Allan C. Halpern MD1
Patricia L. Myskowski MD2
1Professor, Joan and Sanford I. Weill Medical College of Cornell University, Chief, Department of Dermatology, Memorial Sloan-Kettering Cancer Center
2Joan and Sanford I. Weill Medical College of Cornell University
Allan C. Halpern, M.D., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Patricia L. Myskowski, M.D., has received grant or research support from Merck & Co., Inc., and is a consultant for Ligand Pharmaceuticals Inc.
Topical corticosteroids, topical nitrogen mustard, and carmustine have not been approved by the FDA for treatment of cutaneous T cell lymphoma; interferon alfa, sirolimus, and HAART have not been approved by the FDA for treatment of Kaposi sarcoma.
Malignant tumors can arise from cells of any layer of the skin—keratinocytes, melanocytes, fibroblasts, endothelial cells, or adipocytes—as well as from cells such as lymphocytes, which normally transit through the skin. Cutaneous metastases may also arise from other primary sites. In this chapter, we review the most common malignant cutaneous tumors in their order of frequency.
Malignant Tumors of the Epidermis
Epidermal skin cancers are the most common cancers in humans. They arise in the keratinocytes and the melanocytes of the epidermis. Epidermal skin cancers present a unique opportunity for effective intervention with both early detection and primary prevention. They are amenable to clinical diagnosis by simple visual inspection and to pathologic diagnosis by minimally invasive biopsy.
Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) originate from the keratinocytes of the epidermis. Because these two cancers share many features, they are often lumped together under the term nonmelanoma skin cancer (NMSC).
Malignant melanoma is a malignancy arising from a melanocyte. Although malignant melanomas can arise in any melanocyte of the body, including the eye, the vast majority occur in the skin. Cutaneous malignant melanoma has been categorized into four major histogenetic types: lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, and acral lentiginous melanoma.
SUN EXPOSURE AND SKIN CANCER
Several lines of evidence implicate ultraviolet (UV) radiation in the pathogenesis of all three of the major epidermal skin cancers.1Epidemiologic data implicate long-term cumulative sun exposure in the development of SCC and intense intermittent sun exposure in the development of BCC and melanoma. Laboratory studies indicate that both UVA (320 nm to 400 nm) and UVB (290 nm to 320 nm) radiation from sunlight can damage DNA both directly and through oxidative damage. In addition, UV radiation can suppress the cutaneous immune system.2 The association of some SCCs with chemical carcinogens and the occurrence of acral lentiginous and mucosal melanomas in unexposed areas of the body underscore the need for studies to identify additional etiologic agents.
Recognition of the important role of sunlight in the etiology of skin cancer affords an opportunity for primary prevention through the use of sun protection. Unfortunately, the exact timing and doses of UV exposure involved in the development of skin cancer in humans are not known and likely vary among the types of skin cancer. Accordingly, patients should be educated about the deleterious effects of sun exposure and tanning. Sun-protection efforts should be geared to an overall reduction of sun exposure through the avoidance of sun-seeking behavior and the use of sun-protective clothing. Broad-spectrum sunscreens with a sun protection factor (SPF) of 15 or greater are a useful adjunct to sun protection, but they should not be used to increase the amount of time spent in direct sunlight.3 The use of tanning beds should be avoided. The use of sunless tanning agents is safe, but the darkening of the skin that results from the use of these agents does not offer significant UV protection. For individuals who are assiduous in their sun protection efforts, attention should be given to adequate vitamin D intake through diet or supplements.4
NONMELANOMA SKIN CANCER
NMSC typically occurs as pink lesions on the sun-exposed skin surface. Any pink skin lesion that persists or recurs in the same location, especially if easily irritated by minor trauma, should raise the suspicion of NMSC. Some forms of NMSC will fade with changes in season (i.e., with reduced sun exposure) or with the application of topical steroids, and the clinician should advise patients that any lesion that recurs warrants further attention.
Basal Cell Carcinoma
BCC is a malignant cutaneous tumor arising from the basal keratinocytes of the epidermis.
BCC is the most common skin cancer. The reported incidence ranges from 3.4 per 100,000 per year in African Americans to over 1,100 per 100,000 per year in Townsville, Queensland, Australia.5,6 Although rare, metastases and death from BCC do occur.
Etiology and risk factors
UV radiation—specifically, intense intermittent sun exposure—appears to play an important role in the development of BCC. Studies of basal cell nevus syndrome (Gorlin syndrome) have yielded dramatic insights into the genetics of BCC. The patched gene, which was first recognized as a developmental gene in the fruit fly Drosophila, has been identified as playing a critical role in the development of BCC. Almost all patients with basal cell nevus syndrome appear to inherit a mutated copy of the patched gene, and studies of sporadic BCC suggest that mutations in the patched gene pathway (i.e., the sonic hedgehog pathway) are a necessary and often sufficient step in the development of most BCCs.7
The majority of BCCs occur on the head and neck. They occur in nodular and superficial forms, as well as in a variety of less common forms.
Nodular BCC appears as a raised, pearly, translucent, pink bump on the skin surface. It is often easily irritated, fragile, and associated with episodes of superficial ulceration or hemorrhage. When ulceration is prominent, it can lead to the appearance of a so-called rodent ulcer, in which the pearly translucent border is barely appreciable. Some nodular BCC lesions appear more white than pink and, on close observation, often demonstrate small telangiectasias. They tend to have a smoother, shinier surface and a firmer texture than common dermal nevi [seeFigures 1a, 1b, and 1c].
Figure 1a. Rodent's Ulcer
Nodular basal cell carcinoma—shown here above a patient's lip, with a so-called rodent's ulcer.
Figure 1b. Nodular Basal Cell Carcinoma
Nodular basal cell carcinoma commonly presents as a raised, pearly, translucent pink bump on the skin surface.
Figure 1c. Superficial Form of Nodular Basal Cell Carcinoma
A superficial form appears as a pink patch of skin.
Superficial BCC appears as a pink patch of skin. On close inspection, most superficial BCCs demonstrate a thready, translucent border, with areas of seemingly normal or slightly fibrotic skin within the lesion. Superficial BCC is usually found on the upper trunk, arms, and legs.
Less common clinical variants of BCC include morpheaform, pigmented, and cystic lesions. Morpheaform BCCs have an infiltrative pattern that histologically and clinically resembles a scar. Pigmented BCCs typically contain specks of blue-black pigment, but they may be deeply pigmented throughout. Pigmented lesions are most commonly a variant of nodular BCC. Cystic BCCs tend to be softer than typical nodular BCCs and may have a clear to blue-gray appearance.
Patient history plays a critical role in the diagnosis of BCC. When questioned about lesions that become easily irritated or bleed from minor trauma, patients can often alert the clinician to early lesions that would otherwise elude detection. With the patient under local anesthesia, a biopsy should be obtained of any suspicious lesion.
