General Principles and Management



General Principles and Management


Louis B. Harrison

Par S. Mehta

Matthew Halpern

Desiree Ratner



Nonmelanoma skin cancers (NMSCs) are the most frequently occurring cancers in the United States, with basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) being the most common histologies. More than 1 million cases are expected annually in the United States, and the incidence has been rising rapidly over the last decade.1 The head and neck are the most common sites of presentation, accounting for >80% of all basal and SCCs.2 These lesions are typically slow growing and infrequently metastasize. If neglected, they can cause significant local destruction and invade critical structures. These lesions can cause significant morbidity, especially cosmetic deformity. Metastasis can occur and can be life threatening. Treatment of these cancers is important, and multidisciplinary considerations are essential.


EPIDEMIOLOGY


Basal Cell Carcinoma

BCCs are thought to originate from pluripotent cells in the basal layer of the epidermis. Although formal statistics are not maintained for the incidence of BCCs of the skin, the American Cancer Society estimates 800,000 to 900,000 BCCs in the United States per year,1 equating to 300 to 350 per 100,000 patient years. The incidence is significantly higher with increased age and is much greater in Whites than in African Americans. Men are also more likely to develop BCCs than are women. The incidence of BCC has also increased approximately 100% in the last decade, but still account for <1% of cancer deaths.3 Whites in the United States have a 30% lifetime risk of developing a BCC, and those previously diagnosed with a BCC have a 35% to 50% chance of developing a second tumor over a 5-year period. BCCs are typically present over sun-exposed areas of the skin, accounting for the increased incidence in the head and neck. Geographic location also plays a significant role, with the highest incidence worldwide in Australia.


Squamous Cell Carcinoma

Cutaneous SCC is a malignant tumor of epithelial keratinocytes and represents the second most common form of skin cancer. This neoplasm was first described in the literature in 1775 by Sir Percival Pott, who noted the relationship between scrotal carcinoma and exposure to chimney soot. Although most of the cases are easily treated with a high cure rate, a subset of tumors will behave more aggressively and recur or metastasize, resulting in most NMSC mortalities in the United States.4

The precise incidence of SCC is difficult to ascertain because the National Cancer Institute only collects data on tumors of the genitalia. Epidemiologic studies suggest, however, that in the United States, the rate approaches 100 to 150 cases per 100,000 persons per year. The age-specific incidence among persons older than 75 years is increased by a factor of 10.4,5,6,7,8 In addition, it appears that this rate has increased by 50% to 200% over the last 10 to 30 years.4,5,6,8,9,10 Geographic variations in sun exposure also contribute to differences in regional incidence data, with rates in Arizona of approximately three to six times those reported in more northern areas.11 Similarly, in Australia, incidence rates are significantly elevated relative to the United States, with 1% to 2% reported most recently.12


RISK FACTORS


Basal Cell Carcinoma

Exposure to ultraviolet radiation is recognized as the major etiology of BCC, with ultraviolet B (UVB) more implicated than ultraviolet A (UVA). Ultraviolet radiation induces covalent bonds in DNA between adjacent pyrimidines, resulting in mutagenic lesions if not repaired. Both cumulative exposure and less frequent but intense exposure to direct sunlight are implicated in the pathogenesis of BCC. The amount of ultraviolet radiation exposure is especially important for patients with Fitzpatrick skin types I—II.


Exposure to ionizing radiation is also a risk factor for developing BCC. This increase is limited to the surface area exposed to radiation therapy. Lichter et al. showed in a population-based case-control study that the relative increase in incidence of BCC was 3.3 in skin previously irradiated for acne treatment, with lower increase in patients receiving radiation therapy for malignancies, at 2.0.13 Lower-dose exposure to ionizing radiation is associated with more mutagenesis and may account for this discrepancy, and this study showed that there was no increase in the incidence of NMSC in adjacent areas of nonirradiated skin.

Other risk factors include chemical carcinogen exposure with arsenic or coal tar, and immunosuppression. Smoking and human papillomavirus (HPV) infection are also risk factors for development of BCC,14 with smoking likely functioning as a carcinogen.

Each of the aforementioned risk factors is thought to contribute to genetic mutations responsible for BCC. Several pathways have been implicated, most commonly mutations in tumor suppressor genes. The p53 mutations are the most common genetic aberrations involved in NMSC, although more common in SCC than in BCC. p53 plays an important role in apoptosis, and effects of involvement of ataxia-telangiectasia mutated gene (ATM gene), p38, and mitogen-activated protein (MAP) kinases in the phosphorylation of p53 serine residues are seen in response to ultraviolet radiation.15 Exposure to ultraviolet radiation can result in the loss of Fas ligand interaction, with resulting accumulation of p53 mutations in the skin.

