15 - Melanomas and Other Skin Malignancies | Handbook of Cancer Chemotherapy

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

> Table of Contents > Section III - Chemotherapy of Human Cancer > Chapter 15 - Melanomas and Other Skin Malignancies

Chapter 15

Melanomas and Other Skin Malignancies

Karen S. Milligan

Walter D.Y. Quan Jr.

More than 1 million Americans were diagnosed with skin cancer in 2006. Melanoma accounted for approximately 62,190 cases and was responsible for approximately 7,910 deaths, far surpassing the total deaths due to all other skin malignancies combined. Melanoma is increasing in incidence at a higher rate than any other cancer (except for non small cell lung cancer in women) in the United States. Less common tumors of the skin include Merkel cell cancer, Kaposi's sarcoma (see Chapter 26), and mycosis fungoides (MF).

I. Melanoma

A. Natural history

Etiology and epidemiology. Melanoma arises from pigment-producing melanocytes that migrate to the skin and eye during embryologic development. Approximately 5% of melanoma occurs in extradermal sites such as the eye and mucous membranes of the oropharynx, vagina, and anus. In approximately 5% of cases, patients present with either regional lymph node involvement or metastatic organ involvement without any obvious primary being identified. Melanoma occurs more commonly in men than in women and has a peak age at incidence of approximately 50 years. Owing to the young age of many melanoma patients, this disease takes a striking toll in terms of the average number of years of life lost per patient in this country. The incidence of the disease has increased rapidly in the United States to the point where melanoma is now the sixth most common cancer. The substantial increase in incidence is presumably due to increased exposure to sunlight (primarily ultraviolet radiation), with the greatest risk of melanoma felt to be in those who have intermittent intense sun exposure, particularly in fair-skinned, lighthaired individuals. The cultural emphasis on suntanned skin as an indicator of physical health and beauty has played a major role in this increase. Depletion of the ozone layer may contribute as well. Sunny parts of the United States have the highest incidence of the disease, especially Southern California, Florida, and Texas. One particular melanoma subtype, lentigo malignant melanoma, may be more closely associated with long-term occupational sun exposure as is seen in farmers and fishermen, for instance. Patient education in prevention, including use of sunprotective clothing, performing outdoor activities at times other than the brightest sunlit hours of the day, use of topical sunscreens, refraining from use of suntan parlors, use of skin self-examination, and avoiding suntanning ( tanned
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skin = damaged skin ), should be emphasized. Individuals with xeroderma pigmentosa, an autosomal recessive disorder, typically incur multiple basal and squamous skin cancers and melanoma because their skin lacks the ability to repair damage induced by ultraviolet radiation.
Precursor lesions, genetics, and familial melanoma. Melanoma may arise not only from dysplastic nevi but also from congenital and acquired nevi. Dysplastic nevi may be sporadic or familial. Individuals who have more than 100 benign nevi may also be at risk for melanoma. Ten percent of patients with melanoma have a family history of this cancer. Careful follow-up should be carried out in patients with these risk factors. Suspicious-appearing lesions or lesions that appear to have changed should be excised. The familial atypical multiple mole melanoma (FAMMM) syndrome is characterized by earlier mean age at diagnosis (34 years) and multiple lesions. The most common germline mutation seen in familial melanoma occurs in the tumor suppressor gene CDKN2A. CDKN2A, PTEN, NRAS, and BRAF mutations have been seen in nonfamilial melanoma. Multiple chromosomal abnormalities have been identified and associated with melanoma, including chromosomal regions 10q, 9p, 6q, 6p, 7, 1p, and 11.
Types and appearance of primary lesions. Clinical features ( ABCD ) suspicious for melanoma are as follows:
- Asymmetry of a lesion
- Borders that are irregular
- Color that is multihued
- Diameter greater than 6 mm (i.e., larger than the diameter of a pencil eraser )
Other characteristics of concern could include history of recent growth, change in pigmentation, ulceration, itching, or bleeding. Nonpigmented skin lesions that behave like melanoma should be examined with the immunochemical stains S-100 and HMB-45 as 1% to 2% of melanoma lesions are amelanotic.

There are four clinical types of primary cutaneous melanoma. Superficial spreadingmelanoma is the most common type, accounting for 70% of melanomas. It is commonly found on the trunks of men and lower extremities of women. Nodular melanoma comprises 10% to 15% of melanomas and has an early vertical growth phase. It is commonly found on the trunks of men. Lentigo malignant melanoma accounts for approximately 10% of cases. It is characterized by flat, large (1- to 5-cm) lesions located on the arms, hands, and face of the elderly (median age 70 years) in particular and is known for a relatively longer radial phase. Acral lentiginous melanomais seen in approximately 3% to 5% of cases and occurs primarily on the palmar surfaces of the hands, plantar surfaces of the feet, and under nails on the digits. This melanoma subtype is most commonly seen in individuals with darker-pigmented skin.

