Figure 107-4. Technique of groin dissection.

For patients with primary melanoma equal to or greater than 1-mm thickness with clinically negative

nodes, SLN biopsy is recommended.42 For patients with thin melanoma, SLN should not be performed

routinely but can be considered for patients with melanoma Brelsow depth of 0.76 to 0.99, particularly

if they have other risk factors for regional micrometastases, including a mitotic rate of 1 mitosis/mm2

or greater, extensive dermal regression >1 mm, ulceration, angiolymphatic invasion, younger age, or a

broadly transected or positive deep margin on shave biopsy.20,58,59 Reasons not to perform SLNB include

significant medical comorbidities or the patient does not desire SLNB after an informed discussion.

Radiation therapy has also been utilized as an adjuvant to the resection of high-risk nodal metastases

(extranodal extension, nodes greater than 3 to 4 cm in size, or multiple nodes). Several retrospective

studies had suggested improved regional control rates when radiation was combined with surgery,

particularly for cervical metastases. A large, prospective randomized trial from the Tasman Radiation

Oncology Group randomized patients at high-risk of nodal relapse to adjuvant radiation versus

observation. With a median follow-up of 40 months, the risk of relapse in the lymph-node field was

reduced with radiation (HR = 0.56, 95% CI: 0.32 to 0.98; P = 0.041) but there was no significant

difference in either relapse-free or overall survival.60 Adjuvant radiation after lymph node dissection

will increase the overall morbidity, but this depends on the basin being irradiated, with ilioinguinal

Radiation therapy (RT) being more problematic than cervical or axillary RT.61,62 The decision to

consider adjuvant radiation after completion node dissection should be individualized on the basis of the

predicted risk of regional recurrence, expected survival, and associated toxicities.

Adjuvant Therapy

Although the prognosis for patients with early-stage cutaneous melanoma is quite good, fewer than 50%

of patients with thick primaries (i.e., >4 mm) or regional node involvement are cured by surgery

alone. The development of effective adjuvant therapy capable of increasing postsurgical survival in

high-risk groups of patients has been a long-standing goal of clinicians. Unfortunately, numerous

randomized trials evaluating systemic chemotherapeutic agents (most notably dacarbazine), nonspecific

immunotherapy (such as Bacille Calmette–Guérin), and tumor-specific vaccines in the adjuvant setting

have failed to demonstrate any impact on survival.63–67

Interferon-α2b (IFN-α2b) has a variety of modulatory effects on the immune system that could

enhance antitumor reactivity. In 1996, Kirkwood et al.68 reported the results of the Eastern Cooperative

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Oncology Group E1684 trial, which studied the effectiveness of high-dose IFN-α2b to improve diseasefree and overall survival rates of patients with stage IIb (>4 mm) or III disease after surgery. Highdose IFN-a2b includes a 1-month induction phase (IV 20 MU/m2 M-F) followed by 11 months of

maintenance (SC 10 MU/m2 3 days/week). In this multi-institutional prospective randomized trial, 287

high-risk patients with deep primary (>4-mm) tumors or positive nodes were randomly assigned after

surgery to either postoperative adjuvant treatment with IFN-α2b or observation. IFN-α2b therapy

significantly increased median overall survival by 1 year and produced a 24% improvement in the 5-

year overall survival rate (46% for IFN-α2b patients vs. 37% for observation patients). On the basis of

these results, the Food and Drug Administration (FDA) approved the use of adjuvant IFN-α2b after

surgical resection of stage IIb or III melanoma. Two large, prospective randomized trials followed.

E1690 compared high-dose interferon with both observation and low-dose interferon. The effect of highdose interferon on 5-year relapse-free survival was significant (44% vs. 35%, P = 0.03) but neither

high-dose nor low-dose interferon had any significant impact on overall survival.69 Elective node

dissection was not mandated in E1690 (nor E1684), and many patients who had regional recurrences on

observation subsequently received IFN-α salvage therapy, which may have impacted the overall

survival analysis. The third trial, E1694, compared high-dose IFN to the GMK vaccine; the ganglioside

GM2 coupled to kehole limpet hemocyanin and combined with the QS-21 adjuvant. The trial was

stopped early when an advantage was seen for interferon in both relapse-free (HR = 1.47; P = 0.001)

and overall (HR = 1.52; P = 0.009) survival.

