Research Article

Reappraisal of Bone Scintigraphy and Computed Tomography Data in Patients with Metastatic Prostate Cancer: Initial Appearance of Bone Metastasis between the Staging and Follow-up Periods

Koizumi M*, Koyama M, Terauchi T, Motegi K, Fukai S, Umeda T, Miyaji N and Makino T
Department of Nuclear Medicine, Cancer Institute Hospital, Japan


*Corresponding author: Mitsuru Koizumi, Department of Nuclear Medicine, Cancer Institute Hospital, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan


Published: 11 May, 2016
Cite this article as: Koizumi M, Koyama M, Terauchi T, Motegi K, Fukai S, Umeda T, et al. Reappraisal of Bone Scintigraphy and Computed Tomography Data in Patients with Metastatic Prostate Cancer: Initial Appearance of Bone Metastasis between the Staging and Follow-up Periods. Remed Open Access. 2016; 1: 1003.

Abstract

Objective: To compare bone scintigraphy (BS) and computed tomography (CT) data between the staging and follow-up periods, clarify the differences in the characteristics of initial skeletal metastasis from prostate cancer, and reappraise the appearance of skeletal metastasis.
Patients and Methods: Initial presentation on BS and CT wasanalysed in 110 patients with bonemetastaticprostate cancer. BS data were classified according to the extent of disease (EOD) and visual uptake grade. CT data were grouped as follows: osteoblastic (dense, ground glass, miliary, and blastic mixed), osteolytic, mixed lytic and blastic, and invisible. These findings were compared between the staging and follow-up periods. Skeletal metastatic sites were analysed in patients with a few metastatic sites (EOD=I). The appearance of skeletal metastasis was evaluated by comparing CT patterns and BS uptake.
Results: Skeletal metastasis from prostate cancer during the follow-up period tended to have a lower EOD, denser appearance on CT, and lower BS uptake than that during the staging work-up. The skeletal metastatic distribution was not different between the staging and follow-up periods in patients with EOD=I. The distribution of the CT appearance was 67.3% (74/110) osteoblastic, 22.7% (25/110) osteolytic component, and 10.0% (11/110) invisible. A dense CT appearance tended to have lower BS uptake than did the ground glass and blastic mixed CT patterns.
Conclusion: Skeletal metastasis from prostate cancer during the follow-up period tended to have a lower EOD, denser appearance on CT, and lower BS uptake than that during the staging workup. The CT appearance was variable; the blastic type was predominant, but osteolytic and invisible lesions were not rare.

Keywords: Prostate cancer; Skeletal metastasis; Bone scintigraphy; Computed tomography

Introduction

Prostate cancer is the most common solid cancer in men in the US [1] and the third most common in Japan, and its incidence is rapidly increasing [2]. Screening by prostate specific antigen has resulted in a significant stage migration to earlier stages in patients with prostate cancer [3]. Recent advances in imaging modalities have highlighted the utility of positron emission tomography (PET), such as NaF and magnetic resonance imaging, which have improved the accuracy of diagnosis of skeletal metastasis [4-8]. However, bone scintigraphy (BS) and computed tomography (CT) are the modalities of choice for the diagnosis of skeletal metastasis in patients with prostate cancer in routine clinical practice.
Skeletal metastases from prostate cancer are usually osteoblastic in contrast to those from other cancers, which are mostly osteolytic [9]. Skeletal metastasis is believed to originate from bone marrow metastasis [10-12]. Although skeletal metastases from prostate cancer are mostly osteoblastic, there is extensive evidence showing the importance of osteoclastogenesis in skeletal metastasis from prostate cancer [13-18]. Keller and Brown [14] proposed that when prostate cancer cells metastasize to bone, they initially induce bone resorption. As bone is broken down, the extracellular matrix releases a variety of growth factors that act in a paracrine fashion on prostate cancer cells and diminish their ability to induce osteoclastogenesis, while promoting their ability to grow and induce osteoblastic activity. Indeed, systemic bone metabolic markers of both bone formation and bone resorption are increased in patients with bone-metastatic prostate cancer [19]. Recently developed antiosteolytic therapies, such as bisphosphonates and the anti-RANKL antibody, are effective for the treatment of skeletal metastasis from prostate cancer [20,21].
We questioned whether there is any difference in initial skeletal metastasis from prostate cancer between the staging and followup periods. Therefore, the appearance of metastases on BS and CT was investigated and compared between the staging and follow-up periods. We also reappraised the appearance of skeletal metastasis from prostate cancer by comparing the CT patterns and BS uptake grades.

