**7. Treatment**

### **7.1. Staging workup**

Any lesion that is clinically suspicious for melanoma should ideally undergo an complete elliptical excisional biopsy with narrow margins (such as 2 mm) [12]. Wide excisions should be avoided for obtaining an accurate result of the subsequent sentinel lymph node biopsy, if necessary. Examination of the entire pigmented lesion allows for the greatest chance of accurate diagnosis and also for the measurement of *Breslow* thickness and the assessment of other prognostic factors [142]. Although there is evidence that an incisional biopsy does not adversely affect survival, this approach should be an exception and reserved for cases in which the tumor is too large to be excised, or when it is not practical to perform an excision. If the lesion is large or located on certain anatomical sites such as palm/sole, digit, face or ear, a fullthickness incisional biopsy can be performed, reaching to the adipose tissue. This biopsy should be obtained from the most elevated or darkest area of the lesion, although there is not always a correlation between clinical appearance and the thickest part of the lesion. If initial biospy confirms melanoma with subtotal excision and if there is significant amount of residual lesion, a narrow margined re-excision should be immediately made, to evaluate if the patient is a candidate for sentinel lymph node biopsy.

Although cutaneous melanoma is rare in children and young adults, the incidence is rising annually in this population. Staging work up is almost similar, in children and adults [143].

#### **7.2. Evaluation for regional metastasis**

#### *7.2.1. Macroscopic metastases*

from 75-92% and 95-100%, respectively. It is less positive in lesions with metastatic melanomas

MIB-1, also known as Ki-67, is a proliferation marker that is expressed by proliferating cells. It provides guidance about presence or absence of "maturation". MIB-1 has an important role in distinguishing between melanocytic nevi and melanoma. While less than 5% of nuclei is positive in melanocytic nevi, this ratio is greater (25% or more) in melanoma [114, 141].

Tyrosinase is an enzyme that plays a role in hydroxylation of tyrosine in the synthesis of melanin. Its sensitivity for melanoma is slightly better than HMB-45 at 84-94%. The sensitivity is reduced in advanced diseases and metastatic lesions (79-93%). The specificity is very high

Microphthalmic transcription factor (MITF) is expressed in most benign melanocytic nevi and melanomas. Nuclear staining occurs with MITF unlike cytoplasmic markers. MITF expression

There are also numerous immunohistochemical markers such as epithelial markers (keratin, EMA, CEA), histiocytic markers (eg. CD68, Mac 378, alpha-1 antitrypsin), Bcl-2, Cyclin D1,

Any lesion that is clinically suspicious for melanoma should ideally undergo an complete elliptical excisional biopsy with narrow margins (such as 2 mm) [12]. Wide excisions should be avoided for obtaining an accurate result of the subsequent sentinel lymph node biopsy, if necessary. Examination of the entire pigmented lesion allows for the greatest chance of accurate diagnosis and also for the measurement of *Breslow* thickness and the assessment of other prognostic factors [142]. Although there is evidence that an incisional biopsy does not adversely affect survival, this approach should be an exception and reserved for cases in which the tumor is too large to be excised, or when it is not practical to perform an excision. If the lesion is large or located on certain anatomical sites such as palm/sole, digit, face or ear, a fullthickness incisional biopsy can be performed, reaching to the adipose tissue. This biopsy should be obtained from the most elevated or darkest area of the lesion, although there is not always a correlation between clinical appearance and the thickest part of the lesion. If initial biospy confirms melanoma with subtotal excision and if there is significant amount of residual lesion, a narrow margined re-excision should be immediately made, to evaluate if the patient

Although cutaneous melanoma is rare in children and young adults, the incidence is rising annually in this population. Staging work up is almost similar, in children and adults [143].

than primary melanoma [139].

100 Highlights in Skin Cancer

for melanoma (97-100%) [139].

**7. Treatment**

**7.1. Staging workup**

has been reported in 81-100% of melanomas [51, 113].

is a candidate for sentinel lymph node biopsy.

p16, CD40, CD44, melanoma cell adhesion molecule (Mel-CAM) [114].

First step should always be history taking and physical examination. A careful lymph node examination of the whole body should be made, particulary the regions close to the site of the primary lesion. Also because of the aberrant lymphatic drainage pathways to unexpected nodal basins and to interval nodes between the primary site and expected regional nodal basin, a search for clinically detectable nodal disease in unexpected locations is crucial. If there is a palpable lymph node during physical examination, first a fine needle aspiration biopsy should be performed to make a histological confirmation. If the result of the fine needle aspiration is inconclusive, an excisional biospy can be made. For the detection small nodal metastases, best noninvasive methods seem to be ultrasound imaging and positron emission tomography, with sensitivity and specificity being lower than tissue diagnosis [144].

#### *7.2.2. Microscopic metastases*

Sentinel lymph node biopsy (SLNB) as elective lymph node dissection (ELND) does not offer a survival advantage to melanoma patients, a new approach, SLNB has become the choice of biopsy type. *Morton* developed sentinel node biopsy as a means of ensuring that the node biopsied was the one most likely to be the first draining lymph node. This technique was widely adopted although the first randomized clinical trial to evaluate it was only published in 2006. In SLNB, lymphoscintigraphy is used to identify the lymphatic drainage pattern from the site of the primary melanoma, by injecting radiolabelled colloid and/or blue dye at the site of the primary melanoma [145]. The tracer/dye is concentrated in the sentinel node and is detected using a hand-held gamma probe (neoprobe) and examination by naked eye for the blue stained node. Sometimes there is more than one sentinel node and sometimes these sentinel nodes are in different lymph node basins. The node is removed and subjected to pathological examina‐ tion using immunohistochemistry (S100 and HMB-45) The surgical technique must be learnt and false-negative results are more common in trainees, so an experienced medical team is vital. The pathological examination of the nodes is also a skilled procedure; naevus cells may be seen, for example, in the subcapsular area of the node and must be distinguished from melanoma cells. The likelihood of a positive SLNB result is correlated with *Breslow* thickness. Use of SLNB to stage patients for trials of adjuvant therapies would appear reasonable but the patient should be aware that the risk of positivity is low. In patients with melanoma of *Breslow* thickness from 1.5 to 4.0 mm, the risk of positive SLNBs is significantly higher at 23% [146]. The value of SLNB in patients with tumours of *Breslow* thickness 4 mm or thicker is question‐ able (if the intent is therapeutic as well as being a staging tool) because the risk of haematog‐ enous spread is so high. At present SLNB is of proven staging value but of no established therapeutic value. Its use in identifying patients for adjuvant therapies means that it will continue to be used, but its role must be evaluated in the long term.

#### **7.3. Evaluation for distant metastasis**

For the evaluation of distant metastases, a thorough examination of the neurologic, psychiatric, musculoskeletal, skin, lymphatic, endocrine, cardiovascular, and respiratory systems is necessary. Patients with newly diagnosed melanoma require a complete cutaneous and physical examination with particular attention to lymphadenopathy and hepatomegaly, and a baseline chest radiograph. If the latter examinations fail to detect any evidence of metastatic disease and the patient has no other symptoms or signs, no further laboratory evaluation is indicated. Current imaging technics like computed tomography, magnetic resonance imaging, PET, chest X-ray and laboratory tests like LDH are not routinely indicated as their sensitivity ans specificity are low. According to current guidelines, no additional work up is necessary in stage 0 and 1A, optional chest X-ray may be performed in stage 1B and 2, optional chest X-ray and LDH for stage 3 and chest X-ray and/or chest CT and LDH for stage 4 can be done [146].

