- Email: [email protected]
The value of TNM tumour staging and serum alkaline phosphatase levels in predicting the presence of bone metastases in patients with renal cell carcinoma
British Journal of Medical and Surgical Urology (2010) 3, 59—64
ORIGINAL ARTICLE
The value of TNM tumour staging and serum alkaline phosphatase levels in predicting the presence of bone metastases in patients with renal cell carcinoma M.J. George a,b,∗, J. Buscombe a, M. Al-Akraa b a b
Department of Nuclear Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom Department of Urology, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom
Received 1 June 2009 ; received in revised form 22 December 2009; accepted 4 January 2010
KEYWORDS Renal cell carcinoma; RCC; Bone scintigraphy; Metastases
Summary Objectives: To determine if the TNM tumour staging and serum alkaline phosphatase levels (SAP) can be used to identify which patients with renal cell carcinoma (RCC) are at greatest risk of osseous metastases. Patients and methods: A retrospective review of patients with histologically proven RCC was conducted. All patients had initial CT or MRI staging scans of the chest and abdomen. Patients also underwent bone scintigraphy and all abnormal areas were further evaluated with either serial or collaborative imaging to determine their nature. Results: 91 patients including 66 men and 25 women, with a mean age of 61, were included in the study. The incidence of bone metastases was 17.6%. The incidence of bone metastases in T1-4 disease was 4%, 31.3%, 31.8% and 66.7%, respectively. Patients with >T1N0M0 disease, as defined by initial staging scans, accounted for 53% of the cohort and included all instances of proven osseous disease. Thus ‘>T1N0M0’ was 100% sensitive and 57.3% specific as a predictor of bone metastases. Conversely, a raised SAP (>129 U/L) was only 25% sensitive but had a specificity of 94.3%. Conclusions: Patients with >T1N0M0 staging should undergo bone scintigraphy. SAP is a far less sensitive predictor and its concurrent use is unwarranted. © 2010 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.
∗ Corresponding author at: Department of Nuclear Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom. Tel.: +44 0 20 8203 4663/78 1382 0614; fax: +44 0 20 8518 3486. E-mail addresses: [email protected] (M.J. George), [email protected] (J. Buscombe), [email protected] (M. Al-Akraa).
1875-9742/$ — see front matter © 2010 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjmsu.2010.01.001
60
Introduction Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers [1]. The prevalence of bone metastases at presentation is reported to be between 5% and 34% [2—4] and it is important to identify these lesions given that their early treatment has been shown to improve ambulation, relieve pain and increase survival [5].Bone scintigraphy is currently the standard imaging modality for detecting bone metastases. Current policy at our institution is that all patients with a suspected diagnosis of RCC should have such a bone scan as part of their routine tumour staging. This contrasts to the 2007 European Association of Urology (EAU) guidelines, which state that ‘There is no role for routine bone scans in the standard clinical work-up of asymptomatic patients’ [6]. It recommends that bone scans only be done in ‘high-risk’ patients as defined by raised serum alkaline phosphatase (SAP) or bone pain [6]. However, the EAU guidelines are not without controversy. Although the clinical importance of bone pain is widely accepted [7—10], it’s prevalence amongst patients with proven osseous disease is as low as 35% [8]. In addition, there is an ongoing debate in the literature about the usefulness of SAP measurements in this setting [7,8,11,12]. Furthermore, it has been suggested by Koga et al. that the TNM classification, as defined by initial CT and MRI staging scans, can be used as a far more sensitive means of identifying those at risk of bone metastases [8]. Clearly, the most efficient use of resources would involve appropriately stratifying RCC patients, and using bone scintigraphy in a targeted fashion. Given this, and the discordance between the EAU guidance and much of the relevant literature, we evaluated both the TNM staging and serum alkaline phosphatase levels as predictors of osseous disease, to establish clear screening criteria for using bone scintigraphy in patients with RCC.
Materials and methods Patients with a confirmed histological diagnosis of RCC were identified by interrogating the hospital’s pathological database from 1/1/2001 to 31/12/2008. Patients with suspected RCC, but for whom no confirmatory histology was obtained were not included. The medical records of all identified patients, including relevant histology, radiology, blood tests and bone scan reports were subsequently retrospectively reviewed. Only patients with complete available data were included. It was
M.J. George et al. not possible to satisfactorily assess the presence or absence of bone pain retrospectively in this cohort, as there were no standardised means of collecting and recording this subjective data during the period under study.
Staging All included patients underwent CT or MRI initial staging scans (ISS) of the abdomen and thorax and subsequently underwent a bone scan. The tumours were staged based on imaging alone according to the modified TNM classification [13] as follows: T1a: tumour 4 cm or less and limited to the kidney, T1b: 4—7 cm and limited to the kidney, T2: greater than 7 cm and limited to the kidney, T3a: perinephric extension, T3b: extension into renal veins or vena cava below the diaphragm, T3c: extension into the vena cava above the diaphragm and T4: invasion through Gerota’s fascia. Lymph node involvement was classified as N0: no regional lymph node involvement and N1: metastasis to at least 1 regional lymph node. Distant metastatic involvement was classified as M0: no metastatic involvement and M1: at least one site of metastasis (including bone). SAP measurements were considered to be high when above >129 U/L (the upper limit of normal at our institution). Suspicious lesions identified on bone scan were further evaluated with either collaborative imaging such as plain radiographs, CT or MRI, and if these were inconclusive, they were re-imaged at a later date to determine if the lesion had progressed. Patients were considered to have osseous disease only once initially suspicious lesions were confirmed as malignant in this manner. The distant metastasis or ‘M’ component of the staging was based initially on the ISS alone and subsequently revised, with reference to the bone scan results, to give the final, definitive tumour stage.
