Cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the most common malignant neoplasms in the world and occur at epidemic rates in some countries such as Australia.¹ Collectively, these two carcinomas account for most (95%) patients with nonmelanoma skin cancer (NMSC) and are markedly more common than malignant melanomas, which account for only 5% of all skin malignancies. Most BCCs and SCCs occur in individuals older than 50 years old with fair complexions or outdoor occupations mostly on the sun-exposed head and neck or extremities, although NMSC does occur in younger people. Skin cancers may be disfiguring and associated with local morbidity in certain locations but are rarely lethal. The frequency of BCC is four times that of SCC, and BCCs tend to be more indolent and rarely metastasize.

Other NMSCs that are infrequently encountered include Merkel cell carcinoma (MCC) and adnexal cancers. MCC, also known as primary cutaneous neuroendocrine carcinoma, is a rare small cell carcinoma originally described by Toker in 1972.² Sebaceous gland carcinomas account for less than 1% of all skin neoplasms.³ Eccrine or sweat gland carcinomas are very rare, estimated to account for less than 0.01% of malignant epithelial neoplasms of the skin.

Etiology And Epidemiology

The main etiologic factor for cutaneous carcinoma is sun exposure in individuals, usually whites, whose skin is susceptible to the chronic carcinogenic effect of ultraviolet (UV) light.⁴ Approximately 90% of NMSC can be attributed to excessive sun exposure. Other, less common etiologic factors include exposure to chemical carcinogens (e.g., arsenic, tar, anthracene, and crude paraffin oil), chronic irritation or inflammation, and ionizing radiation.

The incidence and aggressiveness of SCC and MCC (both immunogenic carcinomas) are markedly increased in individuals with compromised immune function, including patients with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia ⁵ and organ transplant recipients with iatrogenic immunosuppression.⁶ In contrast, the incidence of BCC is not increased and the outcome is similar as for immunocompetent patients.

Some genetic syndromes are also associated with a higher risk of developing skin carcinoma. Individuals with xeroderma pigmentosum are prone to developing BCC and SCC at a very young age because of defective repair of UV light–induced DNA damage.⁷ These patients usually die in their early 20s from disseminated SCC or melanoma. The basal cell nevus syndrome (or Gorlin syndrome) is a genetic form of BCC inherited through an autosomal dominant gene.⁸ Individuals with epidermodysplasia verruciformis tend to develop nodules of SCC within large verrucous plaques in the 3rd and 4th decades of life.

Prevention And Screening

Unprotected sun exposure, especially during the summer, is the main determinant for the subsequent development of skin cancer. Children and adolescents should be especially educated in regard to sun protection. The damage of excessive UV exposure is irreversible, but despite this adults can still reduce their risk by avoiding further excessive UV exposure. Authorities worldwide have made recommendations regarding appropriate measures. A panel of the American College of Preventive Medicine issued practice policy statements with regard to skin cancer prevention, as summarized by Hill and Ferrini,⁹ and recommended preventive measures to reduce skin cancer to include avoidance of sunlight exposure—particularly limiting time spent outdoors between 10 A.M. and 3 P.M.—and wearing protective physical barriers, such as hats and clothing. If sun exposure cannot be limited because of occupational, cultural, or other factors, the use of sunscreens that are either opaque or that block UVA and UVB radiation is recommended. The use of tanning booths is also a factor in the risk of developing skin cancer, and guidelines regarding their appropriate use should be followed.

Early intervention is another means aimed at reducing the morbidity and mortality of skin cancers. The American College of Preventive Medicine also recommends periodic screening, consisting of a total cutaneous examination and a 2- to 3-minute visual inspection of the entire integument by adequately trained physicians, either individually or through mass screening, for high-risk individuals. The risk factors include family history of skin cancer, fair skin, multiple nevi, and a history of other skin cancers.

Clinical Manifestations, Pathobiology, And Pathways Of Spread

Basal Cell Carcinoma

Clinical Presentation and Pathology

BCC constitutes approximately 80% of all NMSC and is the most common malignancy worldwide. Most BCCs arise on the sun-exposed head and neck (80% to 85%); lesions occur less frequently on the trunk or extremities. Lesions may manifest as an asymptomatic nodule, a pruritic plaque, or a bleeding ulcer that characteristically waxes and wanes.10,11 Many patients treated for BCC develop at least one or more further BCCs.¹² Careful evaluation of sun-exposed skin should be part of any follow-up examination.

BCC has numerous variants, each of which has distinctive clinical and histologic features and natural history. The characteristics of commonly occurring types are briefly summarized. Nodular BCC, colloquially referred to as rodent ulcer, is the most frequently observed variant and accounts for approximately 50% of all lesions (Fig. 39-1). This type of skin cancer begins as a distinct papule that may develop central umbilication, progressing to central ulceration as the lesion grows. The margins of the lesion appear pearly (pale and translucent) and contain enlarged capillaries (telangiectasia). Histologic features include the presence of large islands of monomorphous basaloid cells, varying in size and shape, embedded in a fibroblastic stroma in the dermis. The basaloid cells have large, oval hyperchromatic nuclei, scant cytoplasm, and no intercellular bridges. The peripheral cell layer of the aggregate frequently shows palisading, whereas central cells are less organized. Nodular BCC may show a varying degree of pigmentation (blue, brown, or black), depending on the number of melanocytes present in the lesion, and may be difficult to differentiate clinically from malignant melanoma.¹³

Figure 39-1 A 75-year-old white male with a long-standing nodular basal cell carcinoma occupying the left side of the lower nose with associated destruction and nostril retraction. The margins have a pearly appearance, and there are scattered telangiectasia. He was treated with definitive RT with the understanding that further retraction was likely to follow as the tumor regressed.