*7.5.2. Micrometastatic nodal disease*

*7.5.3. Adjuvant therapy*

should be done.

For micrometastatic disease, elective lymph node dissection was the procedure of choice, historically. It is the dissection of regional lypmh nodes draining the site of a primary cutaneous melanoma, with no clinically palpable lymph nodes or overt metastatic disease. With today's knowledge, according to multiple prospective randomized-controlled trials, survival rates of the patients undergoing elective lymph node dissection were found to be no higher than other patients. Thus there is no role for elective lypmh node dissection today, especially considering its significant morbidity and the availability of sentinel lypmh node biopsy [144]. For the identification of micrometastatic nodal disease, sentinel node biopsy is the tool of choice. The only handicap of sentinel node biopsy is that, it can not be classified as therapeutic yet. If the result of the sentinel lymph node biopsy returns as positive, always a complete lymph node dissection should be performed. According to current trials of investigations, immediate

Current Management of Malignant Melanoma: State of the Art

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

103

complete lymph node dissection has a higher survival rate than delayed dissection.

headache, depression, elevated levels of transaminases and myelosupression [147].

Melanoma vaccines: Vaccines stimulate specific immune response against melanomaassociated antigens. They can be of autologous, allogenic or peptide type and also immuno‐ logic adjuvants like bacille Calmette-Guérin or DETOX are added. Target of the vacines can be autologous tumor cells, allogenic melanoma cells, or more specifically heat shock proteins and T cell defined antigens glycoprotein 100, tyrosinase, MART-1. Up to now, none of the trials showed increased survival for the patients using these vaccines but more research on this area

Adjuvant therapy is usually given after surgical resection of the primary lesion. It is preferred in patients with increased relapse risk. When thickness of the primary lesion is higher than 4 mm or when there is nodal involvement, adjuvant therapy is necessary. Up to now, interferonα2b (IFN- α2b) is the only form of adjuvant therapy, which is approved by U.S. Food and Drug Administration. It has been shown that interferon-α2b improves disease-free survival for stage 2B and 3 melanoma, and it also improves overall survival. Interferon-α2b is used in high doses. There are two phases of treatment with interferon, first phase is induction phase. During induction, 20 million units per square meter of body surface area per day, are given intrave‐ nously, 5 days a week, for 4 weeks. After this high dose period, during the maintenance period, 10 million units per square meter per day, given subcutaneously three times a week for 48 weeks. During or after interferon treatment, autoantibodies like antithyroid, anti-nuclear, anti-DNA, anticardiolipin autoantibodies may appear in blood tests of the patients and some autoimmune diseases may develop. Both autoantibody positivity and development of autoimmune diseases are associated with increased survival in those patients. High dose interferon treatment may cause flu-like symptoms, fatigue, malaise, fever, nausea and

#### **7.4. Treatment of primary melanoma**

The Standard treatment for primary cutaneous melanoma is wide local excision. The aim of wide excision is to reach histopathologically confirmed tumor-free margins, as well as preventing local recurrence. Recommended clinical margins around the residual lesion or biopsy scar for melanoma in situ, non lentigo maligna pattern, is 0.5 to 1 cm; for melanoma <1 mm *Breslow* depth a 1-cm margin; for melanoma 1 to 2 mm a 1- to 2-cm margin as anatomically possible; for melanoma ≥ 2 mm a 2-cm margin. lesion excision at special sites, such as the digits, soles, ears, vagina or anus, also requires individual surgical and functional consideration. For subungal melanoma, partial or complete amputation of the digit is the choice of treatment.

Lentigo maligna and lentigo maligna melanoma have high potential for sub-clinical peripheral extension, as their clinical margins are usually poorly defined and obscured by background photo-damage. For lentigo maligna melanoma, the probability of a macular invasive desmo‐ plastic component is increased. Thus, standard surgical safety margins recommended, are often insufficient for these two subtypes [12, 51].

#### **7.5. Treatment of regional metastasis**

#### *7.5.1. Macrometastatic nodal disease*

One of the main causes of melanoma-related morbidity with an important negative effect on quality of life is the poor control of the nodal disease. Therefore, current standard of therapy for microscopic or macroscopic melanoma in lymph nodes is complete dissection of the node in the involved regional basin. According to the current guidelines, adequate lymphadenec‐ tomy is described as at least 10 nodes in the groin region, 15 lymph nodes in the axillary region and 15 lymph nodes in the neck area. There are also some complications, leading to significant morbidity, of the lymph node dissection, like wound infection, delayed wound healing, seroma, lymphedema and nerve damage. In the case of regional metastatic melanoma, complete lymph node dissection is associated with long-term survival rates [87].

#### *7.5.2. Micrometastatic nodal disease*

**7.3. Evaluation for distant metastasis**

102 Highlights in Skin Cancer

**7.4. Treatment of primary melanoma**

often insufficient for these two subtypes [12, 51].

**7.5. Treatment of regional metastasis**

*7.5.1. Macrometastatic nodal disease*

For the evaluation of distant metastases, a thorough examination of the neurologic, psychiatric, musculoskeletal, skin, lymphatic, endocrine, cardiovascular, and respiratory systems is necessary. Patients with newly diagnosed melanoma require a complete cutaneous and physical examination with particular attention to lymphadenopathy and hepatomegaly, and a baseline chest radiograph. If the latter examinations fail to detect any evidence of metastatic disease and the patient has no other symptoms or signs, no further laboratory evaluation is indicated. Current imaging technics like computed tomography, magnetic resonance imaging, PET, chest X-ray and laboratory tests like LDH are not routinely indicated as their sensitivity ans specificity are low. According to current guidelines, no additional work up is necessary in stage 0 and 1A, optional chest X-ray may be performed in stage 1B and 2, optional chest X-ray and LDH for stage 3 and chest X-ray and/or chest CT and LDH for stage 4 can be done [146].

The Standard treatment for primary cutaneous melanoma is wide local excision. The aim of wide excision is to reach histopathologically confirmed tumor-free margins, as well as preventing local recurrence. Recommended clinical margins around the residual lesion or biopsy scar for melanoma in situ, non lentigo maligna pattern, is 0.5 to 1 cm; for melanoma <1 mm *Breslow* depth a 1-cm margin; for melanoma 1 to 2 mm a 1- to 2-cm margin as anatomically possible; for melanoma ≥ 2 mm a 2-cm margin. lesion excision at special sites, such as the digits, soles, ears, vagina or anus, also requires individual surgical and functional consideration. For subungal melanoma, partial or complete amputation of the digit is the choice of treatment.

