|Year : 2021 | Volume
| Issue : 2 | Page : 248-258
Why is it important to report early possible COVID-19 PET/CT findings in cancer patients? Explaining with a case series
Duygu Tekin1, Emine Budak2, Banu Yoldas3, Adnan Budak4
1 Department of Microbiology, Tepecik Training and Research Hospital, Izmir, Turkey
2 Department of Nuclear Medicine, Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital, Izmir, Turkey
3 Department of Thoracic Surgery, Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital, Izmir, Turkey
4 Department of Obstetrics and Gynecology, Tepecik Training and Research Hospital, Izmir, Turkey
|Date of Submission||12-Jun-2020|
|Date of Decision||15-Jun-2020|
|Date of Acceptance||12-Dec-2020|
|Date of Web Publication||11-May-2021|
Department of Nuclear Medicine, Izmir Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital, Izmir
Source of Support: None, Conflict of Interest: None
Background: Coronavirus disease-2019 (COVID-19) causing a pandemic mostly results in mild symptoms; however, it can evolve into serious complications. It is emphasized that if the term from the recent anticancer treatment to the diagnosis of COVID-19 was short, the probability of serious events increased in cancer patients. Therefore, early detection of COVID-19 and prevention of serious events is very important. We aimed to investigate whether it is possible to detect COVID-19 early by positron emission tomography (PET)/computed tomography (CT).
Methods: We retrospectively evaluated the images and clinical findings of patients who underwent PET/CT due to malignancy and whose COVID-19 polymerase chain reaction (PCR) test were detected positive subsequently.
Results: Eight cancer patients with positive COVID-19 PCR tests were included in the study. PET/CT revealed subpleural ground-glass opacities (GGOs) showing mild fluorodeoxyglucose (FDG) uptake that could be compatible with COVID-19 in 4 of 8 patients. The number of affected lobes ranged from 1-4. All patients were diagnosed with COVID-19 by PCR test when symptoms and/or lung findings worsened on the days after PET/CT. The time interval between the last anticancer treatment and COVID-19 diagnosis in five patients was ≤7 days. During the follow-up, six of the cases (75%) needed mechanical ventilation and died later.
Conclusion: COVID-19 may be recognised early by detecting incidental findings in PET/CT, especially in asymptomatic cancer patients. Potential complications may be prevented by early diagnosis and anticancer therapy changes. Therefore, possible COVID-19 findings in PET/CT should be reported and the patient should be referred to relevant clinician.
Keywords: COVID-19, malignancy, mortality, PET-CT
Asymptomatic patients infected with COVID-19 may be detected incidentally on PET/CT during cancer screening. Incidental PET/CT findings should be reported and the patient should be referred to relevant clinician for differential diagnosis.
|How to cite this article:|
Tekin D, Budak E, Yoldas B, Budak A. Why is it important to report early possible COVID-19 PET/CT findings in cancer patients? Explaining with a case series. Indian J Cancer 2021;58:248-58
|How to cite this URL:|
Tekin D, Budak E, Yoldas B, Budak A. Why is it important to report early possible COVID-19 PET/CT findings in cancer patients? Explaining with a case series. Indian J Cancer [serial online] 2021 [cited 2021 Sep 24];58:248-58. Available from: https://www.indianjcancer.com/text.asp?2021/58/2/248/315808
| » Introduction|| |
A new coronavirus called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused coronavirus disease-2019 (COVID-19). COVID-19 may be asymptomatic or result in symptoms such as fever, dyspnea, cough, myalgia, fatigue, headache, hemoptysis and diarrhea. Particularly, asymptomatic patients with COVID-19 constitute a great risk for the spread of the disease. Although COVID-19 mostly causes mild symptoms, it can evolve into serious complications such as acute respiratory distress syndrome (ARDS) or multiorgan failure. According to current data, in the presence of severe findings, the mortality rates seem to be high. It is stated that immunosuppression caused by the related malignancy or treatment makes cancer patients more sensitive to infections. Therefore, early detection of COVID-19 and prevention of serious events is very important, especially in cancer patients. Although the diagnosis of COVID-19 is currently based on real-time reverse transcriptase polymerase chain reaction (RT-PCR), it may lead to false negative results. Therefore, thorax computed tomography (CT) and recurrent swab assay are recommended in patients with negative PCR test results but having concordant clinical findings with COVID-19. Typical CT findings of COVID-19 are bilateral multiple lobular and subsegmental ground-glass opacity (GGO) and consolidation areas., F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is primarily utilized to evaluate malignancy, but can also be used to assess infectious and inflammatory processes. In this study, we aimed to investigate the early probable PET/CT findings of COVID-19 by retrospectively evaluating the images of patients who underwent PET/CT due to a diagnosis of malignancy and whose COVID-19 PCR test were detected positive subsequently. Our another objective is to share the clinical characteristics of cancer patients infected with COVID-19.
