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Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
Acs0304 Surgical Management Of Melanoma And Other Skin Cancers
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Acs0304 Surgical Management Of Melanoma And Other Skin Cancers

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  • 1. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 1 4 MALIGNANT SKIN LESIONS Jennifer A.Wargo, M.D., and Kenneth Tanabe, M.D., F.A.C.S. Physical Examination Given the variable natural history and prognosis of skin malignan- cies, clinical assessment and management of these lesions can be Physical examination should include a complete skin examina- challenging. Malignant skin lesions have become increasingly preva- tion, as well as examination of mucosal membranes. In the case of a lent over the past several years. In the United States, approximately possible melanoma, particular attention should be paid to the pres- 1.2 million cases of nonmelanoma skin cancer are diagnosed annu- ence or absence of surrounding nodules or nodules between the ally.1 More alarming is the observation that approximately 80,000 skin lesion and the closest nodal basins that may represent in-transit cases of melanoma are now diagnosed each year2—a figure that that metastases. Attention should be paid to the draining nodal basins has been steadily rising,3 to the point where the current lifetime risk because lymph node metastases are known to occur in both squa- for the development of melanoma is 1 in 75.2 This disturbing in- mous cell carcinoma (SCC) and melanoma. crease in the incidence of both nonmelanoma skin cancer and If the lesion is not clinically suspicious, conservative monitoring melanoma can largely be attributed to prevailing social attitudes to- through patient self-examination and regular follow-up with a ward sun exposure.4 healthcare provider is appropriate. Given the increasing prevalence of skin cancers and the pivotal INVESTIGATIVE STUDIES role surgeons play in their treatment, it is critical that surgeons be well informed about the recognition, workup, and manage- ment of these conditions. Accordingly, in what follows, we address Biopsy evaluation and management of malignant skin lesions in detail; Any clinically suspicious lesion should undergo either excisional management of benign skin lesions is beyond the scope of this biopsy (if the lesion is small) or incisional biopsy (if the lesion is chapter. large). Excisional biopsy typically incorporates a 1 to 4 mm margin of normal skin, depending on the clinical characteristics of the le- sion.With some types of lesions (e.g., a dysplastic nevus), the use of Assessment of Potentially Malignant Skin Lesions this margin may eliminate the need for subsequent reexcision if the lesion proves to contain high-grade cytologic atypia. In any case, no CLINICAL EVALUATION attempt should be made to perform a definitive radical excision un- til a diagnosis is established by means of biopsy. History A full-thickness excision that extends into the subcutaneous fat A careful history should be obtained, with particular attention should be performed, and the specimen should be marked for paid to the extent of previous sun exposure. A history of blistering orientation to help the pathologist evaluate the margins for possi- sunburn in childhood or adolescence is a significant risk factor and ble microscopic involvement with tumor cells. As a rule, electro- is reported by virtually all white persons with melanomas.5 A per- cauterization should not be employed to remove the specimen, be- sonal or family history of skin cancer is also a risk factor: the likeli- cause it creates artifacts that can substantially distort cells at the hood that melanoma will develop is increased eight- to 12-fold margins. Shave biopsy is discouraged for evaluation of pigmented when a first-degree relative has a history of melanoma.6 Previous lesions because it may create a positive deep margin, thereby com- immunosuppression or transplantation should be inquired about as promising determination of the true depth of penetration of a well; both place the patient at higher risk for the development of skin melanoma. In the case of an elliptically shaped excisional biopsy cancer. on an extremity, the long axis of the specimen should be oriented A detailed history of the lesion’s development, starting with the along the long axis of the extremity to facilitate subsequent reexci- time when it was first noted and including any changes in its size or sion if necessary. appearance, should be elicited. Such a history will help the clinician EXCISION OF MALIGNANCY make the initial judgment regarding whether the lesion is suspicious or nonsuspicious. Generally speaking, lesions are considered non- If the lesion proves to be benign, no further treatment is usually suspicious if they remain stable and uniform in terms of their physi- required. If it proves to be malignant, further excision with appropri- cal characteristics (e.g., size, shape, color, profile, and texture). An ate margins is usually necessary, and tumor staging becomes an im- example of a nonsuspicious lesion is a simple nevus, which typically portant concern. Appropriate excision margins for different skin becomes apparent at 4 to 5 years of age, darkens with puberty, and cancers are discussed in more detail elsewhere [see Management of fades in the seventh to eighth decades of life. Pigmented lesions that Specific Types of Skin Cancer, below]. have an irregular border or demonstrate a change in size, color, or For lesions excised in an ellipse of skin and fat, the length of the texture are considered suspicious. Careful attention should also be ellipse should be approximately 3.5 to 4 times the width to allow paid to constitutional symptoms. Patients who present with tension-free closure without dog-ears. If an area cannot be closed metastatic disease may have systemic or focal complaints, such as primarily, skin grafting may be necessary [see 3:7 Surface Reconstruc- headaches or, in the case of melanoma that has metastasized to the tion Procedures]. For very large lesions or lesions in difficult areas brain, visual changes. (e.g., the face), specialized flaps may be required.