Lentigo maligna and lentigo maligna melanoma have high potential for sub-clinical peripheral extension, as their clinical margins are usually poorly defined and obscured by background photo-damage. For lentigo maligna melanoma, the probability of a macular invasive desmo‐ plastic component is increased. Thus, standard surgical safety margins recommended, are

One of the main causes of melanoma-related morbidity with an important negative effect on quality of life is the poor control of the nodal disease. Therefore, current standard of therapy for microscopic or macroscopic melanoma in lymph nodes is complete dissection of the node in the involved regional basin. According to the current guidelines, adequate lymphadenec‐ tomy is described as at least 10 nodes in the groin region, 15 lymph nodes in the axillary region and 15 lymph nodes in the neck area. There are also some complications, leading to significant morbidity, of the lymph node dissection, like wound infection, delayed wound healing, seroma, lymphedema and nerve damage. In the case of regional metastatic melanoma,

complete lymph node dissection is associated with long-term survival rates [87].

For micrometastatic disease, elective lymph node dissection was the procedure of choice, historically. It is the dissection of regional lypmh nodes draining the site of a primary cutaneous melanoma, with no clinically palpable lymph nodes or overt metastatic disease. With today's knowledge, according to multiple prospective randomized-controlled trials, survival rates of the patients undergoing elective lymph node dissection were found to be no higher than other patients. Thus there is no role for elective lypmh node dissection today, especially considering its significant morbidity and the availability of sentinel lypmh node biopsy [144]. For the identification of micrometastatic nodal disease, sentinel node biopsy is the tool of choice. The only handicap of sentinel node biopsy is that, it can not be classified as therapeutic yet. If the result of the sentinel lymph node biopsy returns as positive, always a complete lymph node dissection should be performed. According to current trials of investigations, immediate complete lymph node dissection has a higher survival rate than delayed dissection.

#### *7.5.3. Adjuvant therapy*

Adjuvant therapy is usually given after surgical resection of the primary lesion. It is preferred in patients with increased relapse risk. When thickness of the primary lesion is higher than 4 mm or when there is nodal involvement, adjuvant therapy is necessary. Up to now, interferonα2b (IFN- α2b) is the only form of adjuvant therapy, which is approved by U.S. Food and Drug Administration. It has been shown that interferon-α2b improves disease-free survival for stage 2B and 3 melanoma, and it also improves overall survival. Interferon-α2b is used in high doses. There are two phases of treatment with interferon, first phase is induction phase. During induction, 20 million units per square meter of body surface area per day, are given intrave‐ nously, 5 days a week, for 4 weeks. After this high dose period, during the maintenance period, 10 million units per square meter per day, given subcutaneously three times a week for 48 weeks. During or after interferon treatment, autoantibodies like antithyroid, anti-nuclear, anti-DNA, anticardiolipin autoantibodies may appear in blood tests of the patients and some autoimmune diseases may develop. Both autoantibody positivity and development of autoimmune diseases are associated with increased survival in those patients. High dose interferon treatment may cause flu-like symptoms, fatigue, malaise, fever, nausea and headache, depression, elevated levels of transaminases and myelosupression [147].

Melanoma vaccines: Vaccines stimulate specific immune response against melanomaassociated antigens. They can be of autologous, allogenic or peptide type and also immuno‐ logic adjuvants like bacille Calmette-Guérin or DETOX are added. Target of the vacines can be autologous tumor cells, allogenic melanoma cells, or more specifically heat shock proteins and T cell defined antigens glycoprotein 100, tyrosinase, MART-1. Up to now, none of the trials showed increased survival for the patients using these vaccines but more research on this area should be done.

#### *7.5.4. Satellite metastases*

For localized disease, limited to one extremity only, first choice of treatment should ideally be surgical excision with clear margins if possible. But in case of multiple lesions, chance of performing an ideal excision may be low, so in that case, isolated limb perfusion can be considered. It is a simple and less invasive, yet more effective treatment. Main idea about isolated limb perfusion is giving high doses of chemotherapeutic agents locally, to avoid systemic toxicity, and obtain more therapeutic effect. The technique of this method involves perfusing an isolated arm or leg, in a hyperthermic environment, with cytotoxic agents. Conventinally chemotherapeutic agent used in this procedure is melphalan. Approximately in half of the patients, complete disappearance of the lesion is observed. Although systemic side effects of this method is fairly less, when compared to conventinal chemotherapy, local side effects can be serious. Significant tissue damage due to high concentrations of cytotoxic agent can be seen. Compartment syndrome is one of the most severe morbidities. Advanced age and patients with serious co-morbidities are usually not preferred for this type of treat‐ ment. A new approach is isolated limb infusion, which is a less invasive method, for appliance on patients with older age or worse general health conditions. Isolated limb infusion can be done with melphalan and actinomycin D [51, 67].

disease, particularly as postoperative treatment after lymph node dissection. A recently completed randomized trial confirmed the benefit of adjuvant radiotherapy in improvement in nodal field control after nodal dissection for patients who are at moderate to high risk for

Current Management of Malignant Melanoma: State of the Art

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

105

For primary melanoma, adequate surgery is usually the best option for local control and cure. Factors often considered indicative of the need for adjuvant radiation therapy include primary site in the head and neck region, close or positive margins not amenable to further excision, lymphatic space invasion, multiple recurrences, and desmoplastic neurotropic growth [149]. Apart from its use in an adjuvant setting, radiation therapy has been used as the definitive treatment of primary melanomas, locally advanced acral lentiginous melanoma, and as a

Radiation therapy has a well-established role in patients with metastatic melanoma. Symptoms of pressure, mass effect, and bleeding from metastases in a variety of locations may benefit from palliative radiation. The development of stereotactic techniques has improved the efficacy of radiation for brain metastases. Expansion of this methodology to stereotactic body radiation

For systemic chemotherapy, first line chemotherapeutic agent is dacarbazine, an alkylating agent. It is an U.S. Food and Drug Administration (FDA) approved chemotherapy drug for metastatic melanoma. It is thought to be the most effective single agent therapy. Approxi‐ mately 10 to 20% of the patients response to treatment and the mean duration of response is 4 to 6 months. Dose of the treatment does not affect the response rate. Major side effects of dacarbazine are nausea and vomiting. Temozolomide is also an alkylating agent. This chemotherapeutic agent can also be used orally. Another advantage is that, temozolomide can cross the blood-brain barrier. Thus for patients with central nervous system involvement, temozolomide can be preferred. According to a randomized phase 3 study, its efficacy is equal to dacarbazine. For metastatic melanoma to brain, a combination of temozolomide and thalidomide, along with radiation, can be benefical. For dacarbazine, increased response rates are reported, when combined with other cytotoxic agents like cisplatin, vinblastine, carmustine

Among immunotherapeutic agents, interleukin 2 (IL-2) is the only agent, which has an approval form FDA. Overall response rate of this agent is 16%, but a durable response rate is 5 to 8%. Approximately the time for the duration of response is 9 months. Of the 28% of the patients with metastatic melanoma who responded to IL-2 treatment, no progression was observed at a follow-up period of 62 months. Also patients who responded longer than 30 months, did not show any sign of relapse afterwards. On the other hand, there are some

metastases has the potential to improve further palliation of unresectable metastases.

regional relapse [150].

**7.8. Systemic therapies**

*7.8.1. Chemotherapy*

or tamoxifen [144].