Superficial BCC manifests as red, scaly macules with indistinct margins, usually located on the trunk (Fig. 39-2). It enlarges into a crusted, erythematous patch without induration that may be difficult to differentiate clinically from solar keratosis, psoriasis, SCC in situ, or extramammary Paget’s disease. Histologic examination shows multiple foci of buds of neoplastic cells with peripheral palisading originating from the undersurface of the epidermis.¹⁰

Figure 39-2 A, A 45-year-old white male with a large superficial spreading basal cell carcinoma located on the left shoulder. He was treated with definitive RT (55 Gy in 25 fractions using superficial energy photons) because surgery to excise this tumor would require reconstruction and result in possible shoulder impairment. The RT field margins are generous (1.5 to 2 cm) to encompass any subclinical extension. B, Completion of RT with confluent in-field erythema, patchy moist desquamation, and marked flattening of the treated tumor.

Morpheaform (sclerosing) BCCs appear as single, flat, indurated, ill-defined macules. The lesions generally have a smooth, shiny surface that becomes depressed as it grows into a plaque. It is characterized histologically by the presence of small groups and narrow strands of basaloid cells embedded in a dense, fibrous connective tissue; there is little peripheral palisading.¹⁴ Perineural invasion is often reported to be present.

Infiltrative BCC has an opaque yellowish appearance and blends subtly with the surrounding skin.¹⁴ Histologically, the lesion is characterized by poorly circumscribed spiky cell aggregates in the superficial portion and the main bulk, consisting of strands of neoplastic cells infiltrating the reticular dermis and subcutis.

Location is important in defining high-risk BCC. The midface, or so-called H zone (Fig. 39-3), including the periauricular region, glabella, medial canthus, nose, nasolabial region, and columella, contains embryonal fusion planes.¹⁵ The extent of tumors in this region is frequently underestimated, leading to inadequate surgical excision, especially deep, and a higher rate of local recurrence. Histologic examination often reveals extensive infiltration of deeper structures by small nests of undifferentiated basal cells. This type of lesion may invade the orbit, nose, and maxilla, resulting in significant deformity. It should be readily recognized and treated promptly often necessitating extensive surgery with or without adjuvant RT.

Figure 39-3 Diagram of H zone. Especially problematic areas are the medial canthus, glabella, nasolabial folds, and periauricular region.

Biology and Pattern of Spread

The biologic behavior of BCC varies with the histologic type. A superficial BCC may remain stable for a long time or enlarge gradually over many years to become a nodulo-ulcerative variant. Nodular BCC grow slowly over many years by peripheral and deep invasion, particularly along embryonal fusion planes, and perineural spread. Morpheaform, infiltrative, and terebrant BCCs are more aggressive variants that may spread through peripheral invasion or infiltration of deeper structures, or both. Perineural (or neurotropic) invasion in BCC is rare, occurring in only 2% to 3% of patients, and generally occurs in the setting of recurrent disease or in morpheaform histology.¹⁶ Lesions located around the orbit may gain access to the orbit via the first or second division of the trigeminal nerve (or fifth cranial nerve).

BCCs rarely spread to the regional lymph nodes or distant organs with an overall incidence of metastasis less than 0.01%.¹⁷ Most metastases occur in the regional lymph nodes with distant spread usually preceded by regional metastasis. Regional disease typically develops with large, ulcerated lesions in the head and neck that have recurred after repeated surgery and RT.

Squamous Cell Carcinoma

Clinical Presentation and Pathology

SCC arises from keratinocytes of the epidermis. This type of NMSC most commonly develops from skin exhibiting solar (or UV) damage. Actinic (or solar) keratosis (intradermal malignant neoplasm) is generally a precursor or premalignant lesion; at least 50% to 60% of all invasive SCCs arise from actinic keratoses. Despite this, only a few (<5%) actinic keratoses actually progress to invasion. In a large study of 169 patients with 7784 documented actinic keratoses, the risk of malignant progression was reported in 2.6% at 4 years.¹⁸ Less frequently, SCC occurs from other preexisting skin lesions, such as arsenic keratosis, a thermal burn scar, or a chronic ulcer. Rarely, it arises from normal-appearing skin.¹³

Clinically, SCC in situ (Bowen’s disease) manifests as a soft, erythematous, scaly, well-circumscribed patch (Fig. 39-4). Superficial carcinoma manifests as a scaly, crusted plaque or ulcer with a verrucous or papillate border, and infiltrating SCC manifests as a firm, ulcerated mass with an elevated nodular border (Fig. 39-5).

Figure 39-4 A 55-year-old male with multiple patches of in situ squamous cell carcinoma (SCC) occupying the right temple and forehead. Previous surgery was performed on his right ear for a large SCC.

Figure 39-5 An 80-year-old white female with two ulcerative and bleeding squamous cell carcinomas. The larger lesion is located inferior and posterior to the right ear with the smaller lesion located in the superior and anterior neck. Both lesions were treated with palliative RT (25 Gy in 5 fractions using orthovoltage photons).

Microscopically, SCC is composed of strands and sheets of atypical keratinocytes. It is referred to as SCC in situ when atypical keratinocytes are confined to the epidermis. Superficial SCC represents atypical keratinocyte proliferation confined to the upper reticular dermis, whereas infiltrating SCC denotes disease extension into and beyond the lower reticular epidermis.

Histologically, SCC is graded as well, moderately, or poorly differentiated, based on the magnitude of cellular polymorphism, keratinization, and mitosis. The spindle cell variant mimics other skin tumors, such as amelanotic melanoma, and may require a panel of immunohistochemical studies for complete characterization.

Biology and Pattern of Spread

SCC generally has a more aggressive course than BCC. Carcinoma in situ (or Bowen’s disease) may evolves gradually into superficial carcinoma in 5% of cases.¹⁹ Untreated, it may progress further into an infiltrating type that invades the surrounding and underlying structures. The rate of progression depends on the degree of cellular differentiation.

