Comparison between solitary and multiple skeletal metastatic lesions of breast cancer patients

M. Koizumi1,+, M. Yoshimoto2, F. Kasumi2 and E. Ogata3

Departments of 1 Nuclear Medicine, 2 Breast Surgery and 3 Internal Medicine, Cancer Institute Hospital, Tokyo, Japan

Received 4 November 2002; revised 22 April 2003; accepted 22 April 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Breast cancer has been the subject of many recent studies because it is a significant cause of death in women. This study was performed to clarify whether solitary skeletal metastasis has clinical significance compared with multiple skeletal metastasis.

Patients and methods:

Seven hundred and three patients who developed metastatic bone lesions up to September 2002 after beginning treatment for breast cancer from 1988 to 1998 were included. The lesions were classified first as solitary or multiple based on bone scan results and then according to anatomical distribution. Next, solitary-to-multiple conversion was investigated in patients with solitary skeletal metastasis. Then factors related to solitary or multiple skeletal metastasis were analyzed. The prognosis of skeletal metastasis was compared between patients with solitary or multiple metastatic bone lesions. A Cox proportional hazards model was used to test whether solitary skeletal metastasis compared with multiple skeletal metastasis was an independent factor of survival.

Results:

Two hundred and eighty-nine patients (41%) had solitary skeletal metastasis and 414 patients (59%) showed multiple skeletal metastasis. The sternum was a frequent site for solitary skeletal metastasis (98 of 289, 34%), while other skeletal sites were more frequent in patients with multiple metastatic bone lesions (P <0.001). Solitary sternal metastatic lesions remained solitary longer than solitary metastatic bone lesions to places other than the sternum (P <0.001), but did not lengthen patient survival times (P = 0.871). The factors related to solitary skeletal metastasis are TNM stage (tumor–node–metastasis) and histology. The patients with earlier stage and favorable histology tend to have solitary skeletal metastasis. The patients with solitary skeletal metastasis lived longer than those with multiple metastatic bone lesions (P <0.001). Multivariate analysis revealed that a solitary metastatic bone lesion (P = 0.002) is an independent favorable prognostic factor in patients with skeletal metastasis.

Conclusions:

Solitary skeletal metastasis has a different anatomical distribution and is an independent prognostic factor in patients with skeletal metastasis.

Key words: breast cancer, skeletal metastasis, solitary and multiple, sternum


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Breast cancer has been the subject of many recent studies because it is a significant cause of death in women. Metastasis of breast cancer to bone is a common complication, observed in up to 70% of patients during post-mortem examination [1, 2]. Consequently, new therapies are actively being developed to treat osseous metastasis [3, 4]. Kwai et al. [5] found a high prevalence of isolated sternal lesions in patients with metastatic breast cancer. Many of these lesions were caused by local tumor invasion from either the primary site or adjacent lymph nodes. A subsequent survey of distribution of metastatic bone disease in breast cancer revealed that a solitary lesion is not uncommon in breast cancer [6]. Since metastatic breast cancer confined to the skeletal system is a common complication that can be diagnosed relatively easily, is highly responsive to treatment and whose treatment is frequently associated with extended patient survival [7, 8], identification of these patients is very important to clinicians.

An analysis of metastatic bone lesions in patients with breast cancer was performed to determine whether solitary lesions have distinctive characteristics compared with multiple lesions. Solitary and multiple skeletal metastases were compared with their anatomical distribution and related risk factors. Then, the difference between solitary and multiple skeletal metastasis was analyzed to determine whether it might be an independent prognostic factor.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Breast cancer patients treated between January 1988 and December 1998 at the Cancer Institute Hospital, Tokyo, Japan were included in the study. During this period, a total of 5538 breast cancer patients were treated; of all patients under treatment, 703 had developed metastatic bone lesions by September 2002. One hundred and twenty patients (120 of 5538; 2.17%) had bone lesions at the time of initial treatment. Other patients developed skeletal metastasis during the follow-up period until September 2002. Bone scanning was performed at the time of initial treatment to stage the cancer and once a year thereafter. Bone scanning was also conducted when the patient’s physician suspected skeletal metastasis. When evidence of metastasis to other tissues was detected, a bone scan was performed to determine the extent of metastasis. Patients received a physical examination every 3 months for the first 2 years and every 6 months thereafter for 10 years after surgery.