| » Methods|| |
For this study, 502 patients who underwent F-18 FDG PET/CT at Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital between March 12, 2020 to April 30, 2020 were analyzed retrospectively. Eight cancer patients with positive COVID-19 RT-PCR tests were included in the study. Age, gender, contact history, clinical and laboratory findings, and comorbidities of the patients, treatment and complications of the disease were recorded. The date of symptom onset, PET/CT, positive PCR test, and last anticancer therapy were noted. If the patients had any other PET/CT or chest CT images, they were evaluated together with the current PET/CT. Thus, parenchymal lung and pleura abnormalities that assumed not to be associated with primary malignancy or metastatic involvement were assessed and the maximum standardized uptake value (SUVmax) of these areas was measured on PET/CT. The affected lung lobes detected by PET/CT were noted.
F-18 FDG PET/CT
PET/CT images were obtained by a PHILIPS GEMINI TF 16 Slice PET/CT scanner. Following at least 6 hours of fasting, 0.15 mCi/kg F-18 FDG was administered intravenously to patients with a blood glucose value below 200 mg/dL. Approximately 60 minutes after the injection, the images of the patients from the vertex to thigh were acquired. CT (140 kV, 100 mAs, 5-mm slice) and PET emission (1.5 minutes/bedside) images were performed sequentially and then merged on workstations.
COVID-19 RT-PCR test
Viral RNA was isolated from the nasopharyngeal swab samples of the patients through Bio-speedy Viral Nucleic Acid Isolation kit (Bioksen, Turkey) in accordance with the manufacturer's recommendations. RT-PCR were performed in one step using the Bio-speedy COVID-19 RT-qPCR kit (Bioksen, Turkey).
| » Results|| |
The age of COVID-19 infected eight patients (1 women, 7 men) included in this study ranged from 60 to 73 years (mean ± standard error = 66.5 ± 1.3 years). One patient was diagnosed with brain tumor, others with advanced stage (stage 3–4) lung cancer. One of the patients infected with COVID-19 (case 6) was considered a nosocomial infection that was thought to be transmitted from a roommate. At the time of PET/CT, six patients were asymptomatic, one patient suffered from chronic cough and dyspnea (case 8), one patient had acute fever, cough and dyspnea (case 1). When evaluated retrospectively, PET/CT revealed subpleural GGOs showing mild FDG uptake (SUVmax: 1.3–2.1) that could be compatible with COVID-19 in four of eight patients (50%). The number of affected lobes ranged from 1 to 4. Laboratory tests performed during COVID-19 detected high C-reactive protein (CRP) and hemogram abnormalities in all patients, increased renal function tests and/or liver function tests in 6 patients, and coagulation abnormalities in three patients.
During the follow-up, six of the cases (75%) needed mechanical ventilation in the intensive care unit (ICU) and died later. Clinical characteristics of the patients are shown in [Table 1]. All patients were diagnosed with COVID-19 by PCR test when symptoms and/or lung findings worsened on the days after PET/CT. The time interval between the last anticancer treatment and COVID-19 diagnosis in five patients was ≤7 days. [Table 2] presents the dates of symptom onset, PET/CT, positive PCR test, and last anticancer therapy.
