Artículo Clínico

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The role of the sentinel node biopsy in the diagnosis and therapeutic management
of melanoma of the head and neck
Papel de la biopsia de ganglio centinela en el manejo diagnóstico-terapéutico del melanoma
de cabeza y cuello

 

A. García-Rozado González¹, C. Peña², V. Vieira², I. Uriarte³, J.L. López-Cedrún⁴

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Abstract: Objective. The ongoing incidence of malignant cutaneous melanoma of the head and neck has become a challenge in many regions of the world, in spite of prophylactic trials such as popular education and screening. Although non-surgical therapies are performed, most melanomas are actually treated by surgical excision. In the last few years, sentinel node biopsy has evolved as a diagnostic and therapeutic tool, and it has permitted a significant minimizing of the morbidity associated with the surgical management of the neck. This article is aimed at providing a thorough review of our experience in head and neck melanoma, as well as a retrospective analysis of locoregional metastases and the predictability of sentinel node biopsy for the staging of melanoma. Design. A retrospective review of our experience over the last two years has been carried out that includes 12 cases of head and neck melanoma where lymphoscintigraphy and sentinel node biopsy were performed. Results. Sentinel lymph nodes were identified using preoperative lymphoscintigraphy and intraoperative gamma probe in 11 cases (91.6%). A total of 21 nodes were identified in the 12 patients, with an average number of 1.75 nodes per patient. The most frequent site where nodes were located was level II of the neck. Two nodes (9.52%) were affected by melanoma. There was minimal morbidity related to this procedure. Conclusions. In spite of the reduced size of the sample and the short-term follow-up, our results are similar to those obtained by other authors, which leads us to believe that sentinel lymph node mapping with biopsy is a reliable technique for the diagnosis of regional spread in head and neck cutaneous melanoma, even in early development stages. Key words: Head and Neck Melanoma; Sentinel Node; Lymphoscintigraphy.

Resumen: Objetivo. La creciente incidencia del melanoma facial constituye un auténtico reto en muchas regiones del mundo, a pesar de medidas como la educación sanitaria de la población y realización de screenings poblacionales. Aunque también se emplean terapias no quirúrgicas, la mayoría de los melanomas se tratan en la actualidad mediante excisión quirúrgica. En los últimos años, la biopsia del ganglio centinela se ha incorporado como una técnica diagnóstica y terapéutica adicional, y ha permitido una reducción significativa de la morbilidad asociada al manejo quirúrgico del cuello. En el presente artículo pretendemos revisar la experiencia de nuestro equipo con el melanoma de cabeza y cuello en los últimos años, así como analizar retrospectivamente la incidencia de metástasis locoregionales, y la predictibilidad de la biopsia de ganglio centinela para su estadiaje. Diseño del estudio. Se ha revisado retrospectivamente nuestra experiencia en los dos últimos años con 12 casos de melanoma de cabeza y cuello en que se realizó linfoescintigrafía y biopsia de ganglio centinela. Resultados. La identificación del ganglio centinela mediante sonda de captación gamma se consiguió en 11 de los casos (91,6%). Se identificaron un total de 21 ganglios centinela, es decir, 1,75 ganglios por paciente, siendo el nivel II cervical la localización más frecuente. Dos de ellos (9,52%) resultaron afectados por melanoma. La morbilidad residual como consecuencia de la biopsia de los ganglios centinelas ha sido mínima. Conclusiones. A pesar del reducido tamaño de la muestra y de la falta de seguimiento a largo plazo, nuestros resultados son similares a los obtenidos por otros autores, lo que nos induce a considerar la linfoescintigrafía y biopsia de ganglio centinela como una técnica fiable, incluso ya desde fases iniciales de su implantación. Palabras clave: Melanoma de Cabeza y Cuello; Ganglio Centinela; Linfoescintigrafía.

Recibido: 14.01.2005

Aceptado: 21.03.2005

 

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1 Médico Adjunto. S. de Cirugía Maxilofacial. Complejo Hospitalario Juan Canalejo.
2 Médico Adjunto. S. de Dermatología. Complejo Hospitalario Juan Canalejo.
3 Médico Adjunto. S. de Medicina Nuclear. Centro Oncológico de Galicia.
4 Jefe de Servicio. S. de Cirugía Maxilofacial. C. H. Juan Canalejo. La Coruña. España.