Histology From the histology reports, Fuhrman nuclear grade, tumour size and type were obtained. Lymphadenectomy data were available but not used to revise the original imaging-based ‘N’ stage.
Evaluation of predictors of osseous disease Each element of the TNM staging, as defined by ISS, and SAP levels were evaluated as predictors of osseous disease, by calculating key measures such as their sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). These separate predictors were then combined to
TNM tumour staging and serum alkaline phosphatase levels
61
predominant type with 80 cases (88%), followed by chromophobe with 6 (7%), collecting-duct with 3 (3%) and papillary with 2 (2%). The Fuhrman nuclear grade was 1 in 15 cases (16%), 2 in 37 (41%), 3 in 27 (30%), 4 in 8 (9%) and unspecified in 4 (4%). The mean tumour size was 6.8 cm (range 1.5—16 cm). There was a trend between nuclear grade and tumour size (Fig. 1). This sequential enlargement was only statistically significant between grades 2 and 3 (p = 0.0473). Figure 1 Fuhrman nuclear grade v mean tumour size. The graph demonstrates a trend between nuclear grade and tumour size. This was statistically significant between grades 2 and 3 (p = 0.0473).
identify the most sensitive potential screening criteria. For categorical data, 2-tailed p values were calculated using either the 2 or Fisher’s exact test as appropriate, and the unpaired Student’s t-test was used for numerical data. Results were considered significant at p < 0.05 and highly significant at p < 0.01. Where required, 95% confidence intervals (95% CI) were calculated using the modified Wald method.
Tumour stage The tumour stage was T1a in 21 cases (23%), T1b in 29 (32%), T2 in 16 (18%), T3a in 8 (9%), T3b in 14 (15%) and T4 in 3 (3%) of cases. Lymph node stage was N0 in 76 cases (84%) and N1 in 15 (16%). The provisional distant metastases stage, based on ISS, was M0 in 65 cases (71%) and M1 in 26 (29%). The sites of distant metastases in the 26 patients with M1 disease were as follows: pulmonary (20), hepatic (5), bone (3), adrenal glands (3), brain (1), omentum (1) and skin (1). 7 patients had sites of metastasis in multiple organs identified by ISS.
Bone metastases
Results 124 patients with RCC were initially identified, however complete data were only available for 91, and therefore only these patients were included in the analysis. The mean age of this cohort was 61 years and there were 66 men (73%) and 25 women (27%).
Histology Histological diagnosis was based on a radical nephrectomy specimen in 76 cases (83%), partial nephrectomy in 8 (9%), and renal or metastatic biopsy in 7 (8%). Clear cell carcinoma was the most
Bone scintigraphy revealed suspicious lesions in 32 patients, 50% of which were proven to represent metastases. Therefore 16 patients (17.6%) were found to have osseous disease. Only 3 (19%) of these patients had been identified by ISS. Of the 16 patients, 3 did not have metastases in other organs and therefore required their staging to be revised from M0 to M1. Given this, the final staging was M0 in 62 cases (68%) and M1 in 29 (32%). 8 patients had multiple sites of bone metastases on their bone scan. The sites of bone metastasis were spine (7 patients), long bones (7 patients), ribs (3 patients), iliac crests (2 patients) and skull (1 patient).
Figure 2 Percentage of patients with bone metastasis for each initial tumour stage. The increase in the incidence of bone metastases from T1 to T2 disease was statistically significant (4% v 31.3% p = 0.002).
62 Table 1
M.J. George et al. Analysis of the predictors of osseous disease.
Number Sensitivity (%) Specificity (%) PPV (%) NPV (%) 2-tailed p-value
rSAP
>T1
>T2
N1
M1
8 (9%) 25 94.3 50 84.6 0.0363
41 (45%) 87.5 64 34.1 96 0.0002
25 (27%) 56.3 78.7 36 89.4 0.0107
15 (16%) 68.8 94.7 73.3 93.4 <0.0001
26 (29%) 81.2 82.7 50 95.4 <0.0001
The percentage of patients with bone metastases for each initial tumour stage is shown in Fig. 2. Of note is the marked and statistically significant increase in the incidence of bone metastases from T1 to T2 disease (4% v 31.3% p = 0.002) but no such increase from T2 to T3 disease (31.3% v 31.8%).
