Handbook of Cancer Chemotherapy (Lippincott Williams & Wilkins Handbook Series), 8th Ed.

14. Melanomas and Other Cutaneous Malignancies

Ragini Kudchadkar and Jeffrey S. Weber

More than 1 million Americans were diagnosed with skin cancer in 2009, making it the most common malignancy in the United States and accounting for considerable morbidity. Melanoma accounted for approximately 68,720 cases and was responsible for an estimated 8650 deaths in 2009, which far surpasses the number of deaths due to all other skin malignancies combined. Melanoma continues to increase in incidence at a higher rate than any other cancer in the United States, except for non–small-cell lung cancer in women. Approximately 5890 cases of nonepithelial skin cancer cases were diagnosed in 2009. These less common tumors of the skin include Merkel cell cancer, Kaposi sarcoma (see Chapter 25), and mycosis fungoides (MF).

I. MELANOMA

A. Natural history

1. Etiology and epidemiology. Melanoma arises from pigment-producing melanocytes that migrate to the skin and eye from the neural crest during embryologic development. Approximately 5% of melanoma occurs in noncutaneous sites such as the eye and mucous membranes of the oropharynx, sinuses, vagina, and anus. Patients can present with regional lymph node involvement or distant metastatic disease without any primary being identified. This occurs in approximately 5% of patients. Melanoma occurs more commonly in men than 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 the United States. The incidence of the disease has increased in the United States to the point where melanoma is now the sixth most common cancer in men or women. The substantial increase in incidence is presumably due to increased exposure to sunlight (primarily ultraviolet B radiation), with the greatest risk of melanoma felt to be in those who have intermittent intense sun exposure, particularly in fair-skinned, light-haired individuals with red and blonde hair, and blue or green eyes. Te cultural emphasis on sun-tanned 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 California, Florida, Arizona, and Texas, which include three of the four most populous states in the United States. One particular melanoma subtype, lentigo maligna melanoma, which often occurs on the face, may be more closely associated with long-term occupational sun exposure and is seen in farmers and other outdoor workers. Patient education in prevention, including use of sun-protective clothing, performing outdoor activities at times other than the brightest sunlit hours of the day, use of topical sunscreens, refraining from use of sun-tan parlors, use of skin self-examination, and avoiding sun-tanning (“tanned 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.

2. Precursor lesions, genetics, and familial melanoma. Melanomas arise not only from sporadic or familial atypical nevi but also from other congenital and acquired nevi; however, approximately half of cutaneous melanomas arise without a clear cut precursor lesion. Individuals who have more than 20 benign nevi are at increased risk for melanoma. Approximately 10% of patients with melanoma have a family history of this cancer. Careful surveillance should be carried out in patients with these risk factors. Suspicious-appearing lesions or lesions that appear to have changed coloration, shape, height, or have bled should be excised. The familial atypical multiple mole melanoma syndrome is characterized by a young mean age at diagnosis (34 years) and multiple lesions. The most common germline mutation seen in familial melanoma occurs in the tumor sup-pressor gene CDKN2A. CDKN2A, PTEN, NRAS, and BRAF mutations have also been seen in nonfamilial melanoma.

3. Types and appearance of primary lesions. Clinical features, classically known as “ABCD,” that raise suspicion for melanoma include:

bullAsymmetry of a lesion

bullBorders that are irregular

bullColor that is multihued

bullDiameter greater than 6 mm (i.e., “larger than the diameter of a pencil eraser”).

Other characteristics of concern include history of recent growth, change in pigmentation, ulceration, itching, or bleeding. Any pigmented lesion that returns after excision should be re-evaluated with biopsy. Nonpigmented skin lesions that behave like melanoma should be examined with immunohistochemical stains S-100 and HMB-45 as 1% to 2% of melanomas are amelanotic.

There are four clinical types of primary cutaneous melanoma. Superficial spreading melanoma 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. Those lesions associated with intermittent sun exposure are often (50% to 60%) B-RAF mutated but C-KIT wild-type. 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 melanoma is 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 and is felt not to be as closely related to sun exposure as the other subtypes. Mutations in exons 9 and 11 of the C-KIT gene are more commonly observed in acral lentiginous and mucosal melanomas than other subtypes, but still only occur in about 20% to 30% of these cases.

