The role of sentinel node mapping in malignant melanoma: experience with 99mTc-phytate and a review of the literature

Abstracts

FUNDAMENTOS: A progressão linfática do melanoma maligno habitualmente se inicia pelo linfonodo sentinela (LNS), cuja análise histopatológica permite predizer o acometimento de toda a cadeia. OBJETIVO: O trabalho tem por objetivo descrever a utilização do 99mTc-Fitato na detecção do LNS em pacientes com melanoma maligno, revisando as indicações e informações fornecidas por sua biópsia. MÉTODO: A pesquisa de LNS foi realizada por meio da linfocintilografia com 99mTc-Fitato em 92 pacientes com melanoma (54,0±14,3 anos). Após 18-24 horas, 88 pacientes foram submetidos à localização intra-operatória com detector portátil, seguida da ressecção e análise histopatológica do LNS. RESULTADOS: A linfocintilografia permitiu a identificação do LNS em todos os estudos, havendo detecção intra-operatória em 98,8% dos casos. O LNS estava acometido em 23 pacientes (26%). O valor preditivo negativo foi de 100% e não se observaram reações adversas pelo uso do 99mTc-Fitato. CONCLUSÃO: A detecção do LNS pode ser realizada com diferentes radiofármacos, incluindo o 99mTc-Fitato, que apresenta vantagens de custo e disponibilidade no Brasil. A pesquisa de LNS resulta em maior acurácia e menor morbidade no estadiamento de pacientes com melanoma maligno

biópsia de linfonodo sentinela; cintilografia; melanoma

CLINICAL, LABORATORY AND THERAPEUTIC INVESTIGATION

The role of sentinel node mapping in malignant melanoma: experience with ^99mTc-phytate and a review of the literature^*

Marcelo T. Sapienza^I; Marcia G. M. Tavares^II; Irene S. Endo^II; Guilherme C. Campos Neto^II; Margarida M. M. F. Lopes^III; Sérgio Nakagawa^III; Francisco A. Belfort^III; Jose Soares Jr.^I; Shlomo Lewin^II; Marilia M. S. Marone^I

^IMD, PhD, Bone Densitometry and Diagnosis Unit - Uddo, São Paulo - Brasil

^IIMD, Bone Densitometry and Diagnosis Unit - Uddo, São Paulo - Brasil

^IIIMD, Brazilian Cancer Control Institute - IBCC, São Paulo - Brasil

^{Correspondence}

SUMMARY

BACKGROUND: Sentinel lymph node (SLN), corresponding to the first lymph node draining the tumor, is usually the first one to receive its metastasis, and its biopsy is used to define the status of the whole lymphatic basin.

OBJECTIVE: The aim of this paper is to describe the use ^99mTc-Fitato in SLN localization in malignant melanoma patients, and to review the main indications and information provided by SLN biopsy.

METHOD: A total of 92 patients with malignant melanoma was studied. Lymph node scintigraphy was carried out after the subdermal injection of ^99mTc-Phytate. After 18-24 hours, intra-operative SLN localization was carried out using the gamma-probe and lymph node dissection was then performed.

RESULTS: Lymphoscintigraphy identified the sentinel node in all studies and intra-operative detection using gamma-probe was reached in 98.8% of the cases. The SLN was involved in 23 patients (26%). The method's negative predictive value was 100%, and there were no side effects related to ^99mTc-Phytate.

CONCLUSION: Scintigraphic and intra-operative sentinel node detection was satisfactorily performed using ^99mTc-Phytate, an easily available and low cost radiopharmaceutical. SLN mapping allows the use of more accurate tumor staging techniques and reduces surgical morbidity.

Keywords: sentinel lymph biopsy; radionuclide imaging; melanoma.

INTRODUCTION

The incidence of malignant melanoma is growing worldwide. Three-thousand fifty new cases are detected in Brazil yearly, which results in 1,085 deaths (1.7 new cases and 0.57 deaths per 100,000 inhabitants).¹ The treatment of primary melanoma of the skin begins by resection with an ample margin of the tumor. Resection may lead to a cure in cases of localized disease. However, the likelihood of ganglionar involvement increases with thicker lesions, notably affecting 20% of melanoma patients who have intermediary Breslow thickness (1-4 mm). The removal of the entire lymphatic basin may be carried out as complementary treatment in these patients. There is no clear impact of this procedure upon survival rates, apart from its morbidity factor-for lymphedema frequently ends up developing. This is why its indication has been questioned.²

