Abstract
Purpose
We investigated the clinical role of F-18 fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) in the identification of the primary site and the selection of the optimal biopsy site in patients with suspected bone metastasis of unknown primary site.
Methods
The patients with suspected bone metastasis who underwent PET-CT for evaluation of primary site were enrolled in this study. The primary sites were identified by the histopathologic or imaging studies and were classified according to the FDG uptake positivity of the primary site. To evaluate the guiding capability of PET-CT in biopsy site selection, we statistically analyzed whether the biopsy site could be affected according to the presence of extra-skeletal FDG uptake.
Results
Among 74 enrolled patients, 51 patients had a metastatic bone disease. The primary site was identified in 48 of 51 patients (94.1%). Forty-six patients were eligible to test the association of clinical choice of biopsy site with PET positivity of extra-skeletal lesion. The extra-skeletal biopsies were done in 42 out of 43 patients with positive extra-skeletal uptake lesions. Bone biopsies were inevitably performed in the other three patients without extra-skeletal uptake lesions. The association came out to be significant (Fisher’s exact test, P < 0.001).
Conclusion
F-18 FDG PET-CT significantly contributed not only to identify the primary site but also to suggest optimal biopsy sites in patients with suspected bone metastasis.
Keywords: Bone metastasis, Unknown primary site, PET-CT, Biopsy
Introduction
The bone is the third most frequent site for distant metastasis of cancer, after the lung and liver [1, 2]. About 30.0% of patients showed bone metastasis at the initial manifestation of malignancy before the identification of the primary site [3]. The prostate, breast, and lung is the most common primary malignancy spread to the bone [4]. Proper management planning requires differentiation between malignant and benign lesions and identification of the primary site in patients at risk for bone metastasis. Needle core biopsy or surgical biopsy of the suspected lesion is recommended for evaluation of the carcinoma of unknown primary site [5]. However, the biopsy is an invasive procedure with associated complications of bleeding, infection, or unintended organ injury, and inadequate results may contribute to diagnostic failure [6]. Therefore, selecting the optimal biopsy site for pathologic confirmation is a key step in the diagnosis and management of patients.
F-18 fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) has been widely used for the detection of the primary site, staging, treatment planning, and treatment monitoring in different types of cancers [7, 8]. Especially, PET-CT has clinical value to identify the primary site based on its ability to independently screen the whole body in patients with suspected metastasis of unknown primary site [9–13]. However, only a few studies have reported the clinical role of PET-CT for clinicians to establish the next management plan in the presence of multiple hypermetabolic lesions on PET-CT [14, 15]. In this study, we investigated the clinical role of PET-CT in the identification of the primary site and guidance of the biopsy site selection by clinicians in patients with suspected bone metastasis of unknown primary site.
Methods
Patients
This retrospective study was approved by our Institutional Review Board, and the requirement for the patient’s written informed consent was waived. A total of 94 patients with suspected bone metastases through prior imaging studies, who were referred to our institute for PET-CT between January 2016 and March 2018, were initially enrolled. Exclusion criteria were as follows: presence of previously known malignancy (n = 4) and inadequate follow-up records (n = 16). Finally, 74 patients were included in the study; none of these patients had any history of chemotherapy or radiotherapy before PET-CT.
F-18 FDG PET-CT
PET-CT was performed using the Discovery ST PET-CT system (GE Medical Systems, Milwaukee, WI, USA) following standard institutional protocol. In all patients, fasting was carried out for 6 h before the intravenous injection of 5.5 MBq/kg F-18 FDG, and blood glucose levels were maintained below the level of 7.2 mmol/L. Low-dose CT was performed for attenuation correction at 50 min after F-18 FDG injection. After completion of CT, PET scans were acquired at 150 s per bed position. The data obtained were submitted for ordered-subset expectation maximization reconstruction (128 × 128 matrix, 3.7-mm slice thickness, 21 subsets, and 2 iterations).
Imaging Analysis
PET-CT images were reviewed by two nuclear medicine physicians. F-18 FDG uptake positivity of the suspected lesion was defined as measurable focal uptake at the bones or extra-skeletal tissues in comparison with the background uptake or blood-pool activity. Each focal extra-skeletal uptake site was judged as a primary or metastatic lesion according to the FDG uptake pattern and distribution of the uptake sites. Extra-skeletal accumulation due to physiological causes and inflammation was considered insignificant if the uptake pattern appeared non-focal, symmetrical, linear, or tracked along the soft-tissue boundary [16–19]. The PET-CT finding was compared with the patient’s final diagnosis which was followed up by histopathology, imaging, or clinical judgment based on other biomarkers.
