Epidemiology
Increased exposure to ultraviolet radiation is associated with an increased development of all three of the common skin malignancies; basal cell carcinoma, squamous cell carcinoma, and melanoma. Chemical carcinogens such as tar, arsenic, and nitrogen mustard are known carcinogens. Human papillomavirus
has been found in certain squamous cell cancers and may be linked with oncogenesis. Radiation therapy in the past for skin lesions such as acne vulgaris, when it resulted in radiation dermatitis, is associated with an increased incidence of basal and squamous cell cancers in the treated areas. Any area of skin subjected to chronic irritation, such as burn scars (Marjolin ulcers), repeated sloughing of skin from bullous diseases, and decubitus ulcers, all have an increased chance of developing squamous cell cancer. Immunosuppressed patients receiving chemotherapy for other malignancies or immunosuppressants for organ transplants have an increased incidence of basal cell and squamous cell cancers and malignant melanoma. Acquired immune deficiency syndrome (AIDS) is associated with an increased risk of developing skin neoplasms.
Basal Cell Carcinoma Basal cell carcinomas contain cells that resemble the basal cells of the epidermis. It is the most common type of skin cancer and is subdivided into several types by gross and histologic morphology. The nodulocystic or noduloulcerative type accounts for 70 percent of basal cell carcinomas. It is a waxy, cream-colored lesion with rolled, pearly borders. It often contains a central ulcer. When these lesions are large they are called “rodent ulcers.” Pigmented basal cell carcinomas are tan to black in color and should be distinguished by biopsy examination from melanoma. Superficial basal cell cancers occur more commonly on the trunk and form a red, scaling lesion that is sometimes difficult to distinguish grossly from Bowen disease. A rare form of basal cell carcinoma is the basosquamous type, which contains elements of basal cell and squamous cell cancer. These lesions can metastasize more like a squamous cell carcinoma and should be treated aggressively. Other types include morpheaform, adenoid, and infiltrative carcinomas. Basal cell carcinomas usually are slow growing, and patients often neglect these lesions for years. Metastasis and death from this disease are extremely rare, but these lesions can cause extensive local destruction. The majority of small (less than 2 mm), nodular lesions may be treated by dermatologists with curettage and electrodesiccation or laser vaporization. A drawback to these procedures is that no pathologic specimen is obtained to confirm the diagnosis or evaluate the tumor margins. Larger tumors, lesions that invade bone or surrounding structures, and more aggressive histologic types (morpheaform, infiltrative, and basosquamous) are best treated by surgical excision with a 2–4-mm margin of normal tissue. Histologic confirmation that the margins of resection do not contain tumor is required. Because nodular lesions are less likely to recur, the smaller margin may be used, whereas other types need a wider margin of resection.
Squamous Cell Carcinoma Squamous cell carcinomas arise from keratinocytes of the epidermis. It is less common than basal cell carcinoma but is more devastating because it can invade surrounding tissue and metastasize more readily. In situ lesions have the eponym of Bowen disease, and in situ squamous cell carcinomas of the penis are referred to as erythroplasia of Queyrat. Contrary to previous reports, Bowen’s disease is not a marker for other systemic malignancies. Tumor thickness correlates well with its biologic behavior. Lesions that recur locally are more than 4 mm thick
or more. The location of the lesion also is important. Tumors arising in burn scars (Marjolin ulcer), areas of chronic osteomyelitis, and areas of previous injury metastasize early. Lesions on the external ear frequently recur and involve regional lymph node basins early. Squamous cell cancers in areas with solar damage behave less aggressively and usually require only local excision. Lesions should be excised with a 1-cm margin if possible, and histologic confirmation that the margins are tumor-free is mandatory. Tumor-invading bone should be excised if recurrence is to be avoided. Regional lymph node excision is indicated for clinically palpable nodes (therapeutic lymph node dissection). Lesions arising in chronic wounds behave aggressively and are more likely to spread to regional lymph nodes. For these lesions lymphadenectomy before the development of palpable nodes is indicated (prophylactic lymph node dissection). Metastatic disease is a poor prognostic sign, with only 13 percent of patients surviving after 10 years
Alternative Therapy
Alternatives to surgical therapy for squamous and basal cell cancers consist of radiation therapy or topical 5-fluorouracil for patients unable or unwilling to undergo surgery. Radiation therapy for small and superficial lesions obtains cure rates comparable to surgical excision. Radiation damage to surrounding normal skin with inflammation and scarring can be a problem. The development of cutaneous malignancies in irradiated skin also is a serious long-term risk with this treatment modality. For lesions on the face or near the nose or eye, resection of a wide rim of normal tissue to remove the entire tumor can cause significant functional and cosmetic problems. These lesions can be removed by Mohs micrographic surgery. Mohs fresh tissue chemosurgery technique, developed in 1932, is a method to serially excise a tumor by taking small increments of tissue until the entire tumor is removed. Each piece of tissue removed is frozen and immediately examined microscopically to determine whether the entire lesion has been resected. The advantage of the Mohs fresh tissue chemosurgery technique is that the entire margin of resection is evaluated, although with wide excision and traditional histologic examination, only selected samples of the surgical margin are examined. The major benefit of Mohs fresh tissue chemosurgery technique is the ability to remove a tumor with the least sacrifice of uninvolved tissue. This technique is effective for treating carcinomas around the eyelids and nose, where tissue loss is most conspicuous. Cure rates are comparable to those of wide excision. Patients with basal cell carcinomas have been treated with intralesional injection of interferon. The majority of the lesions were eliminated or controlled by the injections. The major disadvantages of this treatment are the need for multiple office visits over several weeks for injections, the systemic side effects of interferon, and a potential need for surgery if the lesions do not respond to injections. Clinical trials with combinations of retinoids (vitamin A derivatives) and interferon have demonstrated good response rates in patients with advanced, inoperable squamous cell carcinomas.