Skeletal metastasis was surveyed by bone scan and confirmed by other imaging methods. Bone scan was performed 2.5–4.0 h after injection of 740 MBq of hydroxymethylene diphosphonate or methylene diphosphonate Tc 99m. Scanning was performed using the whole-body moving camera technique (anterior and posterior) and the static image technique (anterior skull, anterior chest oblique and additional views at the physician’s requests). However, due to its low specificity, if a bone scan was positive or equivocal for skeletal metastasis, other imaging techniques including X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) scans were used to confirm the diagnosis [9]. When other imaging modalities could not determine skeletal metastasis, the diagnosis was made by follow-up studies or biopsy. All 703 patients included in this study had clinically confirmed skeletal metastasis, as determined by the agreement of at least two different imaging or diagnostic techniques.

Data from the 703 patients with skeletal metastasis were analyzed as follows: (i) Skeletal metastasis was first classified as solitary or multiple at the initial diagnosis of skeletal metastasis. The anatomical distribution of skeletal metastasis was determined. (ii) The time of conversion from solitary metastatic bone lesions to multiple lesions was measured (time from the solitary date to the first multiple date in bone scan). (iii) Relationships to skeletal metastatic state (solitary and multiple) among patient demographic data (age, menstrual status), tumor characteristics (tumor size, nodal status, histology and hormone receptor status), other site metastasis and time to skeletal metastasis were analyzed. (iv) Survival analysis after skeletal metastasis development was performed. Cause-specific death was used as an end point.

TNM (tumor–node–metastasis) classification was performed according to International Union Against Cancer criteria [10] as stages I, II, III and IV. Histological classification was done according to Japanese Breast Cancer Society criteria [11, 12] as papillotubular cancer, solid tubular cancer, scirrhous cancer, invasive lobular cancer and other cancer. If the estrogen receptor (ER) concentration and progesterone receptor (PgR) concentration were >=10 fmol/mg total protein, the results were regarded as positive. Other site metastasis is divided as follows: (i) first recurrence is restricted to bone, (ii) first recurrence is not only bone but also another site, and (iii) first recurrence is another site.

Statistical analyses are carried out using an unpaired t-test and Fisher’s exact test. A Kaplan–Meier estimate with a log-rank test was used to evaluate conversion to multiple metastatic bone lesions and comparison of survival between solitary and multiple osseous metastasis. A logistic regression analysis was used to analyze the factors that related to solitary and multiple skeletal metastasis. A Cox proportional hazards analysis was used in the evaluation of prognostic factors. All P values were two-tailed. P <0.05 was taken to be significant, and the 95% confidence interval (CI) for such results was calculated.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Solitary and multiple skeletal metastasis
Of 703 patients with metastatic bone lesions, 289 (41%) had a solitary bone lesions and 414 (59%) had multiple bone lesions at the time of diagnosis. For 206 patients with a solitary bone lesion, skeletal metastasis was the first evidence of recurrence (206 of 289; 71%), and for 291 patients with multiple bone lesions, bone metastasis was the first evidence of recurrence (291 of 414; 70%). For patients whose bone metastasis was the first recurrence, patients whose metastasis was restricted only to bone at initial diagnosis of osseous metastasis were 169 for the solitary metastatic bone lesion group (169 of 206; 82%) and 230 for the multiple metastatic bone lesion group (230 of 291; 79%).

Anatomical distribution of skeletal metastasis.
The whole-body distribution of metastatic bone lesions is shown in Table 1. Distribution of solitary metastatic bone lesions is different from that of multiple metastatic bone lesions. Metastasis to sternum occurred most frequently (34%, P <0.001, Fisher’s exact test) in patients with a solitary metastatic bone lesion, while metastasis to other skeletal sites occurred more frequently in patients with multiple metastatic bone lesions.