*7.8.2. Immunotherapy*

substitute for wide excision after limited excision.

#### **7.6. Treatment of distant or disseminated metastasis**

In case of stage 4 melanoma, with distant metastasis, mean survival is 6 to 8 months and there is currently no effective systemic treatment, to increase survival rate. For this reason, main treatment goal is the palliation of symptoms. For the patients with increased age and serious comorbidities, observation and conservative treatment may also be the option of choice [146]. If there are symptomatic visceral metastasis, surgical excision to perform metastasectomy can be tried. Also excision of skin metastasis or lymph node metastasis may improve the locore‐ gional control of the disease and may help to decrease morbidity.

In one case report [148], a 44-year-old *Caucasian* woman who underwent extensive surgical resection of a melanoma on the right side of her scalp, came with a new metastasis, a large nodule in her right cheek. The patient underwent two sessions of electrochemotherapy with intravenous injections of bleomycin, as neoadjuvant treatment permitting conservative surgery three months later. In this case, electrochemotherapy offers the option of more conservative surgery and an improved cosmetic effect with complete local tumor control.

Although melanoma is known to be radiotherapy resistant, for brain metastasis, spinal cord compression and painful bone metastasis, local radiation can be used.

#### **7.7. Radiation therapy**

Radiation therapy plays a role in the management of primary cutaneous melanoma in definitive, adjuvant, and palliative settings. The role for radiation therapy in early stage primary melanom is limited as the treatment is adequate excision. However desmoplastic melanoma and those with neurotropism invasion are exceptions, due to frequent local recurrence [149]. The greatest controversy regarding radiotherapy lies with its use in stage III disease, particularly as postoperative treatment after lymph node dissection. A recently completed randomized trial confirmed the benefit of adjuvant radiotherapy in improvement in nodal field control after nodal dissection for patients who are at moderate to high risk for regional relapse [150].

For primary melanoma, adequate surgery is usually the best option for local control and cure. Factors often considered indicative of the need for adjuvant radiation therapy include primary site in the head and neck region, close or positive margins not amenable to further excision, lymphatic space invasion, multiple recurrences, and desmoplastic neurotropic growth [149]. Apart from its use in an adjuvant setting, radiation therapy has been used as the definitive treatment of primary melanomas, locally advanced acral lentiginous melanoma, and as a substitute for wide excision after limited excision.

Radiation therapy has a well-established role in patients with metastatic melanoma. Symptoms of pressure, mass effect, and bleeding from metastases in a variety of locations may benefit from palliative radiation. The development of stereotactic techniques has improved the efficacy of radiation for brain metastases. Expansion of this methodology to stereotactic body radiation metastases has the potential to improve further palliation of unresectable metastases.

#### **7.8. Systemic therapies**

#### *7.8.1. Chemotherapy*

*7.5.4. Satellite metastases*

104 Highlights in Skin Cancer

**7.7. Radiation therapy**

done with melphalan and actinomycin D [51, 67].

**7.6. Treatment of distant or disseminated metastasis**

gional control of the disease and may help to decrease morbidity.

compression and painful bone metastasis, local radiation can be used.

For localized disease, limited to one extremity only, first choice of treatment should ideally be surgical excision with clear margins if possible. But in case of multiple lesions, chance of performing an ideal excision may be low, so in that case, isolated limb perfusion can be considered. It is a simple and less invasive, yet more effective treatment. Main idea about isolated limb perfusion is giving high doses of chemotherapeutic agents locally, to avoid systemic toxicity, and obtain more therapeutic effect. The technique of this method involves perfusing an isolated arm or leg, in a hyperthermic environment, with cytotoxic agents. Conventinally chemotherapeutic agent used in this procedure is melphalan. Approximately in half of the patients, complete disappearance of the lesion is observed. Although systemic side effects of this method is fairly less, when compared to conventinal chemotherapy, local side effects can be serious. Significant tissue damage due to high concentrations of cytotoxic agent can be seen. Compartment syndrome is one of the most severe morbidities. Advanced age and patients with serious co-morbidities are usually not preferred for this type of treat‐ ment. A new approach is isolated limb infusion, which is a less invasive method, for appliance on patients with older age or worse general health conditions. Isolated limb infusion can be

In case of stage 4 melanoma, with distant metastasis, mean survival is 6 to 8 months and there is currently no effective systemic treatment, to increase survival rate. For this reason, main treatment goal is the palliation of symptoms. For the patients with increased age and serious comorbidities, observation and conservative treatment may also be the option of choice [146]. If there are symptomatic visceral metastasis, surgical excision to perform metastasectomy can be tried. Also excision of skin metastasis or lymph node metastasis may improve the locore‐

In one case report [148], a 44-year-old *Caucasian* woman who underwent extensive surgical resection of a melanoma on the right side of her scalp, came with a new metastasis, a large nodule in her right cheek. The patient underwent two sessions of electrochemotherapy with intravenous injections of bleomycin, as neoadjuvant treatment permitting conservative surgery three months later. In this case, electrochemotherapy offers the option of more conservative surgery and an improved cosmetic effect with complete local tumor control.

Although melanoma is known to be radiotherapy resistant, for brain metastasis, spinal cord

Radiation therapy plays a role in the management of primary cutaneous melanoma in definitive, adjuvant, and palliative settings. The role for radiation therapy in early stage primary melanom is limited as the treatment is adequate excision. However desmoplastic melanoma and those with neurotropism invasion are exceptions, due to frequent local recurrence [149]. The greatest controversy regarding radiotherapy lies with its use in stage III For systemic chemotherapy, first line chemotherapeutic agent is dacarbazine, an alkylating agent. It is an U.S. Food and Drug Administration (FDA) approved chemotherapy drug for metastatic melanoma. It is thought to be the most effective single agent therapy. Approxi‐ mately 10 to 20% of the patients response to treatment and the mean duration of response is 4 to 6 months. Dose of the treatment does not affect the response rate. Major side effects of dacarbazine are nausea and vomiting. Temozolomide is also an alkylating agent. This chemotherapeutic agent can also be used orally. Another advantage is that, temozolomide can cross the blood-brain barrier. Thus for patients with central nervous system involvement, temozolomide can be preferred. According to a randomized phase 3 study, its efficacy is equal to dacarbazine. For metastatic melanoma to brain, a combination of temozolomide and thalidomide, along with radiation, can be benefical. For dacarbazine, increased response rates are reported, when combined with other cytotoxic agents like cisplatin, vinblastine, carmustine or tamoxifen [144].

