30
Skin and Soft Tissues
M. Nerissa Prieto and Philip D. Wey
Objectives
1. To understand indications for and methods of biopsy, and to establish diagnoses for patients with skin lesions.
2. To describe characteristics of nonmelanoma skin cancers (basal cell and squamous cell carcinoma).
3. To develop a management plan for a patient with basal cell carcinoma.
4. To develop a management plan for a patient with squamous cell carcinoma.
5. To describe characteristics of atypical and dys- plastic nevi.
6. To describe characteristics of malignant melanoma.
7. To develop a management plan for a patient with malignant melanoma.
8. To understand indications for and methods of biopsy for soft tissue masses.
9. To develop a management plan for a patient with possible soft tissue sarcoma.
Cases
Case 1
A 52-year-old woman presents with a lesion that has persisted for 1 year and slowly has become larger and more raised over time. There is no family history of skin cancer. Physical exam reveals a flesh-colored raised nodule on the left cheek at the nasolabial fold measuring approx- imately 7 mm in diameter. The lesion has a pearly appearance and is smooth with rolled borders and surface telangiectasia.
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Case 2
A 60-year-old man with a long history of sun exposure presents for evaluation of a nonhealing wound of the forehead of approximately 18 months’ duration. Physical examination reveals widespread actinic sun damage to the skin, with multiple scaly patches measuring 2 to 3 mm.
Facial skin is deeply wrinkled, with a few small tan macules 3 to 4 mm in diameter. On the forehead is a 15-mm erythematous, indurated, slightly raised plaque with distinct borders and central ulceration.
Case 3
A 25-year-old woman presents with multiple pigmented lesions of the arms and trunk. She states that they have been present nearly all her life and have not changed in appearance. She is concerned because a distant family member recently was diagnosed with melanoma. Exam reveals multiple discrete 2- to 4-mm homogeneously colored brown to black lesions, some of which are slightly raised.
Case 4
Further examination of the patient described in Case 3 reveals an 8-mm homogeneously pigmented, dark brown lesion on her abdomen.
It is asymmetric in shape with scalloped borders and is slightly raised with a variegated surface texture.
Case 5
A 45-year-old man presents with a pigmented lesion on his shoulder.
It first appeared in his thirties and slowly enlarged over many years before nearly doubling in size and becoming more raised and nodular over the past year. He is fair-skinned, and his natural hair color is sandy blond. He is an avid outdoorsman, but he does not wear sunscreen.
His father has been diagnosed with melanoma. Examination reveals an 18-mm raised, nodular, darkly pigmented lesion with variegated color and surface texture with scalloped borders. There is no palpable lymphadenopathy.
Case 6
A 37-year-old man presents with painless swelling of the right thigh, with rapid progression over the past 4 to 6 months. Physical exam reveals a poorly circumscribed mass measuring 10 ¥ 8 cm over the prox- imal anterior right thigh. It is deep and firm on palpation, nonfluctu- ant, and immobile.
Skin Lesions
Introduction
Most skin lesions are benign and can be diagnosed on examination based solely on physical characteristics.The identification and diag-
nosis of malignant skin lesions, however, is critical given their mor- bidity, mortality, and frequency. It is estimated that nearly half of all persons who live to the age of 65 will have one or more skin cancers in their lifetime. Well over one million new cases of skin cancer were identified in 2001, and that number was expected to rise slightly in 2002, accounting for approximately half of all new cancer diagnoses and making the skin the most common site of human malignancy.
When distinguishing malignant from benign lesions, the patient’s history, ethnicity, and genetic predisposition, as well as the physical characteristics of the lesion on exam, may serve to raise or lower the clinician’s index of suspicion. The distinction often is still difficult to make, and, ultimately, biopsy of the lesion and pathologic assessment are necessary for diagnosis when there is concern of malignancy.
General Evaluation
Elements of the patient’s history that should raise suspicion of malignancy include changes in color, surface texture, shape or ele- vation of a lesion, appearance of a new lesion with suspicious char- acteristics, family or personal history of skin cancer, and history of sun or toxic exposure. Focused examination of the presenting lesion should follow. In addition, the physician should perform a thorough examination of the entire skin surface, including scalp, palms, soles, and nail beds, noting any atypical lesions and documenting their size and appearance for future comparison.
While close observation of a lesion may be appropriate in some instances, biopsy of suspicious lesions is highly recommended. One also should understand approaches to precancerous lesions, since biopsy is indicated in some but not in others. Small lesions may be biopsied by full excision, while large lesions may be approached with full-thickness incisional biopsy or punch biopsy. Techniques that compromise pathologic evaluation, such as shave biopsy, which often is used in the treatment of benign lesions, are contraindicated in the workup of potentially malignant lesions.
Basal Cell Carcinoma
The patient described in Case 1 exhibits a facial lesion that fits the classic description of basal cell carcinoma (BCC) of the nodular type, the most commonly occurring of the four clinical subtypes of BCC described in Table 30.1. Basal cell carcinoma is the most common
Table 30.1. Four clinical subtypes of basal cell carcinoma.
Superficial Erythematous scaly macules that may exhibit ulceration, crusting, or atrophic scarring
Sclerosing or Poorly defined, firm, yellow-white plaques morpheaform
Nodular Flesh-colored nodule with telangiectasia, with or without central ulceration and pearly borders Pigmented May be deeply pigmented, often confused with
melanoma
malignancy in the general population, usually occurring on the head and neck. Sun exposure is considered to be a primary causative factor, similar to other skin cancers, and patients almost always are fair- skinned Caucasians. Tumors of the nasolabial fold (as in this patient), medial and lateral canthi, and postauricular regions often are associ- ated with worse outcomes. Skin biopsy of suspected BCC is manda- tory to confirm diagnosis and would be an appropriate next step in the management of this patient.
