**4. Clinical presentation**

The most common sites that melanomas are found include the trunk (back) followed by the upper extremities, and head and neck for men; and the lower extremities followed by the back, upper extremities, and head and neck for women. Amelanotic melanoma and those resembling keratoses are particularly difficult to diagnose without a high index of suspicion. Acral melanoma is the most frequent form of melanoma among Asians, Africans, and other ethnic groups of color. Subungual melanoma (SM) is a distinctive variant of acral melanoma that most often involves the nail bed of the great toe or thumb. Clinical types include;

patients with lentigo maligna progress to lentigo maligna melanoma, and it usually takes several years. Several methods of therapy can be used to treat lentigo maligna including cryotherapy, superficial radiation therapy, and surgical excision with mapping and modified

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Some imaging methods before proceeding to the treatment of lentigo maligna melanoma can be made. Especially, in patients with suspected metastatic disease, PET scan, CT scan and MR

The treatment of the melanoma is as for other sites in that the margin of excision for tumours thinner than 2 mm is 1 cm minimum and for thicker tumours should be 2 to 3 cm. It is recognized, however, that on the face these margins may not be attainable without unaccept‐ able cosmetic deficit. The surgery is also subject to the same constraints as described above for lentigo maligna, in that there is a high local recurrence rate of the in situ component [12, 58].

Superficial spreading melanoma is the most common type of cutaneous melanoma. It accounts for nearly 70% of cutaneous melanoma. The mean age at diagnosis is in the fifth decade. The commonest sites are the female leg and the male back (Figure 1), but every

can be made to detect lymph node and internal organ metastases [57].

**Figure 1.** Superficial spreading melanoma with characteristic asymmetry, irregular borders.

*Mohs* surgery [55, 56].

**4.2. Superficial spreading melanoma**

site may be affected [12].

#### **4.1. Lentigo malign melanoma**

Lentigo maligna melanoma is one of the 4 main subtypes of invasive melanoma and constitutes 10 to 15% of cutaneous melanomas. Generally, patients with lentigo maligna are older than 40 years, with a mean age of 65 years. The peak incidence occurs in the seventh to eighth decades of life [51]. The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising in the United States [52].

Sir *John Hutchinson* first described lentigo maligna in 1890; the disease continues to be called *Hutchinson* melanotic freckle on occasion. The lesion has subsequently been characterized as malignant lentigo of elderly people, junctional nevus, and melanoma in situ. Most authors currently refer to it as lentigo maligna when it is confined to the epidermis and lentigo maligna melanoma when it violates the dermis [39].

Lentigo maligna melanoma has evolved from a lentigo maligna.They are usually found on chronically sun damaged skin such as the face and the forearms of the elderly people. The risk increases as the number of years spent in sunny districts increases, as well as with increased hours of exposure to sunlight. The incidence of melanoma is highest in Australia, where lentigo maligna accounts for 10-15% of all melanomas. Approximately 10-30% of all cutaneous melanoma arise in head and neck regions. The other risk factors for lentigo malign melanoma are large or giant congenital naevi, fair skin and history of severe sunburn [53].

Many authors consider lentigo maligna to be a preinvasive lesion induced by long-term cumulative ultraviolet injury. Conceptually, the term melanoma is used when atypical melanocytes invade the rich vascular and lymphatic networks of the dermis, thereby estab‐ lishing metastatic potential [12, 51, 53].

Most malignant melanomas arise as superficial tumors confined to the epidermis, which is often known as horizontal growth. At some point, a stepwise accumulation of genetic abnor‐ malities leads to proliferation and progression to the vertical growth phase, which leads to dermal and deeper involvement and subsequently nodal metastases [54].

Initially the lentigo maligna is a flat, brown or black, irregularly shaped lesion. These lesions will grow very slowly, over months or years, and there may be central regression while the peripheral margin continues to extend. In time, a raised central nodule will develop, indicating transition to the vertical growth phase [12, 51, 53, 54].

Differantial diagnosis of lentigo malign melanom are solar lentigo, pigmented actinic keratosis, seborrheic keratosis, common acquired nevi and dysplastic nevi [12].

Lentigo maligna is basically in situ melanoma and is characterized by epidermal atrophy, extensive solar, lentiginous, and back-to-back proliferation of melanoma cells. Only 5% of patients with lentigo maligna progress to lentigo maligna melanoma, and it usually takes several years. Several methods of therapy can be used to treat lentigo maligna including cryotherapy, superficial radiation therapy, and surgical excision with mapping and modified *Mohs* surgery [55, 56].

Some imaging methods before proceeding to the treatment of lentigo maligna melanoma can be made. Especially, in patients with suspected metastatic disease, PET scan, CT scan and MR can be made to detect lymph node and internal organ metastases [57].

The treatment of the melanoma is as for other sites in that the margin of excision for tumours thinner than 2 mm is 1 cm minimum and for thicker tumours should be 2 to 3 cm. It is recognized, however, that on the face these margins may not be attainable without unaccept‐ able cosmetic deficit. The surgery is also subject to the same constraints as described above for lentigo maligna, in that there is a high local recurrence rate of the in situ component [12, 58].

