Bethesda Handbook of Clinical Oncology, 2nd Edition

Skin Cancer

22

Skin Cancers and Melanoma

Upendra P. Hegde*

Barry Gause

*Division of Hematology/Oncology, University of Connecticut Health Center, Farmington, Connecticut

Medical Oncology Clinical Research Unit, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

The skin is the largest organ of the human body. It is embryologically derived from the neuroectoderm and the mesoderm. It consists of three layers: epidermis, dermis, and subcutis. Skin cancers can arise from various cell types and structures in various layers of the skin (1). The exposure of the skin to the environment has a special relevance because a wide variety of carcinogens can interact directly with the genetic components of skin cells. Such exposure has increased the incidence of skin cancers. The cells of origin in various types of skin cancers are outlined in Tables 22.1 and 22.2. The skin cancers are best divided into melanoma and nonmelanoma.

TABLE 22.1. Cells of Epidermis and Respective Tumor Type

Cells of epidermis

Tumor type

Incidence (%)

Melanocyte

Melanoma

5–7

Epidermal basal cell

Basal cell carcinoma

60

Keratinocyte

Squamous cell carcinoma

30

Merkel cell

Merkel cell tumor

1–2

Langerhans cell

Histiocytosis X

<1

Appendage cells

Appendageal tumors

<1

TABLE 22.2. Cells of Dermis and Respective Tumor Type

Cells of dermis

Tumor type

Incidence (%)

Fibroblast

Benign and malignant fibrous histiocytic tumors

<1

Mast cell

Mast cell tumor

<1

Vasculature

Angioma and angiosarcoma

<1

Lymphangioma

<1

MELANOMA

Melanoma is a skin tumor that originates from the melanocyte, which is derived from the neural crest, and migrates during embryogenesis predominantly to the skin and less commonly to other tissues, such as the meninges, the ocular choroid, the mucosa of the respiratory tract, the gastrointestinal tract, and the genitourinary tract, where melanoma is rarely encountered.

Epidemiology

  • Melanoma ranks as the seventh leading type of cancer in the United States.
  • Its incidence in women is increasing faster than that of any other cancer except lung cancer.
  • The incidence of melanoma is 10 times greater in whites than in the African Americans. The incidence in U.S. whites is 10 per 100,000 population, although some geographic areas have higher rates.

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  • In 2004, it was estimated that 55,100 new cases of cutaneous melanoma would have been diagnosed in the United States, with 7,910 deaths.
  • Australia has the highest incidence of melanoma in the world, approximately 17 cases per 100,000 per year.
  • In the year 2000, the estimated lifetime risk of melanoma in American whites was 1 person in 75.

Etiology

  • Sunlight exposure: ultraviolet B rays
  1. Intermittent intense exposure
  2. Exposure at a young age
  3. Individuals with propensity for sunburns and poor tanners
  4. Individuals with fair skin, blue eyes, blonde or red hair
  • Age: Higher incidence in young and middle-aged adults (except lentigo maligna melanoma on sun-exposed surfaces in the elderly)
  • Sex: Slightly more common in female subjects than in male subjects
  • Ethnicity: Higher incidence in northern Europeans than in eastern and southern Europeans
  • Familial melanoma: One in ten patients with melanoma has a family history of melanoma.

Following are the Characteristic Features of Familial Melanoma:

  1. Multiple melanomas
  2. Melanoma at young age
  3. Melanoma often associated with dysplastic nevi
  4. Locus for melanoma or the dysplastic nevus resides in the distal portion of the short arm of chromosome 1
  5. Other genetic loci are possible, which include chromosome 9 (loss of 9p21).

Precursor Lesions of Melanoma:

  • Dysplastic nevi
  • Congenital nevi
  • Acquired melanocytic nevi.

Risk Factors for Melanoma

  • Xeroderma pigmentosum
  • Familial atypical mole melanoma syndrome (FAMMS)
  • Numerous acquired melanocytic nevi
  • Dysplastic nevi
  • Giant congenital nevus
  • Prior melanoma
  • Sun exposure/sun-sensitive phenotype

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  • Immunosuppression
  • Melanoma in a first-degree relative
  • Freckling.

Differences between acquired melanocytic nevus and dysplastic nevus are listed in Table 22.3 and Fig. 22.1.

TABLE 22.3. Differences Between Acquired Melanocytic and Dysplastic Nevus

Acquired melanocytic nevus

Dysplastic nevus

Develops in early childhood through fourth decade

Develops throughout life

<5 mm in diameter, sharp borders, evenly pigmented

>6–8 mm in diameter, irregular borders, variegated pigment, and topographic asymmetry

If >100 in number, risk of melanoma increases by 10 times

Presence of dysplastic nevus increases the risk of melanoma

 

FIG. 22.1. Model of ultraviolet B light mediated pathogenesis of cutaneous melanoma.

Common Chromosomal Abnormalities in Malignant Melanoma

Early chromosomal abnormalities:

  • Loss of 10q
  • Loss of 9p.

Late chromosomal abnormalities:

  • Deletion of 6q
  • Loss of terminal part of 1p
  • Duplication of chromosome 7
  • Deletion of 11q23.

Clinicohistologic Types of Melanoma

The measurement of melanoma cells in the dermis and subcutaneous fat has been defined in a reproducible manner by two groups: Clark et al. (2) and Breslow (3) (see Table 22.4). Clark et al. subdivided the invasion of the papillary dermis into a deep group, in which melanoma cells accumulate at the junction of the papillary and reticular dermis, and a superficial group, in which these cells do not accumulate (seeFig. 22.2).