Pegylated IFN-α2b (peg-IFN), where the IFN molecule is bound to a polyethylene glycol moiety,

allows for sustained absorption and a longer half-life. This regimen has an induction phase of peg-IFN

SC 6 μg/kg a week for 8 weeks followed by a maintenance dose of SC 3 μg/kg a week for up to 5 years.

In the European Organization for Research and Treatment of Cancer (EORTC) trial 18991 of peg-IFN

versus observation in patients with resected stage III melanoma, peg-IFN was associated with an

improved RFS (HR = 0.87; 95% CI, 0.76 to 1.00; P = 0.05), with no difference in overall survival.70 In

2011, the FDA approved peg-IFN as an alternative to high-dose IFN in the adjuvant therapy of

melanoma.

Biochemotherapy (BCT) combines chemotherapy and immunotherapy and has been examined in stage

IV melanoma for many years.71,72 It was studied as a potential adjuvant therapy in the Southwest

Oncology Group (SWOG) trial S008, which compared a 9-week BCT regimen composed of cisplatin,

vinblastine, dacarbazine, interleukin-2 (IL-2), and IFN-α to high-dose interferon.73 While there was a

significant improvement in RFS compared with HDI (4.0 years vs. 1.9 years; P = 0.029), there was a

higher rate of grade III/IV toxicity and no difference in overall survival (56% 5-year survival in both

groups). The use of BCT may be considered for adjuvant therapy in stage IIIA–IIIC melanoma.

Treatment of In-Transit Disease

In-transit disease and satellitosis develop in 5% to 8% of patients with melanomas thicker than 1.5

mm.74 These are classified as stage III disease but portend not only a poor prognosis but can be a

challenge to treat. Treatment involves either local excision or ablation, or regional chemotherapy.

Surgical excision is the optimal management when the number of lesions is small and complete excision

is possible. Prior to proceeding with surgery, a complete staging workup for metastatic disease is

recommended, as these patients often harbor distant disease. When surgery is not feasible, a number of

intralesional therapies have been utilized: Bacille Calmette–Guérin, IL-2, granulocyte-macrophage

colony stimulating factor (GM-CSF), and rose bengal. A new agent, talimogene laherparepvec (T-VEC),

is an oncolytic immunotherapy derived from herpes simplex virus type-1. Injected intralesionally, T-VEC

is designed to replicate in tumors and release GM-CSF to enhance systemic antitumor immune

responses. In a randomized phase III trial, T-VEC demonstrated an improved durable response rate (16%

vs. 2%; P < 0.0001) and a trend toward an improved overall survival.75

When the in-transit disease is unresectable but limited to an extremity, regional administration of

high-dose chemotherapy can be effective in controlling disease. Isolated limb perfusion (ILP) uses an

extracorporeal membrane oxygenator (as is used with cardiac surgery) to deliver chemotherapy doses

15 to 25 times higher than can be obtained with systemic delivery. The surgeon isolates the vessels and

uses a tourniquet to prevent systemic uptake of the agent(s). Using the bypass machine, the limb is

perfused with hyperthermic (38°C to 40°C) chemotherapy solutions, most commonly melphalan. After

60 to 90 minutes of treatment, the drug is flushed from the circulation and systemic circulation is

restored. Response rates between 80% and 90% are reported, with complete response rates between

40% and 65%.74,76–78 In some cases, these can be quite durable. Toxicities can range from mild

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erythema and edema to epidermolysis, functional impairment, and in extremely rare cases a need for

amputation.

Isolated limb infusion (ILI) is a minimally invasive alternative to ILP. Rather than surgical isolation of

the vessels, percutaneous catheters are placed radiologically in the artery and vein and connected to an

extracorporeal circuit incorporating a heating coil. A tourniquet is placed on the extremity, but because

some systemic uptake is anticipated, lower doses of chemotherapeutic agents are used. Some studies

have reported response rates equal to ILP, although others report slightly lower response rates.79–82

However, the role of both ILP and ILI is evolving as new systemic therapeutic options become

available.