#### **4.2. Superficial spreading melanoma**

upper extremities, and head and neck for women. Amelanotic melanoma and those resembling keratoses are particularly difficult to diagnose without a high index of suspicion. Acral melanoma is the most frequent form of melanoma among Asians, Africans, and other ethnic groups of color. Subungual melanoma (SM) is a distinctive variant of acral melanoma that

Lentigo maligna melanoma is one of the 4 main subtypes of invasive melanoma and constitutes 10 to 15% of cutaneous melanomas. Generally, patients with lentigo maligna are older than 40 years, with a mean age of 65 years. The peak incidence occurs in the seventh to eighth decades of life [51]. The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising

Sir *John Hutchinson* first described lentigo maligna in 1890; the disease continues to be called *Hutchinson* melanotic freckle on occasion. The lesion has subsequently been characterized as malignant lentigo of elderly people, junctional nevus, and melanoma in situ. Most authors currently refer to it as lentigo maligna when it is confined to the epidermis and lentigo maligna

Lentigo maligna melanoma has evolved from a lentigo maligna.They are usually found on chronically sun damaged skin such as the face and the forearms of the elderly people. The risk increases as the number of years spent in sunny districts increases, as well as with increased hours of exposure to sunlight. The incidence of melanoma is highest in Australia, where lentigo maligna accounts for 10-15% of all melanomas. Approximately 10-30% of all cutaneous melanoma arise in head and neck regions. The other risk factors for lentigo malign melanoma

Many authors consider lentigo maligna to be a preinvasive lesion induced by long-term cumulative ultraviolet injury. Conceptually, the term melanoma is used when atypical melanocytes invade the rich vascular and lymphatic networks of the dermis, thereby estab‐

Most malignant melanomas arise as superficial tumors confined to the epidermis, which is often known as horizontal growth. At some point, a stepwise accumulation of genetic abnor‐ malities leads to proliferation and progression to the vertical growth phase, which leads to

Initially the lentigo maligna is a flat, brown or black, irregularly shaped lesion. These lesions will grow very slowly, over months or years, and there may be central regression while the peripheral margin continues to extend. In time, a raised central nodule will develop, indicating

Differantial diagnosis of lentigo malign melanom are solar lentigo, pigmented actinic keratosis,

Lentigo maligna is basically in situ melanoma and is characterized by epidermal atrophy, extensive solar, lentiginous, and back-to-back proliferation of melanoma cells. Only 5% of

are large or giant congenital naevi, fair skin and history of severe sunburn [53].

dermal and deeper involvement and subsequently nodal metastases [54].

seborrheic keratosis, common acquired nevi and dysplastic nevi [12].

transition to the vertical growth phase [12, 51, 53, 54].

most often involves the nail bed of the great toe or thumb. Clinical types include;

**4.1. Lentigo malign melanoma**

76 Highlights in Skin Cancer

in the United States [52].

melanoma when it violates the dermis [39].

lishing metastatic potential [12, 51, 53].

Superficial spreading melanoma is the most common type of cutaneous melanoma. It accounts for nearly 70% of cutaneous melanoma. The mean age at diagnosis is in the fifth decade. The commonest sites are the female leg and the male back (Figure 1), but every site may be affected [12].

**Figure 1.** Superficial spreading melanoma with characteristic asymmetry, irregular borders.

Superficial spreading melanoma occurs in two phases: At first, superficial spreading melano‐ ma grows horizontally on the skin surface (radial growth phase). The lesion constitutes as a slowly-enlarging flat area of discoloured skin. At second, superficial spreading melanoma becomes invasive, the melanoma cells cross the basal membrane of the epidermis. A rapidlygrowing nodular melanoma can start to proliferate more deeply within the skin [59].

The main risk factors for superficial spreading melanoma are: age, previous invasive melano‐ ma or melanoma in situ, nonmelanoma skin cancer, many melanocytic moles, multiple atypical naevi, family history of melanoma, fair skin and sun damage. Other risk factors include blue or green eyes and red or blond hair [60, 61].

Superficial spreading melanoma presents as a slowly growing or changing flat patch of discoloured skin. At first, it often resembles a mole or freckle. It becomes more distinctive in time, often growing over months to years or even decades before it is detected. Like other flat forms of cutaneous melanoma, it can be detected by the ABCDE rule: Asymmetry, border irregularity, colour variation, large diameter and evolving [51].

The characteristics of superficial spreading melanoma are larger size, irregular shape, variable pigmentation (colours may include light brown, dark brown, black, blue, grey) and irregular surface. It is generally greater than 6 mm in diameter. Irregular asymmetric borders are characteristic [12, 51, 59, 60].

Dermoscopy can be very helpful in distinguishing superficial spreading melanoma from other skin lesions, such as melanocytic naevi, solar lentigines, seborrhoeic keratoses and pigmented basal cell carcinoma (Figure 2) [62].

The initial treatment of a primary melanoma is to cut it out; the lesion should be completely excised with a 2-3 cm margin of normal tissue. Further treatment depends mainly on the *Breslow* thickness of the lesion. After initial excisional biopsy; the radial excision margins are measured clinically from the edge of the melanoma. Occasionally, the pathologist will report incomplete excision of the melanoma, despite wide margins. This means further surgery or radiotherapy will be recommended to ensure the tumour has been completely removed [12].

#### **4.3. Acral lentiginous melanoma**

Acral lentiginous melanoma (ALM) is a rare variant occuring exclusively on the sole, with the palm and subungual locations [7, 63]. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Subungual melanoma may show itself as a longitudinal pigmented band (melanonychia striata) within the nail plate. This variant of melanoma may also affect the oral and nasal mucosa and involve the anogenital area [64]. This is the least common subtype of melanoma in white people (2-8% of melanoma cases). It is the most common subtype of melanoma in dark skinned patients (ie, Afro-American, Asian, and Hispanic people), representing 29-72% of melanoma cases [65, 66]. Not all palmo-plantar melanomas are ALMs; a minority are superficial spreading or nodular melanomas [7]. ALM shows typically as an asymmetric, brown to black macule with variegations in colour and irregular borders [67]. They usually arise from the nail matrix or, less often, from the nail bed

or nail fold. ALM is similar to lentigo maligna melanoma in that an irregular pigmented macule

**Figure 2.** Macroscopic view of a superficial spreading melanoma (A), dermoscopic view characterized by blue-white

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Although the pathogenesis of ALM remains unknown, it has been theorized that the more intense and chronic trauma experienced in acral locations may be a predisposing factor [69].