Predictors of osseous disease Table 1 illustrates the value of a raised SAP (‘rSAP’) and each of the separate components of the TNM staging system, in predicting the presence of osseous disease. Raised serum alkaline phosphatase The average SAP was 77.27 U/L (normal range 35—129 U/L). The average SAP for patients with proven osseous disease was significantly higher than those without: 98.75 U/L v 72.36 U/L (p = 0.0061). TNM classification All the separate components of the TNM classification were far more sensitive than rSAP. The use of tumour stage >T1 was the most sensitive (87.5%) and the presence of metastatic lymph nodes (N1) was the most specific predictor (94.7%). Combined screening criteria Table 2 illustrates how the various predictors may be used in combination to provide screening criteria with greater sensitivity. Most importantly, the table identifies 3 potential screening criteria with a sensitivity of 100%: ‘>T1M0’, ‘>T1N0M0’ and ‘>N0M0 or rSAP’.
Discussion The demographic and histological features of our cohort are in keeping with those described in the literature. 73% of patients were male, which compares to figures of 65—79% found by previous studies [7,8,11,12] and the average age of 61 is consistent with that quoted by several papers [8,9]. The proportion of each histological type of RCC was broadly
in keeping with figures published by Cheveille et al., who retrospectively reviewed the histology of over 2000 patients with RCC [14]. After complete staging, including bone scan, 32% of patients were found to have metastatic disease. This compares with figures of 30—37% quoted in the literature [8,9]. 17.6% (95% CI 11—26.7%) of patients were confirmed to have bone metastases. This is comparable to the two most recent, relevant studies, where the incidence was reported as 17% [8] and 14% [11]. The 50% positive predictive value of an initial bone scan is comparable with that quoted by Koga et al. (57%) [8] and Bos et al. (38%) [12].
Serum alkaline phosphatase The predictive value of SAP has been questioned, mainly on the grounds of its low sensitivity [8,9,12]. Indeed in our study, a raised SAP had a sensitivity of just 25%. This suggests that it is a poor independent predictor of osseous disease, which would miss the majority of cases. Despite this however, a raised SAP was found to have a relatively high specificity (94.3%) and PPV (50%), thus it may well be useful as part of a broader set of predictive criteria. In the context of the current EAU guidance [6], a raised SAP would indeed add value, as ‘bone pain’ also has a low sensitivity of just 35% [8].
Screening criteria The primary aim of this study was to establish clear screening criteria for using bone scintigraphy in patients with RCC. Table 2 illustrates that although several potential screening criteria offer sensitivities >90%, including that suggested by Koga et al.: ‘>T3aN0M0’ [8], there are only 3 with 100% sensitivity. Initially, it appears that the most attractive of these 3 criteria is ‘>N0M0 or rSAP’ as it is the most specific, and would incur scanning the fewest patients (37.4%). However, given that only 25% of patients with bone metastases have a raised SAP, it appears rather fortuitous that the single patient
TNM tumour staging and serum alkaline phosphatase levels Table 2
Analysis of combined screening criteria.
Number Sensitivity (%) Specificity (%) PPV (%) NPV (%) 2-tailed p-value a
63
>T1M0a
>T1N0
>N0M0
>N0M0 or rSAP
>T1N0 or rSAP
>T1N0M0
>T2N0M0
>T3aN0M0
46 (51%) 100 60 34.8 100 <0.0001
44 (48%) 87.5 60 31.8 95.7 0.0007
30 (33%) 93.8 80 50 98.4 <0.0001
34 (37%) 100 76 47 100 <0.0001
47 (52%) 87.5 56 29.8 95.5 0.0019
48 (53%) 100 57.3 33.3 100 <0.0001
40 (44%) 93.8 66.7 37.5 98 <0.0001
36 (40%) 93.8 72 41.7 98.2 <0.0001
‘>T1M0’ refers to >T1 or >M0. This applies to the other TNM combinations used in this table.
with N0M0 disease who had bone metastases also had a raised SAP. Thus, it appears likely that in a larger cohort, there will be patients with N0M0 disease with normal SAP levels who have bony deposits. ‘>T1M0’, appears to be a more reliable criterion as both components have a sensitivity >80%. The addition of ‘>T1’ component is also important as there was a marked and statistically significant increase in the incidence of bone metastases from T1 to T2 disease (4% v 31.3% p = 0.002), which is likely a consequence of T2 tumours being larger, and thus of a higher grade with greater metastatic potential [14—16]. It is debatable as to whether ‘>T1N0M0’ would be a better screening criteria, as both specificity and PPV go down marginally when the ‘N’ component is added. However, although there were no cases encountered in this study, it is feasible a patient may present with T1N1M0 disease, and it is clear that they would be at high risk of bone metastases as N1 caries a PPV of 73.3%. Thus of the 3 screening criteria which yielded 100% sensitivity in this study, the most robust appears to be ‘>T1N0M0’. We would therefore recommend the use of this screening criterion when selecting patients with RCC for bone scintigraphy.
Implications of employing the ‘>T1N0M0’ screening criterion In employing the ‘>T1N0M0’ criterion, roughly half (53%) of all patients would need to have a bone scan. A third of these will be found to have osseous disease. This is twice as efficient as scanning all patients with RCC (PPV 33.3% v 17.6%) and would thus represent a financial saving to the health system and be of benefit to those patients for whom a bone scan is unnecessary. This criterion is simple to employ, and negates the need to perform SAP levels on patients. Although a clinical assessment of bone pain is not a necessary component of this screening criterion, clinical suspicion of osseous involvement
can be highly specific [7—10] and therefore must be investigated thoroughly.