Nodular BCC can be confused with angiofibromas, dermal nevi, amelanotic melanoma, cutaneous metastases, dermatofibroma, and a host of benign adnexal tumors (e.g., trichoepithelioma). Superficial BCCs mimic several inflammatory dermatoses (e.g., eczema and tinea) and share several clinical features with actinic keratoses. Pigmented BCC can easily be confused with a primary melanocytic neoplasm. Cystic BCCs can be confused with cystic adnexal tumors and inflammatory lesions.
The goal of therapy is to adequately eradicate the lesion and ensure the best cosmetic and functional outcome. Multiple factors—such as the size, location, and histologic subtype of the lesions and attributes of the patient, including age, general health, skin color, and skin laxity—should be taken into consideration in choosing an optimal therapy.
The vast majority of BCCs are amenable to surgical treatment. The primary options include curettage and electrodesiccation, excision, and Mohs micrographic surgery. A small but significant subset of BCCs can be treated effectively with Mohs micrographic surgery, which entails microscopic examination of frozen sections of the entire undersurface of the excised specimen at the time of surgery. The technique may be indicated for recurrent lesions and lesions that have a high likelihood of recurrence. Such lesions include ill-defined lesions, large lesions (> 2 cm), lesions with a high-risk histology (i.e., aggressive growth pattern, sclerosing pattern, or perineural involvement), and lesions overlying embryonal fusion planes (e.g., ocular canthi or nasofacial sulcus). The cure rate of Mohs micrographic technique is significantly higher than the cure rates of other treatments of these high-risk lesions.8
Radiation therapy can be an effective, painless, and well-tolerated alternative that is typically reserved for older patients who are poor surgical candidates. Radiation therapy should be avoided, however, in patients with basal cell nevus syndrome. Cryotherapy is another therapeutic option for BCC in patients who are poor surgical candidates.
Topical therapy combined with pharmacotherapy using the immune response modifier imiquimod five times weekly for 6 weeks has been approved by the Food and Drug Administration for the treatment of superficial BCC of the trunk and extremities. One packet (250 mg) of imiquimod 5% cream is applied to 25 cm2 of affected skin.
Experimental therapies under investigation include intralesional chemotherapy, next-generation topical immune modulators, and photodynamic therapy.
All patients treated for BCC are at risk for local recurrence, and they are at significant risk for the development of additional skin cancers. Patients should be instructed in the self-examination of their skin, as well as in methods of sun protection. In addition, they should receive routine professional follow-up.
The risk of local recurrence relates to the lesion's size, location, and histology. Metastases are very rare: a prevalence of 0.0028% was reported in a series of 50,000 Australians.9 Metastases occur through both the lymphatic and the hematogenous routes; risk factors include basal cell nevus syndrome, immunosuppression, and previous exposure to ionizing radiation. Metastases that are not amenable to surgical management are associated with a poor outcome.
Squamous Cell Carcinoma
Like BCC, cutaneous SCC arises from the keratinocytes of the epidermis. Histologically, the cells of well-differentiated SCC resemble the cells of the superior portion of the epidermis.
An estimated 150,000 to 250,000 new cases of cutaneous SCC were diagnosed in the United States in 1994.10 The estimated mortality from SCC in the United States in 1988 was approximately 0.5 per 100,000. Several lines of data suggest significant increases in SCC incidence. In Australia, for example, the incidence of SCC increased by 51% between the years 1985 and 1990.11 In the United States, some of the highest rates of NMSC have been detected in the southwest. A population-based survey in New Mexico found the incidence of SCC doubled in both males and females between 1978 and 1999.12
Etiology and risk factors
In addition to sunlight, other known etiologic agents that contribute to the development of cutaneous SCC are ionizing radiation, chemical carcinogens, thermal burns, and chronic nonhealing wounds. Sun-related SCCs demonstrate a lower risk of metastases and death than SCCs related to other exposures. Factors involved in predisposition to SCC from sun exposure include light skin color, a tendency to burn, and an inability to tan.
Pathophysiology and pathogenesis
Sun-related SCC is often associated with a precursor lesion called an actinic keratosis. Such lesions occur on the scalp, the face, the extensor surfaces of the forearms, and the backs of the hands. They tend to be rough-surfaced, irregularly shaped, and pink. They are often more readily felt than seen. The majority of patients with actinic keratoses have multiple lesions. The risk of SCC in these individuals has been estimated to be as high as 20%.13 SCC may also appear on normal-looking skin.
SCC of the oral or genital mucosa may arise in precursor lesions termed leukoplakia or erythroplakia. Mucosal SCCs are associated with a significant risk of metastases. Immune surveillance affects the progression of SCC. Immunosuppression, as occurs in transplant recipients and patients with lymphoma, is associated with a high incidence of SCC.14 In these patients, infection with human papillomavirus appears to play an etiologic role in conjunction with sun exposure. SCCs tend to be more aggressive in immunosuppressed persons.
Most lesions occur in areas of the body that are usually exposed to the sun. The lesions are pinkish, firm plaques that often have a rough, scaly surface [see Figures 2a and 2b]. Biopsy is required for definitive diagnosis.
Figure 2a. Squamaous Cell Carcinoma on Arm
A squamous cell carcinoma is shown on an arm.
Figure 2b. Squamaous Cell Carcinoma on Lip
A squamous cell carcinoma is shown on the lower lip.
The differential diagnosis of SCC includes keratoacanthoma, Bowen disease, verrucous carcinoma, BCC, hypertrophic actinic keratosis, and common warts.
Keratoacanthomas share many features with SCC, both clinically and histologically. They arise de novo on normal-looking skin and grow very rapidly. They are typically pink, dome-shaped, shiny bumps with a central crateriform keratotic plug that occur on the surface of the skin. They may become very large. Although keratoacanthomas are not associated with a risk of metastasis, they can be locally destructive. Spontaneous regression of keratoacanthoma over the course of months has been well documented.
Bowen disease is SCC that is confined to the epidermis. It appears as red, scaly, minimally elevated plaques with well-defined, irregular borders. The reported association of Bowen disease with internal malignancy has not held up to closer scrutiny.15
SCCs that lack a scaly keratotic surface can be confused with a host of other adnexal and dermal skin tumors.
Small SCCs evolving from an actinic keratosis can be adequately treated with simple curettage and electrodesiccation. Larger actinic lesions, as well as lesions arising in non-sun-exposed areas of skin, are best treated with definitive surgical excision with confirmation of negative margins. High-risk, ill-defined lesions, especially those occurring in the surgically sensitive areas of the face, genitalia, hands, and feet, are often best treated by Mohs micrographic surgery.
Fractionated radiation therapy is an alternative treatment of primary SCC in older patients who are poor surgical candidates. The benefits of adjuvant radiation therapy are less clear, as are the benefits of sentinel lymph node biopsy and elective lymph node dissection (ELND) for patients with high-risk SCC of the head and neck.