ALM has key demographic and life-style differences to differentiate ALM from other mela‐ noma subtypes: it occurs in an older patient population, and is associated with a lower number of common and atypical nevi, a lower incidence of familial melanoma, and a lower incidence

of sunburn but a higher personal and family history of noncutaneous cancers [69].

is present for a long time [68].

veil (B).

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Superficial spreading melanoma occurs in two phases: At first, superficial spreading melano‐ ma grows horizontally on the skin surface (radial growth phase). The lesion constitutes as a slowly-enlarging flat area of discoloured skin. At second, superficial spreading melanoma becomes invasive, the melanoma cells cross the basal membrane of the epidermis. A rapidly-

The main risk factors for superficial spreading melanoma are: age, previous invasive melano‐ ma or melanoma in situ, nonmelanoma skin cancer, many melanocytic moles, multiple atypical naevi, family history of melanoma, fair skin and sun damage. Other risk factors include blue

Superficial spreading melanoma presents as a slowly growing or changing flat patch of discoloured skin. At first, it often resembles a mole or freckle. It becomes more distinctive in time, often growing over months to years or even decades before it is detected. Like other flat forms of cutaneous melanoma, it can be detected by the ABCDE rule: Asymmetry, border

The characteristics of superficial spreading melanoma are larger size, irregular shape, variable pigmentation (colours may include light brown, dark brown, black, blue, grey) and irregular surface. It is generally greater than 6 mm in diameter. Irregular asymmetric borders are

Dermoscopy can be very helpful in distinguishing superficial spreading melanoma from other skin lesions, such as melanocytic naevi, solar lentigines, seborrhoeic keratoses and pigmented

The initial treatment of a primary melanoma is to cut it out; the lesion should be completely excised with a 2-3 cm margin of normal tissue. Further treatment depends mainly on the *Breslow* thickness of the lesion. After initial excisional biopsy; the radial excision margins are measured clinically from the edge of the melanoma. Occasionally, the pathologist will report incomplete excision of the melanoma, despite wide margins. This means further surgery or radiotherapy will be recommended to ensure the tumour has been completely removed [12].

Acral lentiginous melanoma (ALM) is a rare variant occuring exclusively on the sole, with the palm and subungual locations [7, 63]. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Subungual melanoma may show itself as a longitudinal pigmented band (melanonychia striata) within the nail plate. This variant of melanoma may also affect the oral and nasal mucosa and involve the anogenital area [64]. This is the least common subtype of melanoma in white people (2-8% of melanoma cases). It is the most common subtype of melanoma in dark skinned patients (ie, Afro-American, Asian, and Hispanic people), representing 29-72% of melanoma cases [65, 66]. Not all palmo-plantar melanomas are ALMs; a minority are superficial spreading or nodular melanomas [7]. ALM shows typically as an asymmetric, brown to black macule with variegations in colour and irregular borders [67]. They usually arise from the nail matrix or, less often, from the nail bed

growing nodular melanoma can start to proliferate more deeply within the skin [59].

or green eyes and red or blond hair [60, 61].

characteristic [12, 51, 59, 60].

78 Highlights in Skin Cancer

basal cell carcinoma (Figure 2) [62].

**4.3. Acral lentiginous melanoma**

irregularity, colour variation, large diameter and evolving [51].

**Figure 2.** Macroscopic view of a superficial spreading melanoma (A), dermoscopic view characterized by blue-white veil (B).

or nail fold. ALM is similar to lentigo maligna melanoma in that an irregular pigmented macule is present for a long time [68].

Although the pathogenesis of ALM remains unknown, it has been theorized that the more intense and chronic trauma experienced in acral locations may be a predisposing factor [69].

ALM has key demographic and life-style differences to differentiate ALM from other mela‐ noma subtypes: it occurs in an older patient population, and is associated with a lower number of common and atypical nevi, a lower incidence of familial melanoma, and a lower incidence of sunburn but a higher personal and family history of noncutaneous cancers [69].

There is often a delay in the diagnosis of ALM.The presence of invasion can be deceptive and may be present in entirely flat lesions [63]. The clinical differential diagnosis of ALM include a planter wart, which is common reason of delayed diagnosis, black heel (talon noir), lentigines, melanocytic nevi, tinea nigra, traumatic haemorrhage and tattoos such as by silver nitrate. Any growing, tender nodule, or an "ulcer" won't heal, on the sole of the foot, should give rise to concern that the lesion is a melanoma and biopsy should be considered [12, 70].

#### **4.4. Subungual melanoma**

Subungual melanoma, considered a variant of ALM, generally arises from the nail matrix. They are the most common on the thumb or great toe. It may manifest as diffuse nail discol‐ oration, a longitidunal pigmented band (melanonychia striata) within the nail plate or growth in the nail bed. Furthermore, 20% of subungual malignant melanomas may present with amelanocytic lesions rather than melanonychia [7, 71].

Pigment spread to the proximal or lateral nail folds is termed the *Hutchinson* sign, which is a hallmark for subungual melanoma. Benign lesions that can mimic subungual melanoma include longitidunal melanonychia (Figure 3), subungual hematoma, pyogenic granuloma or even onychomycosis with pigmentation or hemorrhage [7]. Nonresponsiveness to antifungal drugs should prompt more thorough evaluation, including potential biopsy. Subungual melanomas are most commonly confused with traumatic hemorrhage. This process is persis‐ tent, often lasting for more than 1 year, but in contrast to melanoma the dark area moves forward with the nail plate, leaving a normal appearing proximal component. Moreover, melanoma usually shows distal tapering, with the proximal portion being wider. The possi‐ bility of melanoma should be considered for all pigmented nail bands in fair-skinned patients, especially if they are darkly pigmented and/or have a width >3mm [67]. If any pigmented lesion of the nail unit that is strongly suspected of being melanoma, an excisional or incisional biopsy of the affected area that includes nail matrix should be performed [70].