Since this is the patient’s first presentation, the physician should elicit the patient’s history of sun exposure and history of predisposing medical conditions, including such rare conditions as xeroderma pig- mentosum and basal cell nevus syndrome. Since patients with BCC may develop multiple tumors over time and since recurrent disease is not uncommon, personal history of BCC and other skin cancers should be obtained. Physical examination should be performed meticu- lously, since different types of BCC may mimic scar tissue or dermati- tis, and should include examination of local lymph node basins.
Basal cell carcinoma expands locally over long periods of time, and the tendency for metastasis is low: only 2% of cases involve regional lymph nodes. As a result of its indolent and nonaggressive behavior, excisional biopsy of localized primary BCC with 2- to 3-mm margins is curative in 95% of cases.Pathologic assessment of frozen sections intraoperatively can provide preliminary confirmation of complete excision of the tumor. Alternatively, Mohs’ micrographic excision, usually performed by a dermatologist, is highly effective as well, with a similar cure rate. This technique involves progressive excision and mapping of the tumor bed by microscopic examination of tissue as it is excised until a clear margin is identified. It commonly is reserved for lesions in anatomically sensitive areas such as the lip, nasal rim, and eyelid. Using Mohs’ technique, the amount of normal tissue removed in the course of excision is minimized. Other methods also have been used to treat BCC; these typically are reserved for patients with con- traindications to surgery or for patients with multiple tumors in whom numerous excisions would be unfeasible. Electrodesiccation and curet- tageis one such method, used for ablation of a lesion <2 cm in diame- ter. Radiation therapy also is acceptable if tissue preservation is important. Both of these techniques are associated with a lower cure rate and accordingly are not appropriate as first-line treatment.
Squamous Cell Carcinoma
The patient described in Case 2 exhibits several manifestations of sig- nificant sun damage to the skin, including solar lentigo (tan macules), deep wrinkling, and actinic keratosis (scaly patches and plaques).
Actinic keratoses are the result of ultraviolet damage to epidermal cells, and, while they may persist in a benign state for long periods of time, they may progress to squamous cell carcinoma (SCC). Alterna- tively, they may regress with cessation of sun exposure. The physician should monitor this patient closely and consider treatment of extensive actinic keratoses with topical fluorouracil, cryosurgery, electrodesicca-
tion and curettage, dermabrasion, or laser therapy. Biopsy should be performed if actinic lesions exhibit suspicious changes, including increasing erythema or induration, enlargement, ulceration, or bleed- ing. In this patient, whose nonhealing wound likely represents SCC, malignancy may have developed from a preexisting site of actinic keratosis.
A nonhealing wound or ulcer is a classic presentation of SCC.But SCC also may appear as an indurated, erythematous papule or plaque, which can be hyperkeratotic, as in this case, or smooth, with or without ulceration. Invasive SCC has a 5-year metastasis rate of 5%, although the likelihood of metastasis is two to three times greater with lesions
>2 cm and location on the lip or ear. Similarly at high risk of recurrence and metastasis are lesions of mucous membranes, nose, scalp, fore- head, and eyelid. Malignant transformation to SCC can occur within nonhealing wounds of various etiologies, as in scar tissue following burn or trauma (Marjolin’s ulcer), tissue damaged by radiation therapy, or at sites of chronic infection or draining sinus tracts; these tumors also tend to be particularly aggressive. Table 30.2 summarizes charac- teristics of SCC that confer high risk of metastasis and poor outcome.
As in other skin cancers, sun exposure is a primary causative factor in SCC. Other risk factors include toxic exposure to arsenic, nitrates, or hydrocarbons, as well as immunosuppression, particularly in organ transplant patients. Premalignant lesions that may degenerate into SCC include actinic keratosis, as described in the patient in Case 2, Bowen’s Table 30.2. Features of cutaneous squamous cell carcinoma (SCC) associated with increased risk of recurrence and metastasis.
Approximate relative riskaof:
Feature Recurrence Metastasis
Clinical
Rapid growth + +
Size>2cm 2 2
Location on lip 2 3
Location on ear 2 3
Immunosuppression + 2
History of radiation therapy + +
History of treatment for SCC 3 4
Histologic
Tumor depth >4mm or to Clark level IV or Vb 2 5
Poorly differentiated 2 3
Infiltrative margins + +
Spindle cell or acantholytic features + +
Perineural invasion 5 5
a Relative risk of 1 is defined as the likelihood of recurrence or metastasis of a small primary SCC.
b Tumor invasion to Clark level IV involves the reticular dermis, to Clark V involves the subcutaneous fat.
+ Indicates association with increased risk, but lacking sufficient data to calculate rela- tive risk.
Source: Reprinted from Alam M, Ratner D. Primary care: cutaneous squamous cell carcinoma. N Engl J Med 2001;344(13):975–983, with permission. Copyright © 1994 Massachusetts Medical Society. All rights reserved.
disease (SCC in situ), and keratoacanthoma. There also is a significant association between cutaneous SCC and human papillovirus infection, particularly types 6 and 11 in SCC of the genital region and type 16 in periungual tumors.
Early detection of SCC is critical, since early disease is largely curable and late disease has a dismal prognosis.The physician should perform a thorough history of potential predisposing conditions, including sun or other radiation exposure, exposure to carcinogens, immunosuppression, and family and personal history of skin cancer.
Patients with a positive skin cancer history or extensive actinic skin damage should undergo regular screening examinations for new or changing lesions.
Physical examination of the patient in Case 2 should include exam- ination of the entire skin surface and palpation of regional nodal basins surrounding questionable lesions. Given this patient’s history of sun exposure and evidence of extensive sun damage and because of the suspicious size and characteristics of the presenting lesion, a full-thickness biopsy is warranted. Radiologic and laboratory tests are not indicated unless there are symptoms of or reason to suspect metastasis.