Cytotoxic chemotherapy and biologic response modifiers have been used in patients who have advanced SCC; this therapeutic approach has been reported to have complete response rates of up to 68%, but there are few long-term survivors.16 Actinic keratoses are treated with cryotherapy, curettage, topical therapies (e.g., fluorouracil, imiquimod, or diclofenac), photodynamic therapy, and laser resurfacing to prevent progression to SCC.17 Regularly updated guidelines for the treatment of SCC and BCC are available through the National Comprehensive Cancer Network (NCCN).18
Regardless of the therapy employed, high-risk lesions have a significant rate of local recurrence at 5 years. High-risk SCCs include those in specific anatomic sites (e.g., ears, lips, genitalia, and other non-sun-exposed areas), those greater than 2 cm in diameter, those with aggressive histologic features (depth > 4 mm, Clark level IV and above, and poorly differentiated histology), and those in immunosuppressed patients.19 The primary route of SCC metastasis is via lymphatic spread to regional lymph nodes. Reported rates of metastasis vary from as low as 0.3% in small, sun-derived lesions to 33% in larger, poorly differentiated lesions.19 Reported overall 5-year survival rates for patients with regionally metastatic SCC have ranged from 25% to 47%.19
In the United States, a person's lifetime risk for developing melanoma is about 1 in 75 (1.3%).20 Between 1973 and 1994, the incidence of melanoma rose by 121%, and the mortality rose by 39%.21 Encouraging trends include a shift toward the detection of earlier disease, as well as a stabilization of incidence rates in some segments of the population. In terms of both morbidity and mortality, however, the burden of melanoma-related disease continues to increase. Although melanoma can occur in anyone, it is primarily a disease of whites. Melanomas occurring in blacks are more commonly of the acral lentiginous variety.
Etiology and Risk Factors
Although strong epidemiologic and basic-science evidence supports an association between melanoma and sun exposure, the relationship appears to be complex.22 Lentigo maligna melanoma is associated with long-term cumulative sun exposure. Superficial spreading melanoma and nodular melanoma appear to be associated with intense intermittent sun exposure, especially in youth. Acral lentiginous melanoma has no apparent association with sun exposure. Basic-science studies and animal models have implicated different wavelengths of UV in melanoma carcinogenesis; UV wavelength may vary among types of melanoma.
Melanoma can occur in all racial/ethnic groups but is much more common in lighter-skinned individuals. Among whites, several additional risk factors have been identified, such as fair complexion, a tendency to burn, an inability to tan, freckling, and a family history of melanoma.22 Screening of the family members of patients with melanoma (particularly multiple melanomas) may be a useful preventive and diagnostic measure.23
Moles and dysplastic nevi
The strongest phenotypic markers of melanoma risk are moles (nevi)—more specifically, increased numbers of moles and the presence of atypical moles (dysplastic nevi). Melanoma can arise in a preexisting mole or may arise de novo on normal-appearing skin.
Several epidemiologic studies have correlated dysplastic nevi with melanoma risk. Clinically, dysplastic nevi are large (> 5 mm) moles with variegate pigmentation and ill-defined borders [see Figures 3a and 3b]. Histologically, dysplastic nevi are characterized by the presence of architectural atypia and random cytologic atypia. The degree of melanoma risk associated with dysplastic nevi depends on the genetic context. In families with familial melanoma-dysplastic nevus syndrome, the abnormal mole phenotype appears to be inherited in an autosomal dominant fashion. Members of these families with dysplastic nevi have a lifetime melanoma risk that approaches 100%.24 Outside the context of familial melanoma, dysplastic nevi occur in approximately 5% to 15% of whites. In this general population, dysplastic nevi are markers of increased melanoma risk [see Table 1].25
Table 1 Adjusted Estimated Relative Risks of Melanoma by Nevus Type and Number19
Figure 3a. Dysplastic Nevi
Dysplastic nevi typically are larger than common moles.
Figure 3b. Dysplastic Nevi
Dysplastic nevi typically have variegate pigmentation and ill-defined borders.
Approximately 5% of patients with melanomas have a family history of melanoma. Mutations in the cell-cycle regulatory gene p16 (cyclin-dependent kinase inhibitor-2a) are associated with melanoma in approximately 40% of familial-melanoma families, with linkage of the gene to chromosome 9p.26 A highly specific activating somatic mutation in the BRAF proto-oncogene (a member of the RAF family of kinases) is found in the majority of melanomas and benign nevi, suggesting a pivotal role for this genetic pathway in melanocytic tumor progression.27Genomic analyses are beginning to distinguish biologically distinct subsets of melanoma.28
As a pigmented lesion occurring on the surface of the skin, melanoma is amenable to early detection by simple visual inspection at an easily curable stage. Left untreated, melanoma is among the deadliest and most therapeutically unresponsive forms of cancer.
Early recognition of melanoma requires attention to pigmented lesions on all body surfaces. Despite the strong association of melanoma with sun exposure, melanomas can occur anywhere on the skin or mucosa. Patients' self-examination, as well as physician examination, must therefore include all skin surfaces, including the scalp, genitalia, and soles of the feet. Any pigmented skin lesion with recent change or with features described by the ABCD mnemonic (asymmetry, border irregularity, color variation, diameter > 6 mm) warrants consideration of the possibility of melanoma. Although any mole may change gradually over time, any that change color, shape, or size relative to a patient's other moles deserve special attention [see Figures 4a, 4b, 4c, and 4d].29 Dysplastic nevi present both opportunity and challenge in melanoma detection. On one hand, their recognition allows efficient targeting of a high-risk group. On the other, they can complicate attempts at melanoma detection by clinically mimicking early melanomas. Although some dysplastic nevi may progress to melanoma, the overwhelming majority remain benign. Furthermore, not all melanomas arising in patients with dysplastic nevi develop in a preexisting mole. Wholesale removal of dysplastic nevi is an impractical approach to melanoma prevention. In patients with dysplastic nevi, melanoma detection is predicated on specialized visual examination aided by self-examination and professional follow-up to identify changing lesions.30
Figure 4a. Superficial Malignant Melanoma
Superficial spreading malignant melanoma begins as a small, irregular brown lesion.
Figure 4b. Lentigo Malignant Melanoma
Variation in color and contour is characteristic of lentigo maligna melanoma.
Figure 4c. Nodular Melanoma
Nodular melanoma often grows more in thickness than in diameter.
Figure 4d. Acral Letiginous Melanoma
Acral lentiginous melanoma can resemble a hematoma under the nail.