Malignant Melanoma
What was a relatively rare disease 50 years ago has now become alarmingly more common. The rise in the rate of melanoma is the highest of any cancer in the United States. In 1935, the annual incidence of the disease was 1 per 100,000 people. By 1991, the incidence had risen to 12.9 per 100,000 people. The 1998 age-adjusted rate for invasive melanoma is 18.3 per 100,000 for white males and 13.0 per 100,000 for white females in the United States.
Melanoma arises from transformed melanocytes and occur anywhere that melanocytes have migrated during embryogenesis. The eye, central nervous system, gastrointestinal tract, and even the gallbladder have been reported as primary sites of the disease. More than 90 percent of melanomas are found on the skin; however, 4 percent are discovered as metastases without an identifiable primary site. Nevi are benign melanocytic neoplasms found on the skin of most people. Once the melanocyte has transformed into the malignant phenotype, the growth of the lesion is radial in the plane of the epidermis. Even though microinvasion of the dermis can be observed during this radial growth phase, metastases do not occur. Only when the melanoma cells form nests in the dermis are metastases observed
Types The most common type of melanoma, representing up to 70 percent of melanomas, is the superficial spreading type. These lesions occur anywhere on the skin except the hands and feet. They are flat, commonly contain areas of regression, and measure 1–2 cm in diameter at the time of diagnosis. There is a relatively long radial growth phase before vertical growth begins. The nodular type accounts for 15–30 percent of melanomas. These lesions are darker and raised. Nodular melanoma lack radial growth peripheral to the area of vertical growth; hence, all nodular melanomas are in the vertical growth phase at the time of diagnosis. Although it is an aggressive lesion, the prognosis for a patient with a nodular-type lesion is the same as that for a patient with a superficial spreading lesion of the same depth of invasion. The lentigo maligna type, accounting for 4–15 percent of melanomas, occurs mostly on the neck, the face, and the back of the hands of older adult people. These lesions are always surrounded by dermis with heavy solar degeneration. They tend to become quite large before a diagnosis is made, but also have the best prognosis because invasive growth occurs late. Only 5–8 percent of lentigo malignas are estimated to evolve to invasive melanoma. Acral lentiginous type is the least-common subtype, representing only 2–8 percent of melanoma in whites. It occurs on the palms and soles and in the subungual regions. Although melanoma among dark-skinned people is relatively rare, the acral lentiginous type accounts for 29–72 percent of all melanomas in dark-skinned people (African Americans, Asians, and Hispanics) than in people with less-pigmented skin. Subungual lesions appear as blue-black discolorations of the posterior nail fold and are most common on the great toe or thumb. The additional presence of pigmentation in the proximal or lateral nail folds (Hutchinson sign) is diagnostic of subungual
Prognostic Factors
The most current staging system, from the American Joint Committee on Cancer (AJCC), contains the best method of interpreting clinical information in regard to prognosis of this disease (Table 15-1). The T classification of lesions comes from the original observation by Clark that prognosis is directly related to the level of invasion of the skin by the CHAPTER 15 SKIN AND SUBCUTANEOUS TISSUE 337 melanoma. Whereas Clark used the histologic level (I, superficial to basement membrane [in situ]; II, papillary dermis; III, papillary/reticular dermal junction; IV, reticular dermis; and V, subcutaneous fat), Breslow modified the approach to obtain a more reproducible measure of invasion by the use of an ocular micrometer. The lesions were measured from the granular layer of the epidermis or the base of the ulcer to the greatest depth of the tumor (I, 0.75mm or less; II, 0.76–1.5 mm; III, 1.51–4.0 mm; IV, 4.0 mm or more). These levels of invasion have been subsequently modified and incorporated in the AJCC staging system. Evidence of tumor in regional lymph nodes is a poor prognostic sign. This is accounted for in the staging system by advancing any T classifications from stage I or II to stage III (Table 15-2). The 15-year survival rate drops precipitously with the presence of lymph node metastasis. The number of positive lymph nodes also is correlated with survival rates. The presence of distant metastasis is a grave prognostic sign (stage IV). The median survival ranges from 2–7 months, depending on the number and site of metastases, but survival up to a few years has been reported. TABLE 15-1 TNM Classification of Melanoma of the Skin Primary tumor (T) T1 1.0 mm in thickness or less T1a Without ulceration and Clark level II/III T1b With ulceration or level IV/ V T2 1.01–2.0 mm in thickness T2a Without ulceration T2b With ulceration T3 2.01–4.0 mm in thickness T3a Without ulceration T3b With ulceration T4 4.01 mm or greater in thickness T4a Without ulceration T4b With ulceration Nodal status (N) N1 1 node N1a Micrometastasis (as diagnoses after sentinel lymph node or lymphadenectomy) N1b Macrometastasis (clinically detectable, confirmed by pathology) N2 2–3 nodes N2a Micrometastasis N2b Macrometastasis N2c In-transit met(s) without metastatic nodes N3 4 or more metastatic nodes, or matted nodes, or in-transit met(s)/satellite(s) with metastatic node(s) Metastasis (M) M1 Distant skin, subcutaneous or nodal matastasis, serum LDH normal M2 Lung metastasis, normal LDH M3 All other visceral metastasis with normal LDH or any distant mets with elevated LDH
