114 Melanoma - Dr. Crutchfield

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114 Melanoma | |

|Frank O Nestle |

|Helmut Kerl |

|Key features |

|Melanoma is a malignant tumor arising from melanocytes |

|Melanoma has been increasing in incidence and mortality in recent decades |

|Many deaths will occur at a younger age than for other solid tumors |

|Early detection is an important factor in melanoma management |

|Appropriate surgical treatment of low-risk melanoma (1 cm in diameter. Histologically, elements of a classic |

|benign blue nevus are associated with nodular areas of atypical spindle-shaped and bipolar dendritic melanocytes, mitotic |

|figures, necrosis, and melanophages35. The clinical course is characterized by a high rate of recurrence and metastasis. |

|Desmoplastic/Spindled/Neurotropic melanoma |

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| |Figure 114.18 Melanoma in association with blue nevus (malignant blue nevus). Satellite metastases |

| |at the periphery. |

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| |Figure 114.19 Histopathology of desmoplastic malignant melanoma. A Loosely textured spindle cells in|

| |focally fibroblastic stroma. In the epidermis there are changes of melanoma in situ with |

| |proliferation of atypical melanocytes. Note lymphoid infiltrates. B Positive S-100 spindle cells |

| |within the dermis. |

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|While this type of melanoma is histologically defined, the typical clinical lesion consists of a skin-colored, red to |

|hyperpigmented nodule or plaque, mostly on sun-exposed skin. It may arise de novo, but is also the most common melanoma arising |

|in lentigo maligna, ALM and mucosal melanoma. Metastasis is uncommon, but the tumor is highly infiltrative and thus, locally |

|aggressive with recurrence after incomplete excision. Deep tissue samples are necessary to establish the diagnosis (Fig. 114.19)|

|as superficial portions of the tumor show subtle or nondiagnostic findings which may be mistaken for fibrosis of a scar or other|

|spindle cell neoplasms. |

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| |Figure 114.20 Ciliary body melanoma. |

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|Clear Cell Sarcoma: Melanoma of Soft Parts |

|Clear cell sarcoma most often presents on the distal extremities of adolescents and young adults. Several features point to |

|melanocytic derivation (expression of HMB45, S-100 protein and melanosomes on electron microscopy), but clear cell sarcoma and |

|cutaneous melanoma may be two distinct clinicopathological entities36. The tumors usually arise in association with tendons and |

|aponeuroses. The tumor is composed of nests and fascicles of oval to spindled cells with vesicular nuclei, basophilic nucleoli, |

|and eosinophilic to clear cytoplasm. Multinucleated giant cells and melanin can be frequently demonstrated. Upon incomplete |

|excision, local recurrence and metastasis may ensue. |

|Animal-type Melanoma |

|Animal type melanoma is characterized by nodules and fascicles of epithelioid melanocytes with pleomorphic nuclei and striking |

|hyperpigmentation, dendritic cells, numerous melanophages and sometimes an inflammatory infiltrate of lymphocytes37. Clinically,|

|blue to jet black plaques or nodules have been described. The prognostic features are not well known; metastases have been |

|observed in several patients. It is so named because it resembles melanocytic neoplasms with similar morphological features seen|

|in gray horses and laboratory animals. |

|Ocular Melanoma |

|Primary ocular melanomas, which are very rare (5% of all melanomas), can be divided into conjunctival melanomas and uveal |

|melanomas (iris-, choroidal- and ciliary-body melanomas) (Fig. 114.20). Little is known about the pathogenesis of these tumors. |

|Patients with dysplastic nevus syndrome have an increased number of conjunctival and uveal nevi. Although the true association |

|between dysplastic nevus syndrome and ocular melanoma is controversial, it has been suggested that patients with ocular melanoma|

|have an increased risk for cutaneous melanoma. Patients with type I neurofibromatosis and melanosis oculi (nevus of Ota) may |

|also be at higher risk for uveal melanoma. The prognostic features and the treatment of ocular melanoma differ from cutaneous |

|tumors38. |

|Mucosal Melanoma |

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|Table 114-3. Melanocytic lesions that simulate melanomas clinically and/or histopathologically39. |


|Acral nevi |

|Ancient nevi |

|Black (hypermelanotic) nevi |

|Blue nevi and variants |

|Combined nevi |

|Congenital nevi biopsied shortly after birth |

|Deep penetrating nevus |

|Dysplastic (Clark's) nevi |

|Halo nevi |

|Hyperplasia of melanocytes in sun-damaged skin or in the epidermis |

|Melanocytic proliferation over some benign neoplasms* |

|Longitudinal melanonychia |

|Melanosis of mucosal regions* |

|Nevi exposed to UV radiation |

|Nevi in genital regions (including milk-line nevi and flexural nevi) |

|'Nevus sur nevus' (Nevus on nevus) |

|Pigmented streaks in melanoma scars* |

|Proliferating nodules in giant congenital nevi in newborns |

|Recurrent (persistent) nevi |

|Reticulated (ink-spot) lentigo* |

|Spitz nevi and variants |

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| |*These are not melanocytic diseases strictu sensu. |

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|Melanomas may occur in the mouth, nasopharynx, larynx, vagina and anus. These are rare, but tumors tend to be advanced, perhaps |

|because early detection is difficult. |


|A variety of conditions may simulate malignant melanoma either clinically, histopathologically or both. Awareness of these |

|simulators is of great practical importance to avoid over-diagnosis of melanoma39. Tables 114.3 and 114.4 list several |

|melanocytic and non-melanocytic lesions that can mimic malignant melanomas and which should be included in the differential |

|diagnosis. |


|During pregnancy levels of melanocyte-stimulating hormones are elevated. Increased pigmentation occurs in some patients. More |

|than 10% of women experience darkening of melanocytic nevi in the first 3 months of pregnancy40. However, an association between|

|hormonal changes during pregnancy and development of melanoma or worsening of the prognosis of an existing melanoma has not been|

|demonstrated41. Transplacental metastases may arise in pregnant women with melanoma. Surgery with local anesthesia is the |

|treatment of choice in stage I or II melanoma patients (see Table 114.8). In more advanced stages discussions with the patient |

|of the advantages and disadvantages of possible termination of the pregnancy is recommended. There have been no studies |

|demonstrating an adverse effect of hormonal contraception on melanoma development42. Due to the presence of estrogen receptors |

|on a certain percentage of melanomas, alternative forms of contraception are recommended in women after excision of thick tumors|

|(>1.5 mm) with increased risk of recurrence41. In women with a history of high risk melanoma it may be reasonable to wait 2 |

|years after diagnosis before becoming pregnant, because two-thirds of recurrences occur within this time period. |