In general, melanoma is felt to show two distinct growth phases: an initial radial phase during which the melanoma enlarges in a horizontal/superficial pattern above the basal lamina of the skin, followed eventually by a vertical growth phase characterized by invasion deeply with exposure to lymphatic vessels and the vasculature. It is during the vertical growth phase that metastases are felt to be most likely to occur.

4. Patterns of metastases. Melanoma has a proclivity for direct nodal spread presumably through the lymphatics, but a significant proportion of lesions exhibit 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 and can imitate virtually any solid malignancy in its pattern of spread. Following diagnosis, approximately 25% of patients will develop visceral metastases. An additional 15% may develop disease limited to lymph nodes. Patients who present with lymph nodal 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. Interestingly, those patients may have a better outcome than similarly staged patients with known primaries. Patients with “cancer of unknown primary” should have their biopsy material analyzed with the immuno-histochemical stains S-100 and HMB-45 to consider the possibility of melanoma.

5. 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, followed by 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. A recently published large randomized study of those two treatments revealed that for primary uveal tumors less than 5 mm in depth, the outcome for survival was identical. This tumor metastasizes most frequently to the liver and appears to be no less sensitive to both biologic agents and chemotherapy than is cutaneous melanoma.

B. Staging

Melanoma is staged according to the American Joint Committee on Cancer staging system (see Tables 14.1 to 14.3). 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, serum creatinine, liver panel, alkaline phosphatase, and serum lactate dehydrogenase at baseline. A baseline chest radiograph is obtained to evaluate for pulmonary lesions. A computed tomography (CT) scan can be considered if clinically warranted. Elevation of liver function tests warrants further imaging of the liver, most typically with CT. Unexplained bone pain should also be evaluated with CT or magnetic resonance imaging. 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 mapping is recommended for lesions between 0.76 and 1 mm and above.

C. Surgical treatment

The standard treatment for skin lesions suspected of being melanoma is excisional biopsy rather than incisional or “shave” biopsies. A subsequent wide and deep excision is required to provide adequate tumor-free margins as melanoma has a known propensity for local recurrences. While there is some variation in recommendations, most experts would advocate a 1-cm tumor-free margin for melanomas less than 1 mm in thickness and 1- to 2-cm margins for deeper primary lesions if technically possible, following current National Comprehensive Cancer Network guidelines. Additionally, for primary lesions of at least 1 mm, sentinel node mapping is recommended. Lymph node “drainage areas” are assessed via a specific lymph node (sentinel node(s)—sometimes more than one) into which lymphborne metastases generally first occur. The absence of tumor involvement in the lymph node is associated with a reduced risk of nodal spread and relapse in general and eliminates the need for subsequent dissection of that nodal basin. In the recent Multi-Center Sentinel Lymph Node Trials 1, 1347 patients with primary melanomas of 1.2 to 3.5 mm, felt to be at intermediate risk of recurrence, were randomly allocated to receive either observation or a sentinel node biopsy, with completion lymphadenectomy if the sentinel node was positive and observation only if negative. A delayed lymph node dissection was performed in case of nodal recurrence in either group. Preliminary results from that trial suggest that there was no survival advantage for the performance of a sentinel lymph node biopsy in this risk group, although it reduced the relative risk of recurrence at any site by 26%, reduced the absolute chance of recurrence locoregionally from 15.6% to 3.4%, and confirmed that those with a positive sentinel node had a worse outcome than those with a negative sentinel node biopsy.

