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10.1245/s10434-006-9106-9
Annals of Surgical Oncology 13:1511-1516 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Ultrasonography and Fine-needle Aspiration Cytology in the Preoperative Evaluation of Melanoma Patients Eligible for Sentinel Node Biopsy

Maartje C. van Rijk, MD1, H. Jelle Teertstra, MD, PhD2, Johannes L. Peterse, MD3, Omgo E. Nieweg, MD, PhD1, Renato A. Valdés Olmos, MD, PhD4, Cornelis A. Hoefnagel, MD, PhD4 and Bin B. R. Kroon, MD, PhD, FRCS1

1 Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CXAmsterdam, The Netherlands
2 Department of Radiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CXAmsterdam, The Netherlands
3 Department of Pathology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CXAmsterdam, The Netherlands
4 Department of Nuclear Medicine, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CXAmsterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Maartje C. van Rijk, MD; E-mail: m.v.rijk{at}nki.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Ultrasonography with fine-needle aspiration cytology (FNAC) has proven to be a valuable diagnostic tool in the preoperative workup of patients with breast cancer or penile cancer eligible for sentinel lymph node biopsy. The aim of this study was to evaluate the use of this technique in the initial assessment of patients with primary cutaneous melanoma.

Methods: A total of 107 patients with cutaneous melanoma eligible for sentinel node biopsy with clinically negative nodes were studied prospectively. Patients underwent ultrasonography of potentially involved basins and FNAC in case of a suspicious lymph node. The sentinel node procedure was omitted in patients with tumour-positive lymph nodes in lieu of lymph node dissection.

Results: Ultrasonography with FNAC correctly identified disease preoperatively in two of the 107 patients (2%). Thirteen of the 22 patients (59%) with a suspicious node on ultrasonographic imaging but a tumour-negative fine-needle aspirate were shown to have involved nodes. Of the 85 patients with ultrasonographically normal nodes, 25 (29%) were shown to have metastases. Of the total of 43 involved basins, 16 contained metastases > 2 mm and 25 ≤ 2 mm.

Conclusions: In our hands, the sensitivity and specificity of preoperative ultrasonography to detect lymph node involvement in patients with melanoma are 34% and 87%, respectively. In combination with FNAC, this is 4.7% and 100%, respectively. This yield is insufficient for this technique to be used as a routine diagnostic tool in the selection of patients eligible for sentinel node biopsy.

Key Words: Melanoma • Ultrasonography • Sentinel lymph node • Lymphatic metastases • Fine-needle aspiration biopsy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Several studies suggest that ultrasound may aid in the preoperative detection of involved lymph nodes in patients with breast cancer, carcinoma of the vulva and melanoma and can potentially improve selection of patients for sentinel lymph node biopsy.1–6 Encouraged by the results of these studies and by our own favourable results in breast and penile cancer,7,8 we retrospectively investigated all patients who underwent preoperative ultrasound with fine-needle aspiration cytology (FNAC) in patients with melanoma. The purposes were to evaluate the sensitivity to detect of lymph node metastases and assess how often sentinel node biopsy can be avoided.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
At The Netherlands Cancer Institute, patients with a clinically localised cutaneous melanoma with a Breslow thickness of at least 1 mm or at least Clark level IV are eligible for lymphatic mapping. Between November 2000 and December 2004, all patients with clinically node-negative disease who were eligible for sentinel lymph node biopsy underwent ultrasonography with additional FNAC if a suspicious lymph node was identified. A total of 107 patients were evaluated. Their characteristics are provided in Table 1Go.


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  		TABLE 1. Characteristics of all 107 patients
 
Ultrasonography was performed one or several days prior to lymphatic mapping. A 7.5-MHz transducer (Siemens Elegra, Erlangen, Germany) or a Kretz Voluson 730 expert (GE Medical Systems, Zipf, Austria) with a 6–12 MHz transducer was used. Criteria to classify a lymph node as suspicious were a length–depth ratio of less than two, conversion of a fatty hilum to a hypoechoic hilum, substantial cortical asymmetry or a focal area of low-level echoes in the subcapsular sinus of the node. Based on a study by Van den Brekel et al., lymph nodes in the neck at levels 1, 3 and 4 were also classified as suspicious when the diameter exceeded 5 mm.9 Fine-needle aspiration of suspicious lymph nodes was performed with a 21-gauge (0.8-mm) or 22-gauge (0.7-mm) needle (Fig. 1Go). The aspirated material was air dried, methanol fixated and stained according to the May-Grunwald-Giemsa method. Patients with tumour-positive FNAC were scheduled for formal dissection of the involved basin and wide local (re-)excision of the primary tumour. Patients without tumour cells in their aspirate were scheduled for sentinel node biopsy and wide local (re-)excision.


