high incidence of positive margins following excision. These tend to present as an “enlarging scar” without history of trauma and have a flat or slightly elevated scarlike appearance. Infiltrative subtypes are also aggressive, whereas nodular and superficial subtypes are fairly low risk. Despite this, nodular subtypes are still best treated surgically. The classic described appearance of a BCC is a raised lesion with a rolled edge, visible telangiectasia, and central ulceration. This appearance is most in keeping with a nodular subtype, which was traditionally referred to as a “rodent ulcer.” Superficial spreading BCCs are located in the epidermis with no dermal invasion. They are pink, flat scaly patches with ulceration and crusting rather than the classic nodular appearances described above. Accordingly, they can be confused with fungal infections or eczema. Pigmented subtypes represent 6% of all BCCs and are most likely to be confused with melanomas.1–4

5. Netscher DT, Leong M, Orengo I, Yang D, Berg C, Krishnan B. Cutaneous malignancies: melanoma and nonmelanoma types. Plast Reconstr Surg 2011;127(3):37e–56e RISK FACTORS FOR BASAL CELL CARCINOMA 2. Which one of the following is a risk factor more typical of squamous cell carcinoma (SCC) rather than basal cell carcinoma (BCC)? Human papilloma virus (HPV) is not associated with development of BCCs. It is however associated with SCC of the skin and mucous membranes such as the oropharynx and oral cavity. It is also implicated in cervical cancer. Risk factors for BCC include skin type and color (Fitzpatrick types I and II), increasing age, male sex, sun exposure, immune compromise (e.g., human immunodeficiency virus [HIV], steroid, or organ transplant medication), genetic predisposition, and carcinogen exposure (e.g., UV and ionizing radiation, hydrocarbons). Risk factors for SCC generally parallel those of BCC but also include chronic wounds, psoralen and ultraviolet A light (PUVA) treatment for psoriasis, and irradiation.1–7

6. Kimyai-Asadi A, Alam M, Goldberg LH, Peterson SR, Silapunt S, Jih MH. Efficacy of narrow-margin excision of well-de- marcated primary facial basal cell carcinomas. J Am Acad Dermatol 2005;53(3):464–468 its use should be limited to treating superficial BCCs. Photodynamic therapy (PDT) uses the light-activated photosensitizing drug 5-aminolevulinic acid to create oxygen free radicals that selectively destroy target cells. It can be used in premalignant or superficial lesions, but should not be used in deeper or high-risk lesions. Radiation therapy provides an alternative to surgery and can be effective for most BCCs. It tends to be reserved for older patients (age 60 and older) and has cure rates >90%. One of the caveats of radiation therapy is that multiple treatments are required over a 4- to 6-week period and it requires a diagnostic biopsy to be obtained before treatment. Furthermore, completeness of excision cannot be confirmed and subsequent surgery to the area is more challenging. Topical treatments with either Imiquimod or 5-fluorouracil (5-FU) can be effective in low-risk superficial lesions because they can destroy the surface cells. They should not be used in deeper lesions because they cannot destroy deeper cells and risk growth recurrence due to residual tumor cell presence. Standard cryotherapy involves cooling the tissues to –40° C during repeated freeze–thaw cycles, but it is not indicated for tumors deeper than 3 mm. It has a more useful role in management of early actinic keratosis. Vismodegib is a hedgehog inhibitor with FDA approval for use in locally advanced BCC when other treatment forms have been exhausted, and therefore is not a first-line treatment. Unfortunately, it is an expensive drug and no longer has approval in UK National Health Service because of this in relation to its perceived benefits. Adverse effects include muscle spasm, alopecia, ageusia, and fatigue.1–5

7. Motley RJ, Preston PW, Lawrence CM. Multi-professional Guidelines for the Management of the Patient with Primary Cutaneous Squamous Cell Carcinoma. London, United Kingdom: British Association of Dermatology; 2009

