Malignant Coetaneous Tumors Part 2

Genetic Factors

Approximately 5% of patients with melanomas have a family history of melanoma. Mutations in the cell-cycle regulatory gene p16 (cyclin-dependent kinase inhibitor-2a) are associated with melanoma in approximately 40% of familial-melanoma families, with linkage of the gene to chromosome 9p.26 A highly specific activating somatic mutation in the BRAF proto-oncogene (a member of the RAF family of kinases) is found in the majority of melanomas and benign nevi, suggesting a pivotal role for this genetic pathway in melanocytic tumor progression.27 Genomic analyses are beginning to distinguish biologically distinct subsets of melanoma.28

Diagnosis

As a pigmented lesion occurring on the surface of the skin, melanoma is amenable to early detection by simple visual inspection at an easily curable stage. Left untreated, melanoma is among the deadliest and most therapeutically unresponsive forms of cancer.

Physical examination Early recognition of melanoma requires attention to pigmented lesions on all body surfaces. Despite the strong association of melanoma with sun exposure, melanomas can occur anywhere on the skin or mucosa. Patients’ self-examination, as well as physician examination, must therefore include all skin surfaces, including the scalp, genitalia, and soles of the feet. Any pigmented skin lesion with recent change or with features described by the ABCD mnemonic (asymmetry, border irregularity, color variation, diameter > 6 mm) warrants consideration of the possibility of melanoma. Although any mole may change gradually over time, any that change color, shape, or size relative to a patient’s other moles deserve special attention [see Figure 4].29 Dysplastic nevi present both opportunity and challenge in melanoma detection. On one hand, their recognition allows efficient targeting of a high-risk group. On the other, they can complicate attempts at melanoma detection by clinically mimicking early melanomas. Although some dys-plastic nevi may progress to melanoma, the overwhelming majority remain benign. Furthermore, not all melanomas arising in patients with dysplastic nevi develop in a preexisting mole. Wholesale removal of dysplastic nevi is an impractical approach to melanoma prevention. In patients with dysplastic nevi, melanoma detection is predicated on specialized visual examination aided by self-examination and professional follow-up to identify changing lesions.30


Diagnostic aids Several specialized aids to the diagnosis of melanoma in patients with dysplastic nevi are under development. Dermoscopy entails the use of a handheld otoscopelike device to magnify a pigmented lesion while applying pressure and oil to the surface. The technique allows the visualization of pigment patterns and features not apparent with simple visual inspection. With experience and training, der-moscopy can be a useful aid in distinguishing melanoma from benign pigmented lesions; however, when used inexpertly, dermoscopy may actually decrease diagnostic accuracy.30,31 Another aid to melanoma detection in high-risk individuals is photographically assisted follow-up.32 A baseline set of whole-body photographs of the skin are used during self-examination and professional follow-up examination to assess change in the lesions. This procedure helps to prevent unnecessary excision of stable lesions and improves the sensitivity of examinations in detecting change. New imaging technologies such as in vivo confocal scanning laser microscopy hold promise for future improvements in the noninvasive diagnosis of melanoma.

Superficial spreading malignant melanoma begins as a small, irregular brown lesion (a). Variation in color and contour is characteristic of lentigo maligna melanoma (b). Nodular melanoma often grows more in thickness than in diameter (c). Acral lentiginous melanoma can resemble a hematoma under the nail (d).

Figure 4 Superficial spreading malignant melanoma begins as a small, irregular brown lesion (a). Variation in color and contour is characteristic of lentigo maligna melanoma (b). Nodular melanoma often grows more in thickness than in diameter (c). Acral lentiginous melanoma can resemble a hematoma under the nail (d).

Full-thickness excision and biopsy Any lesion that raises a clinical suspicion of melanoma requires definitive diagnosis. Full-thickness excision is the preferred technique for biopsy of a suspicious pigmented lesion. Partial biopsy can lead to misdiagnosis through sampling error or by depriving the pathologist of a view of the overall architecture and cytology of the lesion. Inci-sional biopsies with good clinicopathologic correlation may be appropriate, however, in the assessment of large lesions and of lesions occurring in surgically sensitive areas. There is no evidence to suggest that incisional biopsy increases the risk of metastasis.

Differential Diagnosis

Dysplastic nevi share many features with early superficial spreading melanoma. Other common lesions that may mimic melanoma include lentigines, sunburn freckles, traumatized nevi, thrombosed angiomas, pigmented BCCs, pigmented Bowen disease, dermatofibromas, and atypical seborrheic ker-atoses. Two other challenges in the differential diagnosis of melanoma deserve special mention. Amelanotic melanomas (melanomas without pigment) present as pink lesions that may be misdiagnosed as BCCs or Spitz nevi. Spitz nevi can be difficult to differentiate from melanoma both clinically and histolog-ically. Spitz nevi occur most commonly in children, but they also occur in adults. Like nodular melanomas, Spitz nevi tend to appear suddenly and range in color from red to reddish brown.