TABLE 22.4. Revised American Joint Committee for Cancer Staging System for Cutaneous Melanoma (2001) (4)

Melanoma TNM Classification

T classification

Thickness

Ulceration status

The AJCC Melanoma Database consisted of a total of 30,450 melanoma patients, of which 17,600 patients (58%) had information available for all of the factors required for the proposed TNM classification and stage grouping.
a Micrometastases are diagnosed after sentinel or elective lymphadenectomy.
b Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastases exhibit gross extracapsular extension.
c Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation for metastasis. By convention, it should be used after complete excision of the primary melanoma, with clinical assessment for regional and distant metastasis.
d 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 IA patients are the exception; they do not require pathologic evaluation of their lymph nodes.
e There is no stage III subgroup for clinical staging.

T1

≤ 1.0 mm

a: without ulceration and level II/III

       

b: with ulceration or Clark 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

>4.0 mm

a without ulceration

       

b: with ulceration

       

N classification

No. of metastatic nodes

Nodal metastatic mass

       

N1

1 node

a: micrometastasesa

       

b: macrometastasesb

       

N2

2–3 nodes

a: micrometastasesa

       

b: macrometastasesb

       

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, subcutaneous, or nodal mets

Normal

       

M1b

Lung metastases

Normal

       

M1c

All other visceral metastases

Normal

       

Any distant metastases

Elevated

       

Proposed stage groupings for cutaneous melanoma

       

Clinical stagingc

Pathologic stagingd

 

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

III e

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

IIIC

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

       
 

FIG. 22.2. Schematic diagram of Clark levels of invasion.

Breslow measured the thickness of melanoma lesions by using an ocular micrometer, which measured the vertical depth of penetration from the granular layer of the epidermis or from the base of the ulcer to the deepest identifiable contiguous melanoma cell (Breslow thickness), and showed it to be a more reproducible and accurate prognostic parameter than the Clark method of microstaging.

Clark Method of Microstaging (Level of Invasion)

Clark Level

  1. Melanoma limited to the epidermis
  2. Invasive melanoma with superficial infiltration to the papillary dermis

III.      Melanoma extending to the superficial vascular plexus in the dermis

  1. Primary melanoma involving the reticular dermis
  2. Melanoma involving the subcutaneous fat.

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Salient Features of the New Cancer Staging System for Cutaneous Melanoma by the American Joint Committee for Cancer (2001)

  1. The new version retains the anatomic compartmentalization: Stages I and II represent localized melanoma to skin, stage III represents metastasis to the regional lymph node/s, and stage IV represents distal metastasis.
  2. T-category thresholds of melanoma thickness are defined by even integers (i.e., 1.0, 2.0, and 4.0 mm).
  3. Thick melanoma (>4 mm in thickness) is assigned to stage II.

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  1. The level of invasion as described by Wallace Clark is an independent predictive feature for thin (T1) melanoma but not for thicker lesions (5).
  2. Melanoma ulceration, defined as the absence of an intact epidermis overlying a major portion of the primary melanoma on the basis of microscopic examination of the histologic sections, predisposes patients to a high risk for metastasis.
  3. The new staging system incorporates the pathologic information obtained after lymphatic mapping and sentinel lymph adenectomy that is included in the definition of clinical and pathologic staging.
  4. When patients present with multiple primary melanomas, the T-category staging is based on the melanoma with the worst prognostic features.
  5. Stage III melanoma patients include those with regional metastasis either in the regional lymph nodes or in the intralymphatic metastases, manifesting as either satellite or in-transit metastases.
  6. There are four major determinants of outcome for pathologic stage III melanoma:
  • Number of metastatic lymph nodes: N1 = one metastatic lymph node, N2 = 2 to 3 metastatic lymph nodes, and N3 = 4 or more metastatic lymph nodes
  • Tumor burden in the lymph node is either (a) microscopic or (b) macroscopic
  • Presence or absence of ulceration of the primary tumor and
  • Presence or absence of satellite or in-transit metastases.
  1. Size of the metastatic lymph node does not demonstrate independent prognostic value.
  2. The presence of clinical or microscopic satellite metastases around a primary melanoma as well as in-transit metastases between the primary melanoma and the regional lymph nodes represent intralymphatic metastases and portend a poor prognosis. In addition, patients with a combination of satellites and in-transit metastases plus nodal metastases have a worse outcome than patients who experience either event alone.
  3. In patients with distant metastases, the site(s) of metastases and elevated serum levels of lactate dehydrogenase (LDH) are used to delineate the M categories into three groups: M1a, M1b, and M1c, with 1-year survival rates ranging from 41% to 59%. There are no subgroups of stage IV disease because the survival differences between the M categories are small.

PROGNOSTIC FACTORS

The prognostic factors of melanoma are listed in Table 22.5 and Fig. 22.3.

TABLE 22.5. Prognostic Factors

Good prognostic factors

Poor prognostic factors

1.

Tumor involving an extremity

Melanoma of the skin of the trunk, head, and neck

2.

Thin tumor

Thick tumor

3.

No ulceration of tumor

Tumor ulceration present

4.

Radial growth pattern

Nodular histology

5.

Early stage (stage I and II)

Late stage at presentation (stage III and IV)

6.

Absence of foci of regression and satellites of the tumor in the reticular dermis and subcutaneous fat

Presence of foci of regression and/or tumor satellites in reticular dermis and subcutaneous fat

7.

Absence of vascular and/or lymphatic invasion

Presence of vascular and/or lymphatic invasion

8.

Low tumor cell mitotic rate

High tumor cell mitotic rate

 

FIG. 22.3. Fifteen-year survival results for more than 4,000 melanoma patients treated at the University of Alabama at Birmingham and the Sydney Melanoma Unit, staged according to the American Joint Committee on Cancer four-stage system. Distribution of patients is shown in parentheses. Note that patients with clinically localized melanoma (stage I in the original three-stage system) are divided into two stages according to tumor thickness and histologic level of invasion (designated stages I and II). (From Ketcham AS, Moffat FL, Balch CM. Classification and staging. In: Balch C, ed. Cutaneous melanoma. 2nd ed. Philadelphia: JB Lippincott, 1992:213–220, with permission.)