Mohs micrographic surgery involves sequential horizontal excision using a topographic map of the lesion with repeated excision until all positive tumor margins are clear. The main benefits are that completeness can be confirmed because tissue is assessed at every margin and this is confirmed at the time of surgery. In contrast, standard histological analysis does not sample every margin so completeness cannot be guaranteed. Furthermore, the procedure would need to be staged if confirmation of excision is required before reconstruction. Reported cure rates are higher than standard excision at 99%, but 100% cure is still not achieved. A further benefit is that tissue conservation is increased because only involved margins are re-excised in contrast to the standard surgical approach where an arbitrary margin is taken. For this reason, Mohs is indicated in both primary and recurrent tumors, particularly those in cosmetically sensitive areas. It is also useful in treating aggressive tumor subtypes such as morpheaform and sclerosing variants and those with poorly delineated peripheral margins. The problem with Mohs is that it takes significantly longer to treat each patient and the patients must wait for the analysis to be performed at each excision stage. Patients still require complex reconstruction in many cases with flaps or grafts. Some Mohs surgeons can and do reconstruct the defects created, but many will return the patient back to the reconstructive plastic surgeon once excision is complete. Therefore, many patients still have a staged procedure with regard to reconstruction.1–4

All of the options represent risk factors for SCC. However, the risk of developing an SCC after immunosuppression for renal transplant is increased by 253 times, making this the most significant single-risk factor Immunosuppression after transplant usually involves combination therapy with steroids (prednisolone) and immunomodulators such as mycophenolate mofetil (MMF) and tacrolimus. Patients with lighter skin tones (Fitzpatrick I to II) have an increased risk. Overall lifetime sun exposure, episodes of sunburn, and the use of tanning beds can further increase the risk. Carcinogens implicated include pesticides, arsenic, and organic hydrocarbons. Viruses such as HPV and herpes are also implicated. This emphasizes the importance of assessing these areas during history taking in patients with suspected SCCs and providing prevention advice.1–7

SCCs arising on the external ear are particularly high-risk lesions that can spread through the lymphatics to the parotid gland and neck. Of all the head and neck skin SCC sites, the ear is considered to be the most likely site to result in death. Other high-risk sites include the temple, forehead, scalp, and lower lip. In each of these sites, metastatic spread can occur in the neck or parotid nodes. Other high-risk factors for metastases should also be considered such as tumor diameter (>2 cm), depth (>4 mm), poor differentiation, incomplete margins, and perineural invasion as a tumor spread can proceed along nerves.1–4

Many factors are used to classify SCCs as low risk or high risk.1 Factors that characterize low-risk lesions include the following: sun-exposed sites, excluding the lip and the ear, diameter less than 2 cm, depth less than 4 mm, tumor confined to the dermis, well-differentiated or verrucous subtypes, and no evidence of host immune suppression. Factors that characterize high-risk lesions are the following: involvement of the ear or lip, diameter greater than 2 cm, depth greater than 4 mm, moderate or poor differentiation, host immune suppression, recurrence, and sites not exposed to the sun such as the perineum (Table 20.1).1–3

Keratoacanthomas are premalignant skin lesions with a typical domed-shaped appearance and a keratin plug. Their clinical and histologic appearance closely resembles a well-differentiated SCC and it can be difficult to differentiate between the two. They usually progress rapidly over a number of weeks before spontaneous regression begins. They are frequently excised to exclude an SCC diagnosis as the initial history and clinical appearances are so similar. Treatment is complete once full excision is achieved. Actinic keratosis represents such damage leading to dry crusting of the skin in sun-exposed sites such as the scalp, face, ears, and limbs. Malignant transformation to SCC can occur and so more progressive lesions are often biopsied. Nonsurgical management of actinic keratoses includes cryotherapy and topical agents such as 5-FU or Imiquamod. Bowen’s disease presents with an erythematous plaque with sharp borders and slight scaling. It represents in situ SCC and has a 10% chance of malignant transformation. Erythroplasia of Queyrat is Bowen’s disease of the glans penis, vulva, or oral mucosa and is associated with a 30% malignant transformation. Leukoplakia is a premalignant condition affecting the oral mucosa. There are mucosal changes with a visible white patch. Malignant transformation occurs in around 15% of cases.1–5

Wide local excision is the most suitable management for this patient and a peripheral margin greater than 6 mm is required. Many surgeons would opt for a 1-cm margin in this case given the size and thickness of the tumor and its anatomic location. Cure rates for primary surgery are around 95%. Wound closure in patients of this age group is usually achieved with local flap techniques given the skin laxity in the cheek and neck at this age. Primary radiotherapy has a cure rate of 90% and is reserved for patients in whom surgery is not advisable, or as adjuvant therapy in high-stage large or recurrent tumors. Elective lymph node dissection is not advocated for cutaneous SCC, in contrast to an equivalently sized intraoral tumor. The technique is, however, indicated in cases where there is evidence of tumor spread to the parotid capsule or contiguous nodal basin drainage as may be suggested by adherence of the tumor to underlying deep structures. Sentinel lymph node biopsy (SLNB) is sometimes indicated for node-negative patients with high-risk tumors. Mohs surgery is not required in this case given the high cure rates with standard surgical techniques. Following surgical excision, the patient should be followed up in clinic for an extended period. This should be on a 3–6 months basis for 2 years, then every 6–12 months for 3 years, then annually thereafter.1–4