Correspondencia:
Alvaro García-Rozado González
Rúa Perseo 15
15179 Oleiros, La Coruña, España
E-mail: agrozado@canalejo.or

 

Introduction

Of the new cancer cases diagnosed in developed countries, cutaneous melanoma has been estimated in men and women at 5% and 4% respectively.¹ These figures place it in fifth or sixth position of the most common cancers in men and women. It has been calculated that in the USA alone during the year 2002 some 53.600 new cases of melanoma were diagnosed together with 34.300 of in situ melanoma, and that there were 7.400 deaths from melanoma. However, the most alarming aspect is that the incidence of melanoma is increasing at a rate of approximately 5% each year, and that this growing incidence is linked with a proportional annual increase in mortality in absolute numbers. The five-year survival rate has at least increased and it currently stands at 89%. This is chiefly due to an increase in the early detection of the disease that allows more effective treatment during the initial stages rather than to real therapeutic advances.

Primary melanoma of the head and neck represents 25% to 40% of the total melanoma count, despite the fact that the head and neck represents just 9% of the whole body surface. ² Among the reasons attributed to this disproportion there is sun exposure and regional variation of cutaneous melanocyte distribution, to the extent that the number of melanocytes in the head and neck is two to three times higher than in the rest of the organism.³ The most common location of head and neck melanoma is the skin on the cheek (46%), neck (20%), scalp (18%), outer ear (12.5%), nose (2%) and eye lids (1%).⁴The BANS areas (Back, Arm, Neck Scalp) have a worse prognosis traditionally, and it has been demonstrated that the skin of the scalp has the worst survival figures of the head and neck, followed by the area of the temples, outer ear, cheek and neck.⁵

Although the therapeutic protocols have practically not been modified over the last decades, and surgical excision continues to be the basic therapeutic tool for the management of melanoma of the head and neck, the early 90’s witnessed the development of the sentinel node biopsy technique, first described by Morton et al.⁶ in 1992. These authors based their studies on Wong et al⁷ who demonstrated with an experimental feline model that each specific area of skin drained into a first lymph node, the sentinel node, and from here it drained to the rest of the regional nodes.

As occurs with other malignant diseases of the head and neck, the information provided by the sentinel node biopsy improves tumor staging and it is of great prognostic interest. It is currently felt that the sentinel node biopsy has been completely incorporated into the protocol for the diagnostic and therapeutic management of N0 cases of head and neck melanoma. Proof of this is the publication of numerous articles on the subject in the medical literature.^8-14It is also a technique that has been accepted and integrated by the majority for the diagnosis and treatment of other cancers, including epidermoid carcinoma of the head and neck or Merkel cell carcinoma, which are of interest in our anatomic region.^15-17 International conferences are even held with the aim of adopting universal protocols with the indications for this procedure and its technical details.¹⁸

The purpose of the present article is to describe our experience with the sentinel node biopsy for head and neck melanoma, as well to define the indications for its use and to analyze the predictability of the technique.

Material and Method

A retrospective study was carried out of 12 patients with melanoma of the head and neck, with stage N0 that underwent sentinel node biopsies. The first case was in July 2002 and the last one was in November 2004. All the cases had been referred to our Service by Dermatology Service that had previously carried out an excisional biopsy of the primary lesion. Table 1 shows the principal data corresponding to the patient series.

During the period 2002- 2004, a total of 176 melanomas were registered by the Dermatology Service of the Juan Canalejo Hospital of La Coruña. Of these, 68 cases (38.64%) were located in the area of the head and neck. The 12 cases that underwent sentinel node biopsies represent 17.65% of the melanoma cases of the head and neck. The criteria used to determine if a sentinel node biopsy was needed were the following:

• Removable tumor
• Absence of palpable swelling (N0).
• No evidence of metastasic disease.
• Melanomas of 1 mm or more on the Breslow scale.
• Melanomas of less than 1 mm on the Breslow scale that were ulcerated and/or Clark level IV or above.
• The exclusion criteria used related to cases where there could be a modification of the lymphatic drainage pattern due to a previous surgical procedure or any other circumstance. This situation did not arise in any of the cases evaluated in our study.

The distribution according to anatomic location in the head and neck of the cases included in out study was as follows (Fig. 1): 6 melanomas in the skin of the cheek, 2 in the region of the temples, 2 in the preauricular region, 1 in the neck, and 1 mucosal melanoma of the top lip. Of the 12 patients that had biopsies, 9 were female (75%) and 3 were males (25%). The mean age of the patients when the sentinel node biopsy was carried out was 63.25 years, with ages ranging between 40 and 82.