Several specialized aids to the diagnosis of melanoma in patients with dysplastic nevi are under development. Dermoscopy entails the use of a handheld otoscopelike device to magnify a pigmented lesion while applying pressure and oil to the surface. The technique allows the visualization of pigment patterns and features not apparent with simple visual inspection. With experience and training, dermoscopy can be a useful aid in distinguishing melanoma from benign pigmented lesions; however, when used inexpertly, dermoscopy may actually decrease diagnostic accuracy.30,31 Another aid to melanoma detection in high-risk individuals is photographically assisted follow-up.32 A baseline set of whole-body photographs of the skin are used during self-examination and professional follow-up examination to assess change in the lesions. This procedure helps to prevent unnecessary excision of stable lesions and improves the sensitivity of examinations in detecting change. New imaging technologies such as in vivo confocal scanning laser microscopy hold promise for future improvements in the noninvasive diagnosis of melanoma.33
Full-thickness excision and biopsy
Any lesion that raises a clinical suspicion of melanoma requires definitive diagnosis. Full-thickness excision is the preferred technique for biopsy of a suspicious pigmented lesion. Partial biopsy can lead to misdiagnosis through sampling error or by depriving the pathologist of a view of the overall architecture and cytology of the lesion. Incisional biopsies with good clinicopathologic correlation may be appropriate, however, in the assessment of large lesions and of lesions occurring in surgically sensitive areas. There is no evidence to suggest that incisional biopsy increases the risk of metastasis.
Dysplastic nevi share many features with early superficial spreading melanoma. Other common lesions that may mimic melanoma include lentigines, sunburn freckles, traumatized nevi, thrombosed angiomas, pigmented BCCs, pigmented Bowen disease, dermatofibromas, and atypical seborrheic keratoses. Two other challenges in the differential diagnosis of melanoma deserve special mention. Amelanotic melanomas (melanomas without pigment) present as pink lesions that may be misdiagnosed as BCCs or Spitz nevi. Spitz nevi can be difficult to differentiate from melanoma both clinically and histologically. Spitz nevi occur most commonly in children, but they also occur in adults. Like nodular melanomas, Spitz nevi tend to appear suddenly and range in color from red to reddish brown.
Primary cutaneous melanoma is managed surgically with definitive reexcision. The wide excisions of the past have given way to resections with more modest margins. Multiple prospective, randomized trials have investigated the surgical resection of primary cutaneous melanoma utilizing different margins of resection; these studies have focused on varied and overlapping patient populations. On the basis of these data, the NCCN recommends resection margins of 1 cm for melanomas less than 1 mm in thickness, margins of 1 to 2 cm for melanomas between 1 and 2 mm in thickness, and margins of 2 cm for melanomas greater than 2 mm in thickness.34,35 Primary closure and reconstructive flaps are preferable, cosmetically and functionally, to skin grafts and should be used instead of grafts whenever possible.
Patients with clinically evident regional lymph node disease are treated with therapeutic lymph node dissection.34 Elective lymph node dissection in patients with primary melanoma and who have no clinical evidence of lymph node involvement has been abandoned on the basis of the failure of multiple randomized trials to demonstrate an overall survival benefit with this procedure.
Sentinel lymph node biopsy is being increasingly used in patients with primary cutaneous melanoma. This technique utilizes lymphoscintigraphy to identify the draining regional lymph node basins for the skin at the site of the primary melanoma. At the time of definitive reexcision of the melanoma, a blue dye and radioisotope are injected into the dermis around the melanoma site. A small incision is made over the spot that has been identified on lymphoscintigraphy as the proximal area of drainage of the regional lymph node basin. The first lymph node identified as taking up the blue dye and radioisotope (i.e., the sentinel node) is then excised.
The sentinel node is then histologically evaluated, often with the use of immunohistochemical techniques and occasionally with the use of polymerase chain reaction, which is more sensitive. The absence of melanoma in the sentinel node is highly sensitive for ruling out the presence of metastases in the remainder of the lymph node basin when the procedure is performed by an experienced team. When the sentinel node is found to be positive for melanoma, a “completion” lymph node dissection of the affected basin is typically performed. Prospective studies have demonstrated sentinel node status to be strongly correlated with 5-year survival.36 Patients with positive sentinel nodes are appropriate candidates for consideration of adjuvant therapy [see Adjuvant Therapy, below]. Several multicenter trials are currently under way to assess the clinical utility of this procedure.37 Initial reports from the first of these trials have failed to indicate an overall survival advantage associated with the procedure.38
In-transit metastases are metastases that establish tumors within regional dermal and subcutaneous lymphatics before reaching the regional lymph nodes. In-transit metastases can remain confined to a single limb for prolonged periods. Amputation does not appear to provide a long-term survival benefit in this setting.34 Slow-growing individual in-transit metastases can be managed surgically. More extensive disease can be treated with sensitization therapy with dinitrochlorobenzene (DNCB), intralesional interferon, or topical agents for modifying the immune response. For extensive in-transit metastases confined to an extremity, limb perfusion therapy can result in dramatic palliation and limb salvage. The procedure entails isolation of the vasculature of the involved extremity from the systemic vasculature and perfusion of the isolated limb with chemotherapeutic agents, biologic agents, or both at doses that could not be tolerated if given systemically.39
Despite the development of several novel approaches to the treatment of patients with metastatic melanoma, including multiagent chemotherapy, biologic therapy, immunotherapy, and combinations of these treatments, no regimens have demonstrated a clear survival advantage over single-agent chemotherapy. Monotherapy with dacarbazine (2 to 4.5 mg/kg daily for 10 days, repeated every 4 weeks) or recombinant interleukin-2 (IL-2) (600,000 IU/kg every 8 hours for up to 14 doses) are the only treatment regimens approved by the FDA for the treatment of metastatic melanoma. Objective responses to dacarbazine are seen in approximately 5% to 20% of patients; durable complete responses are rare.40 Objective responses to IL-2, a significantly more toxic agent, are seen in approximately 15% of patients; durable responses are seen in about 5%. Radiation therapy can play an important palliative role. In the absence of more effective clinically proven therapy, patients with distant metastases should be offered the opportunity to participate in clinical trials of experimental therapy. Many current experimental therapies are predicated on decades of experience with immunotherapy of melanoma, as well as the recent availability of pharmacologic inhibitors of elements of the Ras signaling pathway that are implicated in melanoma pathogenesis.40
Patients with cutaneous or regional disease who have been surgically rendered disease free but who are at high risk for recurrence or metastasis are potential candidates for adjuvant therapy.41 Various adjuvant therapies have been used in melanoma, including immunostimulants such as bacillus Calmette-Guérin, Corynebacterium parvum, and levamisole. Several chemotherapeutic agents have been tried as well. More recently, immunotherapies with cytokines, such as interferons, and active immunization with vaccines have been studied. A high-dose regimen of interferon alfa (20 million units/m2 I.V. daily for 1 month followed by 10 million units/m2 S.C. three times a week for 48 weeks) has been approved by the FDA for use as adjuvant therapy for melanoma. Two studies have demonstrated a small but statistically significant improvement in overall survival with this regimen. Multiple studies have failed to demonstrate improved long-term overall survival with the use of adjuvant interferon in intermediate-dose or low-dose regimens.42,43