In general, melanoma is felt to show two distinct growth phases: an initial radial phase during which the melanoma
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enlarges in a horizontal/superficial pattern above the basal lamina of the skin, followed eventually by a vertical growth phase characterized by the cancer diving deep toward subcutaneous fat. It is during the vertical growth phase that metastases are felt to be at highest risk.
Patterns of metastases. Although much attention is rightly attached to assessing lymph node status (see following text), melanoma has a proclivity for hematogenous spread as well. Common sites of metastases include lung, liver, bone, subcutaneous areas, and, primarily in late stages, brain. However, melanoma can spread to virtually any site. Following diagnosis, approximately 25% of patients will develop visceral (non lymph node) metastases. As many as an additional 15% may develop disease limited to lymph nodes alone. Patients who present with lymph node or metastatic involvement without any obvious primary site may have undergone spontaneous remission of the primary, a phenomenon that may be attributable to some degree of immune system involvement. Patients with cancer of unknown primary should have their biopsy material stained with the immunohistochemical stains S-100 and HMB-45 in consideration of the possibility of melanoma.
Ocular melanoma. Ocular melanoma is the most common malignancy of the eye in adults. It may occur in any eye structure that contains melanocytes, although uveal tract sites predominate, with choroid, ciliary body, and iris in decreasing frequency. Standard therapy may consist of either enucleation (often utilizing a no touch technique) or brachytherapy with radioisotopes such as iodine 125 (¹²⁵I). This tumor metastasizes most frequently to the liver and appears to be less sensitive to both biologic agents and chemotherapy than cutaneous melanoma.

B. Staging

Melanoma is staged according to the updated American Joint Committee on Cancer staging system (see Tables 15.1, 15.2 and 15.3). All patients should have a careful history and physical examination with special attention to the skin including scalp, mucous membranes, and regional lymph nodes. Laboratory studies should include complete blood count, blood urea nitrogen (BUN), serum creatinine, liver panel, alkaline phosphatase, and serum lactate dehydrogenase. A chest x-ray or computed tomography (CT) scan of the chest is done to evaluate for pulmonary lesions. Elevation of liver function tests warrants CT scan of the liver. Elevation of alkaline phosphatase level or unexplainable bone pain suggests the need for bone scanning. Primary lesions equal to or thicker than 1.0 mm are at higher risk of regional lymph node involvement; therefore, the use of sentinel node surgery is recommended (see Section I.C).

C. Surgical treatment

The standard surgery for suspected melanoma lesions is excisional biopsy rather than incisional or shave biopsies. Importantly, a subsequent wide excision is required to provide adequate tumor-free margins as melanoma is notorious for local recurrences. Although there is some variation in recommendations, most would advocate a 1-cm

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tumor-free margin for melanomas less than 1 mm in thickness and 1- to 2-cm margins for deeper primary lesions if technically possible. Additionally, for primary lesions equal to or greater than 1 mm, sentinel node mapping is recommended. On the basis of work by Morton and others, lymph node drainage areas are assessed through a specific lymph node (sentinel node[s] sometimes more than one) into which

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lymph-borne metastases generally first occur. The absence of tumor involvement in this lymph node precludes the need for elective lymph node dissection. Although blue dye was originally used in this procedure, current refinements of this technique include the use of technetium-based radionuclides.

Table 15.1. TNM classification for melanoma

T Status
Classification	Thickness (mm)	Ulceration
T1	1.0	a = No ulceration and Clark's level III or less b = With ulceration or Clark's level IV or V
T2	1.01 2.0	a = No ulceration b = With ulceration
T3	2.01 4.0	a = No ulceration b = With ulceration
T4	>4.0	a = No ulceration b = With ulceration
N status
Classification	Number of Lymph Nodes	Involvement
N1	1	a = Microscopic b = Macroscopic
N2	2 3	a = Microscopic b = Macroscopic c = In-transit met or satellite present but no lymph nodes involved
N3	4	Note: This classification also applies if in-transit met or satellite lesions present with metastatic nodes
M status
Classification	Metastatic Site	Serum LDH
M1a	Distant subcutaneous, skin, or node	Not elevated
M1b	Lung	Not elevated
M1c	All other visceral sites	Not elevated
M1c	Any	Elevated
LDH, lactate dehydrogenase.