than people with melanomas of the head and neck or trunk (82 percent 10-year survival rate for localized disease of the extremity, compared to a 68 percent survival rate with a lesion of the face). Ulceration. The 10-year survival rate for patients with local disease (stage I) and an ulcerated melanoma was 50 percent, compared to 78 percent for the same stage lesion without ulceration. Early studies identified that the incidence of ulceration increases with increasing thickness, from 12.5 percent in melanomas less than 0.75 mm–72.5 percent in melanomas greater than 4.0 mm. Gender. Numerous studies demonstrate that females have an improved survival compared to males. After correcting for thickness, age, and location, females continue to have a higher survival rate than men (80 percent 10-year survival rate forwomen vs. 61 percent 10-year survival rate for men with stage I disease). Histologic type. Nodular melanomas have the same prognosis as superficial spreading types when lesions are matched for depth of invasion. Lentigo maligna types, however, have a better prognosis even after correcting for thickness, and acral lentiginous lesions have a worse prognosis. Treatment The treatment of melanoma is primarily surgical. The indication for procedures such as lymph node dissection, sentinel lymphadenectomy, superficial parotidectomy, and resection of distant metastases have changed somewhat over time, but the only hope for cure and the best treatment for regional control and palliation remains surgery. Most cases of cutaneous melanoma are cured by excision of the primary tumor alone. Radiation therapy, regional and systemic chemotherapy, and immunotherapy are effective in a limited set of circumstances, but none are a first-line option. All suspicious lesions should undergo biopsy. A 1-mm margin of normal skin is taken if thewound can be closed primarily. If removal of the entire lesion creates too large a defect, then an incisional biopsy of a representative part is recommended. Biopsy incisions should be made with the expectation that a
of melanoma is made, the biopsy scar and any remains of the lesion need to be removed to eradicate any remaining tumor. Four randomized prospective trials suggest that lesions 1 mm or less in thickness can be treated with a 1-cm margin. For lesions 1–4-mm thick, a 2-cm margin is recommended. There is little data to support the use of margins wider than 2 cm. The surrounding tissue should be removed down to the fascia to remove all lymphatic channels. If the deep fascia is not involved by the tumor, removing it does not affect recurrence or survival rates, so the fascia is left intact. If the defect cannot be closed primarily, a skin graft or local flap is used. All clinically positive lymph nodes should be removed by regional nodal dissection. When groin lymph nodes are removed, the deep (iliac) nodes must be removed along with the superficial (inguinal) nodes. For axillary dissections the nodes medial to the pectoralis minor muscle must also be resected. For lesions on the face, anterior scalp, and ear, a superficial parotidectomy to remove parotid nodes and a modified neck dissection is recommended. Disruption of the lymphatic outflow does cause significant problems with chronic edema, especially of the lower extremity. Treatment of regional lymph nodes that do not obviously contain tumor in patients without evidence of metastasis (stages I and II) is determined by considering the possible benefits of the procedure as weighed against the risks. In patients with thin lesions (less than 0.75 mm), the tumor cells are still localized in the surrounding tissue, and the cure rate is excellent with wide excision of the primary lesion; therefore treatment of regional lymph nodes is not beneficial. With very thick lesions (more than 4 mm), it is highly likely that the tumor cells have already spread to the regional lymph nodes and distant sites. Removal of the lymph nodes has no effect on survival. Most of these patients die of metastatic disease before developing problems in regional nodes. Because there are significant morbid effects of lymphadenectomy, most surgeons defer the procedure until clinically evident disease appears. Approximately 40 percent of these patients eventually develop disease in the lymph nodes and require a second palliative operation. Elective lymphadenectomy is sometimes performed in these patients as a staging procedure before entry into clinical trials. In patients with intermediate-thickness tumors (T2 and T3, 0.76–4.0 mm) and no clinical evidence of nodal or metastatic disease, the use of prophylactic dissection (elective lymph node dissection on clinically negative nodes) is controversial. Numerous retrospective studies suggested that patients with primary melanoma who underwent elective lymph node dissection had improved survival. However, prospective, randomized studies have not demonstrated that elective lymph node dissection improves