The outcome of treatment basically depends on the initial stage of the disease, because most systemic treatments (including chemistry and immunotherapy) have little impact upon survival. The exception here is high-dose interferon-alpha treatment, which has shown encouraging results.^3,4 The main prognosis factors of cutaneous melanoma are tumor thickness, presence of ulceration and detection of ganglionar metastases.^5,6 The five-year survival rate is also related to the number of lymph nodes affected, and the presence of micro- or macroscopic affection.⁷

The concept of sentinel lymph node (SNL) was widely used during the last decade. It has had a large impact upon the staging and prognosis of diverse tumors, including melanoma. SNL corresponds to the first lymph node of the lymphatic basin to receive drainage from a determined region. The latter virtually always corresponds to the first tumoral implantation site (Figure 1), since dissemination typically occurs in an orderly and sequential way. Nevertheless, SNL analysis allows one to define the status of the entire lymphatic basin. Beyond lower morbidity rates resulting from resection of the entire lymphatic basin, ganglion staging starting from the sentinel lymph node may prove to have greater accuracy than a complete resection, for it allows a guided use of existing techniques, such as immunohistochemistry.

The very first SNL studies were performed by Cabanas in 1977. They evidenced lower mortality in patients with penile carcinoma when the first lymph node draining the tumor proved to be disease free.⁸ In 1992, Morton and cols. undertook SNL mapping of melanoma patients with a preoperative injection of blue dye in the lesion. This was followed by mapping the lymphatic and stained lymph node pathways during surgery.⁹

The use of dyes has shown good results,¹⁰ though within certain limits only. Visual analysis as a means of identifying stained lymph nodes is based upon the assumption that the tumor's drainage basin is known beforehand. Such is not usually the case (especially in patients with melanoma of the trunk). Likewise, lymph node detection in atypical localizations can also be difficult. The required interval for the appearance of dye in the lymph node varies. This leads to an increased risk of lymphatic dissection prior to the staining of SNL or after the dye's progression to a larger number of lymph nodes.

In 1993, Alex and Krag proposed intradermal injection of colloidal sulfur marked with 99mTc-Phytate around the melanoma, followed by scintigraphy to determine the lymphatic drainage path and identify SNL.¹¹ Marking the lymph node projection on the skin prior to surgery helps guide surgeons. Furthermore it allows for less aggressive incisions and dissections. Development of a portable radiation detector, a.k.a. the gamma-probe, allows intraoperative application of radioisotope techniques to localize sentinel lymph nodes. A combined use of lymphoscintigraphy and the probe enhances detection rates and allows rapid access to the ganglionic chain with a lower mortality rate.

SNL detection in patients with malignant melanoma was one of the first situations in which the SNL concept gained validity. These initial studies have been widely confirmed ever since.^6,12,13 Improved staging and prognostic information obtained from SNL biopsies are extra reasons for explaining the speed with which the technique has acquired such widespread acceptance. This paper describes the group's experience in detecting SNL by the use of ^99mTc-Phytate. It also offers revised indications, and discusses the main information gathered from a SNL biopsy.

MATERIAL AND METHODS

Lymphoscintigraphy used for detecting SNL was carried out on 92 patients (32 male and 60 female, 54±14.3 years of age) between March 1998 and July 2002. The Institution's Ethics Board approved the study, and patients were previously informed as to the procedures involved.

None of the patients subjected to melanoma resection showed any suspected clinical ganglionar involvement. The first lesion was localized on the trunk in 38 patients, lower limbs in 35, upper limbs in 15 and the throat in four cases. The medial depth of the tumor was 4 mm ± 3.9 (varying from 0.4-20 mm), with a level of Clark equal to I for 1.5% of lesions, II for 13%, III for 42%, IV for 25% and V for 18%.

Lymphoscintigraphy was carried out after subdermal injection of 0.8 ml of Phytate marked with the 99mTechnique (Ipen, São Paulo), set at 55-74 MBq (1.5-2 mCi). The injection was applied to four or more points around the resection wound of the primary tumor.