  • 2. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 2 Management of Specific Types of Skin Cancer often turn out to be larger than they appear clinically, and they gen- erally have a more aggressive natural history than other BCCs; as a BASAL CELL CARCINOMA result, complete excision can be highly challenging. Incidence and Epidemiology Treatment Basal cell carcinoma (BCC) is the most common malignancy in Surgical excision remains the mainstay of treatment for primary white persons7 and the most prevalent type of skin cancer overall. BCCs.Typically, a surgical margin of 4 mm is recommended when The incidence varies widely across the globe (e.g., 146/100,000 in possible.11 With small defects, primary closure is generally feasible; the United States, compared with 726/100,000 in Australia).8 The with larger defects, rotation flaps or skin grafting may be necessary. lifetime risk of BCC for a white person in the United States is ap- Lymphatic spread identified in the primary tumor, though present proximately 30%.1 Although BCCs have a very low metastatic po- only in extraordinarily rare cases, may be an indication for lymphat- tential, they impose heavy economic and social burdens on patients ic mapping.12 and society. Other surgical techniques used to treat BCC include cryo- The vast majority of BCCs are found on the head and neck. surgery, curettage and cauterization, and Mohs’ micrographic There is no known precursor lesion. The risk of development of surgery. Cryosurgery and curettage are generally contraindicated BCC seems to be most closely related to exposure to ultraviolet ra- for large or morpheaform BCCs or tumors in high-risk areas (e.g., diation. Whereas substantial sun exposure during childhood and the central face), because surgical margins cannot be assessed. adolescence increases the risk of BCC, no studies have demonstrat- Mohs’ micrographic surgery involves excision of serial sections with ed any significant correlation between the development of BCC intraoperative histologic examination of frozen sections to control and cumulative exposure to ultraviolet light in adulthood.9 Several surgical margins. It is particularly useful in treating morpheaform heritable conditions are associated with an increased risk of BCC, BCCs, recurrent BCCs, and BCCs in high-risk sites (with 5-year including albinism, xeroderma pigmentosum, and Gorlin syn- cure rates approaching 95%).13 drome. Patients with Gorlin syndrome typically have multiple Nonsurgical modalities available for treatment of BCC include BCCs, as well as anomalies of the spine and the ribs, jaw cysts, radiotherapy, photodynamic therapy, and the application of topical pitting of the palms and the soles, and calcification of the falx cere- agents (e.g., 5-fluorouracil [5-FU], imiquimod, and intralesional bri. This syndrome is inherited in an autosomal-dominant interferon alfa [IFN-α]). Radiation therapy is generally reserved for fashion.10 elderly patients with extensive lesions that preclude excision; 5-year cure rates in this population approach 90%.14 Photodynamic ther- Histologic Subtypes apy involves the application of a 20% emulsion of δ-aminolevulinic Several subtypes of BCC have been identified. Typical patterns acid to the lesion, followed by exposure to light in the wavelength seen in more mature lesions include nodular or cystic BCC, superfi- range of 620 to 640 nm.This therapy is based on the uptake of the cial BCC, morpheaform BCC, and pigmented BCC. Nodular porphyrin metabolite by the tumor with subsequent conversion to BCC, also known as rodent ulcer, is the classic type. Nodular BCCs protoporphyrin IX, which results in destruction of the tumor in the typically present as solitary lesions, often on the face, and are usually presence of light.10 The response rates observed with photodynam- shiny and red with central telangectasias [see Figure 1a], an indurat- ic therapy are somewhat lower than those observed with other ther- ed edge, and an ulcerated center. If the contents of the lesion are soft apies: the overall clearance rate is 87%, but the clearance rate for and can be expressed, the condition is referred to as cystic BCC. Su- nodular BCC is only 53%.15 5-FU, in the form of a 5% cream, perficial BCC is typically found on the trunk and appears as a slow- may be used in the management of multiple BCCs of the trunk growing erythematous patch that is often mistaken for eczema or and limbs. Imiquimod is also given in a 5% cream to treat BCCs, psoriasis.10 Morpheaform BCC [see Figure 1b] accounts for only a with clearance rates ranging from 70% to 100%.16 INF-α may be minority of these lesions, but it exhibits clinical features that are es- administered directly into the lesion; in a series of 140 patients pecially noteworthy for surgeons. In particular, morpheaform BCCs treated in this manner, a 67% cure rate was reported.17 a b Figure 1 Shown are (a) a typical basal cell carcinoma and (b) a morpheaform basal cell carcinoma.
  • 3. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 3 a b Figure 2 Shown are squamous cell carcinomas related to (a) radiation exposure and (b) sun exposure. Patients who have been treated for any skin cancer, including keratosis to invasive SCC.The lesions are typically located on sun- BCC, are at higher risk for the development of additional skin can- exposed areas of the head, neck, trunk, or legs; when they are locat- cers and should therefore perform self-examinations at frequent in- ed on the genitalia, the condition is referred to as erythroplasia of tervals to check for suspicious lesions. Such patients should also re- Queyrat. Lesions that develop on non–sun-exposed areas may be as- ceive counselling to reduce sun exposure, with the aim of limiting sociated with internal malignancy.22 Intraepithelial SCCs typically further damage from ultraviolet irradiation. High-risk patients (e.g., appear as erythematous, slightly keratotic plaques and are usually those with Gorlin syndrome and those who are receiving immuno- larger than the lesions of actinic keratosis. They should be excised suppressive therapy after renal transplantation) should be offered with a 5 mm to 1 cm margin. oral retinoid therapy in an effort to prevent the development of oth- er nonmelanoma skin cancers.17 Diagnosis As noted (see above), SCCs are most often associated with sun SQUAMOUS CELL CARCINOMA exposure, though they may also be seen in patients with old scars, radiation-damaged skin [see Figure 2a], or chronic open wounds.23 Incidence and Epidemiology Chronic inflammation and irritation appear to be the common de- SCC of the skin is the second most common form of non- nominators. SCC that arises in a burn scar or a chronic, open melanoma skin cancer overall. It is the most common tumor in el- wound overlying osteomyelitis is often referred to as a Marjolin ul- derly patients, probably as a consequence of cumulative doses of sun cer. SCCs that develop from Marjolin ulcers are characterized by exposure over the course of their lifetimes. In white persons, the life- aggressive regrowth after incomplete biopsy. time risk for the development of SCC is nearly 10%. SCCs typically appear as reddish-brown, pink, or flesh-colored The majority (50% to 60%) of cutaneous SCCs are found on the keratotic papules [see Figure 2b]; ulceration is sometimes, though not head and neck. In one series, nearly 50% of fatal cases of SCC oc- always, present. If there is extensive hyperkeratosis, a cutaneous curred in patients in whom the lesion arose on the ear.18 The mor- “horn” may be evident.18 Symptoms that may suggest malignant tality associated with SCC is estimated to be approximately transformation of actinic keratosis into SCC include pain, erythema, 1/100,000.19 ulceration, and induration. Histologically, SCCs are characterized by nests of atypical keratinocytes that have invaded into the dermis, Precursor Lesions which may be either well or poorly differentiated. Unlike BCCs, SCCs often arise in precursor lesions, such as ac- Once the diagnosis of SCC is suspected, careful attention should tinic keratoses.20 Actinic keratoses, sometimes referred to as solar be paid to the draining nodal basins with the aim of detecting possi- keratoses, develop in chronically sun-damaged areas of the body. ble lymph node metastasis. The risk of such metastasis is between These lesions are often multiple, are generally ill-defined and irregu- 2% and 4% overall but is somewhat higher in patients with relative- lar, and may range in size from about 1 mm to a few centimeters. ly large and poorly differentiated lesions and in patients with lesions They have a scaly appearance and exhibit a wide variety of colors, located on the scalp, the nose, the ears, the lips, or the extremities. from dark brown to flesh-pink. Biopsy may be necessary to rule out The most common sites of metastasis are regional lymph nodes, the the presence of a SCC. Although the rate at which actinic keratosis lungs, and the liver. When metastasis or recurrence develops, it is undergoes malignant transformation to SCC is less than 0.1% per typically within 3 years after treatment of the index lesion. year,21 lesions should nevertheless be treated to reduce the chances of progression. Treatment options include cryotherapy, curettage, Treatment and topical therapy. Surgical excision of actinic keratoses is rarely For primary SCC, as for BCC, surgical excision remains the necessary but may be indicated if there is a high level of suspicion for mainstay of treatment; however, the recommended margin of concurrent SCC. excision for SCCs is generally larger than that for BCCs, rang- Intraepithelial SCC (carcinoma in situ), also known as Bowen ing from 0.5 to 2 cm. Smaller lesions can often be closed pri- disease, is thought to be the next step in the progression from actinic marily; larger lesions may require rotation flaps or skin grafting.
