Dermoscopic observations help the diagnosis in the early stage of ALM. In 66 cases of volar skin melanomas, irregular diffuse pigmentation (60%) with variable shades from tan to black without parallel disposition of pigment (figure 1a) and the parallel ridge pattern (53%) with pigmentation along the ridges (figure 1b) were the two most prevalent patterns [23]. According to Saida et al., the sensitivity and specificity of the parallel ridge pattern in diag‐ nosing all melanoma on volar skins were 86% and 99% respectively and those of irregular diffuse pigmentation were 85% and 97% respectively. Only in diagnosing melanoma in situ on volar skin, the sensitivity of parallel ridge pattern (86%) was significantly higher than that of irregular diffuse pigmentation (69%) [24]. A parallel furrow pattern with pigmenta‐ tion along the furrows (figure 1c) and a lattice-like pattern with longitudinal and transversal thicker lines surrounding the eccrine pores (figure 1d) are more common in melanocytic ne‐ vi. The sensitivity and specificity of a parallel furrow pattern or lattice-like pattern in diag‐ nosing melanocytic nevi were 67% and 93% respectively [24].

es occurred on the thumbnail, 27% on the nail of the great toe, 2-4% on the nail of the index,

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It is known that subungual melanoma has a very poor prognosis among all subtypes of cu‐ taneous melanomas. The reason for this is because the majority of subungual melanomas are already been quite deep when diagnosed [28]. Delayed diagnosis of subungual melanoma is common because it is very difficult to distinguish the early stage of subungual melanoma from longitudinal melanonychia. According to Cohen et al., 38 of 43 patients (88%) had de‐

Subungual melanomas begin with fine pigmented striata which could not be clinically dis‐ tinguished from benign longitudinal melanonychia at an early stage and grow wider with colour variegation and the presence of nail plate fissuring or splitting eventually forming a triangular shape which has a broader proximal lesion rather than a distal lesion, blurred lat‐ eral borders and Hutchinson's sign - indicating the peripheral pigmentation beyond the nail

Baran et al. mentioned the clinical clues to the diagnosis of subungual melanoma in detail. Hutchinson's sign is the most important sign of subungual melanoma. Other clues are when longitudinal melanonychia (a) begins in a single digit of a person over six decades or more, (b) develops abruptly in a previous normal nail plate, (c) becomes suddenly darker or wider, (d) occurs in either the thumb, index finger or giant toe, (e) is accompanied by nail destruc‐

In addition to these clinical clues, dermoscopy provides useful information for the diagnosis of subungual melanoma. The prominent dermoscopic features of subungual melanoma are brown pigmentation of the background with longitudinal brown to black lines which are ir‐ regular in their colouration, spacing, thickness and parallelism [32]. This irregularity was significantly associated with melanoma when compared with all other benign diseases. The micro-Hutchinson's sign is the suspicious dermoscopic feature, which consists of the irregu‐

Since the early stage of subungual melanoma has minimal histopathological change, it may be difficult to distinguish subungual melanoma from benign lesion with only histopatholog‐ ical findings. Thus, both clinical features, including present history and histopathological

We propose a diagnostic algorithm for the early stage of subungual melanoma (figure 2). When a case falls under any of the clinical features mentioned above (a-g), dermoscopic ex‐ amination is recommended. If Hutchinson's sign and colour change in overall nail to dark black are present, excisional biopsy is recommended. When those characteristic appearances are absent, but a nail streak has irregularity, biopsy is also recommended. On the contrary, when nail streaks are monotonous pale brown, subungual melanoma is not suspicious. Even if a streak is dark brown or black, no irregularity of lines on dermoscopy allows careful fol‐ low-up without biopsies. If the streak increases in width or has colour variegation during a period of follow-up, the necessity of excision or biopsy should be discussed according to

tion or disappearance, (f) has colour variegation, (g) has a wide band and so on [31].

lar lines in the cuticle area and can be observed only on dermoscopy [32,33].

findings, are necessary for diagnosis.

further dermoscopic examination.

layed diagnosis and the median delay time was 24 months (range 4 to 132) [29].

middle and ring finger, 1.6% on the nail of the second toe [27].

apparatus [30].

**Figure 1.** Dermoscopy of early stage ALM (a,b) and melanocytic nevi (c,d). (a) Irregular diffuse pigmentation, (b) paral‐ lel ridge pattern, (c) parallel furrow pattern, (d) lattice-like pattern with longitudinal and transversal thicker lines sur‐ rounding the eccrine pores (arrows).

Ulceration on nodules following pigmented macules reveals a polymorphous vascular pat‐ tern with a combination of milky-red areas (95%) which are larger areas of fuzzy or unfo‐ cused milky-red colour corresponding to an elevated part of the lesion, linear irregular vessels (49%), dotted vessels (43%) and hairpin vessels (41%) [25].

## **2. Subungual melanoma**

The incidence of subungual melanoma also has a racial difference. It is more frequent in Asian and Blacks than in Caucasians. Its frequency has been reported to be approximately 2-4% in all cutaneous melanomas in Caucasians and 10% in Japanese [26]. Of the 108 subun‐ gual melanomas in Japan, the cases involving fingers and toes were 76% and 24% respec‐ tively. On both fingers and toes, the thumb and the great toe were the most common sites [26]. Among the subungual melanoma, the occurrence rate of ALM on the fingernail is high‐ er than on toenails. According to the literature, of 64 cases of subungual melanoma, 55% cas‐ es occurred on the thumbnail, 27% on the nail of the great toe, 2-4% on the nail of the index, middle and ring finger, 1.6% on the nail of the second toe [27].

It is known that subungual melanoma has a very poor prognosis among all subtypes of cu‐ taneous melanomas. The reason for this is because the majority of subungual melanomas are already been quite deep when diagnosed [28]. Delayed diagnosis of subungual melanoma is common because it is very difficult to distinguish the early stage of subungual melanoma from longitudinal melanonychia. According to Cohen et al., 38 of 43 patients (88%) had de‐ layed diagnosis and the median delay time was 24 months (range 4 to 132) [29].

Subungual melanomas begin with fine pigmented striata which could not be clinically dis‐ tinguished from benign longitudinal melanonychia at an early stage and grow wider with colour variegation and the presence of nail plate fissuring or splitting eventually forming a triangular shape which has a broader proximal lesion rather than a distal lesion, blurred lat‐ eral borders and Hutchinson's sign - indicating the peripheral pigmentation beyond the nail apparatus [30].

Baran et al. mentioned the clinical clues to the diagnosis of subungual melanoma in detail. Hutchinson's sign is the most important sign of subungual melanoma. Other clues are when longitudinal melanonychia (a) begins in a single digit of a person over six decades or more, (b) develops abruptly in a previous normal nail plate, (c) becomes suddenly darker or wider, (d) occurs in either the thumb, index finger or giant toe, (e) is accompanied by nail destruc‐ tion or disappearance, (f) has colour variegation, (g) has a wide band and so on [31].

In addition to these clinical clues, dermoscopy provides useful information for the diagnosis of subungual melanoma. The prominent dermoscopic features of subungual melanoma are brown pigmentation of the background with longitudinal brown to black lines which are ir‐ regular in their colouration, spacing, thickness and parallelism [32]. This irregularity was significantly associated with melanoma when compared with all other benign diseases. The micro-Hutchinson's sign is the suspicious dermoscopic feature, which consists of the irregu‐ lar lines in the cuticle area and can be observed only on dermoscopy [32,33].

**Figure 1.** Dermoscopy of early stage ALM (a,b) and melanocytic nevi (c,d). (a) Irregular diffuse pigmentation, (b) paral‐ lel ridge pattern, (c) parallel furrow pattern, (d) lattice-like pattern with longitudinal and transversal thicker lines sur‐

Ulceration on nodules following pigmented macules reveals a polymorphous vascular pat‐ tern with a combination of milky-red areas (95%) which are larger areas of fuzzy or unfo‐ cused milky-red colour corresponding to an elevated part of the lesion, linear irregular

The incidence of subungual melanoma also has a racial difference. It is more frequent in Asian and Blacks than in Caucasians. Its frequency has been reported to be approximately 2-4% in all cutaneous melanomas in Caucasians and 10% in Japanese [26]. Of the 108 subun‐ gual melanomas in Japan, the cases involving fingers and toes were 76% and 24% respec‐ tively. On both fingers and toes, the thumb and the great toe were the most common sites [26]. Among the subungual melanoma, the occurrence rate of ALM on the fingernail is high‐ er than on toenails. According to the literature, of 64 cases of subungual melanoma, 55% cas‐

vessels (49%), dotted vessels (43%) and hairpin vessels (41%) [25].

rounding the eccrine pores (arrows).

478 Melanoma - From Early Detection to Treatment

**2. Subungual melanoma**

Since the early stage of subungual melanoma has minimal histopathological change, it may be difficult to distinguish subungual melanoma from benign lesion with only histopatholog‐ ical findings. Thus, both clinical features, including present history and histopathological findings, are necessary for diagnosis.

We propose a diagnostic algorithm for the early stage of subungual melanoma (figure 2). When a case falls under any of the clinical features mentioned above (a-g), dermoscopic ex‐ amination is recommended. If Hutchinson's sign and colour change in overall nail to dark black are present, excisional biopsy is recommended. When those characteristic appearances are absent, but a nail streak has irregularity, biopsy is also recommended. On the contrary, when nail streaks are monotonous pale brown, subungual melanoma is not suspicious. Even if a streak is dark brown or black, no irregularity of lines on dermoscopy allows careful fol‐ low-up without biopsies. If the streak increases in width or has colour variegation during a period of follow-up, the necessity of excision or biopsy should be discussed according to further dermoscopic examination.

bone. However, not all cases of nail destruction are accompanied with invasion. Some cases of nail destruction may be melanomas in situ. Since the distance between nail bed and bone is wider at the distal side than at the proximal side, the possibility of avoiding amputation is

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Moehrle et al. proposed 'functional' surgery for subungual melanoma, by which the ampu‐ tation of the distal phalanx could be avoided and the more digital function could be pre‐ served [35]. The tumour was surgically removed with measurable excision margins and a partial resection of the distal part of the distal phalanx was performed with a Luer instru‐ ment. After the resection, three-dimensional histology was performed as described in the lit‐ erature [36]. Two of 31 patients had local recurrence after this operation. This method did not lead to shorter survival when compared to amputation, thus, it is worth considering.

According to a review of the literature on the margins of radical excision for melanomas thinner than 2mm, the French Cooperative Group Trial [37] and the Scandinavian Melano‐ ma Group Study [38] compared 2cm with 5cm margins and the World Health Organization (WHO) Melanoma Program Trial 10 [39] compared 1cm with 3cm margins. All three trials

Although a 5mm margin for melanoma in situ is frequently recommended in some national guidelines, Kunishige et al. demonstrated that 86% of 1120 melanomas in situ were success‐ fully excised with a 6mm margin and 98.9% with a 9mm margin. They concluded that a 6mm margin for melanomas in situ was inadequate and a 9mm margin was necessary [40]. A 1cm margin of excision has been proposed for melanomas less than 1mm thick and a wid‐ er margin for more than 1mm thick [41,42]. Although many national guidelines recommend that a 1 cm margin is appropriate for 1-2mm thick invasive melanoma, this is less clear be‐ cause there has been very little data indicating that a 1cm margin for 1-2mm thick melano‐ ma is safer than 2cm margin [43]. For more than 2mm thick melanomas, a 2cm margin is considered to be sufficient in almost all cases. Depth of excision has been recommended to be at least the level of muscle fascia and deeper excision under it has not been shown to im‐

For melanomas on the extremities, especially on fingers, amputation impairs the function. Thus, even if finger amputation is necessary, it is desirable that the defect is smaller so that functional impairment can be minimal. Detailed histopathological examination of resected specimens may allow surgeons to excise a smaller part of the fingers. We show the patho‐ logical specimen as illustrated on Figure 3. Because the resected margins are usually intri‐ cately curved, the specimen is divided into several parts so that a marginal side of each part becomes planar and paraffin sections can be made so that the whole surface of the marginal side can be examined. This technique provides highly accurate detection of continuous le‐ sions with a small possibility of missing skip lesions. If the margin is negative, additional

excision is not necessary and that provides preservation of more digital functions.

higher when the nail destruction is modest and located at the distal side of the nail.