The primary site was identified and classified based on the follow-up results. First, the biopsy sites were classified into the primary or metastatic site to evaluate the impact of PET-CT in the identification of the primary site. Second, the PET positivity of extra-skeletal lesions was cross-tabulated against the tissue types of biopsy site (skeletal or extra-skeletal) to evaluate the impact of PET-CT on clinician’s selection of biopsy site. The analysis was performed to determine whether biopsy-site selection differed according to the presence of extra-skeletal F-18 FDG uptake on the PET-CT images.
Statistical Analysis
Continuous variables were expressed as mean ± standard deviation. The Fisher’s exact test was used in the comparison of categorical variables. The results were considered statistically significant if the P value was < 0.05. IBM Statistical Package for the Social Sciences (SPSS) software for Windows, version 20.0 (IBM Corp., Armonk, NY, USA) was used for statistical analyses.
Results
Patient Classification
The patients’ characteristics are summarized in Table 1. The mean age of the 74 patients was 67.5 ± 13.9 years (range, 10–91 years). On PET-CT examination, the absence of bone uptake of F-18 FDG was observed in seven (9.5%) patients for whom malignancy was not detected at follow-up with further work-up (step 1 in Fig. 1). Other 67 (90.5%) patients showed F-18 FDG uptake in the suspected bone lesion. Bone lesions were diagnosed as malignant lesions in 57 (77.1%) patients while the other 10 patients confirmed to have benign bone diseases with further work-up.
Table 1.
Patient characteristics (n = 74)
| Variable | Value (range or %) |
|---|---|
| Age (years) mean ± SD | 67.5 ± 13.9 (10–91) |
| Male/female | 44 (59.5%)/30 (40.5%) |
| F-18 FDG positivity of the suspected bone lesion | |
| Negative uptake | 7 (9.5%) |
| Positive uptake | 67 (90.5%) |
| Extra-skeletal uptake on PET-CT | |
| Present | 47 (63.5%) |
| Absent | 27 (36.5%) |
| Final diagnosis of the suspected bone lesion on PET-CT | |
| Benign bone disease | 17 (22.9%) |
| Primary malignant bone disease | 6 (8.1%) |
| Metastatic bone disease from identified primary site | 48 (64.9%) |
| Metastatic bone disease from unknown primary site | 3 (4.1%) |
| Follow-up method | |
| Histopathology | 55 (74.3%) |
| Imaging study | 9 (12.2%) |
| Clinical follow-up | 10 (13.5%) |
Fig. 1.
Diagnostic flow chart with biopsy site in enrolled patients. aAll patients were diagnosed as a benign bone disease by imaging and clinical follow-up; bfour patients were diagnosed by biopsy and other 6 patients were diagnosed by imaging and clinical correlation; call patients were confirmed by biopsy; dtwo patients underwent biopsy in the suspicious extra-skeletal primary lesion after PET-CT. However, there was no significant primary malignancy. Another patient was diagnosed by imaging and clinical follow-up (MCUPS, metastatic cancer from unknown primary site)
In the malignant bone lesions, the metastatic bone disease was present in 51 (69.0%) patients, and primary malignant bone disease was present in six (8.1%) patients (step 2 in Fig. 1). The primary sites were identified in 48 of 51 patients who had metastatic bone disease. The other three patients have remained as a group with metastatic lesions from the unknown primary site as further work-up including extra-skeletal biopsy failed to detect primary lesion.
Among the patients who identified the primary site, 36 of 48 patients underwent biopsy in the primary sites (step 3 in Fig. 1). Seven patients biopsied in the metastatic lymph node or soft tissue and three patients biopsied in the metastatic bone lesion.
Identification of Biopsy Site According to F-18 FDG Uptake Positivity
In 43 patients, the lung was the most frequent primary site (19 of 43 patients), followed by the prostate, hepatobiliary system, thyroid, stomach, colon, pancreas, and kidney (Table 2). The extra-skeletal tissue biopsy was done in the 42 of 43 patients who had positive F-18 FDG uptake in the primary site. One patient who suspected pancreatic carcinoma did not undergo pathologic examination and followed up using imaging (CT, MR) and laboratory studies. Among the 42 patients, 35 patients underwent biopsy in the primary site and 7 patients underwent biopsy in the extra-skeletal metastatic sites. Six patients were biopsied in the lymph nodes (LN) (three patients in cervical LN, three patients in mediastinal LN), and then another was biopsied in the soft tissue mass of scalp.