Figure 1
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  		FIG. 1. Fine-needle aspiration cytology (FNAC) of a lymph node that looks suspicious on ultrasonography. Note the hypoechoic central region.

 
Lymphatic mapping was performed with the aid of 99mTc-nanocolloid (Nanocoll, General Electric Health Care, Eindhoven, The Netherlands), lymphoscintigraphic images (ADAC Vertex, Milpitas, CA, USA), patent blue dye (Laboratoire Guerbet, Aulnay-Sous-Bois, France) and a gamma ray detection probe (Neoprobe, Johnson & Johnson Medical, Hamburg, Germany). The procedure has been described in detail previously.10 A hot spot on the lymphoscintigraphic image was considered to be a sentinel node if an afferent lymphatic channel was visualised, if the hot spot was the first one seen in a sequential pattern or if the hot spot was the only one depicted.11 An afferent blue lymphatic vessel coming directly from the tumour site also defined a node as the sentinel node.

All sentinel nodes were formalin fixated, bisected, paraffin embedded and cut at a minimum of six levels at 50- to 150-µm intervals. Pathological evaluation included both hematoxylin-eosin and immunohisto-chemical staining (S-100 and HMB-45). Metastases were classified as either > 2 mm in diameter or ≤ 2 mm, as 2 mm is the current spatial resolution of ultrasonography according to Rossi et al.3 Patients with tumour cells in the sentinel node were offered dissection of the involved basin. After April 2002, patients with a small solitary subcapsular deposit did not undergo node dissection in accordance with the guidelines proposed by Starz et al.12


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Twenty-two of the 107 patients (21%) had suspicious nodes when examined with ultrasound, and they underwent fine-needle aspiration (Fig. 2Go). This approach demonstrated metastatic melanoma in two of these patients (overall yield 1.9%). The first patient had a melanoma in the right scapular region with a Breslow thickness of 4.5 mm and an ultrasonographically suspicious node with an asymmetrical cortex diameter of 3 mm. Cytology showed meta-static cells, and the axillary lymph node dissection revealed that two of the eight nodes found in the specimen were involved. Both metastases were 8 mm in diameter. No recurrences have been observed during ten months of follow-up. The second patient had a melanoma with a Breslow thickness of 1.5 mm on his right shoulder, and ultrasound showed a lymph node of 7 mm in the right supraclavicular fossa. FNAC showed this node to be involved, and a modified radical neck dissection level I–V was performed. A total of 39 nodes were removed, but no metastases were identified in the specimen. Even detailed pathological workup including step-sectioning and immunohistochemical staining did not reveal any metastases. It was assumed the metastasis had regressed.13 Twenty-four months later, the patient is alive and well.


Figure 2
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  		FIG. 2. Flow chart of axillary ultrasonogra-phy results, fine-needle aspiration cytology (FNAC) results and final histological outcome.

 
The other 105 patients underwent lymphatic mapping. The lymphoscintigraphic visualisation rate of a sentinel node was 100%, and the surgical identification rate was also 100%. Thirty-six of the 105 patients (34%) had metastatic disease in their involved sentinel node(s). Thirty-one patients had one involved lymph node basin and five had two involved nodal basins. Sixteen of these 41 basins contained metastases > 2 mm and 25 ≤ 2 mm. Completion lymph node dissection was performed in 27 patients.

Eleven of the 20 patients (55%) with a suspicious lymph node on ultrasound but negative cytology had a tumour-positive sentinel node (Fig. 2Go). Eight of the 85 nodal basins with an ultrasonographically normal node contained metastatic disease with a size > 2 mm (9%). Sensitivity of ultrasound alone was 34%; specificity was 87%. Sensitivity of ultrasound combined with FNAC was 4.7%. No complications occurred as a result of axillary FNAC.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
This study showed a low yield of preoperative ultrasonography and FNAC in melanoma patients eligible for sentinel node biopsy: some 2% of patients were spared sentinel node biopsy in lieu of immediate regional node dissection. An important aim of sentinel lymph node biopsy in patients with melanoma is to provide staging information. Tumour status of the lymph node is the most important prognostic factor for melanoma patients, and sentinel lymph node biopsy is the most accurate diagnostic tool for this purpose. Sentinel lymph node biopsy also enables early regional node dissection in patients at risk of having additional metastases in the nodal basin. Recent data suggests that early lymph node dissection in patients with clinically occult sentinel node metastases prolongs survival compared with delayed lymph node dissection.14–16

Lymphatic mapping entails lymphoscintigraphy and a surgical procedure. It is understandable that several investigators evaluated the role of preoperative ultrasonography and FNAC to reduce the number of sentinel node procedures (Table 2Go). On average, their yield was 9% (range 5–12%), and all investigators concluded that this diagnostic tool is valuable in the preoperative workup of patients with a melanoma.2,3,17 Compared with these other studies, the 1.9% yield in the present study is meagre, especially when the percentage of involved sentinel nodes is taken into consideration.