Study limitations This study’s main limitation is that of the 124 patients with RCC initially identified, 27% of patients were not included as they did not have a bone scan. In some instances these scans were done at referring institutions and were unavailable, in others, the patient did not, or could not attend for their scan and in a small number the bone scan was not included in the staging process as required. An analysis of these patients’ other staging scans and histology demonstrated a similar prevalence of each T-stage and histological type to those that had a bone scan and thus it is unlikely the exclusion of these patients has significantly skewed our data.
Conclusions Patients with RCC have a high prevalence of metastases at presentation, and the second most common site is the bones. Bone scintigraphy may be used in a targeted fashion to identify bone lesions in highrisk patients. The patients at high risk of osseous disease can be readily identified from initial staging scans utilising the TNM threshold of >T1N0M0. This should be supplemented by a clinical evaluation of bone pain. Given the high sensitivity of this predictive tool, there is no role for SAP measurements, despite their high specificity. At our institution we will be implementing this simple and objective method of risk stratification, to determine which patients with RCC warrant bone scintigraphy.
Nomenclature Fuhrman nuclear grade The most common method of nuclear grading in renal cell carcinoma. Originally proposed by
64
M.J. George et al.
Fuhrman et al.1 , it is based on the nuclear size and prominence of nucleoli. Grade 1: Nuclei round, uniform, approximately 10 microns; nucleoli inconspicuous or absent. Grade 2: Nuclei slightly irregular, approximately 15 microns; nucleoli evident. Grade 3: Nuclei very irregular, approximately 20 microns; nucleoli large and prominent. Grade 4: Nuclei bizarre and multilobated, 20 microns or greater, nucleoli prominent, chromatin clumped.
Conflicts of interest statement The authors of this article declare that there are no conflicts of interest.
References [1] Motzer RJ, Bander NH, Nanus DM. Renal cell carcinoma. N Engl J Med 1996;335:865—75. [2] Blacher E, Johnson DE, Haynie TP. Value of routine radionuclide bone scans in renal cell carcinoma. Urology 1985;26:432—4. [3] Rosen PR, Murphy KG. Bone Scintigraphy in the initial staging of patients with renal-cell carcinoma: concise communication. J Nucl Med 1984;25:289—91. [4] Swanson DA, Orovan WL, Johnson DE, Giacco G. Osseous metastases secondary to renal cell carcinoma. Urology 1981;18:556—61. [5] Althausen P, Althausen A, Jennings LC, Mankin HJ. Prognostic factors and surgical treatment of osseous metastases secondary to renal cell carcinoma. Cancer 1997;80:1103—9. [6] Ljungberg B, Hanbury DC, Kuczyk MA, Merseburger AS, Mulders PFA, Patard JJ, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502—10.
[7] Seaman E, Goluboff ET, Ross S, Sawczuk IS. Association of radionuclide bone scan and serum alkaline phosphatise in patients with metastatic renal cell carcinoma. Urology 1996;48:692—5. [8] Koga S, Tsuda S, Nishikido M, Ogawa Y, Hayashi K, Hayashi T, et al. The diagnostic value of bone scan in patients with renal cell carcinoma. J Urol 2001;166: 2126—8. [9] Shvarts O, Lam JS, Hyung KL, Han K, Figlin R, Belldegrun A. Eastern Cooperative Oncology Group Performance Status predicts bone metastasis in patients presenting with renal cell carcinoma: implication for preoperative bone scans. J Urol 2004;172:867—70. [10] Kim H, Cho NH, Kim D, Kwon YM, Kim EK, Rha SH, et al. Renal cell carcinoma in South Korea: a multicenter study. Hum Pathol 2004;35:1556—63. [11] Jung K, Lein M, Ringsdorf M, Roigas J, Schnorr D, Loening SA, et al. Diagnostic and prognostic validity of serum bone turnover markers in metastatic renal cell carcinoma. J Urol 2006;176:1326—31. [12] Bos SD, Piers DA, Mensink HJA. Routine bone scan and serum alkaline phosphatase for staging in patients with renal cell carcinoma is not cost-effective. Eur J Cancer 1995;31A:2422—3. [13] Guinan P, Sobin LH, Algaba F, Badellino F, Kameyama S, MacLennan G, et al. TNM staging of renal cell carcinoma, Workgroup No. 3 Union International Control Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80:992—3. [14] Chevelle JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003;27:612—24. [15] Patard J, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23:2763—71. [16] Ficarra V, Martignoni G, Maffei N, Brunelli M, Novara G, Zanolla L, et al. Original and reviewed nuclear grading according to the Fuhrman system: a multivariate analysis of 388 patients with conventional renal cell carcinoma. Cancer 2005;103:68—75.
Available online at www.sciencedirect.com
1 Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6(7):655—63.