Table 15.2. Clark's levels of invasion

Level	Description
I	Limited to the epidermis
II	Invades papillary dermis
III	Extends to papillary reticular dermal junction
IV	Invades reticular dermis
V	Invades subcutaneous fat

D. Adjuvant therapy

Eastern Cooperative Oncology Group (ECOG)1684 (protocol number) was a large randomized adjuvant trial of interferon _2b (IFN- _2b) in patients with deep primary lesions (>4 mm thick) or regional lymph node involvement that showed statistically significant improvement in overall survival in the treated group as compared to the observation group.

IFN 20 MIU/m² IV 5 days/week for 4 weeks (as a loading phase ) followed by 10 MIU/m² SC 3 days/week for 48 weeks as a maintenance phase.

Table 15.3. Approximate survival in melanoma based on stage grouping

Stage	TNM (Pathologic)	5-year Survival (%)
IA	T1a	95
IB	T1b T2a	90 89
IIA	T2b T3a	77
IIB	T3b T4a	65
IIC	T4b	45
IIIA	N1a N2a	53 49
IIIB	N1b N2b	51 46
IIIC	N3	27
IV	M1a	19
All others	M	<10
From Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635 3648.

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Toxicity (flu-like symptoms, hepatic dysfunction, and neurologic symptoms) was significant, but quality-of-life analysis demonstrated overall benefit. The follow-up study, ECOG 1690, also showed a significant disease-free survival advantage over the observation arm but not a benefit in overall survival. The difference between these two studies may be that patients on the observation arm in the subsequent trial (1,690) may have been treated with immunotherapy (including IFN or interleukin 2 [IL-2]) at the time of relapse. Given that it is clear that patients with deep cutaneous primaries and/or lymph node involvement are at high risk for metastatic recurrence and that most patients who suffer metastatic relapse will die of their disease, it is reasonable to treat such high-risk patients with either IFN or entrance into a clinical trial.

Chemotherapy as a single modality has not been shown to be more beneficial than observation alone, and high-dose IFN with chemotherapy confers no difference in relapse-free or overall survival between the single agent and combined therapy arms. An ongoing trial is examining the use of only the loading phase of IFN therapy in patients with lesions 1.5 to 4 mm Breslow depth or evidence of only microscopic lymph node involvement. A particularly fertile area of exploration is the administration of therapeutic vaccines. Granulocytemacrophage colony-stimulating factor (GM-CSF) has been utilized by some investigators and warrants further examination. Regional perfusion chemotherapy in patients with high-risk extremity melanoma has been reported by the European Organisation for Research and Treatment of Cancer (EORTC)/World Health Organization (WHO), which found no substantial benefit.

E. Therapy of metastases

General considerations about systemic therapy
- Patient selection. Although, in general, melanoma is considered relatively resistant to systemic therapy, certain favorable prognostic factors do lend themselves to a higher chance of response. These include ECOG performance status 0 or 1; subcutaneous, lymph node, or pulmonary metastasis; no prior chemotherapy; normal marrow, renal, and hepatic function; and absence of central nervous system (CNS) metastases. Some investigators have noted that women are more likely than men to respond to chemotherapy. The biologic basis for this finding has not been fully elucidated. Newer genomic and proteomic profilingmay lead to a better understanding of prognostic factors. These response rates are highly dependent upon site of metastasis. When reviewing potential therapy for patients, patient characteristics as well as the natural history of the disease must be considered, including the median survival of patients in phase II studies that have 0% response rates can reach 7 months.

Biologic agents. This class of agents, along with experimental therapy through clinical trials, represents the most significant hope for the future in the treatment of

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this disease. Currently available agents in this class are as follows:

Interleukin 2 (IL-2; Proleukin, aldesleukin) appears to be the most active single agent for patients with visceral metastases. It is most commonly used in a high-dose regimen of IL-2 at 600,000 IU/kg given in 15-minute IV infusions every 8 hours for a total of 14 doses.