The risk of developing metastases, usually nodal, is markedly higher in SCC than in BCC. However, most immunocompetent patients with small (<2 cm), thin (<4 to 5 mm thick), nonrecurrent lesions are at low (<5%) risk of developing nodal metastases. Patients not meeting these criteria can be considered high-risk patients (>10% risk), and appropriate awareness and management are required.²⁰ Recurrent lesions in close proximity (forehead, temple, ear, cheek) to the parotid gland increase this risk (Fig. 39-6). Data suggest that tumor thickness greater than 6 mm is a powerful, independent predictor of patients at risk for regional metastases.²¹

Figure 39-6 A, A 57-year-old white male with a recurrent left temple squamous cell carcinoma arising from the posterior edge of his previous graft site and associated with a concomitant 2-cm metastatic parotid lymph node. B, The patient underwent wide excision of the recurrent primary tumor in association with a superficial parotidectomy and upper neck dissection. He then underwent adjuvant parotid RT in the setting of multiple nodes with extracapsular spread.

The most frequent sites for the development of metastatic cutaneous SCC are the parotid gland, the cervical lymph nodes, or both.²² In 20% to 25% of cases, an obvious index lesion is not identified. Invariably, these patients have a long-standing history of actinopathy with previous NMSC. The development of distant metastases (e.g., lung, liver) rarely occurs as a first site of relapse and is more often encountered after initial treatment for nodal metastases.

Metastatic cutaneous SCC occurs less frequently in other nodal regions, such as the axilla and groin. Although difficult to quantify, the ratio of metastatic head and neck SCC to non–head and neck SCC is approximately 9 : 1. There are much fewer published data on the management of these patients, but analogous generalizations from the evidence on parotid and neck nodal metastases suggest operable patients should have surgical resection, and many have unfavorable features, such as extranodal spread and incomplete margins, and require adjuvant RT.²³ The combination of surgery and adjuvant RT often leads to extremity lymphedema, and patients should be warned about this.

Merkel Cell Carcinoma

Clinical Presentation and Pathology

MCC is a small cell cutaneous malignancy that often manifests as a rapidly enlarging firm, painless, pink-red, dermal-based nodule, most frequently on the head and neck or extremities in older (>60 to 70 years old) individuals (Fig. 39-7). In contrast to other types of NMSC, MCCs frequently arise in women. Diagnosis is often delayed by clinicians because of the uncommon nature of this disease. The median size of the primary lesion at diagnosis is approximately 2 cm, and the incidence of clinical nodal involvement at presentation is approximately 20% to 25%, although the risk of harboring occult nodal disease is high (30% to 40%).²⁴ Based on the U.S. Surveillance, Epidemiology, and End Results (SEER) database, the annual incidence in men is 0.34 per 100,000 with most patients older than 65 years and white (94%). In this study, slightly less than half (46%) of all lesions occurred in the head and neck, and at diagnosis half of all patients had localized disease with nodal metastases present in approximately 25%.²⁵

Figure 39-7 An 83-year-old white male with a rapidly progressing right lower eyelid Merkel cell carcinoma. There is an enlarged right metastatic parotid lymph node. The patient underwent definitive RT.

The cell of origin of this neoplasm is thought to be the dermal neurotactile cell arising from the neural crest first described by Merkel.²⁶ The lesion usually involves the reticular dermis and subcutaneous tissues, with minimal extension to the papillary dermis and sparing of the epidermis. Vascular and lymphatic permeation is common, and clinically such permeation often manifests as in-transit metastasis. The neoplastic cells exhibit cytoplasmic extensions and small, uniform, membrane-bound neurosecretory granules on ultramicroscopic examination.²⁷ Several immunohistochemical markers have been identified in MCC. The neoplastic cells stain most consistently with polyclonal antisera to neuron-specific enolase and calcitonin, monoclonal antibody to neurofilament, and cytokeratin (CK 20 positive).²⁸ More recent evidence suggests a possible viral association in the development of MCC. In the study by Feng and colleagues,²⁹ 8 of 10 tumors were found to contain Merkel cell polyomavirus compared with only 8% in control tissues.

Biology and Pattern of Spread

The results of many retrospective studies confirm that MCC has an aggressive course characterized by propensity for contiguous spread, reflected in high local recurrence rates after wide surgical excision alone and a high incidence of nodal involvement and hematogenous dissemination.²⁹ Most series document a cancer-specific death rate of around 30%.³⁰ Patients may also present with metastatic nodal disease without an obvious index lesion. In one large study, 19% of patients had metastatic disease to nodes from an unknown primary.³¹ MCC is a highly immunogenic carcinoma, and immunosuppressed patients (organ transplant recipients) and patients diagnosed with non-Hodgkin’s lymphoma and chronic lymphocytic leukemia are at higher risk of developing MCC and having a poor outcome. In a study of 41 organ transplant recipients with MCC, many were younger, most (68%) had nodal disease at diagnosis, and almost 60% died of their disease.³²

Adnexal Carcinoma

Sebaceous Carcinoma

Clinical Presentation and Pathology

Sebaceous carcinomas are rare (approximately 400 reported) and arise most commonly (75% of cases) from the sebaceous glands of the ocular adnexa, the meibomian glands in the tarsus or glands of Zeis at the lid margin, and the caruncle. Extraocular locations, in decreasing frequency, are head and neck region, trunk and extremities, and external genitalia.³ Histologically, these carcinomas are composed of dermal-based lobules and cords of tumor cells, with varying degrees of sebaceous differentiation and infiltration into the surrounding tissues. Differentiated cells contain foamy or vacuolated, slightly basophilic cytoplasm, whereas less differentiated cells contain more deeply basophilic cytoplasm. Clinical and pathologic features that indicate a poor prognosis include size of the primary lesion (>1 cm is associated with 50% mortality rate), vascular and lymphatic invasion, poor sebaceous differentiation, highly infiltrative growth pattern, and intraepithelial carcinomatous changes in the overlying epithelia.³³

For malignant neoplasms of the eyelids, sebaceous carcinomas are second only to BCC in frequency and second only to malignant melanoma in lethality. The most common location of ocular sebaceous carcinomas is the upper eyelid, followed by the lower eyelid and caruncle. Sebaceous carcinomas predominantly affect individuals older than 60 years. There is a slight preponderance for women. These lesions manifest clinically as slow-growing, nontender, deep-seated, firm nodules. They often produce a chalazion or manifestations suggestive of inflammatory processes, such as conjunctivitis, blepharitis, or tarsitis. Small primaries may be overlooked until orbital invasion or spread to preauricular or cervical nodes occurs.