There are a number of different melanoma subtypes and the most common cutaneous variant is superficial spreading, representing more than half of all melanomas (50–70%). Nodular subtypes are the next most common, representing 15–30% of all cases. Lentigo maligna and acral-lentiginous usually each represent less than 10% of all melanomas, and desmoplastic subtypes are least common, representing around 1% of all cases.1–5

Acral-lentiginous melanoma can occur on the palms and soles, subungually, or in other sun-protected sites. Melanonychia represents a linear pigmented streak within the nail and is associated with this melanoma subtype. Although melanonychia is often a benign finding, if it involves a single digit and has a recent onset, it should raise concerns. In this situation, the entire nail should be examined closely with magnification or dermatoscopy. The skin borders surrounding the nail must also be carefully reviewed. In the event that concern remains following clinical examination, further investigation with removal of the nail plate and biopsy of the nailbed and/or eponychium would be indicated.1,2

Development of melanoma commonly differs between subtypes. For example, nodular melanoma typically arises de novo in normal skin. It appears as a dome-shaped pigmented lesion that may resemble a blood blister. It displays a lack of horizontal growth so keeps sharp demarcation. Nodular melanomas are aggressive and more commonly affect men. Superficial spreading subtypes tend to arise from long-standing junctional or compound nevi, and patients may have noticed a change in the color, size, or borders of the lesion. These tumors tend to have a prolonged horizontal growth before vertical growth commences. A Hutchinson freckle is also known as a senile freckle or lentigo maligna and this is an in situ melanoma. It can progress to form lentigo maligna melanoma, which is the least aggressive subtype and is related to sun exposure. The Hutchinson freckle represents the horizontal growth phase and the vertical growth phase represents the transition to melanoma. Melanomas in sun-protected sites tend to be acral-lentiginous and are seen on the soles or palms. They have a long radial growth phase followed by transition to a vertical growth phase. A spitz nevus is a smooth dome-shaped benign lesion seen in children or young adults that represents a proliferation of enlarged spindle melanocytes. It does not represent a precursor to melanoma, although there is a melanoma subtype call spitzoid melanoma that has a similar histologic appearance to a spitz nevus.1–3

All of the options are important factors in melanoma, but Breslow thickness (BT) is the single most important factor. It represents the measurement of tumor depth from the granular layer of the epidermis to the deepest extension of the tumor. BT is used to stage the disease using the tumor, node and metastasis (TNM) classification system and to plan subsequent treatment. A number of key features will be displayed on a histological report for melanoma including those listed in answer options A, B, C, and E. For example, the mitotic rate (especially relevant to tumors less than 1 mm deep) and ulceration (relevant to all tumors), perineural or perivascular invasion, and Clark’s level which relates to the anatomic depth of the tumor. Completeness of excision is also critical to plan further management, and subtype and growth phase are both important to provide information on prognosis.1–5