#### *7.8.2. Immunotherapy*

Among immunotherapeutic agents, interleukin 2 (IL-2) is the only agent, which has an approval form FDA. Overall response rate of this agent is 16%, but a durable response rate is 5 to 8%. Approximately the time for the duration of response is 9 months. Of the 28% of the patients with metastatic melanoma who responded to IL-2 treatment, no progression was observed at a follow-up period of 62 months. Also patients who responded longer than 30 months, did not show any sign of relapse afterwards. On the other hand, there are some important side effects of IL-2 treatment. Most common side effect of IL-2 is hypotension. It can also cause capillary leak syndrome, supraventricular tachycardia, transient renal insufficiency, respiratory distress, increased susceptibility to infections. There are also newer investigations about combining IL-2 with tumor-infiltrating lymphocytes and lymphokine activated killer cells. These immunologically active cells are considered to be helpful in transferring and adoptive immune force, to generate an antitumor effect.

investigation includes SB590885, dabrafenib (GSK2118436), AZ628, XL281, GDC-0879, and vemurafenib (RG704, PLX4032/4720) [153]. PLX4032 (and its analogue PLX4720) are adenosine triphosphate (ATP)-competitive RAF inhibitors (wild-type BRAF 50% inhibitory concentration [IC50]-100 nmol/L, mutated BRAF IC50-31 nmol/L) that selectively inhibit growth in melano‐ ma cell lines harboring the BRAF V600E mutation in both in vitro and in vivo mouse xenograft

Current Management of Malignant Melanoma: State of the Art

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

107

Much of the foundation for the development of these treatments is the realisation that melanoma growth and progression is driven by somatic activating mutations in signalling molecules such as BRAF, KIT, NRAS and GNAQ/GNA11 [147]. Active drugs targeting BRAF and KIT are available and and the anti-CTLA4 antibody ipilimumab has shown an overall survival benefit and the possibility of prolonged disease control in the metastatic setting.

Although there are many phase III trials in progress, about treatment of metastatic melanoma, up to now, no curative adjuvant or systemic therapies have been approved for stage 4 metastatic melanoma. Among these treatments some may have serious side effects. According to one study [7], patients with metastatic melanoma are treated with the selective BRAF inhibitor, dabrafenib. Keratinocyte proliferation is characteristic of BRAF inhibitor induced cutaneous toxicities, and the spectrum of lesions ranges from benign seborrhoreic keratoses, *Grover*'s disease and plantar hyperkeratosis through to verrucal keratoses of undetermined

In the future of metastatic melanoma treatment, molecular profiling of patient tumors will play an important role in the part of therapy selection for medical oncologists. Recent preclinical studies shows that inhibitors of BRAF paradoxically activate MAPK signaling in tumors that lack activating BRAF mutations [153]. Reports from six independent groups have shown that BRAF inhibition activates MAPK in cell lines with NRAS and KRAS mutations, as well as those cell lines where the MAPK pathway is activated through other oncogenes such as HER2. Studies showed that although vemurafenib and other BRAF inhibitors were able to profoundly inhibit the activity of BRAF V600E-containing complexes in melanoma cells, they instead promoted the activity of CRAF-CRAF dimers in cells with RAS mutations, leading in turn to MEK activation. There is also evidence that PLX4032 increases the invasive potential of NRASmutated melanoma cells through the activation of ERK and FAK signaling. Additional studies demonstrated that BRAF inhibitors may even contribute to the progression of NRAS-mutated melanomas in part by suppressing apoptosis through the modulation of Mcl-1 expression.

According to one study [155], data of 97 patients with melanoma show substantial clinical activity of trametinib, MEK inhibitor. Differences in response rates during this treatment,

These studies are extremely important for approaching the development of new cancer therapies as they indicate that simple empiric evaluation of novel cancer therapeutics in patients could be associated with adverse outcomes. Instead they affirm the approach of rationally developing therapies in cancer patients based on strong preclinical data and

according to mutations indicate the importance of mutational analyses.

individual patient molecular profiling.

prognosis and malignant well differentiated SCCs.

models [154].

In a case study [151], patient with cutaneous metastasis with significant comorbidities, including advanced age, anticoagulation for a metallic valve, chronic anemia, macular degeneration, and history of hematopoietic malignancy (high-grade lymphoma, *Walden‐ strom* macroglobulinemia) was treated with a novel method. 1% gentian violet was applied to the wounds, and the patient was instructed to apply gentian violet and imiquimod to the base of the lesions daily. This was accompanied by a brisk inflammatory response. At the time of reexamination, 4 months after the procedure, no clinical recurrence was noted. This method can be useful when surgery is not an option.

In another case [152], 82-year-old man who presented with rapidly progressing cutaneous melanoma metastases, together with inguinal lymph nodes and bilateral pulmonary involve‐ ment, treated with topical immunotherapy with diphencyclopropenone (DPCP) in aqueous cream weekly to elicit moderate contact hypersensitivity. Larger lesions were also treated with intralesional 5-fluorouracil (50 mg/mL). One month later, cutaneous metastases began to regress, and during the following 4 months his inguinal lymphadenopathy and pulmonary lesions disappeared. He remains clinically disease free 18 months after his metastases began to regress. This can show the potential for some patients to overcome even widespread and extensive disease, presumably via immune-mediated regression, and raises the possibility that topical immunotherapy may play a role even in patients with bulky disease.

#### *7.8.3. Biochemotherapy*

Biochemotherapy alone has not shown any increase in overall survival rate, but when compared to other systemic chemotherapeutic agents like dacarbazine, or interferon, vaccines, IL-2, it can show better results.

#### *7.8.4. Novel therapies*

About the etiopathology of intrinsic resistance of malignant melanoma to chemotherapy, the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) is found to play an important role. A new antisense Bcl-2 oligonucleotide, Oblimersen, is targeting Bcl-2 messenger RNA selectively and this leads to the degradation of the Bcl-1, thus decreasing the levels of Bcl-2 in the body. Oblimersen can also be used in combination with conventional systemic chemotherapeutic agents, like dacarbazine.

Also in two-thirds of melanomas, there is a mutation in B-raf gene. A RAF inhibitor, Sorafenib, inhibits both B-raf and C-raf, and also used orally. Since the evaluation of sorafenib, a new generation of BRAF inhibitors has been developed. These drugs show higher potency against mutated BRAF and have fewer off-target effects; the list of those currently under preclinical investigation includes SB590885, dabrafenib (GSK2118436), AZ628, XL281, GDC-0879, and vemurafenib (RG704, PLX4032/4720) [153]. PLX4032 (and its analogue PLX4720) are adenosine triphosphate (ATP)-competitive RAF inhibitors (wild-type BRAF 50% inhibitory concentration [IC50]-100 nmol/L, mutated BRAF IC50-31 nmol/L) that selectively inhibit growth in melano‐ ma cell lines harboring the BRAF V600E mutation in both in vitro and in vivo mouse xenograft models [154].

important side effects of IL-2 treatment. Most common side effect of IL-2 is hypotension. It can also cause capillary leak syndrome, supraventricular tachycardia, transient renal insufficiency, respiratory distress, increased susceptibility to infections. There are also newer investigations about combining IL-2 with tumor-infiltrating lymphocytes and lymphokine activated killer cells. These immunologically active cells are considered to be helpful in transferring and

In a case study [151], patient with cutaneous metastasis with significant comorbidities, including advanced age, anticoagulation for a metallic valve, chronic anemia, macular degeneration, and history of hematopoietic malignancy (high-grade lymphoma, *Walden‐ strom* macroglobulinemia) was treated with a novel method. 1% gentian violet was applied to the wounds, and the patient was instructed to apply gentian violet and imiquimod to the base of the lesions daily. This was accompanied by a brisk inflammatory response. At the time of reexamination, 4 months after the procedure, no clinical recurrence was noted. This method