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Clinical Features of Malignant Melanoma

Cutaneous melanoma can occur anywhere in the body. The most common sites are the lower extremities in the women and the trunk in men. The classic signs include a pigmented skin lesion that demonstrates a change in color or variegated color, a change in lesion size, and irregular borders. Progressive lesions show nodularity and ulceration or bleeding, with or without pruritus.

Most lesions are pigmented, although less than 1% of lesions lack pigment and are called amelanotic melanomas.

Diagnosis

The types of skin biopsies used in the diagnosis of malignant melanoma are listed in Tables 22.6 and 22.7.

TABLE 22.6. Diagnosis of Melanoma

Immunohistologic tests for the diagnosis of malignant melanoma

Antigen

Result

S-100 protein

+

Cytokeratin

Premelanosomal protein (HMB-45)

+

Vimentin

+

Nerve growth factor receptor

+

Tyrosinase-related protein-1 (MEL-5)

+

TABLE 22.7. Types of Skin Biopsy for Melanoma Diagnosis

Types of skin biopsy

Characteristics

Shave biopsy—contraindicated in melanoma because it may not yield adequate deep specimen for accurate microstaging.

Excisional skin biopsy

1. Completely removes the tumor. Curative if the tumor is small, and tumor-free margins of 2 mm could be obtained.

2. May not be feasible because of anatomic or cosmetic restraints constraints.

Incisional skin biopsy

1. Performed if a tumor is large.

2. For flat lesions, the darkest area should be sampled. If the lesion is raised, the thickest area should be sampled.

Prognosis

Most melanomas are diagnosed in the early stages and are thin. More than 95% of thin melanomas are curable, and approximately 85% of stage I and II melanomas are cured. The prognosis is inversely proportional to the stage of the cancer, and only 40% to 50% of persons with stage III melanoma live for 5 years. Less than 5% of patients with stage IV melanoma live for 5 years (6).

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Table 22.8 shows a graph depicting the survival in relation to the stage of the melanoma.

TABLE 22.8. Relationship Between Microstage of Primary Melanoma, Incidence of Regional Lymph Node Metastases, and Long-term Survival in Patients from John Wayne Cancer Institute

 

Microstage

Patient number

Lymph node metastases (%)

10-Year survival (%)

Breslow thickness

<0.75 MM

768

8.3

97

0.76–1.5 MM

802

20.2

87

1.51–3.99 MM

765

36.6

67

≥4 MM

205

40.0

40

Clark level

I/II

622

9.2

97

III

1,046

23.9

85

IV

785

35.0

68

V

87

38.0

46

Management

The algorithm for the management of primary melanoma is reviewed in Fig. 22.4.

 

FIG. 22.4. Algorithm for the management of primary melanoma (American Joint Committee for Cancer stage I/II) (7).

Prevention:

  • Patients should be educated about the risk factors for developing melanoma—ultraviolet light (intense mid-day sun between 11 AM and 1 PM). Use of sunblock [sun protection factor (SPF) >15] and light clothing should be encouraged.
  • Patients should be educated about clinical features of melanoma and precursor lesions and should be taught to perform self-examination of the skin.

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  • Close surveillance is required in high-risk patients.
  • Digital photographs are used for comparing the multiple pigmented skin lesions and for assessing any changes as described previously, as in dysplastic nevus syndrome.
  • Dermoscopy (epiluminescence microscopy) is a technique used to visualize a variety of structures in pigmented lesions that are not discernible to the naked eye. Lotion or mineral oil is applied to the surface of the lesion to make the epidermis more transparent. Examination of the lesion with a 10 × ocular scope, a microscope ocular eyepiece (held upside down), or a dermatoscope (available from surgical supply houses) then reveals several features that are helpful in differentiating between benign and malignant pigmented lesions. This technique provides additional criteria for the diagnosis of melanoma.

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General Principles and Issues in Treatment:

  • Surgical excision is the primary treatment for melanoma.
  • Regional lymph node dissection for metastasis is performed before any distant spread of the tumor occurs.
  • Adjuvant radiation therapy after lymph node dissection is used in selected instances.
  • Isolated limb perfusion with chemotherapy is given in selected instances.
  • Interferon-α is provided as adjuvant therapy in patients with high-risk resected cutaneous melanomas.
  • Multiple options in metastatic melanoma include single-agent chemotherapy such as oral temozolomide, combination chemotherapy, biologic therapy such as high-dose interleukin-2 (IL-2), interferon-α, and chemobiotherapy. Radiation therapy may be used in select instances such as in patients who present with brain metastasis or as an adjuvant to surgery in head and neck melanoma or in postlymphadenectomy lymph node basins with extracapsular spread of metastatic melanoma.
  • Newer experimental immunotherapy includes vaccines.

Surgical Management of Primary Melanoma

Principle: Complete surgical excision of the primary melanoma, confirmed by comprehensive histologic examination of the entire excised specimen, forms the basis for surgical treatment of primary melanoma (8).

Risk of local recurrence is not significantly associated with the extent of surgical margin of excision (see Table 22.9).

TABLE 22.9. Recommended Margin of Surgical Excision Based Upon Pathologic Stage of Primary Cutaneous Melanoma

Pathologic stage

Thickness

Margin of excision

From Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999;17:2745–2751, with permission.

pTis

Melanoma in situ

5 mm

pT1 and pT2

0–1.5 mm

1 cm

pT3

>1.5–4 mm

1–2 cm

pT4

>4 mm

2–3 cm

Ocular Melanoma

Early and limited-stage ocular melanomas are usually managed by close observation. Various methods of treatment include radiation therapy, photoradiation, cryotherapy, ultrasonic hyperthermia, local resection, and enucleation.