It tends to lack the typical ABCDE melanoma warning signs and thus, may elude early detection. Histologically, it is believed to lack a preceding radial or in situ growth phase. The prognosis of NM is generally worse than other forms of melanoma because there is involve‐ ment of the dermis and the lesion is in the "vertical growth phase" at the time of diagnosis. The clinical differential diagnosis includes hemangioma, pyogenic granuloma, blue nevi, dermatofibroma, pigmented basal cell carcinoma, as well as other cutaneous neoplasms (Figure 5). As a general rule, a firm papule or nodule should never be subjected to any form

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Mucosal melanoma is a rare cancer that is clearly distinct from its cutaneous counterpart in biology, clinical course, and prognosis. It accounts for 1.3%-1.4% of all melanomas; that they tend to occur near the mucocutaneous junctions of squamous and columnar epithelia. The most common sites are the head and neck region (conjuctival, intranasal, sinus and oral cavities), vulva, anorectal, or even urethral melanoma. Activating mutations in the c-KIT gene

Sun exposure does not play a role in the pathogenesis of these lesions. Irritants and carcino‐ genic compounds in the air, such as tobacco smoke and formaldehyde, have been implicated in the devolepment of head and neck melanoma, the potential role of these compounds is not clear. The most common presenting trait of mucosal melanoma is the presence of extensive,

are detected in a significant number of patients with mucosal melanoma [72].

of monitoring-biopsy if the diagnosis is in doubt [63, 70].

**Figure 3.** Longitidunal melanonychia: longitudinal pigmented band within the nail plate.

**4.6. Mucosal melanoma**

Overall 5 year survival is disproportionately poor (25-51%) compared to other histological subtypes [71].

#### **4.5. Nodular melanoma**

Nodular melanoma (NM) is the second most common subtype after superficial spreading melanoma and accounts for approximately 15% to 30% of all melanomas. It is diagnosed most frequently in patients in their sixth decade of life [63, 67]. NM tends to affect men more than women. The most common locations are head, neck, the trunk in men (Figure 4) and legs in women [70].

NM clinically lacks an apparent radial growth phase. It is more common for NM to begin de novo than to arise in a pre-existing nevus. Typically, it presents as a black or blue-black nodule, but 5 percent are amelanotic and often misdiagnosed clinically. Thus, any rapidly growing flesh-colored lesion that persists after 1 month or ulcerates or bleeds should prompt medical evaluation [7].

**Figure 3.** Longitidunal melanonychia: longitudinal pigmented band within the nail plate.

It tends to lack the typical ABCDE melanoma warning signs and thus, may elude early detection. Histologically, it is believed to lack a preceding radial or in situ growth phase. The prognosis of NM is generally worse than other forms of melanoma because there is involve‐ ment of the dermis and the lesion is in the "vertical growth phase" at the time of diagnosis.

The clinical differential diagnosis includes hemangioma, pyogenic granuloma, blue nevi, dermatofibroma, pigmented basal cell carcinoma, as well as other cutaneous neoplasms (Figure 5). As a general rule, a firm papule or nodule should never be subjected to any form of monitoring-biopsy if the diagnosis is in doubt [63, 70].

#### **4.6. Mucosal melanoma**

There is often a delay in the diagnosis of ALM.The presence of invasion can be deceptive and may be present in entirely flat lesions [63]. The clinical differential diagnosis of ALM include a planter wart, which is common reason of delayed diagnosis, black heel (talon noir), lentigines, melanocytic nevi, tinea nigra, traumatic haemorrhage and tattoos such as by silver nitrate. Any growing, tender nodule, or an "ulcer" won't heal, on the sole of the foot, should give rise to

Subungual melanoma, considered a variant of ALM, generally arises from the nail matrix. They are the most common on the thumb or great toe. It may manifest as diffuse nail discol‐ oration, a longitidunal pigmented band (melanonychia striata) within the nail plate or growth in the nail bed. Furthermore, 20% of subungual malignant melanomas may present with

Pigment spread to the proximal or lateral nail folds is termed the *Hutchinson* sign, which is a hallmark for subungual melanoma. Benign lesions that can mimic subungual melanoma include longitidunal melanonychia (Figure 3), subungual hematoma, pyogenic granuloma or even onychomycosis with pigmentation or hemorrhage [7]. Nonresponsiveness to antifungal drugs should prompt more thorough evaluation, including potential biopsy. Subungual melanomas are most commonly confused with traumatic hemorrhage. This process is persis‐ tent, often lasting for more than 1 year, but in contrast to melanoma the dark area moves forward with the nail plate, leaving a normal appearing proximal component. Moreover, melanoma usually shows distal tapering, with the proximal portion being wider. The possi‐ bility of melanoma should be considered for all pigmented nail bands in fair-skinned patients, especially if they are darkly pigmented and/or have a width >3mm [67]. If any pigmented lesion of the nail unit that is strongly suspected of being melanoma, an excisional or incisional

concern that the lesion is a melanoma and biopsy should be considered [12, 70].

biopsy of the affected area that includes nail matrix should be performed [70].

Overall 5 year survival is disproportionately poor (25-51%) compared to other histological

Nodular melanoma (NM) is the second most common subtype after superficial spreading melanoma and accounts for approximately 15% to 30% of all melanomas. It is diagnosed most frequently in patients in their sixth decade of life [63, 67]. NM tends to affect men more than women. The most common locations are head, neck, the trunk in men (Figure 4) and legs in

NM clinically lacks an apparent radial growth phase. It is more common for NM to begin de novo than to arise in a pre-existing nevus. Typically, it presents as a black or blue-black nodule, but 5 percent are amelanotic and often misdiagnosed clinically. Thus, any rapidly growing flesh-colored lesion that persists after 1 month or ulcerates or bleeds should prompt medical

**4.4. Subungual melanoma**

80 Highlights in Skin Cancer

subtypes [71].

women [70].

evaluation [7].

