Rev Esp Med Nucl.

2009;28(6):273-277

Original

Indication of bone scans in early breast cancer staging

L. de la Cueva, a,* P. Livano, a P. Navarro, a E. Arroyo, a M. Aaos, a M. Gonzlez, a M.C. Garca, b A. Fuerte, c F. Colmenarejo F, d T. Baringo a and M.D. Abs a
NuclearMedicineDepartment,MiguelServetUniversityHospital,Zaragoza,Spain Radiodiagnostics,MiguelServetUniversityHospital,Zaragoza,Spain c PathologyDepartment,MiguelServetUniversityHospital,Zaragoza,Spain d BreastUnit,MiguelServetUniversityHospital,Zaragoza,Spain
a b

information on the article

abstract

Historyofthearticle: Received 30 March 2009 Accepted 22 May 2009

Keywords: Bone scintigraphy Primary breast cancer Staging Guideline

Objective:Evaluate the indication for bone scanning during initial staging of early breast cancer in the light of scientific evidence to assess the need to modify practices with scant effectiveness. Materialandmethods: The bone scans carried out in our Nuclear Medicine Department in 2007 on patients with primary breast cancer were reviewed retrospectively. Results were analyzed in relation to the clinical and histopathologic findings for each tumor. Bone scan results of tumors >2 cm and 5 cm (T2) were analyzed in two groups stratified by tumor size, 3 cm or >3 cm, and pre-treatment clinical stage. Results: Out of 245 bone scans of patients with breast cancer, 237 (97%) were negative for metastatic disease and 8 (3%) were positive. Lesions <2 cm (Tis and T1) were diagnosed in 131 patients (53.5%), none of which had bone metastasis at time of diagnosis. Lesions >2 cm and 5 cm (T2) were diagnosed in 84 patients (34%), of which 3.6% had bone metastasis. There were no differences in the rate of bone metastases in patients with stage T2 disease and lesions 3 cm vs. >3 cm. The bone scan findings did not modify staging in any of the 66 patients with T2 tumors stage IIA, but it did modify staging in 2 of 12 patients with stage IIB tumors. Twenty percent of 15 patients with T3 tumors and 13% of patients with T4 tumors had bone metastasis at time of diagnosis. Conclusions: Ineffective practices should be modified and bone scanning should not be indicated in patients with early breast cancer Tis, T1 and T2 with tumor 2 cm, clinical stage IIA. Pre-treatment bone scanning is still indicated in T2 IIB, T3 and T4 disease. 2009 Elsevier Espaa, S.L. and SEMN. All rights reserved.

Indicacin del rastreo seo en la estadificacin del cncer de mama de inicio

resumen

Palabrasclave: Gammagrafa sea Cncer de mama de inicio Estadificacin Gua de prctica clnica

Objetivos: Revisar nuestra experiencia y reflexionar a la luz de la evidencia cientfica sobre la indicacin del rastreo seo (RO) en la estadificacin del cncer de mama de inicio en estadios precoces, con el fin de contribuir en la modificacin de rutinas de baja eficacia. Materialymtodos: Revisin retrospectiva de los RO hechos en nuestro Servicio de Medicina Nuclear durante 2007 en las pacientes con cncer de mama de inicio, analizando su resultado en funcin del tamao clnico o anatomopatolgico tumoral. Los RO para tumores T2 se analizaron estratificando las lesiones en dos grupos, o > de 3 cm y en funcin de su estadio clnico pretratamiento. Resultados: Se incluyeron 245 rastreos, 237 de stos (97%) fueron negativos y 8 de stos (3%) fueron positivos para metstasis seas. En 131 pacientes (53,5%) se diagnosticaron lesiones < 2 cm (Tis y T1) y ninguna tena metstasis seas. Se hallaron 84 lesiones (34%) que eran >2 cm y 5 cm (T2) y entre stas, el 3,6% de las pacientes present metstasis seas, sin diferencias entre lesiones 3 cm y >3 cm. El RO no modific el estadio en ninguna de las 66 pacientes con tumores T2 en estadio IIA clnico, mientras que s lo hizo en 2 de las 12 pacientes en estadio clnico IIB. El 20% de las 15 pacientes con lesiones T3 y el 13% de las 15 pacientes con T4 presentaron metstasis seas en el diagnstico. Conclusiones: Es necesario modificar rutinas poco eficientes excluyendo de las indicaciones del RO la estadificacin de las neoplasias de mama de inicio con lesiones 2 cm y lesiones en estadio clnico IIA, siendo necesaria su realizacin previa al tratamiento en el resto de los casos. 2009 Elsevier Espaa S.L. y SEMN. Todos los derechos reservados.