This schedule produces responses in 15% to 20% of patients, many of long duration. A previous review of National Cancer Institute data showed a response rate of 50% in patients with disease limited to cutaneous/subcutaneous sites. Because this drug is associated with a capillary leak syndrome that can include hypotension, fluid retention, renal and hepatic hypoperfusion, and pulmonary edema, the dose and schedule mentioned in the preceding text require inpatient care. It should be used only by those experienced in its administration. Inpatient continuous-infusion schedules (18 MIU/m² given over 24 hour for up to 5 consecutive days) may also be administered. Patients receiving this dose must also be closely monitored. Moderate-dose IL-2 (22 MIU/m² given by 15-minute infusions for 5 consecutive days for 2 consecutive weeks) when given with low-dose cyclophosphamide (see Section I.E.6. and Table 15.4.) can be administered on an outpatient basis but requires significant premedication and daily physician examination. The role of low-dose SC administration of IL-2 is unclear; some investigators feel that such low-dose regimens are less likely to yield durable responses. It should be noted that the earlier literature may express IL-2 dosing in units other than International Units. Therefore, when comparing various studies, a rule of thumb for conversions is 1 mg = 3 106 Cetus Units = 6 10⁶ Roche Units = 18 10⁶ IU.
Interferon 2b (Intron-A) and interferon 2a (Roferon-A) have been examined with a wide range of doses, schedules, and routes from 3 to 50 106 IU/m² given SC, IM, or IV, administered three to five times per week. These agents have been found to have response rates of approximately 10% to 15% in a variety of studies. Additionally, some patients may have stable disease lasting many months or longer. In regards to dosing, some investigators believe that higher doses of IFN (20 MIU/m² IV, such as those given in adjuvant therapy) act more by inhibiting tumor cell proliferation, whereas lower doses of IFN ( 5 MIU/m² SC) may be more immunostimulatory.

A recommended starting dose for subcutaneous IFN is IFN 3 MU SC three times per week.

Thalidomide, an inhibitor of angiogenesis, does not appear to be active as a single agent in melanoma but is being explored as an adjunct to temozolomide in brain metastases.

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Table 15.4. Multiagent systemic therapy for melanoma

Regimen	Drug Dosages
BCDT ( Dartmouth regimen )	BCNU (carmustine) 150 mg/m²/day on day 1 every 6 weeks Cisplatin 25 mg/m²/day on d 1 3 every 3 weeks DTIC (dacarbazine) 220 mg/m²/day on days 1 3 every 3 weeks Tamoxifen 20 mg PO daily
CVD	DDP (cisplatin) 20 mg/m²/day on days 1 4 every 3 weeks VLB (vinblastine) 2 mg/m²/day on days 1 4 every 3 weeks DTIC (dacarbazine) 800 mg/m² on day 1 only every 3 weeks
Biochemotherapy	Cisplatin 20 mg/m²/day on days 1 4 Vinblastine 1.5 mg/m²/day on days 1 4 Dacarbazine 800 mg/m² on day 1 Interleukin-2 9 MIU/m² daily by continuous IV infusion on days 5 8 (96 hours) and 17 20 (96 hours) Interferon -2b 5 MU/m² SC on days 5 9 and 17 21 Cycles repeated every 3 weeks Maximum of 5 cycles for maximum of four cycles
Cyclophosphamide and moderate-dose interleukin-2	Cyclophosphamide 350 mg/m² IVPB on day 1 Interleukin 2 22 MIU/m² IVPB on days 4 8, 11 15 Repeat cycle every 21 days for three cycles. Thereafter give every 28 42 days

Tyrosine kinase inhibitors. These small molecule inhibitors, including sorafenib and sunitinib, of tumor angiogenesis are currently being investigated.
Combinations of biologic agents. The role of combinations of biologic agents remains an area of ongoing study. IL-2 and IFN- have been utilized together, but most studies have found no advantage in response rates or response durations due to this combination as compared with IL-2 alone. The use of IFN following therapeutic vaccine therapy resulted in higher response rates than what is usually seen with IFN alone. Current studies are examining IFN and thalidomide in combination. A study utilizing histamine with low-dose
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subcutaneous IL-2 suggested improved survival in patients with liver metastases as compared to low-dose subcutaneous IL-2. A recent study combining the antihistamine famotidine and high-dose continuous infusion IL-2 also suggested activity in metastatic melanoma.