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D. Adjuvant therapy

Eastern Cooperative Oncology Group (ECOG) protocol E1684 was a large randomized adjuvant trial of interferon (IFN)-α2b 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 compared to the observation group. The regimen used was IFN 20 million IU/m2 intravenously (IV) 5 days/week for 4 weeks (as a “loading phase”) followed by 10 million IU/m2 subcutaneously (SC) 3 days/week for 48 weeks as a maintenance phase. Toxicity was significant, but quality-of-life analysis demonstrated overall benefit. The follow-up study of observation versus the same IFN regimen versus a lower dose regimen, ECOG 1690, also showed a significant disease-free survival advantage over the observation arm but not a benefit in overall survival for the high-dose regimen. The difference between these two studies may be that patients on the observation arm in the subsequent trial (1690) may have been treated with immunotherapy (including IFN or interleukin [IL]-2) at the time of relapse. Several recent meta-analyses of randomized trials of high-dose IFN have shown that while there is a statistically significant and consistent advantage in relapse-free survival, the benefit for overall survival is very modest, at 2% to 3%. Nonetheless, given that patients with deep cutaneous primaries and/or lymph node involvement are at high risk for metastatic recurrence and that the majority of patients who suffer metastatic relapse will die of their disease, it is reasonable to treat such high-risk patients with either adjuvant high-dose IFN or to consider entrance into a clinical trial.

Chemotherapy as a single adjuvant 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. Peginterferon, which prolongs the half-life of the drug, allowing it to be delivered weekly, has been tested in several adjuvant trials in resected melanoma. Only in patients whose lesions were detected at sentinel node biopsy was there an advantage in disease-free survival for peginterferon.

E. Therapy of metastases

1. General considerations about systemic therapy

a. Patient selection. While melanoma is considered relatively resistant to chemotherapy, certain favorable prognostic factors do lend themselves to longer survivals with single-agent or multiagent chemotherapy, or even high-dose IL-2. These include ECOG performance status 0 or 1; subcutaneous, lymph node, or pulmonary metastasis with normal lactate dehydrogenase (M1a or M1b disease); no prior chemotherapy; normal marrow, renal, and hepatic function; and absence of central nervous system (CNS) metastases. The biologic basis for these findings has not been fully elucidated. When reviewing potential therapy for stage IV melanoma patients, patient characteristics as well as the natural history of their metastatic disease must be considered. Surgical resection should be considered for one or even two sites of metastases that are resectable with a reasonable surgical procedure associated with modest morbidity. Failing that, for unresectable disease, an evaluation should be made whether the patient has indolent disease, suggesting that immunotherapy might be useful, or more aggressive disease, indicating that other approaches are warranted. While a clinical trial should be a first consideration for patients with metastatic disease, high-dose IL-2 should be considered for the subset of patients that qualify for that rigorous therapy.

2. Biologic agents. This class of agents has been extensivelytested in melanoma, a histology where they have met with some success.

a. Interleukin-2 (IL-2) appears to be the most active, currently approved 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 infusions IV every 8 hours for a maximum of 14 doses on a day 1 and day 15 schedule every 6 to 8 weeks. This schedule produces responses in 15% to 20% of patients, with 5% to 6% complete response, many of long duration. A review of National Cancer Institute data with high-dose IL-2 showed a response rate of 50% in patients with disease limited to cutaneous/subcutaneous sites only (i.e., M1a disease). Because this drug is associated with a capillary leak syndrome that can include hypotension, fluid retention, renal and hepatic hypoperfusion, and pulmonary edema, the previously discussed dose and schedule require inpatient care in a monitored setting with nursing staff and physicians that are experienced and skilled in its use. Given these effects, patients must be in relatively good health, and a cardiac stress test should be performed prior to treatment in anyone above 50 years of age or any patient with multiple cardiac risk factors. It should be noted that the older literature may express IL-2 dosing in other than international units. Therefore, when comparing various studies, a rule of thumb for conversions is 1 mg = 3 × 106Cetus Units = 6 × 106 Roche Units = 18 × 106 IU.

b. Interferon (IFN) (alfa2b and alfa2a) has been examined with a wide range of doses, schedules, and routes from 3 to 50 × 106 IU/m2 given SC, intramuscularly, 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, while lower doses of IFN (5 MIU/m2SC) may be more immunostimulatory. IFN is in general not commonly used in the metastatic setting, though a select population of patients with limited disease may benefit from this treatment.