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Table 1. Sites of solitary and multiple skeletal metastases in patients with breast cancer
 
Time from breast cancer diagnosis to the development of skeletal metastasis
The time from breast cancer diagnosis to the development of first metastatic bone lesions in 703 patients was examined. The median period was 1130 days for solitary metastatic bone lesion and 992 days for multiple metastatic bone lesions, but there was no significant difference (P = 0.06, unpaired t-test).

Conversion of solitary-to-multiple metastatic bone lesions
Patients with solitary bone metastasis were studied to determine incidence of multiple conversion (solitary-to-multiple metastatic bone lesion development). Of 289 patients with a solitary metastatic bone lesion, 161 developed multiple metastatic bone lesions. Patients with a solitary sternal lesion showed a lower conversion that those with a solitary bone lesion at other sites (Figure 1; Table 2), (P <0.001, Kaplan–Meier with log-rank test).



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Figure 1. The solitary remaining ratio of solitary sternum metastasis (open circle, upper line) and solitary skeletal metastasis to sites other than sternum (+, lower line). The symbols indicate evented or multiple-converted patients. There is a statistically significant difference in multiple conversion (P <0.0001, log-rank test) between the sternum and other bone metastatic sites.

 

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Table 2. Patients at risk
 
Comparison of skeletal metastasis (solitary versus multiple lesions) with patient demographics and tumor characteristics
Table 3 shows the relationship of solitary or multiple metastatic bone lesions with patient demographics, tumor characteristics, first metastasis organs (bone only, bone and other, and other) and time to skeletal metastasis (or skeletal metastasis-free interval). Table 4 shows a logistic regression analysis with uni- and multivariate analysis. Although a significant difference is shown in TNM and histology, other factors are not significant. When TNM stage is earlier (I or II) and histology is favorable (papillotubular or solid tubular cancer), solitary skeletal metastasis is more likely (odds ratio is 1.50–1.84).


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Table 3. Patient demographics and tumor characteristics for the study population, compared with solitary and multiple skeletal metastases
 

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Table 4. Comparison of various factors regarding solitary and multiple skeletal metastases
 
Survival analysis after developing skeletal metastasis
Figure 2 (and Table 5) shows survival time estimates after the development of solitary (sternal metastasis and osseous metastasis at other sites) and multiple metastatic bone lesions. Because the mechanism of development of a solitary metastatic sternal lesion is thought to be a mixture of bone infiltration from parasternal lymph nodes and hematogenous metastasis, subgroups (sternal and other) of metastatic solitary bone lesions were made. However, there was no significant difference between solitary sternal and other solitary lesions (P = 0.872, log-rank test). Patients with solitary metastatic bone lesions had longer survival times than those with multiple metastatic bone lesions (solitary versus multiple, P <0.001, log-rank test).



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Figure 2. Survival curves of solitary sternal metastasis patients (open circle), solitary metastatic bone lesions other than sternum patients (X) and multiple metastatic bone lesion patients (+, the lowest line). The symbols indicate evented or cause-specifically dead patients. The survival of patients with a solitary osseous metastasis is significantly better than that of patients with multiple osseous metastasis (solitary sternum versus multiple P <0.0001, and solitary other versus multiple P <0.0001). However, there was no significant difference in survival between solitary sternal and solitary metastatic lesions other than sternum groups (P = 0.872).

 

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Table 5. Patients at risk
 
The probability of survival after developing metastatic bone lesions was further assessed according to available clinical and tumor characteristics using a Cox proportional hazards model. As the survival of solitary sternal and other lesions was not different, patients with solitary bone lesions was analyzed regardless of the anatomical sites. The variables tested, along with their univariate and multivariate significance, are shown in Table 6. The ER status, PgR status, disease-free interval (bone metastasis-free interval), first metastasis organs and the type of bone lesions (solitary versus multiple) were the significant factors determining length of survival. Patients with positive ER and PgR show longer survival. The longer the disease-free interval was, the better the prognosis. Patients with a solitary metastatic bone lesion had a better prognosis than those with multiple metastatic bone lesions. The other variables tested (age, menstrual status, TNM, histology and hormone receptors status) did not significantly affect the survival time. It is of note that solitary skeletal metastasis is an independent prognostic factor compared with multiple skeletal metastasis by multivariate analysis.