Chemotherapy
- Single-agent chemotherapy. Most cytotoxic agents commonly used in other tumor types are inactive in this disease. Several agents possess modest activity in melanomawith responses obtained primarily in lung and nonvisceral sites and typically in ambulatory patients with few or no symptoms of their disease.
  - Dacarbazine (DTIC) has historically been the most widely utilized single agent for the treatment of metastatic melanoma. The most commonly used doses are 200 mg/m² IV on days 1 to 5 every 3 weeks or 750 to 800 mg/m² IV on day 1 every 4 to 6 weeks. Most responses to this agent occur in subcutaneous or lymph node sites.
  - Platinum-containing drugs. Cisplatin 100 mg/m² IV every 3 weeks or carboplatin 400mg/m² IV every 3 weeks appears to have similar efficacy.
  - Taxanes. Docetaxel 60 to 100 mg/m² is given in 1-hour IV infusions every 3 weeks, or paclitaxel 135 to 215 mg/m² is given in 3-hour IV infusions every 3 weeks.
  - Temozolomide (an oral imidazole) is an oral DTIC derivative with significant CNS penetrance and therefore the potential for clinical responses in the difficult subpopulation of patients with CNS metastases. Typical doses are 150 to 200 mg/m² PO daily for 5 days every 28 days.
  - Vinca alkaloids such as vinblastine and nitrosoureas such as carmustine have been used primarily in combinations.
- Multiagent chemotherapy. Despite decades of trials, no combination chemotherapy has emerged as a standard therapy. Whereas multiple regimens have shown high response rates in single-arm phase II or nonrandomized trials, there is no convincing randomized trial data to show statistically significant improvements in both response rate and median survival as compared with single-agent therapy (usually dacarbazine alone). In the 1990s, the Dartmouth regimen (dacarbazine, carmustine, cisplatin, and tamoxifen) was the most commonly employed chemotherapy regimen in stage IV melanoma. Whereas phase II studies suggested a higher response rate than dacarbazine alone, a phase III trial demonstrated no significant difference as compared to dacarbazine alone. Cisplatin, vinblastine, and dacarbazine currently comprise the most commonly used combination regimen (shown in Table 15.4).
Hormones. Although hormone receptors have been identified on some melanoma cell lines, these, unlike the ones seen in breast cancer, do not appear to be functional. Tamoxifen and megestrol acetate have no significant
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antitumor activity when used alone in patients with metastatic disease. There has been some in vitro evidence and some indirect clinical evidence that these drugs may potentiate the activity of some cytotoxic agents.
Biochemotherapy. Three randomized studies have compared the combination of polychemotherapy (cisplatin, vinblastine, and dacarbazine) and the biologic agents IL-2 and IFN versus the chemotherapy regimen alone. The first published randomized comparison showed improved response rate and median time to progression (4.9 vs. 2.4 months) in favor of the combined chemotherapy with biotherapy. Unfortunately, confirmatory studies have shown no difference in median time to disease progression or median survival.
Other biochemotherapy regimens. An alternative approach involving biochemotherapy utilizes IL-2 with doses of chemotherapeutic agents that are chosen to theoretically augment an immune response. Cyclophosphamide, for instance, may increase lymphokine-activated killer (LAK) cell activity, decrease the dampening effect of regulatory T cells on the immune response, or allow for space in the bone marrow for repopulation by LAK cells. Mitchell et al. have shown activity of an outpatient combination of low-dose cyclophosphamide and IL-2 with an overall response rate (5% complete response [CR], 21% partial response [PR]) similar to those seen with high-dose inpatient IL-2 regimens. However, no randomized study data using this regimen has been published.

F. Regional therapy

Local perfusion. For patients with subcutaneous metastases limited to a single extremity, arteriovenous cannulation and perfusion of that limb with agents such as melphalan, cisplatin, or tumor necrosis factor often with hyperthermia yield higher tissue concentrations of the drugs than what are achievable by IV administration. Phase II studies often show impressive response rates. Whether there is any survival advantage to this therapy as compared with systemic treatment remains controversial. Because of issues involving factors such as cost, the equipment required, and the physician training needed to implement this approach, its practicality is unclear. Hepatic arterial infusion therapy is theoretically appealing for ocular melanoma metastatic only to the liver. This therapy looks to be more active than systemic chemotherapy in ocular melanoma, although it is unclear that such an approach improves median survival.
Intralesional therapy with bacillus Calmette-Gu rin (BCG), IFN- , GM-CSF, and other agents has also been used with varying degrees of success.
Treatment of CNS metastases. Dexamethasone 10 mg IV followed by 6 mg every 6 hours IV or PO is given to reduce cerebral edema. As soon as possible, radiation should be started by either stereotactic, gamma knife, or three-dimensional conformal techniques. For solitary lesions, surgical resection followed by radiotherapy may yield a significant group of survivors over 1 year who
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experience good quality of life. The role of temozolomide needs to be further explored in this group of patients.
Radiotherapy is of variable efficacy in the treatment of the regional or bonymetastases but sometimes may yield gratifying symptomatic benefit.
Surgery, when utilized judiciously, can result in long-term disease-free survivals of up to 20% in individuals with isolated metastatic sites. Special considerations for surgical resection of metastases include gastrointestinal metastases that threaten of significant morbidity such as impending bowel obstruction or even mortality due to perforation and single brain metastasis before the start of biologic therapy (as long-term steroid use, which is frequently needed in the setting of brain metastasis, is antagonistic with biologic agents). The role of adjuvant therapy in patients who have undergone metastatectomies needs to be elucidated. A reasonable approach is to treat such patients with IFN as described in the preceding text.