survival in patients with intermediate-thickness melanomas. Careful examination of specimens in patients undergoing elective lymph node dissection have found that, in 25–50 percent of the cases, specimens contain micrometastases. Among patients who do not have an elective lymph node dissection, 20–25 percent eventually develop clinically evident disease and require lymphadenectomy. More evidence suggests that there may be improved survival with elective lymph node dissection in patients with a higher risk of developing metastasis (i.e., lesions with ulceration or those located on the trunk, head, and neck). The most compelling argument for the potential benefits of elective lymph node dissection comes from evidence in large clinical trials; patients with intermediate-thickness melanomas without elective node dissection continue 340 PART II SPECIFIC CONSIDERATIONS to die of the disease 10 years later, whereas patients who had an elective lymph node dissection do not. However, these differences are not statistically significant. Sentinel lymphadenectomy for malignant melanoma is rapidly becoming the standard procedure. The sentinel node may be preoperatively located with the use of a gamma camera, or by intraoperative injection of 1 percent isosulfan blue dye into the site of the primary melanoma. These techniques enable the surgeon to identify the lymphatic drainage from the primary lesion and determine the first (sentinel) lymph node draining the tumor. The node is removed, and if micrometastases are identified in frozen-section examination, a complete lymph node dissection is performed. Whether this procedure actually improves survival in these patients awaits the results of clinical trials. When patients develop distant metastases, surgical therapy may be indicated. Once melanoma has spread to a distant site, median survival is 7–8 months and the 5-year survival rate is less than 5 percent. Solitary lesions in the brain, gastrointestinal tract, or skin that are symptomatic should be excised when possible. Although cure is extremely rare, the degree of palliation can be high and asymptomatic survival prolonged. A decision to operate on metastatic lesions must be made after careful deliberation with the patient. A promising area in the nonsurgical treatment of melanoma is the use of immunologic manipulation. Interferon-α (INF-α) 2b is the only Food and Drug Administration (FDA)-approved adjuvant treatment for AJCC stages IIB/III melanoma. Several randomized trials of INF-α adjuvant therapy have been conducted. In these patients, both the relapse-free interval and overall survival were improved with use of INF-α. Side effects were common and frequently severe. Vaccines have been developed with the hope of stimulating the body’s own immune system against the tumor. All treatments are currently investigational. One defined-antigen vaccine has entered clinical testing, the ganglioside GM2. Gangliosides are carbohydrate antigens found on the surface of melanomas and many other tumors. Although initially thought to be ineffective in the treatment of melanoma, radiation therapy has been shown to be useful. High-dose-per-fraction radiation produces a better response rate than low-dose large-fraction therapy. It has been found that postoperative radiation to the neck or axilla after radical lymph node dissections decreases regional recurrence rates in node-positive patients. Radiation therapy is the treatment of choice for patients with symptomatic multiple brain metastases. Up to 70 percent of treated patients show measurable improvement in tumor size, symptomatology, or performance status. Hyperthermic regional perfusion of the limb with a chemotherapeutic agent (e.g., melphalan) is the treatment of choice for patients with local recurrence or in-transit lesions (local disease in lymphatics) on an extremity that is not amenable to excision. In-transit metastases develop in 5–8 percent of melanoma patients with a high-risk primary melanoma (>1.5 mm). The goal of regional perfusion therapy is to increase the dosage of the chemotherapeutic agent to maximize tumor response while limiting systemic toxic effects. Prospective clinical trials are under way to evaluate the use of regional perfusion for melanoma of the limbs as adjuvant therapy for patients with stage I disease. Additionally, regional perfusion therapy for metastatic disease to the liver is under investigatio
OTHER MALIGNANCIES Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of the Skin) Merkel cell carcinomas are of neuroepithelial differentiation. These tumors are associated with a synchronous or metasynchronous squamous cell carcinoma 25 percent of the time. These tumors are very aggressive, and wide local resection with 3-cm margins is recommended. Local recurrence rates are high, and distant metastases occur in one third of patients. Prophylactic regional lymph node dissection and adjuvant radiation therapy are recommended. Overall, the prognosis is worse than for malignant melanoma. Extramammary Paget Disease This tumor is histologically similar to the mammary type. It is a cutaneous lesion that appears as a pruritic red patch that does not resolve. Biopsy demonstrates classic Paget cells. Paget disease is thought to be a cutaneous extension of an underlying adenocarcinoma, although an associated tumor cannot always be demonstrated.