**3. Wide local excision**

prove outcome [43-45].

demonstrated no benefits for wider margins.

**Figure 2.** Diagnostic algorithm for early stage subungual melanoma.

Since nail biopsies cause cosmetic problems, biopsy methods should be selected as follows. If streaks are more likely to be melanoma, complete excisional biopsies are desirable. If it is less likely, punch biopsies around the origin of the longitudinal melanonychia (which is fre‐ quently located on the nail matrix) can be chosen. When excisional biopsies are performed, we should keep in mind that an insufficient margin at the proximal side of the nail may cause incision in between the lesional nail matrix without including the whole lesion. Ultra‐ sound echography provides useful information on the location of the nail matrix [34], so that a sufficient margin can be ensured. Furthermore, it is desirable that extent of the excisional biopsy includes the periosteum of the distal phalanx. Since the distance between the nail matrix and bone is extremely close at the proximal side, excisional biopsies excluding peri‐ osteum may incise the nail matrix and leave some lesion on the body. Excisional biopsies including the periosteum causes very little disadvantage compared with those excluding the periosteum and afterwards good granulation tissue will be formed on the bone when the ar‐ tificial dermis is used. If it is histopathologically diagnosed as subungual melanoma, a local wide excision is selected, excluding the case when a sufficient margin is ensured at the pre‐ vious excisional biopsy.

Excisional biopsies in a good manner allow us to determine correct tumour thickness, which provides important information on the choice of SLNB, local wide excision and chemothera‐ py. However, biopsy specimens easily break down if the biopsy procedure for histological examination is not performed well, which may cause incorrect choices for treatment.

If nail destruction is present under diagnosis of subungual melanoma, amputation of the distal phalanx will be applied on the assumption that the lesion invades the periosteum or bone. However, not all cases of nail destruction are accompanied with invasion. Some cases of nail destruction may be melanomas in situ. Since the distance between nail bed and bone is wider at the distal side than at the proximal side, the possibility of avoiding amputation is higher when the nail destruction is modest and located at the distal side of the nail.

Moehrle et al. proposed 'functional' surgery for subungual melanoma, by which the ampu‐ tation of the distal phalanx could be avoided and the more digital function could be pre‐ served [35]. The tumour was surgically removed with measurable excision margins and a partial resection of the distal part of the distal phalanx was performed with a Luer instru‐ ment. After the resection, three-dimensional histology was performed as described in the lit‐ erature [36]. Two of 31 patients had local recurrence after this operation. This method did not lead to shorter survival when compared to amputation, thus, it is worth considering.

## **3. Wide local excision**

**Figure 2.** Diagnostic algorithm for early stage subungual melanoma.

480 Melanoma - From Early Detection to Treatment

vious excisional biopsy.

Since nail biopsies cause cosmetic problems, biopsy methods should be selected as follows. If streaks are more likely to be melanoma, complete excisional biopsies are desirable. If it is less likely, punch biopsies around the origin of the longitudinal melanonychia (which is fre‐ quently located on the nail matrix) can be chosen. When excisional biopsies are performed, we should keep in mind that an insufficient margin at the proximal side of the nail may cause incision in between the lesional nail matrix without including the whole lesion. Ultra‐ sound echography provides useful information on the location of the nail matrix [34], so that a sufficient margin can be ensured. Furthermore, it is desirable that extent of the excisional biopsy includes the periosteum of the distal phalanx. Since the distance between the nail matrix and bone is extremely close at the proximal side, excisional biopsies excluding peri‐ osteum may incise the nail matrix and leave some lesion on the body. Excisional biopsies including the periosteum causes very little disadvantage compared with those excluding the periosteum and afterwards good granulation tissue will be formed on the bone when the ar‐ tificial dermis is used. If it is histopathologically diagnosed as subungual melanoma, a local wide excision is selected, excluding the case when a sufficient margin is ensured at the pre‐

Excisional biopsies in a good manner allow us to determine correct tumour thickness, which provides important information on the choice of SLNB, local wide excision and chemothera‐ py. However, biopsy specimens easily break down if the biopsy procedure for histological

If nail destruction is present under diagnosis of subungual melanoma, amputation of the distal phalanx will be applied on the assumption that the lesion invades the periosteum or

examination is not performed well, which may cause incorrect choices for treatment.

According to a review of the literature on the margins of radical excision for melanomas thinner than 2mm, the French Cooperative Group Trial [37] and the Scandinavian Melano‐ ma Group Study [38] compared 2cm with 5cm margins and the World Health Organization (WHO) Melanoma Program Trial 10 [39] compared 1cm with 3cm margins. All three trials demonstrated no benefits for wider margins.

Although a 5mm margin for melanoma in situ is frequently recommended in some national guidelines, Kunishige et al. demonstrated that 86% of 1120 melanomas in situ were success‐ fully excised with a 6mm margin and 98.9% with a 9mm margin. They concluded that a 6mm margin for melanomas in situ was inadequate and a 9mm margin was necessary [40].

A 1cm margin of excision has been proposed for melanomas less than 1mm thick and a wid‐ er margin for more than 1mm thick [41,42]. Although many national guidelines recommend that a 1 cm margin is appropriate for 1-2mm thick invasive melanoma, this is less clear be‐ cause there has been very little data indicating that a 1cm margin for 1-2mm thick melano‐ ma is safer than 2cm margin [43]. For more than 2mm thick melanomas, a 2cm margin is considered to be sufficient in almost all cases. Depth of excision has been recommended to be at least the level of muscle fascia and deeper excision under it has not been shown to im‐ prove outcome [43-45].

For melanomas on the extremities, especially on fingers, amputation impairs the function. Thus, even if finger amputation is necessary, it is desirable that the defect is smaller so that functional impairment can be minimal. Detailed histopathological examination of resected specimens may allow surgeons to excise a smaller part of the fingers. We show the patho‐ logical specimen as illustrated on Figure 3. Because the resected margins are usually intri‐ cately curved, the specimen is divided into several parts so that a marginal side of each part becomes planar and paraffin sections can be made so that the whole surface of the marginal side can be examined. This technique provides highly accurate detection of continuous le‐ sions with a small possibility of missing skip lesions. If the margin is negative, additional excision is not necessary and that provides preservation of more digital functions.

institution study in Japan, SLNs were identified in 253 nodal basins from 117 patients and interval SLNs were found in six patients. They recognized 41 (17%) SLN metastases in 246

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Tumours on upper extremities almost always drain to the axillary region. The axillary re‐ gion is divided into three parts based on the pectoralis minor. Level 1, 2 and 3 are located lateral, deep and medial to the pectoralis minor respectively. Outside this conventional re‐ gion, SLNs are recognized in the cubital region and other areas. Figure 4 is the local sites of

SLNs were identified in all 10 cases (100%) for the axillary region, three cases (30%) for the cubital region, three cases (30%) for the upper arm, one case (10%) for the forearm, one case (10%) for the subclavicular region (level 3) and one case (10%) for the supraclavicular re‐ gion. In all 10 cases, SLNs were present in anatomic level 1 of the axillary region. Although it has been considered that there is very little chance of finding SLNs in level 3, one case

SLNs between the primary lesion and the axillary region are regarded as interval nodes on the upper extremities. Manganomi et al. reported that the interval SLN identification rate on upper extremities was 0.4% (two out of 480 cases) [53] and Kelly et al. reported 3.8% (16 out of 423 cases) [54]. Cubital region is the most common site of interval SLN on upper extremi‐ ties. In our 3 cases of interval SLNs identified in cubital region, those were present on cubital

conventional nodal basins and one (14%) in seven interval SLNs [52].

**5. Sentinel lymph node biopsy on upper extremities**

**Figure 4.** The sites of SLNs in primary melanomas on upper extremities.

with SLN in level 3 was present in our data.

SLNs in our experience of 10 cases.

**Figure 3.** How to make pathological specimen of an amputated finger tip was illustrated. In order to examine the tumor cells at the marginal side accurately and continuously, curved rim of the excised margin was cut as linear as possible, and the outside of the margin is examined. (arrow)

## **4. Sentinel lymph node biopsy**

Sentinel lymph node biopsy (SLNB) has become the standard procedure used to determine whether a tumour has metastasized to lymph nodes and more accurate staging of the mela‐ noma. It is a less invasive technique than lymph node dissection allowing patients with node negative (N0) melanoma to avoid unnecessary lymph node dissection. In the case of SLN positive melanoma, additional surgery of lymph node dissection is necessary.

The false-negative rate in SLN mapping for melanoma has been reported to be very low with a rate of 0 to 2 % [46-49]. The multicenter selective lymphadenectomy trial-1 (MSLT-1) demonstrated immediate lymph node dissection following microscopic positive node at SLNB could bring about better prognosis than the lymph node dissection after clinical nodal observation [50].

For more correct mapping of SLNs, a combination of blue dye and radioisotope 99mTc label‐ led phytate is generally used. SLNs are identified by the presence of blue stained lymph ves‐ sels and lymph nodes, and the radioactivity measured by gamma probe. Furthermore, distinction between SLNs and secondary non-SLNs is achieved by using pre-operative dy‐ namic cutaneous lymphoscintigraphy [51].

Although most melanomas drain to conventional regional nodes, unexpected drainage out‐ side of these basins is observed in some cases. Pre-operative lymphscintigraphy and a hand‐ held gamma probe are required for detection of these interval SLNs. According to a singleinstitution study in Japan, SLNs were identified in 253 nodal basins from 117 patients and interval SLNs were found in six patients. They recognized 41 (17%) SLN metastases in 246 conventional nodal basins and one (14%) in seven interval SLNs [52].

## **5. Sentinel lymph node biopsy on upper extremities**

Tumours on upper extremities almost always drain to the axillary region. The axillary re‐ gion is divided into three parts based on the pectoralis minor. Level 1, 2 and 3 are located lateral, deep and medial to the pectoralis minor respectively. Outside this conventional re‐ gion, SLNs are recognized in the cubital region and other areas. Figure 4 is the local sites of SLNs in our experience of 10 cases.

**Figure 4.** The sites of SLNs in primary melanomas on upper extremities.

**Figure 3.** How to make pathological specimen of an amputated finger tip was illustrated. In order to examine the tumor cells at the marginal side accurately and continuously, curved rim of the excised margin was cut as linear as

Sentinel lymph node biopsy (SLNB) has become the standard procedure used to determine whether a tumour has metastasized to lymph nodes and more accurate staging of the mela‐ noma. It is a less invasive technique than lymph node dissection allowing patients with node negative (N0) melanoma to avoid unnecessary lymph node dissection. In the case of

The false-negative rate in SLN mapping for melanoma has been reported to be very low with a rate of 0 to 2 % [46-49]. The multicenter selective lymphadenectomy trial-1 (MSLT-1) demonstrated immediate lymph node dissection following microscopic positive node at SLNB could bring about better prognosis than the lymph node dissection after clinical nodal

For more correct mapping of SLNs, a combination of blue dye and radioisotope 99mTc label‐ led phytate is generally used. SLNs are identified by the presence of blue stained lymph ves‐ sels and lymph nodes, and the radioactivity measured by gamma probe. Furthermore, distinction between SLNs and secondary non-SLNs is achieved by using pre-operative dy‐

Although most melanomas drain to conventional regional nodes, unexpected drainage out‐ side of these basins is observed in some cases. Pre-operative lymphscintigraphy and a hand‐ held gamma probe are required for detection of these interval SLNs. According to a single-

SLN positive melanoma, additional surgery of lymph node dissection is necessary.

possible, and the outside of the margin is examined. (arrow)

**4. Sentinel lymph node biopsy**

482 Melanoma - From Early Detection to Treatment

namic cutaneous lymphoscintigraphy [51].

observation [50].