Figure 1

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Figure 1
Figure 1: Bone scintigraphic uptake patterns are shown. Faint lesion uptake is shown in the right iliac wing (1-a), usual lesion uptake is shown at the left ilio-sacral site (1-b), and intense lesion uptake is shown at the ilio-sacral site (c).

Patients and Methods

Patients
From February 2013 to February 2016, consecutive patients with histologically proven prostate cancer who showed typical or suspected skeletal metastasis on BS were analysed. These patients were reviewed regarding the presence of skeletal metastasis, and both BS and CT scans of the osseous metastatic sites were performed at the time of the first diagnosis of skeletal metastasis. The diagnosis of skeletal metastasis was established by agreement of at least two modalities, follow-up studies, or biopsy.
Eligible patients had a diagnosis of skeletal metastasis and the interval between the BS and CT scans was within 1month.These patients were further divided into the staging period and followup period after initial therapy. The follow-up period was further divided into non-castration-resistant prostate cancer (non-CRPC) or castration-resistant prostate cancer (CRPC). This retrospective study was approved by the local institutional review board.
Bone scintigraphy
BS was performed at about 3 hours after the injection of 99mTcmethylene diphosphonate or hydroxymethylene diphosphonate. After obtaining anterior and posterior whole-body scans, local images including the pelvic axial view were acquired. Patients with probable and suspected metastasis on BS were selected. The bone metastatic burden of these patients was scored according to the Solo way's extent of disease (EOD) classification [22]. The intensity of skeletal metastatic uptake was visually graded as faint, usual, or intense on whole-body images. Figure 1 shows the BS uptake patterns; faint uptake was a visually weak hot spot, intense uptake was very intense uptake that could be intense in both the anterior and posterior views, and usual uptake ranges from faint to intense. This visual classification was independently performed by two radiologist-nuclear physicians, and discordant cases were decided through discussion.
Computed tomography
CT scans were performed with a 2-mm thickness and a 5-mm interval. The usual morphological classification of skeletal metastasis was osteoblastic, osteolytic, mixed osteoblastic and osteolytic, and intertrabecular (invisible on CT). We used the detailed CT classification proposed by Vargas et al. [23], which is based on the sub-classification of osteoblastic skeletal metastasis. CT bone lesions were classified as follows: a) osteoblastic dense; b) osteoblastic ground glass (GG); c) osteoblastic miliary; d) osteoblastic mixed (mixture of osteoblastic subtypes, mainly GG and dense); e) osteolytic; f) mixed osteolytic and osteoblastic; and g) invisible (bone marrow metastasis). CT attenuation of bone lesions was measured: dense was defined as >500 HU and G Gas <500 HU (mostly 200–300 HU). Figure 2 and 3 show the various morphologic lesion patterns on CT scans. This classification was independently performed by two radiologistnuclear physicians, and discordant cases were decided through discussion.
Data analysis
Data analysis was performed as follows:

  1. EOD was investigated as a function of the diagnostic setting (staging or follow-up). Patients during the follow-up period were further divided into non-CRPC and CRPC.
  2. The skeletal metastatic site or distribution was examined in patients with a low number of metastases (patients with EOD=I).
  3. The CT appearance was examined as a function of the diagnostic setting (staging or follow-up).
  4. BS visual uptake grades were compared with CT subtypes and diagnostic settings.
  5. Temporal changes in the CT appearance were examined. CT changes were compared between the initial study and later studies.

Statistical analysis using Fisher's exact test for contingency tables was performed. Two-sided P values of <0.05 were considered statistically significant. IBM SPSS version 23 was used for all statistical analyses.

Figure 2

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Figure 2
Representative examples of different CT morphologies of osteoblastic patterns are shown. (a) Osteoblastic dense (left ilium), (b) osteoblastic GG (left ilium), (c) osteoblasticmiliary (thoracic vertebra), and (d) osteoblastic mixed (right ilium acetabular joint, dense; and left ilium acetabular joint, GG and mixture of various osteoblastic patterns).

