Head-to-Head Comparison of Chest X-Ray/Head and Neck MRI, Chest CT/Head and Neck MRI, and ¹⁸F-FDG PET/CT for Detection of Distant Metastases and Synchronous Cancer in Oral, Pharyngeal, and Laryngeal Cancer

Setting and Participants

Consecutive patients with suspected primary oral, pharyngeal, or laryngeal carcinoma who were referred to the Head and Neck Cancer Center, Odense University Hospital, from September 2013 to March 2016 were considered for the study. At the initial contact, a clinical head and neck examination, including nasopharyngo laryngoscopy and ultrasound of the neck, was performed by an experienced head and neck cancer specialist. If the suspicion of HNSCC was confirmed, the patient was offered inclusion in the study.

Exclusion criteria were allergy or intolerance to contrast, treatment with high doses of systemic steroids (>50 mg/d), reduced kidney function (defined as elevated serum creatinine or diagnosed kidney disease), or being considered unable to cooperate.

Patients underwent CXR/MRI, CHCT/MRI, and PET/CT on the same day, and upfront (i.e., before biopsy and histologic evaluation). To minimize irradiation, the CHCT was derived from the PET/CT examinations, which were performed as full diagnostic CTs (not attenuation-correction scans). Patients with histologically verified HNSCC constituted the study population and were used for analysis regarding detection of distant metastasis or synchronous cancer.

Imaging Techniques

PET/CT data were acquired on a hybrid PET/CT scanner (Discovery 690, 710, VCT, or RX; GE Healthcare).

¹⁸F-FDG (4 MBq/kg) was injected intravenously after a fasting period of at least 4 h. The PET scan was obtained using a standard whole-body acquisition protocol extending the vertex to the thigh, and an acquisition time of 2.5 min per bed position. PET data were reconstructed into transaxial slices with a matrix size of 128 × 128 (pixel size, 5.47 mm) or 256 × 256 (pixel size, 2.73 mm) and a slice thickness of 3.27 mm using iterative 3-dimensional ordered-subset expectation maximization. Multislice, diagnostic-quality CT scans with intravenous contrast medium (Ultravist [Bayer]; 370 mg/mL) were acquired after the PET scan. The CT scan was obtained with continuous shallow breathing. Data were reconstructed with a standard filter into transaxial slices with a field of view of 50 cm, matrix size of 512 × 512 (pixel size, 0.98 mm), and a slice thickness of 3.75 mm. The scan field of view was 70 cm for both PET and CT scans. PET/CT was analyzed on an Advantage Workstation (version 4.4 or 4.3; GE Healthcare) or AW Server (version 3.1 or 3.2; GE Healthcare).

MRI was performed using Achieva, Achieva dStream, or Ingenia 1.5T (Philips) hardware with 20-channel (dStream) head–neck coil. The examination protocol was kept unchanged for the duration of the study and consisted of short tau inversion recovery (STIR), turbo spin echo (TSE)-T2, and TSE-T1 with and without contrast enhancement, in axial or coronal planes with coverage from skull base to aortic arch using 5-mm slices. Diffusion-weighted imaging with spectral fat saturation and apparent diffusion coefficient maps derived from b values 0 and 1,000 mm²/s were done in axial 6-mm slices. Images were read on a Centricity RA1000 PACS workstation (GE Healthcare). The acquisition parameters of the MRI sequences are displayed in Supplemental Table 1 (supplemental materials are available at http://jnm.snmjournals.org).

CXR was performed to departmental standards in full inspiration anteroposterior and lateral projections with 130–145 kV and automatic exposure control. FD-X hardware systems (Siemens Healthineers) were used, and studies were read using a Centricity RA1000 PACS workstation (GE Healthcare) with dual 3MP medical-grade monitors.

Image Interpretation

The 3 applied imaging modalities were evaluated separately. The MRIs and the CXRs were evaluated by 2 experienced head and neck radiologists. The chest CTs were all evaluated by 1 radiologist. PET/CT was evaluated by a team consisting of 2 experienced radiologists and 2 nuclear physicians. Standard forms including variables concerning distant metastasis or synchronous cancers were filled out by each team during imaging evaluation. The same referral text was used for each of the evaluation sessions and the teams were masked to one another (Fig. 1).

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FIGURE 1.

Diagram of patient inclusion and image interpretation. *Extracted from PET/CT.

The interpretation of distant metastases and synchronous cancers relied on pattern recognition of anatomic information (i.e., morphologic changes, altered signal intensity, contrast enhancement, changes in diffusivity) and metabolic information regarding ¹⁸F-FDG avidity for PET. Malignant lesions were suspected when considered more likely than benign lesions.