SLNs were identified in all 10 cases (100%) for the axillary region, three cases (30%) for the cubital region, three cases (30%) for the upper arm, one case (10%) for the forearm, one case (10%) for the subclavicular region (level 3) and one case (10%) for the supraclavicular re‐ gion. In all 10 cases, SLNs were present in anatomic level 1 of the axillary region. Although it has been considered that there is very little chance of finding SLNs in level 3, one case with SLN in level 3 was present in our data.

SLNs between the primary lesion and the axillary region are regarded as interval nodes on the upper extremities. Manganomi et al. reported that the interval SLN identification rate on upper extremities was 0.4% (two out of 480 cases) [53] and Kelly et al. reported 3.8% (16 out of 423 cases) [54]. Cubital region is the most common site of interval SLN on upper extremi‐ ties. In our 3 cases of interval SLNs identified in cubital region, those were present on cubital fossa and on ulnar side of cubital region. We have experienced five cases of other interval region rather than cubital region.

cases for external iliac lymph nodes and one case for the obturator region). Three of the 23 cases with SLN on the inguinal region had positive nodes and there were no positive nodes

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One of the problems with SLNB of lower extremities is the presence of pelvic SLNs. Kaout‐ zanis et al. showed 11 of 82 cases with tumour on lower extremities had SLNs on the pelvic region and underwent SLNB [60]. They also showed that 19 of 82 cases (24%) had positive SLNs and all the positive SLNs were located in the inguinal region. No positive SLNs were

Even in SLNB, removing the lymph nodes in the external iliac and obturator region is a rela‐ tively invasive technique. It is still controversial whether or not SLNs in the pelvic region should be harvested because SLNs in the pelvic region may be considered as secondary or third lymphatic basin, even when radioisotope is accumulated in pelvic lymph nodes.

Even now there is no consensus on the clinical definition of an SLN [61]. The SLN has been described as the hottest node, the blue node, first node visualized on lymphoscintigraphy and a node with radioactivity greater than twice or three times background radioactivity [61-63]. McMaster et al. recommended that all blue nodes and all nodes that measure 10% or higher of the 'ex vivo' radioactive count of hottest SLNs should be removed in order to de‐ crease false-negative cases [64]. In our institute, SLN is defined as the node which showed higher than one tenth of the radioactivity of the hottest node. Because radioactivity depends on the distance from the surface of skin to the nodes, the measured radioactivity of the pel‐ vic lymph nodes from the surface of skin is much less than superficial lymph nodes and tends to be underestimated [65]. Therefore, Bagaria et al. provided an answer that the back‐

on the popliteal and pelvic region.

**Figure 6.** The sites of SLNs in primary melanomas on lower extremities.

present in the pelvic region as our cases.

Tumours on upper extremities rarely drain to the subclavicular region (level 3) rather than to level 1 or 2. Our case with SLNs on the subclavicular region had positive with non-posi‐ tive SLNs in level 11 and no SLNs in level 2 (Figure 5).

**Figure 5.** The case with positive SLN in level 3 and non-positive SLNs in level 1 and the upper arm. This metastatic pattern is extremely rare.

There may be cases where it is uncertain whether or not SLNB should be applied when tu‐ mour thickness is unknown. Some literature demonstrated that the patients with primary le‐ sions on their extremities have a lower risk of misidentification of SLNs, even after wide local excision, than patients with axial primary lesions [55-59]. Tumors on central trunk may drain to both bilateral, or both axillary and inguinal regions. By contrast, tumours on ex‐ tremities tend to drain more simply to the expected region. Although it is preferable that wide local excision and SLNB are performed at the same time, SLNB after wide local exci‐ sion is less disruptive to lymphatic drainage in the case of primary lesions on the extremities than on axial sites.

## **6. Sentinel lymph node biopsy on lower extremities**

In almost all cases, tumours on lower extremities drain to the inguinal region. Figure 6 dem‐ onstrates lymphatic drainage for 23 cases with tumours on lower extremities in our institute. Of all 23 cases, the lymph node identification rate was 23 cases (100%) for the inguinal re‐ gion, five cases (21%) for the popliteal region and 10 cases (43%) for the pelvic region (nine cases for external iliac lymph nodes and one case for the obturator region). Three of the 23 cases with SLN on the inguinal region had positive nodes and there were no positive nodes on the popliteal and pelvic region.

**Figure 6.** The sites of SLNs in primary melanomas on lower extremities.

fossa and on ulnar side of cubital region. We have experienced five cases of other interval

Tumours on upper extremities rarely drain to the subclavicular region (level 3) rather than to level 1 or 2. Our case with SLNs on the subclavicular region had positive with non-posi‐

**Figure 5.** The case with positive SLN in level 3 and non-positive SLNs in level 1 and the upper arm. This metastatic

There may be cases where it is uncertain whether or not SLNB should be applied when tu‐ mour thickness is unknown. Some literature demonstrated that the patients with primary le‐ sions on their extremities have a lower risk of misidentification of SLNs, even after wide local excision, than patients with axial primary lesions [55-59]. Tumors on central trunk may drain to both bilateral, or both axillary and inguinal regions. By contrast, tumours on ex‐ tremities tend to drain more simply to the expected region. Although it is preferable that wide local excision and SLNB are performed at the same time, SLNB after wide local exci‐ sion is less disruptive to lymphatic drainage in the case of primary lesions on the extremities

In almost all cases, tumours on lower extremities drain to the inguinal region. Figure 6 dem‐ onstrates lymphatic drainage for 23 cases with tumours on lower extremities in our institute. Of all 23 cases, the lymph node identification rate was 23 cases (100%) for the inguinal re‐ gion, five cases (21%) for the popliteal region and 10 cases (43%) for the pelvic region (nine

**6. Sentinel lymph node biopsy on lower extremities**

region rather than cubital region.

484 Melanoma - From Early Detection to Treatment

pattern is extremely rare.

than on axial sites.

tive SLNs in level 11 and no SLNs in level 2 (Figure 5).

One of the problems with SLNB of lower extremities is the presence of pelvic SLNs. Kaout‐ zanis et al. showed 11 of 82 cases with tumour on lower extremities had SLNs on the pelvic region and underwent SLNB [60]. They also showed that 19 of 82 cases (24%) had positive SLNs and all the positive SLNs were located in the inguinal region. No positive SLNs were present in the pelvic region as our cases.

Even in SLNB, removing the lymph nodes in the external iliac and obturator region is a rela‐ tively invasive technique. It is still controversial whether or not SLNs in the pelvic region should be harvested because SLNs in the pelvic region may be considered as secondary or third lymphatic basin, even when radioisotope is accumulated in pelvic lymph nodes.

Even now there is no consensus on the clinical definition of an SLN [61]. The SLN has been described as the hottest node, the blue node, first node visualized on lymphoscintigraphy and a node with radioactivity greater than twice or three times background radioactivity [61-63]. McMaster et al. recommended that all blue nodes and all nodes that measure 10% or higher of the 'ex vivo' radioactive count of hottest SLNs should be removed in order to de‐ crease false-negative cases [64]. In our institute, SLN is defined as the node which showed higher than one tenth of the radioactivity of the hottest node. Because radioactivity depends on the distance from the surface of skin to the nodes, the measured radioactivity of the pel‐ vic lymph nodes from the surface of skin is much less than superficial lymph nodes and tends to be underestimated [65]. Therefore, Bagaria et al. provided an answer that the back‐ ground radioactivity of the regional nodal basin was measured before incision and all blue nodes and all hot nodes that have radioactivity greater than the background were harvested [61]. According to Soteldo et al., the rate of the cases that had metastasized lymph nodes in the pelvic region after SLNB that had indicated non-positive SLNs in the inguinal region was 2.4% [65]. This indicated that there might be cases with positive lymph nodes in the pel‐ vic region with non-positive lymph nodes in the inguinal region. This rate should not be un‐ derestimated and gives a reason for removing SLNs in the pelvic region.

dissection including level 1 and 2was 5 % (14 cases out of 270 cases) [67]. Guggenheim et al. also reported a rate of 4.5% after axillary dissection which mainly included level 1 and 2 [68]. On the other hand, according to Kretschmer et al., the local recurrence rate was 9.5% (six out of 63 cases) after dissection including level 1,2 and 3. There is no direct evidence that

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487

The complication rate of dissection for level 1and 2 is less severe than that of dissection for level 1,2 and 3. The rates of infection and seroma after the former operation were 8% and 2%

There are very few reported cases in which positive SLNs in level 3 were harvested except for our case. In addition, the lymph node ratio (LNR: the ratio of involved lymph nodes to total retrieved nodes in lymph node dissection) provides prognostic information [71-73]. There is very little possibility that positive lymph nodes are harvested only in level 3 with‐ out positive SLNs in level 1 or 2. Although there is data not on upper extremities but on lower extremities, a larger number of cases involved lymph nodes in the inguinal region with a higher rate of pelvic lymph node metastases [74]. This indicates that the number of superficial involved lymph nodes is related to the possibility of metastasis in the deep re‐ gion. It has been reported that the size of SLN metastases predicts other nodal disease and survival in malignant melanoma [75,76]. Due to these findings, axillary dissection including level 3 is not always necessary when there are one or two micrometastatic lymph nodes in

dissection including level 3 is superior to dissection without level 3 [69].

respectively, whereas those for the latter operation were 20% and 18% [67,70].

level 1, but it is necessary when a case falls under any of the following conditions:

**•** There is a relatively large clinically involved lymph node in level 1 or 2.

**•** There is negative SLNs in level 3 with positive lymph nodes in level 1 or 2.

**•** There are involved lymph nodes in level 3 evaluated with radiological examination such

There is also controversy surrounding inguinal and pelvic lymph node dissection. The most controversial question is whether routine dissection with the primary tumour on lower ex‐ tremities includes only a superficial inguinal lymph node dissection (SLND) or includes ad‐ ditional iliac and obturator lymph node dissection (deep pelvic/inguinal lymph node dissection : DLND) [77]. Like the axillary dissection, decision on the area to be dissected is

Hughes et al. reported that in cases of palpable inguinal lymph node metastases, pelvic lymph node recurrence occurred in one of 72 patients who had DLND and seven of 60 pa‐ tients who had SLND (p=0.01) [74]. In this study, patients with one positive superficial node

difficult from the viewpoint of local control, overall survival and complications.

**•** There are many metastatic lymph nodes in level 1 or 2.

**9. Inguinal and pelvic lymph node dissection**

**•** There are positive SLNs in level 3.

as computed tomography (CT).

On the other hand, there have been no published results of positive pelvic lymph nodes with negative inguinal SLNs for melanoma located below the knee. Pelvic lymph nodes for melanoma located below the knee were considered as secondary lymphatic basin because they were not stained blue and the radioactivity of the pelvic lymph nodes was significantly less than that of the inguinal nodes removed from the same patients [66]. By contrast, the pelvic lymph nodes for melanoma located on the trunk and thigh are possibly SLNs. In the case of melanoma below the knee in which there is a risk or difficulty in removing the pelvic lymph nodes, for example the case of pelvic adhesion after surgery in the pelvis, SLNB could be clinically avoided in terms of the cost-benefit relationship.