Mutations in the patched tumor suppressor gene also play a role in the development of BCC.16 Located on chromosome 9, the PTCH1 gene is a component of the sonic hedgehog (SHH) signaling pathway and encodes for a transmembrane protein which, along with another transmembrane protein, smoothened, inhibits transcription factors regulating genes involved in tissue morphogenesis. This pathway is implicated in the increased incidence of BCC seen in genetic syndromes, including Gorlin syndrome and xeroderma pigmentosum, as well as sporadic BCC.17

Gorlin syndrome (basal cell nevus syndrome) is a rare autosomal dominant disorder, with a prevalence of approximately 1 in 100,000 found mostly in whites.18,19 Patients with this disorder have a variety of clinical abnormalities, including early development of multiple BCCs, palmar and plantar pitting, craniofacial abnormalities, and bifid ribs. These patients are also at increased risk of medulloblastoma with a 3% to 5% incidence.20

Xeroderma pigmentosum is characterized by a deficit in nucleotide excision repair. This results in accumulation of defects induced by exposure to ultraviolet radiation and an increase in BCC. Xeroderma pigmentosum clinically presents with excessive skin reaction to sunlight, photosensitivity, multiple solar keratoses, and skin cancers.


Squamous Cell Carcinoma

Table 23.1 lists known risk factors for the development of SCC. UVA (320-400 nm) and UVB (290-320 nm) result in thymidine dimer DNA mutations in the p53 tumor suppressor gene and is the most common cause of SCC.21,22,23 The highest risk exists among people with light skin, hazel or blue eyes, and blonde or red hair, and in those with chronic accumulated lifetime sun exposure.24,25 Not surprisingly, the use of oral methoxsalen in combination with ultraviolet A radiation (PUVA) for the treatment of psoriasis and other conditions has been definitively associated with an elevated risk of SCC.26,27 Ionizing radiation including x-rays, gamma rays, and grenz rays used either therapeutically or as occupational exposures also contribute to the risk of SCC.28 This risk is directly related to the cumulative dose of radiation.28 There are several genodermatoses that predispose individuals to SCC. In oculocutaneous albinism, patients have absent or decreased production of protective melanin resulting in increased SCC in sun-exposed areas.29 Patients with xeroderma pigmentosum are deficient in the enzymes responsible for repairing ultraviolet-induced DNA damage and develop skin cancers beginning from an early age. Other inherited conditions associated with SCC include Ferguson-Smith syndrome and dystrophic epidermolysis bullosa.30 HPV is associated with SCC development, especially with the periungual and genital regions. This is particularly evident in patients with epidermodysplasia verruciformis and in patients with HIV who develop the verrucous carcinoma subtype of SCC.31,32 Multiple chemical exposures are associated with SCC development, including arsenic and polycyclic aromatic hydrocarbons.21 Patients who are immunosuppressed are also at an increased risk of developing SCC. In particular, solid organ transplant recipients have a 40 to 250 times increased incidence of SCC compared with the general population.33 In fact, the ratio of SCC to BCC is reversed in organ transplant recipients.21 Patients with AIDS have a slightly increased risk of SCC, with a particular increase in anal lesions that are notable for a more aggressive clinical course.30 SCCs are also known to occur more commonly in areas of skin affected by chronic inflammation, including ulcers (so-called Marjolin ulcers), osteomyelitis, radiation dermatitis, and vaccination scars, and a variety of inflammatory conditions such as discoid lupus erythematosus, lichen sclerosis, lichen planus, and cutaneous tuberculosis.21 Infection with HPV has also been definitively linked to the development of nongenital SCC. In particular, HPV types 5, 16, and 18 have been shown to have increased oncogenicity relative to other subtypes.34 Although the specific pathway by which HPV induces carcinogenesis has not been determined, it is known that HPV infection results in synthesis of the viral proteins encoded by the E6 and E7 genes that bind and inactivate the p53, pRB, and Bak tumor suppressor genes.35 In addition, it appears that infection with HPV alone is insufficient to produce SCCs and that cocarcinogens such as ionizing radiation or ultraviolet radiation are required to produce malignant transformation.36 It also appears that HPV infection in the setting of immunosuppression leads to carcinogenesis as evidenced by the increased risk of SCC and cutaneous warts in organ transplant recipients.37








TABLE 23.1 Risk Factors for Development of Squamous Cell Carcinoma



























Exposure to ultraviolet radiation (UVA/UVB)


Therapy with methoxsalen and ultraviolet radiation (PUVA)


Ionizing radiation


Genodermatoses (Albinism, XP)


HPV (types 5, 6,11,16,18)


Chemical carcinogens (arsenic, polycyclic hydrocarbons)


Immunosuppression/immunosuppressive medications


Chronic inflammation (ulcers, osteomyelitis, dystrophic epidermolysis bullosa)


Radiation dermatitis


Actinic keratosis


Arsenical keratosis


XP, xeroderma pigmentosum.