Figure 3

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Figure 3
Representative examples of different CT morphologies of (a) osteolytic pattern (left ilium), (b) mixed osteolysis and osteoblastic pattern (lumbar vertebra), and (c) invisible pattern are shown. (d) On a later CT scan of this patient with an invisible lesion, the osteoblastic lesion is obvious.

Table 1

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Table 1
Diagnostic situations (staging or follow-up) and skeletal metastasis extent (EOD).

Results

In total, 136 prostate cancer patients with typical or suspected skeletal metastasis on BS were evaluated. Of these, 12 patients were negative for skeletal metastasis, seven patients did not undergo a CT study within 1 month, and seven patients received therapies for skeletal metastasis at previous hospitals. These 26 patients were excluded from the study; therefore, 110 patients were eligible for the present study. All patients were male, and the mean age was 70.5 years (standard deviation, 8.8; range, 39–91 years).
As shown in Table 1, 63 patients were diagnosed with skeletal metastases during staging procedures, and 47 patients were diagnosed during the follow-up period. The EOD was significantly lower in patients during the follow-up period (P= 0.002).
Table 2 shows the skeletal metastatic sites in patients with EOD I (≤5 lesions). There was no significant difference in the distribution of metastases between the patients in the staging and follow-up periods (P=0.621). Skeletal metastases occurred most frequently in the pelvic bones. However, other sites were not rare.
Table 3 shows the bone metastasis type on CT scans in the staging and follow-up periods. Of these patients, 67.3% (74/110) showed an osteoblastic appearance on CT, and the subtypes were as follows: 30 dense, 22 GG, three miliary, and 19blastic mixed. A total of 22.7% (25/110) showed lytic components on CT (six lytic and 19 mixed lytic and blastic). Furthermore, 10.0% (11/110) showed invisible bone lesions on CT. This lack of detection is a problem associated with diagnosis of skeletal metastasis by CT. These patients with invisible lesions were referred for bone marrow metastasis or intertrabecular metastasis. In a later CT study, the invisible lesions became evident. In patients in the staging period, the blastic mixed type, mixed lytic and blastic type, and invisible type were dominant; conversely, the dense type was dominant in patients in the follow-up period (P =0.001). The CT appearance in patients in the follow-up period tended to be denser than that in patients in the staging period.
Table 4 shows the relationship between the BS uptake grade and morphologic CT lesion patterns in patients in the staging and followup periods. Table 5 shows the relationship between morphologic CT lesion patterns and the BS uptake grade in the function of size category: the largest diameter on the axial view was <10mm, 11- 20mm, or >21mm in patients with EOD I disease. As shown in Table 4, dense and military lesion patterns on CT tended to show weaker BS uptake and GG, blastic mixed, and mixed lytic and blastic CT lesion patterns tended to show stronger BS uptake (Fisher's exact test, P< 0.001). Interestingly, a dense CT pattern in the follow-up period tended to show weaker BS uptake. Because lesion size is related to BS uptake, the lesion size (longer diameter on axial CT) was measured in patients with EOD I disease; patients were grouped into those with a diameter of <10mm, 11-20mm, and >21mm, and the relationship between BS uptake and CT subclass is shown in Table 5. The BS uptake was related to lesion size; however, CT lesion patterns were related to BS uptake.
Table 6 shows the temporal changes in the CT appearance after initial diagnosis. In this analysis, later CT data were not available in several patients. Most patients had received additional systemic therapy for osseous metastasis. Although the temporal changes were not the natural course (almost all patients had received therapy for bone metastasis), most of the temporal changes consisted of increased density.

Table 2

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Table 2
Sites of bone metastasis in patients with EOD = I bone disease.

Table 3

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Table 3
Type of bone metastasis on CT

Table 4

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Table 4
Relation between Bone scan uptake grade and CT subclasses