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|Table 114-4. Non-melanocytic simulators of melanoma39. |


|Paget's disease |

|Extramammary Paget's disease |

|Pigmented epidermotropic metastasis of breast carcinoma |

|Epidermotropic neuroendocrine carcinoma |

|Bowen's disease (pagetoid or pigmented) |

|Pagetoid reticulosis |

|'Clear-cell' artefacts around keratinocytes |

|Complete regression of skin tumors other than malignant melanoma (e.g., lichen planus-like keratosis, basal cell |

|carcinoma) |

|Pigmented basal cell carcinoma |

|Pigmented actinic keratosis |

|Dermatofibroma |

|Seborrheic keratosis |

|Pigmented poroma and pigmented porocarcinoma |

|Pigmented pilomatrixoma |

|Subungual hematoma |

|Black heel (hemorrhage in stratum corneum caused by trauma) (Fig. 114.21) |

|Pyogenic granuloma |

|Tinea nigra |

|Thrombosed hemangioma |

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| |Figure 114.21 Black heel. Traumatically induced subcorneal hematoma simulating acral melanoma. |

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|Table 114-5. Dermatoscopic criteria and their corresponding histopathological features. |


|Criterion |Morphological definition |Associated histopathological changes|Diagnosis |

|Pigment network |Network of brownish lines over a |Pigmented rete ridges |Melanocytic lesion |

| |diffuse tan background | | |

|Typical network |Brown pigmented, regularly meshed |Regular and elongated rete ridges |Benign melanocytic |

| |and narrowly spaced network | |lesion |

|Atypical network |Black, brown, or gray network with |Irregular and broadened rete ridges |Melanoma |

| |irregular meshes and thick lines | | |

|Dots/globules |Black, brown, and/or gray round to |Pigment aggregates within stratum |If regular: benign |

| |oval, variously sized structures |corneum, epidermis, dermo-epidermal |melanocytic lesion; If|

| |regularly or irregularly distributed|junction, or papillary dermis |irregular: melanoma |

| |within the lesion | | |

|Streaks |Irregular, linear structures not |Confluent junctional nests of |Melanoma |

| |clearly combined with pigment |melanocytes | |

| |network lines at the margins | | |

|Blue-whitish veil |Irregular, confluent, gray-blue to |Acanthotic epidermis with focal |Melanoma |

| |whitish-blue diffuse pigmentation |hypergranulosis above sheets of | |

| | |heavily pigmented melanocytes in the| |

| | |dermis | |

|Blotches |Black, brown, and/or gray pigmented |Hyperpigmentation throughout the |If regular: benign |

| |areas with regular or irregular |epidermis and/or upper dermis |melanocytic lesion; if|

| |shape/distribution | |irregular: melanoma |

|Regression |White (scar-like) areas, blue |Thickened papillary dermis with |Melanoma |

|structures |(pepper-like) areas, or combinations|fibrosis and/or variable amounts of | |

| |of both |melanophages | |

|Milia-like cysts |White-yellowish, roundish dots |Intraepidermal horn globules, also |Seborrheic keratosis |

| | |called horn pseudocysts | |

|Comedo-like |Brown-yellowish, round to oval or |Keratin plugs situated within |Seborrheic keratosis |

|openings |even irregularly shaped, sharply |dilated follicular openings | |

| |circumscribed structures | | |

|Leaf-like areas |Brown-gray to gray-black patches |Pigmented, solid aggregations of |Basal cell carcinoma |

| |revealing a leaflike configuration |basaloid cells in the papillary | |

| | |dermis | |

|Red-blue lacunas |Sharply demarcated, roundish to oval|Dilated vascular spaces situated in |Vascular lesion |

| |areas with a reddish, red-bluish, or|the upper dermis | |

| |red-black coloration | | |

|Vascular structures|Comma-like vessels |  |Benign melanocytic |

| |Arborizing vessels | |lesion |

| |Hairpin vessels | |Basal cell carcinoma |

| |Dotted or irregular vessels | |Seborrheic keratosis |

| | | |Melanoma |

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| |With permission from Argenziano & Soyer46, Lancet Oncology 2:443-9. © 2001 Elsevier. |

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|Childhood melanomas are extremely rare. Between 1 and 4% of melanoma cases occur in patients younger than 20 years of age, and |

|0.3% are younger than 14 years43. Tumors may arise de novo or in association with congenital melanocytic nevi. Children with |

|xeroderma pigmentosum, inherited or acquired immunodeficiencies or a family history of melanoma have an increased risk of |

|melanoma development. Histologically, these tumors may resemble those of adults, but small cell melanomas and melanomas with |

|features of Spitz tumor are reported44. The diagnosis is difficult because the clinical and histological distinction is often |

|subtle. Of special importance is the differentiation of melanoma from Spitz nevi with atypical features. Overall survival and |

|prognosis seems to be stage dependent and similar to adults45. Treatment follows the same rationale as in adults with the aim of|

|early detection and appropriate resection of primary melanoma. |


|Most melanocytic lesions of the skin can be correctly diagnosed based on unaided clinical observation. That said, certain |

|melanocytic and non-melanocytic tumors may prove to be diagnostically challenging. |

|Dermatoscopy, also known as skin surface microscopy or epiluminescence microscopy (ELM), is a helpful noninvasive tool in this |

|setting46. For dermatoscopic examination the skin lesion is covered with mineral oil, alcohol or even water, and a hand-held |

|lens, stereomicroscope, camera or digital imaging system is used to inspect it. The magnifications of these instruments range |

|from sixfold to 100-fold. The most widely used dermatoscope provides a tenfold magnification and is sufficient for routine |

|assessment of pigmented skin lesions. The fluid placed on the lesion eliminates surface reflection and renders the cornified |

|layer translucent, so that morphologic structures within the epidermis, the dermo-epidermal junction, and the superficial dermis|

|can be better visualized. The most important practical application for dermatoscopy is differentiation of the early stages of |

|melanoma in situ and melanoma from benign lesions. Differentiation of melanocytic tumors in general from non-melanocytic |

|pigmented skin lesions such as seborrheic keratosis, pigmented basal cell carcinoma and vascular proliferations is also |

|possible. |

|A crucial aspect of dermatoscopy is the observation of the pigment-network in melanocytic tumors, which histologically |

|corresponds to elongated and pigmented rete ridges with an increased number of melanocytes in the basal layer. Other structures |

|that can be seen are brown globules, black dots, irregular streaks and the blue-whitish veil. Table 114.5 lists the |

|dermatoscopic criteria and their corresponding histopathological features. |

|The clinical application of dermatoscopy requires training and experience. Various steps can be used. The approach of pattern |

|analysis (Table 114.5) correlates individual criteria with each other and puts them into the context of a pattern that is |

|typical for the specific pathology of a lesion (Fig. 114.22). Other diagnostic approaches, including the ABCD rule47, Menzies |

|method48 and the seven-point checklist49, represent advances in dermatoscopic diagnosis in terms of sensitivity and specificity.|

|Clinical examination allows a correct diagnosis in 65 to 80% of melanomas, based on physician experience, whereas the proportion|

|of correct diagnoses based on dermatoscopic observation ranges from 70 to 95% and depends on training50. |