Treatment of this patient’s low-risk lesion would involve surgical resection with 4-mm margins, with frozen section to confirm clear margins.This approach is associated with a 95% chance of a cure. As in BCC, Mohs’ excision also would be an appropriate first-line treat- ment and is, in fact, the procedure with the highest rate of cure for high- risk primary or recurrent lesions. Acceptable alternative therapies for limited low-risk SCC include electrodesiccation and curettage, cryosurgery, and radiation. Indications may include inoperable tumors, large lesions in cosmetically sensitive areas, or patient con- traindications to surgery.
Nevi (Moles)
Many patients present for evaluation of nevi (melanocytic nevocellu- lar nevior moles). Moles are extremely common in all races, and it is not uncommon to find several dozen on a single individual. While most such lesions are entirely benign, the incidence of and mortality from malignant melanoma has increased markedly over recent years, bring- ing to the forefront the importance of the physician’s ability to recog- nize suspicious lesions.
Freckles (ephelides) should be distinguished from nevi.These tan to light brown, small macules with irregular borders are lesions of the basal and upper dermis that result from increased melanin produc- tion by nonneoplastic melanocytes. They are benign and require no treatment.
The common nevi seen in the patient presented in Case 3 are made up of benign neoplastic melanocytes, called nevus cells, and are clas- sified according to the site of nevocellular proliferation. They are typ- ically small, well-circumscribed macules or papules that, with the exception of the dermal nevus described below, regress spontaneously
by the sixth decade of life. History of childhood sunburn may increase the likelihood of developing a greater number of nevi, and those with numerous nevi (more than 40) have a greater likelihood of developing melanoma and should be monitored closely. The vast majority of nevi do not undergo malignant transformation.
All three of the common benign nevus types are represented among the many lesions of this patient. In junctional nevi, nevus cells are clus- tered at the dermal–epidermal junction above the basement membrane.
These are dark brown to black, macular to slightly raised lesions that appear in young children after age 2. They are round to oval, with smooth regular borders. Compound nevi are composed of nevus cells both at the dermal–epidermal junction and within the dermis. They also are brown to black in color, are usually slightly raised, and are frequently hairy, with sharply defined but often irregular borders and smooth to slightly papillary surfaces. A compound nevus sur- rounded by an area of hypopigmentation is called a halo nevus. Intra- dermal nevi are made up of nevus cells primarily occupying the dermis, sometimes extending into subcutaneous fat. These are flesh- colored to brown, raised, fleshy papules that distort normal skin anatomy, with hairs and dark flecks sometimes present on the surface.
The occasional presence of telangiectasia may make differentiation from BCC difficult. Malignant transformation of any of these nevi is rare when they are small in size (<6mm), stable in appearance over time, and lacking suspicious characteristics, including ulceration, bleeding, or pruritis. No intervention is indicated for this patient’s lesions at this time, although she should be instructed to monitor their appearance and to follow up with her physician for periodic screening exams.
Atypical and Dysplastic Nevi
Case 4describes a specific lesion on the same young woman as in Case 3. Unlike the many pigmented lesions on her arms and trunk that easily are classified as benign, this particular lesion should come to the physi- cian’s attention because of its size and irregular shape and surface texture. This lesion is termed atypical on the basis of its gross clinical characteristics. Any nevus is classified as clinically atypical if rela- tively large in size, i.e., >6mm, asymmetric, or having an irregular, raised surface or color variegation. While often referred to as dys- plastic nevi, atypical nevi may or may not demonstrate histologic dysplasia.
A single atypical nevus can be found in 5% of whites in the United States, and, in the absence of family history of melanoma, this finding is associated with a 6% lifetime risk of developing melanoma. In persons with one or more atypical nevi and a strong family history, the risk of developing melanoma may be as high as 80%. In these persons, the atypical nevus itself may undergo malignant transforma- tion, or disease may develop de novo elsewhere; hence, annual skin screening exams by a physician strongly are recommended. In all patients with a single atypical nevus or nevi, education regarding melanoma risk and self-examination is essential. Because atypical nevi
are associated with increased risk of developing melanoma, full- thickness biopsy of this patient’s lesion should be performed.
Melanoma
The lesion of the patient described in Case 5 is worrisome for several reasons. He has a significant history of sun exposure and sunburn, which is a strong risk factor in fair-complexioned individuals. Inter- mittent but intense sunlight exposure in particular appears to increase risk. Additionally, melanoma in a first-degree relative, in this case his father, increases risk by at least eight times. The patient also reports a recent history of rapid change in the size and texture of the lesion, which should alert the physician to the likelihood of a malignant process. Other suspicious changes not seen in this patient include changes in color, ulceration, bleeding, or pruritis. Given the high like- lihood of malignant melanoma in this patient, one also should ques- tion him about recent weight loss or other constitutional symptoms that may be indicative of metastatic disease. Table 30.3 summarizes ele- ments of a patient history that should be considered significant in the evaluation of a possible melanoma.
On exam, this patient’s lesion possesses many characteristics typical of malignant melanoma, including heterogeneous color and nodular- ity and relatively large (1.8 cm) diameter. The mnemonic ABCDE as described in Table 30.4 summarizes key characteristics of pigmented lesions that should raise suspicion of malignancy. Table 30.5 lists other physical findings that the physician also should take into con-
Table 30.3. Elements of history to consider in evaluation for melanoma.
Intermittent but intense exposure to sunlight Blistering sunburns in childhood
Tendency to sunburn rather than tan
Living in sunny climates close to the equator Positive family history of melanoma
Positive personal history of melanoma or other skin cancer
History of atypical nevi Recent changes in mole(s)
Table 30.4. The ABCDE of melanoma: charac- teristics of pigmented lesions suggestive of melanoma.
A: Asymmetry B: Border irregularity
C: Color variation or variegation D: Diameter greater than 6 mm
E: Elevated area or palpable nodule within a formerly flat lesion
Also: ulceration, inflammation, bleeding, satellite nodules, local lymphadenopathy
sideration. The ABCDE mnemonic is a useful guideline, and the diag- nosis of melanoma based on history and physical exam alone is highly sensitive when made by an experienced physician. Nonetheless, not all melanomas are clinically obvious, as different histologic types present very differently. Amelanotic melanoma, for instance, is a dangerous, albeit rare entity, because of its tendency to go unrecognized, and hence, it tends to be diagnosed at a later stage when therapy becomes more problematic.