Table 2.
Distribution of primary sites in patients with suspected bone metastasis (n = 48)
| Primary site | Detected on PET-CT (n = 43) |
Biopsy site (n = 42) | Not detected on PET-CT (n = 5) |
Biopsy site (n = 5a) | ||
|---|---|---|---|---|---|---|
| Primary site (n = 35) | Other site (n = 7) | Primary site (n = 2) | Other site (n = 3) |
|||
| Lung | 19 | 13 |
2 cervical LN 3 mediastinal LN 1 scalp |
0 | – | – |
| Prostate | 9 | 9 | – | 3 | – | 3 bone |
| Hepatobiliary system | 4 | 4 | – | 0 | – | – |
| Thyroid | 4 | 3 | 1 cervical LN | 1 | 1 a | – |
| Stomach | 3 | 3 | – | 0 | – | – |
| Colon | 2 | 2 | – | 1 | 1 | – |
| Pancreas | 1 b | – | – | 0 | – | – |
| Kidney | 1 | 1 | – | 0 | – | – |
LN, lymph node
aIncluded one patients who underwent biopsy before PET-CT
bPrimary site was identified using imaging studies alone
F-18 FDG uptake in the primary site was not found on PET-CT in five patients. Among the five patients, one patient underwent thyroid ultrasound and biopsy before PET-CT due to suspicious nodular lesion in the thyroid lobe on CT and therefore excluded from Fisher’s test. Three patients underwent bone biopsies which revealed metastatic lesions from prostate. Another patient underwent colonoscopic biopsy due to the markedly increased level of carcinoembryonic antigen (CEA) and CA19-9, which revealed colonic malignancy.
Contribution of PET-CT to a Selection of the Biopsy Site
The diagnostic impact of PET-CT on the localization of the biopsy site was investigated in 46 patients who undergo extra-skeletal or skeletal biopsy based on PET positivity of extra-skeletal lesion (Table 3). The selection of the biopsy site was affected by the presence of extra-skeletal uptake lesions on PET-CT with statistical significance by using Fisher’s exact test (P < 0.001). Representative cases are shown in Fig. 2.
Table 3.
Impact of PET-CT on the selection of the biopsy site according to extra-skeletal uptake positivity (n = 46)
| Biopsy from extra-skeletal lesion | Biopsy from metastatic bone lesion | Total | P value | |
|---|---|---|---|---|
|
PET-positive extra-skeletal uptake lesion |
42a | 0 | 42 | <0.001 |
|
PET-negative extra-skeletal uptake lesion |
1b | 3 c | 4 | |
| Total | 43 | 3 | 46 |
aBiopsy site identified using PET-CT
bBiopsy site identified using other modalities
cBiopsy was performed with localization of the same sites using conventional modalities and/or PET-CT
Fig. 2.
Selection of biopsy site according to the extra-skeletal uptake in F-18 FDG PET-CT. (a) A 79-year-old woman with lower back pain and suspected skeletal metastatic lesion in the sacrum on CT. PET-CT shows a hypermetabolic lesion in ascending colon (arrow) with metastatic lesions in the left adrenal gland, sacrum, and right femur. Colonoscopic biopsy at the ascending colon revealed adenocarcinoma. (b) A 64-year-old man with multiple bone lesions on CT. PET-CT shows a hypermetabolic lesion in the central area of the left upper lobe of the lung (arrow). Additional extra-skeletal uptake is seen in both mediastinal, lower neck, left axillary, and retroperitoneal areas. Histopathological examination of the lymph node at the left neck (arrowhead) reveals metastatic squamous cell carcinoma from the lung. (c) A 68-year-old man with radiating lower back pain and suspected metastatic bone lesion in lumbar vertebra on CT. PET-CT shows a hypermetabolic lesion in the L4 vertebral body (arrow). There was no extra-skeletal uptake lesion. Bone needle biopsy at the L4 vertebra revealed metastatic prostate carcinoma
Discussion
Our results revealed that PET-CT enabled both identifications of the primary malignancy and guidance of the tissue biopsy sites in patients with suspected bone metastasis; especially, the positivity of extra-skeletal F-18 FDG uptake on PET-CT was a significant influencing factor for the selection of the extra-skeletal biopsy site.