In another case [152], 82-year-old man who presented with rapidly progressing cutaneous melanoma metastases, together with inguinal lymph nodes and bilateral pulmonary involve‐ ment, treated with topical immunotherapy with diphencyclopropenone (DPCP) in aqueous cream weekly to elicit moderate contact hypersensitivity. Larger lesions were also treated with intralesional 5-fluorouracil (50 mg/mL). One month later, cutaneous metastases began to regress, and during the following 4 months his inguinal lymphadenopathy and pulmonary lesions disappeared. He remains clinically disease free 18 months after his metastases began to regress. This can show the potential for some patients to overcome even widespread and extensive disease, presumably via immune-mediated regression, and raises the possibility that

Biochemotherapy alone has not shown any increase in overall survival rate, but when compared to other systemic chemotherapeutic agents like dacarbazine, or interferon, vaccines,

About the etiopathology of intrinsic resistance of malignant melanoma to chemotherapy, the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) is found to play an important role. A new antisense Bcl-2 oligonucleotide, Oblimersen, is targeting Bcl-2 messenger RNA selectively and this leads to the degradation of the Bcl-1, thus decreasing the levels of Bcl-2 in the body. Oblimersen can also be used in combination with conventional systemic chemotherapeutic

Also in two-thirds of melanomas, there is a mutation in B-raf gene. A RAF inhibitor, Sorafenib, inhibits both B-raf and C-raf, and also used orally. Since the evaluation of sorafenib, a new generation of BRAF inhibitors has been developed. These drugs show higher potency against mutated BRAF and have fewer off-target effects; the list of those currently under preclinical

topical immunotherapy may play a role even in patients with bulky disease.

adoptive immune force, to generate an antitumor effect.

can be useful when surgery is not an option.

*7.8.3. Biochemotherapy*

106 Highlights in Skin Cancer

*7.8.4. Novel therapies*

agents, like dacarbazine.

IL-2, it can show better results.

Much of the foundation for the development of these treatments is the realisation that melanoma growth and progression is driven by somatic activating mutations in signalling molecules such as BRAF, KIT, NRAS and GNAQ/GNA11 [147]. Active drugs targeting BRAF and KIT are available and and the anti-CTLA4 antibody ipilimumab has shown an overall survival benefit and the possibility of prolonged disease control in the metastatic setting.

Although there are many phase III trials in progress, about treatment of metastatic melanoma, up to now, no curative adjuvant or systemic therapies have been approved for stage 4 metastatic melanoma. Among these treatments some may have serious side effects. According to one study [7], patients with metastatic melanoma are treated with the selective BRAF inhibitor, dabrafenib. Keratinocyte proliferation is characteristic of BRAF inhibitor induced cutaneous toxicities, and the spectrum of lesions ranges from benign seborrhoreic keratoses, *Grover*'s disease and plantar hyperkeratosis through to verrucal keratoses of undetermined prognosis and malignant well differentiated SCCs.

In the future of metastatic melanoma treatment, molecular profiling of patient tumors will play an important role in the part of therapy selection for medical oncologists. Recent preclinical studies shows that inhibitors of BRAF paradoxically activate MAPK signaling in tumors that lack activating BRAF mutations [153]. Reports from six independent groups have shown that BRAF inhibition activates MAPK in cell lines with NRAS and KRAS mutations, as well as those cell lines where the MAPK pathway is activated through other oncogenes such as HER2. Studies showed that although vemurafenib and other BRAF inhibitors were able to profoundly inhibit the activity of BRAF V600E-containing complexes in melanoma cells, they instead promoted the activity of CRAF-CRAF dimers in cells with RAS mutations, leading in turn to MEK activation. There is also evidence that PLX4032 increases the invasive potential of NRASmutated melanoma cells through the activation of ERK and FAK signaling. Additional studies demonstrated that BRAF inhibitors may even contribute to the progression of NRAS-mutated melanomas in part by suppressing apoptosis through the modulation of Mcl-1 expression.

According to one study [155], data of 97 patients with melanoma show substantial clinical activity of trametinib, MEK inhibitor. Differences in response rates during this treatment, according to mutations indicate the importance of mutational analyses.

These studies are extremely important for approaching the development of new cancer therapies as they indicate that simple empiric evaluation of novel cancer therapeutics in patients could be associated with adverse outcomes. Instead they affirm the approach of rationally developing therapies in cancer patients based on strong preclinical data and individual patient molecular profiling.

#### **7.9. Vaccines**

Melanoma is considered as a rather "immunogenic" tumor. One can understand it by the spontaneous immune-mediated regression of primary tumors, association between infiltrating T lymphocytes and improved survival, response to nonspecific immunothera‐ py agents, including interferon-alpha, IL-2, and ipilimumab and identification of tumorassociated melanoma antigens and human leukocyte antigen (HLA)-restricted epitopes within these anti- gens [156].

5-year survival. In general, the higher the *Breslow* thickness, the worse the prognosis (Table

Current Management of Malignant Melanoma: State of the Art

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

109

**Breslow thickness 5-year survival** ≤1 mm (T1) 95% to 100% 1.01 to 2 mm (T2) 80% to 96% 2.01 to 4 mm (T3) 60% to 75% >4 mm (T4) 37% to 50%

The depth of the tumor is most accurately measured by evaluating the entire tumor via an excisional biopsy. Determination from specimens obtained using other biopsy techniques, such as a wedge or punch biopsy, is less accurate. Tumor depth cannot be calculated from a shave biopsy that only contains a portion of the tumor because it leads to an underestimation of its thickness. Excisional biopsy should extend down to the subcutaneous fat tissue [163].

*Clark* level of invasion is a method for determining the prognosis (outlook) with melanoma. This method was devised by the pathologist *Wallace Clark* and measured the depth of pene‐ tration of a melanoma into the skin according to anatomic layer. There are five *Clark* levels of

The *Clark* levels provide a system to relate the degree of penetration of melanoma into the skin

Ulceration is the second most powerful factor for poor prognosis. The presence of ulcerations on the surface of the tumour causes a reduction in the survival rate. Ulcerations appear when an intact epidermis is not present around the tumour and is usually a result of an aggressive tumour. The presence of ulceration in tumours less than 1mm, causes a reduction in survival rate by 4% compared to non-ulcerated tumour. Survival rates can be reduced by up to 22% if the tumour thickness is greater than 4mm.This therefore, indicates that tumour thickness and ulceration have strong relationship with survival rates and so the prognosis of thin non-

Current studies have shown that tumor mitotic rate is a powerful independent prognos‐ tic factor. But the prognostic importance of mitotic rate in melanoma recurrences is not known. A high mitotic rate also correlates with a greater likelihood of having a positive sentinel lymph node biopsy. The mitotic rate is measured by simply examining the excised tumor with a microscope and manually counting the number of cells exhibiting mitosis, an easily identifiable characteristic of dividing cells. Most often, the mitotic rate is reported as

to the 5-year survival rate after surgical removal of the melanoma [158, 161, 164].