Besides a complete history and examination of the suspect lesion, a thorough examination of the skin over the entire body is essential to the initial evaluation and follow-up of this high-risk patient.
While 60% of melanomas arise de novo from epidermal melanocytes, 40% arise from malignant degeneration of a preexisting atypical or dys- plastic nevus. Identification and monitoring of atypical nevi permits early detection and intervention, which are critical, since the depth of melanoma invasion at the time of diagnosis is the most accurate pre- dictor of survival. Regional lymph node basins also should be pal- pated for clinical evidence of nodal involvement.
Given the highly suggestive appearance and suspect history of the presenting lesion, further evaluation is mandatory. The management of this patient would begin with excisional biopsy, to include a 1- to 2-mm margin of grossly normal skin and subcutaneous tissue. Inci- sional or punch biopsy also would be an acceptable approach and would be indicated for larger lesions or those in cosmetically sensitive areas. Full-thickness biopsy techniques are absolutely necessary to provide adequate tissue for pathologic assessment and staging, while allowing for reexcision at the site should the malignancy be confirmed.
Shave biopsy, cryosurgery, and electrodesiccation should not be used, since they compromise histologic assessment and primary staging of disease, which are the cornerstones of establishing progno- sis and defining treatment.
An excisional biopsy of the patient’s shoulder lesion in Case 5 was performed. The biopsy results showed superficial spreading melanoma of intermediate thickness at 2.8 mm.
Superficial spreading melanoma is the most common type of melanoma, accounting for approximately 70% of all cases.It begins as a brown, slightly elevated lesion, progressing to have irregular, raised borders, a variegated brown to black color pattern, and a diam- eter of 2 to 3 cm, sometimes with central pigment loss. It exhibits a pro- longed radial growth phase, with lateral extension confined to the epidermis and papillary dermis. This noninvasive growth pattern can
Table 30.5. Elements of physical examination to consider in evaluation for melanoma.
Caucasian, fair skin with freckles Red or blond hair, blue eyes Presence of atypical nevi
Evidence of sun-induced skin damage The ABCDE (see Table 30.4)
last as long as a decade, and, as a result, it generally is associated with a good prognosis. In this patient’s case, however, increasing nodular- ity may be indicative of vertical growth into deeper layers of skin and increased likelihood of metastasis.
There are three other distinct histologic types of melanoma, each exhibiting its own characteristic features, growth patterns, and prog- noses. Nodular melanoma represents 8% to 10% of all melanomas, with characteristically uniform gray-blue to brown or black color, although they also can be nonpigmented. These demonstrate almost immediate vertical growth, and hence, they are associated with early metastasis and poor prognosis. Lentigo maligna melanoma accounts for approximately 10% of cutaneous melanomas. They are typically flat, tan macules of up to 3 cm or more in diameter that grow slowly and radially within the upper dermis. Elevated nodules and irregular areas of dark brown or black pigmentation arising within these lesions may represent invasive melanoma. The precursor lesion is known as lentigo maligna (Hutchinson’s freckle). Acral-lentiginous melanoma represents only 1% of melanoma cases and occurs exclusively on the palms, soles, and nail beds. Its prognosis ranges from good to poor.
Unlike the other subtypes, it occurs with equal frequency among Caucasians and dark-skinned persons. Lesions generally are flat with irregular borders, variably pigmented brown-black to black, but they also may be amelanotic.
As in other forms of cancer, disease staging of melanoma using a TNM (tumor-node-metastasis) classification schemeis ideally predic- tive of prognosis and useful in guiding therapy. The most recent TNM classification and staging system for melanoma of the American Joint Committee on Cancer (AJCC) was published in 2002 and is shown in Tables 30.6and 30.7.
Depth of tumor invasion as measured in millimeters (Breslow depth) is the defining variable in determining the next appropriate step in this patient’s management.Lesion thickness has been found to be inversely related to survival, and it is a good predictor of prognosis in node-negative patients. Melanomas are referred to as thin (less than 1 mm thick), intermediate (1.0 to 4.0 mm thick), and thick (greater than 4 mm) with regard to prognosis and management. The Clark level (Table 30.8) describes the level of invasion relative to the histologic layers of the skin. While these levels correlate reasonably well with Breslow depth, the basis of the Clark system is flawed, in that no true barriers to tumor invasion exist in the subepidermal layers and, in that dermal thickness varies greatly in different parts of the body. It is, however, an independent prognostic feature of thin (T1, i.e., <1.0 mm) melanomas. Chest x-ray, serum alkaline phosphatase, and lactate dehydrogenase are recommended as screening measures for pul- monary and liver metastasis in patients with melanoma greater than 1 mm thick.
Treatment of Melanoma
Definitive treatment of melanoma is surgical control of both local and metastatic disease. The recommended surgical approach to the
patient’s primary lesion of intermediate thickness (2.8 mm) is excision with a margin of 2 cm (Intergroup Melanoma Surgical Trial, level I evidence),1which may be performed at the time of initial diagnostic biopsy, or the recommended margin may be taken as a reexcision at the biopsy site once malignant pathology is confirmed. As in Case 5, inter- mediate-thickness lesions demonstrate a 15% to 45% chance of regional nodal involvement with no distant metastasis. Recommended surgical margins for excision of melanomas of various thicknesses are summa- rized in Table 30.9.
Surgical excision of a primary melanoma lesion and any diseased lymph nodes may be curative in the absence of distant metastasis, and Table 30.6. Melanoma TNM classification.