ORIGINAL ARTICLE
The value of TNM tumour staging and serum alkaline phosphatase levels in predicting the presence of bone metastases in patients with renal cell carcinoma M.J. George a,b,∗, J. Buscombe a, M. Al-Akraa b a b
Department of Nuclear Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom Department of Urology, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom
Received 1 June 2009 ; received in revised form 22 December 2009; accepted 4 January 2010
KEYWORDS Renal cell carcinoma; RCC; Bone scintigraphy; Metastases
Summary Objectives: To determine if the TNM tumour staging and serum alkaline phosphatase levels (SAP) can be used to identify which patients with renal cell carcinoma (RCC) are at greatest risk of osseous metastases. Patients and methods: A retrospective review of patients with histologically proven RCC was conducted. All patients had initial CT or MRI staging scans of the chest and abdomen. Patients also underwent bone scintigraphy and all abnormal areas were further evaluated with either serial or collaborative imaging to determine their nature. Results: 91 patients including 66 men and 25 women, with a mean age of 61, were included in the study. The incidence of bone metastases was 17.6%. The incidence of bone metastases in T1-4 disease was 4%, 31.3%, 31.8% and 66.7%, respectively. Patients with >T1N0M0 disease, as defined by initial staging scans, accounted for 53% of the cohort and included all instances of proven osseous disease. Thus ‘>T1N0M0’ was 100% sensitive and 57.3% specific as a predictor of bone metastases. Conversely, a raised SAP (>129 U/L) was only 25% sensitive but had a specificity of 94.3%. Conclusions: Patients with >T1N0M0 staging should undergo bone scintigraphy. SAP is a far less sensitive predictor and its concurrent use is unwarranted. © 2010 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved.
∗ Corresponding author at: Department of Nuclear Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, United Kingdom. Tel.: +44 0 20 8203 4663/78 1382 0614; fax: +44 0 20 8518 3486. E-mail addresses: [email protected] (M.J. George), [email protected] (J. Buscombe), [email protected] (M. Al-Akraa).
1875-9742/$ — see front matter © 2010 British Association of Urological Surgeons. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bjmsu.2010.01.001
60
Introduction Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers [1]. The prevalence of bone metastases at presentation is reported to be between 5% and 34% [2—4] and it is important to identify these lesions given that their early treatment has been shown to improve ambulation, relieve pain and increase survival [5].Bone scintigraphy is currently the standard imaging modality for detecting bone metastases. Current policy at our institution is that all patients with a suspected diagnosis of RCC should have such a bone scan as part of their routine tumour staging. This contrasts to the 2007 European Association of Urology (EAU) guidelines, which state that ‘There is no role for routine bone scans in the standard clinical work-up of asymptomatic patients’ [6]. It recommends that bone scans only be done in ‘high-risk’ patients as defined by raised serum alkaline phosphatase (SAP) or bone pain [6]. However, the EAU guidelines are not without controversy. Although the clinical importance of bone pain is widely accepted [7—10], it’s prevalence amongst patients with proven osseous disease is as low as 35% [8]. In addition, there is an ongoing debate in the literature about the usefulness of SAP measurements in this setting [7,8,11,12]. Furthermore, it has been suggested by Koga et al. that the TNM classification, as defined by initial CT and MRI staging scans, can be used as a far more sensitive means of identifying those at risk of bone metastases [8]. Clearly, the most efficient use of resources would involve appropriately stratifying RCC patients, and using bone scintigraphy in a targeted fashion. Given this, and the discordance between the EAU guidance and much of the relevant literature, we evaluated both the TNM staging and serum alkaline phosphatase levels as predictors of osseous disease, to establish clear screening criteria for using bone scintigraphy in patients with RCC.
Materials and methods Patients with a confirmed histological diagnosis of RCC were identified by interrogating the hospital’s pathological database from 1/1/2001 to 31/12/2008. Patients with suspected RCC, but for whom no confirmatory histology was obtained were not included. The medical records of all identified patients, including relevant histology, radiology, blood tests and bone scan reports were subsequently retrospectively reviewed. Only patients with complete available data were included. It was
M.J. George et al. not possible to satisfactorily assess the presence or absence of bone pain retrospectively in this cohort, as there were no standardised means of collecting and recording this subjective data during the period under study.
Staging All included patients underwent CT or MRI initial staging scans (ISS) of the abdomen and thorax and subsequently underwent a bone scan. The tumours were staged based on imaging alone according to the modified TNM classification [13] as follows: T1a: tumour 4 cm or less and limited to the kidney, T1b: 4—7 cm and limited to the kidney, T2: greater than 7 cm and limited to the kidney, T3a: perinephric extension, T3b: extension into renal veins or vena cava below the diaphragm, T3c: extension into the vena cava above the diaphragm and T4: invasion through Gerota’s fascia. Lymph node involvement was classified as N0: no regional lymph node involvement and N1: metastasis to at least 1 regional lymph node. Distant metastatic involvement was classified as M0: no metastatic involvement and M1: at least one site of metastasis (including bone). SAP measurements were considered to be high when above >129 U/L (the upper limit of normal at our institution). Suspicious lesions identified on bone scan were further evaluated with either collaborative imaging such as plain radiographs, CT or MRI, and if these were inconclusive, they were re-imaged at a later date to determine if the lesion had progressed. Patients were considered to have osseous disease only once initially suspicious lesions were confirmed as malignant in this manner. The distant metastasis or ‘M’ component of the staging was based initially on the ISS alone and subsequently revised, with reference to the bone scan results, to give the final, definitive tumour stage.