3) [161,162].

invasion (Table 1).

ulcerated melanoma is excellent [51].

one of three categories :

**•** less than 1 per square millimeter

**•** 1 to 4 per square millimeter

**Table 3.** The relation of *Breslow* thickness and prognosis

A variety of strategies, including peptide and protein vaccines, recombinant DNA and viral vectors, and the use of autologous and allogeneic whole cell vaccines, have been tested in patients. Although many studies have not had significant clinical benefit, there are some important data that have emerged from these clinical trials. There also have been at least two randomized phase III vaccine trials that have shown a clinical benefit in melanoma [157].

There has been considerable interest in the identification of patient-specific and tumor-specific biomarkers that may predict therapeutic response and clinical outcomes. These studies would help select patients more likely to respond to a particular vaccine approach and might identify new strategies for improving the potency of individual vaccines so that more patients might benefit from immunotherapy.

#### **8. Prognosis**

Malignant melanoma is the most fatal type of the skin cancers. The best survival rates of melanoma arise if it is detected at the early stages, this is generally when the size of the tumours is small and treatable. After detection the prognosis of the melanoma can be determined by assessing a number of histopathological (morphological) factors such as the thickness of lesions, levels of invasion, presence of ulceration and the number of metastatic lymph nodes involved. Clinical prognostic factors such as age, sex, anatomical location of the tumour can also be used to determine the possible progression of the cancer and the likely survival rates of the patient. The thickness of the tumor is the dominant prognostic factor in determining risk of metastasis and prognosis for cutaneous melanoma [158, 159]. The American Joint Commit‐ tee on Cancer (AJCC) tumor node metastasis committee has approved a new melanoma staging system, which was implemented in 2009 [160]. The prognostic factors included in AJCC staging system are tumor thickness, ulceration, level of invasion (*Clark*'s level) and mitotic rate [160, 161].

In the AJCC staging system, tumor thickness is the most powerful independent prognostic factor for patients with cutaneous melanoma. Melanoma thickness is measured from the granular layer of the epidermis to the greatest depth of tumor invasion, this was originally described by *Breslow* in 1970. Now it is correlated with a thickness of ≤1 mm (T1), 1.01 to 2 mm (T2), 2.01 to 4 mm (T3), or ≥4 mm (T4) [159]. In it, invasive tumor thickness is used to predict 5-year survival. In general, the higher the *Breslow* thickness, the worse the prognosis (Table 3) [161,162].


**Table 3.** The relation of *Breslow* thickness and prognosis

**7.9. Vaccines**

108 Highlights in Skin Cancer

[157].

within these anti- gens [156].

benefit from immunotherapy.

**8. Prognosis**

[160, 161].

Melanoma is considered as a rather "immunogenic" tumor. One can understand it by the spontaneous immune-mediated regression of primary tumors, association between infiltrating T lymphocytes and improved survival, response to nonspecific immunothera‐ py agents, including interferon-alpha, IL-2, and ipilimumab and identification of tumorassociated melanoma antigens and human leukocyte antigen (HLA)-restricted epitopes

A variety of strategies, including peptide and protein vaccines, recombinant DNA and viral vectors, and the use of autologous and allogeneic whole cell vaccines, have been tested in patients. Although many studies have not had significant clinical benefit, there are some important data that have emerged from these clinical trials. There also have been at least two randomized phase III vaccine trials that have shown a clinical benefit in melanoma

There has been considerable interest in the identification of patient-specific and tumor-specific biomarkers that may predict therapeutic response and clinical outcomes. These studies would help select patients more likely to respond to a particular vaccine approach and might identify new strategies for improving the potency of individual vaccines so that more patients might

Malignant melanoma is the most fatal type of the skin cancers. The best survival rates of melanoma arise if it is detected at the early stages, this is generally when the size of the tumours is small and treatable. After detection the prognosis of the melanoma can be determined by assessing a number of histopathological (morphological) factors such as the thickness of lesions, levels of invasion, presence of ulceration and the number of metastatic lymph nodes involved. Clinical prognostic factors such as age, sex, anatomical location of the tumour can also be used to determine the possible progression of the cancer and the likely survival rates of the patient. The thickness of the tumor is the dominant prognostic factor in determining risk of metastasis and prognosis for cutaneous melanoma [158, 159]. The American Joint Commit‐ tee on Cancer (AJCC) tumor node metastasis committee has approved a new melanoma staging system, which was implemented in 2009 [160]. The prognostic factors included in AJCC staging system are tumor thickness, ulceration, level of invasion (*Clark*'s level) and mitotic rate

In the AJCC staging system, tumor thickness is the most powerful independent prognostic factor for patients with cutaneous melanoma. Melanoma thickness is measured from the granular layer of the epidermis to the greatest depth of tumor invasion, this was originally described by *Breslow* in 1970. Now it is correlated with a thickness of ≤1 mm (T1), 1.01 to 2 mm (T2), 2.01 to 4 mm (T3), or ≥4 mm (T4) [159]. In it, invasive tumor thickness is used to predict The depth of the tumor is most accurately measured by evaluating the entire tumor via an excisional biopsy. Determination from specimens obtained using other biopsy techniques, such as a wedge or punch biopsy, is less accurate. Tumor depth cannot be calculated from a shave biopsy that only contains a portion of the tumor because it leads to an underestimation of its thickness. Excisional biopsy should extend down to the subcutaneous fat tissue [163].

*Clark* level of invasion is a method for determining the prognosis (outlook) with melanoma. This method was devised by the pathologist *Wallace Clark* and measured the depth of pene‐ tration of a melanoma into the skin according to anatomic layer. There are five *Clark* levels of invasion (Table 1).

The *Clark* levels provide a system to relate the degree of penetration of melanoma into the skin to the 5-year survival rate after surgical removal of the melanoma [158, 161, 164].

Ulceration is the second most powerful factor for poor prognosis. The presence of ulcerations on the surface of the tumour causes a reduction in the survival rate. Ulcerations appear when an intact epidermis is not present around the tumour and is usually a result of an aggressive tumour. The presence of ulceration in tumours less than 1mm, causes a reduction in survival rate by 4% compared to non-ulcerated tumour. Survival rates can be reduced by up to 22% if the tumour thickness is greater than 4mm.This therefore, indicates that tumour thickness and ulceration have strong relationship with survival rates and so the prognosis of thin nonulcerated melanoma is excellent [51].

