SPECT-CT: A new tool for localisation of sentinel lymph nodes in breast cancer patients

original articles

SPECT-CT: A new tool for localisation of sentinel lymph nodes in breast cancer patients J. MUCIENTES RASILLAa, L. FARGE BALBÍNa, J. CARDONA ARBONIÉSa, A. MORENO ELOLA-OLASOb, R. DELGADO-BOLTONa, L. IZARDUY PEREYRAa, C. RODRÍGUEZ REYa, L. LAPEÑA GUTIÉRREZa, A. GONZÁLEZ MATÉa, J.M. ROMÁN SANTAMARÍAb AND J.L. CARRERAS DELGADOa a

Department of Nuclear Medicine. Hospital Clínico San Carlos. Madrid. Spain. bDepartment of Obstetric and Gynecology. Hospital Clínico San Carlos. Madrid. Spain.

Abstract.—Introduction. Sentinel lymph node biopsy has become a widely accepted procedure for axillary lymph node staging in patients with breast cancer. Aim. The aim of this study was to determine the advantages of using SPECT-CT instead of planar scintigraphy in the presurgical localisation of sentinel lymph nodes. Methods. We prospectively included 25 consecutive patients with breast cancer who were admitted to our department for SLN localisation. Patients were divided into two groups, depending on whether neoadjuvant chemotherapy had been received (B, n = 6) or not (A, n = 19). Four doses (1.0 mCi each) of 99mTc-nanocolloid were injected intradermallly in all patients, and SPECT-CT and planar images were acquired. All patients underwent surgery and SLN localisation with a hand-held gamma probe. Any axillary “hot spots” were resected. The kappa index (ki) was calculated using surgical findings as the gold standard. Results. In group A, the SLN was correctly detected in 17/19 patients (89.5 %) with SPECT-CT and in 12/19 (63.2 %) with planar images. The correlation between SPECT-CT and surgical findings (ki 0.91) was better than between planar images and surgical findings (ki 0.57). In group B, the results of SPECT-CT and planar images were identical, with accurate localisation of the SLN in 5/6 patients (ki 0.76). Conclusions. The results of this study suggest that SPECT-CT may be useful for locating the SLN in breast cancer patients, as it provides accurate localization of the SLN with useful anatomical information. This may allow the surgeon to search exclusively for SLN viewed on SPECT-CT, and avoid false negative and false positive results. KEY WORDS: SPECT/CT, lymphoscintigraphy, breast, cancer, fusion, sentinel node.

SPECT-TAC: UNA NUEVA HERRAMIENTA PARA LA LOCALIZACIÓN DEL GANGLIO CENTINELA EN PACIENTES CON CÁNCER DE MAMA Resumen.—Introducción. La biopsia selectiva del ganglio centinela es una herramienta que ha demostrado ser eficaz en la estadificación linfática, evitando realizar linfadenectomías a pacientes que no van a beneficiarse de ellas. Objetivo. Determinar las ventajas de la SPECT-TAC frente a la gammagrafía convencional en la localización prequirúrgica del ganglio centinela. Material y métodos. Se trata de un estudio prospectivo con 25 pacientes divididas en dos grupos, según hubiesen recibido o no quimioterapia neoadyuvante (grupo A, n = 19 sin quimioterapia previa; grupo B, n = 6 con quimioterapia), a las que se les realizó la gammagrafía planar convencional y un estudio con un equipo híbrido SPECT-TAC de baja dosis. Se realizó la localización intraoperatoria con sonda portátil resecando todos los depósitos existentes en la axila. Resultados. La SPECT-TAC determinó correctamente el número y localización de los ganglios en 17 de 19 pacientes del grupo A, frente a 12 de 19 pacientes en las que lo hizo la gammagrafía. La concordancia de la SPECT-TAC con los hallazgos de la cirugía fue muy buena (índice kappa 0,91), mientras que la gammagrafía presentó una concordancia moderada (índice kappa 0,57). Conclusiones. La SPECT-TAC se constituye como una herramienta nueva que aporta al cirujano una información exacta de la localización de los ganglios centinela, permitiendo orientar de inicio el acto quirúrgico a la búsqueda exclusiva de los ganglios observados en las imágenes. PALABRAS CLAVE: SPECT-TAC, ganglio centinela, cáncer de mama, fusión.