* Correspondence author. E-mail: ldelacueva@salud.aragon.es (L. Cueva). 0212-6982/$ - see front matter 2009 Elsevier Espaa, S.L. y SEMN. Todos los derechos reservados

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AsyousetoutforIthaca,hopethatyourroadisalongone,fullof adventure,fullofdiscovery...Andifyoufindherpoor,Ithacawonthave fooled you. Wise as you will have become, so full of experience, youll haveunderstoodbythenwhattheseIthakasmean. Cavafy C. Ithaca.Anthologyofpoems.[Anon.translator]

Given this scenario, we made a retrospective study to try to implement the protocol recommended by the FIGO and SEGO. The following questions were raised: It is necessary to perform staging BS in all patients with initial breast cancer? Does preoperative BS modify treatment? Material and Method The database of the Nuclear Medicine Department was used to retrospectively select all the scintigraphic bone studies performed in 2007 in patients with breast cancer. In every case, scintigraphy was performed before surgery or primary systemic therapy, 2 to 3 hours after the injection of 740 MBq of 99mTc-methylenediphosphonate (MDP), using one of two dual-head gamma cameras in the department (Vertex, Philips or Symbia T, Siemens). All patients underwent a whole body BS and, if necessary according to the criterion of the physician, low-dose focal imaging and/or SPECT or SPECT-CT. Next, the electronic clinical records were reviewed to select cases that fulfilled the following inclusion criteria: patients diagnosed and operated on in this hospital who had initial breast cancer and a clinical record containing complete data on the diagnosis, staging, and treatment. For all the patients, the diagnostic, staging, and therapeutic process was the same by protocol: the diagnosis was always histologic and TNM staging7 was based on preoperative locoregional breast and lymph node clinical staging by means of physical examination, mammography, ultrasonography, and magnetic resonance (MR), in addition to abdominal and gynecologic ultrasonography. In the cases treated initially with surgery, postoperative histopathologic staging was added, with the sentinel node as indicated. Treatment, which was decided by consensus in committee and according to protocol,4,8-10 was surgical except in cases with an indication for primary systemic treatment, in which hormone therapy or chemotherapy was used before surgery to reduce tumor size and help to conserve the breast, to assess tumor chemosensitivity and/or to improve the axillary surgical results. After surgery, primary irradiation was indicated if the breast was conserved. Chemotherapy and/or adjuvant radiotherapy were indicated depending on the involvement of lymph nodes, the chest wall, age, tumor size, histologic grade, existence of hormone receptors and Her2/neu, among other factors. Patients of advanced age received hormone therapy if a contraindication existed or the patient refused surgery. Patients with systemic metastasis on diagnosis received primary chemotherapy with or without palliative hormone therapy.

Introduction The need to unify criteria for studying the extension of malignant pathologies in Oncologic Gynecology in order to compare the results of different centers and countries first began to take shape in 1929, the year in which the Radiological Sub-Commission of the Cancer Commission of the Health Organisation of the League of Nations published its first recommendations.1 As of 1958, the International Federation of Gynecology and Obstetrics, FIGO, took responsibility for the preparation and publication of the annual reports of the United Nations. Since 1973, these reports have been made public every three years. In our country, the Spanish Society of Obstetrics and Gynecology (SEGO) has accepted the staging protocols of the Committee on Gynecologic Oncology of the International Federation of Gynecology and Obstetrics (FIGO) that have been prepared in collaboration with the Guidelines Committee of the International Gynecologic Cancer Society (IGCS) since 2000. The most recent revision was prepared in 2006.2 The SEGO reviewed their protocols in 2005, but they made no changes in breast cancer staging with respect to the FIGO 2002 update, in which the use of the sentinel node technique was included.3 Therefore, the SEGO includes in the preoperative clinical staging of breast cancer, in addition to the examination and histologic study of the breast or other suspicious tissues, imaging studies to establish the extension of disease. The recommendation is generic and does not specify the imaging studies that should be made nor the patients in which they should be made. However, according to the FIGO protocol, routine bone scan (BS) in asymptomatic patients in clinical stages T1 and T2 is not recommended if they are N0, because it is not likely that they have bone metastasis. The indication is thus limited to tumors larger than 5 cm, elevation of alkaline phosphatase, palpable axillary lymph nodes, or suspicious clinical manifestations.4 Although most practitioners in Spain believe that the use of bone scintigraphy is not cost-effective in the initial stages of breast cancer, our routine clinical practice, like that of other centers,5,6 traditionally includes a BS of all patients diagnosed of breast cancer as part of preoperative oncologic staging.