  • 4. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 4 Nonexcisional therapeutic options for SCC are similar to those Table 1—ABCD Guidelines for Pigmented Lesions for BCC. Surgical choices include cryosurgery, curettage and cau- terization, and Mohs’ micrographic surgery. Nonsurgical choices in- Characteristic Comments clude radiotherapy, photodynamic therapy, and topical therapy with agents such as 5-FU, imiquimod, and intralesional IFN-α. Most early lesions grow at uneven rate, resulting in an Asymmetry asymmetrical appearance Posttreatment recommendations for SCC patients are essentially the same as for BCC patients [see Basal Cell Carcinoma,Treatment, Border irregularity Uneven growth rate also results in irregular border above]: frequent self-examination to look for suspicious lesions, Irregular growth also causes new shades of black and counseling to reduce sun exposure, and the offer of oral retinoid Color variegation of light and dark brown therapy for high-risk patients.17 Lesions with ABC features and diameter > 6 mm Diameter MELANOMA should be considered suspicious for melanoma Incidence and Epidemiology 5. A history of 3 or more years of an outdoor summer job as a Although melanoma is less common than BCC or SCC, it is teenager; and clearly more deadly than either. It is currently the sixth leading cause 6. Marked freckling on the upper part of the back. of cancer-related death in the United States, and its incidence is in- For a person with one or two of these factors, the risk of melanoma creasing faster than the incidence of any other malignancy. is increased 3.5-fold; for a person with three or more, the risk is in- Melanoma is slightly more common in men than in women, and the creased 20-fold. median age at diagnosis is 57 years.6 An average of 18.8 life-years The recommended frequency for melanoma screening should be are lost for each melanoma death,24 and it is estimated that one based on these six risk factors. Routine screening of low-risk patients United States citizen dies of melanoma every hour.25 through total body skin examinations performed by healthcare Melanoma results from the malignant transformation of providers is not a supported practice. Self-screening, however, is melanocytes, which are responsible for pigment production.The ge- clearly recommended, and excellent educational materials on this netic factors implicated in this transformation have not been well subject are available from the American Academy of Dermatology characterized. As noted [see Assessment of Potentially Malignant and the American Cancer Society. Nevertheless, physicians should Skin Lesions, Clinical Evaluation, History, above], patients with a take every opportunity to screen patients as the occasion arises; in family history of melanoma are at substantially higher risk for the general, the lesions found by physicians are significantly thinner than development of melanoma.6 Somatic mutations in the p16 tumor those detected by patients or their spouses.28 suppressor gene have been identified in both familial and sporadic For effective treatment of melanomas, early recognition is critical. cases of melanoma.26 Environmental factors—specifically, exposure The ABCD (Asymmetry, Border irregularity, Color variegation, Di- to ultraviolet radiation—are also implicated in the maligant transfor- ameter) guidelines for pigmented lesions are frequently used as aids mation of melanocytes. Increased risk of melanoma is associated to melanoma identification [see Table 1].29 Melanomas often occur with intermittent intense sun exposure rather than with the cumula- on sun-exposed areas of the upper trunk and the extremities, and tive effect of long-term mild exposure, though the exact mechanism they are typically asymmetric, with irregular borders and variegated behind the pathogenesis remains unknown. pigmentation [see Figure 3a]. Occasionally, they lack pigmentation or Screening and Diagnosis are associated with significant gross ulceration. Any lesion that ap- pears suspicious for melanoma should undergo biopsy. Histological- In one study, multivariate analysis identified the following six risk ly, melanomas are characterized by atypical melanocytes with mitot- factors as important in the development of malignant melanoma27: ic figures. Special staining, most commonly with HMB-45 or S100, 1. A family history of melanoma; may also be performed. 2. A history of three or more blistering sunburns before the age of 20; Histologic Subtypes 3. Blonde or red hair; Melanoma may be classified into histologic subtypes on the basis 4. The presence of actinic keratosis; of growth pattern and anatomic location. It should be kept in mind, a b Figure 3 Shown are (a) a typical melanoma and (b) an acral lentiginous melanoma.