Lymph node scintigraphy was carried out with a model SPX-6 scintigraphy camera (Elscint, Haifa) with a low-energy, high-resolution collimator, at the UDDO/Brazilian Cancer Control Institute Nuclear Medicine Service. The study's dynamic phase consisted of 30-second images obtained over five minutes after injection of the radiopharmaceutical. Static images were obtained in 10-60 minute intervals after the injection. When SNL identification within the first hour of study was not possible, images were obtained up to four hours later. The patient's position varied according to the progression observed during the study's dynamic phase and localization of the primary lesion (trunk, thorax/axilla and basin projections; lower limbs-basin projections; upper limbs-thorax/axilla projections; head and throat-thorax, axilla and cranial projections). Additional images of the popliteal region and elbows were taken for the tumors found at the extremities. Lymph nodes identified by scintigraphy were marked on the skin. Moreover, it is preferable for the patient to be in the position designated for surgery.

Surgery was performed 18-24 hours after lymph node scintigraphy. The intraoperative localization of SNL was made with the use of patent blue dye and the gamma-probe. The GAMMED II (Eurorad) gamma-probe was used to assess the number of radioactive counts detected on the skin (a region previously marked during the lymphoscintigraphy). This procedure thus confirmed the SNL position prior to the initial incision. The probe was then covered by a sterile protector and utilized by the surgeon to guide the intraoperative SNL mapping. The number of SNL counts in vivo, and following the resection, was measured and registered. Should radioactivity persist during surgery at over 1/10 of the counts detected prior to the SNL removal, mapping and resection would then have to be performed on the other traced lymph nodes. By the end of SNL mapping, the peritumoral margin had grown. At the initial phase of implementing the procedure, total resection of the ganglionic chain was also performed on all of the 36 patients.

After SNL removal, we moved on to macroscopic analysis of the tumor, and measured its three diameters and longitudinal incision. The lymph node was then embedded in paraffin, thus obtaining 3 µm cuts and hematoxylin-eosine staining. Immunohistochemical techniques were not applied systematically with this group due to routine unavailability at the hospital.

RESULTS

Lymphoscintigraphy with ^99mTc-Phytate revealed rapid progression of the radiopharmaceutical. SNL identification was still in the dynamic phase for most patients (Figure 2). There were no local or systemic adverse reactions observed after injecting the radiopharmaceutical.

Simultaneous draining of two or more lymphatic basins was observed in nine patients. Draining of unexpected basins by lesion topography was found in six, and popliteal lymph nodes detected in seven cases (Figure 3). Of the seven patients with sentinel lymph nodes in popliteal areas (always associated with inguinal lymph nodes), two showed tumor involvement, while in one, the inguinal chain was free from disease.

Intraoperative SNL detection with the gamma probe was performed in 88 patients. It was not performed on four individuals since the equipment was not available on the day set aside for surgery. SNL was identified and achieved in 87 cases (98.8%) (Figure 4), with an average of 2.1 sentinel lymph nodes per patient. The sole patient in whom SNL was not found, either by the gamma-probe or blue staining, showed a tumor on the medial line of the high dorsal region. Lymphoscintigraphy revealed drainage to the posterior cervical chain.

The SNL biopsy revealed lymphatic dissemination of the melanoma in 23 patients. SNL resection was followed by removal of the whole ganglionic chain in 36 patients, including those who had disease-free SNL during the initial phase of implementing the method at our service. Among these 36 patients there was no single case of SNL false negative results from conventional histopathological analysis. And the SNL was the sole lymph node affected by a tumor in 16 cases (44%). The histopathological analysis of SNL, nonetheless, proved to have a predictive potential over whether or not the basin would be affected in all of the 36 patients (Table 1).

DISCUSSION

Lymphoscintigraphy and radiopharmaceuticals used in SNL detection

The skin shows a rich network of lymphatic vessels localized primarily in the most superficial layer of the dermis, i.e. near the epidermis.¹⁴ Sub- or intra-dermal injections of different substances allow the study of lymphatic drainage and a few variations in draining velocity and lymphatic retention that depend on the physical characteristics of the injected composite. Progression in the lymphatic pathways depends primarily on particle size. Particles with the highest molecular weight are among the least and slowest to progress. On the other hand, low molecular weight composites are not retained in lymph nodes, as opposed to particulate materials (such as colloids), which are retained most likely by phagocytosis. Colloids consist of the majority of radiopharmaceuticals used to detect sentinel lymph nodes. SNL detection is made possible because a colloid is linked to a radioactive tracer, usually the 99mTc. The radioactivity of latter may be detected in images obtained by the scintillation camera or gamma probe.