Table 1 Tumor staging according to classification of the International Federation of Gynecology and Obstetrics (FIGO) Tx T0 Tis Tis (DCIS) Tis (LCIS) Tis (Paget) T1 T1mic T1a T1b T1c T2 T3 T4 T4a T4b T4c T4d Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ; ductal carcinoma in situ; lobular carcinoma in situ; Paget disease of the nipple with no breast tumor Ductal carcinoma in situ Lobular carcinoma in situ Paget disease of the nipple with no underlying tumor Tumor 2 cm in largest diameter Microinvasion 0.1 cm in the largest dimension Tumor size > 0.1 cm but 0.5 cm Tumor size > 0.5 cm but 1 cm Tumor size > 1 cm but 2 cm Tumor size > 2 cm but 5 cm Tumor size > 5 cm Tumor of any size with direct extension to chest wall or skin Extension to chest wall (not considering the pectoralis major muscle) Edema (including peau dorange), or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast Extension to skin and chest wall (T4a + T4b) Inflammatory carcinoma of the breast

 Table 2 Frequency of tumors found, according to histologic type Tumor type Infiltrating ductal carcinoma Infiltrating lobular carcinoma Ductal carcinoma Papillary carcinoma Tubular carcinoma Paget disease Medullary carcinoma

L.delaCuevaetal/RevEspMedNucl.2009;28(6):273-277 Table 4 Frequencies of each tumor stage found, in relation to the BS findings N 207 12 16 5 3 1 1 % of total 84.5% 6.5% 5% 2% 1.2% 0.4% 0.4% Negative BS N T0 Tis T1 T2 T3 T4 Total BS: bone scan. 0 4 127 81 12 13 237 % of T 100 100 96.43 80 86.67 96.73 Positive BS N 0 0 0 3 3 2 8 % of T 3.57 20 13.33 3.27

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Total N 0 4 127 84 15 15 245

Table 3 Frequency of tumors found, according to their size and the treatment given Surgery T0 Tis T1 T1mic T1a T1b T1c T2 T3 T4 T4a T4b T4c T4d Total 0 4 121 2 8 24 87 59 7 2 1 1 0 0 193 PST 0 0 6 0 0 0 6 25 8 13 0 12 0 1 52 N 0 4 127 0 8 24 93 84 15 15 1 13 0 1 245 % (N) 0 1.6 51.8 0.8 3.3 9.7 38 34.3 6.1 6.1 0.4 5.3 0 0.4 Table 5 Number of patients with T2 tumors who changed stage after BS Pre-BS clinical stage IIA IIB IIIA IV Total BS: bone scan. 66 12 3 3 84 Negative BS 66 10 3 2 81 Positive BS 0 2 0 1 3 Post-BS clinical stage 66 10 3 5 84

PST: primary systemic therapy.