CLINICAL PRESENTATION AND HISTOLOGY


Basal Cell Carcinoma

Unlike SCC of the skin, there are no precursor lesions associated with BCC. Patients typically present with a slow-growing, nonhealing papule, most commonly of the head and neck, although multiple clinical variants exist. Locally advanced tumors can show symptoms of disease progression into adjacent structures, including numbness, pain, and weakness.

There are several histologic subtypes of BCC, with nodular, superficial, and micronodular being the most common (Fig. 23-1).43 Other less common variants include infiltrative, basosquamous, morpheaform, and clear cell.44

Nodular-type BCC resembles a translucent papule with telangiectatic-rolled borders, often with a central ulcer (Fig. 23-2). When these tumors are neglected, they may become large and exophytic (Fig. 23-3). Histologically, these lesions have islands of tumor cells encased in a mucin-rich stroma. When pigmented, these tumors can often be confused clinically with melanoma. However, the melanocytes have a benign histologic appearance. Nodular BCC tends to be slow growing and is rarely associated with aggressive disease.

Superficial-type BCC presents as red, scaly lesions, often on the trunk or extremities, which may be confused clinically with eczema or psoriasis. They are also less aggressive clinically, but may become large when neglected, forming crusted, scaling erythematous patches. These lesions are also associated with younger women. Unlike nodular subtype, which increases in incidence with advancing age, the superficial subtype tends to peak and then steadily decrease into the late 70s.2

The morpheaform BCC, also described as sclerosing type, presents as flat, indurated, whitish, ill-defined plaques. As they enlarge, they often become depressed and resemble a scar and, because of this subtle clinical appearance, may not be diagnosed until they are relatively large. The morpheaform histology is associated with small islands of tumor cells with dense fibrosis. At the periphery, there is often microscopic extension into the surrounding dermis. This histologic subtype is among the more aggressive BCCs.






FIGURE 23-1. Incidence of specific basal cell carcinoma histologies.

Source: From Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol. 1990;23(6 Pt 1):1118-1126, with permission.






FIGURE 23-2. Retroauricular basal cell carcinoma presenting as apearly plaque with numerous telangiectasias.

Source: Photo courtesy of Dr. Ratner.

Tumors with mixed histologies should be treated as tumors of the more aggressive subtypes. This includes patients with basosquamous carcinomas, which behave more like SCC. Infiltrative BCCs are also more aggressive than the more common nodular and superficial subtypes.


Squamous Cell Carcinoma

SCCs are believed to arise primarily from precursor lesions known as actinic keratoses (Fig. 23-4). These scaly 1- to 3-mm, pink, skin-colored, or brown papules have a characteristic rough
texture and are oftentimes more easily palpated than visualized. These lesions commonly occur in a typical sun-exposed distribution, including the face, scalp, and dorsal hands. Histologically, actinic keratoses consist of atypical keratinocytes confined to the basilar layers of the epidermis with overlying parakeratosis. Estimates of the rate of progression to SCC vary from 0.025% to 20% per year.45,46






FIGURE 23-3. Basal cell carcinoma of the antihelix. Central erosion of the lesion is characteristic and referred to as a rodent ulcer.

Source: Photo courtesy of Dr. Ratner.






FIGURE 23-4. Numerous actinic keratoses on the temple of a man with extensive photo damage.

Source: Photo courtesy of Dr. Ratner.

SCC in situ (Bowen disease) presents as solitary, welldemarcated, pink, brown, or erythematous scaly plaques. Most commonly, these lesions occur in sun-exposed areas. Erythroplasia of Queyrat is SCC in situ occurring as smooth red plaques on the glans penis of uncircumcised men. Histologically, SCC in situ is characterized by keratinocyte atypical that involves the full thickness of the epidermis, but does not penetrate the basement membrane. SCC in situ may progress to invasive disease if not treated completely.28

Invasive SCCs are commonly scaly, pink- or skin-colored papules, or plaques that occur on the head, neck, trunk, and other sun-exposed areas. Patients may complain of pruritus, pain, or bleeding, with mild trauma to affected areas. Biopsy reveals keratinocyte atypia that traverses the basement membrane and involves the dermis and underlying structures. Tumors may be well differentiated, with minimal cytologic atypia, obvious keratinization, or they may be poorly differentiated with significant atypia and mitotic figures seen, with immunohistochemistry required for diagnostic confirmation.