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Table 6. Comparison of prognosis of patients with skeletal metastasis to various factors: analysis of a Cox proportional hazard model
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The routes of skeletal metastasis are direct extension or invasion, lymphatic spread, hematogenous dissemination and intraspinal spread. Skeletal metastases of breast cancer will mainly occur from lymphatic spread and hematogenous dissemination. Two potential vascular routes are possible for hematogenous dissemination [13]. One is the arterial system and the other the venous system. The mechanism or a route of venous system dissemination to develop skeletal metastasis was proposed by Batson [14]. He insisted that owing to the extensive communications of this venous system and to the variability of the direction of this blood flow, tumors arising in many sites release cells that could be deposited anywhere along the course of vessels, including the skeleton, even in the absence of pulmonary and hepatic metastasis. A part of the sternal metastasis could occur via lymphatic vessels to parasternal lymph node [13]. Indeed, our present results of site distribution and solitary-to-multiple conversion support the hypothesis. The prognosis of patients with solitary metastatic bone lesions, especially sternal metastasis, may be different from that of multiple skeletal metastasis, because sternal metastasis is caused by local tumor invasion from either the primary site or adjacent lymph nodes [5].

Data collected in this study show that solitary metastatic bone lesions account for 41% of initially diagnosed metastatic bone lesions. This is a higher incidence rate than previously reported [6]. Boxer et al. [6] reported that solitary lesions constituted 21% of metastatic bone lesions from breast cancer initial diagnosis and also stated that their figure was higher than previously reported. Our data show a higher figure than that of Boxer et al. The difference may be due to the frequent follow-up used in the present study, which may be more frequent than current clinical procedure in breast cancer. Our follow-up plan of bone scans after initial breast cancer treatment is principally once a year. Another possibility for the high detection incidence of solitary metastatic bone lesions in this study is the use of improved gamma camera techniques, both improved equipment and scanning techniques, and the use of other imaging techniques, including MRI, to confirm diagnosis. These technical improvements may have contributed to both the early detection of skeletal metastasis and the high incidence of solitary metastatic bone lesions detected in this study.

The incidence of sternal metastasis founded in this study was 34% (98 of 289) of all solitary metastatic bone lesions. This figure is also more frequent than previously reported [5, 6]. The bone scanning procedure using an anterior oblique view of the thorax may have contributed to this difference. Indeed, many metastatic sternal lesions, normally difficult to diagnose from an anterior-only bone scan image, were readily detected by the anterior oblique view of the thorax used in this study. Additionally, CT, MRI or both techniques confirmed all sternal lesions in this study. As the prognosis of patients with solitary metastatic bone lesions is better than that of patients with multiple metastatic bone lesions, and the incidence of solitary sternal metastatic bone lesions is high, the anterior oblique bone scan view should be a standard measurement taken in assessing breast cancer patients.

Data were analyzed using the hypothesis that prognosis of patients with solitary sternal lesions might be different from that of solitary metastatic bone lesions at sites other than the sternum. This is because breast cancer patients often develop isolated sternal lesions, many of which are caused by local tumor invasion from adjacent parasternal lymph nodes metastasis [5]. Analysis revealed that earlier TNM stage and favorable histology were significantly predictable factors for development of solitary metastatic bone lesions. Additionally, although the multiple conversion rate was lower in patients with solitary sternal metastasis than in patients with a solitary bone lesion at other sites, there was no difference in survival time between the two groups. Patients with a solitary metastatic bone lesion, regardless of the site, had better prognosis compared with patients with multiple metastatic bone lesions at initial appearance of skeletal metastasis. This may result from a leading effect (early diagnosis effect). However, time from initial diagnosis to development of skeletal metastasis was longer in patients with a solitary metastatic bone lesion. Furthermore, a solitary metastatic bone lesion often resolves during treatment, and complete remission is not unusual. The reason for these differences may be due to biological difference; that is, patients who develop solitary skeletal metastasis have favorable biological factors compared with those who develop multiple skeletal metastasis at initial osseous metastatic events. The patients who developed solitary osseous metastasis received chemotherapy, hormone therapy, radiotherapy, or the combination of these therapies in the present study. The early commencement of therapy may contribute the prolonged survival of the patients with solitary bone lesion.