There are two approaches to removing the pelvic lymph nodes. One is the technique with incision above the inguinal ligament and the other is the technique with median incision in the lower abdomen. Each technique has an advantage. With median incision, it is easier to approach a deep site in the pelvic region such as the obturator area or the external iliac re‐ gion near to the common iliac region. By contrast, it is easier and less invasive to approach the external iliac region near to the inguinal ligament with an incision above the inguinal ligament.

## **7. Lymph node dissection**

Lymph node dissection is the primary management for regional lymph node metastasis. It is applied in cases of clinical metastasis, positive SLNs after SLNB and histological lymphatic invasion for a resected or biopsied primary lesion. Surgical technique, extent of dissection, morbidity and complication vary widely in the published literature. Although lymph node dissection has been a standard treatment and the technique has not drastically changed for many years, even now there is much controversy surrounding lymph node dissection. Some of the controversies will be mentioned in the following section.

## **8. Axillary lymph node dissection**

Since the tumours on upper extremities drain to the axillary region, axillary dissection is necessary and performed by way of cure or local control of the metastatic melanoma in the upper extremities. On the area of axillary dissection, it is controversial whether a level 3 dis‐ section should be included. Namm et al. reported that the local recurrence rate of axillary dissection including level 1 and 2was 5 % (14 cases out of 270 cases) [67]. Guggenheim et al. also reported a rate of 4.5% after axillary dissection which mainly included level 1 and 2 [68]. On the other hand, according to Kretschmer et al., the local recurrence rate was 9.5% (six out of 63 cases) after dissection including level 1,2 and 3. There is no direct evidence that dissection including level 3 is superior to dissection without level 3 [69].

The complication rate of dissection for level 1and 2 is less severe than that of dissection for level 1,2 and 3. The rates of infection and seroma after the former operation were 8% and 2% respectively, whereas those for the latter operation were 20% and 18% [67,70].

There are very few reported cases in which positive SLNs in level 3 were harvested except for our case. In addition, the lymph node ratio (LNR: the ratio of involved lymph nodes to total retrieved nodes in lymph node dissection) provides prognostic information [71-73]. There is very little possibility that positive lymph nodes are harvested only in level 3 with‐ out positive SLNs in level 1 or 2. Although there is data not on upper extremities but on lower extremities, a larger number of cases involved lymph nodes in the inguinal region with a higher rate of pelvic lymph node metastases [74]. This indicates that the number of superficial involved lymph nodes is related to the possibility of metastasis in the deep re‐ gion. It has been reported that the size of SLN metastases predicts other nodal disease and survival in malignant melanoma [75,76]. Due to these findings, axillary dissection including level 3 is not always necessary when there are one or two micrometastatic lymph nodes in level 1, but it is necessary when a case falls under any of the following conditions:

ground radioactivity of the regional nodal basin was measured before incision and all blue nodes and all hot nodes that have radioactivity greater than the background were harvested [61]. According to Soteldo et al., the rate of the cases that had metastasized lymph nodes in the pelvic region after SLNB that had indicated non-positive SLNs in the inguinal region was 2.4% [65]. This indicated that there might be cases with positive lymph nodes in the pel‐ vic region with non-positive lymph nodes in the inguinal region. This rate should not be un‐

On the other hand, there have been no published results of positive pelvic lymph nodes with negative inguinal SLNs for melanoma located below the knee. Pelvic lymph nodes for melanoma located below the knee were considered as secondary lymphatic basin because they were not stained blue and the radioactivity of the pelvic lymph nodes was significantly less than that of the inguinal nodes removed from the same patients [66]. By contrast, the pelvic lymph nodes for melanoma located on the trunk and thigh are possibly SLNs. In the case of melanoma below the knee in which there is a risk or difficulty in removing the pelvic lymph nodes, for example the case of pelvic adhesion after surgery in the pelvis, SLNB

There are two approaches to removing the pelvic lymph nodes. One is the technique with incision above the inguinal ligament and the other is the technique with median incision in the lower abdomen. Each technique has an advantage. With median incision, it is easier to approach a deep site in the pelvic region such as the obturator area or the external iliac re‐ gion near to the common iliac region. By contrast, it is easier and less invasive to approach the external iliac region near to the inguinal ligament with an incision above the inguinal

Lymph node dissection is the primary management for regional lymph node metastasis. It is applied in cases of clinical metastasis, positive SLNs after SLNB and histological lymphatic invasion for a resected or biopsied primary lesion. Surgical technique, extent of dissection, morbidity and complication vary widely in the published literature. Although lymph node dissection has been a standard treatment and the technique has not drastically changed for many years, even now there is much controversy surrounding lymph node dissection. Some

Since the tumours on upper extremities drain to the axillary region, axillary dissection is necessary and performed by way of cure or local control of the metastatic melanoma in the upper extremities. On the area of axillary dissection, it is controversial whether a level 3 dis‐ section should be included. Namm et al. reported that the local recurrence rate of axillary

derestimated and gives a reason for removing SLNs in the pelvic region.

could be clinically avoided in terms of the cost-benefit relationship.

of the controversies will be mentioned in the following section.

ligament.

**7. Lymph node dissection**

486 Melanoma - From Early Detection to Treatment

**8. Axillary lymph node dissection**

**•** There are involved lymph nodes in level 3 evaluated with radiological examination such as computed tomography (CT).

## **9. Inguinal and pelvic lymph node dissection**

There is also controversy surrounding inguinal and pelvic lymph node dissection. The most controversial question is whether routine dissection with the primary tumour on lower ex‐ tremities includes only a superficial inguinal lymph node dissection (SLND) or includes ad‐ ditional iliac and obturator lymph node dissection (deep pelvic/inguinal lymph node dissection : DLND) [77]. Like the axillary dissection, decision on the area to be dissected is difficult from the viewpoint of local control, overall survival and complications.

Hughes et al. reported that in cases of palpable inguinal lymph node metastases, pelvic lymph node recurrence occurred in one of 72 patients who had DLND and seven of 60 pa‐ tients who had SLND (p=0.01) [74]. In this study, patients with one positive superficial node and those with more than one positive superficial node were 17% and 51% of 72 patients with DLND respectively. The number of positive superficial lymph nodes and the presence of extracapsular spread were significant prognostic factors for overall survival [77].

**•** There is a palpable inguinal metastasis.

**10. Molecular targeted therapy**

sary to confirm the effect of this agent.

ternational guidelines are yet to be established.

metastasis.

**11. Conclusion**

scopic findings.

tion and follow-up are necessary.

**•** CT indicates metastatic pelvic lymph nodes. **•** There is a Cloquet's lymph node metastasis.

**•** There is more than one superficial lymph node metastasis.

**•** Lymphoschintigraphy indicates SLNs in the pelvic region with a superficial lymph node

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489

Recent discoveries in cell signalling have provided greater understanding of the biology that underlines melanoma and these advances are being exploited to provide targeted drugs and new therapeutic approaches [81]. In some cases of ALM and mucosal melanoma, the muta‐ tions of KIT, a transmenbrane receptor tyrosine kinase, are reported and these mutations lead to marked expression of KIT in tumour cells. These cases have marked a tendency to respond to imatinib mesylate which inhibits tyrosine kinase. Although case reports are accu‐ mulating [82,83], more data, including long-term control and prognostic data, will be neces‐

Controversies remain regarding the surgical treatment of ALM as described above, thus, in‐

It is not still known whether the thickness of the nail tumour is the same as that on other sites because the distance between the nail bed and bone is very narrow and a mild degree of invasion can reach the bone easily. Considering the poor prognosis of cases with subun‐ gual melanoma, the tumour thickness of the subungual melanoma needs to be evaluated. Because biopsies of the nail bed may cause cosmetic and occasionally functional problems, surgeons may hesitate to do biopsies and lose a vital chance of early diagnosis. Suspicious lesions should be actively biopsied with fully informed consent. When taking a wait-and-see approach, careful observation is necessary so as not to overlook any minor change of dermo‐

On the excision margins around the primary lesion, 2cm is regarded as sufficient for inva‐ sive melanomas. Although some guidelines suggest a 0.5 cm margin for melanomas in situ, some data indicated that resection with 0.5 cm margin caused significant high rates of local recurrence. As mentioned here according to the report, a 1cm surgical margin is a better an‐ swer for melanomas in situ, except for tumours on cosmetic or functional sites such as the face or fingers. When an excision margin is less than 1cm, more careful histological examina‐

In addition, the patients who had DLND with the presence of pelvic lymph node metastases had significantly poorer five year survival than the patients without the pelvic lymph node metastases. However, there was no difference in postoperative morbidity between SLND and DLND [74]. Van der Ploeg et al. also reported that survival and local control did not differ for patients with palpable inguinal metastases treated by DLND or SLND and pelvic lymph node metastases was a significant prognostic factor [78]. In their series of 169 patients with palpable nodes in the inguinal region, five year estimated overall survival rates were 33% for DLND and 29% for SLND.

However, there is no evidence on how the recurrence affects quality of life when DLND is not performed and how the recurrence occurs in the pelvic region for melanomas on lower extremities. It is likely that enlargement of a tumour in pelvic region causes lymphedema, congestion of lower extremities, ileus and so on. Although these symptoms may be due to DLND, also it is possible that DLND increases patients' quality of life during the remaining life time by decreasing the risk of recurrence in the pelvic region. However, there is no evi‐ dence indicating this.

Cloquet's node is an indicator of pelvic lymph node metastases. According to Shen et al.'s study, positive pelvic lymph nodes were identified in the DLND specimen from 20 of 30 (67%) patients with a positive Cloquet's node and negative pelvic lymph nodes were identi‐ fied from 27 of 35 (77%) patients with a negative Cloquet's node (p=0.0019) [79].

Pre-operative computed tomography (CT) is also a good tool to use in predicting the meta‐ stasis. Out of 44 patients with negative pelvic lymph nodes evaluated with pre-operative CT, 40 patients had in fact histologically negative pelvic lymph nodes (negative predictive value = 90.9%). On the other hand, the positive predictive value of pre-operative CT for pel‐ vic metastases, was 59% [78].

A recent study shows pre-operative lymphoscintigraphy can be used to guide the extent of inguinal lymph node dissection [66]. Chu et al. reported on 42 cases of DLND with positive inguinal SLNs. The frequency of synchronous pelvic disease was five of 42 (11.9%) [80]. All five cases with pelvic disease had primary melanomas on extremities. Upon review on the lymphoscintigraphic findings, pelvic drainage was present in four of five cases with pelvic disease (80%) and in 18 of the 32 cases (56%) without pelvic disease, though neither was statistically significant. This strategy is based on the idea that when lymphoscintigraphy shows secondary nodes to be located in the next drainage basin, this basin should be includ‐ ed as the dissecting area [66]. More data is necessary to prove that treatment based on the idea improves the mortality and local control.