Verrucous carcinoma is an uncommon variant of SCC that is characterized by a slow growth rate and exophytic, wart-like clinical appearance. This tumor occurs most commonly in the oral cavity (oral florid papillomatosis), anogenital region (giant condyloma of Buschke-Lowenstein), and the plantar surfaces of hands and feet (carcinoma cuniculatum).28 It is associated with multiple HPV subtypes, including HPV 6, 11, 16, and 18.47 Unlike other SCCs, irradiation is specifically contraindicated for verrucous carcinoma because it can result in increased tumor aggressiveness.48

Keratoacanthoma (Fig. 23-5) is a more common variant of SCC that presents as a rapidly growing solitary papule or nodule with a central keratin plug. These lesions are believed to regress without treatment in 6 to 9 months and most closely resemble well-differentiated SCC on histology.49 Ultimately, however, the diagnosis of keratoacanthoma requires clinicopathologic correlation, and indeterminate lesions should be regarded as SCC for treatment purposes because metastasis has been reported in rare cases.50






FIGURE 23-5. Rapidly growing keratoacanthoma of the left ear with characteristic central keratin core.

Source: Photo courtesy of Dr. Ratner.


NATURAL HISTORY


Basal Cell Carcinoma

Most BCCs are localized at presentation. Growth of these tumors is slow, estimated at 5 mm or less per year for the vast majority of tumors, but neglected tumors can become quite large. With adequate treatment, the recurrence rate is <10%, but more advanced lesions are associated with lower cure rates. The histology of the tumor may also predict the natural history. Sexton et al. examined 1,039 patients with BCC and noted that negative margins were achieved in >93% of patients with nodular or superficial tumors, compared with 81.4% for micronodular, 73.5% for infiltrative, and 66.7% for morpheaform histologies.43 Location of the primary tumor is also important for prognosis. Tumors along the H-zone (Fig. 23-6) include the nose, nasolabial regions, upper lip, columella, periauricular skin, and frontozygomatic areas. These locations are associated with deeper invasion and higher recurrence rates.51 This zone is also a cosmetically
prominent region where cosmetic results of treatment are particularly important. Local extension is through pathway of least resistance, including fascial planes, periosteum, perichondrium, and nerve sheaths. High-risk features of BCC are shown in Table 23.2. The primary tumor stage may be the most significant factor in determining the progression of disease. BCCs rarely metastasize to lymph nodes or distantly, and most cases are associated with T3 or T4 tumors. In addition, locally advanced tumors are more likely to have perineural invasion, which can result in cranial nerve palsies. Periorbital lesions have potential for invasion into the ethmoid sinuses and subsequently to the base of skull. The incidence of nodal metastases from BCC is exceedingly rare, between 0.01% and 0.5%, and associated with high-risk tumor features.44,52 However, the prognosis is poor after spread of disease, with median survivals between 8 months to 3 years. Distant spread of disease is to the lymph nodes, followed by bone, the lung, and the liver.






FIGURE 23-6. Anatomic depiction of the “H-zone” including areas associated with higher recurrence rates.








TABLE 23.2 Risk Factors for Basal Cell Carcinoma (BCC) Recurrence



















T stage >T1


Histology: Infiltrative/morpheaform/basosquamous


Margin status <4 mm


Location—“H-zone”


Perineural invasion


Site of prior radiation therapy


Poorly defined borders


Recurrent



Squamous Cell Carcinoma

Most patients with cutaneous SCC have an excellent prognosis. Invasive SCC does, however, have the potential to recur and metastasize. Although estimates vary, the approximate 5-year recurrence rates for primary cutaneous lesions is reported to be 8%, whereas the 5-year metastasis rate is 1.4% to 6%.53,54,55 In 1992, Rowe, Carroll, and Day reviewed all relevant studies on recurrence and metastasis rates of SCC from 1940 to 1992 (Table 23.3). Large lesions (>2 cm) have been reported to metastasize at a rate of 30% .53 Rapidly growing lesions on the eyelid or ear are also thought to be more aggressive and may metastasize in up to one-third of cases.56 Similarly, rates of metastasis are relatively high for lesions on the ear (11%) and the lip (13.7%), with associated 5-year survival rates that range from 25% to 40%.28,57,58,59 It should be noted that with improved abilities to diagnose and treat SCC, current rates of recurrence and metastasis may be lower than previously reported, but more recent prospective studies have not been performed.

