Diagnostic performance of a computer-assisted diagnosis system for bone scintigraphy of newly developed skeletal metastasis in prostate cancer patients: search for low-sensitivity subgroups

Between February 2013 and January 2017, consecutive patients with histologically proven prostate cancer and who showed typical or suspected skeletal metastases on BS were enrolled. These patients were reviewed regarding the presence of skeletal metastasis, and the both BS and CT scan of the osseous metastatic sites were performed at the time of the first diagnosis of skeletal metastasis, which was established by agreement of at least two different modalities, follow-up studies, and/or biopsy.

Eligible patients had a diagnosis of skeletal metastasis and the interval between BS and CT scan was within a month. These patients were then divided into the following diagnostic groups depending on the time of staging and the follow-up 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). The criterion for CRPC was a testosterone level of below 50 ng/dl.

Consecutive prostate cancer patients who showed negative for skeletal metastasis on BS were enrolled between January and April 2013. These patients were followed up for at least 3 years and were confirmed negative for skeletal metastasis.

This retrospective study was approved by the local institutional review board.

BS was performed about 3 h after the injection of ^99mTc-MDP. After obtaining anterior and posterior whole-body scans, local images including the pelvic axial view were acquired or, in some patients, bone SPECT/CT was performed as follow-up to the whole-body images. Patients in whom BS revealed metastasis were further analyzed. The bone metastatic burden of these patients, as shown on BS, was scored using Soloway’s extent of disease (EOD) system [9]. Briefly, EOD scores were decided on the basis of number and extent of metastases. The bone scans were divided into 5 EOD grades, 0 normal or abnormal due to benign bone disease, I number of bony metastases less than 6, each of which is less than 50% of vertebral body (one lesion about the size of a vertebral body would be counted as two lesions), II number of bone metastases between 6 and 20, size of lesions described above. III number of metastases more than 20 but less than a ‘super scan’, and IV ‘super scan’ or its equivalent, i.e., more than 75% of ribs, vertebrae, and pelvic bones. The intensity of skeletal metastatic uptake was visually graded as faint, usual, or intense on whole-body images. Figure 1 shows BS uptake patterns; faint uptake was visualized as a weak hot spot, whereas intense uptake was very strong uptake, which could be seen in both anterior and posterior views. Usual uptake was visualized somewhere between faint and intense uptake. This visual classification was independently performed by two radiologists-nuclear physicians, and 15 discordant cases were decided through discussion.

BONENAVI analysis was performed as previously reported [10]. Briefly, the CAD system “BONENAVI version 2.1.7” (FUJIFILM RI Pharma Co., Ltd., Tokyo, Japan) was used to analyze BS scans using anterior and posterior whole-body images. This BONENAVI system shows two imaging markers: ANN and a bone scan index (BSI). The ANN value indicates the probability of having skeletal metastasis. The range of ANN is 0–1, where “0” means no possibility of skeletal metastasis, and “1” means there is a high suspicion of having skeletal metastasis. The BSI indicates the tumor metastatic burden (proportion of bone metastatic area to whole body skeleton). In the present study, the ANN values were used.

CT scans were performed with a 2-mm thickness at 5-mm intervals.

The CT morphological classification of skeletal metastasis included the categories osteoblastic, osteolytic, mixed osteoblastic and osteolytic, and intertrabecular (invisible on CT). Figure 2 shows the morphologic lesion patterns on CT scans. This classification was independently performed by two radiologists-nuclear physicians, and discordant cases were decided through discussion. The confirmation of skeletal metastasis of intertrabecular or invisible on CT was performed by follow-up CT studies. All invisible lesions turned to osteoblastic or mixed CT appearance on later CT studies.

The patient-base was evaluated as follows:

Then, sensitivity and specificity were calculated with the cutoff level set at ANN = 0.5 for both skeletal metastasis positive and negative patients. The cutoff level was set at ANN = 0.5 throughout the study according to other Japanese studies [7, 8].