|Table 2: The dates of symptom onset, PET/CT, positive PCR test, and last anticancer therapy|
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CASE 1. A 69-year-old man was operated due to a brain tumor (grade 4 glioblastoma multiforme) in December 2019. In March 2020, the patient's complaints of cough, high fever and dyspnea appeared. There were multiple cavitary and non-cavitary nodules in both lungs on thorax CT. PET/CT was performed for restaging the case, and FDG avid cavitary and non-cavitary multiple nodules were detected in both lungs (SUVmax: 3.8) [Figure 1]a, [Figure 1]b, [Figure 1]c, metastasis or infection could not be differentiated. Then, gram negative bacilli growth in the respiratory secretion culture of the patient suggested that the nodules were caused by bacterial infection. Thorax CT was performed in the patient whose complaints did not decrease despite antibacterial therapy. CT [Figure 1]d and [Figure 1]e revealed progressed nodules and also extensive GGOs and consolidation areas in both lungs, not observed in PET/CT. PCR test of the patient was found to be positive. During the follow-up, the patient developed acute vein thrombosis. Due to increase in symptoms, the patient was taken to the ICU and died soon after.
|Figure 1: Positron emission tomography (PET)/computed tomography (CT), (a-c): Maximum intensity projection (MIP) (a), axial PET, fused and CT images, respectively (b and c). Axial CT images (d and e)|
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CASE 2. A 73-year-old asymptomatic man with lung cancer underwent PET/CT [Figure 2]a, [Figure 2]b, [Figure 2]c for staging. PET/CT showed subpleural GGOs with faint FDG uptake (SUVmax: 1.6) [Figure 2]b and [Figure 2]c, red arrows] in both lungs. About 1 week later, the patient developed fever and dyspnea, then an increase in GGOs was observed in thorax CT [Figure 2]d and [Figure 2]e. The patient with positive PCR test got worse while being followed-up in the ICU and died later.
|Figure 2: Positron emission tomography (PET)/computed tomography (CT), (a-c): Maximum intensity projection (MIP), (a), axial PET, fused and CT images, respectively (b and c). Axial CT images (d and e)|
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CASE 3. A 60-year-old asymptomatic man with lung adenocarcinoma was performed a PET/CT [Figure 3]a, [Figure 3]b. [Figure 3]c, [Figure 3]d for staging purpose. Primary lung malignancy and multiple metastases (bilateral lung nodules, bone and brain) were detected in PET/CT. Although both lungs appeared slightly blurred, it could not be distinguished from artifact and no parenchymal finding other than malignancy was reported. Since other common findings of COVID-19 could not be identified, the pleural effusion observed in PET/CT was considered non-COVID-19 causes. The patient presented with dyspnea in the following days and the subsequent COVID-19 PCR test was positive. CT detected bilateral GGOs, more prominent in the mid-lower zones of both lungs [Figure 3]e, [Figure 3]f, [Figure 3]g and the patient died soon after.
|Figure 3: Positron emission tomography (PET)/computed tomography (CT) (a-d): Maximum intensity projection (MIP) (a), axial PET, fused and CT images, respectively (b-d). Axial CT images (e-g)|
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CASE 4. A 66-year-old asymptomatic man diagnosed with lung adenocarcinoma underwent PET/CT [Figure 4]a, [Figure 4]b, [Figure 4]c, [Figure 4]d, [Figure 4]e for staging. Subpleural GGOs and linear opacities with faint FDG uptake (SUVmax: 1.6) [Figure 4]b, [Figure 4]c, [Figure 4]d, [Figure 4]e, red arrows] were observed in both lungs. Some of the nodular pleural thickening observed in the right hemithorax in PET/CT was connected with the primary tumor and was evaluated in favor of malignancy. The patient complained of dyspnea and cough 3 days after PET/CT. Thorax CT [Figure 4]f, [Figure 4]g, [Figure 4]h, [Figure 4]i showed widespread GGOs and accompanying consolidation and interlobular septal thickening areas (crazy paving) in all lobes of both lungs. In addition, vascular enlargement [Figure 4]h, red arrows], bronchiectasis and left pleural fluid/thickening [Figure 4]i, red arrow] were detected. The patient with positive PCR test developed ARDS and died.