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| |Figure 114.22 Dermatoscopy. This pair of images from an invasive malignant melanoma illustrates the |

| |clinical pictures (A) and the same lesion viewed with dermatoscopy (B). Note the multicomponent |

| |pattern with an atypical pigment network, black dots, irregular streaks, focally a blue-whitish |

| |veiland a white regression zone with hairpin vessels. All these dermatoscopic criteria are |

| |suggestive of a melanoma. |

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|Dermoscopy is also useful in follow-up examinations of pigmented skin tumors to document morphological changes including growth |

|and/or alterations in color. This approach is especially important for monitoring patients, who have many atypical melanocytic |

|nevi or the familial dysplastic nevus syndrome. Teledermatoscopy, the combined use of dermatoscopy and telemedicine |

|technologies, enables general practitioners and specialists to exchange digital image information. It has been shown that |

|excellent diagnostic results can be achieved in this manner. |

|Computer-assisted diagnosis based on systems analyzing symmetry and color are available. Dermatoscopy has opened a new dimension|

|in determining clinical morphology. The method is a useful addition to the clinical evaluation of pigmented skin tumors by |

|improving the diagnostic accuracy and allowing a more reliable preoperative assessment of malignant melanoma. |


|Since the basic histologic criteria for melanoma are the same at all anatomic sites, it has been proposed that the |

|classification of malignant melanoma into distinct histopathologic subtypes should be omitted51. The criteria listed in Table |

|114.6 overlap variably in individual tumors but generally enable distinction of melanoma from melanocytic nevi. |

|It has been proposed that tumor progression in melanoma exhibits two patterns, which are correlated with prognosis52. The first |

|is the horizontal (radial) growth pattern, characterized by intraepidermal centrifugal spread of neoplastic melanocytes and |

|infiltration of the papillary dermis as single cells or small nests. In the vertical growth phase, large dermal nodules with |

|melanocytes that differ cytologically from the intraepidermal cells are found. It has been further postulated, that the |

|horizontal growth phase lacks metastatic potential even in the presence of dermal invasion, whereas the vertical growth phase |

|correlates with the capacity for metastasis. |

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|Table 114-6. Criteria for histopathologic diagnosis of malignant melanoma. |


|Architectural pattern |

|Asymmetry |

|Poor circumscription of intraepidermal melanocytic component |

|Silhouette of tumor base uneven (except in nevoid melanoma) |

|No maturation of melanocytes with progressive descent into the dermis |

|Nests of melanocytes within the epidermis not equidistant from one another |

|Nests of melanocytes vary in size and shape |

|Some nests of melanocytes become confluent |

|Scatter of melanocytes above the dermo-epidermal junction |

|Melanocytes arranged as solitary units predominate over nests within the epidermis |

|Melanocytes in some nests are not cohesive |

|Melanocytes extend down adnexal epithelium |

|Sheets of melanocytes within the dermis |

|Nests at base of lesions occasionally large |

|Cytomorphology |

|Atypical melanocytes (with pleomorphic nuclei) |

|Mitotic figures |

|Necrotic melanocytes |

|Other features |

|Signs of regression |

|Actinic elastosis |

|Melanin is not distributed in uniform fashion |

|Plasma cells at base of the lesion |

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| |Adapted from Ackerman et al51. |

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|Early diagnosis and accurate identification of malignant melanoma is crucial in order to remove lesions at a stage when complete|

|cure can still be achieved. The majority of melanomas evolve in a similar way. The earliest histological changes ('melanoma in |

|situ') are characterized by increased numbers of individually disposed atypical melanocytes in the basal layer (Fig. 114.23). |

|Some melanocytes, singly or in nests, are scattered higher in the epidermis and often reach the granular layer (pagetoid |

|spread)53. After a variable period of time, neoplastic melanocytes invade the papillary dermis, either as coalescent nests or as|

|multiple single cells. |

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| |Figure 114.23 Pathology of melanoma in situ. Increased number of melanocytes with atypical nuclei |

| |not only in the basal zone, but also at the upper levels of the epidermis. |

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| |Figure 114.24 Pathology of melanoma. Pagetoid melanocytes organized as solitary units and nests |

| |varying in size and shape are present throughout the entire epidermis. Neoplastic melanocytes extend|

| |into the dermis. Absence of maturation at deeper levels of the dermis. |

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|A classic melanoma (Fig. 114.24)51,54 is asymmetrical, poorly circumscribed and characterized by nests of melanocytes within the|

|epidermis that are not equidistant from one another, vary in size and shape, and have become confluent in foci. Melanocytes |

|disposed as solitary units within the epidermis predominate over nests. Some solitary melanocytes and nests of melanocytes are |

|present well above the dermo-epidermal junction, at times extending into the upper epidermis, even the cornified layer. One |

|element of this histologic asymmetry is the observation of these intraepidermal changes away from the invasive intradermal |

|component. Similar findings are present in the adnexal epithelium of pilosebaceous units and eccrine ducts. Within the dermis, |

|nests of melanocytes do not become smaller with progressive descent (absence of maturation). In parallel, nuclei of melanocytes |

|do not become smaller. |

|Nests of melanocytes within the dermis also vary in size and shape and become confluent, sometimes forming sheets of cells. The |

|base of the neoplasm is uneven. Melanin is sometimes more plentiful at the base than at the surface of the neoplasm. Frequently,|

|an infiltrate of lymphocytes can be observed. The neoplastic melanocytes show a wide spectrum of cytomorphological features |

|including spindled, pagetoid, small and large round-shaped, polygonal, multinucleate and dendritic characteristics. Certain |

|cytological features of the melanocytes are more common in particular anatomical sites than in others. For example, the finding |

|of increased numbers of intraepidermal atypical melanocytes with elongated branching dendritic processes are a very helpful |

|diagnostic sign of early melanomas on palms and soles. |

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| |Figure 114.25 Pathology of melanoma in situ on sun-exposed surfaces. Atypical melanocytes both |

| |singly and in small nests within the epidermis and along the follicular epithelium. |

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|Identifying atypia of melanocytes may be quite subjective. Generally, atypia is defined by nuclear features including variable |

|nuclear size, shape and basophilia. Even in highly anaplastic tumors, the intranuclear pseudoinclusions typical of benign |

|melanocytic tumors, may be identified. Mitotic figures in the dermal component of benign melanocytic tumors are distinctly |

|uncommon. In melanoma, atypical mitotic forms may be observed in addition to more typical ones with tripolar and other bizarre |

|configurations. The absence of mitotic figures in the dermal component of a melanocytic tumor does not exclude the diagnosis of |

|melanoma. |

|LMM differs from the stereotypical melanoma by its presence on sun-damaged skin of older patients, and the tendency to have |

|little pagetoid spread within the epidermis. The atypical melanocytes are commonly present along the epithelium of adnexal |

|structures especially along the external root sheath of hair follicles (Fig. 114.25). The invasive component is more often |

|composed of spindle cells. Desmoplastic stromal change and neurotropism of tumor cells are common findings. Epidermal atrophy |

|and signs of solar elastosis can be observed in the upper dermis. |

|ALM often shows a proliferation of atypical melanocytes within the basal layer of a hyperplastic epidermis. Atypical melanocytes|

|are arranged singly and in irregularly shaped nests, at all levels of the epidermis ('pagetoid scatter') with predominance of |

|single cells. In the cornified layer numerous melanocytes and melanin granules are usually found in a diffusely scattered |

|distribution. Notably, melanomas in volar and subungual sites display strikingly dendritic melanocytes (Fig. 114.26). |

|Microstaging |

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| |Figure 114.26 Melanoma in situ on the plantar surface of a foot. Atypical melanocytes are scattered |

| |throughout the hyperplastic epidermis including the horny layer. Note dendritic melanocytes. |