A host of novel strategies, including active immunization, passive immunization, and myriad biologic therapies, are currently being studied and may provide opportunities for patients who are appropriate candidates for trials.44
The single strongest prognostic factor for melanoma is stage of disease. Various staging classifications have been used over the years. All staging systems for melanoma take into account the classic TNM classification of tumor size (T), lymph node involvement (N), and distant metastases (M). The differences across staging systems relate largely to the staging of the primary site. New staging systems attempt to use the attributes of the primary tumor that strongly correlate with outcome. These attributes include thickness, ulceration, and, in the case of thin melanomas measuring less than 1 mm thick, the Clark level of invasion. The advent of sentinel node biopsy has led to the inclusion of microstaging of lymph nodes in the staging system [see Tables 2 and 3].45,46
Table 2 AJCC 2002 TNM Classification39
Table 3 AJCC Staging System and Survival Rate45
Attributes of the primary tumor
Several attributes of the primary tumor have been identified as predictors of outcome from primary cutaneous melanoma. A strong predictor of outcome is the Breslow tumor thickness, which is measured in millimeters from the granular layer of the epidermis to the deepest tumor cell. Other important histologic parameters are the Clark level of tumor invasion, the presence or absence of ulceration, the rate of mitosis, the presence of tumor-infiltrating lymphocytes, and vascular invasion. For thin primary melanomas, one of the strongest predictors of outcome is growth phase.47 Radial-growth-phase melanoma does not appear to metastasize, whereas vertical-growth-phase melanoma (characterized by the formation of a tumor nodule in the dermis) is associated with significant risk of metastasis even in lesions less than 1 mm thick.48 Patient characteristics associated with improved survival from melanoma include young age (< 60 years), female sex, and location of the melanoma on an extremity other than the palms or soles. Multivariable models for predicting outcome from melanoma have been developed [see Table 4].49
Table 4 Estimated Probability of 10-Year Survival in Patients with Primary Cutaneous Melanoma41
Malignant Tumors of the Dermis
Cutaneous metastases occur in approximately 5% of patients with solid tumors and are usually associated with widespread disease. The relative frequency of skin metastases is gender specific, reflecting the rates of the primary cancers.50 In women, two thirds of metastases are from breast cancer, but lung cancer, colorectal cancer, melanoma, and ovarian cancer are also frequent. In men, lung cancer is most common, followed by cancer of the large intestine, melanoma, SCC of the head and neck, and cancer of the kidneys.50 The anatomic distribution of skin metastases is not random. Cutaneous metastases from breast cancer often involve the chest wall and may appear as nodules, lymphedema, or cellulitis. The scalp is a common site for metastasis, especially of cancer from the lung and kidney (in men) and breast (in women). Head and neck cancers may invade the skin by local extension, giving rise to a firm, dusky-red edema of the skin that resembles cellulitis. Abdominal wall metastases, often called Sister Joseph's nodules, may occur with gastrointestinal or ovarian malignancies.50 Clinically, cutaneous metastases are often minimally symptomatic dermal papules or nodules and are flesh-colored or pink; dissemination occurs via lymphatic or vascular pathways. Cutaneous metastases may clinically reflect the histology of the primary tumor (e.g., black, brown, or gray nodules with metastatic melanoma, and vascular nodules with renal cell or thyroid carcinoma).
Primary malignancies of the dermis may develop from any of the myriad structures of the skin, including sebaceous glands (sebaceous carcinoma), connective tissue (dermatofibrosarcoma protuberans), smooth muscle (leiomyosarcoma), and other adnexal tissue (eccrine carcinoma). Most of these primary dermal neoplasms are rare; they may exhibit aggressive biologic behavior. Although these neoplasms are quite varied histologically, many share a common clinical presentation of a rapidly growing flesh-colored to pink or red subcutaneous nodule that occasionally resembles a sebaceous cyst.
Merkel cell carcinoma
This neoplasm is a dermal malignancy of neuroendocrine origin. It usually appears as a red to violaceous dermal papule or nodule on the head and neck of elderly patients, although all age groups are affected. The treatment of choice is wide local excision with or without lymphadenectomy. Sentinel node biopsy has been proposed by some for evaluation of the regional lymph nodes. Adjuvant radiation therapy can be considered. Local recurrences are frequent, and distant metastases occur in more than one third of patients. Chemotherapy of metastases is generally disappointing.51,52
A rare malignancy of the skin associated with an underlying adenocarcinoma,50,51 Paget disease usually presents as an erythematous, often weeping unilateral dermatitis of the breast that involves the nipple and areola. The differential diagnosis includes eczema, psoriasis, contact dermatitis, and impetigo. For this reason, biopsy of an inflammatory, nonresolving dermatitis of the nipple or areola is imperative. In Paget disease, the biopsy will reveal typical pale-staining Paget cells in the epidermis. Appropriate surgical resection of the cutaneous and underlying neoplasm is the treatment of choice; lymph node metastases often occur.51
Extramammary Paget disease
Extramammary Paget disease is even more uncommon than Paget disease. It typically presents as red, often ulcerated, plaques in the perineal areas of elderly persons.50,51 Lesions may be pruritic or asymptomatic, are often long-standing, and may have been misdiagnosed as psoriasis, contact dermatitis, or chronic fungal infection. Underlying associated tumors include rectal and genitourinary carcinomas. Even without an associated internal malignancy, extramammary Paget disease is difficult to treat, and it is associated with a high local recurrence rate.51
A rare, often highly aggressive vascular malignancy,51 angiosarcoma may appear as multicentric reddish-purple patches or nodules in a lymphedematous limb, such as on a lymphedematous arm after a mastectomy (Stewart-Treves syndrome). Another presentation is violaceous patches or plaques on the head or neck (especially scalp) of elderly persons. Patients with angiosarcoma have a poor prognosis, with pulmonary metastases frequently developing despite surgery or radiation.51
Dermatofibrosarcoma protuberans is a slow-growing, locally aggressive malignancy that rarely metastasizes but often recurs. Lesions typically present as firm reddish-brown or purple nodules, usually on the trunk or non-sun-exposed extremities. The differential diagnosis includes keloids and benign dermatofibroma. Young adults are most often affected, although the tumor may occur at any age. Wide local excision with or without Mohs micrographic surgery offers the best chance of cure.51
Kaposi sarcoma (KS) is a multicentric cutaneous neoplasm that has four distinct clinical variants.53,54,55,56 In spite of its name, KS is not a true sarcoma. Although the cell of origin has not been clearly established,53,54 KS cells share phenotypic markers with lymphatic endothelium, as well as vascular smooth muscle cells, suggesting a vascular or pluripotent mesenchymal cell origin.56 In its classic form, KS is an indolent disease of elderly men of Mediterranean or eastern European origin, in which violaceous nodules and plaques develop on the lower extremities.53,54,55 A second variant, lymphadenopathic KS, is endemic to some areas of Africa. African KS, which typically affects young adults and children, pursues a more aggressive course than classic KS, with frequent bone, lymph node, and visceral involvement.53,54,55 A third variant of KS occurs in iatrogenically immunosuppressed patients, especially organ transplant recipients.57 In this variant, men are affected slightly more often than women.53,54,55 The fourth variant is an aggressive epidemic KS that occurs in AIDS patients.