The differential diagnosis includes sebaceous adenoma and BCC with sebaceous differentiation (basosebaceous epithelioma). Distinction between basosebaceous epithelioma and sebaceous carcinoma is important because of the difference in the biologic behavior.

Biology and Pattern of Spread

Sebaceous carcinoma behaves more aggressively than SCC, with a propensity for nodal and hematogenous spread.³⁴ Of the 104 patients registered by the Ophthalmic Pathology of the Armed Forces Institute of Pathology, 23 patients (22%) experienced local recurrence once, and 11 patients experienced local recurrence two or more times. Metastatic disease was the cause of death in 23 patients.³³

Eccrine Carcinoma

Clinical Presentation and Pathology

Sweat gland (eccrine, apocrine, apoeccrine) carcinomas are exceedingly rare, arise most frequently in the skin of the head and neck or the extremities, and manifest as painless papules or nodules that grow slowly. This type of neoplasm is usually diagnosed in individuals 50 to 70 years of age.

Histologically, eccrine or sweat gland carcinomas may resemble carcinomas of the breast, bronchus, and kidney and are difficult to differentiate from cutaneous metastases. Many histologic variants are reported and include ductal eccrine carcinoma, mucinous eccrine carcinoma, porocarcinoma, syringoid eccrine carcinoma, clear cell carcinoma, and microcystic adnexal carcinoma.³⁵

Biology and Pattern of Spread

Eccrine carcinoma also has more aggressive behavior than BCC and SCC. In a series of 14 patients who underwent surgical excision with free microscopic margins, 11 developed at least one local recurrence, and 5 failed at regional nodes or distant sites. One patient died of uncontrolled local relapse, and four died of distant metastasis 2 months to 10 years after diagnosis.³⁵ Apocrine carcinoma arises most commonly from apocrine glands of the axilla, but it can originate from apocrine glands of the vulva and eyelids and from ceruminal glands of the external auditory canal. It manifests clinically as a red-purple single or multinodular, firm or cystic dermal mass in elderly individuals. Because of its rarity, the natural history of apocrine carcinoma is not well known. Nodal and distant spread has been reported.^36,³⁷

Microcystic Adnexal Carcinoma

Clinical Presentation and Pathology

Microcystic adnexal carcinoma is a rare locally aggressive carcinoma that belongs to the spectrum of adnexal carcinomas and most often arises on the head and neck.³⁸ It usually grows slowly over years and often is deeply invasive when diagnosed. It arises equally in males and females and tends to occur in adults 55 to 60 years old and occasionally in children.

Histologically, the tumor is composed of keratin horn cysts, nests, or cords of basaloid cells that are usually more prominent in the superficial dermis. Tumor strands and cystically dilated tubules are arranged in sold islands and embedded in deeper desmoplastic stroma. The cells usually show no atypia or mitoses, and the differential diagnosis may include trichoadenoma, syringoma, desmoplastic trichoepithelioma, or morpheaform BCC.³⁹

Biology and Pattern of Spread

Patients with a diagnosis of microcystic adnexal carcinoma often present with advanced and deeply invasive lesions after years of slow growth and misdiagnosis. Perineural invasion is reported to be present in many cases particularly in the recurrent setting. Lymph node metastases rarely occur. Microcystic adnexal carcinoma tends to be a locally recurrent tumor with morbidity related to local invasion and destruction.

Patient Evaluation And Staging

Clinical evaluation of skin cancers consists of inspection and palpation of the involved area and the regional lymph nodes. Symptoms suggestive of perineural invasion, such as pain, tingling, and hypesthesia, should be specifically sought from the patient. Up to 60% of patients with perineural invasion may be clinically asymptomatic, and a crawling sensation on the skin termed formication is very suggestive for sensory nerve involvement.⁴⁰ The most common primary sites associated with perineural invasion are the frontozygomatic (supraorbital nerve) and infraorbital (infraorbital nerve) regions. Patients may present with a cranial nerve palsy as the first sign of perineural invasion. Facial nerve involvement is usually preceded by muscle fasciculations followed by frank paralysis.⁴¹

Imaging studies (chest radiography, computed tomography [CT], or magnetic resonance imaging [MRI]) generally are not required in most patients with NMSC but should be obtained as indicated (e.g., clinically suspicious lymph nodes). Lymph node metastasis and bone involvement are best assessed with contrast-enhanced CT scan acquired with soft tissue and bone windows (Fig. 39-8). MRI, with and without contrast enhancement and fat suppression, should be obtained for all patients in whom perineural invasion is suspected, with the findings of an enlarged or abnormally enhancing nerve raising the possibility of perineural invasion.⁴² Patients often need to undergo biopsy of the suspected nerve to confirm the diagnosis.⁴³

Figure 39-8 Axial computed tomography (CT) scan showing metastatic cancer in the left parotid. There is concentric nodal enlargement, contrast enhancement of the rim, and central necrosis—all features consistent with a metastatic node from squamous cell carcinoma.

Staging of Basal and Squamous Cell Carcinoma

Official staging systems are available for BCC and SCC but have been criticized for lacking clinical and prognostic relevance, especially for patients with SCC.44,45 More recent changes include reporting of important pathologic high-risk features, such as tumor depth and the presence of perineural invasion. The previous American Joint Committee on Cancer (AJCC) TNM (primary tumor, regional nodes, metastases) staging systems were based primarily on clinical findings and were of limited usefulness. In regard to T stage, only maximum horizontal dimension determined stages T1 to T3. The newer staging system (AJCC seventh edition) incorporates important clinicopathologic factors and does not rely purely on size as a T stage determinant. High-risk features can now upstage a tumor, for example from T1 to T2, even if horizontal size is unchanged.