G. Experimental and future therapies are of great importance in this disease

Only a few salient approaches will be discussed here. A variety of references are available for further reading in the following text.

Therapeutic vaccines remain an area of intense interest, and much potential is expected in the coming years, although current clinical results have shown limited activity. In general, toxicity from vaccine therapy tends to be quite low, usually limited to local reactions to the vaccine or the immunologic adjuvant that may be combined with the antigenic stimulus. Most vaccine studies have dealt primarily with patients who have been rendered surgically free of all macroscopic disease. A purified ganglioside, GM-2KLH/QS-21, which demonstrated prolongation of survival of patients in whom the vaccine is optimally immunogenic, was tested in an adjuvant setting (ECOG E1694) but found to be inferior to IFN. Recently, an adjuvant phase III trial evaluating the Canvaxin polyvalent whole-cell vaccine in resected stage IV melanoma did not show significant benefit. Fewer studies have been done in patients with metastatic disease. A polyvalent melanoma cell vaccine and Melacine, a vaccine derived from allogeneic melanoma cell lines (approved for use in metastatic disease in Canada) are examples of vaccines that have achieved objective responses in patients with metastatic tumors. Vaccination with peptides derived from tumor-associated antigens specifically designed to associate with T cells in the context of major histocompatibility complex (MHC) class I or II molecules and vaccines based on vaccinia-infected melanoma cell lysates, are examples of other approaches of note. Potential advantages to vaccine-based therapy include relatively little toxicity, the possibility of long-term disease stabilization, and an immunologic effect that may continue long after dose administration.
Cellular therapy. The administration of ex vivo activated cells such as cytotoxic T cells theoretically specific for melanoma continues to be of interest. Currently, there is no evidence that the addition of bulk cultured T cells to
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IL-2 therapy, for instance, is superior to IL-2 alone. The use of gene-modified T cells that might be more potent or cytotoxic T cells immunized to specific tumor epitopes offer theoretical potential. The addition of LAK cells to IL-2 has not been clearly shown to be better than IL-2 alone, although Rosenberg and colleagues identified a survival trend (p = 0.064) in favor of the LAK/IL-2 arm. Recent studies have examined the infusion of dendritic cells that have been pulsed with melanoma antigen.

II. Nonmelanoma skin cancer

A. Etiology and epidemiology

The American Cancer Society estimates that there were 1 million new cases of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the United States in 2006. These lesions occur twice as frequently in men as in women. BCC occurs four times more commonly than SCC (70% 80% vs. 10% 30%). Both are seen predominantly in the elderly. Risk factors for these two lesions include age more than 60, prior heavy sun exposure, fair complexion, and light-colored eyes or hair. Sun exposure, especially sunburns early in life, is the most important risk factor for development of these lesions. Other etiologic factors include prior irradiation to the skin for benign disorders, chronic inflammation, scarring or burns, and arsenic exposure. Patients who are chronically immunosuppressed such as in chronic lymphocytic leukemia and renal transplantation are also at increased risk, as are individuals with genetic disorders including xeroderma pigmentosum. There is evidence that human immunodeficiency virus infection may predispose to a clinically more aggressive SCC or BCC. Multiple BCCs or SCCs frequently occur in 30% to 50% of individuals.

B. Diagnosis and clinical features

Diagnosis of both SCC and BCC is made by biopsy, including incisional, excisional, or sometimes shave, depending on the clinical situation. Staging systems are not typically utilized for these tumors as both have generally low potential for metastases. BCC originates in the basal layer of the epidermis and often presents as a nodular, ulcerative lesion ( rodent ulcer ) with pearly or translucent edges and central ulceration. Approximately 30% of BCCs are found on the nose. Only approximately 0.1% of BCCs metastasize. Metastases typically occur when a long-standing lesion has been neglected. Lymph node metastases are the most common site (60%), with lung and bone metastases occurring less frequently. Despite being uncommon, once metastases occur survival is significantly decreased to 8 to 10 months.