Image guided-biopsy can be performed with various imaging modalities. Li et al. showed 90% of diagnostic accuracy of sub-centimeter lung nodule by using CT-guided biopsy [20]. In the meta-analysis, MRI-targeted biopsy showed a higher detection rate than standard transrectal ultrasound-guided biopsy to find prostate cancer [21]. However, those imaging modalities only reflect anatomic information of the target lesion; whereas, PET-CT has the capability to provide metabolic information of the lesion with anatomic information. PET-CT can suggest a metabolically active lesion for the biopsy site, which may result in higher diagnostic yields [14, 22]. Previous reports showed that PET-CT-directed biopsy has a large incremental benefit (47.3%) to select an intratumoral biopsy site when adding to conventional CT-guided biopsy in staging/restaging of primary malignancy [15].
It is also important how clinicians select biopsy sites especially in patients with multiple hypermetabolic lesions on PET-CT, regardless of the determination of primary or metastatic lesions. Our results showed the practical determining power of the biopsy site by referring physicians. In our results, all tissue biopsy was conducted in the extra-skeletal lesion when PET-CT reveals F-18 FDG uptake. Bone biopsy has a risk of inaccurate biopsy results through inadequate tissue sampling [6] and combined complications such as hematoma, infection, and organ damage [23, 24]. Therefore, it would be better to perform a biopsy in the soft tissue than in the bone lesion to avoid complications. Furthermore, 7 of 42 patients underwent tissue biopsy at superficial extra-skeletal metastatic sites localized through PET-CT although primary lesions were identified.
In patients with metastasis from an unknown primary site, PET-CT is indicated because of its ability to screen the whole body in a single set-up. A meta-analysis reported an overall detection rate of the primary site of 37% with a sensitivity of 84% and specificity of 84% for PET-CT in patients with metastasis of unknown primary site [9]. Our results showed that the detection rate of the primary site was 84.3% and the management plan was significantly affected according to the presence of extra-skeletal uptake on PET-CT.
In our study, PET-CT failed to identify the extra-skeletal primary site in five patients, and the prostate was the most frequent site (three of five patients). Liu Y. et al. also showed the low detection sensitivity (33%) of the primary site in newly diagnosed prostate cancer patients [25]. The low metabolic activity of the prostate tumor could explain the low rate of detection on PET-CT [26]. Moreover, the physiological F-18 FDG accumulation of the urinary bladder can mask the metastatic pelvic lymph nodes in prostate cancer patients [27]. Despite the prostatic primaries were missed by PET-CT, we observed that the prostate was the second most common primary site identified on PET-CT (21.0%), followed by the lung (44.3%). Our result is similar to the findings of previous reports among patients who had skeletal metastasis as the initial manifestation of unknown primary cancer, with the prevalence of prostate cancer next to lung cancer [3, 28].
Our study has several limitations. First, the study had a retrospective design, and case-selection bias may have affected its representativeness and reliability. Second, all bone lesions were not histologically confirmed, especially in patients with benign bone diseases. Third, we were unable to use other imaging modalities or analysis of other tumor markers in the diagnostic process, especially in patients without extra-skeletal uptake. Future studies that address these issues and are focused on the optimization of the diagnostic process are needed to overcome the drawbacks of PET-CT in these patients.
Conclusion
F-18 FDG PET-CT had a significant role in clinical procedure not only to detect primary malignancy but also to suggest optimal biopsy sites in patients with suspected bone metastasis. Clinicians should consider PET-CT as the diagnostic procedure of choice in those patients with a difficult approach to the biopsy site such as the bone.
Compliance with Ethical Standards
Conflict of Interest
Su Woong Yoo, Md. Sunny Anam Chowdhury, Subin Jeon, Sae-Ryung Kang, Changho Lee, Zeenat Jabin, Jahae Kim, Sang-Geon Cho, Ho-Chun Song, Hee-Seung Bom, Jung-Joon Min, and Seong Young Kwon declare that they have no conflict of interest.
This research was supported by a grant from KOICA, Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF-2019M3E5D1A02067958), the National Research Foundation Korea (NRF) grants funded by the Korean government (MSIT) (No. NRF-2018R1D1A1B07050011).
Ethical Approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.
Informed Consent
The institutional review board of our institute approved this retrospective study, and the requirement to obtain informed consent was waived.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Su Woong Yoo and Md. Sunny Anam Chowdhury contributed equally to this work.
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