|Figure 4: Positron emission tomography (PET)/computed tomography (CT) (a-e): Maximum intensity projection (MIP) (a), axial PET, fused and CT images, respectively (b-e). Axial CT images (f-i)|
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CASE 5. PET/CT [Figure 5]a and [Figure 5]b performed to evaluate the response of treatment to a 66-year-old asymptomatic man with squamous cell lung carcinoma did not reveal any parenchymal lung findings suggesting viral infection. During the follow-up, the patient stated onset of cough. Chest CT detected GGOs in the right lung middle lobe that were not observed in PET/CT [Figure 5]c, red arrow], and the PCR test was positive. In subsequent CT, total consolidative atelectasis developed in the middle and lower lobes of the right lung [Figure 5]d, black arrows], and consolidation areas occurred in the upper lobe of the left lung [Figure 5]d, red arrows]. During this study, the patient continued to receive antibacterial, antiviral and immunomodulatory therapy in the hospital.
|Figure 5: Positron emission tomography (PET)/computed tomography (CT) (a and b): Maximum intensity projection (MIP) (a), axial CT, fused and PET images, respectively (b). Axial CT image dated 07.04.2020 (c). Axial CT images dated 15.05.2020 (d and e)|
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CASE 6. A 63-year-old asymptomatic man with the diagnosis of lung cancer was applied PET/CT for staging. The patient had a high fever that started in the evening after PET/CT [Figure 6]a, [Figure 6]b, [Figure 6]c, [Figure 6]d, [Figure 6]e, [Figure 6]f . There was a consolidation area in the left lung lower lobe and pleural thickening/fluid in the left hemithorax [Figure 6]b and [Figure 6]c, red arrows]. However, these findings were thought to be due to peritoneal carcinomatosis invading the left diaphragm [Figure 6]b and [Figure 6]c, white arrows]. Furthermore, subpleural GGOs showing mild FDG uptake in both lungs were seen in PET/CT (SUVmax: 1.5) [Figure 6]d and [Figure 6]e, red arrows]. Then, PCR test of the patient was found to be positive. In the following CT [Figure 6]g, [Figure 6]h, [Figure 6]i, some GGOs disappeared, while others turned into consolidation [Figure 6]h, red arrows]. In addition, new GGOs developed in the right lung lower lobe posterobasal segment [Figure 6]i, red arrow]. The consolidated area on the left showed partial regression. The patient who developed dyspnea during the follow-up was taken to the ICU and then died.
|Figure 6: Positron emission tomography (PET)/computed tomography (CT) (a-f): Maximum intensity projection (MIP) (a), sagittal (b) and axial (c) fused image in mediastinum window, axial PET, fused and CT images, respectively (d-f). Axial CT images (g-i)|
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CASE 7. A 67-year-old man who underwent upper lobectomy because of left lung cancer was applied PET/CT for restaging. On the day of PET/CT, the patient was asymptomatic. PET/CT revealed recurrence [Figure 7]d and [Figure 7]e white arrows] in the residual left lung, as well as in the lower lobe superior segment of the right lung, and showed radiotherapy-related paramediastinal fibroatelectatic changes [Figure 7]d, yellow arrows]. Furthermore, PET/CT determined subpleural GGOs (SUVmax: 2.1) [Figure 7]f, red arrow] with mild FDG uptake not seen in previous CT [Figure 7]a, [Figure 7]b, [Figure 7]c in the right lung lower lobe posterobasal segment. PCR test was positive in the patient whose fever and dyspnea emerged 4 days after PET/CT. In the next CT, new GGOs and consolidated areas developed in the right lung [Figure 7]g and [Figure 7]i, red arrows]. Then the patient died.
|Figure 7: Axial computed tomography (CT) images dated 25.05.2019 (a-c). Axial CT, fused and positron emission tomography (PET) images of PET/CT, respectively (d-f). Axial CT images dated 27.03.2020 (g-i)|
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CASE 8. Widespread patchy GGOs and consolidation areas [Figure 8]a, red arrows] showing slightly increased FDG uptake in bilateral lungs were observed in PET/CT performed for staging intent to a 68-year-old woman with lung mucoepidermoid carcinoma. Antibiotics were given to the patient who was considered to have a bacterial infection. The patient was then given chemotherapy and PET/CT was applied to assess the response to the treatment. Bilateral lung findings showed mild regression in the latter PET/CT [Figure 8]b, red arrows]. During the follow-up, the patient's complaints of cough and dyspnea increased, fatigue and decreased appetite developed. Then, the PCR test was found to be positive. CT showed GGOs, patchy consolidation areas, interlobuler septal thickening and fibrous stripes in both lungs. There was an increase in findings [Figure 8]c, red arrows] compared to latter PET/CT. Antiviral therapy was also added to antibacterial drugs. Slight decline in findings was observed in the next CT [Figure 8]d and the PCR test got negative.