Indications for Enucleation of the Eye in Ocular Melanoma:

  • Tumor growing in a blind eye
  • Melanoma involving more than half of the iris
  • Tumor involving the anterior chamber of the eye or extraocular extension
  • Failure of previous local therapy.

Lymph Node Dissection

Invasion of the lymphatics by a vertically growing melanoma causes the tumor to lodge in the local lymph node basin. The tumor, uninterrupted at this lymph node basin, may spread to deeper lymphatics or hematogenously to systemic organs. This principle forms the rationale for complete surgical resection of the tumor from the lymph node basin before the tumor spreads to distant organs, and is considered a potentially curative procedure.

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Lymph Node Dissection can be Classified as Follows (See Table 22.10):

  • Elective: Lymph node dissection is said to be elective when the lymph nodes that are not clinically palpable are dissected from the lymph node basin because of the high suspicion that the melanoma has spread to the lymph nodes without evidence of distant spread.
  • Therapeutic: When the lymph nodes are clinically palpable and are suspected to be involved without distant organ spread, the dissection is therapeutic.
  • Delayed: When initially nonpalpable lymph nodes appear to enlarge over a close follow-up period without distant organ spread, the dissection is considered delayed.

TABLE 22.10. Lymph Node Dissection

Advantages

Disadvantages

Helps eradicate occult lymph node metastasis

Overtreatment in 50%–60% patients

Correctly stages the tumor

Invasive procedure

Efficacy proved in melanoma of thickness between 1.1 and 2 mm in patients younger than 60 yr

Morbidity of the procedure

Sentinel Lymph Node Dissection

Characteristics of a sentinel lymph node are as follows:

  • First lymph node in the lymph node basin to which the primary melanoma drains.
  • Lymph node at the greatest risk for metastasis.
  • Histology of sentinel node reflects the histology of all lymph nodes in the basin.
  • Easily accessible.
  • If the lymph node is negative for metastasis, it spares the patient major surgical morbidity.

Surgical Approach to Obtain a Sentinel Lymph Node

Preoperative lymphoscintigraphy uses vital blue dye and provides a road map of the lymph node basin. Intraoperative lymphoscintigraphy uses radiocolloid injection around the primary tumor, and a gamma camera detects the radioactivity from the involved lymph node, thereby acting as a navigator to the involved lymph node. The combination of vital blue dye and technetium-labeled sulfur colloid identifies the sentinel lymph node in 94% of cases (9).

Isolated Limb Perfusion

Principle: To deliver maximally tolerated chemotherapy doses to a regionally confined tumor area while limiting systemic toxicity. Hyperthermia and oxygenation of the circulation potentiate the tumoricidal effects of the chemotherapeutic agents. Chemotherapeutic agents used in this method of treatment are

  • melphalan
  • thiotepa (response rate, 50% to 60%)
  • mechlorethamine
  • one of the above agents along with tumor necrosis factor and interferon-α (response rate, 91%).

Isolated limb perfusion is described in Table 22.11.

TABLE 22.11. Isolated Limb Perfusion

Advantages

Disadvantages

1. Local control of the disease

2. Resolution of edema, bleeding, or ulceration

3. Relieves pain

1. Expensive

2. Invasive

3. May cause ischemia of the limb, peripheral neuropathy, and bone marrow suppression

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Indications for Isolated Limb Perfusion:

  • Adjuvant to lymph node dissection
  • Recurrent melanoma of extremity (10)
  • Bulky symptomatic melanoma of the extremity, with bleeding, ulceration, or edema.

Role of radiation therapy for melanoma treatment in the adjuvant setting:

Although melanoma is generally considered as a “radioresistant tumor,” radiation therapy has been found to be of clinical benefit after surgical lymph node resection in the following instances:

  • Head and neck melanomas (11)
  • Multiple large lymph nodes
  • Extracapsular spread
  • Local recurrence in a previously dissected lymph node basin
  • Parotid gland lymph nodes
  • Desmoplastic melanoma with neurotropism
  • Brain metastasis of melanoma.

Studies by Skibber et al. (12) suggested that external radiation to the brain after surgical resection of the solitary brain metastasis with malignant melanoma has survival benefit.

Biologic Agents in Malignant Melanoma

Interferon-α was the first recombinant cytokine that was investigated in phase I/II trials, in the metastatic setting, on the basis of its antiproliferative as well as immunomodulatory effects.

  • The response rate in metastatic melanoma was approximately 16%.
  • One third of these responses were complete responses.
  • Responses could be observed up to 6 months after the therapy was initiated.
  • Up to one third of the responses were durable.
  • Patients with frequent interruptions due to side effects of interferon therapy did less well than those patients without interruptions.
  • Patients with small-volume tumors did better than those with large-volume tumors.

Interferon in Metastatic Melanoma

The study by Falkson et al. (13) showed a response rate of 53% and a median survival of 17.6 months with interferon-α 2b along with dacarbazine compared to a response rate of 20% and a median survival of 9.6% months with dacarbazine alone. These results were not reproducible by the European Organization for the Research and Treatment of Cancer (EORTC) studies.

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Interferon in the Adjuvant Setting in Malignant Melanoma

Principle: There is a high incidence of relapse among patients with stage III melanoma after therapeutic or elective lymph node dissection and in those with thick melanoma lesions (>4 mm). The effect of interferon on disease-free survival has been evaluated in this setting (seeTable 22.12) (14).

TABLE 22.12. Use of Adjuvant Interferon

Study group (accrual)

Treatment regimen

Outcomes analysis

ECOG, Eastern Cooperative Oncology Group; AJCC, American Joint Committee for Cancer; UKCCCR, The UK Coordinating Committee on Cancer Research; EORTC, European Organization for the Research and Treatment of Cancer; i.v. intravenous; s.c., subcutaneous; vs., versus.
Adapted from Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon α-2b adjuvant therapy of high risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996;14:7–17, with permission.