  • 5. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 5 Table 2—Clark System for Staging Melanoma low system or the Clark system [see Table 2]. In the Breslow system, a calibrated ocular micrometer is employed to measure tumor thick- Clark Level Degree of Tumor Invasion 5-Year Survival (%) ness from the epidermal surface to the deepest point of the tumor’s extension into tissue.31 In the Clark system, the levels are defined by Level I Malignant melanocytes are confined to 99 the presence or absence of malignant melanocytes in each of the fol- epidermis lowing layers: epidermis, papillary dermis, reticular dermis, and sub- Malignant melanocytes infiltrate papillary cutaneous fat [see Figure 4].32 Level II 95 dermis singly or in small nests Over the past several years, extensive research has been conduct- Malignant melanocytes fill and expand pap- ed on factors that affect prognosis in both early-stage and late-stage illary dermis, with extension of tumor to melanoma. Clinical factors that have been shown to possess signifi- Level III 82 papillary-reticular dermal interface (usually signifying vertical growth phase) cant prognostic value include age, sex, the location of the melanoma, the number of lymph nodes involved, the presence of Malignant melanocytes infiltrate reticular distant metastasis, and the serum lactate dehydrogenase (LDH) Level IV 71 dermis in significant fashion level.33 In general, the prognosis is better when the patient is Malignant melanocytes infiltrate subcuta- younger than 65 years of age, when the patient is female, when the Level V 49 neous fat tumor is located on an extremity, when no lymph nodes are in- volved, when there is no evidence of distant metastasis, and when however, that the specific subtype a tumor falls into, in itself, is not the serum LDH level is normal. as important as the pattern of growth (i.e., radial versus vertical) and Melanomas are usually staged according to the system developed the depth of penetration.30 The main subtypes are lentigo maligna by the American Joint Committee on Cancer (AJCC), the latest ver- melanoma, superficial spreading melanoma, acral lentiginous sion of which was approved in 2002 [see Tables 3 and 4].34 The AJCC melanoma, and nodular melanoma. Of these, superficial spreading stage correlates well with the 5-year survival rate [see Table 5].34 melanoma is the most common, accounting for more than 70% of melanomas. These lesions occur most frequently in white adults, Stage I and II melanoma The vast majority of melanoma pa- typically on the back or the legs. Nodular melanoma is the second tients have a clinically localized form of the disease (i.e., stage I or II). most common subtype, accounting for between 15% and 30% of all Several clinical factors have been identified and employed for risk melanomas.These lesions often appear dome-shaped and may oc- stratification and prognosis in this heterogeneous group. The most cur anywhere on the body.They typically manifest an early vertical important prognostic factors in early-stage melanoma are tumor growth phase and thus tend to invade the dermis early in their nat- thickness (T1 through T4) and the presence or absence of ulceration: ural history. Lentigo maligna melanoma accounts for approximately 5-year survival in patients with stage I and II melanomas falls signifi- 5% of all melanomas and is believed to arise in a focus of lentigo cantly as tumor thickness increases and is substantially reduced (from maligna (Hutchinson freckle). These lesions demonstrate a pro- 80% to 55%) in the presence of ulceration.30 In the past few years, the longed radial growth phase before exhibiting an invasive compo- mitotic rate in the primary tumor has also been identified as an im- nent. Acral lentiginous melanoma occurs on the hands or the feet portant prognostic factor, one that may eventually prove more impor- [see Figure 3b], often under the nailbed, where the dermis is thinner tant than the presence or absence of ulceration in this population.35 (subungual melanoma).There also exists a relatively rare histologic Accordingly, it is likely that tumor mitotic rate will be incorporated subtype known as desmoplastic melanoma, which typically occurs into the next iteration of the AJCC’s melanoma staging system. in areas of sun damage and tends to recur locally more often than Study of thin (< 1 mm) melanomas, in particular, has led to fur- other subtypes do. ther refinement of risk stratification.The Clark level has prognostic implications for these lesions, in that tumors extending to Clark lev- Staging and Prognosis el IV are considered T1b regardless of their actual thickness and are An important variable in the prognosis of melanoma is the thick- associated with a worse prognosis. A 2004 report from the Universi- ness of the primary tumor, as assessed by means of either the Bres- ty of Pennsylvania described a prognostic model that made use of a I II III IV V Epidermis Figure 4 The Clark system classifies skin tumors according to the level of Papillary Dermis invasion, determined by the presence or absence of malignant melanocytes in the epidermis, papillary dermis, reticular Reticular Dermis dermis, and subcutaneous fat. Subcutaneous Fat
  • 6. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 6 Table 3—American Joint Committee on Cancer TNM tases), with or without in-transit or satellite lesions.The presence of Clinical Classification of Melanoma85 lymph node metastases is associated with a substantially worse prog- nosis, with fewer than 50% of node-positive patients surviving for 5 years.34 The number of involved nodes is also a significant prognos- TX Primary tumor cannot be assessed (e.g., shave biopsy or regressed melanoma) tic factor and is included as such in the current version of the AJCC Tis Melanoma in situ melanoma staging system. T0 No evidence of primary tumor Four prognostic factors have been identified that influence sur- T1 Lesion thickness ≤ 1.0 mm vival in patients with stage III melanoma: (1) the number of lymph T1a: ulceration absent and Clark level II or III nodes with metastases; (2) the presence of microscopic tumor de- T1b: ulceration present or Clark level IV or V posits in lymph nodes, as opposed to macroscopic deposits; (3) the T2 Lesion thickness 1.01–2.0 mm presence of in-transit or satellite metastases; and (4) the presence of Primary tumor (T) ulceration in the primary lesion.34 At one time, the size of the in- T2a: ulceration absent T2b: ulceration present volved lymph node was believed to be a significant prognostic factor, T3 Lesion thickness 2.01–4.0 mm and it was included in earlier staging systems; currently, it is under- T3a: ulceration absent stood that this variable does not in fact exhibit a significant correla- T3b: ulceration present tion with survival.37 However, macroscopic disease (i.e., disease that T4 Lesion thickness > 4.0 mm is identified clinically and confirmed histologically) does have a sig- T4a: ulceration absent nificant impact: the survival rate is much poorer in patients with T4b: ulceration present macroscopic disease than in those with microscopic disease.34 In-transit and satellite metastases represent dissemination of tu- NX Regional lymph nodes cannot be assessed mor via lymphatic channels. The 5-year survival rates observed in N0 No regional lymph node metastasis patients with these findings are similar to those observed in