Coleman et al. [8] reported that important prognostic factors for survival after the development of osseous metastasis in breast cancer were the histopathological grade of the primary tumor, ER status, presence of skeletal metastasis at initial breast cancer diagnosis, disease-free interval and age. In the present study, multivariable Cox proportional hazards analysis showed that ER status, PgR status, disease-free interval (bone metastasis-free interval) first metastasis organs and the type of bone lesions (solitary versus multiple) were independent prognostic factors. Patients with a solitary metastatic bone lesion, who had longer disease-free interval and who had positive hormone receptor status had a better prognosis. Age, TNM stage and histology did not affect survival after the development of skeletal metastasis. Consequently, diagnosing solitary metastatic bone lesions and starting treatment early increases the survival of breast cancer patients.

Summary
Skeletal metastasis was analyzed in a cohort of breast cancer patients treated at the Cancer Institute Hospital, in Tokyo, Japan. Seven hundred and three patients undergoing treatment of breast cancer developed metastatic bone lesions. Solitary metastatic bone lesions were found in 289 patients (41%) and multiple metastatic bone lesions in 414 (59%). Metastasis to the sternum was more frequent in patients with a solitary metastatic bone lesion compared with those with multiple metastatic bone lesions. The prognosis of patients with a solitary metastatic bone lesion was better than that of patients with multiple metastatic bone lesions. Although patients with sternal metastasis remained with a solitary lesion longer than patients with solitary metastatic lesions at other sites, no significant difference in survival was detectable between patients with solitary sternal metastasis and patients with a solitary metastatic bone lesion at sites other than the sternum. Multivariate analysis revealed that a solitary metastatic bone lesion is an independent prognostic factor in patients who developed skeletal metastasis.


    Acknowledgements
 
The authors thank E. Nomura, Y. Yamada and T. Takiguchi for their excellent work in carrying out the bone scintigraphy.


    Footnotes
 
+ Correspondence to: Dr M. Koizumi, Department of Nuclear Medicine, Cancer Institute Hospital, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. Tel: +81-3-3918-0111; Fax: +81-3-3918-0167; E-mail: mitsuru{at}jfcr.or.jp Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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6. Boxer DI, Todd CE, Coleman R, Fogelman I. Bone secondaries in breast cancer: the solitary metastasis. J Nucl Med 1989; 30: 1318–1320.[Abstract]

7. Sherry MM, Greco FA, Johnson DH, Hainsworth JD. Metastatic breast cancer confined to skeletal system. An indolent disease. Am J Med 1986; 81: 381–386.[CrossRef][ISI][Medline]

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9. Krasnow AZ, Hellman RS, Timins ME et al. Diagnostic bone scanning in oncology. Semin Nucl Med 1997; 27: 107–141.[ISI][Medline]

10. Sobin LH, Witterkind CH (eds). International Union Against Cancer. TNM Classification of Malignant Tumours, 5th edition (Japanese edition). Tokyo, Japan: Kinbara 1997.

11. The Japanese Breast Cancer Society. General Rules for Clinical and Pathological Recording of Breast Cancer, 13th edition. Tokyo, Japan: Kinbara 1998.

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13. Resnick D, Niwayama G. Skeletal metastases. In Resnick D (ed): Diagnosis of Bone and Joint Disorders, 3rd edition. Philadelphia, PA: Saunders 1995; 3991–4064.

14. Batson CV. The function of vertebral veins and their role in the spread of metastases. Ann Surg 1940; 112: 138–149.





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