INTRODUCTION Received: 16-01-2008. Accepted: 14-02-2008. Correspondence: J. MUCIENTES RASILLA. Servicio de Medicina Nuclear. Hospital Clínico San Carlos. C/Profesor Martín Lagos s/n. 28040 Madrid. Spain. Correo electrónico: [email protected]

Breast cancer is the most frequent tumour in western women. Lymph node staging is the most important prognostic factor in potentially curable breast cancer1,2, in that it reduces survival at 5 years by up to 40 %3. Historically, the determination of the nodal stage of breast cancer was conducted by Rev Esp Med Nucl. 2008;27(3):183-90

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analysing the lymph nodes following an axillary lymphadectomy not devoid of morbidity (lymphoedema, pain, stiffness, etc...). The most frequent localisation of the lymphatic drainage of breast tumours is axillary, in Berg levels I and II (lateral to the pectoralis minor or between its edges)4. Other breast lymphatic drainage sites are intramammary, intrapectoral, supraclavicular and the internal mammary chain5. The lymphatic drainage pattern is unpredictable, and tumours with the same localisation may drain to different nodal territories. Recently, hybrid equipment with low-dose computed tomography (CT) and a gamma camera in the same gantry have been developed. This equipment permit the acquisition of a low-dose CT and an emission study (Single photon emission computed tomography [SPECT]) without the need to move the patient, which makes a precise fusion of both studies possible6. This combined acquisition of images provides a more exact attenuation correction, besides offering excellent anatomical localisation which was not hitherto possible with conventional gamma cameras. The objective of this study is determine the concordance of the presurgical imaging methods of the sentinel node with surgery findings and to evaluate the advantages offered by the SPECT-CT study with regard to conventional planar scintigraphy in the identification and localisation of sentinel nodes.

MATERIAL AND METHOD

It is a prospective study including 25 consecutive patients diagnosed with breast cancer admitted to our department for the sentinel node technique. The patients were divided into 2 groups, depending on whether they had been given treatment with neoadjuvant chemotherapy prior to surgery.

Group A Inclusion criteria

Patients diagnosed with stage T1 and T2 breast cancer without clinical evidence of nodal involvement (N0), and without evidence of distance metastases (M0) who are candidates for the sentinel node technique. 184

Exclusion criteria

Pregnant patients, patients with evidence of nodal involvement, multicentric tumours, patients having received chemotherapy, patients with distance metastases (M1). Group A of patients corresponded to 19 women with an age range between 34 and 76 years, a mean age (mean ± standard deviation) of 56.47 ± 13.20 years and a tumour size, at its maximum diameter, between 6 and 25 mm (14.09 ± 5.83 mm). The histological types were 2 lobular carcinomas, 4 ductal in situ, 12 infiltrating ductal and one adenocarcinoma. Group B Inclusion criteria

Patients diagnosed with breast cancer in any T and N stage having received neoadjuvant chemotherapy and obtaining a complete response of the axillary disease (clinical, ultrasound or by magnetic resonance) and partial or complete response of the primary tumour. Exclusion criteria

Pregnant patients, patients with evidence of lymph node involvement at time of surgery, patients with distance metastases. Group B of patients includes 6 women with an age range between 36 and 76 years, a mean age of 56.3 ± 14.16 years and a tumour size, at its maximum diameter, at the time of surgery, of between 0 and 42 mm (22.03 ± 15.28 mm). The histological types were 5 infiltrating ductal carcinomas and one invasive lobular carcinoma. Injection protocol

All the patients included in this study were given an injection, on the day before surgery, of nanocolloids labelled with 99mTc with a particle size of less than 80 nm, in four syringes of 1 mCi and 0.2 ml volume each. Four (4) periareolar intradermal injections were made. Image acquisition protocol

The images were acquired between 60 and 90 minutes after the injection. Planar images were taken 60 minutes after the injection and the SPECT-CT

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study was performed immediately afterwards. In the cases in which no migration to the lymph nodes was observed, the images were acquired again 20 hours post-injection. A conventional dual-head gamma camera was used for the planar images (Sopha Camera DST; Sopha Medical Vision International, Bue Cedex, France) with low-energy ultra-high resolution collimators (LEUHR). The energy peak was 140 KeV ± 10 %. A matrix of 128 × 128 with a zoom of 1.0 was used. Planar images lasting 10 minutes were acquired, with two projections, one anterior and one lateral of the side of the lesion, without using transmission images with 57Co for this purpose. The SPECT-CT study equipment was a dual-head gamma camera with a low-dose X-Ray tube (Infinia Hawkeye 4, General Electric Medical System, Milwaukee WI, USA) with low-energy and high resolution collimators (LEHR). Scatter correction was used. A SPECT study with a matrix of 128 × 128 was acquired, with 1.0 zoom and a rotation of 360° with sixty 20-second images (one image every 6°) in step and shot mode. The CT was acquired in helical mode with a pitch of 1.9, an interval of 4.42 mm, a matrix of 512 × 512 and energy of 2.5 mA and 140 Kv.