SCCs often arise from crusty-appearing sun-damaged skin areas and demonstrate a higher rate of metastases (2%) than BCCs. Patients whose SCC arises from causes other than actinic damage (e.g., immunosuppression) may display a more rapid course with higher rates of metastases (20% 50%). Neglected lesions, large ulcerated lesions, and poorly differentiated histology are risk factors for metastases. Most metastases initially occur in lymph nodes (90%), with approximately 50% of patients developing metastases to other sites such as lung and bone.
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SCCs may begin as premalignant lesions called actinic keratoses (AK) that are rough, pink or flesh-colored areas on sun-exposed skin. In situ SCC, known as Bowen's disease, exists before dermal invasion and appears as red-colored patches that are larger than AKs.
Local treatment. Surgical excision, electrodesiccation, curettage, Mohs micrographic surgery, radiation therapy, and cryotherapy all result in similar cure rates of approximately 95% when lesions are identified early. Treatment options are typically based on individual factors including the area involved, available treatment facilities, and physician skill. Surgical excision to attain margins of at least 3 to 10 millimeters is the preferred treatment in SCC because of the higher metastatic potential. BCC, which has a lower metastatic potential, can be treated with any of the techniques mentioned earlier as well as cryotherapy. Radiation therapy is the treatment of choice for areas where extensive surgical resection would result in poor cosmetic outcome, such as near eyelids, ear lobes, or tip of the nose.

Mohs micrographic surgery is an involved procedure in which thin layers are meticulously removed, chemically fixed, and immediately reviewed microscopically to be assured of clear margins. This allows for complete pathologic orientation of the tumor to ensure adequate local control. Mohs surgery is limited in its ability for local control if discontinuous areas of cancer involvement exist. Although this therapy is highly operator dependent, Mohs surgery currently has the highest 5-year cure rate and has become the standard of care for local primary or recurrent BCC and SCC lesions.

Topical treatment delivery of fluorouracil (5-FU) is used for AK and SCC in situ and is applied directly to the involved skin. It is not systemically absorbed, therefore no systemic toxicity is seen. Local side effects include red discoloration of the skin and photosensitivity. Imiquimod (Aldara) is U.S. Food and Drug Administration (FDA)-approved for local therapy of AKs and some small BCCs. It promotes immune system modulation by inducing IFN- , IFN- , and interleukin-12 production. Both agents are used daily for several weeks.

Photodynamic therapy (PDT) has been used to treat AKs by topically applying a photosensitizing porphyrin or aminolevulinic acid (ALA) and then exposing the area to light. This process produces free radical oxygen species, which in turn cause tumor cell death. It has demonstrated effectiveness in less invasive BCCs and SCCs with a high cure rate in several studies. PDT is limited by the size of the lesion and significant photosensitivity after therapy. This therapy is still being evaluated for its future role in the treatment of skin cancers.
Treatment of metastatic disease. Metastases from either BCC or SCC may be treated with cisplatin-containing chemotherapy regimens. One of the more active regimens appears to be cisplatin 75 mg/m² IV and doxorubicin 50 mg/m² IV, both given on day 1 every 3 weeks.

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Despite response rates as high as 70% with chemotherapy, once metastases have occurred cure is no longer possible and survival is typically less than 1 year.

C. Merkel cell carcinoma

Etiology and epidemiology. Merkel cell cancer is a rare cutaneous neuroendocrine tumor that arises in the basal layer of the epidermis. Approximately 500 cases are diagnosed yearly. Its microscopic appearance is that of small blue cells with scant cytoplasm and hyperchromatic nuclei ( small cell cancer of the skin ). Merkel cell cancer is 20 times more likely to occur in whites than nonwhites, occurs more frequently in men than in women, and affects persons at a median age of 65 to 70. Sun exposure is felt to be the major risk factor.
Clinical features. Initially, it may be seen as a blue or bluish red, nontender, firm skin lesion, starting as a nodule but increasing in size rapidly over weeks to months. The most commonly involved sites are the face and neck (50%) and the extremities (40%). There is no universally accepted staging system for this uncommon tumor; however, stage I is considered localized disease, stage II is involvement of regional lymph nodes, and stage III represents systemic metastases. In general, Merkel cell cancer has a tendency toward an aggressive, recurrent course similar in some ways to small cell lung cancer or melanoma. Most patients experience recurrence within 12 months of initial treatment. Fifty percent of patients experience local and regional nodal recurrences and one-third develop metastatic disease later. The most frequent distant metastatic sites are liver, lung, and bones. The overall 5-year survival rate for all stages is 50%.
Treatment. The rarity of this tumor precludes any prospective randomized treatment data. Standard therapy for this disease includes surgical resection with 2-cm margins when possible followed by lymph node dissection. Sentinel lymph node surgery has become the preferred technique since a negative lymph node precludes more extensive surgery.

Because of the risk of local recurrence, radiation therapy to the primary site and to the site of pathologically involved lymph nodes should be considered, especially in stage I disease. There has been no established role for adjuvant chemotherapy. High-risk patients may be offered chemotherapy; however, there is no data that it offers a survival advantage. For metastatic disease, the two most common regimens used have been cyclophosphamide, doxorubicin, and vincristine (CAV) or cisplatin and etoposide (EP) at doses utilized for small cell lung cancer. Response rates for these regimens are approximately 60%.