Similar to previous flaws in staging patients with the primary, or T, stage, patients with nodal metastases from SCC were assigned an N stage via a flawed staging system with all patients indiscriminately assigned as stage N1 regardless of metastatic nodal size, number, or presence of extranodal spread.⁴⁶ O’Brien and colleagues⁴⁷ proposed a staging system for metastatic SCC to the parotid or neck that categorizes N (neck) and P (parotid) stage based on the aforementioned variables. The new AJCC system now delineates using number and size of nodes.

Staging of Merkel Cell Carcinoma

A staging system developed by the Memorial Sloan-Kettering Cancer Center separates patients into patients with primary lesions less than 2 cm (stage I) and patients with primary lesions greater than or equal to 2 cm (stage II). Patients with nodal disease are stage III, and patients with distant disease are stage IV. A few (10% to 15%) patients present with metastatic nodal disease without an obvious index lesion.⁴⁸ This staging system is prognostic with the presence of nodal metastases independently predicting for a worse outcome. In the current AJCC TNM staging system, primary size and clinical and pathologic nodal status are incorporated into new group staging.

Primary Treatment and Results

Basal and Squamous Cell Carcinoma

Primary Tumor

The general strategy for treating the primary lesion is essentially the same for either BCC or SCC. Various approaches are available for the management of cutaneous carcinomas, including curettage and electrodesiccation, Mohs’ micrographic surgery, cryotherapy, surgical resection, and definitive RT.

With proper case selection, evidence suggests that these approaches are similarly effective in curing most skin cancers. The choice of treatment for individual patients is determined by factors such as the site and size of lesion, anticipated functional and cosmetic results, treatment time and cost, patient age, occupation, and general condition. Carcinomas in the H zone or embryonic fusion planes tend to have extensive local spread, so treatment techniques that ensure wide marginal coverage should be selected for such lesions.

Overall, surgery is preferred for most patients. Simple procedures can yield high local control probability for patients with small lesions. Composite resection is necessary, however, for patients with extensive, deeply invasive tumors. Younger patients who have years of future exposure to sunlight are also better managed by surgery than by RT, although in certain cases RT may still be considered a better option.⁴⁹ In numerous settings, such as close or positive margins or the presence of perineural invasion, postoperative RT may be beneficial to reduce the risk of local recurrence.

The indications for postoperative (adjuvant) RT include the presence of positive surgical margins, perineural spread, invasion of bone and cartilage, lymph node metastasis, and extensive skeletal muscle infiltration. Relevant information including size, depth of invasion, differentiation, presence or absence of perineural invasion, and margin status should be obtained from the pathologist. The University of Florida group reported a 100% local control rate in medial canthus BCC treated with adjuvant RT in the setting of positive margins when prescribing a median dose of 50 Gy in 20 daily fractions.⁵⁰

Primary (or definitive) RT is most often indicated for lesions on and around the nose, lower eyelids, medial canthus, and ears, where it yields better functional and cosmetic results than surgery ⁵¹ (Fig. 39-9). Extensive lesions of the cheek, lip, and oral commissures that would require full-thickness resection may also be better irradiated. The lower lip is especially suited for RT when surgery may result in microstomia or require complex reconstruction for lesions occupying more than one-third of the lip. Patients can be easily treated with orthovoltage RT after insertion of a lead oral cavity shield with expected cure rates similar to surgery.⁵²

Figure 39-9 A, A 55-year-old white female with a 2.5-cm nodular basal cell carcinoma located on the right medial canthus. An internal eye shield has been inserted in preparation for RT markup. B, At markup, an RT field margin of approximately 1 cm (solid line) was applied. C, At completion of RT (55 Gy in 25 fractions using superficial energy photons), the tumor has almost completely regressed. At 3-year follow-up, she remained disease-free.

The overall local control rate of all sizes and types of cutaneous carcinoma treated with various modalities is 80% to 90%. RT is an excellent treatment option for patients in whom other modalities may have failed or are considered less optimal. In a series from M.D. Anderson Cancer Center of patients with SCC of the eyelid (Fig. 39-10) treated with definitive RT, an excellent 5-year local control of 89% was achieved.⁵³

Figure 39-10 A 56-year-old white male with squamous cell carcinoma of his lower eyelid. He was treated with definitive RT, receiving a dose of 50 Gy in 20 fractions using superficial energy photons following the daily insertion of an internal eye shield.

Patients with recurrent lesions (vs. de novo lesions) and with SCC (vs. BCC) have lower rates of local control. Similarly, as lesions increase in size, rates of local control decrease. In one study of patients with locally advanced (>T2) SCC and BCC, 4-year locoregional control rates were 86% and 58% for SCC and BCC.⁵⁴ Despite this, RT may still remain the best option.

Although the initial cosmetic result after RT is excellent, fibrosis, soft tissue or epidermal atrophy, and in-field pigmentation changes may become apparent over time. Unprotected sun exposure to irradiated sites is likely to exacerbate these changes, and patients should be warned to take appropriate measures. When RT is delivered to younger patients, daily fraction sizes of 2 to 2.5 Gy are recommended (e.g., 55 Gy in 25 fractions) to minimize late changes. The risk of developing a late in-field radiation-induced malignancy after treatment for skin cancer is rare and poorly documented in the literature. Alternative treatments should be considered for younger patients, however, because many develop further skin cancers as they age. There is no absolute contraindication for offering RT to younger patients if the patient and clinician agree this is the optimal modality.