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|The Breslow tumor thickness (depth of invasion) is measured in millimeters from the top of the granular cell layer of the |

|epidermis (or base of an ulcer) to the deepest point of tumor penetration using an ocular micrometer (Fig. 114.27). Clark's |

|levels of invasion utilize a stair-step determination: level 1 is confined to the epidermis (in situ); level 2 invades the |

|papillary dermis; level 3 fills the papillary dermis to the junction of the superficial reticular dermis; level 4 invades the |

|reticular dermis; and level 5 invades the fat. In addition to tumor thickness, a number of other histological features including|

|ulceration, Clark's level of invasion54, presence of tumor infiltrating lymphocytes, mitoses/mm2, regression, vascular invasion |

|and microscopic satellites may be associated with an unfavorable prognosis. Several studies of interobserver agreement that |

|compared a variety of microstaging criteria, revealed that tumor thickness and ulceration were more reliable than Clark's level |

|of invasion, growth pattern (radial/vertical growth phase) and mitotic index55. Table 114.7 shows a recommendation of the |

|features that should be included in the histopathological report of a malignant melanoma56. |

|Immunohistology |

|A wide range of monoclonal antibodies reactive with melanoma-associated antigens is available. Special stains are not used in |

|routine cases and are mainly employed to confirm derivation of a tumor from melanocytes when this is unclear with H&E stains. |

|Most frequently used and particularly helpful are antisera to S-100 protein and HMB45, which recognizes a pre-melanosomal |

|glycoprotein. The most useful marker in terms of identifying spindled forms of melanoma is S-100, since HMB45 and MART-1 are |

|often negative in spindled melanocytes. Immunohistological markers are not reliable in the differential diagnosis of melanoma |

|from benign melanocytic tumors. |


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|Table 114-7. Histopathological reporting of cutaneous melanoma. |


|Diagnosis |

|Thickness (Breslow depth) |

|Mitoses/mm2 |

|Level of invasion (Clark) |

|Regression, tumor infiltrating lymphocytes, presence of plasma cells |

|Ulceration |

|Vascular invasion |

|Microscopic satellites |

|Associated nevus |

|Margins |

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| |The World Health Organization has recommended notation of radial or vertical growth phase. |

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| |Figure 114.27 Microstaging of malignant melanoma. Breslow's method: measure from the granular layer |

| |of the epidermis to the deepest part of the tumor. |

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|Table 114-8. Proposed stage groupings for cutaneous melanoma. |


|  |Survival (%)* |Clinical staging† |Pathologic staging‡ |

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| |*Approximate five-year survival in percent, modified from Balch et al57. |

| |†Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation |

| |for metastases. By convention, it should be used after complete excision of the primary melanoma |

| |with clinical assessment for regional and distant metastases. |

| |‡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. |

| |#There are no stage III subgroups for clinical staging. |

| |Modified from Balch et al63. |

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| |Figure 114.28 Fifteen-year survival curves comparing different melanoma stages. Survival of |

| |localized melanoma (stage I and II), regional metastases (stage III) and distant metastases (stage |

| |IV) are compared. The numbers in parentheses are patients from the AJCC melanoma staging database |

| |used to calculate the survival rates. The differences between the curves are significant (p 1 mm is|

|usually made. Involvement of regional lymph nodes (stage III) or distant metastases (stage IV) is associated with increasingly |

|worse prognosis. This difference in prognosis is reflected in current staging classifications of melanoma. The American Joint |

|Committee on Cancer (AJCC) staging classification distinguishes localized disease (T1-T4), regional lymph nodes metastases |

|(N1-N3) and distant metastases (M1a-M1c) (Tables 114.8 & 114.9). There has been considerable investigation of clinical and |

|pathological features of melanoma that predict the risk of metastases and survival. A major advance in the ability to stage |

|patients more accurately is provided by a minimally invasive microscopic staging technique: the so-called sentinel node biopsy. |

|This technique has changed our understanding of the natural history of melanoma59,60. Increased ability to detect |

|micrometastasis has caused a significant upward stage migration that has necessitated a revision of older staging |

|classifications. A new tumor-node-metastases (TNM) staging system was introduced by the AJCC in 2000, critically evaluated by |

|the European Union for Research and Treatment of Melanoma group61, and revised in 2001 based on a 17 600 melanoma patient |

|database derived from 13 cancer centers and melanoma cooperative groups (Tables 114.8 & 114.9)57. With the publication of the |

|sixth edition of the AJCC Cancer Staging Manual in 2002 this classification is now in use. |

|The most important modifications are: (1) the noted gradations for tumor thickness are ≤1 mm, 1 to 2 mm, 2 to 4 mm, and >4 mm; |

|(2) the primary determinant of tumor (T) staging is tumor thickness as measured in millimeters. The Clark level of invasion is |

|used only for further defining T1 melanomas; (3) microscopic ulceration has been added as a major prognostic factor of the |

|primary tumor; (4) local recurrence, satellite disease, and in-transit metastases are now all classified together as regional |

|stage III disease because of similar prognosis; (5) size of lymph node as a prognostic factor has been eliminated and replaced |

|with the number of positive nodes; (6) the presence of an elevated serum lactate dehydrogenase (LDH) level is used in the |

|metastasis (M) category; and (7) the site of distant metastases is of importance for prognosis. Furthermore, the intent of the |

|surgical procedure that led to the detection of nodal metastases should be reported, i.e. therapeutic lymphadenectomy, |

|lymphadenectomy for clinically detectable metastatic lymph nodes or either sentinel or elective lymphadenectomy that detected |

|clinically occult metastases. Stage grouping includes clinical and pathologic parameters. Clinical staging requires histological|

|microstaging of the primary melanoma as well as clinical/radiological evaluation for metastases. Pathologic staging includes |

|microstaging of the primary melanoma and pathologic information about regional lymph nodes after selective or complete |

|lymphadenectomy. The revised AJCC staging system includes new prognostic markers and hopefully improves the stratification of |

|patients in future clinical trials. This staging system may not accurately reflect variants of melanoma such as desmoplastic, |

|childhood, mucosal or ocular melanoma. |


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|Table 114-9. Melanoma TNM classification. |


|T classification |Thickness |Ulceration status |

|T1 |≤1.0 mm |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 |> 4.0 mm |a: Without ulceration |

| | |b: With ulceration |

|N classification |Number 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 node(s) |

|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 metastasis |Elevated |

| |

| | |

| |*Micrometastasis 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. |

| |Adapted from Balch et al57. |

|[pic] |

|The prognosis of a patient with melanoma is dependent on its stage at diagnosis (Fig. 114.28). Prognosis for patients with |