For lymph nodes, the following characteristics were considered: enlargement, round shape, absence of fatty hilum, necrosis, dense center, topography of node distribution, and ¹⁸F-FDG avidity for PET.

For CT, lung lesions were considered distant metastases if one or more nodules were present. Small subpleural nodules (especially when calcified) were not considered metastases on CT unless multiple were present. By PET/CT, ¹⁸F-FDG avidity of the nodules assisted in the determination of malignancy or not. Lung lesions in the field of view of the MRI were considered suggestive, when the configuration was nodulary or spiculary and not consistent with infectious pattern. Distant metastases were suspected on CXR, when opacification was not consistent with infectious pattern.

For PET/CT, bone lesions were regarded as metastases, when ¹⁸F-FDG–avid osteolytic (or osteosclerotic) lesions were present. Significantly increased ¹⁸F-FDG uptake in the bone marrow even without the lytic or sclerotic changes was also regarded as metastases. Lesions close to the joints were rarely considered metastases. Regarding MRI, focal signal changes on T2 and STIR and presence of enhancement were observed, but as these may vary, only lesions appearing with low signal of T1 were considered suggestive of metastasis. Osteolytic or osteosclerotic changes on CXR were considered suggestive of bone metastasis.

For PET/CT, liver metastases and malignant pleural effusion were suspected only in lesions with significantly increased ¹⁸F-FDG uptake as compared with the surroundings. Muscle metastases were suspected in patients with randomly distributed focal areas of increased ¹⁸F-FDG uptake in the muscles and corresponding morphologic changes. Longitudinal muscular ¹⁸F-FDG uptake was considered to be physiologic.

Synchronous cancers were suspected if tumors were present in organs, atypical of nesting metastases. Other parameters were also weighted, for instance, the size and the ¹⁸F-FDG intensity (i.e., for PET) of the primary compared with the suspected synchronous tumor. Likewise, the pattern of spread and possible gaps between lymph node stations were taken into consideration. Regarding lung lesions, the presence of spicules and hilar lymph nodes by CT helped determine whether these represented a metastasis or a synchronous cancer.

Reference Standard

Verification of metastatic disease or synchronous cancer (i.e., true detection rate [TDR]) was confirmed by histology, cytology, or follow-up imaging (within 6 mo) as reference standard. When only imaging was available as a validator, we applied the RECIST for measurable lesions and progression (21). Only lesions fulfilling the RECIST for progression were characterized as metastatic disease or synchronous cancer.

Sample Size

We assumed a detection rate of distant metastasis or synchronous cancer of only 4%–8%, as we also included patients with a low risk of distant metastasis (e.g., small glottic cancers). Furthermore, we anticipated a drop-out rate of 20% and that 2% of cases would be detected by both CXR/MRI and PET/CT. This resulted in an estimated sample size of 366 patients. However, a predetermined interim analysis of 149 patients demonstrated a detection rate of 13% for PET/CT and only 1% for CXR/MRI, and a drop-out rate of less than 5%; thus, an adequate sample size was obtained.

Outcomes and Variables

The outcome measure was TDR of distant metastasis and synchronous cancer at the time of diagnosis. TDR was calculated as the proportion of individuals correctly identified as having distant HNSCC metastasis or synchronous cancer (i.e., true-positives). Tables (2 × 2) containing true-positive CXR/MRI versus PET/CT and CHCT/MRI versus PET/CT were produced to match TDR of distant metastasis or synchronous cancer.

Statistical Analysis

Continuous variables are presented by means and SD (normally distributed variables) or medians and ranges. The McNemar test was performed on differences in paired proportions, and the absolute difference in TDR along with a 95% confidence interval was assessed. P values below 0.05 were considered significant. A comparison of TDR for CXR/MRI versus PET/CT and CHCT/MRI versus PET/CT was performed for all subgroups (oral cavity, pharynx, larynx) and presented in forest plots. Moreover, a subgroup analysis for identification of distant metastasis or synchronous cancer in stage 1–2 and stage 3–4, and N0 neck and N+ neck patients, based on clinical examination was performed.

All analyses were performed with Stata/IC 14 (StataCorp LP).

Ethics and Disclosures

This study was conducted in accordance with good clinical practice and the Declaration of Helsinki. Permission was granted from the local ethics committee (project ID S_20120217), and informed consent was obtained from all included patients. The project was implemented without the involvement of private organizations or companies.