For now, there is no guideline on choosing between SLND and DLND. However, many findings provide useful information and surgeons should actively select DLND when a case falls under any of the following conditions:

**•** There is a palpable inguinal metastasis.

and those with more than one positive superficial node were 17% and 51% of 72 patients with DLND respectively. The number of positive superficial lymph nodes and the presence

In addition, the patients who had DLND with the presence of pelvic lymph node metastases had significantly poorer five year survival than the patients without the pelvic lymph node metastases. However, there was no difference in postoperative morbidity between SLND and DLND [74]. Van der Ploeg et al. also reported that survival and local control did not differ for patients with palpable inguinal metastases treated by DLND or SLND and pelvic lymph node metastases was a significant prognostic factor [78]. In their series of 169 patients with palpable nodes in the inguinal region, five year estimated overall survival rates were

However, there is no evidence on how the recurrence affects quality of life when DLND is not performed and how the recurrence occurs in the pelvic region for melanomas on lower extremities. It is likely that enlargement of a tumour in pelvic region causes lymphedema, congestion of lower extremities, ileus and so on. Although these symptoms may be due to DLND, also it is possible that DLND increases patients' quality of life during the remaining life time by decreasing the risk of recurrence in the pelvic region. However, there is no evi‐

Cloquet's node is an indicator of pelvic lymph node metastases. According to Shen et al.'s study, positive pelvic lymph nodes were identified in the DLND specimen from 20 of 30 (67%) patients with a positive Cloquet's node and negative pelvic lymph nodes were identi‐

Pre-operative computed tomography (CT) is also a good tool to use in predicting the meta‐ stasis. Out of 44 patients with negative pelvic lymph nodes evaluated with pre-operative CT, 40 patients had in fact histologically negative pelvic lymph nodes (negative predictive value = 90.9%). On the other hand, the positive predictive value of pre-operative CT for pel‐

A recent study shows pre-operative lymphoscintigraphy can be used to guide the extent of inguinal lymph node dissection [66]. Chu et al. reported on 42 cases of DLND with positive inguinal SLNs. The frequency of synchronous pelvic disease was five of 42 (11.9%) [80]. All five cases with pelvic disease had primary melanomas on extremities. Upon review on the lymphoscintigraphic findings, pelvic drainage was present in four of five cases with pelvic disease (80%) and in 18 of the 32 cases (56%) without pelvic disease, though neither was statistically significant. This strategy is based on the idea that when lymphoscintigraphy shows secondary nodes to be located in the next drainage basin, this basin should be includ‐ ed as the dissecting area [66]. More data is necessary to prove that treatment based on the

For now, there is no guideline on choosing between SLND and DLND. However, many findings provide useful information and surgeons should actively select DLND when a case

fied from 27 of 35 (77%) patients with a negative Cloquet's node (p=0.0019) [79].

of extracapsular spread were significant prognostic factors for overall survival [77].

33% for DLND and 29% for SLND.

488 Melanoma - From Early Detection to Treatment

dence indicating this.

vic metastases, was 59% [78].

idea improves the mortality and local control.

falls under any of the following conditions:

## **10. Molecular targeted therapy**

Recent discoveries in cell signalling have provided greater understanding of the biology that underlines melanoma and these advances are being exploited to provide targeted drugs and new therapeutic approaches [81]. In some cases of ALM and mucosal melanoma, the muta‐ tions of KIT, a transmenbrane receptor tyrosine kinase, are reported and these mutations lead to marked expression of KIT in tumour cells. These cases have marked a tendency to respond to imatinib mesylate which inhibits tyrosine kinase. Although case reports are accu‐ mulating [82,83], more data, including long-term control and prognostic data, will be neces‐ sary to confirm the effect of this agent.

## **11. Conclusion**

Controversies remain regarding the surgical treatment of ALM as described above, thus, in‐ ternational guidelines are yet to be established.

It is not still known whether the thickness of the nail tumour is the same as that on other sites because the distance between the nail bed and bone is very narrow and a mild degree of invasion can reach the bone easily. Considering the poor prognosis of cases with subun‐ gual melanoma, the tumour thickness of the subungual melanoma needs to be evaluated. Because biopsies of the nail bed may cause cosmetic and occasionally functional problems, surgeons may hesitate to do biopsies and lose a vital chance of early diagnosis. Suspicious lesions should be actively biopsied with fully informed consent. When taking a wait-and-see approach, careful observation is necessary so as not to overlook any minor change of dermo‐ scopic findings.

On the excision margins around the primary lesion, 2cm is regarded as sufficient for inva‐ sive melanomas. Although some guidelines suggest a 0.5 cm margin for melanomas in situ, some data indicated that resection with 0.5 cm margin caused significant high rates of local recurrence. As mentioned here according to the report, a 1cm surgical margin is a better an‐ swer for melanomas in situ, except for tumours on cosmetic or functional sites such as the face or fingers. When an excision margin is less than 1cm, more careful histological examina‐ tion and follow-up are necessary.

Although SLNB is the standard technique for the management of malignant melanoma, the definition of SLN itself has not been established. This creates differences in the extent of SLNB between each institute. SLNs in patients with melanomas on upper extremities are very rarely located in level 3. There are very few cases with positive SLNs only in level 3 without positive SLNs in level 1or 2, thus, the lymph nodes in level 3 can be regarded as secondary nodes for melanomas on upper extremities in almost all cases. Surgeons should also pay additional attention to SLNs in other sites such as supraclavicular, the cubital re‐ gion and interval nodes.

[3] Ishihara K, Saida T, Otsuka F, Yamazaki N; Prognosis and Statistical Investigation Committee of the Japanese Skin Cancer Society. Statistical profiles of malignant mel‐ anoma and other skin cancers in Japan: 2007 update. International Journal of Clinical

Management of Acral Lentiginous Melanoma

http://dx.doi.org/10.5772/54266

491

[4] Makredes M, Hui SK, Kimball AB. Melanoma in Hong Kong between 1983 and 2002: a decreasing trend in incidence observed in a complex socio-political and economic

[5] Chang JW. Cutaneous melanoma: Taiwan experience and literature review. Chang

[6] Luk NM, Ho CL, Choi CL, Wong KH, Yu KH, Yeung WK. Clinicopathological fea‐ tures and prognostic factors of cutaneous melanoma among Hong Kong Chinese.

[7] Chen YJ, Wu CY, Chen JT, Shen JL, Chen CC, Wang HC. Clinicopathologic analysis of malignant melanoma in Taiwan. Journal of American Academy of Dermatology

[8] Bradford PT, Goldstein AM, McMaster ML, Tucker MA. Acral lentiginous melano‐ ma. Incidence and survival patterns in the United States 1986-2005. Archives of Der‐

[9] Reed, RJ. New Concepts in Surgical Pathology of the Skin. New York: John Wiley &

[10] Reed RJ, Ichinose H, Krementz ET. Plantar lentiginous melanoma: a distinctive var‐ iant of human cutaneous malignant melanoma. American Journal of Surgical Pathol‐

[11] Clark, W. H., Jr., Elder, D. E. & Van Horn, M. The biologic forms of malignant mela‐

[12] Surveillance, Epidemiology and End Results (SEER) Program. National Cancer Insti‐ tute, DCCPS,Surveillance Research Program, Cancer Statistics Branch. 2008

[13] Markovic SN, Erickson LA, Rao RD, et al. Malignant Melanoma in the 21st Century, Part 1:Epidemiology, Risk Factors, Screening, Prevention, and Diagnosis. Mayo Clin‐

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There is controversy around the management of lymph nodes in the pelvic region. Accord‐ ing to the literature, there were patients without positive SLNs in the inguinal region, who had metastatic lymph nodes in the pelvic region during follow-up. Thus, at the moment, it is better not to regard all pelvic lymph nodes as secondary nodes and not to exclude all pelvic lymph nodes from SLNs. There are no reported cases with primary melanomas below the knee in which only positive pelvic lymph nodes are present without positive inguinal lymph nodes. Thus, surgeons should decide whether to harvest pelvic lymph nodes taking into consideration the sites of primary lesion, Brethlow thickness and the possibility of com‐ plication on a case by case basis.

Whether or not dissection in cases with primary lesions on upper extremities should include the extent of level 3 is controversial. When a case falls under any of the lists described above, the dissection including level 3 should be actively performed. However, not all cases with positive lymph nodes in level 1 or 2 need to undergo dissection including level 3.

Similarly, it is difficult to choose between SLND and DLND in the case of primary melano‐ mas on lower extremities. The cases which are likely to have metastatic lymph nodes in the pelvic region were mentioned above. It is better that the indication of DLND is determined by referring to the list.

## **Author details**

Yoshitaka Kai and Sakuhei Fujiwara\*

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan

## **References**

[3] Ishihara K, Saida T, Otsuka F, Yamazaki N; Prognosis and Statistical Investigation Committee of the Japanese Skin Cancer Society. Statistical profiles of malignant mel‐ anoma and other skin cancers in Japan: 2007 update. International Journal of Clinical Oncology 2008; 13(1) 33-41.

Although SLNB is the standard technique for the management of malignant melanoma, the definition of SLN itself has not been established. This creates differences in the extent of SLNB between each institute. SLNs in patients with melanomas on upper extremities are very rarely located in level 3. There are very few cases with positive SLNs only in level 3 without positive SLNs in level 1or 2, thus, the lymph nodes in level 3 can be regarded as secondary nodes for melanomas on upper extremities in almost all cases. Surgeons should also pay additional attention to SLNs in other sites such as supraclavicular, the cubital re‐

There is controversy around the management of lymph nodes in the pelvic region. Accord‐ ing to the literature, there were patients without positive SLNs in the inguinal region, who had metastatic lymph nodes in the pelvic region during follow-up. Thus, at the moment, it is better not to regard all pelvic lymph nodes as secondary nodes and not to exclude all pelvic lymph nodes from SLNs. There are no reported cases with primary melanomas below the knee in which only positive pelvic lymph nodes are present without positive inguinal lymph nodes. Thus, surgeons should decide whether to harvest pelvic lymph nodes taking into consideration the sites of primary lesion, Brethlow thickness and the possibility of com‐

Whether or not dissection in cases with primary lesions on upper extremities should include the extent of level 3 is controversial. When a case falls under any of the lists described above, the dissection including level 3 should be actively performed. However, not all cases with

Similarly, it is difficult to choose between SLND and DLND in the case of primary melano‐ mas on lower extremities. The cases which are likely to have metastatic lymph nodes in the pelvic region were mentioned above. It is better that the indication of DLND is determined

positive lymph nodes in level 1 or 2 need to undergo dissection including level 3.

Department of Dermatology, Faculty of Medicine, Oita University, Oita, Japan

[1] Sneyd M, Cox B. The control of melanoma in New Zealand. New Zealand Medical

[2] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA: A Cancer

gion and interval nodes.

490 Melanoma - From Early Detection to Treatment

plication on a case by case basis.

by referring to the list.

Yoshitaka Kai and Sakuhei Fujiwara\*

Journal 2006;119 U2169.

\*Address all correspondence to<EMAIL_ADDRESS>
Journal for Clinicians 2005; 55(2) 74-108

**Author details**

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496 Melanoma - From Early Detection to Treatment

18(1) 16-21.

**Chapter 18**

**Sentinel Lymph Node Biopsy for Melanoma and**

The surgical approach to cutaneous melanoma patients with clinically uninvolved regional lymph nodes has been controversial. Although most patients with melanoma have no clini‐ cally palpable nodal disease at the time of presentation, some patients whose primary tumor increases in thickness, has ulceration, and shows a high mitotic rate histologically harbor

While some authors have advocated wide excision of the primary tumor with elective lymph node dissection (ELND), others had recommended excision of the primary site alone and therapeutic lymph node dissection (TLND) only when clinical nodal disease is present. ELND is based on the concept that metastasis arises by passage of the tumor from the pri‐ mary to the regional lymph nodes and distant sites, in which case early LND will prevent this metastatic progression. In contrast, TLND, which is a "watch and wait" approach, sug‐ gests that regional lymph node metastases are markers for disease progression and that hematogenous distant metastases could occur without lymph node metastasis. Four randomized prospective studies comparing ELND with TLND were reported[2-5]. The earli‐ er 2 studies conducted in the 1970s demonstrated no overall survival advantage for ELND[2, 3]. Accordingly, ELND was once contested and largely abandoned. Thereafter, the latter 2 studies conducted in the 1990s suggested the tendency, albeit statistically insignificant, that patients with early regional metastases may benefit from ELND[4, 5]. However, in most melanoma patients with no clinical nodal disease, microscopic nodal disease is absent at presentation. These patients cannot benefit from ELND; if ELND were to be performed, they

would suffer from the cost, time, and morbidity of an unnecessary operation.