|localized melanoma and no nodal or distant metastases is generally good. An overall 5 year survival rate of over 79% for stage |

|I/II disease has been reported62. Clinical variables with prognostic significance in stage I/II disease include tumor thickness,|

|ulceration, sex, age and anatomic site63-65 (Table 114.10). Ulceration is defined as the absence of an intact epidermis |

|overlying a major portion of the primary tumor based on microscopic examination. Women with stage I/II disease tend to have |

|better survival than men. Location of the primary melanoma on the trunk, head or neck portends a poorer prognosis than a |

|location on the extremities. Tumor regression, which can occur in up to 20% of melanomas, has been proposed by some researchers |

|to be of prognostic significance but has not been confirmed by others66. There is evidence that Clark's level, growth phase, |

|tumor-infiltrating lymphocytes and mitotic rate also have prognostic value. However, the applied accuracy of these measurements |

|and the definition of these attributes among pathologists has been questioned in the recent American Academy of Dermatology |

|melanoma guidelines67. |

|UPDATE |Date Added: 25 October 2004 |

|Dr John A. Fisher |

|Metallothionein-overexpression as a prognostic factor in melanoma |

|Although metallothioneins (MTs) are ubiquitous and are known to play a role in the metabolism of heavy metal ions such as |

|copper, cadmium, and zinc, their precise function is yet to be defined. They are small, intracellular proteins that are rich in |

|cysteine, which protect cells against ionizing and ultraviolet radiation, as well as (controversially) conferring resistance to |

|anticancer drugs. Their synthesis is induced by glucorticosteroids, interleukins, interferon-γ, tumor necrosis factor-α and |

|vitamin D3. MT overexpression has been reported to be a useful prognostic sign in certain malignancies, including melanoma and |

|nonmelanoma skin cancers. |

|The authors of this prospective study investigated the role of MT overexpression in melanoma patients in comparison to other |

|factors, as a prognostic factor for progression and survival. |

|Five hundred twenty patients from an original cohort of 760 were evaluated. Measurement end points were the time of detection of|

|lymph node and/or distant metastases, and death due to widespread disease. The 240 patients who dropped out were either lost to |

|follow up or died from other diseases. Of the 520 who were evaluated, men and women were evenly balanced and the median age was |

|57.5 years (mean 56.3). The median observation time was 25 months. Breslow thickness (which varied from in situ to1.9 mm), Clark|

|level, ulceration, site of primary tumor, age and gender were all noted for statistical analysis. |

|The primary monoclonal MT mouse IgG1 antibody E9 was used on routinely fixed and paraffin-embedded tissues. The immunoreactive |

|MT expression in tumor specimens was analyzed visually by two independent observers. The immunohistochemical overexpression of |

|MT was defined as MT reactivity in more than10% of tumor cells. |

|During the 5 years of the study, 45 patients (8.7%) showed disease progression with a median time of 24.0 months (mean 28.7). |

|Thirty of these patients (5.8% of the total group) died due to metastatic disease. None of the patients with a tumor thickness |

|less than 0.75 mm developed metastasis. |

|MT overexpression in the primary melanoma (P1.5 mm depth114. Current evidence does not |

|suggest that ELND should be performed in patients with primary melanoma. |

|Sentinel lymph node biopsy |

|Since in 80% of patients with ELND there is significant morbidity in the absence of microscopic disease. A less traumatic |

|procedure to identify regional metastatic disease was devised based on similar concepts, namely progression of metastatic |

|disease through the lymphatic system before widespread dissemination115. This so-called sentinel lymph node biopsy (SLNB) is |

|based on the concept that the skin involved with melanoma drains to one or more lymph node basins and particularly to one |

|(rarely more) lymph node, the sentinel node, which is the first site of deposition of metastatic cells. The concept and its |

|utility are also based on the ability to accurately identify this node. The sentinel node is identified by intraoperative |

|lymphatic mapping using lymphoscintigraphy and dye injection. Lymphoscintigraphy is performed by injection of 99 mTechnetium |

|sulfur colloids around the tumor site or scar of primary excision. The isotope is transported through the draining lymphatics |

|and phagocytosed by macrophages and concentrated within the sentinel lymph node before draining to other regional lymph nodes. |

|The position of the sentinel node is marked on the skin by a hand-held gamma counter. Additionally, a blue dye is injected |

|around the primary tumor or scar which is also transported through the lymphatics to the sentinel node. The blue dye is helpful |

|in giving visual conformation intraoperatively (Fig 114.30). The 'hot, blue' sentinel node(s) is selectively biopsied through a |

|small incision and examined by serial sectioning using H&E stains combined with immunohistochemistry (S-100, HMB45). If |

|metastatic melanoma is identified, then complete regional lymph node dissection is undertaken. Draining patterns are sometimes |

|difficult to predict, especially on the head, neck and trunk. For example, two sentinel lymph nodes may be identified or the |

|skin may drain into the contralateral site of the original tumor. It is recommended to remove all radioactive nodes116. Since |

|the application of lymphoscintigraphy for SLNB it has been realized that ELND based on classic draining patterns might have led |

|to resection of inappropriate lymphatic basins117. A recent trial comparing SLNB followed by node dissection to ELND showed no |

|difference in survival. |

|page 1807 |

|[pic] |

|page 1808 |

|Training and experience are important in SLNB. SLNB performed with blue dye plus a radiocolloid is more accurate (99.1%) than |

|SLNB performed with blue dye alone (95.2%). Evidence exists that at least 30 SLNBs are required to gain the appropriate skill |

|level118. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. A randomized trial |

|provided further evidence that lymphatic mapping and SLND biopsy accurately reflect the status of the regional nodal basin119. |

|This study also reported a low rate of tumor recurrence (11%) in sentinel node negative patients. In 80% of these cases occult |

|micrometastases were later identified by serial sectioning and appropriate immunohistochemistry using S-100 and HMB45 monoclonal|

|antibodies. The use of RT-PCR to examine sentinel nodes for mRNA of melanoma associated proteins such as tyrosinase or MelanA |

|might increase sensitivity of detection. In one study tyrosinase transcripts were detected in 36-52% of stage I and II melanoma |

|patients with negative sentinel nodes by histopathology alone. Importantly, the recurrence rate was significantly higher in |

|patients with histologically negative sentinel nodes who were found to be positive by RT-PCR than in patients with negative |

|results by both techniques120. Unanswered questions such as the clinical importance of RT-PCR positive sentinel nodes as well as|

|the effect of adjuvant therapy in patients with negative sentinel nodes will hopefully be answered on-going prospective |

|trials121. |

|Based on current data, there are four major reasons to perform SLNB. First, SLNB provides information on subclinical lymph node |

|status with minimal morbidity. As such it is not only a staging tool but provides valuable prognostic information for patients |

|and physicians to guide subsequent treatment decisions. Second, SLNB identifies patients with metastatic lymph nodes for early |

|therapeutic lymph node dissection (see below). Third, SLNB identifies patients who might be candidates for adjuvant therapy with|