Regional Nodes

Elective nodal treatment is not indicated for cutaneous BCC or low-risk SCC because of the low incidence of lymphatic spread. However, certain patients with high-risk SCC may warrant elective treatment (surgery or RT) of clinically node-negative regional nodes in conjunction with treatment of the primary.⁵⁵ A patient with a recurrent temple SCC in whom adjuvant RT was recommended in the setting of a positive deep margin should have the parotid nodes included electively en bloc in the RT field (Fig. 39-11).

Figure 39-11 A 73-year-old white male had wide-field adjuvant RT to a high-risk squamous cell carcinoma (recurrent and positive deep margin) with the field electively encompassing his parotid lymph nodes. The patient received 50 Gy in 20 fractions using orthovoltage energy photons.

Patients who develop metastatic cutaneous SCC to the parotid or neck are optimally treated with surgery and adjuvant RT with few exceptions.⁵⁶ The aim of adjuvant RT is to reduce the risk of regional relapse because most patients have unfavorable features, such as multiple metastatic nodes, extranodal spread, close margins, or the presence of perineural invasion. Approximately 20% to 25% of patients do not have an obvious index lesion to explain the presence of metastatic nodes. With combined treatment, 5-year overall survival (OS) is 70% to 75%. Patients considered medically or technically inoperable can still be treated with RT alone, although the likelihood of cure is reduced.

Sentinel Node Biopsy

The role of sentinel node biopsy in NMSC is unclear because the overall incidence of metastatic nodal disease is low. In contrast to patients with melanoma, there is limited evidence to guide clinicians.⁵⁷ In certain patients considered to have high-risk lesions, however, sentinel biopsy may be useful in guiding clinicians, provided that expertise in undertaking this investigation is available.

Merkel Cell Carcinoma

The initial treatment for MCC is usually surgery to establish tissue diagnosis. The role of radiation in the management of MCC has been evaluated since the early 1980s because of the high rate of locoregional relapse in this very radiosensitive disease after surgery alone.

With few exceptions, most studies report a marked benefit to locoregional control and survival with the addition of adjuvant RT. In the largest study (n = 1665) of its type, the addition of adjuvant RT significantly improved median survival in patients with lesions greater than 2 cm from 21 months to 50 months (p = .0003).⁵⁸ In a meta-analysis of 1254 patients, Lewis and colleagues⁵⁹ reported a significant reduction in local (hazard ratio 0.27, p <.001) and regional (hazard ratio 0.34, p <.001) relapse and a benefit in overall survival (hazard ratio 0.63, p = .04) in patients treated with surgery and adjuvant RT compared with patients treated surgery alone. Clark and colleagues⁶⁰ analyzed data from two Australian Hospitals (Westmead and Royal Prince Alfred Hospitals, Sydney) and from Princess Margaret Hospital in Canada and documented significant improvement in local control (p = .009), regional control (p = .006), and disease-free survival (p = .013) from combined treatment versus surgery alone.

The routine use of adjuvant chemotherapy is unclear. In a phase II single arm study from Australia, 53 patients received concurrent and adjuvant chemotherapy (carboplatin and etoposide) with RT with 3-year OS, locoregional control, and distant control rates of 76%, 75%, and 76%, respectively.⁶¹ These impressive results in patients with poor prognostic features, particularly the presence of nodal metastases in 33 (62%) patients, strongly suggest a potential benefit to the addition of combination chemotherapy in patients with unfavorable features. Another study compared patients treated with the addition of chemotherapy to RT (n = 40) with patients treated without chemotherapy (n = 62).⁶² The authors reported no significant OS benefit to patients receiving chemotherapy (p = .16) and no improvement in distant control (65% vs. 70%; p = .61). Although not excluding a possible benefit to chemotherapy, these results add support for a randomized controlled trial to confirm the hypothesis that chemotherapy would benefit these patients.

With few exceptions, most patients should proceed to wide-field adjuvant RT when a diagnosis has been confirmed. RT should not be delayed by the need for further surgery if excision margins are involved. Patients with small volume (<3 to 4 cm) nodal metastases can be treated adequately with RT without the need to undergo nodal resection. As a guide, treatment fields should encompass, as a minimum, the primary site, in-transit tissue, and first-echelon nodes (Fig. 39-12). Margins of at least 3 to 4 cm are recommended. In the setting of inoperable disease, definitive RT to doses of 50 to 55 Gy in 20 to 25 daily fractions still offers the likelihood of excellent in-field control (75%) and cure in a few patients.⁶³

Figure 39-12 A 49-year-old male undergoing wide-field adjuvant RT after excision of a 12-mm Merkel cell carcinoma from the right upper face. The large field encompasses the excision site, in-transit tissue, and parotid and upper neck lymph nodes. A dose of 55 Gy in 25 fractions using 9 MeV electrons was prescribed. The patient developed confluent brisk in-field erythema by the end of treatment.

Adnexal Carcinoma

The standard treatment of sebaceous carcinoma is wide local excision and therapeutic nodal dissection if lymphadenopathy is present. The role of adjunctive modalities has not been explored systematically. Generally, postoperative irradiation is indicated when the surgical margins are positive or close, multiple lymph nodes are involved, or extracapsular nodal extension is present.

For eccrine and apocrine carcinomas, wide excision of the primary lesion is accepted as the standard treatment in patients with no lymphadenopathy at diagnosis. Postoperative RT to the surgical bed with 2- to 3-cm margins is indicated, particularly for eccrine carcinoma, because of the high incidence of local recurrence after surgery alone. The role of elective treatment of regional lymphatics is controversial in this rare disease. Treatment for patients with palpable lymphadenopathy consists of wide local excision, lymph node dissection, and postoperative irradiation to the primary and nodal bed.