ECOG E1684 (287 patients with stage IIB or stage III malignant melanoma AJCC stage)

Interferon α-2b, 20 million units/m2/dose i.v., 5 d/wk × 4 wk (total dose/wk, 100 million units/m2),

Favored interferon therapy overall survival, 0.047

followed by

 

Interferon α-2b, 10 million units/m2 s.c., three times/wk for 48 wk (total dose/wk, 30 million units/m2)

Relapse-free survival, p = 0.004

Significant toxicity of interferon observed.

vs.

 

Observation

ECOG 1690 (642 patients)

Interferon α-2b, 20 million units/m2/dose i.v., 5 d/wk × 4 wk (total dose/wk, 100 million units/m2),

Survival benefit for high-dose interferon

·   Relapse-free survival p = 0.05 in both node-positive & node-negative patients

·   greatest in those with 2–3 nodes (p = 0.02)

·   No overall 5-yr survival benefit

followed by

Interferon α-2b, 10 million units/m2 s.c., three times/wk for 48 wk (total dose/wk, 30 million units/m2)

vs.

Low-dose interferon: Interferon α-2b, 3 million units/m2 s.c., three times/wk for 104 wk (total dose/wk, 9 million units/m2)

vs.

Observation

ECOG E 1697 (1,444 patients AJCC stage II A) The aim is to know the impact of interferon on relapse-free survival and overall survival in the adjuvant setting in stage IIA disease

Interferon α-2b, 20 million units/m2/dose i.v., 5 d/wk × 4 wk (total dose/wk, 100 million units/m2),

Ongoing

OR

Observation

UKCCCR Study (1,000 patients AJCC stage II or III)

Interferon α-2a, 3 million units/m2 s.c., three times/wk for 2 yr (total dose/wk, 9 million units/m2),

Ongoing

OR

Observation

EORTC study (18-952) (1,000 patients AJCC stage II or III disease) for interferon in adjuvant setting. The goal is to see the impact of the two lower doses and subcutaneously administered interferon on the disease

Interferon α-2b, 10-million units/m2/dose s.c. 5 d/wk for 4 wk (total dose/wk, 50 million units/m2),

Ongoing

followed by

Interferon α-2b, 10 million units/m2 s.c., three times/wk for 1 yr (total dose/wk, 30 million units/m2),

OR

Interferon α-2b, 5 million units/m2 s.c., three times/wk for 2 yr (total dose/wk, 15 million units/m2)

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Interleukin-2 Therapy for Metastatic Melanoma

IL-2, first identified as a T-cell growth factor in 1976, is produced primarily by T-helper cells. It is a 15-kD glycoprotein and interacts with IL-2 receptors expressed on activated T cells, resulting in proliferation and differentiation of both B and T cells and of cytotoxic cells, and stimulates the cascade of cytokines including various interleukins, interferons, and tumor necrosis factors. The antitumor effects of IL-2 are mediated by its ability to cause proliferation of natural killer cells (NKs), lymphokine-activated killer cells (LAKs), and other cytotoxic cells.

IL-2 Doses and Administration Methods: The U.S. Food and Drug Administration (FDA)–approved dosage for treatment of metastatic melanoma is 600,000 IU per kg administered as a bolus over 15 minutes every 8 hours for a maximum of 14 doses. Following a rest period of about 5 to 9 days, the regimen is repeated if tolerated by the patient. Imaging studies are repeated at the end of two courses, and if tumor responses or disease stabilization is documented, the treatment is repeated, with periodic assessment of disease response. The overall response rate is about 16% and a complete response rate of 6%, and responses have been noted in all the disease sites (15,16). Patients who achieved complete responses had the highest chances of achieving prolonged disease-free survival. Patients with good baseline performance status and chemonaive status were most likely to respond to the high-dose IL-2 treatment.

The toxicity profile of IL-2 is dose, route, and administration dependent. Common toxicity profile involves gastrointestinal system (i.e., nausea and vomiting), cardiovascular system (i.e., hypotension or arrhythmias), lung (i.e., hypoxemia and pleural effusions), kidneys (i.e., azotemia), and central nervous system (i.e., confusion and delirium) in addition to fever and fluid retention, most of which are the manifestations of the capillary leak syndrome. Toxicity is accentuated in patients with baseline pulmonary, cardiac, and metabolic disease. Highly skilled nursing and selection of the right patients for high-dose IL-2 have significantly reduced mortality in patients treated with high-dose IL-2. Because high-dose IL-2 therapy causes significant toxicity, it is also administered either subcutaneously or as a continuous intravenous infusion at 9 to 18 million IU/m2/day for 4 to 5 days, and dosages up to 24 million IU/m2/day in patients not eligible for high dose of IL-2. Although total response rates as high as 16.8% have been reported, complete responses are lower than those reported with high-dose IL-2.

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Combination IL-2 regimens: Preclinical data have suggested synergistic immunologic effects of combining IL-2 with interferon-α and chemotherapeutic agents. These observations have resulted in combinations of IL-2 and interferons that did not show a significant advantage in in vivo studies. Concurrent or sequential combination of chemotherapeutic agents with IL-2 and/or interferon-α (biochemotherapy) produces less toxicity than high-dose IL-2 and shows mixed results, with overall responses ranging from 25.3% to 50% (17). Presently, the use of biochemotherapy is experimental until the final results of a large intergroup study comparing biochemotherapy and chemotherapy in metastatic melanoma are reported.

CONCLUSIONS

  • High-dose interferon remains the most active adjuvant agent evaluated to date for high-risk melanoma.
  • It prolongs the relapse-free survival, but its impact on overall survival is less clear.