For each patient who met the inclusion criteria described, the type of tumor and tumor size in millimeters, and the respective tumor stage were obtained from the histopathologic study after surgery (Table 1). In the case of patients treated with primary systemic therapy, tumor size was measured in millimeters during magnetic resonance staging, and the respective clinical tumor stage was noted. In addition, in all cases the scintigraphic report of the pretreatment BS was reviewed and the results were classified as: negative absence of bone metastasis, positive presence of bone metastasis, or indeterminate bone lesions in which malignancy cannot be confirmed and complementary study is recommended. The indeterminate studies were later classified as positive or negative based on the result of complementary studies (plain radiography, CT and/or MR), which were used for the definitive staging. Using the data collected, the frequency of bone metastasis was analyzed in relation to the size in histopathologic study in patients treated with primary surgery or the clinical size in patients treated with primary systemic therapy. In cases with T2 lesions (< 2 5 cm), the result of the BS was analyzed after stratifying the lesions into two groups, depending on whether they were or > of 3 cm and also based on the pre-treatment clinical stage. Results In 2007, 326 BS were performed in women with breast cancer in our department. Eighty-one studies were excluded because they were from patients operated on in other centers or because they were not initial cancers. A total of 245 studies in 245 patients were obtained and analyzed. The mean age of presentation for breast cancer in our series was 58 years, with a minimum of 28 years and a maximum of 90 years. The most frequent histologic type was infiltrating ductal carcinoma, which was diagnosed in 84.5% of patients. The types of tumors diagnosed and their frequency are shown in Table 2.

According to the protocol, 193 of the 245 patients included were treated with primary surgery and 52 with primary systemic therapy. With respect to tumor size, tumor in situ (Tis) was diagnosed in 4 patients (1.6%), a tumor of less than 2 cm (T1) in 127 (51.8%), a tumor greater than 2 cm but 5 cm or less (T2) in 84 (34.3%), and more than 5 cm (T3) in 15 patients (6.1%). The tumor affected the chest wall and/or skin or was an inflammatory tumor (T4) in another 15 patients (6.1%). The frequency of presentation of each tumor size and the treatment given are described in Table 3. Initially, 7 of the 245 patients (3%) presented metastasis in the BS at the time of diagnosis, 210 scans were negative (86%), and 28 were indeterminate for metastasis (11%). After complementary studies were made, 1 of the 27 indeterminate BS for metastasis was found to be positive and 27 were classified as negative, 23 due to degenerative pathology, 1 calcified meningioma, 1 enchondroma, 1 angioma, and 1 cancellous bone hernia. The final result was 8 metastatic BS (3%) and 237 BS negative for metastasis (97%). The final frequencies of the results of BS for each tumor size are summarized in Table 4. Little more than half of the breast tumors (131 patients, 53.5%) were diagnosed with a size of less than 2 cm and none of the patients had metastasis at diagnosis. Patients with tumors greater than 2 cm (114 patients, 46.5%) presented bone metastasis in 7% of cases, with a frequency of 3.6% in T2 tumors, 20% in T3 tumors, and 13% in T4 tumors. Analysis of 84 T2 tumors showed that 2 of 57 patients with lesions 3 cm (3.5%) and 1 of 27 patients with lesions > 3 cm (3.7%) had bone metastasis at diagnosis. Among the BS with negative results, the tumor size of the initially indeterminate tumors was assessed. Nine tumors presented with a size smaller than 2 cm, 18 were T2 and 1 was T3. The BS did not change the stage and, consequently, the treatment in any of the patients with T2 tumors in clinical stage IIA (66 patients), whereas it did change the stage in 2 of 12 patients in clinical stage IIB, who passed to stage IV after the scan was performed (Table 5). Among the patients in which the result of the scan did not modify treatment were 14 of 28 that initially presented a BS with an indeterminate result. The final diagnosis was degenerative pathology in 12, vertebral angioma in one, and meningioma in one. Of the 14, 2 belonged to the stage I group and 12 to stage IIB.