patients N1 1 metastatic lymph node with lymph node metastases. If in-transit or satellite metastases are N1a: micrometastases present present in association with lymph node metastases (N3), the sur- N1b: macrometastases present vival rate is markedly reduced.34 N2 2 or 3 metastatic lymph nodes Regional lymph N2a: micrometastases present nodes (N) Stage IV melanoma For stage IV melanoma, the most im- N2b: macrometastases present portant prognostic factors appear to be (1) the site at which a dis- N2c: in-transit metastases or satellite metas- tant metastasis occurs and (2) the serum LDH level. Within this tases present without metastatic lymph nodes group, patients with cutaneous metastases and normal serum N3 ≥ 4 metastatic lymph nodes; matted lymph LDH levels have by far the most favorable prognosis.There are sig- nodes; or combinations of in-transit metastases, satellite metastases, or ulcerated melanoma and nificant differences in 1-year survival between patients who have metastatic lymph nodes cutaneous, subcutaneous, or distant nodal metastases (M1), those who have lung metastases (M2), and those who have any other MX Distant metastases cannot be assessed visceral metastases or who have any metastases in association with M0 No distant metastasis an elevated serum LDH level (M3).The predicted 1-year survival M1 Distant metastases rates for M1, M2, and M3 patients are 59%, 57%, and 41%, M1a: metastases to skin, subcutaneous tissues, Distant metastases respectively.34 (M) or distant lymph nodes M1b: metastases to lung M1c: metastases to all other visceral sites or dis- tant metastases at any site associated with ele- vated serum LDH Table 4—American Joint Committee on Cancer Staging System for Melanoma LDH—lactic dehydrogenase Stage T N M risk-stratification algorithm based on four factors: (1) mitotic rate (0% versus ≥ 1%), (2) growth pattern (radial or vertical), (3) gender, 0 Tis N0 M0 and (4) tumor-infiltrating lymphocyte (TIL) activity (brisk, non- IA T1a N0 M0 brisk, or absent).36 For minimal-risk and low-risk patients, the pre- IB T1b, T2a N0 M0 dicted risk for metastasis was less than 4%, whereas for moderate- risk and high-risk patients, the predicted risk for metastasis was 12% IIA T2b, T3a N0 M0 and 30%, respectively.36 IIB T3b, T4a N0 M0 Intermediate-thickness (1 to 4 mm) melanomas are clearly asso- ciated with a worse prognosis than thin melanomas: the 5-year sur- IIC T4b N0 M0 vival rate is 89% for patients with nonulcerated T2 lesions and IIIA T1–4a N1a, N2a M0 77.4% for those with ulcerated lesions. For patients with ulcerated T3 lesions, the predicted 5-year survival rate is 63%. IIIB T1–4b N1a, N2a M0 For node-negative patients with thick (> 4 mm) lesions, the 5- T1–4a N1b, N2b M0 year survival rate is 67.4%; this figure drops to 45.1% if the lesion is Any T N2c M0 ulcerated.34 IIIC T1–4b N1b, N2b M0 Any T N3 M0 Stage III melanoma Stage III melanoma is characterized by IV Any T Any N M1 the presence of nodal metastases (micrometastases or macrometas-
  • 7. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 7 Table 5—5-Year Melanoma Survival Correlated Sentinel lymph node biopsy. An important issue in the surgical with AJCC Stage management of melanoma is the use of sentinel lymph node biopsy (SLNB) [see 3:6 Lymphatic Mapping and Sentinel Lymph Node Biop- Stage TNM 5-Year Survival (%) sy], which has essentially replaced elective lymph node dissection. Sentinel lymph node (SLN) status is the single most important pre- IA T1a N0 M0 95.3 dictor of survival in patients with melanoma40 and is now considered T1b N0 M0 90.9 a standard approach in the United States. A positive result is defined IB as the presence of identifiable melanoma cells on routine hema- T2a N0 M0 89.0 toxylin-eosin staining, immunohistochemical staining with S100 or T2b N0 M0 77.4 HMB-45, or both. Preoperative lymphatic mapping via lympho- IIA scintigraphy is often quite helpful, in that many lesions have variable T3a N0 M0 78.7 drainage basins that cannot be predicted clinically, and some lesions T3b N0 M0 63.0 even drain to contralateral nodes.41 The greatest accuracy is IIB achieved with SLNB when both radioactive colloid and blue dye are T4a N0 M0 67.4 used.42 IIC T4b N0 M0 45.1 SLNB should not be performed in patients with clinically positive nodes or in those who would otherwise not be considered for lymph- T1–4a N1a M0 69.5 IIIA adenectomy. It is generally recommended for patients who are at T1–4a N2a M0 63.3 moderate or high risk for harboring occult regional node metastases. In patients with T1 primary tumors, SLNB may be considered in T1–4b N1a M0 52.8 selected scenarios (i.e., primary tumor ulceration or extensive re- T1–4b N2a M0 49.6 gression, a high mitotic rate, a Clark level IV lesion, or a positive IIIB T1–4a N1b M0 59.0 deep margin).38 The impact of SLNB on the management of melanoma has been T1–4a N2b M0 46.3 impressive.The results greatly facilitate accurate staging and play an T1–4b N1b M0 29.0 important role in helping the clinician decide whether to perform completion lymph node dissection (CLND) or to offer adjuvant IIIC T1–4b N2b M0 24.0 therapy. Several studies have demonstrated significant differences in Any T N3 M0 26.7 survival and disease-free interval between SLN-negative patients and SLN-positive patients.43,44 One such study reported a 3-year Any T any N M1a 18.8 disease-free survival rate of 88.5% in SLN-negative patients, com- IV Any T any N M1b 6.7 pared with 55.8% in SLN-positive patients.43 Any T any N M1c 9.5 Surgical treatment of stage III melanoma Completion lymph node dissection. At present, CLND is recommended for management of the regional lymph node drainage basin in the pres- Initial Evaluation ence of a positive SLN. Some clinical trial results do not appear to For initial evaluation of patients with thin melanomas (< 1 mm), support this recommendation. For example, four randomized trials no routine laboratory or radiologic tests are recommended. For pa- failed to demonstrate any overall survival benefit for patients ran- tients with thicker melanomas (≥ 1 mm), some clinicians recom- domly assigned to undergo elective lymph node dissection.45-48 It mend a chest x-ray. For patients with stage III disease, chest radio- should be noted, however, that most of the patients in these studies graphy or computed tomography of the chest, the abdomen, and the did not have lymph node metastases, and thus, the trials did not pelvis may be performed and are indicated for any signs or symp- have sufficient statistical power to detect a small survival benefit.49 toms of metastases. If inguinal lymphadenopathy is apparent, pelvic Other trial results, however, do support the recommendation for CT should be performed to assess the iliac lymph nodes.38 For pa- CLND in node-positive patients, including those of the World tients with stage IV disease, chest radiography should be performed Health Organization Program Trial No. 14, which demonstrated and serum LDH levels obtained. Magnetic resonance imaging of that the 5-year survival rate in patients with occult nodal metastases the brain and CT of the chest, the abdomen, and the pelvis should detected at elective lymph node dissection was significantly better be performed to address any signs or symptoms of metastases and than that in patients who underwent delayed lymphadenectomy at before any therapy is initiated. Any other imaging done will be