Before the advent of AIDS, KS was rare in the United States, with an age-adjusted annual incidence of 0.29 per 100,000 population in men and 0.07 per 100,000 population in women.54 KS was an AIDS-defining illness for 30% to 40% of patients in the earliest years of the HIV epidemic.53 During that period, the incidence of KS in HIV-infected homosexual men was 73,000-fold higher than in the general United States population; in HIV-infected women and HIV-infected nonhomosexual men, the incidence was 10,000-fold higher.52,53 The incidence has significantly declined since the introduction of highly active antiretroviral therapy (HAART). For example, in a large European-based study of HIV-infected patients, there was an estimated 39% annual reduction in the incidence of KS between 1994 and 2003, such that the incidence of KS in 2003 was 10% less than that reported in 1994.58
Etiology and Risk Factors
Human herpesvirus type 8
The epidemiology of KS has long suggested a transmissible infectious agent or cofactor.53,54,55 Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus type 8 (HHV-8), has been detected in all variants of KS.59 HHV-8 has also been found in patients with body cavity-based lymphoma, Castleman disease, and angioblastic lymphadenopathy, as well as in certain skin lesions of organ transplant recipients.53 The mechanism by which HHV-8 infection leads to KS tumorigenesis is unclear but probably involves a complex combination of inflammation, angiogenesis, and neoplastic proliferation.53,54 The prevalence of KS largely parallels the rate of HHV-8 infection in various populations.54 Although the incidence of HHV-8 infection may be as high as 2% to 10% in the general population, the incidence of KS is very low, suggesting that the majority of infections are subclinical.53,54
Host factors, particularly immunosuppression, are crucial in some populations with KS.47,48,50 HIV may play an indirect role in the development of KS through CD4+ T cell depletion and stimulated production of growth factors and cytokines such as IL-1 and IL-6.53,54,56Immunosuppressive drugs, especially cyclosporine, azathioprine, and prednisone, increase the risk of developing KS, primarily in kidney and liver transplant recipients.49
Despite the prevalence of KS in some ethnic groups, the role of any possible genetic factors is unclear. An increased incidence of HLA-DR5 in patients with classic KS has been debated.54 Familial KS is extremely rare, suggesting that genetic factors alone are not responsible.
Finally, gender appears to be a significant risk factor, especially in classic KS, in which the male-to-female ratio may range from 3:1 to 10:1.53,54 The reasons for this male predominance remain unclear.48,49
The clinical manifestations of KS differ among the variants of the disorder.53,54,55 In classic KS, faint reddish-purple macules or patches or purple nodules first appear on the feet, especially the soles. Lymphadenopathy (especially inguinal) is present on rare occasions. Lesions may also occasionally develop on the arms and genital areas. As the disease progresses, the lesions coalesce into violaceous plaques.
HIV-associated KS usually presents as cutaneous lesions, but the first lesions may appear in the oral mucosa or lymph nodes. In contrast to classic KS lesions, HIV-associated KS lesions often begin on the upper body (face, trunk, or arms). Most typically, HIV-associated KS lesions are purple-red, often oval, papules that follow a pityriasis rosea-like distribution [see 2:II Papulosquamous Disorders].53,54,55 Lesions vary from pink macules to deep-purple plaques [see Figure 5] or may resemble ecchymoses, especially in patients with low CD4+ T cell counts. Oral lesions are typically red-purple plaques or nodules on the palate, gingiva, or buccal mucosa. Patients with darker skin may have dark-purple to black lesions or hyperpigmented plaques.54
Figure 5. Kaposi's Sarcoma
HIV-associated Kaposi's sarcoma lesions vary from pink patches (shown) to deep-purple plaques.
As HIV-associated KS progresses, lymphedema may develop in the feet, scrotum, genitalia, and periorbital regions, and lymphadenopathy (especially inguinal) may occur. Gastrointestinal lesions are usually submucosal and asymptomatic but may result in gastrointestinal hemorrhage. Pulmonary KS carries a poor prognosis.54
Laboratory workup of patients with KS should include HIV antibody testing, complete blood count, fecal occult blood testing, and chest radiograph. CD4+ T cell counts are indicated in HIV-positive patients. A complete medical history and physical examination should be performed, with special attention paid to the presence of opportunistic infections in HIV-infected or otherwise immunosuppressed patients. Skin biopsy should be obtained in patients with suspected KS. The histopathology of KS is characterized by the presence of spindle-shaped cells in the dermis, with extravasated red blood cells present in slits between irregular vascular spaces.55
The clinical differential diagnosis of KS includes dermatofibroma, purpura, pyogenic granuloma, bacillary angiomatosis, metastatic melanoma, and BCC. Other histopathologic entities that may resemble KS include angiosarcoma and stasis dermatitis.55
Classic Kaposi sarcoma
The therapy for KS is palliative. In classic KS, where the disease is indolent and the patients are elderly, aggressive systemic therapy is rarely warranted.53,54 Instead, radiation therapy is the treatment of choice.54,60 KS is very radiosensitive: single doses of 800 cGy have been used for rapid palliation in patients with poor prognoses. Total doses of 800 to 3,500 cGy have yielded 50% complete responses and 46% partial responses, with more than half of patients needing no follow-up treatment for as long as 13 years.60 A treatment regimen equivalent to 3,000 cGy in 10 fractions over 2 weeks has been advocated.60
For patients with classic KS who have only one or two papules, excisional biopsy may be sufficient for both diagnosis and treatment. Cryotherapy with liquid nitrogen may be useful for isolated papules. Systemic therapy for classic KS may be indicated in cases of extensive cutaneous disease or visceral involvement. Single-agent chemotherapy with vinca alkaloids (i.e., vincristine or vinblastine) is commonly used. Low-dose recombinant interferon alfa may also be effective in classic KS; however, side effects (e.g., fever, chills, myalgias, and fatigue) may not be well tolerated by elderly patients.53,54
Transplant-associated Kaposi sarcoma
Spontaneous KS regression has been observed in transplant recipients after withdrawal of cyclosporine and corticosteroids.54 Sirolimus (rap amycin), an immunosuppressive drug with antineoplastic and antiangiogenic properties, was successfully used in 15 renal transplant recipients who developed KS. After KS was diagnosed, cyclosporine and mycophenolate mofetil were discontinued and sirolimus was started. Cutaneous KS resolved in all patients, without episodes of acute rejection or changes in renal graft function.58
HIV-associated Kaposi sarcoma
Although KS is more aggressive in HIV-infected patients, the extent of immune suppression and the presence of opportunistic infections or other systemic illnesses may be of equal importance in staging, determining prognosis, and choosing appropriate therapy.53,54 Clinical features that were traditionally associated with a more favorable outcome included a CD4+ T cell count higher than 200 cells/mm3, a lack of systemic illness, KS limited to the skin or lymph nodes, and minimal (i.e., not nodular) oral KS; poor risk factors included a CD4+ T cell count below 200 cells/mm3, KS-associated lymphedema, visceral KS, ulcerated KS, nodular oral KS, and opportunistic infection.61 With the advent of HAART, however, physicians treating patients with HIV-associated KS now have the opportunity to influence and even reverse immune suppression by affecting both HIV viral load and the CD4+ T cell count. Regression of KS has been observed after initiation of HAART, often during the first few months of therapy56,62; consequently, this is often first-line therapy for patients with limited cutaneous HIV-associated KS.54
Local therapy is a reasonable approach in KS patients with limited disease, those with infectious complications, and those who cannot tolerate systemic therapy.62 Radiation therapy is effective in HIV-associated KS in doses similar to those used for classic KS (see above). Responses in HIV-associated KS are generally short-lived, however.54 Topical alitretinoin (9-cis-retinoic acid) gel may be effective in HIV-associated KS and has been approved by the FDA for this use.62 Intralesional injections of vinblastine or interferon have also been useful in selected lesions.53,54 Cryotherapy with liquid nitrogen is effective for small lesions62; however, cryotherapy is contraindicated in dark-skinned patients in whom posttreatment hypopigmentation may appear much worse cosmetically than the original KS lesion.