With respect to this controversy surrounding ELND, the technique of lymphatic mapping and sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive method for

and reproduction in any medium, provided the original work is properly cited.

© 2013 Nakamura and Otsuka; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Surgical Approach to Lymph Node Metastasis**

Yasuhiro Nakamura and Fujio Otsuka

http://dx.doi.org/10.5772/53625

**1. Introduction**

Additional information is available at the end of the chapter

clinically undetectable regional lymph node metastasis[1].

## **Sentinel Lymph Node Biopsy for Melanoma and Surgical Approach to Lymph Node Metastasis**

Yasuhiro Nakamura and Fujio Otsuka

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53625

## **1. Introduction**

The surgical approach to cutaneous melanoma patients with clinically uninvolved regional lymph nodes has been controversial. Although most patients with melanoma have no clini‐ cally palpable nodal disease at the time of presentation, some patients whose primary tumor increases in thickness, has ulceration, and shows a high mitotic rate histologically harbor clinically undetectable regional lymph node metastasis[1].

While some authors have advocated wide excision of the primary tumor with elective lymph node dissection (ELND), others had recommended excision of the primary site alone and therapeutic lymph node dissection (TLND) only when clinical nodal disease is present. ELND is based on the concept that metastasis arises by passage of the tumor from the pri‐ mary to the regional lymph nodes and distant sites, in which case early LND will prevent this metastatic progression. In contrast, TLND, which is a "watch and wait" approach, sug‐ gests that regional lymph node metastases are markers for disease progression and that hematogenous distant metastases could occur without lymph node metastasis. Four randomized prospective studies comparing ELND with TLND were reported[2-5]. The earli‐ er 2 studies conducted in the 1970s demonstrated no overall survival advantage for ELND[2, 3]. Accordingly, ELND was once contested and largely abandoned. Thereafter, the latter 2 studies conducted in the 1990s suggested the tendency, albeit statistically insignificant, that patients with early regional metastases may benefit from ELND[4, 5]. However, in most melanoma patients with no clinical nodal disease, microscopic nodal disease is absent at presentation. These patients cannot benefit from ELND; if ELND were to be performed, they would suffer from the cost, time, and morbidity of an unnecessary operation.

With respect to this controversy surrounding ELND, the technique of lymphatic mapping and sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive method for

detection of microscopic regional lymph node metastases in the early 1990s[6]. Lymphatic mapping is based on the concept that the lymphatic drainage from the skin to the regional lymph node basins runs in an orderly, stepwise fashion. These lymphatic drainage patterns would be the same as the dissemination of melanoma through the lymphatic system and therefore predict the routes of metastatic spread of melanoma cells to the regional lymph nodes (Fig. 1). Morton et al. first reported the details of the SLN technique using intradermal blue dye injection around the primary site and reported that the SLN identification rate was 82% among 237 patients[6], which was considered a high identification rate at that time. In the early 1990s, several authors evaluated this concept by performing synchronous ELND at the time of SLNB[7-9]. A "false-negative" SLN was defined as microscopic metastasis in a non-SLN despite the SLN showing no metastasis. These studies indicated that 5.8% of pa‐ tients had a false-negative SLN. In addition, Gershenwald et al. reported that only 4.1% (10/243) of patients with a histologically negative SLN developed a nodal recurrence in the previously mapped basin during a follow-up period of over 3 years[10]. This low false-nega‐ tive rate supported the SLN concept described above.

**2. Technical advances in SLNB**

as that in the SLN in the regional nodal basins[14].

axillary regions (96.6%)[18].

Although the initial SLN identification rate using blue dye injections alone was approxi‐ mately 82%[6], the advent of lymphoscintigraphy and the intraoperative hand-held gamma probe drastically improved the SLN identification rate. Studies comparing blue dye injection alone with combined techniques using blue dye, lymphoscintigraphy, and an intraoperative hand-held gamma probe showed a significant increase in SLN identification of up to 99% with the combined techniques[11, 12], which has come to be recognized as the standard technique of SLNB (Fig. 2). This combined technique also enables the surgeon to identify the interval (unusual, in-transit, ectopic) nodes located outside the named regional nodal basins (Fig. 3)[13-17]. The rate of interval SLN identification is reported to be approximately 5% to 10%, and the rate of microscopic metastasis in the interval nodes is approximately the same

Sentinel Lymph Node Biopsy for Melanoma and Surgical Approach to Lymph Node Metastasis

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501

However, SLNB in the head and neck has particular problems because the lymphatic drain‐ age in the head and neck is much more complex than those in the axillary and inguinal re‐ gions. Furthermore, the cervical and parotid lymph nodes are smaller and located in sites that are not easily accessible, for example in the parotid gland, through which the facial nerve passes [18, 19]. In addition, it is sometimes difficult to detect the lymphatic drainage and SLN with lymphoscintigraphy because the SLN is often close to the highly radioactive site where the tracer was injected, the so-called shine-through phenomenon[18, 19]. In addi‐ tion, in some cases the naked eye cannot confirm that an SLN has been dyed blue even after injection of the blue dye because of the short staining period for blue dye in cervical SLNs resulting from the rapid and complex cervical lymphatic flow[19]. In our experience too, over half of the SLNs did not show any blue staining. Furthermore, some authors reported a high false-negative rate of up to 44%, which leads to increased morbidity[20-22]. This high rate may be caused by partially obstructed lymphatic vessels that do not allow for smooth flow of nanocolloids with a size of 6 to 12 nm[23]. Although several authors have reported a high identification rate in SLNB for head and neck melanoma[24-26], the identification rate of SLNs for the standard technique in the cervical region is generally less than that in the inguinal or axillary regions. In the MSLT-I trial reported by Morton et al., the SLN identifica‐ tion rate in the cervical region (84.5%) was clearly lower than that in the inguinal (99.3%) or

Several studies on the SLNB technique using indocyanine green (ICG) injection in skin can‐ cer patients have demonstrated high SLN detection and identification rates, although these studies involved mainly axillary and inguinal SLNBs and only a small number of cervical SLNBs[23, 27-29]. ICG is a diagnostic reagent used in various examinations such as exami‐ nation for cardiac output or hepatic function and retinal angiography. It has a size of only 2.1 nm, binds with albumin, and generates a peak wavelength of 840 nm near-infrared fluo‐ rescence when excited with 765-nm light[30]. Using a near-infrared camera intraoperatively, it is possible to observe the ICG as a subcutaneous lymphatic flow as well as SLNs in the fluorescence images after intradermal injection of ICG around the primary tumor. (Fig. 4) In our experience, the mean and median numbers of SLNs per basin were higher in the ICG

**Figure 1. Lymphatic drainage from a primary tumor to sentinel lymph nodes.** A sentinel node is sometimes locat‐ ed between the primary tumor and the regional nodal basins, in which case it is called an interval (unusual, in-transit, ectopic) node. If the SLN has microscopic nodal metastasis, some of the second-tier nodes may also have metastasis.

## **2. Technical advances in SLNB**

detection of microscopic regional lymph node metastases in the early 1990s[6]. Lymphatic mapping is based on the concept that the lymphatic drainage from the skin to the regional lymph node basins runs in an orderly, stepwise fashion. These lymphatic drainage patterns would be the same as the dissemination of melanoma through the lymphatic system and therefore predict the routes of metastatic spread of melanoma cells to the regional lymph nodes (Fig. 1). Morton et al. first reported the details of the SLN technique using intradermal blue dye injection around the primary site and reported that the SLN identification rate was 82% among 237 patients[6], which was considered a high identification rate at that time. In the early 1990s, several authors evaluated this concept by performing synchronous ELND at the time of SLNB[7-9]. A "false-negative" SLN was defined as microscopic metastasis in a non-SLN despite the SLN showing no metastasis. These studies indicated that 5.8% of pa‐ tients had a false-negative SLN. In addition, Gershenwald et al. reported that only 4.1% (10/243) of patients with a histologically negative SLN developed a nodal recurrence in the previously mapped basin during a follow-up period of over 3 years[10]. This low false-nega‐

**Figure 1. Lymphatic drainage from a primary tumor to sentinel lymph nodes.** A sentinel node is sometimes locat‐ ed between the primary tumor and the regional nodal basins, in which case it is called an interval (unusual, in-transit, ectopic) node. If the SLN has microscopic nodal metastasis, some of the second-tier nodes may also have metastasis.

tive rate supported the SLN concept described above.

500 Melanoma - From Early Detection to Treatment

Although the initial SLN identification rate using blue dye injections alone was approxi‐ mately 82%[6], the advent of lymphoscintigraphy and the intraoperative hand-held gamma probe drastically improved the SLN identification rate. Studies comparing blue dye injection alone with combined techniques using blue dye, lymphoscintigraphy, and an intraoperative hand-held gamma probe showed a significant increase in SLN identification of up to 99% with the combined techniques[11, 12], which has come to be recognized as the standard technique of SLNB (Fig. 2). This combined technique also enables the surgeon to identify the interval (unusual, in-transit, ectopic) nodes located outside the named regional nodal basins (Fig. 3)[13-17]. The rate of interval SLN identification is reported to be approximately 5% to 10%, and the rate of microscopic metastasis in the interval nodes is approximately the same as that in the SLN in the regional nodal basins[14].

However, SLNB in the head and neck has particular problems because the lymphatic drain‐ age in the head and neck is much more complex than those in the axillary and inguinal re‐ gions. Furthermore, the cervical and parotid lymph nodes are smaller and located in sites that are not easily accessible, for example in the parotid gland, through which the facial nerve passes [18, 19]. In addition, it is sometimes difficult to detect the lymphatic drainage and SLN with lymphoscintigraphy because the SLN is often close to the highly radioactive site where the tracer was injected, the so-called shine-through phenomenon[18, 19]. In addi‐ tion, in some cases the naked eye cannot confirm that an SLN has been dyed blue even after injection of the blue dye because of the short staining period for blue dye in cervical SLNs resulting from the rapid and complex cervical lymphatic flow[19]. In our experience too, over half of the SLNs did not show any blue staining. Furthermore, some authors reported a high false-negative rate of up to 44%, which leads to increased morbidity[20-22]. This high rate may be caused by partially obstructed lymphatic vessels that do not allow for smooth flow of nanocolloids with a size of 6 to 12 nm[23]. Although several authors have reported a high identification rate in SLNB for head and neck melanoma[24-26], the identification rate of SLNs for the standard technique in the cervical region is generally less than that in the inguinal or axillary regions. In the MSLT-I trial reported by Morton et al., the SLN identifica‐ tion rate in the cervical region (84.5%) was clearly lower than that in the inguinal (99.3%) or axillary regions (96.6%)[18].

Several studies on the SLNB technique using indocyanine green (ICG) injection in skin can‐ cer patients have demonstrated high SLN detection and identification rates, although these studies involved mainly axillary and inguinal SLNBs and only a small number of cervical SLNBs[23, 27-29]. ICG is a diagnostic reagent used in various examinations such as exami‐ nation for cardiac output or hepatic function and retinal angiography. It has a size of only 2.1 nm, binds with albumin, and generates a peak wavelength of 840 nm near-infrared fluo‐ rescence when excited with 765-nm light[30]. Using a near-infrared camera intraoperatively, it is possible to observe the ICG as a subcutaneous lymphatic flow as well as SLNs in the fluorescence images after intradermal injection of ICG around the primary tumor. (Fig. 4) In our experience, the mean and median numbers of SLNs per basin were higher in the ICG group than in the standard-technique group. The small size of ICG allows a smooth flow along the lymphatic vessels. It may lead to detection of SLNs not detectable by lymphoscin‐ tigraphy (Fig. 4C, D) owing to poor flow of the radioactive tracer and may reduce the falsenegative rate. Indeed, Stoffels et al. reported that 2 of 11 additional SLNs that were only identified by the ICG technique showed microscopic metastasis[23].