Locally Advanced Disease And Palliation

Patients with locally advanced (T4) primary skin cancers involving bone and cartilage, muscle, or nerves can still be treated and cured with definitive RT. In many cases, surgical salvage is an option if RT is unsuccessful. Al-Othman and colleagues ⁶⁴ documented an initial local control rate of 53% and an ultimate local control rate of 90% with surgical salvage in 85 patients with previously untreated (n = 43) and recurrent (n = 45) T4 skin carcinomas given RT to doses of 60 to 75 Gy over 6 to 8 weeks. Bone invasion or perineural spread was found to reduce the likelihood of local control in this small series. Cause-specific survival at 5 years was 76%, and 15% developed severe late complications in the form of soft tissue or bone and cartilage necrosis.

Radiation can reduce symptoms (pain, bleeding, fungation) for most patients with advanced inoperable cancer or metastatic disease. Recommended dose-fractionation schedules depend on the tumor location and patient’s life expectancy. The most frequently used regimens include the following:

• 20 to 30 Gy in 5 to 10 fractions over 1 to 2 weeks for skeletal or cerebral metastasis

• 45 to 50 Gy in 18 to 25 fractions over 4 to 5 weeks for patients with tumor deposits in the proximity of critical structures (e.g., parotid, axillary, or ilioinguinal region) but otherwise having a reasonable life expectancy (Fig. 39-13)

Figure 39-13 A, An elderly male with a large fixed prefungation metastatic right parotid lymph node. The patient was unsuitable for combined treatment and underwent high-dose palliative RT alone. B, The patient experienced complete clinical regression 2 months after receiving 50 Gy in 20 fractions using 12-MeV electrons and bolus as well as a significant improvement in his quality of life.

Single, large fractions of 10 to 15 Gy may also be appropriate in debilitated nursing home patients with large neglected lesions that are often painful, bleeding, and infected.

Many SCCs express epidermal growth factor receptor, and targeted treatment using monoclonal antibodies is emerging. In some cases, dramatic results have been obtained using this relatively nontoxic treatment.⁶⁵

irradlation techniques

Carcinoma

As previously documented, definitive RT yields an excellent disease control rate with good functional and cosmetic results for lesions around the nostril, lower eyelids, auricles, and lips. Patients who are poor surgical risks and patients with large lesions are also sometimes best treated with RT. Proper planning and execution of RT are essential to achieve the best outcome.

Target Volume

The RT target volume (or RT field) is determined by the size of the lesion, lesion location, and type of growth (infiltrative lesions require more generous field margins). The treatment field typically encompasses the visible or palpable tumor and 1 to 2 cm of surrounding normal-appearing skin. Margins may be tighter (1 to 1.5 cm) when treating areas close to the eye or when the primary lesion is 1 cm or smaller. More generous margins are appropriate for lesions with ill-defined borders. In this situation, the field size occasionally may be reduced after delivering a dose sufficient to sterilize potential microscopic contiguous extension. Most definitive treatment fields for primary lesions, even up to 10 cm in size, can usually be delivered in one phase.

Occasionally, in patients with SCC presenting with either low-volume lymphadenopathy and concomitant primary disease or high-risk primary lesions and a clinically negative nodal basin, the initial field may encompass the primary lesion and the regional lymphatics with the treatment field subsequently reduced to cover the areas of gross disease with adequate margins. A typical site is a temple primary with parotid metastases in which the initial RT field should receive a prescribed dose of 50 Gy, or equivalent, followed by an extra 10 to 20 Gy to a reduced field (1 to 2 cm around macroscopic disease). In many cases, small treatment fields can be safely treated with hypofractionated schedules using 2.5- to 4-Gy fractions, reducing the overall duration of treatment.

In patients receiving postoperative irradiation in the setting of lymph node metastasis or perineural invasion, the initial portal also may need to encompass the primary tumor bed, if technically feasible. However, if the time interval from primary site treatment exceeds 12 months, and there is no evidence of local recurrence, this may be omitted. The clinical target volume in the setting of perineural invasion depends on the primary site and the relevant cranial nerves involved and in many cases includes the skull base and cavernous sinus.⁶⁶ Electively treating regional lymph nodes in patients with perineural invasion is an option but probably unnecessary.

Setup, Field Arrangement, and Dose Fractionation Schedule

Patients are best immobilized in a position that gives optimal access to irradiate the tumor to ensure daily reproducibility. Preferably, the position is such that the plane of the skin to be treated is horizontal to facilitate the placement of a lead shield for skin collimation. Irradiation is delivered through a single appositional field, in most cases using superficial orthovoltage energy photons (usually 75 to 300 kVp) or electrons (usually 6 to 9 MeV). Low-energy photons are preferable to using small field electrons when treating skin cancers. Lesions can be treated effectively with electrons, provided that clinicians are aware of certain aspects of using electrons (e.g., skin sparing, dose constriction).⁶⁷

The energy of x-rays or electrons is chosen based on the thickness of the lesion to be treated. This decision is critical when using electrons, the energy of which should be selected such that the 90% isodose line including surface bolus is a few millimeters deeper than the base of the lesion. The treatment distance for x-rays also depends on the thickness of the lesion. A shorter 20- to 30-cm focus skin distance cone is appropriate for superficial tumors, but a 50-cm focus skin distance open field with skin collimation is preferable for thicker lesions to avoid a large dose gradient across the lesion. The focus skin distance for electrons is usually 100 cm.

Several techniques and devices are helpful in minimizing radiation exposure to the surrounding normal tissues and obtaining the desired dose distribution. A 3- to 4-mm-thick lead cutout is used for field shaping, conforming to the geometry of the lesion by skin collimation (Fig. 39-14). The overall size of the cutout should be large enough so that the cone or collimator setting for electron beams is at least 4 × 4 cm in size for reliable dosimetry. Skin bolus or a scatter plate is used when treatment is given with electrons to ensure full surface dose. Additional shielding can be applied to protect tissues from “exit radiation.” An internal eye shield is inserted when treating an eyelid lesion with orthovoltage x-rays or electrons of 8 MeV or less (see Fig. 39-9, B). It is important to calibrate commercially available eye shields individually with respect to their electron-attenuating properties because transmission through these shields can be considerable, even for a nominal 6-MeV beam. Similarly, lead oral cavity shields are used to shield the mandible, teeth, and oral cavity when treating a lip cancer (Fig. 39-15).