Treatment of Disseminated Melanoma

Evaluation for Metastatic Disease and Clinical Course

The follow-up evaluation for patients with AJCC stage I, II, or III melanoma who are rendered NED by

surgery should include regular histories and physical examinations. The use of extensive and frequent

radiographic studies and blood work in asymptomatic, clinically disease-free patients is rarely

productive.24 For AJCC stage IA to IIA, the NCCN recommends that patients should undergo a history

and physical examination with emphasis on skin and nodal examinations every 6 to 12 months as

clinically indicated. For AJCC stage IIB to IV NED, patients should undergo a history and physical

examination every 3 to 6 months for 2 years, then every 3 to 12 months for 3 years, and then annually

as clinically indicated. Imaging studies (CXR, CT, or PET/CT) can be considered every 3 to 12 months

for the first 3 to 5 years on the basis of the conditional probability of recurrence at any point in time

after the initial therapy.24

Melanoma can disseminate to any organ. The most common sites of recurrence are skin, subcutaneous

tissues, and distant lymph nodes, followed by visceral sites. Common visceral sites of metastasis, in

order of decreasing occurrence, are the lung, liver, brain, bone, and gastrointestinal tract. Most patients

who die with disseminated disease have multiple organ involvement. Frequently, the cause of death is

respiratory failure or brain complications. Cure with any treatment is rare. However, over the past

several years, there have been tremendous advances in the systemic therapy of melanoma. Whereas

only several years ago there were only two FDA-approved therapies for the treatment of metastatic

melanoma (dacarbazine and high-dose IL-2), there are now new targeted therapies and immune

checkpoint regulators that have been approved for the treatment of advanced melanoma, with several

new therapies and combinations in clinical trial. How to proceed in the management of advanced

melanoma should be based on several factors, including the patient’s medical condition and

comorbidities, the potential for palliation, and the impact of treatment on quality of life.

Chemotherapy

Melanoma is responsive to few chemotherapeutic drugs. The most widely used single chemotherapeutic

agents have been dacarbazine and its oral analogue temozolomide, with objective response rates of 5%

to 12%.83 Most responses are transient; only 1% to 2% of patients achieve a durable long-term

response.84 Attempts to improve upon these results using combination chemotherapy, or BCT (where

chemotherapy is combined with IFN-α2b ± IL-2), failed to significantly improve upon single-agent

therapy alone.71,83–85

High-Dose Interleukin-2

IL-2 is a cytokine secreted by antigen-activated helper T cells, initially discovered to be a T-cell growth

factor but subsequently found to have many other immunologic effects, including an important role in

the enhancement of immune responses. High-dose IL-2 (600,000 IU/kg every 8 hours for up to 14

doses) is associated with an objective response rate of 15% to 20%, with a small percentage of patients

(around 5%) experiencing long-term, durable complete responses (Fig. 107-5).86–88 These results may be

improved upon with the addition of vaccines.89 However, IL-2 treatment requires inpatient intensive

care, as toxicity is severe and can include hypotension, pulmonary edema, decreased renal function,

respiratory insufficiency, and neurotoxicity.

BRAF and MEK Inhibitors

The MAP kinase pathway is a key pathway in melanoma pathogenesis, with nearly half of melanomas

having constitutive activation due to mutations in the BRAF gene.90 Activation of mitogen-activated

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protein kinase (MAPK) signaling leads to unregulated cell proliferation. Vemurafenib and dabrafenib are

targeted therapies that block the constitutively active mutant BRAF. Both have been associated with

significant improvements in both progression-free and overall survival compared with dacarbazine.91,92

Common adverse effects include arthralgia, rash, fatigue, alopecia, and the development of cutaneous

keratoacanthomas and SCCs. Patients treated with BRAF inhibition have dramatic responses, but

unfortunately the survival benefit is limited because of the eventual development of resistance in most

patients.

Figure 107-5. Basal cell carcinoma near the eye.