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  		TABLE 2. Summary of studies on ultrasonography and fine-needle aspiration cytology in melanoma patients
 
Several explanations can be entertained for this observation. Firstly, more than half of the patients with metastases in the study by Rossi and coworkers had tumour deposits > 2 mm.3 In our study, some 60% had metastases ≤ 2 mm. Secondly, seven radiologists in The Netherlands Cancer Institute perform ultrasonography and fine-needle aspiration. This may have affected the results, as it is possible that in other hospitals only a few radiologists perform this procedure in patients with melanoma, which results in greater experience with preoperative nodal evaluation per person. Thirdly, ultrasonographic imaging was performed with a 7.5-MHz transducer in the early days of the study and a 6- to 12-MHz transducer later on. This type of transducer is a relatively low-frequency transducer when compared with other studies, and it is possible this may have affected our results.3,17,18 A fourth explanation could be that our radiologists routinely perform ultrasonography and fine-needle aspiration of the axilla in patients with breast cancer. The criteria for denoting an axillary node as suspicious are different in breast cancer compared with melanoma. However, upon evaluation of the results of this study with the radiologists, several of them remarked that the criteria for the breast cancer nodes had also been applied to patients with a melanoma.7 In retrospect, the criteria for denoting a lymph node as suspicious in patients with a melanoma were not so clearly defined. A fifth explanation could be that the current evaluation of potentially involved basins is performed at a location other than the actual location of sentinel nodes. Sentinel nodes can be located outside the standard nodal basins, i.e. groins, axillae and neck, and these are usually not evaluated during routine ultrasonography. In this study, one patient had a metastasis in such an unusual location.10 Furthermore, many of our radiologists perform ultrasonography of the groin in patients with penile cancer,8 and we have observed that in these patients, sentinel nodes are located cranial from the inguinal fold. In patients with a melanoma on the leg, most sentinel nodes are located caudally from this fold. Due to their experience in penile cancer, some of our radiologists are accustomed to evaluating only the most cranial area and do not perform ultrasonography caudal from the inguinal fold.

Compared with the results of axillary ultrasound in breast cancer patients, the results in melanoma are not very good, neither at our institute nor at other institutes.4,5,7,19–22 One possible explanation for this phenomenon could be the differences in metastasis size. Depending on which study is quoted, metastases > 2.0–4.5 mm can be visualised with ultrasonography, but in the present study the majority of melanoma metastases were smaller than these limits (Fig. 2Go).1,3 These findings are similar to a study performed by Dewar et al.,23 in which only a minority of melanoma patients with metastases had deposits with a mean diameter > 2 mm, and approximately half of this minority had tumour deposits > 5 mm. Breast cancer metastases are more often nodules larger than 2 mm.

Positron emission tomography (PET) and 99m Tc-methoxy-isobutyl-isonitrile (MIBI) scintigraphy have also been evaluated to decrease the number of sentinel node procedures in patients with mela-noma.24,25 Advantages of these techniques are that whole-body images can be obtained and that the 12 results are less dependent on the experience of the operator. The sensitivity of these techniques was found to be 21% and 83% and specificity 97% and 93%, respectively. The authors concluded that sentinel lymph node biopsy remains the first choice of evaluating nodal status.24,25

A recent study showed that magnetic resonance imaging (MRI) with lymphotropic nanoparticles correctly identified all patients with nodal metastases from prostate cancer.26 The specificity was 96%. Although this study was performed in patients with another disease, the outcome holds potential for other types of solid malignancies that spread through the lymphatic system. Another interesting study was performed in a melanoma swine model. Contrast-enhanced lymphatic ultrasonography was used to evaluate the presence or absence of metastases in the sentinel nodes. With this technique, a sensitivity of 95% and specificity of 63% were obtained.27 Unfortunately, the size of the nodal metastases was not stated in the publication and fine-needle aspiration was not performed, but this approach may be a better way of identifying metastases in lymph nodes and improve guidance for FNAC.

Whether every patient with an involved sentinel lymph node requires regional nodal clearance is the subject of debate. Only some 15–20% of patients with an involved sentinel node appear to have additional nodes when regional node dissection is performed. This issue is the subject of the Multicenter Selective Lymphadenectomy Trial II.14


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
In our hands, sensitivity and specificity of preoperative ultrasonography to detect lymph node involvement in patients with melanoma is 34% and 87%, respectively. In combination with FNAC, this is 4.7% and 100%, respectively. With a sensitivity of 5%, preoperative ultrasonography and FNAC does not improve the selection of patients eligible for sentinel node biopsy sufficiently to justify its use as a routine procedure.

Received for publication April 21, 2006. Accepted for publication June 5, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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