Lymphoscintigraphy is an essential step in studying SNL. The images obtained allow an assessment of the draining pattern and accurate identification of one or more related chains at the injection site. As such, the gamma probe (or even the dye) may provide better guidance in its use during surgery. Atypical or unexpected draining patterns were often observed, above all in patients with trunk lesions. The use of lymphoscintigraphy has shown that areas with ambiguous draining are far more extensive than those classically described along the head to truck medial line, and in the thoracic-abdominal transition (areas described in Sappey's studies).¹⁵ In this latter study, 15 patients (16%) showed drainage in more than one lymphatic basin, or in an unexpected basin with respect to the primary lesion site. Another seven showed sentinel lymph nodes in the popliteal region, which is a common finding in cases of tumors in the extremities, though seldom found in reports in the literature.¹⁶

The literature does show relatively homogenous results in SNL detection with radioisotopes in spite of many methodological differences. The most frequent variations match up with the use of different radiopharmaceuticals, radioactivity, volumes and administration pathways. There is almost unanimous agreement to recommend administration of small volumes (0.2 ml) around the primary lesions or surgical wound via intra- or subdermal pathways.

What is also considered ideal is the use of particles (20-500 nm in diameter),¹⁷ since the use of large diameter particles is limited by a slow lymphatic progression. On the other hand, small diameter particles do not experience phagocytosis and may engulf the entire basin. Among the most common radiopharmaceuticals, albumin nanocolloids are used in Europe and antimony composites in Oceania, as well as modified/filtered colloidal sulfur in the USA. Still, availability of the first two radiopharmaceuticals cited is very limited in Brazil. This situation highlights the lack of uniformity and the technical difficulties involved in preparing colloidal sulfur. It is most likely for this reason that we see radiopharmaceuticals being used here more than Dextran and ^99mTc-Phytate.

In spite of how hard it is to measure the particle diameter correctly, about five years ago ^99mTc-Phytate was cited as possibly becoming an alternative in SNL detection. This suggestion was raised due especially to how phytate biodistribution resembles nanocolloids in the reticuloendothelial system. ^99mTc-Phytate was initially described in a study of the reticuloendothelial system in 1973, which has a colloid formation in vivo after a calcium ion reaction. 18 The measures undertaken after adding calcium in a 1:1 or 2:1 molar relation to ^99mTc-Phytate, and performed with the electron microscope and conductibility studies, indicate the formation of particles <500 nm in diameter.^19,20 The spleen imaging observed after intravenously administering the ^99mTc-Phytate in patients is similar to what has been observed with nanocolloids and poorer than with colloidal sulfur. These results confirm the lower-diameter particle formation.

The use of ^99mTc-Phytate for lymphoscintigraphy has already been described.^21,22 The specific use of SNL detection was reported for the group by the authors.²³ The fast-moving progression of ^99mTc-Phytate in the initial phase, with SNL identification still at the dynamic phase in the initial minutes of the study, may be related to migrating low-weight molecular composites prior to the colloid's formation in vivo. On the other hand, retention and concentration of radiopharmaceuticals in SNL, only slowly progressing to the rest of the basin, indicates that colloid formation occurs in the course between the subcutaneous layer and SNL.

Impact of the SNL biopsy on the staging and prognosis of the melanoma

The intraoperative mapping of SNL is widely indicated for patients with thick (>1-mm) lesions and with no clinical evidence of ganglionic metastasis. Roughly 20% of tumor patients showing a 1-4 mm Breslow have SNL metastasis. This value rises to 34% among patients with >4 mm index, and falls to 4.7% in patients with <1 mm index in association with ulcerated lesions or level of Clark IV.⁶ The SNL status has achieved such widespread acceptance that it is now included in the staging proposed by the American Joint Committee on Cancer for Malignant Cutaneous Melanoma.^24,25

SNL detection may also be indicated for patients with more superficial lesions (<1mm),^26,27 in spite of the obvious fact that deeper tumors are more likely to show ganglionar dissemination.^28,29 The prognostic value of sentinel node biopsy is confirmed for thick (>/=4-mm) tumors.³⁰

Proper intraoperative SNL identification is described in 98% of cases with radiomarked colloids, 75-80% with dyes and 98-99% with a combination of both.²⁵ Also described is a greater than 98% accuracy rate from SNL biopsy to predict the affection of the entire lymphatic basin.^6,12,13 In a recent review of 1,135 melanoma cases, SNL was detected with radioisotopes in 97% of patients, with a negative predictive value of 100%.³¹ The results shown in the present study are similar, with rates of 98 and 100%, respectively.