|interferon alpha. Fourth, results of SLNB are a stratification criterion to enter more homogeneous patients into adjuvant |

|clinical trials122. |

|From the perspective of staging, SLNB has caused stage migration. This means that detection of microscopic metastases in |

|patients leads to an upgrading to stage III disease. This is recognized in the recent revision of the AJCC TNM classification |

|system (Tables 114.8 & 114.9). The marked diversity in the natural history of stage III melanoma is demonstrated by fivefold |

|differences in 5-year survival rates for defined substages that range from 69% for patients with non-ulcerated melanoma who had |

|a single clinically occult metastases to 13% for patients with an ulcerated melanoma with four or more clinically apparent nodal|

|metastases as detected by therapeutic lymphadenectomy63. These differences are so great that the AJCC recommends that all |

|patients with a primary melanoma >1.0 mm in tumor thickness have nodal staging with sentinel lymphadenectomy before entry into |

|melanoma clinical trials63. |

|The above mentioned reasons have led some investigators to propose SLNB as standard of care121 which is disputed by |

|others67,123,124. Certainly, the use of SLNB in specialized centers in the context of controlled studies may answer important |

|issues relating to melanoma treatment. Whether SLNB represents a clinical standard of care is debatable67,121,123,124. |

|From a therapeutic perspective there is little evidence that early dissection in sentinel node positive patients affords |

|improved survival compared to dissection performed when clinically detectable nodes develop. However, a recent study suggested |

|that further node dissection in patients with positive lymph nodes might be beneficial114. |

|In conclusion, intraoperative lymphatic mapping and SLNB followed by selective complete lymphadenectomy has revolutionized the |

|management of the regional lymph node basin in patients with melanoma. The sentinel node hypothesis has been validated by a |

|multicenter clinical trial showing that SLNB in melanoma can be accurately performed in a uniform manner by multidisciplinary |

|teams. Although the diagnostic and prognostic accuracy of SLNB has been established, demonstration of the therapeutic use of |

|this procedure awaits analysis of survival data from multicenter randomized trials of wide excision alone versus wide excision |

|plus SLNB/complete lymphadenectomy115, as well as trials linking SLNB to adjuvant therapies. |

|Adjuvant therapy |

|The goal of adjuvant therapy is the active suppression of growth of clinically inapparent micrometastases. A major emphasis in |

|adjuvant therapy are patients with resected high risk stage II and III melanoma. Trials have also targeted resected stage IV |

|patients. A number of postsurgical adjuvant approaches have been tested including systemic chemotherapy, immunotherapy using |

|microbial agents such as Bacillus Calmette-Guerin (BCG) or Corynebacterium parvum125-127. None of these approaches were |

|successful in randomized controlled trials117. |

|The current recommendation is to include appropriate patients in well controlled clinical studies to obtain valid data leading |

|to recommendations about future adjuvant therapy. One of the most promising candidates for adjuvant therapy of patients with |

|malignant melanoma are recombinant biological response modifiers, in particular the intensively studied interferon alpha |

|(IFN-α). IFN-α is a type I member of the interferon family of proteins and has pleiotropic functions. These include complex |

|immunoregulatory functions such as induction of MHC class I expression as well as impact on immune effector cells such as the |

|activation of natural killer (NK) cells and the maturation of dendritic cells. Some of its activities may have direct or |

|indirect anti-tumor effects128. Little anti-tumor activity has been demonstrated in metastatic stage IV melanoma, with overall |

|response rates of 10-15%. However, IFN-α has been most widely studied in the adjuvant setting for stage II and III disease. It |

|is important to distinguish high-dose IFN therapy with the aim to reach maximally tolerated dosage (20 MU/m2 intravenously |

|during the induction phase followed by 10 MU/m2 subcutaneously three times per week) from low-dose IFN therapy which is much |

|better tolerated in terms of side effects (typically 3 MU three times per week) (Table 114.12). |

|High-dose IFN has demonstrated an improvement in relapse-free and overall survival compared to controls in two studies (ECOG |

|1684 as well as ECOG 1694) (Table 114.12). However, a beneficial effect on overall survival was not seen in another high-dose |

|IFN study (ECOG 1690). Toxicity in high-dose IFN include constitutional (flu-like) symptoms, neuropsychiatric (depression, |

|suicidal intention), hematologic, and hepatic effects as well as cases of fatal rhabdomyolysis129,130. These toxicities have a |

|major impact on the patient's quality of life, and on the physician's ability to optimally treat the patient and led to dose |

|modifications in two-thirds of the patients in the first month of high-dose IFN. The application of high-dose IFN was questioned|

|especially in Europe due to the inconsistent impact on overall survival and the considerable dose-dependent toxicity131,132. It |

|is possible that recurrence of metastases might have a worse effect on patient's quality of life than high-dose IFN therapy133. |

|The relative importance of the induction component of this treatment regimen is being addressed in an ongoing Intergroup trial |

|for intermediate-risk melanoma134. For low-dose IFN, randomized studies have consistently reported a benefit with regard to |

|relapse free but not overall survival for patients treated with IFN-α compared to untreated controls135,136. The impact on |

|extension of overall survival remains unclear. Currently, the most important question is the efficacy of very toxic high dose |

|therapy compared to lower dose long-term treatment. This will hopefully be answered by the data from the large US-Intergroup |

|high-dose and EORTC intermediate-dose and long-term maintenance therapy trials. |

|Recently, a meta-analysis has been performed of all available IFN-α trial results, largely based on published reports. The |

|endpoints evaluated were disease-free survival and overall survival in approximately 3700 patients included in ten trials137. |

|For disease-free survival, there was clear benefit for IFN-α, but the advantage was less clear for overall survival. There was |

|no statistically significant evidence that the benefit of IFN-α is greater in higher than in lower dose trials. The authors |

|conclude that 'decisions on the use of IFN-α for melanoma will need to be based on considerations such as the relative |

|importance of benefits on disease-free survival compared to overall survival, patient quality of life and financial costs'. |

|Management of Distant Metastases (Stage IV) |

|page 1808 |

|[pic] |

|page 1809 |

| |

|Table 114-12. Completed trials for adjuvant interferon- α2 therapy in melanoma. |


|  |

| | |

| |RFS, relapse-free survival; +, statistically significant; -, statistically insignificant; wk, weeks;|

| |t.i.w., three times per week; MU, million units; IM, intramuscular; IV, intravenous; SC, |

| |subcutaneous; ECOG, Eastern Cooperative Oncology Group; NCCTG, North Central Cancer Treatment Group;|

| |mo, months; HDI, high-dose interferon; LDI, low-dose interferon; GMK, GM2 ganglioside, keyhole |

| |limpet hemocyanin plus OS21 adjuvant; OS, overall survival. |

|[pic] |

|Despite new treatment options, the prognosis of patients with metastatic melanoma has not changed significantly over the last 22|

|years; with survival rates of 6% and median survival of 7.5 months68. The initial site of metastasis determines prognosis. Nodal|

|or gastrointestinal metastases (median survival of 12.5 months; estimated 5-year survival rate 14%) have a better prognosis than|