The American Joint Committee on Cancer (AJCC) has produced guidelines for melanoma staging based on the TNM (tumor, node, metastasis) system. In this classification, tumors are initially classified by their Breslow depth as T1 to T4 lesions, with lesions less than 1 mm graded as T1, those between 1.01 and 2.0 mm as T2, those between 2.01 and 4.0 mm as T3, and those greater than 4 mm as T4. The presence of ulceration or mitotic rate greater than 1 will upgrade a T1a lesion to T1b. For T2, 3, and 4 tumors the presence of ulceration will upgrade them to T2b, 3b, and, 4b, respectively. The mitotic rate does not alter the T classification for these tumors.1 Nodal status is N0 (no spread), N1 (spread to one nearby lymph node), N2 (spread to 2 or 3 nearby lymph nodes), and N3 (spread to 4 or more lymph nodes). Again, this is further altered by pathological information on micrometastases, in transit satellites, and macrometastases, which may be obtained following sentinel lymph node biopsy (SLNB) or excisional surgery. Metastatic spread is subclassified as M1a, b, or c, depending on the extent and type of metastases present. Once the T, N, and M groups have been determined, they are combined to give an overall stage called stage grouping. This provides prognostic information, which is also used to guide treatment (Tables 20.2 and 20.3). Table 20.2 AJCC TNM Melanoma Staging Classification, 2010 Tumor Classification Depth of Invasion TX Primary tumor cannot be assessed Tis Melanoma in situ T1 <1.0 mm T2 1.01–2.0 mm T3 2.01–4.0 mm T4 >4.0 mm NOTE: a and b subcategories of T: a, without ulceration and mitosis < 1/mm2; b, with ulceration or mitoses >1/mm2. Node Classification NX Cannot be assessed N1 One node N2 Two to three nodes N3 Four or more nodes, matted, or in transit satellites with metastatic nodes NOTE: a, b, and c subcategories of N: a, micrometastasis (diagnosed after sentinel lymph node biopsy); b, macrometastasis (clinically positive nodes); c, in transit satellites without nodes (N2 only). Metastatic Classification M1a Metastases to skin, subcutaneous, distant nodes M1b Metastases to lung M1c Metastases to other viscera or any distant site combined with elevated serum LDH

In patients with positive nodal disease or positive sentinel lymph nodes, therapeutic lymph node dissection is generally advocated. In patients with positive groin disease an extended procedure to include dissection of pelvic nodes is required in some cases. The indications include where multiple groin nodes are clinically palpable, where there is computed tomography (CT) or ultrasound evidence of multiple groin nodes involved, where multiple groin nodes are found to be positive during sentinel lymph node biopsy (SLNB), and where there is a conglomerate of groin nodes. Full-thickness excision biopsies (1–3 mm margins) are required for the vast majority of suspected melanomas in order to confirm diagnosis, completely remove the lesion, and fully assess their histological features including Breslow thickness. However, full-thickness biopsies are not required for subungual melanoma as this offers no prognostic information. Incisional biopsies may be considered for low-suspicion lesions or cosmetically sensitive regions. Shave biopsies are not recommended. Long-term survival is not improved by excising the deep fascial layer and recommendations are to perform the wide local excision down to the fascial layer only. Removal of the fascia may increase metastatic spread. Recommendations for subungual melanoma are that amputation is performed proximal to the distal interphalangeal joint, not the proximal interphalangeal joint. Sentinel lymph node biopsy is a staging procedure and is indicated in both stage Ib and stage II disease but not in stage III, as by definition nodal spread must have already taken place. Following a positive SLNB, patients will be offered the option of elective lymph node dissection or regular ultrasound of the lymphatic basin as part of the ongoing follow-up.1–5

Dacarbazine and cisplatin are chemotherapy agents that may be considered in melanoma to reduce tumor burden, but they are generally only palliative. Sentinel lymph node biopsy is a staging procedure, not a therapeutic procedure that is used in patients with intermediate depth melanomas in order to identify whether the tumor has spread to the sentinel lymph node. If SLNB is positive, then progression to completion lymphadenectomy should proceed. There remains debate about the clinical benefits of SLNB as overall life expectancy does not appear to be improved, but local tumor recurrence may be; further evidence is awaited. Elective lymph node dissection appears to have a survival benefit only in intermediate melanoma (1–2 mm) and is not routinely performed because of the comorbidity involved unless the SLNB or clinical examination is positive for lymph node involvement. Radiation therapy is rarely indicated as a primary treatment of melanoma except for lentigo maligna or desmoplastic lesions. Interferon can be useful in patients with regional nodal disease or deep primary tumors.1–3

Evidence for the selection of excision margins in melanoma is provided by six key papers considering five major studies.1–6 Recommended peripheral margins for melanoma excision vary between different guidelines and this reflects the available evidence and differences in its interpretation (Table 20.4). In situ disease is commonly excised with a 5-mm margin. Melanomas less than 1 mm in depth are commonly excised with a 1-cm margin. Thicker melanomas are excised with a 2-cm margin. Most evidence for peripheral margin selection relates to melanoma on the trunk and excludes the head, neck, and distal limbs. In clinical Table 20.4 United States Excision Margin Guidelines for Melanoma Excision Primary Tumor Type Recommended Peripheral Excision Margin Commonly Recommended Deep In situ disease 5 mm Cuff of subcutaneous tissue Less than 1 mm Breslow depth 1 cm To next fascial plane 1.01–2 mm Breslow depth 1–2 cm (wider is preferable if possible, depending on tumor site, patient, and surgeon preference) To next fascial plane 2.01–4 mm Breslow depth 1–2 cm (wider is preferable if possible, depending on tumor site, patient, and surgeon preference) To next fascial plane Greater than 4.01 mm Breslow depth 2 cm To next fascial plane practice, margins should be tailored to patients on an individual basis depending on site, size, and tumor biology, ideally in a multidisciplinary team setting.7