Trametinib is a small molecule inhibitor of MEK1/2, a downstream regulator of BRAF. As with BRAF

inhibition, MEK inhibition with trametinib was associated with an improvement in both progression-free

and overall survival compared with chemotherapy.93 While MEK inhibition had no efficacy in patients

who failed BRAF therapy, the combination of BRAF and MEK inhibition was associated with an

improvement in objective response, median duration of response, and progression-free survival,

compared with BRAF inhibition alone.94,95 In addition to delaying the development of resistance to

MAPK pathway inhibition, combination therapy is also associated with fewer secondary cutaneous

malignancies. The FDA granted accelerated approval to the combination of dabrafenib and trametinib

for the treatment of patients with advanced melanoma with BRAFV600E/K mutations.

Immune Checkpoint Regulators

For many years, the plethora of immunotherapy research has centered on the generation of an

antitumor immune response, primarily through the use of vaccines and assorted adjuvants. However,

immune checkpoint regulation, which augments existing, yet clinically insignificant, immune

recognition, has rapidly emerged as an alternative and effective form of immunotherapy in melanoma.

Ipilimumab is a human IgG1 mAb that binds to the cytotoxic T-lymphocyte associated antigen-4

(CTLA-4) receptor. This receptor is found on regulatory T-cells and cytotoxic T-cells after they have

been activated, with a primary role of inhibiting T-cell responses. Blocking the binding between CTLA-4

and B7 suppresses this inhibitory function (essentially cutting the brakes) and promotes continued T-cell

activation. In a phase III trial of ipilimumab alone, ipilimumab with a gp100 vaccine, and the vaccine

alone, there was a significant improvement in median overall survival with ipilimumab (10.1 months

vs. 6.4 months, HR = 0.66, P = 0.0026).96 In a meta-analysis of pooled data from several clinical trials,

the 3-year overall survival rate was 22%, with many of them being durable as the rate of additional

deaths between 3 and 10 years was relatively low.97 Ipilimumab is associated with immune-related

toxicities, specifically enterocolitis, hepatitis, endocrinopathies, and dermatitis. While these can be

severe, they are reversible if recognized and treated early. Another anti-CTLA-4 antibody,

tremelimumab, which has a longer half-life than ipilimumab and thus has a longer interval between

doses, is presently being studied.98

Activated CD4+ and CD8+ T cells also express the programmed death 1 (PD-1) receptor, which, once

bound to its ligand PD-L1, triggers a decrease in T-cell proliferation, IL-2 release, and T-cell survival.

Malignant cells often express PD-L1 that binds to the receptors and blocks T-cell killing. Pembrolizumab

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and nivolumab are monoclonal antibodies against PD-1 that prevent binding to PD-L1. Both have shown

response rates in the 25% to 30% range, primarily in patients who have already progressed on or after

treatment with ipilimumab.99,100 They were both approved by the FDA for second-line treatment, after

treatment with ipilimumab. As with anti-CTLA-4, anti-PD-1 can be associated with immune-mediated

toxicities, including colitis, endocrinopathies, and pneumonitis. In a phase III randomized trial

comparing nivolumab with dacarbazine,101 in previously untreated patients, nivolumab was associated

with a significant improvement in overall survival (72.9%, 95% CI: 65.5 to 78.9 vs. 42.1%, 95% CI:

33.0 to 50.9, HR = 0.42, P < 0.001) compared with chemotherapy, leading to a shift toward anti-PD-1

therapy as first-line therapy in advanced melanoma. In addition, early studies of combination therapy

with anti-PD-1 and anti-CTLA-4 mAb have demonstrated improved outcomes with increased but

manageable toxicity.102–104

Surgery

For most cancers, surgery is rarely considered as a curative option in stage IV disease. Historically,

melanoma has been an exception to this, with documented long-term survival among patients who

undergo resection of metastatic lesions. Several retrospective studies, as well as prospective studies,

have suggested that metastasectomy may result in prolonged disease-free survival in select

patients.105–109 The rationale for surgical extirpation of metastatic disease was in part driven by the lack

of effective systemic therapies in melanoma. The role of surgery for stage IV disease is rapidly evolving

as new, highly effective therapies have emerged. Despite the excitement surrounding these new agents,

there may be potential advantages to metastasectomy in select patients, including cost, toxicity, time to

palliation, and disease-free survival.108 Careful patient selection is key, as is a true multidisciplinary

approach. Patients being considered for metastasectomy should undergo a thorough search for

additional sites of disease, including a detailed history and physical, serum LDH, CT or PET scan, and