**4.5. Nodular melanoma**

amelanocytic lesions rather than melanonychia [7, 71].

Mucosal melanoma is a rare cancer that is clearly distinct from its cutaneous counterpart in biology, clinical course, and prognosis. It accounts for 1.3%-1.4% of all melanomas; that they tend to occur near the mucocutaneous junctions of squamous and columnar epithelia. The most common sites are the head and neck region (conjuctival, intranasal, sinus and oral cavities), vulva, anorectal, or even urethral melanoma. Activating mutations in the c-KIT gene are detected in a significant number of patients with mucosal melanoma [72].

Sun exposure does not play a role in the pathogenesis of these lesions. Irritants and carcino‐ genic compounds in the air, such as tobacco smoke and formaldehyde, have been implicated in the devolepment of head and neck melanoma, the potential role of these compounds is not clear. The most common presenting trait of mucosal melanoma is the presence of extensive,

**Figure 4.** Nodular melanoma manifests as a dark brown-to-black dome-shaped nodule.

irreguler macular pigmentation. Most mucosal melanomas are lentiginous (mucosal lentigi‐ nous melanoma), followed in incidence by superficial spreading and nodular types.

Histologically, childhood melanomas may resemble those of adults, but small cell melanomas and melanomas with features of *Spitz* nevus are reported to be more common in this age group. The differentiation of melanoma from Spitz nevi with atypical features remains a major

**Figure 5.** Nodular melanoma must be differentiated from pyogenic granuloma, blue nevi, and pigmented basal cell

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Congenital melanoma is extremely rare; most melanomas in children are acquired after birth. In addition, a mother with visceral metastases can transfer tumor cells transplacentally, giving

Although, it seems that pediatric patients with melanoma may have a better prognosis than adults showing the same type of lesions, a number of children will still develop metastasis and die of their disease, especially when melanoma is diagnosed after puberty. Treatment follows the same rationale as in adults, with the aim of early detection and appropriate resection of

Desmoplastic melanoma (DM) is a rare sub-type melanoma that provokes a scar-like tissue reaction and is frequently associated with neurotropism. It makes up <1% of all melanomas. It is most commonly develops in older persons and has a male predominance 2:1. The head

challenge for physicians.

carcinoma.

birth to a newborn with disseminated metastases.

the primary melanoma [12, 67, 68, 74, 75].

**4.8. Unusual variants of melanoma**

*4.8.1. Desmoplastic-neurotropic melanoma*

Because of its hidden location and rich vascularization, mucosal melanoma usually presents at a more advanced stage and is therefore associated with a higher mortality rate than cutaneous melanoma [7, 12, 73].

#### **4.7. Childhood melanomas**

Childhood melanoma is very rare, particularly before puberty. Approximately 1% to 4% occur in patients younger than 20 years of age, and only 0.3 to 0.4% occur in pubertal children. After puberty the incidence of melanoma starts to rise slowly.

As in adults, childhood melanomas mainly affect the white population. Previous surveys have shown slight female predominance of melanoma in children. The most common primary tumor sites are the extremities, followed by trunk. Location in head and neck and trunk has been related to poor prognosis. The risk factors for melanoma in children are parallel those in adults. There are three known predispositions in childhood melanoma: congenital naevi, the atypical mole syndrome, familial melanoma and other family cancer syndromes such as xeroderma pigmentosum and retinoblastoma. Increasing age, UV exposure, and *Caucasian* background were also found to be important in pediatric melanoma.

**Figure 5.** Nodular melanoma must be differentiated from pyogenic granuloma, blue nevi, and pigmented basal cell carcinoma.

Histologically, childhood melanomas may resemble those of adults, but small cell melanomas and melanomas with features of *Spitz* nevus are reported to be more common in this age group. The differentiation of melanoma from Spitz nevi with atypical features remains a major challenge for physicians.

Congenital melanoma is extremely rare; most melanomas in children are acquired after birth. In addition, a mother with visceral metastases can transfer tumor cells transplacentally, giving birth to a newborn with disseminated metastases.

Although, it seems that pediatric patients with melanoma may have a better prognosis than adults showing the same type of lesions, a number of children will still develop metastasis and die of their disease, especially when melanoma is diagnosed after puberty. Treatment follows the same rationale as in adults, with the aim of early detection and appropriate resection of the primary melanoma [12, 67, 68, 74, 75].

#### **4.8. Unusual variants of melanoma**

irreguler macular pigmentation. Most mucosal melanomas are lentiginous (mucosal lentigi‐

Because of its hidden location and rich vascularization, mucosal melanoma usually presents at a more advanced stage and is therefore associated with a higher mortality rate than

Childhood melanoma is very rare, particularly before puberty. Approximately 1% to 4% occur in patients younger than 20 years of age, and only 0.3 to 0.4% occur in pubertal children. After

As in adults, childhood melanomas mainly affect the white population. Previous surveys have shown slight female predominance of melanoma in children. The most common primary tumor sites are the extremities, followed by trunk. Location in head and neck and trunk has been related to poor prognosis. The risk factors for melanoma in children are parallel those in adults. There are three known predispositions in childhood melanoma: congenital naevi, the atypical mole syndrome, familial melanoma and other family cancer syndromes such as xeroderma pigmentosum and retinoblastoma. Increasing age, UV exposure, and *Caucasian*

nous melanoma), followed in incidence by superficial spreading and nodular types.