Histology From the histology reports, Fuhrman nuclear grade, tumour size and type were obtained. Lymphadenectomy data were available but not used to revise the original imaging-based ‘N’ stage.
Evaluation of predictors of osseous disease Each element of the TNM staging, as defined by ISS, and SAP levels were evaluated as predictors of osseous disease, by calculating key measures such as their sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). These separate predictors were then combined to
TNM tumour staging and serum alkaline phosphatase levels
61
predominant type with 80 cases (88%), followed by chromophobe with 6 (7%), collecting-duct with 3 (3%) and papillary with 2 (2%). The Fuhrman nuclear grade was 1 in 15 cases (16%), 2 in 37 (41%), 3 in 27 (30%), 4 in 8 (9%) and unspecified in 4 (4%). The mean tumour size was 6.8 cm (range 1.5—16 cm). There was a trend between nuclear grade and tumour size (Fig. 1). This sequential enlargement was only statistically significant between grades 2 and 3 (p = 0.0473). Figure 1 Fuhrman nuclear grade v mean tumour size. The graph demonstrates a trend between nuclear grade and tumour size. This was statistically significant between grades 2 and 3 (p = 0.0473).
identify the most sensitive potential screening criteria. For categorical data, 2-tailed p values were calculated using either the 2 or Fisher’s exact test as appropriate, and the unpaired Student’s t-test was used for numerical data. Results were considered significant at p < 0.05 and highly significant at p < 0.01. Where required, 95% confidence intervals (95% CI) were calculated using the modified Wald method.
Tumour stage The tumour stage was T1a in 21 cases (23%), T1b in 29 (32%), T2 in 16 (18%), T3a in 8 (9%), T3b in 14 (15%) and T4 in 3 (3%) of cases. Lymph node stage was N0 in 76 cases (84%) and N1 in 15 (16%). The provisional distant metastases stage, based on ISS, was M0 in 65 cases (71%) and M1 in 26 (29%). The sites of distant metastases in the 26 patients with M1 disease were as follows: pulmonary (20), hepatic (5), bone (3), adrenal glands (3), brain (1), omentum (1) and skin (1). 7 patients had sites of metastasis in multiple organs identified by ISS.
Bone metastases
Results 124 patients with RCC were initially identified, however complete data were only available for 91, and therefore only these patients were included in the analysis. The mean age of this cohort was 61 years and there were 66 men (73%) and 25 women (27%).
Histology Histological diagnosis was based on a radical nephrectomy specimen in 76 cases (83%), partial nephrectomy in 8 (9%), and renal or metastatic biopsy in 7 (8%). Clear cell carcinoma was the most
Bone scintigraphy revealed suspicious lesions in 32 patients, 50% of which were proven to represent metastases. Therefore 16 patients (17.6%) were found to have osseous disease. Only 3 (19%) of these patients had been identified by ISS. Of the 16 patients, 3 did not have metastases in other organs and therefore required their staging to be revised from M0 to M1. Given this, the final staging was M0 in 62 cases (68%) and M1 in 29 (32%). 8 patients had multiple sites of bone metastases on their bone scan. The sites of bone metastasis were spine (7 patients), long bones (7 patients), ribs (3 patients), iliac crests (2 patients) and skull (1 patient).
Figure 2 Percentage of patients with bone metastasis for each initial tumour stage. The increase in the incidence of bone metastases from T1 to T2 disease was statistically significant (4% v 31.3% p = 0.002).
62 Table 1
M.J. George et al. Analysis of the predictors of osseous disease.
Number Sensitivity (%) Specificity (%) PPV (%) NPV (%) 2-tailed p-value
rSAP
>T1
>T2
N1
M1
8 (9%) 25 94.3 50 84.6 0.0363
41 (45%) 87.5 64 34.1 96 0.0002
25 (27%) 56.3 78.7 36 89.4 0.0107
15 (16%) 68.8 94.7 73.3 93.4 <0.0001
26 (29%) 81.2 82.7 50 95.4 <0.0001
The percentage of patients with bone metastases for each initial tumour stage is shown in Fig. 2. Of note is the marked and statistically significant increase in the incidence of bone metastases from T1 to T2 disease (4% v 31.3% p = 0.002) but no such increase from T2 to T3 disease (31.3% v 31.8%).