A summary of the management options of melanoma in advanced tumor stage is found in Table 22.13. Chemotherapy agents and their response rates in metastatic melanoma are listed in Table 22.14. Combination chemotherapy in metastatic melanoma is described in Table 22.15.

TABLE 22.13. Management Options

Management

Metastatic site

Comments

Combination chemotherapy

Systemic metastasis

Palliative in nature, dacarbazine is the drug of choice

Surgical resection

Brain, soft tissue, lung, or liver

Isolated single legion

Radiation therapy

Brain, bone, or symptomatic systemic metastasis

Treatment of symptomatic lesions

Combination chemotherapy + biologic therapy (interleukin-2 and/or interferon α)

Systemic metastatic disease

Promising and effective. Regression of visceral metastasis is seen with possible survival advantage

Immunotherapies

Systemic metastatic disease
Experimental

Experimental

TABLE 22.14. Chemotherapy Agents and Response Rates

Chemotherapeutic agent

Response rates (%)

DTIC, dacarbazine.

Dacarbazine

15–25

Temozolomide (DTIC analog)

21

Nitrosoureas

10–20

Cisplatin

Carboplatin

Vinca alkaloids

15–25

Vincristine

Vinblastine

Vindesine

Taxoids

18

Paclitaxel

Docetaxel

Piritrexim

23

TABLE 22.15. Description of Chemotherapy Regimens

Chemotherapy regimens

Treatment description

Response rates (%)

* From Del Prete SA, Maurer LH, O'Donnell I, et al. Combination chemotherapy with cisplatin, carmustine, dacarbazine, and tamoxifen in metastatic melanoma. Cancer Treat Rep 1984;68: 1403–1405, with permission.
† From Legha SS, Ring S, Papadopoulos N, et al. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer 1989;64:2024–2029.

CBDT, the “Dartmouth regimen”*

Cisplatin, 25 mg/m2/d i.v. for 3 d, d 1–3 (total dose/cycle, 75 mg/m2)

19–55

Carmustine, 150 mg/m2 i.v. d 1 on every odd-numbered cycle (i.e., every 43 d) (total dose every two cycles, 150 mg/m2)

Dacarbazine, 220 mg/m2/d i.v. for 3 d, d 1–3 (total dose/cycle, 660 mg/m2)

Tamoxifen, 10 mg twice daily PO during the therapy

Cycle repeated every 21 d

CVD (MD Anderson Cancer Center)†

Cisplatin, 20 mg/m2/d i.v. for 4 d, d 2–5 (total dose/cycle, 80 mg/m2)

 

Vinblastine, 1.6 mg/m2/d i.v. for 5 d, d 1–5 (total dose/cycle, 8 mg/m2)

Dacarbazine, 800 mg/m2 i.v. on d 1 (total dose/cycle, 800 mg/m2)

Cycle repeats every 21 d

A recent phase III multicenter randomized trial of dacarbazine alone versus the Dartmouth regimen (i.e., cisplatin, carmustine, dacarbazine, and tamoxifen) in patients with metastatic melanoma failed to show a statistical difference in survival or tumor response in patients with melanoma (EORTC study) (18).

Combination of Chemotherapy Regimen and Biologic Therapy (Biochemotherapy) Rationale:

  • Anticancer effects of the combination therapy are additive or synergistic
  • There are different mechanisms of action for different regimens
  • Nonoverlapping toxicity
  • No cross resistance
  • There is a suggestion that biologic agents may produce long-term survivals.

Combination chemotherapy with biologic agents is described in Table 22.16.

TABLE 22.16. Combination Chemotherapy with Biologic Agents

Treatment

Response rates (%)

MIU, million international units; MU, million units.

Dacarbazine, 1,000 mg/m2 as a continuous infusion over 24 h (total dose/cycle, 1,000 mg/m2) Recombinant interleukin-2, administered i.v. over 30 min on an outpatient basis on days 15–19 and d 22–26. The dose of interleukin-2 was 24 MIU/m2 for 10 doses, d 1–5 and 8–12 (total dose/cycle, 240 MIU/m2) Dacarbazine was repeated once every 28 d and supportive treatment given during this protocol

22

Dacarbazine, 200 mg/m2 i.v. for 5 d, start every wk 4 Interferon α-2b, 15 MU/m2 i.v. daily for 5 d/wk for 3 wk, and thereafter, 10 MU/m2 s.c. 3 times/wk. Cycle repeats every 28 d

53

Cisplatin, 100 mg/m2 i.v. on d 1 (total dose/cycle, 100 mg/m2) Interferon α-2a, 10 MU/d s.c. on d 1–5 (total dose/cycle, 50 MU) Interleukin-2 given as continuous infusion for 6 d (d 3–8) in a decrescendo schedule, starting on d 3 with 18 MU/m2 every 6 h, followed by 18 MU/m2 every 12 h, 18 MU/m2 every 24 h, and a maintenance dose of 4.5 MU/m2 every 24 h for 72 h (total dose/cycle, 139.5 MU/m2). Cycle repeats every 28 d

33 (overall response rate)

CVD regimen

64 (overall response rate)

Cisplatin, 20 mg/m2/d i.v. for 4 d, d 2–5 (total dose/cycle, 80 mg/m2) Vinblastine, 1.6 mg/m2/d i.v. for 5 d, d 1–5 (total dose/cycle, 8 mg/m2) Dacarbazine, 800 mg/m2 i.v. on d 1 (total dose/cycle, 8 mg/m2)

 

PLUS

Interleukin-2, 9 million units/m2/d continuous i.v. infusion for 4 d, d 6–9 (total dose/cycle, 36 million units/m2) Interferon α, 5 million units/m2/dose s.c. for 5 d, d 6–10 (total dose/cycle, 25 million units/m2) Note: The therapy schedule with the biologic agents either immediately precedes or follows the CVD regimen. Cycle repeats every 21 d