The mapping of ganglion affection at SNL may be even greater than at the access to the entire basin, thereby allowing a more detailed study and the use of techniques aiming at detecting micrometastases. The lower number of analyzed lymph nodes allows the pathologist not only to boost the number of sections per lymph node, but also to apply more sensitive techniques, such as immunohistochemistry or PCR (polymerase chain reaction).^32,33 Immunohistochemistry with antibodies directed at S100 and HMB45 antigens enhances the sensitivity of metastasis detection by roughly 14%,^34,35 though it was not routinely available for the study of patients at the institution.

The latest recommendations by the American Joint Committee on Cancer for Malignant Cutaneous Melanoma include SNL status in the staging, in addition to using the term "micrometastasis" for lymph nodes that show no macroscopic involvement.²⁴ The clinical significance of a micrometastasis (mainly when detected only by PCR) and its impact on survival rates, however, remain controversial.^32,33

The infiltration of SNL is recognized to be the most important prognostic factor for primary melanoma patients (in the absence of metastases at other sites). SNL involvement is a strong predictor of recurrence and survival. A mortality rate of 6% is found in SNL-negative patients compared to 30% in SNL-positive patients who received follow-up for an average of 37 months.^2,36 Gershenwald^2,36 has reported that SNL is the most important survival indicator in stage I and II melanoma patients. It is therefore more significant than Breslow thickness and presence of ulceration. The percentage of patients who are free of disease for an interval of three years dropped from 96.8 to 69.9% when receiving SNL follow up. Even among patients with thicker melanoma, there is a significant reduction in recurrence when SNL is negative (37 vs. 73% of patients free of disease for three years).⁷

A negative SNL biopsy, however, does not guarantee the patient against showing recurrence in the future. Various authors report recurrence in 1-6% of SNL-negative patients^36,37,38,39 Regional recurrence among SNL-negative patients might be even less when using more sensitive techniques. It has been noted that the review of SNL cuts elucidates a large part of the recurrences in cases initially interpreted to be SNL-negative.⁴⁰ Also, it ought to be observed that 5% frequency rate of close regional recurrence is similar to what can be seen to occur following elective lymphadenectomy,⁴¹ and that complete resection of the basin did not noticeably increase survival rates in melanoma and SNL-negative patients.^28,31

The indications for elective lymphadenectomy are still controversial. Their impact upon survival is not clear when considering a population with a roughly 20% likelihood of ganglionic affection. The best selection of patients for elective lymphadenectomy might perhaps be performed by means of assessing the SNL. SNL-negative patients would thus be exempted from the procedure. In this case, the main cause of morbidity in elective lymphadenectomy would be reduced, since lymphedema is described in only 1.7% of patients after SNL biopsy.⁴²

The fact of micrometastasis patients showing better survival than those with macroscopic involvement⁴³ suggests that early removal of the affected lymph nodes may improve the patient's course. Nevertheless, three clinical randomized trials failed to show significant differences in overall survival rates for SNL-positive patients subjected to a complementation of ganglionic emptying.^44,45,46 These trials were discussed by Balch,⁴⁷ who highlighted the fact that most patients had not undergone preoperative scintigraphy to confirm the correct identification of the draining basin. These data are crucial when considering the high frequency of draining to more than one lymphatic basin or unexpected localizations. New clinical studies meant to assess the therapeutic results of selective lymphadenectomy based on SNL detection are being carried out.⁴⁸ These considerations, namely on the need for better patient stratification to assess therapeutic response, are being applied not only to lymphadenectomy, but also to other protocols, such as interferon or vaccine use.

CONCLUSIONS

SNL biopsy showed a high degree of accuracy for the ganglionic staging of patients with malignant melanoma. It has also proved to be an important prognostic factor. Correctly defining lymphatic staging, then, may have therapeutic implications. The latter specifically include whether the most required indication is to resection the entire lymphatic basin, or use systemic therapies.

The results obtained in SNL detection with ^99mTc-Phytate, which is a widely available radiopharmaceutical in Brazil, were comparable to those described in the literature. q

REFERENCES

Received in June, 13^th of 2003

Approved by the Consultive Council and accepted for publication in October, 07^th of 2003

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*

Work done at "Unidade de Diagnóstico e Densitometria Óssea - Uddo, São Paulo" and "Instituto Brasileiro de Controle do Câncer - IBCC, São Paulo".

Publication Dates

• Publication in this collection
  09 June 2004
• Date of issue
  Apr 2004

History

• Accepted
  07 Oct 2003
• Received
  13 June 2003