c. Ipilimumab is a human immunoglobulin G1 antibody directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4, expressed on activated T-cells. It has been extensively tested in stage IV melanoma and is an active drug, with objective response rates of 7% to 20%. Many responses are sustained over time, and ipilimumab has been shown to induce novel patterns of response, with slow regression over 6 to 12 months, progression followed by regression, and new lesions appearing while other baseline lesions continue to regress. This drug has also demonstrated unique side effects that are directly related to its immune mechanism of action, called immune-related adverse events, consisting of rashes, colitis with diarrhea, hepatitis, pancreatitis, and hypophysitis leading to pituitary insufficiency. In relapsed/refractory melanoma at 3 mg/kg, ipilimumab plus a peptide vaccine has been reported in a 670-patient trial to have superior overall survival compared to the peptide vaccine alone, which is the first positive controlled randomized trial in stage IV melanoma ever conducted, and establishes a new standard of care.

d. Tyrosine kinase/signal transduction inhibitors. These “small molecule” inhibitors, including pan-tyrosine kinase inhibitors sorafenib and sunitinib which likely inhibit tumor-related angiogenesis, have been investigated and have little activity as single agents or when added to chemotherapy in stage IV melanoma. Clinical trials have been conducted with carboplatin and paclitaxel with sorafenib based on promising phase II single center data. Unfortunately, the PRISM trial sponsored by Bayer did not show a median or overall survival difference between carboplatin and paclitaxel with or without sorafenib administered to patients as second-line therapy.

The recent discovery that up to 50% of melanomas have a common activating mutation in the B-RAF gene, at the V600E position, has provoked the testing of a number of small molecule RAF inhibitors in stage IV melanoma. Very promising early data, from a phase II trial of 30 patients with the oral B-RAF inhibitor PLX-4032 from Plexxicon-Roche, resulted in a 70% objective response rate in mostly refractory melanoma patients with a V600E mutation. This drug is now being evaluated in a second-line phase II and a frontline randomized phase III trial, the latter in comparison to dacarbazine alone.

Approximately 20% of patients with mucosal melanoma have been shown to harbor an activating C-KIT mutation in exons 9, 11, or both. This also can lead to amplification of C-KIT. In a small pilot trial, and in a number of anecdotal publications, blockade of C-KIT with the oral inhibitor imatinib induced rapid and dramatic regression in patients with C-KIT mutated mucosal melanoma; however, the duration of these responses are yet to be known.

e. Combinations of biologic agents. The role of combinations of biologic agents remains an area of ongoing study, but they have thus far not shown demonstrable advantage.

3. Chemotherapy

a. Single-agent chemotherapy. Most cytotoxic agents commonly used in other tumor types are inactive in this disease. Several agents possess modest activity in melanoma with responses obtained primarily in lung and nonvisceral sites and typically in ambulatory patients with few or no symptoms of their disease.

(1) Dacarbazine 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. Response rates are between 10% to 20% and the median time to progression is 2 to 3 months.

(2) Platinum-containing drugs. Cisplatin 100 mg/m2 IV every 3 weeks or carboplatin 400 mg/m2 IV every 3 weeks appears to have similar efficacy.

(3) Taxanes. Docetaxel 60 to 100 mg/m2 is given in 1-hour infusions IV every 3 weeks, or paclitaxel 135 to 215 mg/m2 is given in 3-hour infusions IV every 3 weeks.

(4) Temozolomide is an oral imidazole agent that is biochemically converted to the active (dacarbazine) intermediate monomethyl triazeno imidazole carboxamide in an acid environment 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 by mouth daily for 5 days every 28 days, or continuous administration for 6 of 8 weeks at 75 mg/m2, both with equivalent efficacy.