**Figure 4.** Nodular melanoma manifests as a dark brown-to-black dome-shaped nodule.

cutaneous melanoma [7, 12, 73].

puberty the incidence of melanoma starts to rise slowly.

background were also found to be important in pediatric melanoma.

**4.7. Childhood melanomas**

82 Highlights in Skin Cancer

#### *4.8.1. Desmoplastic-neurotropic melanoma*

Desmoplastic melanoma (DM) is a rare sub-type melanoma that provokes a scar-like tissue reaction and is frequently associated with neurotropism. It makes up <1% of all melanomas. It is most commonly develops in older persons and has a male predominance 2:1. The head and neck are the most frequently involved sites, although lesions may develop on the trunk and extremities, palate, gingiva, lip, vulva, anus, and conjunctiva. DMs usually arise on the skin that has been severely damaged by long-standing sun exposure, although they have been reported to develop on skin damaged by ionizing radiation and in burn scars [63, 70, 76-78].

Angiotropism has been suggested to be a prognostic factor strongly predicting risk for

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Nevoid melanoma describes a heterogeneous grup of rare lesions that they may resemble a *Spitz* nevus or an acquired or congenital melanocytic nevus. Nevoid melanoma equally affects women and men and the mean age of diagnosis is 47 years. It occurs anywhere, but lower extremities and trunk are preferential sites. Clinically, this may correspond to a tan nodule typically greater than 1 cm in size, located on the trunk or proximal limbs of a young adult.

Histologically, the architectural pattern appears very similar to that of a compound or intradermal nevus with an overall symmetry, well-defined lateral margins, minimal or no intraepidermal pagetoid spread. Histological features mentioning melanoma include the absence of maturation of dermal tumor cells, slight cytological atypia with some mitoses in

The differential diagnosis includes *Spitz* nevus, congenital melanocytic nevus, minimaldeviation melanoma, nodular melanoma and melanoma arising in a dermal nevus. Although only one study has reported a better biological behavior for this lesion, there is no evidence

Clinically, verrucous melanomas are usually small hyperkeratotic papules without areas of regression and mimic either a verruca, seborrheic keratosis, or a compound or congenital naevus. Some studies reported a greater frequency on the extremities of women, but this has not been confirmed. The back of men also frequently is involved. Histologically, the verrucous component is represented by marked epithelial hyperplasia. It has the same prognosis as

Small cell melanoma describes a heterogeneous group of melanomas arising in different settings whose common denominator is a population of small cells. A first type, developing particularly in adults, is comprised of small cells with roundish, hyperchromatic nuclei, slight cytoplasm, and numerous mitoses resembling *Merkel*'s cells. A second variant of small cell melanoma has been described arising de novo in children and adolescent on the scalp or developing in a congenital nevus. A third type of small cell melanoma has been described in sun-damaged skin of old patients in the setting of solar melanocytic neoplasia or atypical

A recent report suggested that a small-cell morphology in melanomas is significantly associ‐ ated with positive sentinel lymph node involvement. Melanomas manifesting this morphology

are invariably in vertical growth phase and have an aggressive course [77, 78, 83].

that nevoid melanoma has a better prognosis than ordinary melanoma [77, 78, 81].

metastasis of melanoma [77, 80].

the dermal component [77, 78].

*4.8.4. Verrucous melanoma*

*4.8.5. Small cell melanoma*

lentiginous nevi.

conventional melanoma [68, 77, 82].

*4.8.3. Nevoid melanoma*

Its clinical features are similar to nonmelanoma (keratinocytic) skin cancer. It may occur in association with macular, lentigo maligna-type pigmentation, or it may present de novo as a firm, amelanotic nodule or scar. Fifty percent of the time it is amelanotic and may be mistaken for something as innocent as a scar. In the other 50% of cases it is associated with an overlying lentigo maligna or superficial spreading melanoma [64, 78]. Lack of pigmentation and clinical features more suggestive of keratinocytic skin cancer may result in delay in detection and thicker tumors at diagnosis [39].

Histologically, the tumor is composed of collections of spindle cells diffusely infiltrating the dermis and often the subcutis, associated with abundant stromal collagen. Many DMs are deeply invasive at diagnosis and have a tendency to infiltrate perineurally, otherwise called neurotropic melanoma. Neurotropism is related to increase the frequency of local recurrences. Also, it seems that neurotropism is associated with a signifiant decrease in survival in patients with DM. Occasionally, there are some lesions with prominent perineural invasion and no evidence of an intraepidermal component. These lesions are designated neurotropic melano‐ ma. This seen particularly in lesions on the head and neck area, and may cause severe, relentless pain. In the recent studies, the percentage of desmoplastic melanomas with neurotropism ranged from 16.7 to 77.8% [7, 79].

The clinical differential diagnosis is broad, because these lesions often do not have features that suggest melanoma. Some of the clinical diagnoses that may be rendered include, scar, basal cell carcinoma, squamous cell carcinoma, fibroma, recurrent nevus, and metastatic carcinoma. Deep tissue samples are necessary to establish the diagnosis. The use of immuno‐ chemistry (testing for S100 antigen) is suggested as a useful tool in establishing the diagnosis. This sub-type of melanoma usually lacks any valuable dermoscopic features [12, 76-78].

Local recurrence is common, in 22% to 70% of cases, largely because of the tendency of DM to exhibit neurotropism. Although deeply invasive, DM is associated with lower metastatic rates than other sub-types of melanoma when matched for depth of invasion. When they metasta‐ size, these tumors, unlike most melanomas may by-pass regional lymph nodes and spread hematogenously [7, 64, 70].