The histological type of melanoma included in the study was of nodular melanoma (NM) in 6 cases, lentigo maligna melanoma (LMM) in 4 cases, superficial spreading melanoma (SSM) in 2 cases (Fig. 2). It should be pointed out that one of the cases of mucosal melanoma of the upper lip was diagnosed as nodular melanoma on excision by the Dermatology Service, and it was later diagnosed a superficial spreading melanoma when we widened the surgical margins. In 10 of the 12 cases (83.33%) the surgical margins of the primary lesion were widened while the sentinel node biopsy took place.

The average delay between the histological diagnosis by the Dermatology Service to our carrying out the sentinel node biopsy was 50.41 days, with the number of days ranging between 20 and 92. The Clark levels in the 12 cases of the head and neck melanoma where the biopsy of the sentinel node was carried out were as follows (Fig. 3): 6 cases of Level IV, 3 cases of Level V, 2 cases of Level II, and 1 mucosal melanoma. The corresponding Breslow scale ranged between 1.08 mm and 10 mm, with an average of 4.44 mm. The size of the primary lesion, taking the maximum diameter of the surgical specimen from the excisional biopsy carried out by the Dermatology Service was variable, ranging between 7 and 30 mm, with a mean size of 11.75 mm. None of the patients included in the study had ulceration of the primary lesion.

All the sentinel node detection was done with lymphoscintigraphy in order to visualize the lymphatic drainage pattern, and it was carried out on the same day of the surgical intervention. The lymphoscintigraphy was carried out in all cases by the same doctor specialized in Nuclear Medicine. For the lymphatic mapping, perilesional intradermic injections were used in at least 4 points around the primary lesion with technetium (tc 99m) radiotracer sulfur colloid with a dose of 3 mCi in 0.3 ml of serum with a particle size of 10 nm. After approximately 10 minutes static gammagraphic images were taken (Fig. 4). Next, the cutaneous area that corresponded to the node was marked clinically with indelible ink (Fig. 5).

The patients were then sent immediately to the operating room for the biopsy of the nodes that had been marked.

The biopsy was carried out in all cases during the first 4 hours that followed the lymphoscintigraphy.

The biopsy was carried out in all cases under general anesthesia and before amplifying the surgical margins of the primary lesion, if this was planned. In order to locate the node intraoperatively a gamma detector (NeoProbe Neo2000^TM Gamma Detection System, Neoprobe Corporation, Dublin, Ohio) was used (Fig. 6). A characteristic of our technique was that blue dye was not used to identify the node, given our experience with residual tattoos in other malignant lesions in the head and neck. The surgical dissection of the node was carried out in the conventional way, according to the universally accepted standards for neck dissection. A node was considered a sentinel node if the radioactive count agreed with the lymphoscintigraphic findings. Thus, any other node with a high radioactive count (100 or 1000 times greater, according to the sensitivity program of the probe) was considered a sentinel node and/or that was located so close to the injection site of the radio-tracer to another radioactive node that it could not be singled out in the lymphoscintigraphy.

The radioactive count was carried out in vivo and ex vivo using the probe (Fig. 7). Following the established protocol, the existence of residual counts in the nodal bed was checked. Amplification of the margins was carried out when planned, depending on how radical the previous surgery had been, the size of the lesion and how deep the melanoma invasion was (Breslow scale).

The histopathological evaluation of the sentinel nodes was carried out very thoroughly with at least six sections, or up to 12 if the node was larger than 1 cm. A conventional histologic study was carried out with hematoxylin-eosin stain and immunohistochemistry study for S-100, HMB45, and/or Melan-A.

During the clinical follow-up no case was lost, with the exception of one exitus case. The average follow-up time from the date the sentinel node biopsy was 14.33 months (with a range of 2-30 months).

Results

Of the 12 cases studied, a sentinel node was identified in 11 cases (91.6%). The one case where a sentinel node was not identified corresponded to melanoma of the skin of the cheek, and a high radioactive count was noted in the parenchyma of the ipsilateral parotid tail. The tissue with the high radioactive activity was resected and a near total reduction of the count was verified using a probe on the surgical bed. The posterior histopathologic study revealed the presence of glandular tissue and the absence of lymph nodes.

In 5 cases (41.66%) a radioactive node was found that was considered the sentinel node. In one case of scalp melanoma of the midline, four sentinel nodes were observed, two in each side, bilateral neck level II. A total of 21 sentinel nodes were identified, that is 1.75 nodes per patient.

The location of the identified sentinel nodes was as follows (Fig. 8): 17 nodes in Level II neck, one in Level I, one in Level V and 2 intraparotid nodes.