In addition, the recently introduced hybrid single-photon emission computed tomography with computed tomography (SPECT/CT) can visualize the exact anatomic location of the SLN and second-tier nodes, which would be of great help in identifying the SLN, especially those in the head and neck region[31, 32], as well as the interval nodes.

**Figure 3. Detection of interval SLN.** (A) Primary melanoma on the right heel. (B) Lymphoscintigraphy revealed accu‐ mulation in the right popliteal fossa. (C) Radioactive and blue-stained popliteal node, which had microscopic metasta‐

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**Figure 4. SLNB using ICG.** (A) SLNB for melanoma of the nose. The X mark on the left mandible indicates accumulation of radioisotope (arrow). (B) A fluorescent submandibular SLN is visible through the incision using the near-infrared camera (arrow). (C) SLNB for melanoma of the left temporal region. The X marks indicate accumulation of radioisotope. (D) An ad‐ ditional fluorescent SLN (arrow), which was not detected by lymphoscintigraphy, is observed through the overlying skin.

sis. (D) Popliteal lymph node dissection was performed.

**Figure 2. The technique of lymphatic mapping and sentinel lymph node biopsy (SLNB).** (A) Primary melanoma on the left chest. (B) Lymphoscintigraphy shows accumulation of 99Tc-tin colloid which was intradermally injected around the primary tumor in the left axilla (arrow). (C) Intradermal injection of 2% isosulfan blue injection around the primary site. (D) The exploration of the location of SLN using a hand-held gamma-probe and identification of a bluestained SLN. (E) Histopathologic detection of microscopic nodal metastasis.

group than in the standard-technique group. The small size of ICG allows a smooth flow along the lymphatic vessels. It may lead to detection of SLNs not detectable by lymphoscin‐ tigraphy (Fig. 4C, D) owing to poor flow of the radioactive tracer and may reduce the falsenegative rate. Indeed, Stoffels et al. reported that 2 of 11 additional SLNs that were only

In addition, the recently introduced hybrid single-photon emission computed tomography with computed tomography (SPECT/CT) can visualize the exact anatomic location of the SLN and second-tier nodes, which would be of great help in identifying the SLN, especially

**Figure 2. The technique of lymphatic mapping and sentinel lymph node biopsy (SLNB).** (A) Primary melanoma on the left chest. (B) Lymphoscintigraphy shows accumulation of 99Tc-tin colloid which was intradermally injected around the primary tumor in the left axilla (arrow). (C) Intradermal injection of 2% isosulfan blue injection around the primary site. (D) The exploration of the location of SLN using a hand-held gamma-probe and identification of a blue-

stained SLN. (E) Histopathologic detection of microscopic nodal metastasis.

identified by the ICG technique showed microscopic metastasis[23].

502 Melanoma - From Early Detection to Treatment

those in the head and neck region[31, 32], as well as the interval nodes.

**Figure 3. Detection of interval SLN.** (A) Primary melanoma on the right heel. (B) Lymphoscintigraphy revealed accu‐ mulation in the right popliteal fossa. (C) Radioactive and blue-stained popliteal node, which had microscopic metasta‐ sis. (D) Popliteal lymph node dissection was performed.

**Figure 4. SLNB using ICG.** (A) SLNB for melanoma of the nose. The X mark on the left mandible indicates accumulation of radioisotope (arrow). (B) A fluorescent submandibular SLN is visible through the incision using the near-infrared camera (arrow). (C) SLNB for melanoma of the left temporal region. The X marks indicate accumulation of radioisotope. (D) An ad‐ ditional fluorescent SLN (arrow), which was not detected by lymphoscintigraphy, is observed through the overlying skin.

## **3. Does SLNB-guided early lymph node dissection improve survival rate?**

question because only 10% to 25% of patients with positive SLNs will have additional micro‐ scopic metastasis in non-SLNs[40-42], which means that approximately 80% of patients with positive SLNs may be spared CLND. Several authors categorized the SLN as several varia‐ bles and tried to find a reliable indicator of non-SLN status[43, 44]. However, it remains un‐ clear what size of microscopic metastasis of the SLN or which histopathologic location of metastasis in the SLN, such as subcapsular, parenchymal, multifocal, and extensive, would

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The choice of the extent of CLND is ultimately decided by the individual surgeon. Few spe‐ cific recommendations are available in the published guidelines, with the common descrip‐ tion being ''a thorough dissection'' and reports of low levels of evidence supporting the appropriate surgical extent of CLND of the cervical, axillary, and inguinal regions[45-47].

The purpose of neck dissection is to control regional disease; it has little impact on overall sur‐ vival. However, the extent of neck dissection is still controversial and various extents of neck dissection have been advocated by several authors. Radical neck dissection (RND) including removal of level I-V (Fig. 5A) and nonlymphatic tissue such as the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessary nerve has been the gold standard for neck dissection for melanoma[48]. Despite extensive areas of dissection, O'Brien et al. reported that regional control with RND was unsatisfactory, with regional recurrence of 28% in patients with

Generally, RND is associated with significant morbidity. Therefore, some authors have con‐ sidered modified RND (MRND) or functional neck dissection including preservation of any or all of the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve[49, 50]. In studies of patients with clinical nodal disease, several authors demonstrat‐ ed that regional recurrence rates were 14-32% after RND, 0% after MRND, and 23% to 29% after selective neck dissection (SND), which is not statistically significant among the groups[51-53]. Byers also reported a 16% recurrence rate after MRND[54]. From these stud‐

In addition, as an even more selective approach, the lymphatic drainage patterns of head and neck melanoma have been described by O'Brien et al. based on a consecutive series of over 270 neck dissections and parotidectomies (Fig. 5B)[52]. As described above, although several authors reported relatively high regional recurrence rates of 23% to 29% after SND, these studies include clinical N2-N3 (multiple involved nodes) disease, which will have a higher risk of recurrence than N1 disease[51, 52]. In a study of 37 consecutive patients with clinically N1 neck disease reported by White et al., 6 patients underwent RND, 24, MRND, and 7, SND. None of the 3 groups had any cases of local recurrence during a mean followup of 46 months[55], indicating that SND may be an alternative to RND or MRND for the

be a reliable indicator of non-SLN status[44].

**5.1. Extent of dissection and regional recurrence rate**

all nodal disease and of 34% in patients with clinical nodal disease[48].

ies, MRND has been advocated even in the setting of clinical nodal disease.

**5. Neck dissection**

clinically N1 neck in melanoma[55].

Whether patients who undergo complete lymph node dissection (CLND) after confirmation of a positive SLN have a better prognosis than patients who undergo TLND after occurrence of clinical nodal disease is controversial. The results of retrospective studies that compared survival after CLND for a positive SLN with survival after TLND for clinical nodal disease remain controversial. Several retrospective studies, including a multicentric study and a matched control study, demonstrated a significant survival benefit for patients who under‐ went CLND for a positive SLN[33, 34]. In addition, a survival benefit was also demonstrated for patients whose primary tumor thickness was between 1 mm and 4 mm and who under‐ went CLND for a positive SLN[35]. In contrast, other retrospective studies demonstrated no significant difference in overall survival between patients who underwent CLND for a posi‐ tive SLN and those who underwent TLND for clinical nodal disease[36, 37].

The third interim analysis of the Multicenter Selective Lymphadenectomy Trial 1 (MLST-1), the only randomized control trial with available results, failed to demonstrate a 5-year sur‐ vival advantage for the SLNB group when compared with the observation group and only a disease-free survival benefit for the SLNB group[38]. In a subgroup analysis, patients who underwent CLND for a positive SLN showed an improvement in 5-year survival of about 20% when compared with patients who underwent TLND after nodal observation and sub‐ sequently occurring clinical nodal disease (72.3% vs 52.4%; P=.004). The nodal recurrence was lower in patients who had a negative SLN (4.0%) than in those who had a positive SLN but were observed without early CLND (15.6%). From these results, the authors concluded that microscopic metastasis would develop within the lymph nodes and that early LND may lead to accurate staging and survival improvement.

However, whether SLNB and/or CLND would be a therapeutic procedure remains unclear, and several authors have questioned this conclusion from the results of the MLST-1. First, they claim that it was inappropriate to conclude that early CLND would improve survival because this result was based on a postrandomization subgroup analysis[39]. Second, they question whether all microscopic metastases will develop into clinical nodal disease. That is, some microscopic metastases may show indolent behavior and not develop into clinical no‐ dal disease for a long time. In that case, comparison of the nodal recurrence rate between the 2 arms described above is an inappropriate analysis[37]. As a result, all that is currently clear is that SLNB can provide staging information that predicts prognosis and may impact clinical management.

## **4. Complete lymph node dissection**

#### **4.1. The role of complete lymph node dissection**

The therapeutic value of CLND and appropriate selection of patients for CLND remain questionable. The role of CLND in patients with positive SLNs is also a clinically important question because only 10% to 25% of patients with positive SLNs will have additional micro‐ scopic metastasis in non-SLNs[40-42], which means that approximately 80% of patients with positive SLNs may be spared CLND. Several authors categorized the SLN as several varia‐ bles and tried to find a reliable indicator of non-SLN status[43, 44]. However, it remains un‐ clear what size of microscopic metastasis of the SLN or which histopathologic location of metastasis in the SLN, such as subcapsular, parenchymal, multifocal, and extensive, would be a reliable indicator of non-SLN status[44].

The choice of the extent of CLND is ultimately decided by the individual surgeon. Few spe‐ cific recommendations are available in the published guidelines, with the common descrip‐ tion being ''a thorough dissection'' and reports of low levels of evidence supporting the appropriate surgical extent of CLND of the cervical, axillary, and inguinal regions[45-47].

## **5. Neck dissection**

**3. Does SLNB-guided early lymph node dissection improve survival rate?**

Whether patients who undergo complete lymph node dissection (CLND) after confirmation of a positive SLN have a better prognosis than patients who undergo TLND after occurrence of clinical nodal disease is controversial. The results of retrospective studies that compared survival after CLND for a positive SLN with survival after TLND for clinical nodal disease remain controversial. Several retrospective studies, including a multicentric study and a matched control study, demonstrated a significant survival benefit for patients who under‐ went CLND for a positive SLN[33, 34]. In addition, a survival benefit was also demonstrated for patients whose primary tumor thickness was between 1 mm and 4 mm and who under‐ went CLND for a positive SLN[35]. In contrast, other retrospective studies demonstrated no significant difference in overall survival between patients who underwent CLND for a posi‐

The third interim analysis of the Multicenter Selective Lymphadenectomy Trial 1 (MLST-1), the only randomized control trial with available results, failed to demonstrate a 5-year sur‐ vival advantage for the SLNB group when compared with the observation group and only a disease-free survival benefit for the SLNB group[38]. In a subgroup analysis, patients who underwent CLND for a positive SLN showed an improvement in 5-year survival of about 20% when compared with patients who underwent TLND after nodal observation and sub‐ sequently occurring clinical nodal disease (72.3% vs 52.4%; P=.004). The nodal recurrence was lower in patients who had a negative SLN (4.0%) than in those who had a positive SLN but were observed without early CLND (15.6%). From these results, the authors concluded that microscopic metastasis would develop within the lymph nodes and that early LND

However, whether SLNB and/or CLND would be a therapeutic procedure remains unclear, and several authors have questioned this conclusion from the results of the MLST-1. First, they claim that it was inappropriate to conclude that early CLND would improve survival because this result was based on a postrandomization subgroup analysis[39]. Second, they question whether all microscopic metastases will develop into clinical nodal disease. That is, some microscopic metastases may show indolent behavior and not develop into clinical no‐ dal disease for a long time. In that case, comparison of the nodal recurrence rate between the 2 arms described above is an inappropriate analysis[37]. As a result, all that is currently clear is that SLNB can provide staging information that predicts prognosis and may impact

The therapeutic value of CLND and appropriate selection of patients for CLND remain questionable. The role of CLND in patients with positive SLNs is also a clinically important

tive SLN and those who underwent TLND for clinical nodal disease[36, 37].

may lead to accurate staging and survival improvement.

clinical management.