Cisplatin, 25 mg/m2 i.v. 2-h infusion on d 1–3 and 22–25 (total dose/cycle, 175 mg/m2) Carmustine, 150 mg/m2 i.v. 1-h infusion on d 1 (total dose/cycle, 150 mg/m2) Dacarbazine, 220 mg/m2 i.v. 2-h infusion on d 1–3 and 22–25 (total dose/cycle, 1,540 mg/m2) Tamoxifen, 10-mg tablet PO b.i.d. for 6 wk and begin on d 1 Interleukin-2, 1.5 million units/m2 administered i.v. every 8 h, starting d 4 for 15 doses, d 4–8 and 17–21 (total dose/cycle, 45 million units/m2)

55

PLUS

Interferon α-2b, 6 million units/m2/d s.c. for 10 d, d 4–8 and 17–21 (total dose/cycle, 60 million units/m2). Cycle repeats every 6 wk

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Vaccine Therapy in Malignant Melanoma

Immunization principally involves recognition of tumor-specific peptide by cytotoxic T cells when presented by antigen-presenting cells bound to major histocompatibility complex (MHC) molecules. A number of tumor-associated peptide antigens are purified and either administered intradermally with an immune adjuvant (19) or the peptide is “pulsed” onto

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autologous antigen-presenting cells, and the combination is injected intradermally (20). DiFronzo et al. (21) have used polyvalent melanoma vaccine derived from the melanoma cell cultures in patients with AJCC stage II melanoma and have reported enhanced humoral immune response to correlate with improved disease-free survival and overall survival. The seminal observation that heat-shock proteins isolated from cancer cells of mice and rats

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elicited specific immunity to the cancers from which they were derived led to the discovery that heat-shock proteins are associated with peptides, including antigenic tumor-specific peptides, and elicit potent tumor-specific T-cell immunity when injected back. Preliminary phase I and II studies of heat-shock proteins purified from the autologous melanoma tumors in humans have shown clinically relevant significant tumor-specific immune responses (22). A multiinstitutional phase III study is ongoing to elucidate the clinical significance of heat-shock protein vaccine derived from the autologous tumor cells. Other approaches include gene therapy for appropriate peptide expression in the antigen-presenting cells, which then process the peptide intracellularly and bind tightly to the appropriate human leukocyte antigen (HLA) molecule for presentation to cytotoxic T cells.

Some of the melanoma-associated antigen epitopes are listed in Table 22.17. Various studies are in progress, and final results are awaited.

TABLE 22.17. Melanoma-associated Antigen Epitopes

Antigen

HLA restriction

Cellular location

MAGE-1

A1/Cw 1601

Cytoplasm

MAGE-3

A1/A2

Cytoplasm

MART1/Mela-A

A2

Cytoplasm

Tyrosinase

A2/A24

Melanosomal

NONMELANOMA SKIN CANCER

There are two major types of nonmelanoma skin cancers: basal cell carcinoma and squamous cell carcinoma. Together they account for nearly one third of all the cancers in the United States.

Basal Cell Carcinoma

  • Basal cell carcinoma is the most common cancer in the U.S. white population.
  • It accounts for 77% of 77,000 new cases of nonmelanoma skin cancers seen in the United States.

Common Clinical Presentations of Basal Cell Carcinoma Include the Following:

  • Shiny skin, colored pink, with translucent papule with telangiectasia
  • Nodular variant consists of nodule with central depression and rolled margins and may bleed from trauma. Usual location is head and neck area
  • Pigmented basal cell carcinoma: Nodular with brown to black pigment.
  • Sclerosing or morphea-type basal cell carcinoma: Yellowish, infiltrated, with indistinct borders, may not be diagnosed for a long time. Mohs surgery may be appropriate for treatment.
  • Other less common presentations include hyperkeratotic type carcinoma: Usually involves head and neck area, exhibits sessile growth on the lower trunk, is multicentric on face with ulcer and scar tissues, and is of the giant exophytic type and the cystic type that presents as a blue–gray nodule on the face.

Squamous Cell Carcinoma

Squamous Cell Carcinoma Involving the Skin has the Following Characteristics:

  • Usually found in elderly white men with sun-damaged skin
  • Common sites include back of the hand, forearm, face, and neck; single or multiple lesions
  • Firm, indurated, expanding nodule, often at the site of actinic keratosis
  • The nodule may be ulcerated, and regional lymph nodes may be enlarged.

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Squamous Cell Carcinoma of a Mucocutaneous Site:

  • Elderly men with chronic history of smoking, alcohol use, or chewing tobacco or betel nut
  • Common sites include mouth and lower lip
  • Lesions usually start as an erosion or a nodule that ulcerates.

Other Sites Include the Following:

  • Sole of the foot, verrucous form
  • Male genitalia: human papillomavirus (HPV) related, underlying condylomata of Buschke– Lowenstein (see Table 22.18).

TABLE 22.18. Premalignant Lesions of the Epidermis

Actinic keratosis
Chemical keratosis: arsenic, tar, polycyclic aromatic hydrocarbons, thermal keratosis
Radiation dermatitis
Bowen disease
Erythroplasia of Queyrat
Bowenoid papulosis
Epidermodysplasia verruciformis
Leukoplakia
Keratoacanthoma

Table 22.19 lists the comparative features of basal and squamous cell carcinomas of the skin.