Similar analyses were performed in regard to CT appearances, that is, osteoblastic, osteolytic, mixed, and intertrabecular (invisible) types, EOD scores (EOD = I, II, III, and IV), and BS uptake intensities (faint, usual, and intense).

Statistical analysis software (SPSS version 24; IBM, Armonk, NY, USA) was used. A value of p < 0.05 was considered to indicate statistically significance. For ANOVA, Levene’s test for the homogeneity of variance was performed first. When the homogeneity of variance was assumed, a t test was followed by Turkey’s test. When the homogeneity was not assumed, Welch’s test was followed by the Games-Howell test. For contingency table analysis, if the more than 20% of cell boxes was expected numbered <5, Fisher’s exact test was used. Pearson’s Chi-square test was applied to the others.

The ROC curve is shown in Fig. 3. The area under the curve was 0.888 (95% confidence interval 0.843–0.932). The mean ANN values were 0.78 (SD = 0.29) for the skeletal metastasis patients and 0.22 (SD = 0.30) for the non-skeletal metastasis patients. Sensitivity was 82% (102/124), and specificity was 83% (84/101).

Tables 1, 2, 3 and 4 summarized the ANN values with ANOVA analyses and the contingency tables analyses using ANN cutoff value = 0.5 regarding diagnostic situation, CT appearance, EOD and BS uptake grade.

As shown in Table 1, skeletal metastasis at follow-up period showed lower ANN values and lower sensitivity than those at staging with statistically significance.

Mixed type of CT appearance osseous metastasis showed high mean ANN value (mean ± SD, 0.90 ± 0.16) and high sensitivity (95%). Other types of CT appearance showed similar results (both ANN values and sensitivity; Table 2).

There was no statistical difference among the types of CT appearance.

Analysis of EOD differences showed that EOD = I patients had lower mean ANN value and lower sensitivity compared with EOD = II, III, IV patients. The ANN values and the sensitivity between EOD = I and EOD II-IV differed statistical significantly (Table 3).

The ANN value of for those with faint BS uptake was significantly lower than those for patients with usual or intense BS uptake. The sensitivity was also significantly lower in the patients with faint BS uptake group compared with that in those with usual or intense uptake (Table 4).

Table 5 shows the 22 patients with false-negative results (ANN ≤ 0.5). Sub-groups of false-negative results were no suspicion (ANN 0–0.25) and less suspicion (ANN 0.26–0.5) according to Horikoshi [7]. Ten skeletal metastasis patients with no suspicion group (ANN 0–0.25) showed ANN = 0. All patients had a small bone tumor burden (EOD = I); most (9/10) had a solitary skeletal metastasis; most (9/10) were diagnosed during the follow-up period; and the BS uptake was generally faint (8/10). The 8 of 10 patients had lesions in pelvic bone: 2 in the ilium, 3 in the ischium, 1 in the sacrum, and 2 in the pubis. In 12 patients with less suspicion of skeletal metastasis (ANN 0.26–0.50), most patients (11/12) had small tumor burden (EOD = I). The BS uptake was higher (faint = 8, usual = 2, and intense = 2) than those of no suspicion group. Seven patients (7/12) had lesions in pelvic bone.

Table 6 shows the 17 patients with ANN > 0.5. These patients were divided into seven patients of highly suspicion group (ANN 0.76–1.0) and 10 of suspicion group (ANN 0.5–0.74). These patients did not have skeletal metastasis, although BONENAVI analysis had indicated there was a possibility of skeletal metastasis. Most of the patients showed false-positive hot (red) spots on the vertebral column (16/17). Even though the BS hot spots existed at those sites, none of these patients were judged to have skeletal metastasis based on an experienced nuclear physician diagnosing those areas of uptake as degenerative changes. At their follow-up evaluations at least 3 years later, none of the patients had developed skeletal metastasis.