quadrantectomy in group A, and mastectomy (by protocol following the chemotherapy treatment) in group B. Subsequently the search for the sentinel node was undertaken. For this purpose, a gamma detection probe (Europrobe, Eurorad, Strasbourg, France) was used with cadmium tellurium cadmium crystal (CdZnTe) of 5 × 5 × 3 mm3 designed para medium energies (20–170 KeV). Subsequently, following the removal of the sentinel nodes, the surgical bed was measured and a careful search was made for any radioactive activity in the axillary gap in order to check that there was no other sentinel node. The lymph node with the greatest activity (cps) was removed and all the nodes with an activity of more than 10 % of the activity presented by the former. Subsequently, they were sent to the department of pathological anatomy to be studied by means of freezing (and staining with hematoxylin-eosin) and by means of the Papanicolaou smear test. In group A, in the case of the nodes that presented tumour disease, axillary lymphadectomy was indicated. In group B (sentinel node following neoadjuvant chemotherapy) axillary lymphadectomy was indicated, ipsilateral in all cases, since this technique is in the validation period in our hospital.

Interpretation of the images

Statistical analysis

The images were interpreted by two nuclear physicians with experience in the technique. A visual analysis was used in the planar images, considering all the deposits with localisation and morphology compatible with the presence of a node as positive. In the case of the SPECT-CT study, 3 types of images were used for the interpretation of the study. Images reconstructed by filtered back projection were used, images with iterative reconstruction with attenuation correction by means of CT and fusion images with CT. Deposits of radiotracer in the SPECT corresponding in the fusion images to a lymph node territory were regarded as positive, and these deposits were classified following Berg’s classification (level I: lateral to the pectoralis minor, level II: between the edges of the pectoralis minor, level III medial to the internal edge of the pectoralis minor).

The surgery findings were used as the gold standard to evaluate the results. Measures of concordance for qualitative variables were used; Kappa coefficient by groups between the three techniques (scintigraphy/ surgery, SPECT-CT/surgery and scintigraphy/SPECTCT). We regard all the nodes seen in the images and found in surgery as positive. We regard the deposits interpreted as sentinel nodes which are not confirmed in surgery as false positives of each technique. We regarded the nodes that presented radioactive activity in surgery and which had not been observed in the surgery as false negatives of the images. The true negatives would be lymph nodes that were not observed in the images and did not present activity in the operating theatre. These data are used to perform a statistical analysis by nodes to determine the sensitivity (Se) and the positive predictive value (PPV) for the preoperative localisation of the sentinel node of each technique. We do not calculate the specificity data (E) and negative predictive value (NPV) in this study, as the true

Surgery

On the day of surgery, the surgical treatment of the tumour was addressed first, with tumorectomy or

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Table 1

negatives cannot be categorised; since it would be necessary to go against the very concept of the sentinel node to evaluate it.

SUMMARY OF THE FINDINGS IN GROUP A

Patient

Number of nodes observed in conventional scintigraphy

Number of nodes observed in the SPECT-CT study

Number of nodes removed in surgery

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

2 0 1 2 2 2 3 1 2 2 1 1 1 1 2 1 1 1 2

2 1 1 2 1 2 3 1 2 2 2 1 1 1 0 1 1 2 2

2 1 1 2 1 2 5 1 3 2 2 1 1 1 0 1 1 2 2

RESULTS

The surgery findings were used as the Gold Standard for the assessment of the lymphoscintigraphic techniques for the identification of the sentinel nodes. The number of nodes found with the gamma ray detection probe and their localisation were compared to the previous findings in the imaging techniques.