Two cases (16.66%) had sentinel nodes affected by melanoma, which represents 9.52% of all the 21 lymph nodes studied. These two positive glands were found in Level II, and they corresponded to one case of preauricular melanoma and to another case of melanoma of the lip mucosa. In both cases radical node dissection of the neck was carried out, and adjuvant therapy was give with high-dose interferon alfa-2b. The first case with preauricular melanoma had systemic dissemination with liver and lung metastasis, resulting in exitus 12 months after the radical neck dissection. The second positive sentinel lymph node was related to a case of mucosal melanoma of the top lip. Adjuvant treatment was carried out with radiotherapy and high-dose interferon alfa-2b. The patient is currently alive and disease-free after a 13-month follow-up.

The remaining 10 cases with histologically unharmed sentinel nodes are under periodic control on an outpatient basis. One of these cases corresponded to melanoma of the cheek, and melanoma of the intraparotid lymph nodes, which was diagnosed by CAT scan and by cytology, appeared 17 months later. During this time the patient was periodically controlled clinically and radiologically by CAT scan and no locoregional metastatic lesion was observed. This, added to the time elapsed before the appearance of lymphatic metastasis led us to believe that the case was not a false negative of the technique. The patient underwent a total parotidectomy. The lower branches of the facial nerve were sacrificed and radical neck dissection was carried out.

The residual morbidity as a result of the sentinel node biopsies was just the surgical scar and the violation of the facial spaces in the neck. No sequelae in important structures were observed nor in any specific branches of the facial nerve.

Discussion

Melanoma is a malignant disease with an unpredictable clinical course, particularly in the area of the head and neck. It is well-known, however, that lymphatic dissemination often precedes systemic dissemination.^19,20 In fact, in 30% of patients the lymph nodes are affected even though this is not clinically palpable.¹⁴ The risk of occult nodal metastasis increases the thicker the primary tumor.¹¹ Lesions with a thickness that is under 1 mm have a risk of metastases of less than 5% while associated risk increases by 30 to 50% when the lesions is thicker than 1mm.¹¹

The sentinel node is the first nodal echelon that in theory directly receives drainage from the primary tumor site. It would therefore be the first node affected if there was lymphatic dissemination of tumor cells. The concepts behind the sentinel node biopsy are based on this hypothesis.⁶

Even from the first publications, the sentinel node biopsy has proved very useful in various aspect of melanoma management, including diagnosis for regional extension, staging, prognosis and treatment²¹ It is currently accepted that nodal involvement represents an independent factor with the greatest prognostic value for patients with melanoma, that is even more significant than the invasion depth according to Breslow’s scale and to the primary lesion being ulcerated.^22,23 In fact, in the AJCC of 2002 sentinel node status is included as a prognosis factor.²⁴

From the point of view of diagnosis, it appears to be the least aggressive technique and the most effective for revealing the presence of occult nodal metastasis.²⁵ It has a sensitivity that is significantly greater than that of sophisticated imaging techniques such as the CAT scan, MR and PET.²⁶ In addition, early detection of micrometastasis permits immediately carrying out more extensive salvage resection together with the identification of patients with melanoma that require adjuvant treatment with interferon alfa-2b.²⁷

Pu et al²⁸ found that 91.3% of patients with positive sentinel nodes did not have additional positive lymph nodes in the histological study following radical lymphadenectomy. The remaining 8.7% of the cases had one additional positive lymph node. This low prevalence of additional positive lymph nodes in complete lymphadenectomies suggests that when there is micrometastasis in regional lymph nodes, in most early stage head and neck melanoma, this is limited to the sentinel node.

Lymphoscintigraphy and sentinel node biopsies have substituted elective node dissection in early-stage melanoma of the head and neck, thus reducing the morbidity associated with surgical treatment. It has a clear advantage over elective lymphadenectomies as the lymph nodes that can be resected can be individually identified, more closely examined and at a much lower cost.²⁹ Although there is still controversy as to whether the sentinel node biopsy modifies patient prognosis, it has been imposed largely as a strong indicator of disease prognosis.⁸

The utility of the sentinel node biopsy in the pediatric population appears to be as beneficial as it is in adults.³⁰

In view these finding, the indications accepted by most authors for carrying out sentinel node biopsies include melanoma with no evidence of nodal or distant metastasis and with a Breslow thickness of 1 mm or over,³¹ and melanoma with a thickness under 1 mm if the primary lesion is ulcerated and/or with Clark level IV or above.^{3, 24} Other authors defend the indication for melanomas of 4 mm or above if the aim is to provide information on the prognosis of the disease, in spite of the fact that these melanomas carry a high risk of distant metastasis.³²