T classification Thickness Ulceration status
T1 £1.0mm a: without ulceration and level II/III
b: with ulceration or level IV/V T2 1.01–2.0 mm a: without ulceration
b: with ulceration T3 2.01–4.0 mm a: without ulceration
b: with ulceration
T4 >4.0mm a: without ulceration
b: with ulceration
N classification No. of metastatic nodes Nodal metastatic mass
N1 1 node a: micrometastasis*
b: macrometastasis†
N2 2–3 nodes a: micrometastasis*
b: macrometastasis†
c: in-transit met(s)/satellite(s) without metastatic nodes
N3 4 or more metastatic
nodes, or matted nodes, or in-transit met(s)/satellite(s) with metastatic node(s)
M classification Site Serum lactate dehydrogenase
M1a Distant skin, Normal
subcutaneous, or nodal mets
M1b Lung metastases Normal
M1c All other visceral Normal
metastases
Any distant metastasis Elevated
* Micrometastases are diagnosed after sentinel or elective lymphadenectomy.
† Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.
Source: Reprinted from Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19(16):3635–3648. Review. With permission from the American Society of Clinical Oncology.
1 Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1–4 mm): results of a multi-institutional randomized surgical trial. Ann Surg 1993;218:262–267.
the technique of sentinel node biopsy (SNB) described below can be used to identify patients with positive nodes who would benefit from full lymph node dissection. Prior to or at the same time as wide exci- sion of the primary lesion, isosulfan blue and radioactive tracer are injected into the lesion or biopsy site. These are allowed time to drain to the node or nodes that provide primary lymphatic drainage to the Table 30.7. Proposed stage groupings for cutaneous melanoma.
Clinical staginga Pathologic stagingb
T N M T N M
0 Tis N0 M0 Tis N0 M0
IA T1a N0 M0 T1a N0 M0
IB T1b N0 M0 T1b N0 M0
T2a N0 M0 T2a N0 M0
IIA T2b N0 M0 T2b N0 M0
T3a N0 M0 T3a N0 M0
IIB T3b N0 M0 T3b N0 M0
T4a N0 M0 T4a N0 M0
IIC T4b N0 M0 T4b N0 M0
IIIc Any T N1 M0
N2 N3
IIIA T1–4a N1a M0
T1–4a N2a M0
IIIB T1–4b N1a M0
T1–4b N2a M0
T1–4a N1b M0
T1–4a N2b M0
T1–4a/b N2c M0
T1–4b N1b M0
T1–4b N2b M0
Any T N3 M0
IV Any T Any N Any M1 Any T Any N Any M1
aClinical staging includes microstaging of the primary melanoma and clinical/radio- logic evaluation for metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment for regional and distant metastases.
b Pathologic staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after partial or complete lymphadenectomy.
Pathologic stage 0 or stage 1A patients are the exception; they do not require pathologic evaluation of their lymph nodes.
c There are no stage III subgroups for clinical staging.
Source: Reprinted from Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system. J Clin Oncol 2001;19(16):3635–3648.
Review. With permission from the American Society of Clinical Oncology.
Table 30.8. Clark’s classification of melanoma tumor depth
Level I: Confined to the epidermis (melanoma in situ)
Level II: Invades papillary dermis
Level III: Penetrates up to junction of papillary and reticular dermis
Level IV: Invades the reticular dermis Level V: Extends into subcutaneous fat
Table 30.9.Current recommendations for excision margins for cutaneous melanomas. LocationTumor thicknessRecommended marginEvidenceReference Trunk and proximal £1mm1cmRandomized triala Veronesi et al.e , Veronesi et al.f extremity1–2mm2cm if able to be closedRandomized trialsa Karakousis et al.d , Veronesi et al.e , primarily, otherwise 1cmVeronesi et al.f , Balch et al.g 2–4mm2cmRandomized triala Karakousis et al.d , Balch et al.g >4mm or withAt least 2cmNonrandomizedHeaton et al.h satellitosisclinical seriesb Accepted surgical practicec Head and neck and £1mm1cmRandomized triala Veronesi et al.e , Veronesi et al.f distal extremity>1mmAt least 1cmAccepted surgical practicec aLevel I evidence. bLevel II evidence. cLevel III evidence. dKarakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Local recurrence in malignant melanoma: long-term resultsof the multi-institutional ran- domized surgical trial. Ann Surg Oncol 1996;3:446–452. eVeronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3cm. N Engl J Med 1988;318:1159–1162. fVeronesi U, Cascinelli N. Narrow excision (1-cm margin): a safe procedure for thin cutaneous melanoma. Arch Surg 1991;126:438–441. gBalch CM, Urist MM, Karakousis CP, et al. Efficacy of 2cm surgical margins for intermediate-thickness melanomas (1–4mm): results of a multi-institutional random- ized surgical trial. Ann Surg 1993;218:262–269. hHeaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 1998;5:322–328. Source:Reprinted from Sondak VK, Margolin KA. Melanoma and other cutaneous malignancies. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001, with permission. Note:Level I evidence is defined as prospective, randomized clinical trials. Level II evidence is defined as clinical trials without randomization or case-controlled retrospective studies. Level III evidence is defined as retrospective analyses without case controls, accepted clinical practice, or anecdotal case reports.
disease-affected region, called the “sentinel” nodes, of which there is at least one but sometimes as many as four. These sentinel nodes then are identified easily by the presence of radioactivity and dye and are removed selectively. If the sentinel node is free of melanoma, the remainder of the regional lymph basin will be disease-free in more than 95% of cases, and full lymph node dissection usually is not indicated.
Full lymph node dissection is reserved for patients with positive sen- tinel nodes and, in the absence of distant metastases, may be thera- peutic, although therapeutic efficacy is unproven to date. Nonetheless, SNB is widely used in clinical practice in the treatment of interme- diate-thickness melanomas (1–4 mm) and in selection of patients for adjuvant therapy. For the patient in Case 5, then, excision and simul- taneous SNB with possible lymph node dissection would be the next step in management.
For the patient with clinically appreciable lymphadenopathy, fine- needle aspiration (FNA)of regional lymph glands also is an appro- priate means of evaluating the nodal basin. As with SNB, identification of a positive node is indication for full nodal basin dissection in melanoma of intermediate thickness.