Systemic therapy has included conventional chemotherapy and biologic response modifiers. For patients with slowly progressive, limited cutaneous KS (< 25 lesions), systemic antitumor therapy may not be necessary; HAART with or without local therapy may be sufficient.51However, HAART alone has not been demonstrated to be the treatment of choice for advanced HIV-associated KS.63 Liposomal anthracyclines (e.g., doxorubicin, daunomycin) are approved by the FDA as first-line therapy of HIV-associated KS.64,65,66 A reasonable approach to the treatment of advanced HIV-associated KS is the use of a combination of HAART and liposomal anthracyclines, followed by a combination of HAART plus paclitaxel if response to the first regimen is inadequate.56,63,65 Promising investigational approaches for HIV-associated KS include antiangiogenic compounds, thalidomide, matrix metalloproteinase inhibitors, and retinoids. Prevention of HIV-associated KS may also be achieved through antiviral therapy of HHV-8.62
Bacterial infections and sepsis are common in patients with KS and may be associated with ulcerated tumors of the legs and feet. Opportunistic infections may intervene, especially in patients with very low CD4+ T cell counts.
The total CD4+ T cell count is the most important predictor of survival in HIV-associated KS.61 Large tumor burdens, lymphedema, and pulmonary KS are also predictive of poorer outcomes.61,65
Lymphomas may be of B cell or T cell lineage and may involve the skin primarily or secondarily [see 12:IV Principles of Cancer Treatment]. B cell lymphomas, particularly non-Hodgkin lymphomas, may involve the skin secondarily in advanced disease. They typically appear as reddish-purple subcutaneous plaques or nodules. Primary B cell lymphomas of the skin are even rarer. They appear as reddish nodules that often remain localized to the skin but may progress to systemic disease. The vast majority of primary cutaneous lymphomas fall into the spectrum of cutaneous T cell lymphoma (CTCL).
CTCL includes mycosis fungoides (MF) and Sézary syndrome, which is a leukemic variant of MF.66,67 MF is the largest subset of CTCL; the two terms, however, sometimes are used interchangeably. Another variant of CTCL is associated with human T cell lymphotropic virus type I (HTLV-I) and is part of the spectra of adult T cell lymphoma/leukemia and peripheral T cell lymphoma.66
CTCL is a rare disorder. In the United States, approximately 1,000 new cases of CTCL are diagnosed annually.66 From 1973 to 1984, the incidence of CTCL rose from 0.19 per 100,000 population to 0.42 per 100,000 population. CTCL primarily affects middle-aged adults; the median age at presentation is 50 years.68 The male-to-female ratio is approximately 2:1; blacks are twice as likely as whites to develop CTCL.68
Host susceptibility and an environmental antigen, perhaps viral, are hypothesized as playing important roles in the pathogenesis of CTCL.66Genetic factors may be related to major histocompatibility antigens, such as an increase in HLA-DRB1*11 (formerly HLA-DR5) and HLA-DQB1*03.69 Chronic antigenic stimulation (e.g., infection) may play an etiologic role.66 For example, HTLV-I infection may be an etiologic factor in the development of the peripheral T cell lymphoma variant.66
The clinical manifestations of MF typically evolve over many months to years. In one classic study, the mean duration of symptoms before diagnosis was 7.5 years.70 Flat, erythematous patches, often scaling and occasionally atrophic, begin most commonly on the trunk and thighs, especially in a so-called bathing-trunk distribution [see Figures 6a and 6b]. Lesions are asymptomatic or mildly pruritic and may spontaneously remit or respond to topical corticosteroid therapy. Patients may also report improvement after sun exposure. As MF progresses, patches tend to enlarge and thicken into plaques. The color may become dark red; in dark-skinned persons, the lesions may initially be hyperpigmented or hypopigmented and may acquire an ery-thematous or violaceous hue. In advanced MF, tumors may develop or transform to a large-cell lymphoma.66,67,71
Figure 6a. Cutaneous T Cell Lymphoma: Large Patch Stage
Cutaneous T cell lymphoma is shown here in the large-patch stage.
Figure 6b. Cutaneous T Cell Lymphoma: Tumor-Stage
Cutaneous T cell lymphoma is shown as tumor-stage mycosis fungoides [see Figure 6b].
In approximately 10% of cases, tumors are the initial presentation of CTCL (tumor d'emblé). Generalized erythroderma with circulating atypical T cells (in Sézary syndrome) is the presentation in 5% of CTCL patients.66,67
Physical examination of patients with suspected CTCL includes complete skin examination, including classification of lesions (patch, plaque, or tumor) and extent of body surface area involved. Lymph nodes, the liver, and the spleen should be palpated.
Skin biopsy is necessary for the definitive diagnosis of CTCL. The presence of atypical lymphoid cells with hyperconvoluted cerebriform nuclei in clusters in the epidermis (Pautrier microabscesses) and a bandlike lymphocytic infiltrate in the upper dermis are diagnostic of CTCL.66,67 The malignant cell is a T cell, with most of the cells expressing the pan-T cell markers CD2, CD3, and CD5, as well as frequent deletion of CD7, CD26, or both.66,67,72 The use of T cell receptor gene rearrangement studies to confirm clonality in early disease may be an aid to diagnosis.66 Neither immunophenotypic studies nor electron microscopy may be considered to be definitively diagnostic of CTCL; clinicopathologic correlation is necessary.
The laboratory evaluation for CTCL includes complete blood count, eosinophil count, Sézary cell count, lactic dehydrogenase level, and liver function tests. Bone marrow biopsy is unnecessary in the absence of circulating leukemic cells. HTLV-I testing should be considered for patients with risk factors or atypical presentations. Lymph node biopsy should be considered for palpable nodes, especially those larger than 2 cm. Abdominal computed tomography or chest radiography may be important in patients with tumors or suspected visceral involvement.