TABLE 22.19. Features of Basal and Squamous Cell Carcinomas of Skin

Characteristics

Basal cell carcinoma

Squamous cell carcinoma

Incidence

Most common cancer of the skin in whites

Next most common skin cancer in whites

Cell of origin

Basal cells of epidermis and hair follicles

Epidermal keratinocytes

Site of tumor

Sun-exposed areas of head and neck, ear, and extremities

Sun-exposed areas of head, neck, face, forearm, and dorsum of the hand

Ethnic background

Fair skin

Fair skin

Sun exposure

Continuous cumulative exposure

Continuous cumulative exposure

Male/female ratio

Common in men

Common in men

Growth and prognosis

Slow growing and good prognosis

Slow growing and good prognosis

Mucosal origin

None

Involves lip and mouth

Diagnosis of Nonmelanoma Skin Cancer

History should include duration of the lesion, symptoms like pain/itching, and recent changes of the surface:

  • History of sun exposure, and recreational and occupational history
  • Ethnic background and the type of the skin
  • History of radiation exposure, arsenic exposure, chronic ulcer/burn scar, or osteomyelitis.

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Complete Skin Examination Includes the Following:

  • Examination of scalp, ears, palms, soles, interdigital areas, and mucous membranes.
  • Evaluation of the extent of sun damage to skin (i.e., solar elastosis, scaling, erythema, telangiectasia, and solar lentigines).

The skin should be evaluated for enlargement of the locoregional and distant metastases. Skin biopsy should be performed, either excisional when the tumor is small, or incisional when the tumor is large. A shave biopsy with a scalpel may be used in noduloulcerative, cystic, or superficial type.

Treatment Principles

  • Surgery is the primary mode of treatment.
  • Excision of the tumor with negative margins of approximately 4 to 6 mm is sufficient.
  • The procedure is performed under local anesthesia.
  • Locally draining nodes are examined and removed only if they are enlarged.
  • Plastic surgery may be needed to close the defects produced by excision of the tumor.
  • Mohs surgery: This is a progressive excision technique that allows excision of the tumor until the negative margins are achieved. Mohs micrographic surgery uses the fresh-tissue technique with the use of frozen section and is less time-consuming than the original surgery.

Role of Radiation THERAPY

Radiation therapy delivers x-rays at a total dose of 2,000 to 3,000 cGy that penetrate up to 2 to 5 mm, where most of the basal cell and squamous cell carcinomas infiltrate. The total dose is divided into multiple fractions, usually over 3 to 4 weeks, to reduce side effects (seeTable 22.20).

TABLE 22.20. Radiation Therapy

Radiation therapy in nonmelanoma skin cancer

Advantages

Common side effects

Most skin tumors are radiosensitive

Loss of hair follicles and sweat glands

Indicated for skin cancer in elderly patients who have high risk for surgery and large and bulky tumors

Skin atrophy and telangiectasia

Tumors located on the nose, eye, lip, eyelid, and inner and outer canthi of the eye as well as skin cancer along the embryonal fusion planes

Radiation dermatitis

Cure rate for squamous cell carcinoma and basal cell carcinoma are >90%

Radiation-induced precancerous lesions of the skin

Various other types of treatments are listed in Table 22.21.

TABLE 22.21. Other Types of Treatment

Treatment method

Characteristic features

1.

Curettage and electrodesiccation preceded by a shave biopsy

Advantages

Useful to treat basal cell carcinoma, superficial squamous cell carcinoma, Bowen disease, and keratoacanthoma actinic keratosis Cure rates in selected patients, 77%–97%

Disadvantages

Not suitable for tumors in high-risk areas, histologically aggressive tumors, or morphea-type tumors

2.

Cryotherapy kills tumor cells by freezing Liquid nitrogen (-195.5°C) causes tissue necrosis

Advantages

Suitable for small tumors of the eyelids, nose, chest, back, or morphea-type basal cell carcinoma Simple procedure; no anesthesia necessary

Disadvantages

Cannot be used in patients with Raynaud phenomenon or tumors >3 cm in diameter

3.

Fluorouracil cream, 1% or 5%, applied topically to cover the lesions twice daily for a few weeks. An inflammatory response id desired; if it does not occur, the drug concentration or frequency of applications or treatment duration should be increased. Typical treatment duration is 2–6 wk longer

Advantages

Suitable for basal cell carcinoma on the face and extremities, and on superficial tumors

Disadvantages

Photosensitivity, allergic reactions, and not useful in other cancers of skin. Occlusive dressings may increase the incidence of inflammatory reactions in adjacent normal skin. Porous gauze dressings may be used to cover application sites.

4.

Fluorouracil plus 2,4-dinitrochlorobenzene

Selected cases of Bowen disease and in situ epidermoid cancer.

5.

Combination chemotherapy fluorouracil plus cisplatin

As a palliative treatment in metastatic skin cancer when surgery is not curative.

Other Cancers of the Skin

Merkel cell carcinoma arises from the neoplastic proliferation of the Merkel cells.

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Characteristics of the Merkel Cell:

  • Arises from the neural crest cells and is a member of the amine precursor uptake and decarboxylation (APUD) cell system
  • Situated in the basal layer of the epidermis and hair follicles
  • Important for tactile sensations in lower animals
  • Functions as a mechanoreceptor in humans.

Characteristics of Merkel Cell Tumor:

  • Rare tumor seen in elderly whites with sun-exposure history
  • Involves skin of the head and neck and found less commonly in the extremities and genitals

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  • Presents as intracutaneous bluish, firm, and nontender nodule about 0.5 to 1 cm
  • Histologically, a small round cell tumor, containing neurosecretory cytoplasmic granules
  • Neuron-specific enolasepositive and anticytokeratin antibody, CAM 5.2, positive
  • Differential diagnosis includes small cell carcinoma of lung and lymphoma
  • Early spread by lymphatics and hematogenously to the distant site
  • Surgical excision is the primary treatment, and radiation is used in the adjuvant setting.

Tumors Arising from the Skin Appendages, Pilosebaceous Complex:

  • Hair follicle
  • Sebaceous gland
  • Arrector pili muscle
  • Apocrine sweat gland.

Most of these tumors are benign, and carcinomas are rare.

Significance: Of interest to dermatopathologist.

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