guid- the time when palpable nodal metastases developed (48% versus ed by protocol if the patient is enrolled in a clinical trial.38 27%).47 Nonetheless, the impact of CLND on overall survival is still a Treatment matter for debate. The results of the first Multicenter Selective Surgical treatment of stage I and II melanoma Margins of Lymphadenectomy Trial (MSLT suggest that SLNB with imme- -I) excision. Surgical excision remains the mainstay of treatment for diate CLND if the SLN is positive improves disease-free survival melanoma. The width of the recommended surgical margin de- but not overall survival.50 In this trial, 1,973 patients were randomly pends on the thickness of the lesion and has been well defined by a assigned in a 4:6 ratio to undergo either (1) wide excision (WE) fol- series of prospective randomized clinical trials.39 According to most lowed by nodal observation or (2) WE plus lymphatic mapping and current recommendations, a 0.5 cm margin is adequate for melano- sentinel lymph node biopsy (LM/SLNB) with immediate CLND if ma in situ, a 1 cm margin is suggested for melanomas thinner than the SLN was positive.The two groups were comparable in regard to 1.0 mm, a 1 or 2 cm margin should be obtained for melanomas be- both patient variables (i.e., age and gender distribution) and lesion tween 1 and 2 mm thick, and a 2 cm margin is required for melano- variables (i.e., location, thickness, and ulceration status). SLNs were mas thicker than 2 mm.39 analyzed by means of hematoxylin-eosin staining and immunohisto-
  • 8. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 8 chemical staining.The incidence of wound complications at the pri- is 54%.60 Unfortunately, the beneficial effect is often short-lived, mary site was comparable in the two groups, though surgical mor- with recurrence rates reaching 50% within 1 to 1.5 years after ILP.61 bidity was significantly greater when SLNB was followed by In a 2004 series, the overall 5-year survival rate after ILP was 32%.61 CLND.50 A planned interim analysis presented at the American So- Recurrence after ILP may be treated with surgical excision, though it ciety of Clinical Oncology in 2005 demonstrated a significant differ- has also been successfully treated with repeat ILP in patients with ence in disease-free survival between the two groups (73% for WE extensive disease.62 followed by nodal observation versus 78% for WE plus LM/SLNB); however, the difference in overall survival was not statistically signifi- Adjuvant therapy for stage IIB and III melanoma Radio- cant (86% for WE followed by nodal observation versus 87% for therapy. Radiotherapy has been used with some success after ther- WE plus LM/SLNB).51 These data led some to suggest that a sur- apeutic lymph node dissection in patients with high-risk lesions, re- vival benefit might be gained by performing LM/SLNB followed by sulting in a decreased local recurrence rate63 and a modest survival CLND in the event of a positive SLN, but this suggestion has not benefit64 in comparison with historic controls.This modality is typi- been widely accepted.52 A study now under way, the second Multi- cally employed in stage III patients who have poor prognostic patho- center Selective Lymphadenectomy Trial (MSLT -II), will assess the logic factors (e.g., positive surgical margins, multiple positive nodes, therapeutic value of CLND against that of SLNB alone in patients extracapsular spread, or vascular or perineural involvement).65 who have a positive SLN.51 An important factor in considering whether to perform CLND Interferon therapy. Perhaps the most efficacious adjuvant agent after a positive SLNB is the likelihood of finding metastases in the tested to date is IFN-α2b, which is currently approved by the United remaining non-SLNs. In one series, 90 (14%) of 658 patients had a States Food and Drug Administration for adjuvant treatment of stage positive SLN, and only 18 (20%) of the 90 showed evidence of IIB and stage III melanoma. Although a trial reported in 1996 found metastases in additional non-SLNs removed during CLND.53 The that 1 year of high-dose IFN-α2b therapy led to a prolonged relapse- number of positive nodes clearly has an impact on prognosis (as re- free interval and improved overall survival,66 subsequent trials and a flected by its inclusion in the current version of the AJCC’s meta-analysis did not confirm this overall survival benefit.67 Further- melanoma staging system34), and this fact lends support to the argu- more, nearly all patients experience adverse effects (e.g., fatigue, neu- ment for performing a CLND after a positive SLNB. tropenia, headache, fever, and chills) with interferon therapy.66 Another issue that has not yet been resolved is the extent of lymph node dissection required. One group, reviewing their experience Treatment of stage IV melanoma Metastasectomy. There is with lymph node dissection before the use of SLNB, concluded that a large body of literature supporting resection of metastases from the extent of lymph node dissection was a more important concern melanoma.The following five factors are commonly cited as predic- with higher tumor burdens and a less important one with lower tu- tive of survival after metastasectomy: (1) the initial disease stage, (2) mor burdens.54 Patients with micrometastatic disease in an SLN are the disease-free interval after treatment of the primary melanoma, clearly different from patients with bulky nodal disease, and the po- (3) the initial site of metastasis, (4) the extent of metastatic disease tential benefits of aggressive lymph node dissection in either group (single versus multiple sites), and (5) the ability to achieve complete must be carefully weighed against the morbidity of the procedure. resection.57 In well-selected patients, this procedure can yield a rea- Several studies are under way that should help address this issue, in- sonable likelihood of survival: a 1995 series reported a 5-year sur- cluding MSLT 55 The roles of lymphadenectomy and adjuvant in- -II. vival rate of 27% in all patients after pulmonary metastasectomy and terferon alfa-2b (IFN-α2b) may be addressed by results from the a rate of 39% in patients with a single metastatic lesion.68 More Sunbelt Melanoma Trial.56 modest benefits have been observed after resection of metastases to the GI tract: a 1996 series reported a median survival of 44.5 Therapeutic lymph node dissection. Therapeutic lymph node dis- months in patients in whom a complete resection was achieved, section is performed in patients who show evidence of lymph node compared with a median survival of 4 weeks in those in whom com- metastases on physical examination. Some of these patients will sur- plete resection could not be achieved.69 vive for extended periods; most will at least be rendered free of the The five aforementioned factors are of critical importance in pa- signs and symptoms of nodal metastases.57 tient selection for metastasectomy.To improve patient selection for curative procedures, surgeons often treat patients with a single-site Isolated limb perfusion. Most patients with in-transit metastases asymptomatic metastasis by administering chemotherapy for 2 to 3 experience unfavorable outcomes, with 5-year survival rates ranging months before considering resection, the aim being to see whether from 25% to 30%. Surgical excision to clear margins is the mainstay the disease