MRI of the brain. Biopsies should be obtained to document metastases as well as evaluate BRAF, and in

some cases c-kit mutation status, as well as PD-L1 expression. Factors to consider when formulating a

treatment plan include the age and health of the patient, the number and locations of the metastases as

well as the ability to achieve negative margins, the morbidity of the operation, the disease-free interval

between the original diagnosis and the development of distant disease, the need for palliation, either

now or in the near future, and the available systemic options. For select patients, surgery may be

considered as a first-line therapy, potentially delaying the need for systemic therapies, or be used in

conjunction with systemic therapies, either after neoadjuvant therapy or for resection of lesions that fail

to respond. The successful incorporation of surgery in the management of stage IV disease is dependent

upon true multidisciplinary collaboration between surgical, medical, and radiation oncology.

NONMELANOMA SKIN TUMORS

7 BCC and SCC account for 96% of new NMSCs.1,2 These tumors are derived from epithelial origin. The

ratio of BCC to SCC is approximately 4:1. The annual incidence of BCC and SCC in the United States

alone exceeds 1 million cases. The public health burden on the US population from NMSC, for which the

incidence is rapidly rising, is highly significant. Patients with NMSC have an excellent prognosis, with

90% to 99% curable with appropriate treatment and less than 1% resulting in death. SCCs account for

75% of NMSC deaths, which are estimated at 2,000 to 2,500 per year.110

Etiology

Both BCC and SCC are most commonly induced by significant exposure to UV light from the sun or

tanning booths.3 These cancers are the predominant neoplasms of the head, neck, trunk, lower legs, and

extensor arms and hands where sun exposure is common. Skin cancer is a significant occupational

hazard for people who work outdoors. The phenotype at increased risk is one with fair skin who

sunburns and freckles easily, has blue eyes, and has red or blonde hair. Melanin pigment in the skin

appears to be the protective factor.

A number of genetic syndromes are associated with an increased risk of developing NMSC, including

Gorlin syndrome, xeroderma pigmentosa, and albinism. Gorlin syndrome is an autosomal dominant

disorder associated with multiple BCCs, palmoplantar pits, jaw cysts, frontal bossing, and

hypertelorism. Albinism is a disorder characterized by a partial or complete deficiency in melanin

production and, thus, loss of protective pigment. Another factor associated with NMSC, primarily SCC,

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is chronic exposure to chemicals such as arsenic and hydrocarbons (found in coal tars, soot, and

asphalt). Cigarette smoking has been associated with SCC of the lip and mouth. Human papillomavirus

has been associated with cutaneous SCC in the genital and acral/periungual areas. Radiation has been

associated with both SCC and BCC.

Basal Cell Carcinoma

BCC is the most common form of skin cancer. These epithelial-derived tumors can be divided into

various subtypes according to clinical appearance, histologic pattern, and biologic behavior. Although

BCCs rarely metastasize, they are characterized by slow but relentless and destructive local invasion

that results in high morbidity without treatment. The subclinical local invasion may be deep, extensive,

and asymmetric, with fingerlike extensions several centimeters beyond the clinical borders.

The most common subtype of BCC is the well-circumscribed nodular variety. These tumors often

present as pearly papules or nodules with telangiectases. They may be pruritic and bleed occasionally.

With time, the center ulcerates to create peripheral “rolled” borders; such ulcerating BCCs are called

rodent ulcers (Fig. 107-5). Occasionally, the lesions are deeply pigmented and nodular and can be

confused with melanoma. This variant has been called pigmented BCC (Fig. 107-1H). The histologic

features of these tumors demonstrate isolated areas of basaloid tumor islands arising from the epidermis

with peripheral palisading of nuclei and stromal retraction. In some cases, the BCC has histologic

features of squamous metaplasia with keratinization. These tumors have basosquamous differentiation

and can become more aggressive and develop regional lymphatic spread.