(5) Vinca alkaloids such as vinblastine and nitrosoureas such as carmustine have been used primarily in combinations and have modest single-agent activity in melanoma.

b. Multiagent chemotherapy. Despite decades of trials, no combination chemotherapy has emerged as a standard therapy. While multiple regimens have shown high response rates in single arm phase II or nonrandomized trials, there are no convincing data from randomized trials to show both statistically significant improvements in response rate and median survival compared with single-agent therapy (usually dacarbazine). While a phase II study of the “Dartmouth Regimen” suggested a higher response rate than dacarbazine alone, a phase III trial demonstrated no significant difference in progression-free or overall survival compared to dacarbazine alone. Cisplatin, vinblastine, and dacarbazine/temozolomide are currently an acceptable off-protocol combination regimen (Table 14.4). Carboplatin combined with paclitaxel every 3 weeks is emerging as the most common combination treatment used off protocol based on the results of the PRISM trial control arm discussed above (see Section I.E.2.d).

4. Biochemotherapy. Three randomized studies have compared the combination of polychemotherapy (cisplatin, vinblastine, and dacarbazine) with 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 months versus 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. A recently published phase II study of biochemotherapy delivered with IL-2 in a decrescendo regimen, followed in stable or responding patients by maintenance IL-2, resulted in a favorable median survival of over 12 months. While patient selection may have played a role in this favorable outcome, the high response rates seen with that regimen suggest that it is a reasonable alternative for untreated patients with rapidly growing disease, or as a neoadjuvant regimen prior to a planned resection of bulky stage III locoregional disease.

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F. Regional therapy

1. 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-α, often with hyperthermia, yield higher tissue concentrations of the drugs than are achievable by intravenous administration. Phase II studies often show impressive response rates. Whether there is any survival advantage to this therapy compared with systemic treatment remains controversial. Because of issues such as cost, the equipment required, and the physician training needed to implement this approach, its practicality is limited. Hepatic arterial infusion therapy is theoretically appealing for ocular melanoma metastatic only to the liver; ongoing studies are being conducted currently to further evaluate this treatment modality. This therapy looks more active than systemic chemotherapy in ocular melanoma, although it is unclear that such an approach improves median survival.

2. Intralesional therapy with Bacillus Calmette-Guérin (BCG), IFN-α, granulocyte-macrophage colony-stimulating factor, IL-2, and other agents has also been used with varying degrees of success in treatment of very small dermal metastases.

3. Treatment of central nervous system metastases. Dexamethasone 10 mg IV followed by 6 mg every 6 hours IV or by mouth 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 experience good quality of life. The role of temozolomide needs to be further explored in this group of patients.

4. Radiotherapy is of variable efficacy in the treatment of symptomatic regional or bony metastases but sometimes may yield symptomatic benefit. We routinely add daily temozolomide at 75 mg/m2 to whole brain radiation to augment its antitumor activity when administered to patients with multiple CNS metastases.

5. Surgery, when utilized judiciously, can result in long-term disease-free survivals of up to 20% in individuals with isolated metastatic sites. The median survival for those patients is 30 to 36 months. Indications for surgical resection of metastases include gastrointestinal metastases that are chronically bleeding or if there is impending bowel obstruction or perforation and single brain metastases, especially if bleeding prior to 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 and are clinically free of disease is being evaluated in several trials, and such metastasectomy patients should always be considered for vaccine or other adjuvant trials when available. An alternative approach is to treat such patients with IFN as described previously.

G. Experimental and future therapies

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 (see “Selected Readings”).

1. 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 but thus far have been without significant benefit. A polyvalent melanoma cell vaccine and Melacine (GlaxoSmithKline, Middlesex, UK), a vaccine derived from allogeneic melanoma cell lines (approved for use in metastatic disease in Canada), are example 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 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.

2. 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 randomized evidence that the addition of cultured T-cells to IL-2 therapy, for instance, is superior to IL-2 alone. A significant advance may be the development of tumor infiltrating lymphocyte (TIL) therapy. These effector T-cells are grown from enzyme-digested tumors and are expanded in tissue culture over 3 to 6 weeks, often resulting in an oligoclonal population of highly tumor-specific T-cells. On adoptive transfer with high-dose IL-2, response rates of up to 50% were seen. Newer approaches include the use of lymphoid depletion prior to adoptive transfer of TIL, which allows the effectors to proliferate during the process of homeostatic lymphoid proliferation. During that time, many memory effector cells will populate the T-cell pool, resulting in longlasting tumor specific T-cells in the peripheral circulation. The addition of total body irradiation to TIL therapy with high-dose IL-2 results in even higher response rates of up to 72%, with favorable median survivals of greater than 12 months in recurrent melanoma patients who have failed IL-2 and chemotherapy.