GROUP A

In surgery, a mean of 1.6 sentinel nodes was removed (range = 0-5 nodes). In the histopathological analysis, tumour invasion of the sentinel nodes was observed in one of the patients (patient number 2). Thirty-one (31) sentinel nodes were removed in the 19 patients, 30 (96.77 %) of which were negative for malignancy. The results are summarised in table 1. As table 1 shows, there was radiotracer migration in 18 of the 19 patients, which indicates a migration rate of 94.74 %. Compared to the intraoperative findings, the planar scintigraphy properly determined the number and localisation of the nodes in 12 of the 19 patients (63.15 %), whereas the SPECT-CT did so in 17 of the 19 patients (89.49 %). Both techniques coincided in 14 of the 19 patients (73.68 %). Twenty-eight (28) nodes were observed by conventional scintigraphy, 25 (89.29 %) of which were confirmed in surgery, and 3 (10.71 %) provided to be false positives due to dermal contamination by the SPECT-CT (confirmed intraoperatively) (fig. 1). Besides the 25 nodes found by means of the scintigraphy, a further 6 that were not observed in the planar images were removed. In the SPECT-CT, 28 Berg level I and II nodes were observed (25 and 3, respectively), all of them found in surgery (100 %), whereby there were no false positives. There were 3 false negatives with SPECT-CT, two of them in patient 7, with deposits corresponding to five sentinel nodes observed in SPECT-CT 3. One of the deposits was larger, and gave 3 lymph nodes once removed. In patient 9 there was another false 186

SPECT: single photon emission computed tomography; CT: computed tomography.

negative from the images, in the SPECT-CT the existence of two sentinel nodes was interpreted, and three lymph nodes were removed during surgery, two of them forming the same deposit. With SPECT-CT, 3 nodes that were not seen in the scintigraphy were observed, one of them presenting very low activity (fig. 2), another one corresponding to a deposit in the scintigraphy incorrectly identified as a lymph node path (fig. 3), and the last one masked by the activity of a sentinel node. A kappa analysis was used to determine the concordance between techniques. The concordance analysis between the scintigraphy and surgery resulted in a squared Kappa index of 0.57 (moderate concordance) with a p of 0.009 (95 % CI 0.223-0.928). The concordance analysis was subsequently performed between the findings of the SPECT-CT and the nodes removed in surgery. The concordance analysis resulted in a squared Kappa index of 0.91 (very good concordance) with a p of 0.000 (95 % CI 0.837-0.994). Finally, an analysis of the data obtained from the 34 nodes observed overall with the three techniques was performed to determine the statistical parameters of the scintigraphy and the SPECT-CT. Table 2

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A

B

FIG. 1.—There seem to be two sentinel nodes in the planar images (A). In the single photon emission computed tomography-computed tomography (SPECT-CT) (B), with fusion images in the three slices, the deposits are seen to be actually on the skin, and there has been no migration to the axilla. Nevertheless, in the operating theatre it transpired that there is no axillary deposit. It is the only case in this series in which there is no migration of the radiotracer to the lymph nodes.

A

B

FIG. 2.—In this case, the conventional scintigraph did not detect any deposit that might correspond to a sentinel node. (A). In the single photon emission computed tomography-computed tomography (SPECT-CT) (B) with CT images (top), SPECT (middle) and fusion (bottom), in the three slices a deposit was observed at Berg level I with low activity, which was confirmed in surgery, and was positive for malignancy, whereby an axillary lymphadectomy was performed.

compares the deposits found in the planar scintigraphy to the nodes removed in surgery (above), and the deposits found by means of SPECT-CT with the findings of the surgery (below).

The analysis of these data made it possible to determine Se and PPV para the presurgical localisation of the sentinel node of each technique. The results are given in table 3.

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A

B

FIG. 3.—In this case, a single deposit of radiotracer is observed in the planar images (A) presenting a possible path to it. The single photon emission computed tomography-computed tomography (SPECT-CT) shows two sentinel nodes (B), another cranial (on the left) and another caudal (on the right), both at Berg level I, as was subsequently confirmed in the operating theatre.

Table 2

Table 3

ANALYSIS OF RESULTS BY NODES

SENSITIVITY AND POSITIVE PREDICTIVE VALUE OF SCINTIGRAPHY AND SPECT-CT FOR DETERMINING THE PRESENCE OF SENTINEL NODES BEFORE SURGERY

Surgery

Scintigraphy

Positive Negative Total

Positive

Negative

Total

25 6 31

3 0 3

28 6 34

Surgery

SPECT-CT

Positive Negative Total

Positive

Negative

Total

28 3 31

0 3 3

28 6 34

SPECT: single photon emission computed tomography; CT: computed tomography.