Predictors of osseous disease Table 1 illustrates the value of a raised SAP (‘rSAP’) and each of the separate components of the TNM staging system, in predicting the presence of osseous disease. Raised serum alkaline phosphatase The average SAP was 77.27 U/L (normal range 35—129 U/L). The average SAP for patients with proven osseous disease was significantly higher than those without: 98.75 U/L v 72.36 U/L (p = 0.0061). TNM classification All the separate components of the TNM classification were far more sensitive than rSAP. The use of tumour stage >T1 was the most sensitive (87.5%) and the presence of metastatic lymph nodes (N1) was the most specific predictor (94.7%). Combined screening criteria Table 2 illustrates how the various predictors may be used in combination to provide screening criteria with greater sensitivity. Most importantly, the table identifies 3 potential screening criteria with a sensitivity of 100%: ‘>T1M0’, ‘>T1N0M0’ and ‘>N0M0 or rSAP’.
Discussion The demographic and histological features of our cohort are in keeping with those described in the literature. 73% of patients were male, which compares to figures of 65—79% found by previous studies [7,8,11,12] and the average age of 61 is consistent with that quoted by several papers [8,9]. The proportion of each histological type of RCC was broadly
in keeping with figures published by Cheveille et al., who retrospectively reviewed the histology of over 2000 patients with RCC [14]. After complete staging, including bone scan, 32% of patients were found to have metastatic disease. This compares with figures of 30—37% quoted in the literature [8,9]. 17.6% (95% CI 11—26.7%) of patients were confirmed to have bone metastases. This is comparable to the two most recent, relevant studies, where the incidence was reported as 17% [8] and 14% [11]. The 50% positive predictive value of an initial bone scan is comparable with that quoted by Koga et al. (57%) [8] and Bos et al. (38%) [12].
Serum alkaline phosphatase The predictive value of SAP has been questioned, mainly on the grounds of its low sensitivity [8,9,12]. Indeed in our study, a raised SAP had a sensitivity of just 25%. This suggests that it is a poor independent predictor of osseous disease, which would miss the majority of cases. Despite this however, a raised SAP was found to have a relatively high specificity (94.3%) and PPV (50%), thus it may well be useful as part of a broader set of predictive criteria. In the context of the current EAU guidance [6], a raised SAP would indeed add value, as ‘bone pain’ also has a low sensitivity of just 35% [8].
Screening criteria The primary aim of this study was to establish clear screening criteria for using bone scintigraphy in patients with RCC. Table 2 illustrates that although several potential screening criteria offer sensitivities >90%, including that suggested by Koga et al.: ‘>T3aN0M0’ [8], there are only 3 with 100% sensitivity. Initially, it appears that the most attractive of these 3 criteria is ‘>N0M0 or rSAP’ as it is the most specific, and would incur scanning the fewest patients (37.4%). However, given that only 25% of patients with bone metastases have a raised SAP, it appears rather fortuitous that the single patient
TNM tumour staging and serum alkaline phosphatase levels Table 2
Analysis of combined screening criteria.
Number Sensitivity (%) Specificity (%) PPV (%) NPV (%) 2-tailed p-value a
63
>T1M0a
>T1N0
>N0M0
>N0M0 or rSAP
>T1N0 or rSAP
>T1N0M0
>T2N0M0
>T3aN0M0
46 (51%) 100 60 34.8 100 <0.0001
44 (48%) 87.5 60 31.8 95.7 0.0007
30 (33%) 93.8 80 50 98.4 <0.0001
34 (37%) 100 76 47 100 <0.0001
47 (52%) 87.5 56 29.8 95.5 0.0019
48 (53%) 100 57.3 33.3 100 <0.0001
40 (44%) 93.8 66.7 37.5 98 <0.0001
36 (40%) 93.8 72 41.7 98.2 <0.0001
‘>T1M0’ refers to >T1 or >M0. This applies to the other TNM combinations used in this table.
with N0M0 disease who had bone metastases also had a raised SAP. Thus, it appears likely that in a larger cohort, there will be patients with N0M0 disease with normal SAP levels who have bony deposits. ‘>T1M0’, appears to be a more reliable criterion as both components have a sensitivity >80%. The addition of ‘>T1’ component is also important as there was a marked and statistically significant increase in the incidence of bone metastases from T1 to T2 disease (4% v 31.3% p = 0.002), which is likely a consequence of T2 tumours being larger, and thus of a higher grade with greater metastatic potential [14—16]. It is debatable as to whether ‘>T1N0M0’ would be a better screening criteria, as both specificity and PPV go down marginally when the ‘N’ component is added. However, although there were no cases encountered in this study, it is feasible a patient may present with T1N1M0 disease, and it is clear that they would be at high risk of bone metastases as N1 caries a PPV of 73.3%. Thus of the 3 screening criteria which yielded 100% sensitivity in this study, the most robust appears to be ‘>T1N0M0’. We would therefore recommend the use of this screening criterion when selecting patients with RCC for bone scintigraphy.
Implications of employing the ‘>T1N0M0’ screening criterion In employing the ‘>T1N0M0’ criterion, roughly half (53%) of all patients would need to have a bone scan. A third of these will be found to have osseous disease. This is twice as efficient as scanning all patients with RCC (PPV 33.3% v 17.6%) and would thus represent a financial saving to the health system and be of benefit to those patients for whom a bone scan is unnecessary. This criterion is simple to employ, and negates the need to perform SAP levels on patients. Although a clinical assessment of bone pain is not a necessary component of this screening criterion, clinical suspicion of osseous involvement
can be highly specific [7—10] and therefore must be investigated thoroughly.