#### *4.8.2. Angiotropic melanoma*

Angiotropic melanoma is defined by cuffing of (close apposition to) the external surfaces of either blood microvessels or lymphatic channels by melanoma cells in a pericytic location without evidence of intravasation in at least two or more foci. Angiotropic metastasis is not synonymous with vascular invasion. The mechanism of angiotropism of melanoma is not clear. There may be a special affinity between the tumor cells and the vascular wall. Angiotropism is seen with greater frequency in melanomas also showing desmoplasia and neurotropism. Angiotropism has been suggested to be a prognostic factor strongly predicting risk for metastasis of melanoma [77, 80].

#### *4.8.3. Nevoid melanoma*

and neck are the most frequently involved sites, although lesions may develop on the trunk and extremities, palate, gingiva, lip, vulva, anus, and conjunctiva. DMs usually arise on the skin that has been severely damaged by long-standing sun exposure, although they have been reported to develop on skin damaged by ionizing radiation and in burn scars [63, 70, 76-78].

Its clinical features are similar to nonmelanoma (keratinocytic) skin cancer. It may occur in association with macular, lentigo maligna-type pigmentation, or it may present de novo as a firm, amelanotic nodule or scar. Fifty percent of the time it is amelanotic and may be mistaken for something as innocent as a scar. In the other 50% of cases it is associated with an overlying lentigo maligna or superficial spreading melanoma [64, 78]. Lack of pigmentation and clinical features more suggestive of keratinocytic skin cancer may result in delay in detection and

Histologically, the tumor is composed of collections of spindle cells diffusely infiltrating the dermis and often the subcutis, associated with abundant stromal collagen. Many DMs are deeply invasive at diagnosis and have a tendency to infiltrate perineurally, otherwise called neurotropic melanoma. Neurotropism is related to increase the frequency of local recurrences. Also, it seems that neurotropism is associated with a signifiant decrease in survival in patients with DM. Occasionally, there are some lesions with prominent perineural invasion and no evidence of an intraepidermal component. These lesions are designated neurotropic melano‐ ma. This seen particularly in lesions on the head and neck area, and may cause severe, relentless pain. In the recent studies, the percentage of desmoplastic melanomas with neurotropism

The clinical differential diagnosis is broad, because these lesions often do not have features that suggest melanoma. Some of the clinical diagnoses that may be rendered include, scar, basal cell carcinoma, squamous cell carcinoma, fibroma, recurrent nevus, and metastatic carcinoma. Deep tissue samples are necessary to establish the diagnosis. The use of immuno‐ chemistry (testing for S100 antigen) is suggested as a useful tool in establishing the diagnosis. This sub-type of melanoma usually lacks any valuable dermoscopic features [12, 76-78].

Local recurrence is common, in 22% to 70% of cases, largely because of the tendency of DM to exhibit neurotropism. Although deeply invasive, DM is associated with lower metastatic rates than other sub-types of melanoma when matched for depth of invasion. When they metasta‐ size, these tumors, unlike most melanomas may by-pass regional lymph nodes and spread

Angiotropic melanoma is defined by cuffing of (close apposition to) the external surfaces of either blood microvessels or lymphatic channels by melanoma cells in a pericytic location without evidence of intravasation in at least two or more foci. Angiotropic metastasis is not synonymous with vascular invasion. The mechanism of angiotropism of melanoma is not clear. There may be a special affinity between the tumor cells and the vascular wall. Angiotropism is seen with greater frequency in melanomas also showing desmoplasia and neurotropism.

thicker tumors at diagnosis [39].

84 Highlights in Skin Cancer

ranged from 16.7 to 77.8% [7, 79].

hematogenously [7, 64, 70].

*4.8.2. Angiotropic melanoma*

Nevoid melanoma describes a heterogeneous grup of rare lesions that they may resemble a *Spitz* nevus or an acquired or congenital melanocytic nevus. Nevoid melanoma equally affects women and men and the mean age of diagnosis is 47 years. It occurs anywhere, but lower extremities and trunk are preferential sites. Clinically, this may correspond to a tan nodule typically greater than 1 cm in size, located on the trunk or proximal limbs of a young adult.

Histologically, the architectural pattern appears very similar to that of a compound or intradermal nevus with an overall symmetry, well-defined lateral margins, minimal or no intraepidermal pagetoid spread. Histological features mentioning melanoma include the absence of maturation of dermal tumor cells, slight cytological atypia with some mitoses in the dermal component [77, 78].

The differential diagnosis includes *Spitz* nevus, congenital melanocytic nevus, minimaldeviation melanoma, nodular melanoma and melanoma arising in a dermal nevus. Although only one study has reported a better biological behavior for this lesion, there is no evidence that nevoid melanoma has a better prognosis than ordinary melanoma [77, 78, 81].

#### *4.8.4. Verrucous melanoma*

Clinically, verrucous melanomas are usually small hyperkeratotic papules without areas of regression and mimic either a verruca, seborrheic keratosis, or a compound or congenital naevus. Some studies reported a greater frequency on the extremities of women, but this has not been confirmed. The back of men also frequently is involved. Histologically, the verrucous component is represented by marked epithelial hyperplasia. It has the same prognosis as conventional melanoma [68, 77, 82].

#### *4.8.5. Small cell melanoma*

Small cell melanoma describes a heterogeneous group of melanomas arising in different settings whose common denominator is a population of small cells. A first type, developing particularly in adults, is comprised of small cells with roundish, hyperchromatic nuclei, slight cytoplasm, and numerous mitoses resembling *Merkel*'s cells. A second variant of small cell melanoma has been described arising de novo in children and adolescent on the scalp or developing in a congenital nevus. A third type of small cell melanoma has been described in sun-damaged skin of old patients in the setting of solar melanocytic neoplasia or atypical lentiginous nevi.

A recent report suggested that a small-cell morphology in melanomas is significantly associ‐ ated with positive sentinel lymph node involvement. Melanomas manifesting this morphology are invariably in vertical growth phase and have an aggressive course [77, 78, 83].