504 Melanoma - From Early Detection to Treatment

**4. Complete lymph node dissection**

**4.1. The role of complete lymph node dissection**

## **5.1. Extent of dissection and regional recurrence rate**

The purpose of neck dissection is to control regional disease; it has little impact on overall sur‐ vival. However, the extent of neck dissection is still controversial and various extents of neck dissection have been advocated by several authors. Radical neck dissection (RND) including removal of level I-V (Fig. 5A) and nonlymphatic tissue such as the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessary nerve has been the gold standard for neck dissection for melanoma[48]. Despite extensive areas of dissection, O'Brien et al. reported that regional control with RND was unsatisfactory, with regional recurrence of 28% in patients with all nodal disease and of 34% in patients with clinical nodal disease[48].

Generally, RND is associated with significant morbidity. Therefore, some authors have con‐ sidered modified RND (MRND) or functional neck dissection including preservation of any or all of the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve[49, 50]. In studies of patients with clinical nodal disease, several authors demonstrat‐ ed that regional recurrence rates were 14-32% after RND, 0% after MRND, and 23% to 29% after selective neck dissection (SND), which is not statistically significant among the groups[51-53]. Byers also reported a 16% recurrence rate after MRND[54]. From these stud‐ ies, MRND has been advocated even in the setting of clinical nodal disease.

In addition, as an even more selective approach, the lymphatic drainage patterns of head and neck melanoma have been described by O'Brien et al. based on a consecutive series of over 270 neck dissections and parotidectomies (Fig. 5B)[52]. As described above, although several authors reported relatively high regional recurrence rates of 23% to 29% after SND, these studies include clinical N2-N3 (multiple involved nodes) disease, which will have a higher risk of recurrence than N1 disease[51, 52]. In a study of 37 consecutive patients with clinically N1 neck disease reported by White et al., 6 patients underwent RND, 24, MRND, and 7, SND. None of the 3 groups had any cases of local recurrence during a mean followup of 46 months[55], indicating that SND may be an alternative to RND or MRND for the clinically N1 neck in melanoma[55].

Furthermore, the appropriate extent of dissection is also unclear in patients with positive SLNs. Pu et al. reported 23 consecutive patients with positive SLNs who underwent MRND or super‐ ficial parotidectomy. Of those patients, 21 (91.3%) had no additional positive non-SLNs and only 2 (8.7 %) had 1 additional positive non-SLN[56]. No patient developed a regional local re‐ currence during a mean follow-up period of 23.7 months. The low prevalence of additional positive non-SLNs in MRND specimens suggests that when microscopic SLN metastasis ex‐ ists, nodal disease is confined to the SLN alone in most patients [56] and SND may be selected.

**5.2. Complication rate and technical variables**

extent of the neck dissection.

**6. Axillary lymph node dissection**

tients with microscopic metastasis[76].

**6.1. Extent of dissection and regional recurrence**

Significant complications associated with radical neck dissection may include injury to the facial and spinal accessory nerves, chylous fistula, and skin flap necrosis[65]. Although it is generally accepted that the rate of morbidity is reduced by MRND and further reduced by SND, detailed complication rates in the treatment of melanoma have not been reported. Ac‐ cording to the literature, neck dissection and parotidectomy is usually safe when appropri‐

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Technical variables mainly include skin incisions. Commonly used incisions are single Y, T, or double Y-type incisions, which provide optimal exposure of the entire neck. However, the edge of the flap sometimes has a poor blood supply and breakdown can result in the exposure of the major vessels. The three-point suture line gives a high incidence of postoper‐ ative scar contracture[66, 67]. The Mcfee incision was designed to eliminate the three-point exposure line, giving a good cosmetic result. However, the exposure is difficult, particularly in a short fat neck, and excessive traction of the skin flaps can result in damaging of the skin edges[67]. Large, single incisions such as the curtain flap, apron flap, U-flap, and Hockey stick incision offer a good blood supply and most of the scar lies within the relaxed skin ten‐ sion lines of the neck[68]. Each incision should be selected appropriately according to the

Axillary LND for patients with melanoma is performed for local control and staging[69]; the therapeutic value is still unclear. The axillary nodes are divided into level I, II, and III nodes. Level I nodes are lateral to the lateral edge of the pectoralis minor muscle. Level II nodes are between the medial and lateral edges of the pectoralis minor muscle. Level III nodes are me‐ dial to the medial edge of the pectorarlis minor muscle, in the apex of the axilla. The gener‐ ally recommended extent of dissection is from level I to III nodes because of the various drainage patterns in the second-tier nodes as well as the potentially increased risk of recur‐ rence with a lesser dissection[70, 71]. Several authors recommended a more extensive dissec‐ tion including the supraaxillary fat pad because approximately 14% of patients will have metastatic nodes in this area[69, 72]. In contrast, several authors have questioned whether a level III dissection is necessary in all melanoma patients with a positive SLN and advocated that level III dissection should be included only when suspicious nodes are present in this level [73-75]. Namm et al. also advocated that level I and II dissection should be performed for positive-SLN patients because of the low regional recurrence rate and low postoperative morbidity and concluded that level III dissection is not necessary for regional control in pa‐

As for the regional recurrence rate, unfortunately, most studies grouped together all of the dissected levels. Several authors reported a 10% to 19% regional recurrence rate during

ately planned preoperatively and when performed by well-experienced surgeons.

As for parotid gland nodes, patients with clinically palpable parotid nodes have a 28% to 58% risk of microscopic metastasis in the cervical nodes[57-59]. Although neck dissection should be included when clinical parotid disease is present, the need to treat the parotid no‐ des when clinical nodal disease of the neck is present is controversial. In such cases, many surgeons selectively perform superficial parotidectomy combined with a neck dissection based on O'Brien's lymphatic map (Fig. 5B) or the protocol of the individual institute[60].

However, the lymphatic drainage in the head and neck is generally complex and 8% to 43% of patients have unexpected drainage patterns in the occipital, postauricular, and contrala‐ teral nodes (Fig. 5A).[26, 61-64] Therefore, SND should be tailored to the individual patient according to the location of the SLN and second-tier nodes.

**Figure 5.** A)Lymphatic anatomy of the head and neck showing the 5 major lymph node levels and superficial nodes (B) Predicted lymphatic drainage and extent of neck dissection recommended by O'Brien et al.

## **5.2. Complication rate and technical variables**

Furthermore, the appropriate extent of dissection is also unclear in patients with positive SLNs. Pu et al. reported 23 consecutive patients with positive SLNs who underwent MRND or super‐ ficial parotidectomy. Of those patients, 21 (91.3%) had no additional positive non-SLNs and only 2 (8.7 %) had 1 additional positive non-SLN[56]. No patient developed a regional local re‐ currence during a mean follow-up period of 23.7 months. The low prevalence of additional positive non-SLNs in MRND specimens suggests that when microscopic SLN metastasis ex‐ ists, nodal disease is confined to the SLN alone in most patients [56] and SND may be selected.

As for parotid gland nodes, patients with clinically palpable parotid nodes have a 28% to 58% risk of microscopic metastasis in the cervical nodes[57-59]. Although neck dissection should be included when clinical parotid disease is present, the need to treat the parotid no‐ des when clinical nodal disease of the neck is present is controversial. In such cases, many surgeons selectively perform superficial parotidectomy combined with a neck dissection based on O'Brien's lymphatic map (Fig. 5B) or the protocol of the individual institute[60].

However, the lymphatic drainage in the head and neck is generally complex and 8% to 43% of patients have unexpected drainage patterns in the occipital, postauricular, and contrala‐ teral nodes (Fig. 5A).[26, 61-64] Therefore, SND should be tailored to the individual patient

**Figure 5.** A)Lymphatic anatomy of the head and neck showing the 5 major lymph node levels and superficial nodes

(B) Predicted lymphatic drainage and extent of neck dissection recommended by O'Brien et al.

according to the location of the SLN and second-tier nodes.

506 Melanoma - From Early Detection to Treatment

Significant complications associated with radical neck dissection may include injury to the facial and spinal accessory nerves, chylous fistula, and skin flap necrosis[65]. Although it is generally accepted that the rate of morbidity is reduced by MRND and further reduced by SND, detailed complication rates in the treatment of melanoma have not been reported. Ac‐ cording to the literature, neck dissection and parotidectomy is usually safe when appropri‐ ately planned preoperatively and when performed by well-experienced surgeons.

Technical variables mainly include skin incisions. Commonly used incisions are single Y, T, or double Y-type incisions, which provide optimal exposure of the entire neck. However, the edge of the flap sometimes has a poor blood supply and breakdown can result in the exposure of the major vessels. The three-point suture line gives a high incidence of postoper‐ ative scar contracture[66, 67]. The Mcfee incision was designed to eliminate the three-point exposure line, giving a good cosmetic result. However, the exposure is difficult, particularly in a short fat neck, and excessive traction of the skin flaps can result in damaging of the skin edges[67]. Large, single incisions such as the curtain flap, apron flap, U-flap, and Hockey stick incision offer a good blood supply and most of the scar lies within the relaxed skin ten‐ sion lines of the neck[68]. Each incision should be selected appropriately according to the extent of the neck dissection.

## **6. Axillary lymph node dissection**

### **6.1. Extent of dissection and regional recurrence**

Axillary LND for patients with melanoma is performed for local control and staging[69]; the therapeutic value is still unclear. The axillary nodes are divided into level I, II, and III nodes. Level I nodes are lateral to the lateral edge of the pectoralis minor muscle. Level II nodes are between the medial and lateral edges of the pectoralis minor muscle. Level III nodes are me‐ dial to the medial edge of the pectorarlis minor muscle, in the apex of the axilla. The gener‐ ally recommended extent of dissection is from level I to III nodes because of the various drainage patterns in the second-tier nodes as well as the potentially increased risk of recur‐ rence with a lesser dissection[70, 71]. Several authors recommended a more extensive dissec‐ tion including the supraaxillary fat pad because approximately 14% of patients will have metastatic nodes in this area[69, 72]. In contrast, several authors have questioned whether a level III dissection is necessary in all melanoma patients with a positive SLN and advocated that level III dissection should be included only when suspicious nodes are present in this level [73-75]. Namm et al. also advocated that level I and II dissection should be performed for positive-SLN patients because of the low regional recurrence rate and low postoperative morbidity and concluded that level III dissection is not necessary for regional control in pa‐ tients with microscopic metastasis[76].

As for the regional recurrence rate, unfortunately, most studies grouped together all of the dissected levels. Several authors reported a 10% to 19% regional recurrence rate during about a 30-month median follow-up[77-79]; however, in all 3 of those studies, the extent of dissection was not documented. Veenstra et al. reported a 4% regional recurrence rate and documented which levels were included when axillary LND was performed; however, they did not tease out the axillary recurrence rate specifically[80]. In the case of level I and II dis‐ section for patients with a positive SLN, a low recurrence rate of 4% during a median fol‐ low-up of approximately 39-month was reported[76].