In a melanoma thicker than 4 mm, full lymph node dissection after positive SNB or FNA usually is not indicated, as metastasis to distant sites is highly likely, eliminating any advantage of lymph node dissec- tion in preventing disease progression. Thick melanomas should be excised with 2- to 3-cm margins(M.D. Anderson and Moffitt Cancer Centers, level II evidence).2
Thin melanomas (<1 mm), on the other hand, have a very low like- lihood (<5%) of nodal involvement, and SNB typically does not play a role, since excision of thin melanoma lesions with 1-cm margins has been shown to be largely curative (World Health Organization Melanoma Trial, level I evidence).3
Staging and Treatment of Metastatic Disease
Sentinel node biopsy or fine-needle aspiration of clinically involved nodes is necessary for disease staging in melanomas >1mm thick and has implications for outcome and future management. Chest x-ray, serum alkaline phosphatase, and lactate dehydrogenase, which, as stated previously, are recommended for melanomas >1 mm thick, also contribute to the metastatic workup for melanoma. A number of chemotherapeutic and immunotherapeutic agents have been tested for use as adjuvant therapy in the treatment of metastatic melanoma. Only interferon-alpha-2b has shown demonstrated efficacy and was approved for use by the Food and Drug Administration (FDA) in 1996 in therapy of resected high-risk melanoma.A high-dose regimen was demonstrated in randomized controlled studies (Eastern Cooper-
2Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4 mm) primary melanoma. Ann Surg Oncol 1998;5:
322–328.
3Veronesi U, Cascinelli N. Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 1991;126:438–441.
ative Oncology Group, level I evidence)4to have a positive effect on survival in patients with a single positive node or thick primary tumor.
Although no direct evidence of efficacy has been demonstrated in patients with in-transit metastases, local recurrent satellite nodules, or stage IV disease, these patients may be offered adjuvant interferon therapy as well. No benefit of interferon therapy has been shown in node-negative patients.
Malignant Soft Tissue Lesion: Sarcoma
Sarcomas are a group of histologically diverse, albeit rare, tumors of mesodermal and occasionally ectodermal origin, affecting soft tissue or bone.They are grouped together because of their similar biologic features and responses to treatment. Sarcomas of the soft tissue account for approximately 1% of adult malignancies and 15% of pediatric malignancies; 50% or more of all cases are ultimately fatal. Figure 30.1 demonstrates the diversity of soft tissue sarcomas with regard to anatomic site and histology.
Case 6describes a patient with a rapidly expanding, poorly circum- scribed, deep leg mass. A detailed history may elucidate risk factors in this patient. The most common nongenetic predisposing conditions are previous irradiation and chronic lymphedema, either acquired, as after lymphadenectomy, or congenital. Exposure to alkylating chemotherapeutic agents, phenoxy acetic acids, vinyl chloride, arsenic, and other toxins is associated with development of sarcoma.
Certain genetic conditions also impart increased risk, including neurofibromatosis, familial retinoblastoma, and Li-Fraumeni and Gardner’s syndromes. Despite the recognition of numerous factors that confer increased risk, most patients with soft tissue sarcoma present with no identifiable etiology.
Approximately half of all sarcomas affect the extremities, with two thirds presenting as a painless mass, as in the patient described in Case 6. The differential diagnosis of an extremity mass includes benign soft tissue tumor, most often lipoma, as well as hematoma or muscle injury, all of which are extremely common. With the exception of peripheral nerve tumor transformation in neurofibromatosis, benign tumors do not typically degenerate into malignancy.
Physical exam should include an assessment of the size and mobil- ity of the presenting lesion and its relationship to the fascia, i.e., super- ficial versus deep. In this patient, the clinical findings of immobility, large size (>5cm), history of rapid growth, and persistence should raise suspicion of a malignant process and warrant biopsy of the lesion.Indications for biopsy are summarized in Table 30.10.
Local radiologic studies [computed tomography (CT) or magnetic resonance imaging (MRI)] are sometimes performed before biopsy
4 Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alpha-2b adjuvant therapy of high-risk resected cutaneous melanoma: the ECOG Trial EST 1684. J Oncol 1996;14(1):7–17.
to elucidate the extent and compartmentalization of the tumor and to clarify the involvement of neurovascular and other surrounding structures.These studies often can rule out a benign process such as a lipoma and provide anatomic information that may help determine the best biopsy approach. Magnetic resonance imaging has been regarded as the study of choice because of its ability potentially to differentiate tumor and muscle, while providing clear definition of fascial planes and neurovascular structures. The advantage of MRI over CT, however, remains controversial. Computed tomography is indeed a cost-effective option and has been reported to provide as much clinically useful infor- mation as MRI in the diagnosis and staging of soft tissue tumors.
Because of its large size, suspicious history, and deep location, this patient’s lesion should be biopsied by percutaneous core needle
(5%) (11%)
(26%)
(26%) (24%)
Figure 30.1. Anatomic distribution and site-specific histologic subtypes of 1182 consecutive patients with soft tissue sarcomas seen at the University of Texas M.D. Anderson Cancer Center (University of Texas M.D. Anderson Cancer Center Sarcoma Database, June 1996–December 1998). MFH, malignant fibrous histiocytoma; ERMS, embryonal rhabdomyosarcoma; MPNT, malignant peripheral nerve sheath tumor. (Reprinted from Pisters PWT. Soft tissue sarcoma. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Practice. New York: Springer-Verlag, 2001, with permission.
Table 30.10. Indications for biopsy of a soft tissue lesion.
Noticeable enlargement Size>5cm
Persistence beyond 4–6 weeks Deep location on exam
biopsy, a widely used method of biopsy that usually provides ade- quate tissue for diagnosis while being minimally invasive. Fine-needle aspirationis used by some, but tissue obtained using this method can be difficult to assess, and this technique typically is reserved for diag- nosis of suspected recurrence. Many surgeons performing these biop- sies tattoo the biopsy site for later excision, since tumor recurrence within the biopsy needle tract has been reported. The position of the biopsy site for these and other techniques is of significance, since sarcomas exhibit regional morphologic variation, and, as a result, mul- tiple samples may be required for diagnosis.