Several histologic features may portend a worse prognosis. Depth >4 mm, extension into the reticular dermis or subcutaneous fat, and involvement of underlying fascia, muscle, bone, or cartilage are all associated with a greater risk of metastasis.60 Lesions that are poorly differentiated behave more aggressively and metastasize three times as often as well-differentiated tumors.53 Perineural invasion, in which tumor cells invade and travel along nerve fibers, occurs in 5% of SCCs.28,58 Discontinuous skip lesions are characteristic of perineural invasion, and the risk of metastasis approaches 50% despite aggressive surgical excision.28,58,61








TABLE 23.3 Factors Predisposing to Recurrence and Metastasis of Cutaneous Squamous Cell Carcinoma (SCC)





























































Risk Factor


RR of Recurrence


RR of Metastasis


Rapid growth




Size >2 cm


2


3


Site: lip


2


3


Site: ear


2


3


Immunosuppression


2



Radiation




Previous recurrence


3


4


Depth >4 mm or Clark IV/V


2


5


Poor differentiation


2


3


Perineural invasion


5


5


Infiltrative margi ns




Spindle cell histology




Acantholytic histology




Relative risk (RR) for small primary squamous cell carcinoma (SCC) is defined as 1.


For patients with metastatic disease, the long-term prognosis is poor. In patients with regional lymph node involvement, 10-year survival rates are <20%. In patients with distant metastases from SCC, 10-year survival rates are <10%. Eightyfive percent of cases with metastasis involve regional lymph nodes, whereas the remaining 15% of cases involve the lungs, the liver, the brain, and bone.28,57,62,63,64 Primary SCC of the head and neck also metastasizes to the parotid gland and the neck, not uncommonly. In this subset of high-risk patients, approximately 50% develop local recurrence within 1 year of surgical excision. Not surprisingly, positive surgical margins at the time of excision were associated with a greater risk of recurrence. Postoperative radiotherapy was not associated with improved outcomes or prolonged survival.65


STAGING

Staging for primary nonmelanoma cutaneous malignancies is outlined in Table 23.4. Size and invasion of extradermal structures determines T stage, whereas presence of nodal metastasis results in a stage III classification and presence of distant metastases results in stage IV classification. Eyelid tumors are staged differently, and that system is provided in Table 23.5. Note that no stage groupings are currently recommended for eyelid tumors.66


DIAGNOSTIC IMAGING

Most NMSCs are localized to the site of presentation and do not require any type of diagnostic imaging. However, locally advanced tumors as well as tumors located in the medial canthus or fixed to bone should be imaged to determine the extent of disease and to evaluate for invasion. Most commonly, computed
tomography (CT) and magnetic resonance imaging (MRI) are used to evaluate these tumors. For SCC, CT with contrast should be done to evaluate the primary echelon of nodes to determine if the disease has spread regionally. Positron emission tomographic (PET) scan may also play a role for patients with high-risk SCC. Cho et al. showed PET correlation with both local and distant disease extent for all nine patients with high-risk features.67 Another modality is the use of high-frequency ultrasonography to determine the depth of the lesion. A study by Lassau et al. examined 32 patients with BCC and was able to identify each as hypoechoic on ultrasonography.68 Perhaps of more importance, 29% of BCC lesions were found to be larger than that predicted by clinical examination. This may represent an important tool in the pretreatment setting.








TABLE 23.4 American Joint Cancer Committee (AJCC) 6th Edition Staging for Nonmelanoma Skin Cancer (NMSC)















































































Primary tumor (T)


Tx


Primary tumor cannot be assessed


TO


No evidence of primary tumor


Tis


Carcinoma in situ


T1


Tumor 2 cm or less in greatest dimension


T2


Tumor >2 cm, but not >5 cm, in greatest dimensiona


T3


Tumor >5 cm in greatest dimension


T4


Tumor invades deep extradermal structures


Regional lymph nodes (N)


Nx


Regional lymph nodes cannot be assessed


NO


No regional lymph node metastasis


N1


Regional lymph node metastasis


Distant metastasis (M)


Mx


Distant metastasis cannot be assessed


MO


No distant metastasis


M1


Distant metastasis


Stage grouping


0


Tis


NO


MO


I


T1


NO


MO


II


T2/T3


NO


MO


III


T4


NO


MO


IV


Any T


Any N


M1


aFor multiple tumors, the tumor with highest T category will be classified and the number of separate tumors will be indicated in parentheses.


Source: From American Joint Committee on Cancer (AJCC). Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, with permission.



Jun 21, 2016 | Posted by in ONCOLOGY | Comments Off on General Principles and Management

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