|pulmonary metastases (median survival of 8.3 months; estimated 5-year survival rate 4%). The worst prognosis is associated with |

|metastases to the liver, brain or bone (median survival of 4.4 months; estimated 5-year survival rate 3%)68. Thus the focus is |

|on palliative therapy with special emphasis on the quality of life of the patient. To enable progress towards new therapeutic |

|approaches in stage IV patients inclusion in controlled clinical trials should be considered and discussed with every patient. |

|There is evidence that patients included in clinical trials have better outcome143. Recent developments with a favorable |

|benefit/side effect profile include oral chemotherapeutic agents and innovative approaches to therapeutic cancer vaccination. It|

|should be also noted that surgery has its place in management of stage IV patients since randomized trials have demonstrated |

|that the value of surgery for local metastatic disease is probably underestimated while the value of extensive surgery and |

|prophylactic surgical procedures is overestimated132. |

|Evaluation of the patient with suspected metastatic disease |

|Evaluation of the patient with suspected metastatic disease is a demanding task both at the level of interaction with the |

|patient and family as well as the extensive work up which is often necessary. It is essential to get an accurate picture of the |

|metastatic burden before considering therapy. Evaluation and necessary diagnostic tests should be guided by an in depth medical |

|history and a thorough physical examination including a whole-body skin examination as well as palpation of the abdomen and the |

|lymph nodes (see above). Possible symptoms related to metastatic disease are listed in Table 114.13. Further staging |

|investigations include a CT scan of the thorax and abdomen including the pelvis, as well as an MRI of the brain. Ultrasound |

|investigation of the abdomen and lymph nodes are optional. At specialized referral centers FDG PET provides an additional method|

|with high sensitivity for detection of metastases (see above). Measuring soluble melanoma serum markers such as S-100 and MIA |

|gives an early indication of progressive disease as well as treatment response in stage IV patients144,145. Further specialized |

|diagnostic tests are performed according to individual symptoms of the patient (Table 114.13). |

|Surgery |

|page 1809 |

|[pic] |

|page 1810 |

| |

|Table 114-13. Symptoms and diagnostic tests for metastatic melanoma. |


|Metastatic site (TNM) |Symptoms |Diagnostic tests* |

|Skin, soft tissue metastasis |Skin-colored to blue/brownish |Biopsy + histology |

|(TxNxM1), in-transit metastasis |patches/nodules, ulceration, bleeding | |

|(TxN2cM0) | | |

|Brain metastasis (TxNxM3) |Headache, nausea, seizures, |MRI scan |

| |depression, visual disturbance, | |

| |numbness, paralysis | |

|Lung metastasis (TxNxM2) |Chest pain, dyspnea, cough, hemoptysis|Chest radiograph, CT scan |

|Gastrointestinal metastasis |Abdominal pain, anemia vomiting, |Liver function tests, fecal occult blood |

|(TxNxM3) |constipation, melena, jaundice |test, ultrasonography, CT scan, |

| | |radiography, endoscopy |

|Bone metastasis (TxNxM3) |Pain, spontaneous fractures |Bone scan |

| | |

| |*Always include thorough medical history and physical investigation as well as complete blood count |

| |and blood chemistry including LDH. Special procedures such as FDG-PET investigation as well as |

| |detection of soluble melanoma markers (e.g. S-100, MIA) are performed at selected melanoma referral |

| |centers for increased sensitivity of metastasis detection as part of controlled studies. |

|[pic] |

| |

|Table 114-14. Treatment options for metastatic melanoma. |


|Metastatic site (TNM) |Treatment choice |

|In-transit metastasis (TxN2cM0) |1st: 5: extremity perfusion* |

| |2nd: radiotherapy, CO2 laser ablation, intralesional IL-2 |

| |3rd: systemic therapy |

|Brain metastasis (TxNxM3) | |

|Single |1st: surgery |

| |2nd: stereotactic radiosurgery |

|Multiple |1st: radiotherapy |

| |2nd: systemic therapy |

|Lung metastasis (TxNxM2) | |

|Single |1st: surgery |

|Multiple |1st: systemic therapy |

|Gastrointestinal metastasis (TxNxM3) | |

|Single |1st: surgery |

|Multiple |1st: systemic therapy |

|Skin, soft tissue metastasis (TxNxM1) | |

|Single |1st: surgery |

|Multiple |1st: systemic therapy |

|Painful bone metastasis (TxNxM3) |1st: radiotherapy |

|Disseminated metastasis (TxNxM3) |1st: systemic therapy +/- surgery, radiotherapy of symptomatic metastasis |

| | |

| |*Should be performed as part of controlled studies. |

| | |

|[pic] |

|Despite the well-known behavior of melanoma to disseminate to various organs, resection of metastases can often provide |

|excellent palliation and in selected patients long-term survival (Table 114.14). Factors that positively influence prognosis are|

|isolated non-visceral metastasis and complete resection with free surgical margins. In certain cases median 5-year survival can |

|even approach up to 35% after surgical treatment. Complete resection of lung metastases can lead to a median survival of 19 |

|months and a 5-year survival of 25%. Patients rarely survive long-term after brain or gastrointestinal metastases, but surgical |

|resection extends median survival to about 10 months in this group with a significant improvement in quality of life146. The |

|combination of cytoreductive surgery, with the goal of resecting clinically evident disease, and immunotherapy is a valuable |

|future approach to management of stage IV patients147. |

|Radiation therapy |

|Radiotherapy for melanoma never gained acceptance due to unfavorable clinical results observed in early studies. Recent evidence|

|indicates that melanoma is not only highly variable in its radiosensitivity but that radioresistance of melanoma might be |

|overcome using large individual dose fractions148. Radiation therapy has been useful in some extensive lentigo malignas (see |

|Chapter 139). Radiotherapy provides effective palliation in symptomatic advanced melanoma (Table 114.14)149. Special indications|

|include pain associated with bone metastases, spinal cord compression, brain metastases and local control of cutaneous disease. |

|Studies do not support the recommendation of adjuvant radiotherapy following resection of regional lymph node metastases in |

|patients with malignant melanoma150. |

|Whole brain radiotherapy combined with surgical resection have been the mainstay of the treatment of cerebral metastases. This |

|approach results in a median survival of about 10 months151. A new development producing at least similar results is |

|stereotactic radiosurgery using either the so-called 'Gamma Knife' or linear accelerator radiosurgical techniques. Radiosurgery |

|has been shown to be effective in metastatic tumors in surgically inaccessible sites such as the brainstem. A benefit of |

|radiosurgery is the virtual absence of perioperative complications and the reduced adverse impact on quality of life compared |

|either to surgery or to whole brain radiotherapy. Long-term complications of radiosurgery are infrequent and primarily relate to|

|failure of local tumor control (10%) and radiation-induced edema or necrosis151. |

|Chemotherapy |

|Over the past four decades cytotoxic chemotherapy, has had a low but reproducible level of activity against metastatic melanoma |

|(Table 114.14). Drugs employed include DTIC/temozolomide, cisplatin[pic], vindesine/vinblastine, BCNU/fotemustine and |