stabilizes or additional metastases develop.57 If there is a of therapy when the size and number of the lesions permit. Amputa- response to treatment or the disease stabilizes with no evidence of tion is rarely necessary. further metastases, they proceed with resection.57 A therapeutic alternative to surgical excision for patients who have It is extremely important to perform high-quality imaging before extensive in-transit metastases in an extremity is the technique considering resection of metastases.The use of 18-fluorodeoxyglu- known as isolated limb perfusion (ILP).The prime advantage of ILP cose positron emission tomography (FDG-PET) may help detect is that it can achieve high regional concentrations of therapeutic occult metastatic disease more accurately. A 2004 comparison of agents while minimizing systemic side effects.58 The arterial supply FDG-PET with conventional imaging in patients with stage IV and the venous drainage are isolated, and a tourniquet may also be melanoma reported a sensitivity and specificity of 76% and 87% for used to occlude superficial collateral veins. An oxygenated extracor- conventional imaging, 79% and 87% for FDG-PET, and 88% and poreal circuit is employed to circulate a chemotherapeutic agent 91% for conventional imaging combined with FDG-PET.70 With (typically melphalan) for 1 to 1.5 hours.The temperature of the limb FDG-PET, as with any other imaging modality, appropriate use de- is usually elevated to 39° to 40° C.59 In patients who have clinically pends on a clear understanding of its capabilities and limitations. positive nodes, therapeutic lymph node dissection is performed in Another important indication for metastasectomy is palliation; the the same setting, just before limb perfusion.The effect of ILP can be vast majority of patients with stage IV melanoma will not be candi- dramatic; for example, the rate of complete response with melphalan dates for curative-intent metastasectomy.The goal of a palliative pro-
  • 9. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 9 cedure is to control identifiable symptoms (e.g., GI bleeding or patient with a significant antitumor response conferred impressive T pain) caused by an advanced malignancy while minimizing morbid- cell responses.83 ity.57 A thorough discussion should be held among the surgeon, the Despite some advances in therapy, overall survival for patients patient, and the family to address the goals and expected outcomes with stage IV melanoma has not improved over the past 20 years. of the procedure, as well as its potential morbidity.71 Overall 5-year survival remains lower than 5%, with a median sur- vival of only 7.5 months.84 The best hope for future improvements Chemotherapy. To date, the rates of objective response to probably lies in the treatment of micrometastatic disease by means chemotherapy for melanoma have been somewhat disappointing. of targeted chemotherapy and immunotherapy. Darcarbazine (DTIC) is the only currently approved chemothera- peutic agent for melanoma, and it offers no more than marginal therapeutic benefit, with moderate side effects.72 Various combina- Operative Technique tion regimens—including BOLD (bleomycin, vincristine, lomustine The inguinal nodes drain the anterior and inferior abdominal wall, [CCNU], DTIC), CVT (cisplatin, vincristine, DTIC), and CBDT the perineum, the genitalia, the hips, the buttocks, and the thighs. A (cisplatin, carmustine [BCNU], DTIC, tamoxifen)—have been em- superficial groin dissection removes the inguinal nodes, whereas a ployed, with response rates ranging from 9% to 55%.72 The oral deep groin dissection incorporates the iliac and obturator nodes. Pal- alkylating agent temozolamide has been studied in stage IV pable nodes can be marked on the patient before operation. melanoma patients; compared with DTIC, it yields a modest pro- SUPERFICIAL GROIN DISSECTION longation of survival, with an acceptable side-effect profile.73 The patient is placed in a supine position on the operating table, Melanoma vaccines. Several experimental melanoma vaccines with the hip slightly abducted and with the hip and knee slightly are being investigated for possible use in advanced-stage melanoma. flexed and supported by a pillow. A Foley catheter is inserted, and These agents use a variety of modalities to present melanoma anti- the skin is prepared and draped. gens to host immune cells in an immunostimulatory context.74-76 The femoral artery, the anterior superior iliac spine, the pubic tu- There was considerable initial optimism regarding this approach, bercle, and the apex of the femoral triangle are marked. A diagonally but a 2004 review of the experience at the National Cancer Institute oriented skin incision is made that extends from a point medial to found that the response rate for cancer vaccines was only 2.6%77 (a figure comparable to the results obtained by others). The authors concluded that the use of cancer vaccines may still prove to be a vi- MEDIAL DISSECTION Spermatic able strategy, but profound changes will be required to enhance the Cord Inguinal efficacy of these agents. Ligament Immunotherapy. At present, immunotherapy is perhaps the most promising area of investigation with respect to the treatment of ad- Pectineal Muscle vanced melanoma. Immunotherapy has been defined in various ways, but in general, it can be thought of as a form of treatment Long Adductor based on the concept of modulating the immune system to achieve a Lymphatics Muscle therapeutic goal.78 There are several different modalities that can be considered immunotherapy, including monoclonal antibody therapy Skin Fascia and interferon-based therapy. For present purposes, we will focus on Specimen two modalities that are currently under active investigation: high- dose interleukin-2 (IL-2) therapy and adoptive cell transfer. In initial studies, the response rates after high-dose IL-2 therapy for melanoma have ranged from 15% to 20%, with about half of the responding patients experiencing complete regression.79 In those pa- tients who do achieve a complete response, the effect is often durable.80 Unfortunately, IL-2 immunotherapy is associated with se- vere side effects. Adoptive cell transfer involves the administration of activated cy- totoxic T lymphocytes (CTLs) that are generated against specific tu- mor types.These CTLs can be generated either by using specific tu- mor-associated antigens or by culturing lymphocytes with tumor cells.The objective is to encourage the selection of tumor-specific T lymphocytes that are capable of generating a strong immunologic response and thereby help break the body’s immunologic tolerance of the tumor. Unfortunately, initial clinical trials of activated T cell Distal Portion of Great Saphenous transfer for other types of malignancy found that the transferred cells Vein Ligated did not remain present in sufficient concentrations to yield a signifi- cant clinical effect.81 However, the addition of nonmyeloablative lymphodepleting chemotherapy, followed by autologous transfer of tumor-specific CTLs in conjunction with IL-2 administration, was shown to result in rapid clonal expansion of tumor-specific T lym- phocytes in vivo, which was associated with a significant clinical re- Figure 5 Superficial groin dissection. The incision is deepened to sponse.82 In a 2005 study, transfer of a T cell receptor gene from a include the deep muscular fascia.