GROUP B

In surgery a mean of 1.8 sentinel nodes was removed (range = 0-4 nodes). Eleven (11) sentinel nodes were removed from the 6 patients, 3 (27.27 %) of them presenting lymph node tumour metastasis. The results are summarised in table 4. Five (5) of the 6 patients (83.33 %) of this group, on treatment with neoadjuvant chemotherapy, presented migration of the radiotracer. The scintigraphy and the SPECT-CT were concordant in all cases, and properly determined the number and localisation of the sentinel 188

Sensitivity Positive predictive value

Planar scintigraphy

SPECT-CT

80.64 % 82.28 %

90.32 % 100 % 000

SPECT: single photon emission computed tomography; CT: computed tomography.

nodes in 5 of the 6 patients (83.33 %). Both detected 9 nodes out of a total of 11 sentinel nodes removed in surgery (81.82 %). In this there was group one case in which the presurgical imaging techniques did not accurately determine the number of nodes, since in one patient both techniques showed two nodes and four were found intraoperatively. The concordance analysis resulted in a squared Kappa index of 0.765 (good concordance) with a p of 0.039 (95 % CI 95 % 0.420-1.109). No statistical analysis by nodes was performed due to the small sample size (11 nodes).

DISCUSSION

The identification rate of the sentinel node in the group in which the technique is validated was 94.74 %;

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Mucientes Rasilla J et al. SPECT-CT: A new tool for localisation of sentinel lymph nodes in breast cancer patients

a high percentage similar to that which is obtained in publications using this same injection technique7. Until recently, there was a certain difficulty in determining the number and localisation of sentinel nodes before surgery. Sources of 57Co were used to “draw” the outline of the patient and thus obtain a better anatomical localisation, but these sources may mask the activity of some nodes, increasing the number of false negatives8. Some authors have suggested the fusion of SPECT images with a diagnostic CT, but, besides being a complicated process, the dose received by the patient may reach 20 mGy6, while with hybrid equipment a dose of radiation of approximately 1.3 mGy is added to the centre and 5mGy to the patient surface6. There are several studies published using hybrid SPECT-CT equipment for the localisation of the sentinel node in melanomas and squamous cell carcinomas9,10. Regarding the conduct of SPECT-CT for the localisation of the sentinel node in patients with breast cancer, there are currently four published works that all present similar results to those of this study. The first one, published by Lerman et al8 in 2006, presented the first 157 patients, where 4 % of the deposits found in the conventional planar scintigraphy were regarded as false positives, when the SPECT-CT demonstrated that they corresponded to uptake outside the lymph node territory. The second one, published in 2007 by Husarik et al11 with 41 patients, concluded that SPECT-CT improves the Se and the E of the preoperative lymphoscintigraphy. The third article is by the same Lerman group, who published a study with 220 patients in 200712, concluding that SPECT-CT is more beneficial in patients with greater body mass index, due probably to the attenuation correction by CT. Finally, in November 2007, Van der Ploeg et al13 published a study in which they used SPECT-CT in 40 patients (31 breast cancers and 9 melanomas) in whom the localisation of the sentinel node presented doubts by means of the conventional methods. They concluded that SPECT-CT improved the preoperative localisation of the sentinel node and located new drainage areas. This facilitated surgical exploration and finally permitted a more exact staging, whereby they address the possibility of doing it routinely in all patients, and not only in the doubtful cases. All these studies confirm that the Se and E of SPECT-CT is greater than that of the conventional methods. In our study, SPECT-CT detected nodes that

Table 4 SUMMARY OF THE RESULTS OF GROUP B

Patient

Number of nodes observed in conventional scintigraphy

Number of nodes observed in the SPECT-CT study

Number of nodes removed in surgery

1 2 3 4 5 6

3 2 2 1 1 0

3 2 2 1 1 0

3 2 4 1 1 0

SPECT: single photon emission computed tomography; CT: computed tomography.