Current studies have shown that tumor mitotic rate is a powerful independent prognos‐ tic factor. But the prognostic importance of mitotic rate in melanoma recurrences is not known. A high mitotic rate also correlates with a greater likelihood of having a positive sentinel lymph node biopsy. The mitotic rate is measured by simply examining the excised tumor with a microscope and manually counting the number of cells exhibiting mitosis, an easily identifiable characteristic of dividing cells. Most often, the mitotic rate is reported as one of three categories :


#### **•** greater than 4 per square millimeter

The higher the mitotic count, the more likely the tumor is to have metastasized. The logic is that the more cells are dividing, the more likely they will invade the blood or lymphatic systems and thus spread around the body. Research has shown that the odds of survival for patients with stage I melanoma and a mitotic rate of 0 per square millimeter is twelve times better than that of patients with a mitotic rate of greater than 6 per square millimeter. Also, only 4% of lesions with low mitotic rate recur compared to 24% of those with a high mitotic rate. Mitotic rate can also help to predict that your sentinel lymph node biopsy will be positive or not. Although mitotic rate has no role in the current staging system for melanoma, research has demonstrated that it is a more important prognostic factor than ulceration, which does have an important role in staging. The American Academy of Dermatology argues that mitotic rate should be optional in biopsy reports or not. On the other hand, the National Comprehensive Cancer Center recommends that mitotic rate should be reported for all lesions in stage I to II patients. Still other experts argue that measuring the mitotic rate should only be done in large academic medical centers for future research purposes. Increasing mitotic rate is related with a decreasing survival [165, 166].

female. In one study, 11.734 patients were analyzed, 49.3% were male. Between 1978 and 1992, most of the newly registered melanoma patients were female, but after 1992 there was a higher incidence of male patients. Men exhibited a disadvantaged distribution for almost all prog‐ nostic indicators being significantly older at diagnosis, having thicker melanomas, and having more melanomas localized on the trunk or head and neck. In analyses of histological subtypes, females had significantly more lentigo maligna melanomas and acral lentiginous melanomas, but the incidence of superficial spreading melanoma and nodular melanoma did not differ across gender. Males more often presented with lymph node metastases or distant metastases at the time of diagnosis than did females (5.2 vs. 3.0% and 1.7 vs. 1.1%, respectively). Whereas overall disease progression, lymph node metastasis, and distant metastasis occurred signifi‐ cantly more often in males than in females, local recurrence and in-transit/satellite metastases

Current Management of Malignant Melanoma: State of the Art

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

111

If we summarize, prognostic factors include tumor thickness (mm), levels of invasion, presence of ulceration, increased mitotic rate. Prognosis is better if there happens to be tumor-infiltrating lymphocytes around the lesion. There is stil controversy going on about regression. Some studies have shown an adverse outcome while others no effect, or a favorable outcome. Presence of microscopic satellites shows bad prognosis and also angiotropism is a bad prognostic marker. Vascular/lymphatic invasion, although seen very rarely, indicates unfav‐ orable prognosis. Tumor cell type also has an effect on prognosis. Better prognosis with spindle cells versus other cell types. Prognosis worsens with increasing age and women have better prognosis than men. Extremity lesions have better prognosis than axial lesions (trunk, head

Melanoma is the most dangerous form of skin cancer [174]. The incidence of melanoma is increasing worldwide, more than other cancers. The clinicians has the greatest impact on reducing these cases. They educate patients about early detection, treatment and prevention methods [175]. UV light is the most important risk factor for melanoma development. The risk of developing melanom may be reduced by protecting from UV light exposure. We must educate others as to the importance of sun protection [174]. Patients should be educated to avoid intense intermittent sun exposure and minimize cumulative sun exposure [176]. Avoiding overexposure to direct sunlight during the peak daylight hours, wearing protective

Clinicians must educate patients as to the importance of using sunscreens that protects against both UVA and UVB light and with an SPF 30 or greater [174, 175]. It is important to emphasize the correct application of the recommended amount of sunscreen and the need for reapplica‐ tion of sunscreen [176]. Sunscreen should be applied to exposed dry skin 15 to 30 minutes before sun exposure. The standard amount of sunscreen used in SPF testing is 2 mg/cm2

Sunscreen should be reapplied every 2 hours or after swimming or heavy perspiration; many water-resistant sunscreens lose effectiveness after 40 minutes in the water [177]. Clinicians

.

clothing, and applying sunscreen are the ways to protect the skin [177].

were equally common [170-172].

and neck, palms and soles) [12, 173].

**9. Patient education**

Tumor-infiltrating lymphocytes (TILs) describe the patient's immune response to the mela‐ noma. One marker used to determine immune activity in melanoma is the presence in sentinel lymph node biopsy samples, which has been variably associated with a favorable prognosis. Some investigators assessed whether the presence of tumor-infiltrating lymphocytes was an independent predictor of sentinel lymph node biopsy status and survival or not [167, 168].

Microscopic satellites are defined as dermal or subcutaneous nodules. Microscopic satellites in primary melanomas are considered to be localized micrometastases developing in close proximity to the main tumoral portion of melanomas and show bad prognosis. In particular, the presence of angiotropism predicts the detection of microscopic satellites, and microscopic satellites probably develop as a result of extravascular migration. Consequently the linkage between microscopic satellites and angiotropism provides additional support for extravascu‐ lar migratory metastasis as a mechanism of melanoma metastasis. Finally, ongoing investiga‐ tions to develop a more specific biomarker for angiotropism and extravascular migratory metastasis are essential for the more precise recognition of extravascular migratory metastases and the explaining of its biological and prognostic significance. This pericytic angiotropism of melanoma cells, without any sign of intravasation, suggests that melanoma cells may migrate along the external surface of vessels, a mechanism we have termed extravascular migratory metastasis (EVMM), as distinct from intravascular dissemination [51, 169].

Common cell types are epithelioid and spindle cells, although mixed cells may also be seen. Generally, spindle cells are associated with better prognosis than other cell types.

The incidence of malignant melanoma appears to be increasing at an alarming rate throughout the world over the past 35-40 years and continues to increase in the USA, Canada, Asia, Australia, and Europe. The behavior of head and neck melanoma is aggressive, and it has an overall poorer prognosis than that of other skin sites. Correlations between different factors were found, e.g. tumour localisation predominating on the back in males and on the legs in female. In one study, 11.734 patients were analyzed, 49.3% were male. Between 1978 and 1992, most of the newly registered melanoma patients were female, but after 1992 there was a higher incidence of male patients. Men exhibited a disadvantaged distribution for almost all prog‐ nostic indicators being significantly older at diagnosis, having thicker melanomas, and having more melanomas localized on the trunk or head and neck. In analyses of histological subtypes, females had significantly more lentigo maligna melanomas and acral lentiginous melanomas, but the incidence of superficial spreading melanoma and nodular melanoma did not differ across gender. Males more often presented with lymph node metastases or distant metastases at the time of diagnosis than did females (5.2 vs. 3.0% and 1.7 vs. 1.1%, respectively). Whereas overall disease progression, lymph node metastasis, and distant metastasis occurred signifi‐ cantly more often in males than in females, local recurrence and in-transit/satellite metastases were equally common [170-172].

If we summarize, prognostic factors include tumor thickness (mm), levels of invasion, presence of ulceration, increased mitotic rate. Prognosis is better if there happens to be tumor-infiltrating lymphocytes around the lesion. There is stil controversy going on about regression. Some studies have shown an adverse outcome while others no effect, or a favorable outcome. Presence of microscopic satellites shows bad prognosis and also angiotropism is a bad prognostic marker. Vascular/lymphatic invasion, although seen very rarely, indicates unfav‐ orable prognosis. Tumor cell type also has an effect on prognosis. Better prognosis with spindle cells versus other cell types. Prognosis worsens with increasing age and women have better prognosis than men. Extremity lesions have better prognosis than axial lesions (trunk, head and neck, palms and soles) [12, 173].