The most locally aggressive type of BCC is characterized by a diagnostic histopathologic aggressive

growth pattern, known as morpheaform, sclerosing, or fibrosing BCC (Fig. 107-6). Clinically, these

tumors may be more subclinical, are flat, and appear to be scarlike. They have a significant incidence of

recurrence because of the isolated, fingerlike fronds of basal cell tumor cells that may deeply invade the

surrounding structures well beyond the clinical margins of the lesion. These small, fingerlike islands are

often missed with standard histologic margin control.

Clinically, superficial BCCs are scaly pink to red lesions. Frequently, they are confused with psoriasis

or other eczematous, scaly dermatoses. Although these tumors are usually relatively superficial,

extensive superficial subclinical involvement is common. Numerous risk factors are associated with

possible extensive subclinical invasion and increased rates of local recurrence for BCC after standard

treatment, including surgical excision (Table 107-6).

Figure 107-6. Morpheaform basal cell carcinoma of the scalp.

Squamous Cell Carcinoma

SCC is the second most common form of skin cancer and is derived from the epithelial keratinocyte.

SCC can deeply invade surrounding structures and metastasizes most commonly to regional lymph

nodes. In immunosuppressed transplant individuals, SCC is the most common skin cancer, occurring 65

to 250 times more frequently than in the general population. SCC in these individuals tends to have

more aggressive behavior.

Several precursor lesions to invasive SCC exist, most commonly actinic keratoses and Bowen disease

(in situ SCC). Erythroplasia of Queyrat, another precursor lesion, represents SCC in situ on the glans

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penis. Histologically, SCC shows malignant degeneration of epithelial cells with differentiation toward

keratin formation. SCC often appears clinically as a nonhealing sore with ulceration and inflammatory

pink borders or an erythematous papulonodule with overlying keratotic crust or ulceration (Figs. 107-7

and 107-8). These tumors most often arise in chronically actinically damaged skin or within an actinic

keratosis, but they may also develop in burn scars or chronic inflammatory wounds. These lesions may

infiltrate widely. Metastasis to regional lymph nodes accounts for approximately 80% to 90% of

metastatic cases. Distant sites, such as the lung, liver, brain, bone, and skin, account for the other 10%

to 20%. Metastatic SCC portends a poor prognosis with a 10-year survival rate for regional lymph node

disease of less than 20% and for distant disease of 10%.

Table 107-6 Basal Cell Carcinoma: Higher-Risk Factors for Subclinical Invasion

and Recurrence

Figure 107-7. Squamous cell carcinoma of the hand secondary to exposure to arsenic in welding flux.

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Figure 107-8. Ulcerative squamous cell carcinoma.

Table 107-7 Squamous Cell Carcinoma: Higher-Risk Factors for Subclinical

Invasion and Recurrence

Accurate assessment of the higher-risk cutaneous SCCs is handicapped because of the lack of large

prospective studies using multivariate analysis. Nine variables, however, have been identified as

prognostic risk factors by retrospective analysis. Factors that may determine a higher risk for local

recurrence, extensive subclinical invasion, and metastasis are noted in Table 107-7.

Surgical Treatment of the Common Nonmelanoma Skin Cancers

A skin biopsy for diagnosis is important before treatment of any skin cancer. Fortunately, most NMSCs

are small, low-risk lesions that respond with 90% to 95% cure rates to standard treatment techniques,

including curettage and electrodesiccation, cryosurgery, radiation therapy, and surgical resection. Many

skin cancers can be removed with elliptical excisions. Margins for low-risk SCC range from 0.5 to 1.0

cm. Margins for low-risk BCC range from 0.3 to 0.5 cm. Mohs surgery should be considered for BCCs

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and SCCs that exhibit the higher-risk factors in Tables 107-6 and 107-7. If Mohs surgery is not available,

excision with careful frozen section control (with permanent section confirmation) is indicated. The

fundamental oncologic principle of tumor clearance first and reconstruction second should be followed.