Incisional or excisional biopsy of a suspicious soft tissue mass may be performed when definitive diagnosis cannot be achieved by less invasive means.Small, superficial lesions lend themselves to excisional biopsy, if not located nearby critical anatomic structures that would compromise appropriate surgical margins or in turn be compromised by such excision. For both excisional and incisional biopsy, incisions should be placed over the most superficial point of the tumor and should be oriented longitudinally along the axis of the extremity to facilitate wide local excision of the biopsy site and remaining tumor at a later time. Local hemostasis is critical to prevent seeding of tumor cells into adjacent tissues by hematoma.
With more than 30 histologic subtypes and with the anatomic het- erogeneity and rarity of soft tissue sarcomas, a meaningful staging system that accurately describes all forms of the disease is in evolu- tion. The American Joint Committee on Cancer–International Union Against Cancer (AJCC-UICC) system is used widely and incorporates the standard tumor-node-metastasis (TNM) classification as well as histologic grading ranging from well-differentiated to undifferentiated and substaging based on tumor location relative to fascia (Table 30.11).5 It is important to note that, although node status is included in this classification scheme, sarcomas metastasize hematogenously, and, as such, node involvement has no specific prognostic significance except as a site of distant metastasis.
Tissue biopsy of the patient’s lesion in Case 6 revealed a grade 2, moderately differentiated liposarcoma. Staging of this patient’s disease calls for detailed imaging studies if not performed prior to biopsy: CT or MRI of the affected extremity to look for skip metas- tases or local bone involvement and plain film or CT of the chest.
Spread hematogenously, sarcomas of the extremities metastasize most frequently to the lungs. The grade of a sarcoma as determined by biopsy is related to the likelihood of metastasis.Generally, low-grade lesions are an indication for chest x-ray, while chest CT usually is indi- cated in high-grade lesions. Bone metastases are the second most common type of distant disease associated with soft tissue sarcoma;
accordingly, technetium bone scanning also might be used by some in staging disease.
Treatment of extremity sarcomahas centered on surgical resection, which, until 10 to 20 years ago, entailed amputation of the affected
5 Greene FL, Page DL, Fleming ID, et al, eds. AJCC Cancer Staging Manual, 6th ed. New York: Springer-Verlag, 2002.
limb. Prospective randomized studies have shown, however, that limb- sparing surgery with postoperative radiation therapy yields overall survival rates comparable to those achieved with amputation (National Cancer Institute, level I evidence),6and that this approach results in superior local control of disease compared to surgical resec- tion alone (Table 30.12).Limb-sparing surgery requires full excision of the mass with wide margins rather than enucleation of the tumor pseudocapsule, which is associated with very high local recurrence rates. No studies to date have defined the ideal margin of resection, but 2 cm is an arbitrary and commonly used margin. It also should be noted that there is evidence that primary soft tissue sarcomas <5 cm may be treated with resection alone without radiotherapy.
Other therapies used in the treatment of localized soft tissue sarcoma of the extremities include chemotherapy, whose role remains contro- versial despite decades of randomized trials, combined chemotherapy and radiotherapy protocols, and hyperthermic isolated limb perfu- sion, which has shown usefulness in some settings and is currently in clinical trials.
The most effective treatment to date of soft tissue sarcoma metas- tasis, which occurs most frequently in the lungs, is surgical resection of pulmonary lesions. Unfortunately, metstatectomy benefits only a Table 30.11. American Joint Committee on Cancer staging system for soft tissue sarcomas.
T0 No evidence of primary tumor
T1 Tumor 5 cm or less in greatest dimension
T1a Superficial tumor
T1b Deep tumor
T2 Tumor more than 5 cm in greatest dimension
T2a Superficial tumor
T2b Deep tumor
N0 No regional lymph node metastasis N1 Regional lymph node metastasis
M0 No distant metastasis
M1 Distant metastasis
G1 Well differentiated
G2 Moderately differentiated G3 Poorly differentiated
G4 Undifferentiated
Stage I T1a,1b,2a,2b N0 M0 G1–2
Stage II T1a,1b,2a N0 M0 G3–4
Stage III T2b N0 M0 G3–4
Stage IV Any T N1 M0 Any G
Any T N0 M1 Any G
Source: Reprinted from Greene FL, Balch CM, Fleming ID, et al, eds. American Joint Committee on Cancer AJCC Cancer Staging Manual, 6th ed. New York: Springer-Verlag, 2002, with permission.
6Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft tissue sarcoma of the extremities: prospective randomized evaluations of (1) limb sparing surgery plus radia- tion therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315.
sarcomas stratified by grade (level I evidence).
Histologic First author/ Treatment Radiation No. of No. with
grade institution group dose (Gy) patients local failure LRFS OS High grade Pisters/MSKCCb Surgery + BRT 42–45 56 5 (9%) 89% 27%
Surgery — 63 19 (30%) 66% 67%
Yang/NCIa Surgery + XRT 45 + 18 47 0 (0%) 100% 75%
(boost)
Surgery — 44 9 (20%) 78% 74%
Low grade Pisters/MSKCCb Surgery + BRT 42–45 22 8 (36%) 73% 96%
Surgery — 23 6 (26%) 73% 95%
Yang/NCIa Surgery + XRT 45 + 18 26 1 (4%) 96% NR
(boost)
Surgery — 24 8 (33%) 63% NR
LRFS, local recurrence-free survival; OS, overall survival; MSKCC, Memorial Sloan-Kettering Cancer Center; BRT, brachytherapy; NCI, National Cancer Institute; XRT, external-beam radiation therapy.
a Yang JC, Chang AE, Baker AR, et al. A randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998;16:197–203.
b Pisters PWT, Harrison LB, Leung DHY, et al. Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–868.