Treatment

Primary site Primary cutaneous melanoma is managed surgically with definitive reexcision. The wide excisions of the past have given way to resections with more modest margins. Multiple prospective, randomized trials have investigated the surgical resection of primary cutaneous melanoma utilizing different margins of resection; these studies have focused on varied and overlapping patient populations. On the basis of these data, the NCCN recommends resection margins of 1 cm for melanomas less than 1 mm in thickness, margins of 1 to 2 cm for melanomas between 1 and 2 mm in thickness, and margins of 2 cm for melanomas greater than 2 mm in thickness.34,35 Primary closure and reconstructive flaps are preferable, cosmetically and functionally, to skin grafts and should be used instead of grafts whenever possible.

Lymph nodes Patients with clinically evident regional lymph node disease are treated with therapeutic lymph node dissec-tion.34 Elective lymph node dissection in patients with primary melanoma and who have no clinical evidence of lymph node involvement has been abandoned on the basis of the failure of multiple randomized trials to demonstrate an overall survival benefit with this procedure.

Sentinel lymph node biopsy is being increasingly used in patients with primary cutaneous melanoma. This technique utilizes lymphoscintigraphy to identify the draining regional lymph node basins for the skin at the site of the primary melanoma. At the time of definitive reexcision of the melanoma, a blue dye and radioisotope are injected into the dermis around the melanoma site. A small incision is made over the spot that has been identified on lymphoscintigraphy as the proximal area of drainage of the regional lymph node basin. The first lymph node identified as taking up the blue dye and radioisotope (i.e., the sentinel node) is then excised.

The sentinel node is then histologically evaluated, often with the use of immunohistochemical techniques and occasionally with the use of polymerase chain reaction, which is more sensitive. The absence of melanoma in the sentinel node is highly sensitive for ruling out the presence of metastases in the remainder of the lymph node basin when the procedure is performed by an experienced team. When the sentinel node is found to be positive for melanoma, a "completion" lymph node dissection of the affected basin is typically performed. Prospective studies have demonstrated sentinel node status to be strongly correlated with 5-year survival.36 Patients with positive sentinel nodes are appropriate candidates for consideration of adjuvant therapy [see Adjuvant Therapy, below]. Several multicenter trials are currently under way to assess the clinical utility of this procedure.37 Initial reports from the first of these trials have failed to indicate an overall survival advantage associated with the procedure.

In-transit metastases In-transit metastases are metastases that establish tumors within regional dermal and subcutaneous lymphatics before reaching the regional lymph nodes. In-transit metastases can remain confined to a single limb for prolonged periods. Amputation does not appear to provide a long-term survival benefit in this setting.34 Slow-growing individual in-transit metastases can be managed surgically. More extensive disease can be treated with sensitization therapy with dinitrochlorobenzene (DNCB), intralesional interferon, or topical agents for modifying the immune response. For extensive in-transit metastases confined to an extremity, limb perfusion therapy can result in dramatic palliation and limb salvage. The procedure entails isolation of the vasculature of the involved extremity from the systemic vasculature and per-fusion of the isolated limb with chemotherapeutic agents, biologic agents, or both at doses that could not be tolerated if given systemically.

Distant metastases Despite the development of several novel approaches to the treatment of patients with metastatic melanoma, including multiagent chemotherapy, biologic therapy, immunotherapy, and combinations of these treatments, no regimens have demonstrated a clear survival advantage over single-agent chemotherapy. Monotherapy with dacarbazine (2 to 4.5 mg/kg daily for 10 days, repeated every 4 weeks) or recombinant interleukin-2 (IL-2) (600,000 IU/kg every 8 hours for up to 14 doses) are the only treatment regimens approved by the FDA for the treatment of metastatic melanoma. Objective responses to dacar-bazine are seen in approximately 5% to 20% of patients; durable complete responses are rare.40 Objective responses to IL-2, a significantly more toxic agent, are seen in approximately 15% of patients; durable responses are seen in about 5%. Radiation therapy can play an important palliative role. In the absence of more effective clinically proven therapy, patients with distant metastases should be offered the opportunity to participate in clinical trials of experimental therapy. Many current experimental therapies are predicated on decades of experience with immunotherapy of melanoma, as well as the recent availability of pharmacologic inhibitors of elements of the Ras signaling pathway that are implicated in melanoma pathogenesis.40

Table 2 AJCC TNM Classification45

TNM Classification

Tumor Thickness, Node Number, Metastases Site

Subclassification

T classification T1

< 1.0 mm

a: Without ulceration and Clark level II or III b: With ulceration or Clark level IV or 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

> 4.0 mm

a: Without ulceration b: With ulceration

N classification N1

One lymph node

a: Micrometastasis* b. Macrometastasis+

N2

2-3 lymph nodes

a: Micrometastasis* b. Macrometastasis+

c: In-transit met(s)/satellites(s) without metastatic lymph nodes

N3

4 or more metastatic lymph nodes, matted lymph nodes, or combination of in-transit met(s)/satellite(s) with metastatic lymph nodes

M classification M1a

Distant skin, subcutaneous, or lymph node mets

Normal LDH

M1b

Lung mets

Normal LDH

M1c

All other visceral mets Any distant mets

Normal LDH Elevated LDH with any M

*Micrometastases are diagnosed after sentinel or elective lymphadenectomy.

+Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy; the term also applies to nodal metastases that exhibit gross extracapsular extension.

AJCC—American Joint Committee on Cancer LD—lactic dehydrogenase mets—metastases

Adjuvant therapy Patients with cutaneous or regional disease who have been surgically rendered disease free but who are at high risk for recurrence or metastasis are potential candidates for adjuvant therapy.41 Various adjuvant therapies have been used in melanoma, including immunostimulants such as bacillus Calmette-Guerin, Corynebacterium parvum, and levamisole. Several chemotherapeutic agents have been tried as well. More recently, immunotherapies with cytokines, such as interferons, and active immunization with vaccines have been studied. A high-dose regimen of interferon alfa (20 million units/m2 I.V. daily for 1 month followed by 10 million units/m2 S.C. three times a week for 48 weeks) has been approved by the FDA for use as adjuvant therapy for melanoma. Two studies have demonstrated a small but statistically significant improvement in overall survival with this regimen. Multiple studies have failed to demonstrate improved long-term overall survival with the use of adjuvant interferon in intermediate-dose or low-dose regimens.

A host of novel strategies, including active immunization, passive immunization, and myriad biologic therapies, are currently being studied and may provide opportunities for patients who are appropriate candidates for trials.44

Prognosis

Stage The single strongest prognostic factor for melanoma is stage of disease. Various staging classifications have been used over the years. All staging systems for melanoma take into account the classic TNM classification of tumor size (T), lymph node involvement (N), and distant metastases (M). The differences across staging systems relate largely to the staging of the primary site. New staging systems attempt to use the attributes of the primary tumor that strongly correlate with outcome. These attributes include thickness, ulceration, and, in the case of thin melanomas measuring less than 1 mm thick, the Clark level of invasion. The advent of sentinel node biopsy has led to the inclusion of microstaging of lymph nodes in the staging system [see Tables 2 and 3].45,415

Attributes of the primary tumor Several attributes of the primary tumor have been identified as predictors of outcome from primary cutaneous melanoma. A strong predictor of outcome is the Breslow tumor thickness, which is measured in millimeters from the granular layer of the epidermis to the deepest tumor cell. Other important histologic parameters are the Clark level of tumor invasion, the presence or absence of ulceration, the rate of mitosis, the presence of tumor-infiltrating lymphocytes, and vascular invasion. For thin primary melanomas, one of the strongest predictors of outcome is growth phase.47 Radial-growth-phase melanoma does not appear to metastasize, whereas vertical-growth-phase melanoma (characterized by the for-mation of a tumor nodule in the dermis) is associated with significant risk of metastasis even in lesions less than 1 mm thick.48 Patient characteristics associated with improved survival from melanoma include young age (< 60 years), female sex, and location of the melanoma on an extremity other than the palms or soles. Multivariable models for predicting outcome from melanoma have been developed [see Table 4].

Table 3 AJCC Staging System and Survival Rate45

Pathologic Stage

TNM

5-Year Survival

10-Year Survival

IA

T1a

95.3 ± 0.4

87.9 ± 1.0

IB

T1b T2a

90.9 ± 1.0 89.0 ± 0.7

83.1 ± 1.5

79.2 ± 1.1

IIA

T2b T3a

77.4 ± 1.7 78.7 ± 1.2

64.4 ± 2.2 63.8 ± 1.7

IIB

T3b T4a

63.0 ± 1.5 67.4 ± 2.4

50.8 ± 1.7

53.9 ± 3.3

IIC

T4b

45.1 ± 1.9

32.3 ± 2.1

IIIA

N1a N2a

69.5 ± 3.7 63.3 ± 5.6

63.0 ± 4.4 56.9 ± 6.8

IIIB

N1a N2a N1b N2b

52.8 ± 4.1 49.6 ± 5.7 59.0 ± 4.8 46.3 ± 5.5

37.8 ± 4.8

35.9 ± 7.2 47.7 ± 5.8 39.2 ± 5.8

IIIC

N1b N2b

N3

29.0 ± 5.1 24.0 ± 4.4 26.7 ± 2.5

24.4 ± 5.3 15.0 ± 3.9 18.4 ± 2.5

IV

M1a M1b M1c

18.8 ± 3.0 6.7 ± 2.0 9.5 ± 1.1

15.7 ± 2.9 2.5 ± 1.5

6.0 ± 0.9

AJCC—American Joint Committee on Cancer

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