|Figure 8: Axial positron emission tomography (PET), computed tomography (CT) and fused images of PET/CT dated 02.10.2019, respectively (a). Axial PET, CT and fused images of PET/CT dated 23.03.2020, respectively (b). Axial CT image dated 09.04.2020 (c). Axial CT image dated 22.04.2020 (d)|
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| » Discussion|| |
F-18 FDG PET/CT is a widely used imaging method to evaluate malignancy. Since FDG uptake is also observed in inflammatory and infectious processes, it is not always easy to evaluate the signs of infection or malignancy of the lung in cancer patients. Furthermore, clinical symptoms or pulmonary radiological findings may be similar to infectious diseases in patients with malignancies. In our study, we tried to overcome this problem by evaluating the current data of the patient together with the previous or further clinical and imaging findings. The presence of bilateral multiple lobular and subsegmental GGOs and consolidation areas in CT images are typical for COVID-19., Thickening of the pleura adjacent to the parenchymal lung changes may be observed, while pleural effusion is an uncommon finding but may be seen with disease progression. In our study, left pleural fluid/thickening, thought to be due to COVID-19, was detected in the following CT of only the case 4. Different viral agents can cause similar signs of pneumonia on PET/CT, so differential diagnosis is challenging. In COVID-19 pneumonia, GGOs and reticular interlobular septal thickening are reported to be more likely to show peripheral distribution than in non-Covid pneumonia. In addition, the possibility of pleural effusion and lymphadenopathy is lower in COVID-19. However, differential diagnosis based on PET/CT findings alone cannot be made. When imaging findings raise suspicion of viral pneumonia, evaluation with clinical and laboratory tests will guide the differential diagnosis and confirmation with PCR test will lead to a definitive diagnosis.
The RT-PCR test has high specificity in the diagnosis of COVID-19; however, it may lead to false negative results and its sensitivity is reported to be low.,, In a study involving 36 patients with a final diagnosis of COVID-19, at presentation 35 patients had abnormal CT findings (sensitivity 97.2%), while 30 patients were found to have a positive PCR test (sensitivity 83.3%). In another study with 1014 patients, when the PCR test was considered as a reference in the diagnosis of COVID-19 infection, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of CT were 97%, 25%, 68%, 65% and 83%, respectively. In the study of Li et al. with 78 patients infected with COVID-19, cases were grouped as mild, common, severe and critical, according to the Chinese guideline. They obtained a total severity score (TSS) by CT visual quantitative evaluation. The scores of mild, common, and severe-critical type were 0, 1–11, and 8–18, respectively. The TSS cut-off of 7.5 had 82.6% sensitivity and 100% specificity in diagnosis of severe-critical type. Routine PET/CT is not recommended in the management of COVID-19 and the studies in the literature involved a small number of patients and were usually evaluated on a case-by-case basis. Therefore, further investigations are needed to evaluate the value of PET/CT in the diagnosis of COVID-19. However, it was stated that PET/CT contributes to the early diagnosis of COVID-19, especially in patients who are referred for other indications whose clinics are not typical.