Source: Reprinted from Pister PWT. Soft tissue sarcoma. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery:
Basic Science and Clinical Practice. New York: Springer-Verlag, 2001, with permission.
Patient presents with clinically suspicious pigmented lesion
In situ
Complete excision 0.5- to 1.0-cm margins
Observe nodes
Biopsy
<1.0 mm thickness
Wide local excision 1-cm margins
Observe nodes (SNB if ulcerated or high mitotic index)
SNB positive
SLND
Adjuvant IFN INV
Benign nevus
Pigmented basal cell carcinoma
1.0- to 4.0-mm thickness
Wide local excision 2-cm margins (consider 1 cm for
1–2 cm deep)
SNB
SNB negative
Observe
Consider adjuvant IFN for
>4.0 mm SNB negative Consider INV
>4.0-mm thickness
SNB Melanoma
Wide local excision 2- to 3-cm margins
Algorithm 30.1. Management of localized cutaneous melanoma. SNB, sentinel node biopsy; SLND, selective complete lymphadenectomy; IFN, high-dose adjuvant interferon alpha-2b: INV, investiga- tional therapies. (Wagner JD, Gordon MS, et al. Current therapy of cutaneous melanoma. Plast Recon- str Surg 2000;105(5):1774–1801. April 2000. With permission from Lippincott Williams and Wilkins.)
Patient presents with clinically suspicious nonpigmented skin lesion
Basal cell carcinoma
Resectable
Surgical excision with 2- to 3-mm margins OR
Mohs’ excision (may also use EDC,
cryosurgery)
Nonresectable
EDC, cryosurgery, or
radiotherapy
Biopsy
Clinically low-risk (see Table 30.2)
Resectable
Surgical excision with 4-mm margins or Mohs’ excision
(may also use EDC, cryosurgery, radiotherapy)
Clinically negative nodes
Consider prophylactic radiation to regional
lymph nodes
Squamous cell carcinoma
Nonresectable
EDC, cryosurgery, or local radiotherapy
Benign lesion
Amelanotic melanoma
Clinically high-risk (see Table 30.2)
Resectable
Surgical excision with 6-mm margins or Mohs’
excision
Clinically positive nodes
Consider lymph node dissection and/or
radiation Algorithm 30.2. Management of nonmelanoma skin cancer. EDC, electrodesiccation and curettage.
small fraction of such patients (<15%), and hence it is critical that patient selection for pulmonary resection be conducted in an extremely cautious manner. The following commonly are accepted as criteria for patient selection: (1) the primary tumor is controlled or controllable, (2) there is no extrathoracic disease, (3) the patient is an appropriate medical candidate for thoracotomy and pulmonary resection, and (4) complete resection of all metastatic disease seems possible. In this way, the morbidity of thoracotomy can be limited to the few patients most likely to benefit from this aggressive procedure.
Retroperitoneal sarcomas are relatively rare, accounting for approx- imately 15% of all sarcomas. Their diagnosis, treatment, and manage- ment are beyond the scope of this chapter.
Summary
Given the extremely common presentation of skin lesions by patients to surgeons and general practitioners alike, it is vital that all physicians be comfortable differentiating those lesions that are thoroughly benign, those that are somewhat questionable, and those that are most likely malignant. Given the rise in incidence of all forms of skin cancer and
given the dismal outcomes associated with late diagnosis of squamous cell carcinoma and melanoma, recognizing the “red flags” of malignant skin lesions and knowing when to refer to a specialist for biopsy are essential skills. The general approach to the management of skin lesions is summarized in Algorithms 30.1 and 30.2.
Size > 5 cm Location deep to fascia
Rapid enlargement Persistence 4–6+ weeks
Consider malignancy
Biopsy and pathologic evaluation
Local disease: wide resection with or without
radiation; consider amputation, HILP
Patient presents with extremity mass
History and physical exam
Observation
Enlargement, persistence, other suspicious change
Local MRI or CT
Size < 5 cm Superficial
Cystic Stable in size
Likely benign
Appropriate treatment of benign lesion
STAGING X-ray/CT of chest Other appropriate imaging studies
Metastatic disease:
Individualized treatment may include metastatectomy, systemic chemotherapy
Algorithm 30.3. Initial management of extremity mass and soft tissue sarcoma. HILP, hyperthermic isolated limb perfusion. (Adapted from Pisters PWT. Ann Surg Oncol 1998;5:464–472. With permission of Lippincott Williams & Wilkins. Adapted from Peabody TD, Gibbs CP, Simon MA. Current Concepts Review-Evaluation and Staging of Musculoskeletal Neoplasms. J Bone Joint Surg Am 80A(8):1204–1218, August 1998. With permission of The Journal of Bone and Joint Surgery. Adapted with permission from Pisters PWT. Soft Tissue Sarcoma. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery. Basic Science and Clinical Evidence. New York: Springer-Verlag, 2001.)
A similar statement can be made regarding soft tissue masses. Cer- tainly, benign soft tissue lesions of the extremities in the form of lipomas or hematomas are extremely common, but it is the essential role of the physician or surgeon to recognize the symptoms and pre- sentation of sarcoma, a disease that, while it may be relatively uncom- mon, is associated with extremely high rates of morbidity and mortality despite early recognition. Algorithm 30.3 outlines an approach to the initial evaluation of an extremity mass and to soft tissue sarcoma.
Selected Readings
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Pisters PWT. Soft tissue sarcoma. In: Norton JA, Bollinger RR, Chang AE, et al, eds. Surgery: Basic Science and Clinical Evidence. New York: Springer- Verlag, 2001.
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Rosenberg SA, Tepper J, Glatstein E, Bruce AJ, Brodland DG. The treatment of soft tissue sarcomas of the extremities: prospective randomized trial of limb- sparing surgery plus radiation compared with amputation and the role of adjuvant chemotherapy. Ann Surg 1982;196:305–315.
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