One of the problems posed in the therapeutic management of melanoma of the head and neck refers to the unpredictable pattern of lymphatic drainage in the head and neck. According to some publications, in 34 to 84% of patients, lymphatic drainage is discordant with clinical predictions^{33, 34} and in approximately 10% of cases bilateral drainage is observed.²¹ The area that is most discordant corresponds to the retroauricular lymph nodes.³⁴ Other publications on the other hand, conclude that this discrepancy between clinical prediction and pathologic reality appears in only 7.7% of cases, and the predictability of the lymphatic pattern of head and neck melanoma is 92.3%.²⁹ The lymphoscintigraphy provides adequate information on the lymphatic anatomy to prevent these metastases with unpredictable patterns from going undetected.

However, lymphatic mapping of the head and neck has some of its own particular problems. Visualizing lymphatic drainage by means of lymphoscintigraphy is more difficult than in other areas of the organism, as potential sentinel nodes are often found overlapping the injection area of the radiotracer, and there is the additional risk of a false intraoperative reading by the gamma probe.¹⁴ Some authors advocate the use of sulfur colloid at a lower activity level for the head and neck.³⁵ In addition the tracer tends to travel very quickly, and in 10 minutes images of ganglionic activity can be obtained, without the need for dynamic lymphoscintigraphy. However, if more than one node is visible, distinguishing these from sentinel nodes or non-sentinel nodes is difficult. According to some authors, this problem could be solved by using isotopic tracers with larger sized particles that would accumulate chiefly in the first nodal echelon, as they would have less capacity for traveling to more distal ganglionic echelons.¹⁴

The number of nodes that we found per patient in our study was 1.75 nodes. In the series revised the range is between 1.25 and 2.8 nodes per patient.^10-12

Another controversy surrounding the sentinel node biopsy in melanoma of the head and neck concerns the associated morbidity. A high number of these nodes are small and they are found in areas that are not easily reached, such as in the parotid gland parenchyma, with the resulting risk of lesions being produced in important structures. In our study we have not found any sequelae of this type. Neither did we find in the different works published in the medical literature any significant residual morbidity.^{10-13, 27}

In the literature there are references to the absorption of Tc-99m sulfur colloid by glandular tissue.³⁵ This increases the radiation level in the lymphatic network leading to intraoperative difficulties with recording activity levels in the areas close to glandular structures, a situation that frequently arises with facial melanoma. In our study, in the case in which a sentinel node was not identified, there was a high activity level in the area of the parotid tail. The tissue with high radioactivity was resected, even though in the subsequent histologic study no nodal tissue was observed.

The use of certain types of blue dye has also resulted in controversy. Some authors^12,36 defend the use of blue methylene claiming an improvement in intraoperative nodal localization, although they also report that blue dye is less visible in the head and neck than in other areas of the anatomy. In our experience we have found permanent sequelae from blue dye when used in sentinel node biopsies of intraoral epidermoid carcinoma cases. This has led us to systematically avoid its use intraoperatively, especially in melanoma cases when the dye is injected into facial areas that are aesthetically very important.

In the medical literature, the sensitivity of the sentinel node biopsy for melanoma of the head and neck varies between 88 and 100%.^{10,11,14,34,37,38} In our study the sensitivity of the technique was around 91.6%. In the articles revised, the percentage of false negatives varied between 0 and 25%, with a mean of 8.69%. Chao et al¹² found more false negatives in the head and neck than in other areas with melanoma. In our study we did not encounter any false negatives. The case of the negative sentinel node with parotid swelling after 17 months was not considered a false negative given the long period of time that had elapsed before the appearance of swelling. In the complementary studies carried out during this time no suspicious masses had been observed. In any event, there are limitations in our study as we were unable to analyze the false negatives properly given that complete lymphadenectomies were not carried out at the same time as the sentinel node biopsy.

In our study sentinel node involvement was found in 16.66% of patients. In the series revised, the percentage of patients with nodal involvement varied between 9.4% and 30%. In our opinion these are significant figures of occult metastases in N0 melanomas to warrant the sentinel node biopsy technique.

Conclusions

Lymphatic mapping with sentinel node biopsy is a reliable technique for the diagnosis of lymphatic dissemination of head and neck melanoma, for cases that have been properly selected. In addition to the minimal morbidity caused, information is provided that is of great importance when individually assessing the prognosis of the disease. In spite of the promising prospects that we can expect with this technique, we consider that longer follow-ups are necessary together with studies of larger series in order to obtain definitive conclusions.

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