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Discussion Breast cancer is the one of the tumors with the highest incidence among the women of Aragon. In Zaragoza, where the rates are similar to those of Spanish and European registries, the incidence rose progressively in the period 1996-2000, in which the mean was 73.5/100,000 person-years.11 Breast cancer in Aragon was responsible for 13% of all cancers, with an incidence of 320 new cases in women in 2006. The most frequent histologic type, as was previously known and was evident in our series and other patient series, was infiltrating ductal carcinoma.12,13 The presence of bone metastasis at the time of diagnosis is a direct consequence of the tumor stage.14 Our finding of 3.3% of metastasis in the sample was close to the figures reported previously by other groups.5,13,15 Bone scintigraphy is a classic and much used study in the oncologic indications of nuclear medicine. As Bern notes,16 bone scintigraphy is one of the studies most often ordered by many of our departments and is one of the radionuclide techniques that has been least modified despite technological advances, especially with regard to tomographic variants. It is a highly sensitive tool for the diagnosis of bone metastasis and is especially useful in advanced breast cancer in which metastasis is a more frequent complication than in localized tumors. Its high sensitivity makes bone scintigraphy an essential tool in the initial staging of this neoplasm, since a correct diagnosis obviously has implications for treatment selection and the survival and quality of life of patients.10 Nevertheless, just which patients benefit from an initial staging that includes a BS is a question that has been discussed in the literature for decades in protocols, recommendations and guides, as commented by Myers et al.15 in a systematic review in 2001 of the Canadian evidence-based medicine program, which works to improve the survival of patients with cancer, to support specialists in their selection of clinical decision-making tools, and in the development of clinical practice guides. The authors reviewed articles published between 1972 and 1995 and concluded that no evidence exists that patients with stage I (T1N1M0) breast cancer benefit from performing BS in the initial disease staging. Kell et al.17 obtained identical results in an analysis of a series of 200 patients with early stage invasive breast cancer, in which none of the patients with tumors 2 cm presented bone metastasis at diagnosis. The reality is uncontestable, despite studies of the prognostic value of staging by means of bone scintigraphy or the interest of having a baseline study.18 Technical development15 and, especially, scientific evidence indicate that our routine practice should be modified. This need to change our staging habits is also supported by the results of other work groups, our experience, and the recommendations and clinical practice guidelines of the International Federation of Gynecology and Obstetrics (FIGO),2 European Society For Medical Oncology (ESMO),19 National Comprehensive Cancer Network (NCCN),8 American Cancer Society American Joint Committee on Cancer (AJCC),20 Practice Guidelines Initiative (PGI) of Cancer Care Ontario (Ministry of Health, Ontario, Canada),21 Scottish Intercollegiate Guidelines Network (SIGN),22 and British Nuclear Medicine Society,23 which define the indications for BS in breast cancer. These initiatives and associations generally coincide in not recommending initial BS staging in patients with stage I, T1 tumors smaller than 2 cm, no palpable lymph nodes, absence of symptoms, and normal alkaline phosphatase. The initial staging of T2 lesions is somewhat more controversial. Myers et al.,14 reviewed the literature up to 1995 to assess the rate of detection of metastasis by BS, chest radiography, and hepatic ultrasonography. These authors recommend performing a postoperative BS in stage II patients. Studies of more recent series using magnetic resonance imaging in T and N staging are more