Figure 39-14 A patient undergoing RT to the left side of the nose. A lead mask is cut out to define the RT field receiving treatment. There is an extra layer of lead covering the eyes to reduce further any scattered dose.

Figure 39-15 A 45-year-old white male undergoing definitive RT for a T2 N0 lower lip squamous cell carcinoma. The patient received 55 Gy in 25 fractions using orthovoltage energy photons with the daily insertion of an oral cavity lead shield to limit exit dose to the mandible, teeth, and oral cavity.

Several fractionation schedules can been used and are effective in curing primary cutaneous carcinomas. Generally, more protracted fractionation schedules using lower dose (2 to 2.5 Gy) per fraction gives the best cosmetic results. The recommended radiation regimen for individual patients depends on patient age, lesion size, and site. For most skin cancers in older patients, a dose of 40 Gy in 10 fractions, 45 Gy in 15 fractions, or 50 Gy in 20 fractions is an appropriate and effective regimen. If the patient is in poor general condition, hypofractionation (e.g., 32 Gy in 4 fractions, 21 Gy in 3 fractions, or a single dose of 15 to 20 Gy) may be used. Delivering large fractions using superficial energy photons or orthovoltage energy photons can take 20 to 30 minutes, and an uncooperative patient may need to be lightly sedated. For large lesions close to the eye, maximum tolerance is obtained with 60 to 70 Gy in 30 to 35 fractions.

The dose for treatment with x rays is specified at D_max. The dose for irradiation with electrons is prescribed at 90%. Prescription of electron doses at 90% versus D_max for x rays allows for the relative biologic effectiveness difference between the two beam qualities.

After resection of a nodal basin (e.g., parotid or neck), patients with positive nodes (or a single node with extranodal spread) usually receive radiation in 2-Gy fractions to a dose of 60 Gy because of the large treatment volume. Similarly, for patients with inoperable nodal disease treated with RT alone, 2- to 2.5-Gy fractions to a total dose of 60 to 70 Gy with a shrinking field are used unless the intent is palliative.

Merkel Cell Carcinoma and Adnexal Carcinoma

Target Volume

The target volume for MCC consists of the surgical bed with margins of 4 to 5 cm except when the lesion is situated at or close to critical structures (e.g., optic apparatus) and the draining lymphatics. For MCC of the head and neck region, the whole ipsilateral neck is irradiated.

The target volume for adnexal carcinoma consists of the surgical bed with margins of 2 to 3 cm and, depending on the site and size of the primary tumor, the draining lymphatics.

Setup, Field Arrangement, and Dose Fractionation Schedule

The general principles of patient setup and portal arrangement are as outlined for BCC and SCC. As primary treatment, radiation is administered, preferably with electrons, in 2- to 2.5-Gy fractions to a cumulative dose of 45 to 55 Gy for elective irradiation, plus a boost dose of 10 Gy in 5 fractions to the gross disease. A cumulative dose of 60 to 66 Gy may be recommended for the treatment of bulky, inoperable primary tumors. Elderly patients of poor performance status who are unsuitable for an extended course of RT may still benefit from shorter palliative schedules, such as 25 Gy in 5 fractions (Fig. 39-16).

Figure 39-16 A, Multinodular Merkel cell carcinoma located on the distal foot of a 90-year-old male. B, The patient received 25 Gy in 5 fractions to the distal foot and experienced rapid disease regression by the end of treatment. C, At 2 months after RT, there was no evidence of disease; at 18-month follow-up, he remained disease-free.

Radiation regimens used for adnexal carcinoma are 60 to 70 Gy in 30 to 35 fractions, depending on the site and target volume. The portal is generally reduced to encompass areas of known gross disease after 50 to 54 Gy.

Patient Care During and After Radiotherapy

A tumoricidal dose of radiation generally produces moist desquamation of the irradiated skin by the end of, and shortly after, RT. The irradiated skin area should be protected from heat, cold, sunlight, friction, disinfectants, and other sources of irritation to avoid additional tissue injury. During RT, the daily application of a bland emollient is recommended. When moist desquamation occurs, the area should be kept clean to prevent secondary infection and may require the application of a burn-type dressing (e.g., silver sulfadiazine cream) for at least 2 to 3 weeks. Patients are instructed to use sunscreen over the irradiated area after completion of treatment.

Patients should also be informed about the specific acute and late side effects of treatment, such as mucositis of the nasal passages and upper lip, nasal dryness, synechiae (when treating nostril lesions), and conjunctivitis and loss of eyelashes (when treating eyelid cancers). After treatment involving the lacrimal canaliculi, irrigation of the ducts during the healing phase helps to prevent synechiae.

Regular follow-up examinations should include evaluation of the treated area for late complications and search for new lesions. The latter develop in one-third of treated patients occasionally in proximity to a previous treatment field. Late side effects include hypopigmentation, hyperpigmentation, telangiectasis, and skin atrophy. Skin retraction at the lower eyelid may result in ectropion. These are rarely serious after properly administered radiation.

Diagnostic And Treatment Algorithms

Basal Cell Carcinoma and Squamous Cell Carcinoma

Figure 39-17 illustrates the diagnostic and treatment algorithm for BCC and SCC. The choice of treatment for individual patients is determined by factors such as the lesion site and size, anticipated functional and cosmetic results, treatment time, treatment cost, and patient preference. Surgical approaches are preferred for most patients with resectable tumors, but RT can yield better functional and cosmetic results for lesions of the nose, lower eyelids, and ears. A combination of surgery and adjuvant RT is indicated in larger tumors or tumors with perineural spread, invasion of bone, invasion of cartilage, extensive skeletal muscle infiltration, or nodal metastasis.