D. Mycosis fungoides (MF)

Etiology and epidemiology. MF is a cutaneous T cell derived lymphoma with a CD4 T helper cell immunophenotype. It is an uncommon lymphoma, with just over 500 new cases diagnosed in the United States per year. It is seen predominantly in men with a median age of approximately 60 years. The lymphocytic infiltrate seen
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in this disease is present in the upper aspect of the dermis, obscures the junction between the dermis and epidermis, and characteristically infiltrates the epidermis in clusters of cells that are called Pautrier's microabscesses. Involved lymph nodes have similar histologic findings. Biopsies early in the course of the disease (the premycotic phase ) may show nonspecific, nondiagnostic skin changes.
Clinical features. Patients with this disorder tend to display a skin rash that is erythematous, somewhat scaling, and pruritic. Over time, patches, plaques, and even ulcers can be seen. Patients may exhibit erythroderma and lymphadenopathy. S zary's syndrome is a leukemic phase of MF with circulating lymphoma cells noted on peripheral smear. The course of MF can be variable, from a minority of patients having skin-only involvement to patients having extensive visceral metastases to the liver, lungs, spleen, and gastrointestinal tract. Staging is according to the TNM (B) system (Tables 15.5 and 15.6) and is based on the amount of skin involved and the presence of patches, plaques, or tumors. Patients with stage IA to IIA have an excellent prognosis with median survival greater than 11 years. Individuals with stage IIB to III disease have median survival of 3 to 4 years. Among patients with T4 lesions, a subgroup characterized by younger age (<65 years), less advanced stage (III), and no evidence of blood involvement has been shown to have a favorable prognosis with a median survival of approximately 10 years. Stage IVA/IVB has a poor prognosis with a median survival of less than 1.5 years. A subgroup of MF cases may undergo transformation to a large cell lymphoma characterized by CD30 positivity, which also heralds a poor prognosis.

Treatment. For individuals whose disease is confined only to the skin, electron beam radiation, PUVA (the combination of a photosensitizing substance such as psoralen and ultraviolet radiation), extracorporeal photopheresis, bexarotene gel, or topical application of nitrogen mustard or

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carmustine can lead to CR of disease and potential for cure.

Thick plaque disease may be better treated with electron beam therapy because PUVA and topical nitrogen mustard may be less able to penetrate the deep lesions. Imiquimod is being evaluated for this use as well. Patients who fail one of the local/topical therapies can be treated with a different type of local therapy and still have good control of the disease. For visceral disease or S zary's syndrome, systemic therapy such as IFN- 3 million units SC three times a week given continuously or gradually escalated to a cumulative weekly dose of 18 million units can yield response rates of over 60%. Combined regimens of IFN- and retinoids such as bexarotene (150 mg/day) are being evaluated for enhanced immune modulation. Traditional antilymphoma chemotherapy agents such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) appear less active in this type of lymphoma than in other non Hodgkin's lymphomas and are typically reserved for those cases of MF that transform to large B-cell lymphomas or when disease becomes refractory to other systemic or local agents. Purine analogs such as fludarabine and pentostatin have some activity with response rates of 20% to 70%. Novel uses of gemcitabine (1,200 mg/m² weekly times 3 every 28 days) and liposomal doxorubicin (20 to 40 mg/m² every 2 to 4 weeks) used as single agents are being studied with reports of overall response rates of approximately 80% in refractory patients. Another agent, denileukin difitox (ONTAK, an IL-2 diphtheria toxin fusion protein) has been approved for refractory disease with response rates of 30% to 70%.

Table 15.5. TNM (B) classes for Mycosis fungoides

T1	Limited patch/plaque lesions <10% of total skin surface
T2	Generalized patch/plaque lesion 10% of total skin surface
T3	Tumors
T4	Erythroderma, generalized skin involvement
N0	No clinically palpable lymph nodes
N1	Enlarged lymph nodes but microscopically negative
N2	Nonpalpable lymph nodes but microscopically involved
N3	Clinically palpable lymph nodes that are microscopically involved
M0	No visceral involvement
M1	Visceral involvement
B0	Absence of peripheral blood involvement
B1	Peripheral blood involvement

Table 15.6. Clinical stages for mycosis fungoides

Stage	T	N	M
IA	T1	N0	M0
IB	T2	N0	M0
IIA	T1 2	N1	M0
IIB	T3	N0 1	M0
IIIA	T4	N0	M0
IIIB	T4	N1	M0
IVA	T1 4	N2 3	M0
IVB	Any	Any	M1
B symptoms have no specific bearing on this staging system.