ambitious and claim that asymptomatic patients with stage II disease and no clinical lymph node involvement do not benefit from initial bone staging.12,13 In the worst case scenario, based on an incidence of metastasis of 1% as a criterion for the BS indication, patients in stage II with tumors < 3 cm still obtain little benefit.5 The recommendations of the international associations cited above are more prudent and recommend weighing the possibility of not performing a BS in the absence of lymph node involvement. In any case, they advise that BS be performed after surgery. Our results, which showed 3.4% of metastasis in patients with T2 tumors a priori, would not allow us to exclude initial scintigraphic staging from the study of patients with tumors between 2 and 5 cm. Such patients represent 34.3% of initial breast cancers treated annually in our center. Initial BS staging could not even be omitted in smaller tumors of 2 to 3 cm. Likewise, we would not exclude patients with stage IIB disease because 16% of these patients changed their stage and were treated with primary chemotherapy instead of surgery after BS was performed. However, no patient in clinical stage IIA experienced a change in stage and treatment as a result of BS findings. We can also assume, after analyzing the results of the patients who presented an indeterminate result in the initial BS, that complementary tests could have been avoided in half of these cases because the patients had stage I and IIA disease. This would have resulted in an economic saving and reduction of radiation exposure. More importantly, it would have prevented the anxiety generated by undergoing a test that was not really indicated and the concern about possibly finding an incidental lesion. Our task is probably arduous, in view of reports that 25% of BS are poorly indicated despite criteria and recommendations.6 Nevertheless, the results of our series would have allowed initial staging BS to be avoided in 193 of the 245 patients (79%) treated annually in our center for initial breast cancer. In other words, our department would not have performed 59% of the BS done annually in patients with breast cancer. Conclusions No scientific support exists for performing initial staging BS in patients with breast cancer and lesions up to 2 cm in diameter or with clinical stage IIA (T2N0M0) disease because the result is not going to modify treatment. BS is necessary prior to the treatment of patients with clinical stage IIB tumors because a change in stage entails therapeutic modifications. References
1. The FIGO Annual Report (February 2009). Available from: http://www. figo.org/ publications/annual 2. FIGO-IGCS Staging Guidelines (February 2009). Available from: http:// www.igcs. org/professionalEducation/treatmentResources/figoStaging.html 3. Benedet JL, Bender H, Jones 3rd H, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaec Obst. 2000;70:209.62. 4. Bases para la estadificacin clnico-quirrgica en ginecologa oncolgica. Soc Esp Ginec Obst (January 2009). Available from: www.prosego.com 5. Koizumi M, Yoshimoto M, Kasumi F, Ogata E. What do breast cancer patients benefit from staging bone scintigraphy? Jpn J Clin Oncol. 2001;31:263-9. 6. Corts M, Talavera MP, Garca AM, Ruiz S, Poblete VM, Rodrguez B, et al. Se solicitan las gammagrafas seas en pacientes oncolgicos segn criterios clnicos reconocidos? Rev Esp Med Nucl. 2007;26:286-93. 7. ACC Cancer Staging Manual. 6 ed (February 2009). Available from: www.cancerstaging.org 8. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. 2009 (February 2009). Available from: www.nccn.org 9. Cncer de mama: diagnstico. Soc Esp Ginec Obstet (December 2008). Available from: www.prosego.com 10. Cncer de mama: tratamiento. Soc Esp Ginec Obstet (December 2008). Available from: www.prosego.com 11. Registro de Cncer. Direccin General de Salud Pblica. Gobierno de Aragn (January 2009). Available from: http://portal.aragon.es

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12. Jeong Eon L, Sung-Shin P, Wonshik H, Seok Won K, Hyuk Jai S, Kuk Jin C, et al. The clinical use of staging bone scan in patients with breast carcinoma. Cancer. 2005;104:499-503. 13. Puglisi F, Follador A, Minisini AM, Cardellino GG, Russo S, Andreetta C, et al. Baseline staging tests after a new diagnosis of breast cancer: Further evidence of their limited indications. Ann Oncol. 2005;16:263-6. 14. Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987;55:61-6. 15. Myers RE, Johnston M, Pritchard K, Levine M, Oliver T, The Breast Cancer Disease Site Group of the Cancer Care Ontario Practice Guidelines Initiative. Baseline staging tests in primary breast cancer: A practice guideline. CMAJ. 2001;164:143944. 16. Bern Ll. La gammagrafa sea en oncologa. Rev Esp Med Nucl. 2003;22:1-2. 17. Kell MR, Healy CF, Martin Z, Downey R, Potter-Bierne S, Gorey TF, et al. Routine staging radiology is not needed for all breast cancer patients. ASCO Annual Meeting Proceedings Part I. J Clin Oncol. 2006;24:106-48.

18. Furnival CM, Blumgart LH, Citrin DL, McKillop JH, Folgelman I, Greig WR. Serial scinti scanning in breast cancer: Indications and prognostic value. Clin Oncol. 1980;6:25-32. 19. Pestalozzi B, ESMO Guidelines Working Group. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2007;18:ii5-8. 20. Breast. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual, 6th ed. New York, NY: Springer; 2002. p. 171-80. 21. Myers R, Minuk T, Johnston M, and the Diagnostic Imaging Guidelines Panel. Diagnostic imaging in breast cancer recommendations report [cited 12 Apr 2006]. Available from: www.cancercare.on.ca 22. Management of breast cancer in women. A national clinical guideline. Scottish Intercollegiate Guidelines Network, 2005 (January 2009). Available from: http:// www.sing.ac.ukwww.sing.ac.uk 23. 99mTc diphosphonate bone imaging for metastases. Br Nucl Med. March, 2009 (March 2009). Available from: http://www.bnmsonline.co.uk