It is supposed that interstitial pulmonary inflammation with the infiltration of plasma cells and macrophages may be the pathological basis of GGOs at the early phase of COVID-19. As the lesions progress, inflammatory exudate gathers in the alveolar space and connects the alveoli and creates consolidation. Increased anaerobic glycolysis in activated inflammatory cells increases glucose utilization, resulting in FDG uptake and the SUVmax is most FDG-avid pixel within a region of interest. The study of Qin et al. presented four highly suspected COVID-19 patients not confirmed by PCR test but diagnosed rely on history, clinical, laboratory and imaging findings. All those patients were symptomatic and had peripheral GGOs with high FDG uptake (SUVmax: 4.6–12.2) affecting at least 2 lung lobes in PET/CT. Some of them were accompanied by consolidation and/or interlobular septal thickening, and 3 patients had FDG avid lymph node involvement. In the other 2 studies, PET/CT findings of asymptomatic cancer patients were submitted., Setti et al. found peripheral lung GGOs and/or consolidations showing increased FDG uptake (SUVmax 4.3–11.3) in five non-lung cancer patients. Since the patients were asymptomatic, PCR tests were not performed on them. Another study interpreted the PET/CT findings of 6 non-lung cancer patients, four of whom had positive PCR test results. All patients had FDG avid interstitial pneumonia (SUVmax 2–7.7), and additionally there were FDG avid lymph nodes in one of them. In our study, PET/CT findings related to COVID-19, seen as pulmonary GGOs with mild FDG uptake (SUVmax: 1.3–2.1), were detected in four of 8 patients. COVID-19 has different parenchymal lung CT findings according to the period of disease. It is stated that GGOs are major findings in the early phase. In this study, only the detection of GGOs showing low FDG uptake may be due to early stage of COVID-19.
The findings of cancer patients infected with COVID-19 have been analyzed in several studies. In the study involving 1590 patients infected with COVID-19 (18 cancer and 1572 noncancer), Liang et al. asserted that a history of malignancy may be a risk factor for COVID-19. They also found that cancer patients had a higher risk of severe COVID-19 than patients without cancer. Additionally, among the patients with cancer, the rate of serious events (monitoring in the ICU due to invasive ventilation requirement or death) was found to be higher in those experienced surgery or chemotherapy in the past month than in those did not. Therefore, they suggested delaying elective operation or adjuvant chemotherapy for stable malignancy in endemic regions. Yang et al. argued that the study of Liang has a heterogeneous population of few cancer patients, and that the findings may not represent all cancer patients. In a study with 28 cancer patients infected with COVID-19, Zhang et al. found the incidence of serious events (53.6%) and deaths (28.6%) high and claimed cancer patients to have a poor prognosis. They stated that if the term from the recent anticancer treatment to the diagnosis of COVID-19 was ≤ 14 days, the probability of serious events increased. As a remarkable finding, 28.6% of the patients infected with COVID-19 were thought to be associated with nosocomial transmission. The most common cancer type in the study of Liang (28%) and Zhang (25%) was lung cancer. The relatively higher rate of lung cancer (87.5%) in our study was probably due to the fact that we performed this study in a single center in chest diseases and chest surgery hospital and included a subgroup of patients with PET/CT. The rates of severe event and death (75%) in our study were higher than in previous studies. In this study, PET/CT had findings that could be compatible with COVID-19 in the half of the all patients; however, all of them were diagnosed with COVID-19 by PCR test when symptoms and/or lung findings worsened on the days after PET/CT and most of them underwent anticancer treatment within 7 days of COVID-19 diagnosis. Furthermore, most of our patients had additional comorbidity. Advanced age and the presence of comorbid disease such as hypertension and diabetes mellitus are claimed to be a risk factor for severe COVID-19. In addition, all of the lung cancer patients were at an advanced stage and the patient with brain tumor was diagnosed as grade 4 glioblastoma multiforme. These factors may have affected our results. However, this study has limitations such as having no statistical comparison due to the low number of patients. So it is not proper to precisely comment with our findings, statistical analysis involving more patients are needed to identify independent risk determinants.
In conclusion, COVID-19 may be recognised early by detecting incidental findings in PET/CT, especially in asymptomatic patients. Thus, serious complications may be prevented and mortality may be reduced with the initiation of COVID-19 treatment and changes in anticancer treatment protocols in appropriate cases. In addition, thanks to early diagnosis, the spread of the disease may be prevented. Therefore, in the presence of possible COVID-19 findings in PET/CT, they should be reported and the patient should be referred to the relevant clinician. Furthermore, nuclear medicine units should take the essential precautions to prevent possible transmission to the personnel and other patients. The clinical and imaging findings of cancer patients have been evaluated in detail in this study and we consider that it will contribute to the literature.
The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Declaration of Helsinki 1975 that was revised in 2000.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2]