Mohs Surgery

Mohs surgery was developed by Frederick E. Mohs, a general surgeon from the University of Wisconsin,

in the 1940s. Initially, a chemical fixative paste was applied to the skin to fix the tissue in situ; hence,

the now outdated term Mohs chemosurgery. The fresh tissue technique, which omitted the chemical

paste, was developed and refined in the 1970s. Mohs micrographic surgery is most useful for the

treatment of higher-risk NMSC (Tables 107-6 and 107-7). Mohs surgery is usually performed under local

anesthesia in an outpatient Mohs surgical unit. After removal of all gross tumor, the surgeon excises a

thin layer of tissue with 2- to 3-mm margins. The tissue is mapped, color-coded for orientation, and sent

to the technician for frozen section processing. The specimen is flexible and flattened, with the beveled

peripheral skin edge placed in the same horizontal plane with the deep margin. In this plane, both the

deep and peripheral margins are examined in one horizontal cut by frozen section analysis with total

(theoretically 100%) margin control. Good-quality frozen sections may be achieved only by a skilled

and experienced Mohs histotechnician. The Mohs surgeon functions as both a surgeon and pathologist.

After histologic interpretation of the frozen section specimens, the precise anatomic location of any

residual tumor can be identified and reexcised until all margins are tumor free (Fig. 107-9). The Mohs

surgeon’s ability microscopically to track subclinical tumor extensions results in the highest cure rate

with maximal preservation of normal tissue. Soft tissue reconstruction can then be performed on the

same day, after completion of Mohs surgical excision of the tumor (Fig. 107-10). A multidisciplinary

approach involving Mohs, plastic, head and neck, and oculoplastic surgeons and radiation oncologists

may be needed for extensive tumors. Mastering the Mohs technique is based on a steep learning curve

that requires extensive training for optimal competence. Numerous Accreditation Council for Graduate

Medical Education (ACGME) postgraduate fellowship training programs are available.

Figure 107-9. Mohs micrographic surgical technique.

Based on a review of all studies from all disciplines since 1950, the 5-year cure rate for treatment of

previously untreated primary BCC by Mohs surgery is 99%, versus 90% to 93% for all non-Mohs

modalities, including standard surgical excision.83 For previously treated recurrent BCC, the 5-year cure

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rates are 94% for Mohs versus 60% to 84% for non-Mohs modalities.84 In general, Mohs surgery should

be considered for NMSCs that are associated with a higher risk of recurrence after standard treatment

and for tumors for which conservation of normal tissue is important. Risk factors for recurrence after

standard treatment have been mentioned previously. Tumors for which maximal conservation of tissue

may be important include tumors in the high-risk locations and tumors in young patients.

Figure 107-10. A: Patient with a 3- × 3-cm basal cell carcinoma on the right dorsal hand with mixed nodular and aggressive

growth histologic pattern. B: Final Mohs surgery defect measuring 4.0 × 4.8 cm to the underlying tendon with preservation of

tendon and nerve structures. Complete excision of the tumor required two Mohs stages (10 frozen sections). C: The defect was

reconstructed immediately after achievement of clear margins under local anesthesia in the Mohs surgery unit using birhombic flap

soft tissue reconstruction. D: Result 3 months after surgery.

Adjuvant and Primary Radiation Therapy

Radiation therapy may be useful for primary treatment of low-risk NMSCs. In experienced hands,

primary radiation therapy may also be useful for higher-risk tumors with high cure rates. For cutaneous

SCC with many high-risk factors and for those with extensive neurotropism, adjuvant prophylactic

radiation therapy to the primary site and the primary draining lymph nodes may decrease the risks of

local recurrence and regional nodal metastasis. Prophylactic adjuvant radiation therapy should also be

considered for highly aggressive, deeply invasive BCCs that exhibit extensive neurotropism.

Locally Advanced and Metastatic BCC

The occurrence of locally advanced and metastatic BCC is uncommon. Uncontrolled Hedgehog (Hh)

signaling is associated with the pathogenesis of both hereditary and sporadic BCC. Inactivating

mutations on the tumor suppressor patched (PTCH) gene and activating mutations in the protooncogene smoothened (SMO) cause some BCC. These mutations result in the unregulated activation of

the Hh pathway with an associated growth promotion and cancer development in tumor progenitor cells

initially within the epidermis and hair follicle. Vismodegib represents the first hedgehog pathway

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