Adnexal Carcinomas This group includes the rare-type tumors apocrine, eccrine, and sebaceous carcinomas. They are locally destructive and can cause death by distant metastasis. Angiosarcomas Angiosarcomas may arise spontaneously, mostly on the scalp, face, and neck. They usually appear as a bruise that spontaneously bleeds or enlarges without trauma. Tumors also may arise in areas of prior radiation therapy or in the setting of chronic lymphedema of the arm, such as after mastectomy (Stewart- Treves syndrome). The angiosarcomas that arise in these areas of chronic change occur decades later. The tumors consist of anaplastic endothelial cells surrounding vascular channels. Although total excision of early lesions can provide occasional cure, the prognosis usually is poor, with 5-year survival rates of less than 20 percent. Chemotherapy and radiation therapy are used for palliation. Kaposi Sarcoma Kaposi sarcoma (KS) appears as rubbery bluish nodules that occur primarily on the extremities but may appear anywhere on the skin and viscera. These lesions are usually multifocal rather than metastatic. Classic KS is seen in people of Eastern Europe or sub-Saharan Africa. The lesions are locally aggressive but undergo periods of remission. Visceral spread of the lesions is rare, but a subtype of the African variety has a predilection for spreading to lymph nodes. A different variety of KS has been described for people with AIDS or with immunosuppression from chemotherapy. In this form of the disease, the lesions spread rapidly to the nodes, and the gastrointestinal and respiratory tract often are involved. Development of AIDSrelated KS may be associated with concurrent infection with a herpes-like virus. Treatment for all types of KS consists of radiation to the lesions. Combination chemotherapy is effective in controlling the disease, although most 342 PART II SPECIFIC CONSIDERATIONS patients develop an opportunistic infection during or shortly after treatment. Surgical treatment is reserved for lesions that interfere with vital functions, such as bowel obstruction or airway compromise. Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans consists of large nodular lesions located mainly on the trunk. They often ulcerate and become infected. With enlargement, the lesions become painful. Histologically, the lesions contain atypical spindle cells, probably of fibroblast origin, located around a core of collagen tissue. Sometimes they are mistaken for an infected keloid. Metastases are rare and surgical excision can be curative. Excision must be complete because local recurrences are common. Fibrosarcoma Fibrosarcomas are hard, irregular masses found in the subcutaneous fat. The fibroblasts appear markedly anaplastic with disorganized growth. If they are not excised completely, metastases usually develop. The 5-year survival rate after excision is approximately 60 percent. Liposarcoma Liposarcomas arise in the deep muscle planes and, rarely, from the subcutaneous tissue. They occur most commonly on the thigh. An enlarging lipoma should be excised and inspected to distinguish it from a liposarcoma.Wide excision is the treatment of choice, with radiation therapy reserved for metastatic disease. FUTURE DEVELOPMENTS IN SKIN SURGERY Despite three decades of effort, the major challenge in surgical therapy for diseases of the skin remains the lack of an optimum replacement for diseased or damaged tissue. Autologous skin grafts are still the best method to treat skin defects, but donor-site problems and limited availability of autologous skin remain problematic. Tissue expansion with subcutaneous balloon implants produces new epidermis; however, much of this tissue is rearrangement of the old tissue. Expansion of skin produces a limited amount of useful tissue. The future of surgical therapy for diseases of the skin lies in the development of engineered skin replacements. Current research is directed at identifying different materials