Study limitations This study’s main limitation is that of the 124 patients with RCC initially identified, 27% of patients were not included as they did not have a bone scan. In some instances these scans were done at referring institutions and were unavailable, in others, the patient did not, or could not attend for their scan and in a small number the bone scan was not included in the staging process as required. An analysis of these patients’ other staging scans and histology demonstrated a similar prevalence of each T-stage and histological type to those that had a bone scan and thus it is unlikely the exclusion of these patients has significantly skewed our data.
Conclusions Patients with RCC have a high prevalence of metastases at presentation, and the second most common site is the bones. Bone scintigraphy may be used in a targeted fashion to identify bone lesions in highrisk patients. The patients at high risk of osseous disease can be readily identified from initial staging scans utilising the TNM threshold of >T1N0M0. This should be supplemented by a clinical evaluation of bone pain. Given the high sensitivity of this predictive tool, there is no role for SAP measurements, despite their high specificity. At our institution we will be implementing this simple and objective method of risk stratification, to determine which patients with RCC warrant bone scintigraphy.
Nomenclature Fuhrman nuclear grade The most common method of nuclear grading in renal cell carcinoma. Originally proposed by
64
M.J. George et al.
Fuhrman et al.1 , it is based on the nuclear size and prominence of nucleoli. Grade 1: Nuclei round, uniform, approximately 10 microns; nucleoli inconspicuous or absent. Grade 2: Nuclei slightly irregular, approximately 15 microns; nucleoli evident. Grade 3: Nuclei very irregular, approximately 20 microns; nucleoli large and prominent. Grade 4: Nuclei bizarre and multilobated, 20 microns or greater, nucleoli prominent, chromatin clumped.
Conflicts of interest statement The authors of this article declare that there are no conflicts of interest.
References [1] Motzer RJ, Bander NH, Nanus DM. Renal cell carcinoma. N Engl J Med 1996;335:865—75. [2] Blacher E, Johnson DE, Haynie TP. Value of routine radionuclide bone scans in renal cell carcinoma. Urology 1985;26:432—4. [3] Rosen PR, Murphy KG. Bone Scintigraphy in the initial staging of patients with renal-cell carcinoma: concise communication. J Nucl Med 1984;25:289—91. [4] Swanson DA, Orovan WL, Johnson DE, Giacco G. Osseous metastases secondary to renal cell carcinoma. Urology 1981;18:556—61. [5] Althausen P, Althausen A, Jennings LC, Mankin HJ. Prognostic factors and surgical treatment of osseous metastases secondary to renal cell carcinoma. Cancer 1997;80:1103—9. [6] Ljungberg B, Hanbury DC, Kuczyk MA, Merseburger AS, Mulders PFA, Patard JJ, et al. Renal cell carcinoma guideline. Eur Urol 2007;51:1502—10.
[7] Seaman E, Goluboff ET, Ross S, Sawczuk IS. Association of radionuclide bone scan and serum alkaline phosphatise in patients with metastatic renal cell carcinoma. Urology 1996;48:692—5. [8] Koga S, Tsuda S, Nishikido M, Ogawa Y, Hayashi K, Hayashi T, et al. The diagnostic value of bone scan in patients with renal cell carcinoma. J Urol 2001;166: 2126—8. [9] Shvarts O, Lam JS, Hyung KL, Han K, Figlin R, Belldegrun A. Eastern Cooperative Oncology Group Performance Status predicts bone metastasis in patients presenting with renal cell carcinoma: implication for preoperative bone scans. J Urol 2004;172:867—70. [10] Kim H, Cho NH, Kim D, Kwon YM, Kim EK, Rha SH, et al. Renal cell carcinoma in South Korea: a multicenter study. Hum Pathol 2004;35:1556—63. [11] Jung K, Lein M, Ringsdorf M, Roigas J, Schnorr D, Loening SA, et al. Diagnostic and prognostic validity of serum bone turnover markers in metastatic renal cell carcinoma. J Urol 2006;176:1326—31. [12] Bos SD, Piers DA, Mensink HJA. Routine bone scan and serum alkaline phosphatase for staging in patients with renal cell carcinoma is not cost-effective. Eur J Cancer 1995;31A:2422—3. [13] Guinan P, Sobin LH, Algaba F, Badellino F, Kameyama S, MacLennan G, et al. TNM staging of renal cell carcinoma, Workgroup No. 3 Union International Control Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80:992—3. [14] Chevelle JC, Lohse CM, Zincke H, Weaver AL, Blute ML. Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol 2003;27:612—24. [15] Patard J, Leray E, Rioux-Leclercq N, Cindolo L, Ficarra V, Zisman A, et al. Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience. J Clin Oncol 2005;23:2763—71. [16] Ficarra V, Martignoni G, Maffei N, Brunelli M, Novara G, Zanolla L, et al. Original and reviewed nuclear grading according to the Fuhrman system: a multivariate analysis of 388 patients with conventional renal cell carcinoma. Cancer 2005;103:68—75.
Available online at www.sciencedirect.com
1 Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6(7):655—63.