were not detected in the planar scintigraph, thus reducing the number of false negatives, and it was demonstrated that deposits interpreted in the scintigraph as nodes actually corresponded to uptake outside the lymph node territory, thus reducing the number of false positives. The analysis of this study corresponds fundamentally to group A, where the sample size makes it possible to obtain more reliable conclusions. In group B, probably due to the small sample size, the findings of the scintigraph and the SPECT-CT are superimposable. In group A the SPECT-CT delivers better results both in Se (90.32 % versus 80.64 %) and PPV (100 % versus 82.28 %). Although we did not make the exact calculation of the figures of E and NPV for the presurgical localisation of the sentinel node, they may be expected to be better in SPECT-CT, since the latter reduces the number of false positives and false negatives, respectively, and maintains the number of true negatives. The SPECT-CT, besides offering excellent concordance with the surgical findings (Kappa index of 0.91 versus 0.57 of the group A scintigraph), offers the surgeon a new tool for a magnificent anatomical orientation before searching for the sentinel node. This allows the surgeon to know precisely where the sentinel nodes are located, permitting smaller incisions and less time wasted dissecting the axilla. When questioned, the surgeons that participated in this study consider that the information provided by the fusion images facilitated the search in all cases. In terms of the nodes found in surgery that were not visible in the images, in all cases they were nodes clustered in a single deposit, which means that the preoperative studies did not properly evaluate the

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number of nodes, but did determine localisation. Although the sample size is not high, there were no findings in the operating theatre that were not expected in the light of the images, which supports the possibility that the surgeon can use only the images as his guide, without the need to perform meticulous dissections.

CONCLUSIONS

Presurgical SPECT-CT study reduces the false positives and the false negatives of the planar scintigraph, it presents better concordance with the intraoperative findings, and offers the surgeon a reliable tool, besides providing valuable anatomical localisation. Although planar scintigraphy is a good tool for determining the presence and localisation of sentinel nodes, SPECT-CT may reduce the number of unexpected findings in surgery. This may facilitate surgical exploration, with no need for a meticulous dissection to search for possible sentinel nodes. REFERENCES 1. Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989;63:181-7. 2. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, et al. Pathologic findings from the National Surgical Adjuvant Project for Breast Cancers (protocol no.4). X. Discriminants for tenth year treatment failure. Cancer. 1984;53:712-23.

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3. Fisher B, Ravdin RG, Ausman RK, Slack NH, Moore GE, Noer RJ. Surgical adyuvant chemotherapy in cancer of the breast: results of a decade of cooperative investigation. Ann Surg. 1968; 168:337-56. 4. Euhus DM, Peters GN, Leitch AM, Saboorian H, Mathews D, Erdman W, et al. Validating the performance of the mammary sentinel lymph node team. J Surg Oncol. 2002;83:209-15. 5. Estourgie SH, Nieweg OE, Olmos RA, Rutgers EJ, Kroon BB. Lymphatic drainage patterns from the breast. Ann Surg. 2004; 239:232-7. 6. Keidar Z, Israel O, Krausz Y. SPECT/CT in tumor imaging: technical aspects and clinical applications. Semin Nucl Med. 2003;33:205-18. 7. Pelosi E, Bello M, Giors M, Ala A, Giani R, Bussone R, et al. Sentinel lymph node detection in patients with early-stage breast cancer: comparison of periareolar and subdermal/peritumoral injection techniques. J Nucl Med. 2004;45:220-5. 8. Lerman H, Metser U, Lievshitz G, Sperber F, Shneebaum S, Even-Sapir E. Lymphoscintigraphic sentinel node identification in patients with breast cancer: the role of SPECT-CT. Eur J Nucl Med Mol Imaging. 2006;33:329-37. 9. Even-Sapir E, Lerman H, Lievshitz G, Khafif A, Fliss DM, Schwartz A, et al. Lymphoscintigraphy for sentinel node mapping using a hybrid SPECT/CT system. J Nucl Med. 2003;44: 1413-20. 10. Wagner A, Schicho K, Glaser C, Zettinig G, Yerit K, Lang S, et al. SPECT-CT for topographic mapping of sentinel lymph nodes prior to gamma probe-guided biopsy in head and neck squamous cell carcinoma. J Craniomaxillofac Surg. 2004;32:343-9. 11. Husarik DB, Steinert HC. Single-photon emission computed tomography/computed tomography for sentinel node mapping in breast cancer. Semin Nucl Med. 2007;37:29-33. 12. Lerman H, Lievshitz G, Zak O, Metser U, Schneebaum S, Even-Sapir E. Improved sentinel node identification by SPECT/CT in overweight patients with breast cancer. J Nucl Med. 2007;48: 201-6. 13. Van der Ploeg IM, Valdés Olmos RA, Nieweg OE, Rutgers EJ, Kroon BB, Hoefnagel CA. The Additional Value of SPECT/CT in Lymphatic Mapping in Breast Cancer and Melanoma. J Nucl Med. 2007;48:1756-60.

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