II. NONMELANOMA SKIN CANCER

A. Etiology and epidemiology

The American Cancer Society estimates there were nearly 1 million new cases of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in the United States in 2009. These lesions occur twice as frequently in men than in women. BCC occurs 4 times more commonly than SCC (70% to 80% versus 10% to 30%). Both are seen predominantly in the elderly. Risk factors for these two lesions include age greater than 60 years, 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, similar to melanoma. 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 those with chronic lymphocytic leukemia and prior organ transplant 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

1. 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 about 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% to 50%). Neglected lesions, large ulcerated lesions, and poorly differentiated histology are risk factors for metastases. The great majority of metastases initially occur in lymph nodes (90%), with approximately 50% of patients developing metastases to other sites such as lung and bone. SCCs may begin as premalignant lesions called actinic keratoses (AKs) that are rough, pink or flesh-colored areas on sun-exposed skin. In situ SCC, known as Bowen disease, exists prior to dermal invasion and appears as red-colored patches and is larger than AKs.

2. 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 mm 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 above techniques 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 the 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. 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 is used for AK and SCC in situ and is applied directly to the involved skin. It is generally not systemically absorbed, therefore almost no systemic toxicity is seen. Local side effects include red discoloration of the skin and photosensitivity. Imiquimod is approved by the U.S. Food and Drug Administration for local therapy of AKs and some small BCCs. Both agents are applied locally daily for up to 3 weeks.

3. Treatment of metastatic disease. Metastases from either BCC or SCC may be treated with cisplatin-containing chemotherapy regimens. 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. Hedgehog signal transduction inhibitors are showing early promise in the treatment of metastatic BCCs. Clinical trials with these agents are ongoing.

C. Merkel cell carcinoma

1. 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 in the United States. 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 Caucasians than non-Caucasians, occurs more frequently in males than females, and affects persons at a median age of 65 to 70 years. Sun exposure is felt to be the major risk factor. Recent studies have identified a polyomavirus in Merkel cell tumors.

2. Clinical features. Initially, it maybe 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 later develop metastatic disease. The most frequent distant metastatic sites are liver, lung, and bones. The overall 5-year survival rate for all stages is 50%.

3. 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 as 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 or cisplatin and etoposide at doses utilized for small-cell lung cancer. Response rates for these regimens are about 60%.

D. Mycosis fungoides (MF)

1. 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 males with a median age of approximately 60 years. The lymphocytic infiltrate seen 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 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.

2. 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. Sézary syndrome is a leukemic phase of MF with circulating lymphoma cells noted on peripheral smear. The course of MF can be variable, with 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 TMN (B) system (Tables 14.5 and 14.6) and is based on the amount of skin involved and the presence of patches, plaques, or tumors. Patients with stage IA to IIA MF 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 (less than 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/rVB 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.

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3. Treatment. For individuals whose disease is confined only to the skin, electron beam radiation, the combination of a photosensitizing substance such as psoralen and ultraviolet radiation (PUVA), extracorporeal photopheresis, bexarotene gel, or topical application of nitrogen mustard or carmustine can lead to complete response 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 Sézary syndrome, systemic therapy such as interferon-α 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-α and retinoids such as bexarotene (150 mg per day) are being evaluated for enhanced immune modulation. “Traditional” antilymphoma chemotherapy agents such as cyclophosphamide, doxorubicin, vincristine, and prednisone appear less active in this type of lymphoma than in other non-Hodgkin 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 (1200 mg/m2 weekly × 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 diftitox, has been approved for refractory disease with response rates of 30% to 70%.

Acknowledgments

The authors are indebted to Drs. Karen S. Milligan and Walter D.Y. Quan, Jr., who contributed to previous editions of this chapter. Several sections in this revision of the handbook represent their work.

Selected Readings

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