In its early stages, CTCL may resemble any of a number of benign inflammatory disorders (e.g., drug reaction, eczema, psoriasis, or contact dermatitis). These disorders should be ruled out before contemplating therapy.
The staging of CTCL is based on an evaluation of the type and extent of skin lesions and the extent of lymph node, peripheral blood, and visceral involvement.70,71 Early disease is characterized by limited patch or plaque disease (stage IA) or generalized patch or plaque disease without evidence of extracutaneous involvement (stages IB and IIA); more advanced disease is characterized by cutaneous tumors (stage IIB), extracutaneous disease (stage III), and extracutaneous disease involving either lymph nodes (stage IVA) or viscera (stage IVB).
Topical therapy is the mainstay of the treatment of early disease (stage IA, IB, and IIA). Early aggressive therapy with radiation and chemotherapy has not proved to be superior to local approaches in controlling disease or improving survival in patients with limited disease.66,67 A rational approach for treating early limited (or histologically equivocal) disease is topical corticosteroids.73 Topical nitrogen mustard (mechlorethamine), in either aqueous or ointment form, is the most frequently used topical chemotherapy. In one series, the overall response rate to nitrogen mustard was 83%, with a complete response rate of 50%, after a median treatment time of 12 months.74Median time to relapse was also 12 months.74
Carmustine (BCNU) solution, applied daily to lesions, is another useful regimen. Treatment generally lasts 8 to 16 weeks but has been continued for up to 6 months. Because systemic absorption can result in bone marrow suppression, complete blood counts must be monitored.62 Bexarotene, a topical retinoid, has been shown to be effective in CTCL; it is approved by the FDA for use in CTCL.75
Radiation therapy for CTCL takes several forms, from ultraviolet light to ionizing radiation. UVB is useful in stage I disease. In a retrospective study of 21 patients with stage I disease, narrow-band UVB led to complete remission in 81% of patients and to partial remission in 19%; the mean relapse-free interval was 24.5 months.76
Another effective approach to treatment of CTCL is the combination of psoralen and UVA (PUVA). In one study, 65% of patients with stage I CTCL had complete clinical clearing, with a mean relapse-free interval of 43 months; the disease-free survival rates at 5 and 10 years for stage IA were 56% and 30%, respectively.77 In another study, complete remission was observed in 71% of early-stage patients; in this study, the mean relapse-free interval was 22.8 months.76
Total skin electron beam (TSEB) radiation delivers radiotherapy to the skin surface without a significant internal dose. It is especially useful with plaque disease. Typical doses are 2,400 to 3,600 cGy, fractionated over several weeks with 4 to 9 MeV electron beam radiation.78Treatment responses are related to CTCL stage79; early-stage (stage IA) patients have a 95% response rate, but 50% will experience relapse within 10 years. TSEB may also be useful in stage IB disease (90% remission rate), but two thirds of patients treated with this modality will experience relapse within 5 years.73 Patients with tumor-stage (stage IIB) CTCL may receive effective palliation from TSEB, especially in combination with other therapies.79
Systemic therapy has been undertaken as primary therapy in advanced CTCL (stages III through IVB); in early-stage disease, systemic therapy is used as part of sequential therapy to promote more durable responses.66,67
Oral bexarotene has yielded response rates of up to 45% in advanced CTCL, and it is approved by the FDA for use in this disease.80 Another systemic therapy used in the treatment of advanced CTCL is denileukin diftitox [DAB(389) IL-2].81 This receptor-targeted cytotoxic fusion protein binds to the IL-2 receptor on T cells; it achieved a 30% response rate in heavily-pretreated patients.81
Extracorporeal photopheresis, which is an accepted therapy for advanced CTCL, appears most useful in erythrodermic CTCL and Sézary syndrome.66,67 In this treatment, the patient is given a photoactivating drug (8-methoxypsoralen), the patient's white blood cells are collected via leukapheresis and irradiated with UVA, and the irradiated cells are returned to the patient intravenously. Advanced CTCL characterized by cutaneous tumors (stage III) or visceral involvement (stage IV) has also been treated with single-agent and combination chemotherapy using methotrexate, adenosine analogues, interferon alfa, and retinoids.66,67,82
Early aggressive treatment using TSEB followed by combination chemotherapy provides no survival advantage over sequential topical therapy.83,84 In a randomized controlled trial, 103 patients with MF received TSEB followed by either parenteral chemotherapy with cylophosphamide, doxorubicin, etoposide, and vincristine or sequential topical treatment. Patients receiving combined therapy had a significantly higher rate of complete response than those receiving sequential topical therapy; however, there was no difference in the rates of disease-free and overall survival between the two groups after a mean follow-up of 75 months.83 In an uncontrolled study, multimodality therapy was examined in patients with early and advanced disease. In this study, 95 CTCL patients received in consecutive phases of therapy interferon alfa and oral isotretinoin, TSEB, and maintenance therapy consisting of topical nitrogen mustard and interferon alfa. Patients with advanced disease also received six cycles of combination chemotherapy before TSEB. Although multimodality therapy resulted in high response rates (85% response, 60% complete response), the study provided no evidence that this form of combination therapy could improve the overall survival rates currently achieved with sequential topical therapy.80 In general, the heterogeneity of reported combination therapy regimens in CTCL makes it virtually impossible to compare results.
A number of experimental approaches are being investigated in CTCL, including allogeneic bone marrow transplantation, histone deacetylase inhibitors, monoclonal antibodies, and fusion toxins.67 Other investigative modalities include cytokines such as recombinant IL-12 and IL-2.66
The most serious complications of CTCL are infections. Sepsis from ulcerated cutaneous tumors is a common cause of death. Visceral CTCL may occur, as may transformation to large cell lymphoma in some CTCL patients (39% probability after 12 years).71 In long-term survivors with early disease, local therapies (e.g., TSEB or PUVA) may contribute to the development of other skin cancers (e.g., BCC or SCC) and cataracts.85
Many different attempts have been made to classify CTCL into useful prognostic groups. An early and still valid study that used the TNM system identified three major groups: good-risk patients (stages IA, IB, and IIA, with plaque-only skin disease and no lymph node, blood, or visceral involvement [median survival, > 12 years]); intermediate-risk patients (stages IIB, III, and IVA, with cutaneous tumors, erythroderma, or plaque disease and node or blood involvement but no visceral disease or node effacement [median survival, 5 years]); and poor-risk patients (stage IVB, with visceral involvement or node effacement [median survival, 2.5 years]).70
Eosinophilia is also associated with shortened survival.70 Other long-term studies have revealed that stage IA patients do not have a reduced life expectancy and that fewer than 10% of these patients experience disease progression to more advanced stages.86 Survival of patients with generalized patch/plaque MF (stage IB or IIA), at a median of 11.7 years, is significantly worse than that of a race-, age-, and sex-matched control population.87 Gender and race appear to have no effect on survival, but older patients (> 58 years) have shorter disease-specific survivals.68
Editors: Dale, David C.; Federman, Daniel D.