|taxol/taxotere152. Chemotherapeutic treatment of stage IV melanoma has been disappointing and has not had a positive impact on |

|melanoma survival during the last 20 years even though several chemotherapeutic agents have shown activity against melanoma |

|cells in-vitro and in phase I/II clinical trials68. A promising new development is the selection of melanoma chemotherapy |

|according to in vitro chemosensitivity assays153. Recent new developments include oral delivery of the prodrug of a |

|dacarbazine[pic] metabolite: temozolomide[pic], combination chemotherapy as well as combinations of chemotherapy and |

|immunotherapy154. The most widely used single chemotherapeutic agent is dacarbazine[pic] (DTIC). It has shown the greatest |

|effectiveness as a single agent in most trials and was equally effective when combined with IFN-α or tamoxifen155. With DTIC as |

|single agent, an approximately 20% response rate can be achieved with median response duration of 5 to 6 months and complete |

|response rates of 5%156. A novel oral alkylating agent is temozolomide[pic] (a pro-drug of MTIC, the active metabolite of DTIC) |

|with some efficacy in CNS metastasis and equal efficacy to DTIC157,158. Fotemustine is a member of the nitrosourea family and |

|has some efficacy in melanoma including brain metastases159. |

|page 1810 |

|[pic] |

|page 1811 |

|Combination chemotherapy regimens like CVD (cisplatin[pic], vinblastine, DTIC) and BOLD (bleomycin, vincristine, lomustine[pic],|

|DTIC) have induced responses in metastatic lesions typically unresponsive to DTIC alone, including the liver, bone and brain, |

|but have failed to improve overall patient survival. The CBDT (cisplatin[pic], carmustine[pic], DTIC and tamoxifen) or |

|'Dartmouth regimen' has achieved high response rates in earlier trials (up to 55%) but a recent phase III trial did not show a |

|statistical survival benefit compared to DTIC alone160. Therefore DTIC remains the reference standard of chemotherapy in stage |

|IV melanoma. |

|Combination chemo-immunotherapy involves the addition of the biological response modifiers interleukin-2 (IL-2) and IFN-α. These|

|substances have shown modest activity as single agents with response rates between 15-20% but durable responses have been |

|observed especially after IL-2 therapy161. Combination chemotherapy with IFN-α or IL-2 has generally resulted in improved |

|survival but may cause unacceptable levels of myelosuppression162. |

|Biochemotherapy uses combination chemotherapy plus IL-2 and IFN-α. A widely employed combination is cisplatin[pic], vinblastine |

|and DTIC (CVD) IFN-α and IL-2. In phase II trials durable complete remissions have been observed in 10-15% of patients with |

|metastatic melanoma152. In other trials, the combination of IFN-α and IL-2 with cisplatin[pic]163 or cisplatin/DTIC/tamoxifen164|

|did not show significant improvement compared to biochemotherapy. |

|Another approach is chemohormonal therapy using tamoxifen in addition to chemotherapy. Addition of tamoxifen has not been shown |

|to improve survival compared to single agent/combination chemotherapy alone160,165. |

|In conclusion, a survival benefit from chemotherapy in combination with immunotherapy or hormonal therapy has not been shown in |

|metastatic melanoma patients. Patients should therefore be included in randomized controlled trials to hopefully discover new, |

|more effective protocols. Some long term survivors have been reported with high dose IL-2-based regimens, but prospective |

|randomized phase III trials are necessary to establish efficacy156. |

|Immunotherapy |

|Immunotherapy builds on the concept that the immune system is able to fight cancer166. Melanoma is one of the prototypic |

|immunogenic cancers12. Therapeutic effect might be achieved passively by infusing effectors of the immune system such as |

|cytokines, killer cells or antibodies. On the other hand active immunization tries to stimulate the patients own immune effector|

|cells in response to an injected vaccine (antigen plus adjuvant). |

|Treatment of advanced melanoma with single cytokines such as IFN-α or IL-2 has been disappointing, even though high-dose IL-2 |

|might lead to long-term remissions167. Antibody (ab)-based therapies, including the use of anti-ganglioside ab or anti-high |

|molecular weight ab, which might be coupled to a toxin (e.g. ricin) or radioactive isotope (e.g. 131I) has not shown marked |

|effect in melanoma similar to the activity of anti-CD20 ab in lymphoma168. Adoptive immunotherapy using in vitro expansion of |

|tumor infiltrating killer cells targeting melanoma epitopes is an interesting concept but failed to translate into practical use|

|due to low response rates and technical difficulties. However, it led to the identification of new melanoma antigens169. |

|Recently, there has been a marked resurgence of interest in the use of vaccination for the treatment of advanced melanoma. In |

|the past most vaccines under study were whole cell preparations or lysates of melanoma in combination with a variety of |

|adjuvants. Examples are (1) polyvalent allogeneic melanoma cell lines +/- BCG (CancerVax)170; (2) allogeneic melanoma lysates |

|plus 'detox' (a 'detoxified' bacterial endotoxin) (Melacine)171; (3) autologous melanoma cells modified with the hapten |

|dinitrophenol (M-VAX)172; and (4) shed antigen vaccine173. These have shown effects in phase II trials in advanced melanoma |

|patients but were for the most part disappointing in randomized controlled trials174. Cellular vaccines are currently tested in |

|four randomized phase III trials in resected stage II/III/IV melanoma patients174. A study performed by the South West Oncology |

|Group in stage IIA melanoma with a vaccine prepared from two mechanically disrupted allogeneic melanoma patients admixed with |

|'detox' adjuvant led to a significant prolongation of disease free survival but not overall survival175. A prospective |

|randomized study in resected stage III patients with a shed polyvalent vaccine achieved significant improvement of time to |

|disease progression but not overall survival compared to placebo173. Gene modified whole cell vaccines are at an early stage of |

|development but have failed to demonstrate a significant clinical effect176. An antigen based ganglioside vaccine |

|(GM2-KLH/QS21)-induced antibody responses was less effective than high-dose IFN-α in a randomized trial142. |

|Progress in the field of melanoma immunology has allowed the identification of new melanoma antigens. Based on this knowledge |

|the new field of antigen specific peptide vaccination is rapidly expanding. These peptides are defined stretches of amino |

|acids[pic] corresponding to a known melanoma epitope. Peptide epitopes differ depending on HLA class I molecules. An advantage |

|of the peptide approach is the ability to exactly follow the melanoma specific immune response during vaccination. Rosenberg et |

|al.177 have demonstrated clinical responses in patients injected with melanoma peptides, incomplete Freund's adjuvant and IL-2. |

|In other trials tumor regression as well as immunological responses were observed178,179. An innovative approach is the use of |

|dendritic cells to boost a melanoma-specific immune response. Early promising clinical trials using dendritic cells pulsed with |

|melanoma peptides have demonstrated immune responses as well as clinical responses in selected patients180,181. |

|The field of melanoma immunotherapy is rapidly expanding and will hopefully provide potent anti-cancer treatments, especially in|

|the adjuvant/minimal residual disease setting182. |

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