#### *4.8.6. Spitzoid melanoma*

Spitzoid melanoma is a rare sub-type of melanoma that resembles clinically and histologically a *Spitz* nevus. But it tends to be larger and have asymmetry and irregular coloration. It can occur in children but are more common in adults. Clinically, spitzoid melanomas are changing nodular lesions, often reaching 1 cm or more in diameter. The nodules are usually amelanotic. They can mimic hemangiomas, pyogenic granulomas, xanthogranulomas, or basal cell carcinomas. Less often, the lesions are pigmented and variegated in color. Nodular lesions can be crusted and ulcerated. The head and extremities are common sites.

**5. Differential diagnosis**

**5.1. Superficial spreading melanoma**

helpful aid in the diagnosis of pigmented lesions:

D = Diameter greater than 6 mm/Difference

A = Asymmetry

B = Border irregularity

C = Color variegation

E = Elevation/Evolving

Melanoma must be distinguished from a variety of several cutaneous and mucosal lesions.

Current Management of Malignant Melanoma: State of the Art

http://dx.doi.org/10.5772/55304

87

This is the most common type of melanoma. It is usually seen on sun-exposed areas, mostly on the lower extremities of women, and the upper back of men. Superficial spreading mela‐ noma can present as an irregular macule with variation in color and texture. A papule or nodule may arise from the macule as the tumor progresses from radial to vertical growth. Superficial spreading melanoma can present de novo or within a preexisting nevus. Atypical nevus, melanocytic nevus, lentigo, seborrheic keratosis, *Spitz* nevus and superficial basal cell carci‐

There are several features that can aid in distinguishing the common melanocytic nevus from melanoma. The "ABCD" rule, which has been expanded to the "ABCDE" rule, provides a

Atypical nevus may be misdiagnosed as melanoma because of focal or minimal pagetoid spread, confluence of cellular aggregates along the dermal-epidermal junction, prominent variation in nesting pattern, significant cytologic atypia, entrapment of nests of dermal nevus cells in the papillary dermis, and dense mononuclear cell infiltrates. On occasion, the distinction of atypical nevus from melanoma is exceedingly difficult. The discrimina‐ tion of melanoma from atypical nevus is usually possible because of the larger size, greater asymmetry, disorder, cellularity, and cytologic atypia encountered in melanoma. Usually atypical nevus will maintain an overall symmetry, a nevic appearance as exemplified by fairly organized junctional nesting, a basilar proliferation of melanocytes that is still concentrated along the epidermal rete and with greater density toward the lower poles of the rete [89-91]. Melanoma may mimic seborrheic keratoses but also may arise within the seborrheic keratosis. *Spitz* nevus is usually domeshaped but may be soft or hard, sessile or pedunculated. It is usually pink to red but may be brown. In contrast to melanoma, the patient can usually pinpoint the onset of the tumor. The nevus may persist but more commonly evolves into an intradermal melanocytic nevus. Histologically, the spindle and epithelioid nevi are characterized by a cellular uniformity, as opposed to the pleomor‐ phism that characterizes malignancy. The development of an apparent spindle and

epithelioid nevi after puberty should be regarded with concern. [7, 92, 93].

The differential diagnosis change according to the subtype of melanoma.

noma must be distinguished from superficial spreading melanoma [87-89].

Some spitzoid melanomas can evolve from a preexisting *Spitz* nevus, whereas other spitzoid melanomas can develop *de novo*. Differentiation between two of them is sometimes very difficult, especially in younger patients. The presence of mitoses, the nuclear and nucleolar pleomorphism of the cells, the asymmetric distribution of the pigment, and an inflammatory infiltrate with irregular disposition should prompt us to spitzoid melanoma.

The prognosis of spitzoid melanoma in adults is the same as that for other variants of mela‐ noma of equal *Breslow* thickness [7, 77, 84].

#### *4.8.7. Balloon cell melanoma*

Balloon cell malignant melanoma (BCMM) is the rarest histological type of primary cutaneous melanoma and is composed of large, polyhedral, foamy cells with abundant cytoplasmic vacuoles. Clinically, lesions appear as soft, rubbery, or firm nodules with a polypoid or papillomatous contour whose cut surfaces are grayish white or brown. The differential diagnosis includes balloon cell change in benign nevi including blue nevi and common acquired nevi, with which balloon cell melanoma may coexist, as well as other malignant clear cell neoplasms. The presence of cytological atypia, nuclear pleomorphism, and mitoses are important for its distinction from the more common balloon-cell nevus. The expression of the usual immunohistochemical markers such as S-100 protein and HMB-54 helps to distinguish this lesion from other clear cell tumors of the skin. The prognosis is similar to that of other types of melanoma matched for depth of invasion [70, 77, 78, 85].

#### *4.8.8. Clear cell sarcoma: Melanoma of soft parts*

Clear-cell sarcoma (CCS) is a perplexing tumor considered by some authors as a soft tissue sarcoma derived from the neural crest and by others as an unusual variant or subtype of melanoma. CCS shows a predilection for the deep soft tissues of the lower extremities close to the tendon, fascia, or aponeuroses. The tumor presents as a slowly growing deep-seated mass in close relation with tendons and aponeuroses associated with tenderness and pain. It generally appears in young adults between the ages of 20 and 40 years.

Histologically, the tumor has a multilobulated apperance made by nests and fascicles of uniform plump spindle cells seperated by fine to coarse fibrous septa. CCS is an aggressive neoplasm with a poor prognosis similar to that of sarcomas, with a high rate of local recurrences and metastases to lymph nodes and lungs. Both survival and distant metastases seem to correlate with the tumor size more than the histological parameters [12, 67, 77, 86].