Discussion

The EOD in follow-up patients was less than that in staging patients (Table 1). This can be explained by the fact that the follow-up patients frequently underwent bone metastasis surveys by monitoring of their prostate-specific antigen concentration.
The distribution of skeletal metastasis was not different between the staging and follow-up periods. In addition, the area of skeletal metastatic lesions was often distributed to anatomically close sites such as the pelvic bone. However, solitary skeletal metastasis to anatomically remote sites such as the thoracic bones (e.g., ribs, scapula) is not rare (Table 2). Batson [24] suggested that the mechanism of skeletal metastasis involve the presence of a backward venous metastatic pathway from the prostate to the lower spine. This venous pathway is currently known as Batson's plexus, and autopsy studies confirmed his theory [25]. In addition to the anatomical mechanism, the seed and soil theory [crosstalk between selected cancer cells (seed) and specific organ microenvironments (soil)] proposed by Fidler [26] postulates that selected cancer cells (seeds) from the primary tumour can disseminate to various tissues, but succeed in establishing secondary growth only in those that are permissive for their survival and proliferative expansion (fertile soil). Our data on the skeletal metastatic distribution indicate that anatomically close sites (pelvic bones) are the most frequent metastatic bone lesions, which is in agreement with the theory described by Batson [24], and the frequent occurrence of solitary anatomically distant lesions (rib and scapula) are in partial agreement with the seed and soil theory. The soil is very important; however, when soils have similar properties, hemodynamic factors become important.
The results of BS and CT showed variation in both BS uptake (faint to intense) and the CT appearance. Our data show differences in both the CT pattern and BS uptake between the staging and followup periods. The dense CT pattern was abundant (Table 3) and the BS uptake was less in the dense pattern (Table 4) in the follow-up period. The major difference between patients in the staging and follow-up periods was that patients in the staging period received no treatment for prostate cancer while patients in the follow-up period had received treatment for prostate cancer (mainly hormone therapy). Addition of hormonal therapy might be why the dense CT pattern was abundant and BS uptake was less in this dense pattern in patients in the followup period.
Later CT studies, which were performed after therapeutic intervention in most cases, showed that the invisible and GG types became dense and lytic and that the mixed lytic and blastic types increased in density.
Osseous metastasis of prostate cancer begins with cancer cell colonization to bone marrow niches through competition with hematopoietic stem cells [10]. Ten percent of our patients showed bone lesions with positive BS results and invisible lesions on CT scans. These lesions, which were later detected as evident bone lesions on CT scans, are considered early skeletal metastatic lesions. Theoretically, the first stage of a bone marrow lesion should be BSand CT-negative. Eventually, these lesions become BS-positive and CT-invisible and subsequently proceeded to BS-positive and CTevident. Although the presence of CT-invisible lesions is reasonable, this is a problem for the diagnosis of skeletal metastasis by CT. We must keep in mind that a CT-invisible, BS-positive pattern is not rare in the initial diagnosis of skeletal metastasis from prostate cancer.
Skeletal metastasis of prostate cancer was frequently of an osteoblastic nature in the present study. Histomorphometric evidence indicates that sites of osseous metastases from prostate cancer have microscopic evidence of an increased osteoid surface, osteoid volume, and mineralization surface. Some patients have an increased osteoclast resorption surface [27]. Both osteolytic and osteoblastic bone metabolic markers are increased in patients with bone-metastatic prostate cancer [19]. Osteolysis is important even in patients with osteoblastic prostate cancer metastasis and is essential for tumor growth in bone [16]. In prostate cancer, the degree of osteogenesis appears to be in excess of that generally observed as part of the coupling process, tilting the balance towards new bone formation [15,18]. Therapeutic strategies against osteolysis such as bisphosphonate [20] and denosumab [21] are effective in the treatment of bone metastasis of prostate cancer by reducing skeletalrelated events. Moreover, denosumab delays the onset of bone metastasis in castration-resistant prostate cancer [28]. In the present study, 22.7% of patients had osteolytic components (lytic type and mixed lytic and blastic type) at the time of initial skeletal metastasis, and the percentage decreased in the later period.
In conclusion, comparison of the BS and CT skeletal metastasis findings between the staging patients and follow-up periods showed that skeletal metastasis from prostate cancer during the followup period tended to have a lower EOD, denser appearance on CT, and lower BS uptake than that during the staging work-up. We also performed a reappraisal of BS and CT data of skeletal metastasis from prostate cancer in the present study. Osteolysis is considered essential in skeletal metastasis from prostate cancer, and 22.7% of CT studies showed osteolytic components. Initial skeletal metastasis can be associated with negative CT scan, even if the BS is positive, as shown in 10% of our patients.

Table 5

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Table 5
Bone scintigraphic uptake vs. metastatic size and CT pattern in patients with EOD=I.

Table 6

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Table 6
Initial and Later CT findings

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