Vemurafenib is a BRAF inhibitor with FDA approval for use in advanced-stage melanoma. It is indicated in patients who are BRAF-positive (i.e., those who have a mutation of the intracellular signaling kinase BRAF). Mutations in the BRAF gene are present in 40–70% of melanomas, leading to uncontrolled cell proliferation. Vemurafenib has been shown to increase overall survival and progression-free survival when compared with dacarbazine (a standard monochemotherapeutic agent).1 Although the survival improvements have been statistically significant, the real benefits have been modest as lifespan was extended by just a few months in most cases. A further problem with BRAF inhibitors such as vemurafenib is that resistance can occur. For this reason, combination therapy is also being studied. Also, patients have an increased risk of developing SCC while taking this treatment. Furthermore, the financial implications of using this drug are significant with a course of treatment costing many thousands of dollars. Radiotherapy may be indicated as adjuvant treatment following lymphadectomy with more significant disease and can be used in palliation for metastatic disease. Dacarbazine, cisplatin, and vinblastin are standard chemotherapy agents used in combination rather than individually that are generally palliative only with modest response rates.2

Immune-based treatment options for patients with advanced-stage melanoma can be subclassified as immune agents such as interleukin-2, checkpoint inhibitors such as ipilimumab, or signal transduction inhibitors such as vemurafenib and trametinib. Ipilimumab is a monoclonal antibody that blocks the CTLA-4 receptor (a downregulator of T-cells). The resultant stimulation of T-cells may present a risk for immune-related reactions. It received FDA approval in 2011 for patients with advanced-stage melanoma. Imatinib (also known as Glivec) is a tyrosine kinase inhibitor that works by blocking growth pathways within a variety of tumors. Canvaxin and MAGE-A3 have been trialed as vaccines against melanoma in advanced disease, but results have not been particularly successful.1–4

Standard follow-up for melanoma patients varies according to country but in the US, lifelong surveillance is currently advised by the National Comprehensive Cancer Network (NCCN) and American Academy of Dermatology (AAD). The German Cancer Society and German Dermatologic Society recommend 10-year follow-up for most stages as do the Swiss, while the British Association of dermatologists advise follow-up according to stage and this varies from 5 to 10 years. The Australian and New Zealand guidelines also vary according to stage with 5-year follow-up advised for stage I and lifelong for stages II and III. Typical follow-up will involve clinical assessment with review of the primary site and nodal basins as well as review of other skin sites for new or changing pigmented lesions. Local recurrence usually occurs within 5 cm of the original lesion within the first 3–5 years. In the first 5 years patients are typically seen at 3- to 6-monthly intervals. Beyond 5 years patients are seen on an annual basis. Routine imaging beyond 5 years is not recommended.1

Seborrheic keratoses are benign lesions commonly found on the trunk of older patients. They are slow growing and have a raised verrucous appearance with varying degrees of pigmentation. They may often be mistaken for melanomas but do not usually require excision. Care must be taken to examine them fully as many older patients will have multiple seborrheic keratoses but if there is one which is changing or behaving differently to the other, an excision biopsy may still be warranted. Junctional nevi are flat and are generally found on the palms, soles, genitalia, and mucosa. They tend to have a uniform color which ranges from pale to dark brown. They are smooth, macular, and sharply defined with first appearance in childhood. Compound nevi are darker that junctional nevi and are palpable with a raised border. They may be smooth or rough and have hair within them. Blue nevi are blue/black colored lesions often found on the hands, feet, head, neck, or buttocks. They are usually smaller than 5 mm diameter and in rare cases can progress to melanoma. Lentigo are benign pigmented macular lesions most commonly seen in middle age and beyond. Lentiginous lesions that change in appearance may warrant a tissue biopsy as they can progress to melanoma in situ and melanoma itself.1,2