  • 10. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 10 Inguinal Ligament Lymphatics Continue under Inguinal Ligament Medial to Specimen Femoral Vein Retracted Great Saphenous Vein Stump LATERAL DISSECTION Pectineal Muscle Nodal Tissue Fascia Femoral Sheath Being Entered Fascia Branch of Femoral Nerve Figure 6 Superficial groin dissection. The investing fascia overly- Sartorius Muscle ing the femoral nerve and vessels is removed. Figure 7 Superficial groin dissection. The groin dissection is the anterior superior iliac spine down to the apex of the femoral tri- continued on the lateral side. angle; the incision is formed in the shape of an S so as not to cross the thigh flexion crease at a right angle. An incision oriented and shaped in this manner will cause the least possible interference with the musculocutaneous and cutaneous vascular territories of the skin, Fat and will minimize ischemia to the skin flaps, and will avoid a flexion con- Lymphatics tracture. Flaps are raised to allow identification of the medial border of the sartorius, the lateral border of the adductor longus, and the ex- ternal oblique fascia on the lower abdominal wall. Fat and nodal tissue are swept inferiorly off the external oblique aponeurosis, the spermatic cord, and the inguinal ligament [see Fig- ure 5] and are reflected inferiorly.The fat and lymph nodes are then Great dissected from the femoral triangle, starting medially at the lateral Saphenous edge of the adductor longus and proceeding laterally [see Figures 6 Vein Femoral and 7].The femoral vessels are left undisturbed.The saphenous vein Sheath is ligated and divided at the fossa ovalis [see Figure 8]; it is also ligated and divided as it exits the femoral triangle distally.The specimen is Femoral then dissected free from the femoral nerve.This step usually entails Vein sacrificing branches of the lateral femoral cutaneous nerve, thereby Femoral Artery resulting in numbness of the anterolateral thigh. Cloquet’s lymph nodes are located medial to the femoral vein un- der the inguinal ligament.These nodes are dissected out and submit- ted as a separate specimen. If Cloquet’s nodes contain melanoma, the risk that iliac nodes will harbor melanoma is high, and a deep Figure 8 Superficial groin dissection. The great saphenous groin dissection should be performed (see below). vein is ligated and divided.
  • 11. © 2006 WebMD, Inc. All rights reserved. ACS Surgery: Principles and Practice 3 BREAST, SKIN, AND SOFT TISSUE 4 Malignant Skin Lesions — 11 DEEP GROIN DISSECTION external iliac vessels is dissected; the dissection proceeds proximally The inguinal ligament is divided, and the inguinal canal is further to the origins of the internal iliac vessels (avoiding the ureter) and in- exposed by releasing the internal oblique abdominal muscle, the corporates the nodes overlying the obturator foramen while carefully transversus abdominis, and the fascia transversalis and dissecting avoiding injury to the obturator nerve.The deep epigastric vessels are into the retroperitoneal space.The deep circumflex iliac vessels are usually ligated at their origins from the external iliac artery and vein. ligated, and the peritoneum is separated from the preperitoneal fat The lymph node–bearing specimen is then removed as a unit, ori- and nodes by means of blunt finger dissection. Alternatively, rather ented, and marked with sutures for orientation and identification. than dividing the inguinal ligament, one may make a separate inci- The inguinal canal is reconstructed to prevent a hernia. Any defect sion in the external oblique fascia parallel to and above the inguinal medial to the femoral vessels under the ligament is sutured closed ligament. with Cooper’s ligament.The sartorius is detached from the anterior Retractors are inserted to widen the retroperitoneal space, and the superior iliac spine and is sutured to the midportion of the inguinal peritoneum and the abdominal viscera are retracted medially. The ligament to cover the femoral vessels.The skin and the subcutaneous chain of lymph nodes, areolar tissue, and adventitial tissues along the tissues are then closed in layers over a soft suction drain. References 1. Miller DL, Weinstock MA: Nonmelanoma skin medical provider. Mt Sinai J Med 68:243, 2001 patients: validation of the American Joint cancer in the United States: incidence. J Am Acad 19. Weinstock MA, Bogaars HA, Ashley M, et al: Committee on cancer staging system for cuta- Dermatol 30:774. 1994 Nonmelanoma skin cancer mortality: a popula- neous melanoma. J Clin Oncol 19:3622, 2001 2. Rigel DS, Friedman RJ, Kopf AW: The incidence tion-based study. Arch Dermatol 127:1194, 1991 35. Francken AB, Shaw HM, Thompson JF, et al: The of malignant melanoma in the United States: 20. Goldman GD: Squamous cell cancer; a practical prognostic importance of tumor mitotic rate con- issues as we approach the 21st century. J Am Acad approach. Semin Cutan Med Surg 17:80, 1998 firmed in 1317 patients with primary cutaneous Dermatol 34:839, 1996 melanoma and long follow-up. Ann Surg Oncol 21. Marks R: Squamous cell carcinoma. Lancet 347: 11:426, 2004 3. Hall HI, Miller DR, Rogers JD, et al: Update on 735, 1996 the incidence and mortality from melanoma in the 36. 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Grunhagen DJ, Brunstein F, Graveland WJ, et al: 18:2351, 2000] Acknowledgment One hundred consecutive isolated limb perfusions with TNF-alpha and Melphalan in melanoma 74. Morton DL, Foshag IJ, Hoon DS, et al: Figures 5 through 8 Susan E. Brust, C.M.I.

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