Comparison of Transoral and Transcervical Ultrasonography with MRI for the Diagnostic Work-Up of Oropharynx Tumors: A Protocol for a Multicenter Clinical Trial (SPOTUS).

This study protocol for a prospective, multicenter, diagnostic, clinical trial describes the integration of transoral and transcervical ultrasonography (US) in the initial clinical work-up of patients referred to tertiary head and neck cancer centers with suspected oropharyngeal cancer. The study evaluates the blinded detection rate of oropharyngeal tumors and their US-estimated size and T-stage before histopathology and cross-sectional imaging are available. Magnetic resonance imaging (MRI) scans will be prospectively rated while blinded to T-site histopathology and US. The primary outcome measures of diagnostic accuracy, including sensitivity, specificity, positive and negative predictive values, and overall accuracy, will be reported for both US and MRI. A sub-analysis of prospectively rated 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) scans in patients with clinically suspected unknown primary tumors will also be compared to US and MRI. Secondary outcome measures, including a comparison of tumor size estimation between US, MRI, and CT, will also be reported. This prospective multicenter study will provide clinically impactful information regarding the use of transoral and transcervical US for the diagnostic work-up of oropharyngeal cancer.

Clinical Evaluation of Deep Learning for Tumor Delineation on 18F-FDG PET/CT of Head and Neck Cancer.

Artificial intelligence (AI) may decrease 18F-FDG PET/CT-based gross tumor volume (GTV) delineation variability and automate tumor-volume-derived image biomarker extraction. Hence, we aimed to identify and evaluate promising state-of-the-art deep learning methods for head and neck cancer (HNC) PET GTV delineation. Methods: We trained and evaluated deep learning methods using retrospectively included scans of HNC patients referred for radiotherapy between January 2014 and December 2019 (ISRCTN16907234). We used 3 test datasets: an internal set to compare methods, another internal set to compare AI-to-expert variability and expert interobserver variability (IOV), and an external set to compare internal and external AI-to-expert variability. Expert PET GTVs were used as the reference standard. Our benchmark IOV was measured using the PET GTV of 6 experts. The primary outcome was the Dice similarity coefficient (DSC). ANOVA was used to compare methods, a paired t test was used to compare AI-to-expert variability and expert IOV, an unpaired t test was used to compare internal and external AI-to-expert variability, and post hoc Bland-Altman analysis was used to evaluate biomarker agreement. Results: In total, 1,220 18F-FDG PET/CT scans of 1,190 patients (mean age ± SD, 63 ± 10 y; 858 men) were included, and 5 deep learning methods were trained using 5-fold cross-validation (n = 805). The nnU-Net method achieved the highest similarity (DSC, 0.80 [95% CI, 0.77-0.86]; n = 196). We found no evidence of a difference between expert IOV and AI-to-expert variability (DSC, 0.78 for AI vs. 0.82 for experts; mean difference of 0.04 [95% CI, -0.01 to 0.09]; P = 0.12; n = 64). We found no evidence of a difference between the internal and external AI-to-expert variability (DSC, 0.80 internally vs. 0.81 externally; mean difference of 0.004 [95% CI, -0.05 to 0.04]; P = 0.87; n = 125). PET GTV-derived biomarkers of AI were in good agreement with experts. Conclusion: Deep learning can be used to automate 18F-FDG PET/CT tumor-volume-derived imaging biomarkers, and the deep-learning-based volumes have the potential to assist clinical tumor volume delineation in radiation oncology.

Response Evaluation Following Radiation Therapy With 18F-FDG PET/CT: Common Variants of Radiation-Induced Changes and Potential Pitfalls.

Radiation therapy (RT) is one of the cornerstones in cancer treatment and approximately half of all patients will receive some form of RT during the course of their cancer management. Response evaluation after RT and follow-up imaging with 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can be complicated by RT-induced acute, chronic or consequential effects. There is a general consensus that 18F-FDG PET/CT for response evaluation should be delayed for 12 weeks after completing RT to minimize the risk of false-positive findings. Radiation-induced late side effects in normal tissue can take years to develop and eventually cause symptoms that on imaging can potentially mimic recurrent disease. Imaging findings in radiation induced injuries depend on the normal tissue included in the irradiated volume and the radiation therapy regime including the total dose delivered, dose per fraction and treatment schedule. The intent for radiation therapy should be taken in consideration when evaluating the response on imaging, that is palliative vs curative or neoadjuvant vs adjuvant RT. Imaging findings can further be distorted by altered anatomy and sequelae following surgery within the radiation field. An awareness of common PET/CT-induced changes/injuries is essential when interpreting 18F-FDG PET/CT as well as obtaining a complete medical history, as patients are occasionally scanned for an unrelated cause to previously RT treated malignancy. In addition, secondary malignancies due to carcinogenic effects of radiation exposure in long-term cancer survivors should not be overlooked. 18F-FDG PET/CT can be very useful in response evaluation and follow-up in patients treated with RT, however, variants and pitfalls are common and it is important to remember that radiation-induced injury is often a diagnosis of exclusion.

Disseminated Primary Uterine Hepatoid Adenocarcinoma with α-Fetoprotein Production Demonstrated on 18F-FDG PET/CT.

We present the 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) findings in a 57-year-old woman with post-menopausal bleeding diagnosed with hepatoid adenocarcinoma (HAC) with a primary tumour in the uterine corpus and a highly elevated level of serum-α-fetoprotein (S-AFP) at presentation. HAC is a variant of adenocarcinoma with hepatic differentiation representing a heterogeneous group of neoplasms that morphologically and immunphenotypically resemble hepatocellular carcinoma (HCC) but are of extrahepatic origin. Microscopically, they are usually poorly differentiated adenocarcinomas proliferating in solid sheets or in a trabecular or cord-like arrangement. Primary uterine HAC is exceedingly rare with a general poor prognosis, and data is sparse and limited to case reports, making the clinical management challenging. Various primary anatomical sites have been reported in the literature, with the stomach being the most common primary site. 18F-FDG PET/CT plays an important role in staging and follow-up in many gynecological malignancies including uterine corpus cancer. To the best of our knowledge, this is the first report describing a primary uterine hepatoid adenocarcinoma with metastases to bone, vagina and lymph nodes on 18F-FDG PET/CT. By utilizing the ability of PET to detect early metabolic changes prior to visible structural changes on conventional imaging, this case illustrates a potential role of 18FDG-PET/CT in the staging of primary endometrial HAC by depicting distant metastasis that is not readily identifiable on CT alone.

Baseline FDG PET/CT in free breathing versus deep inspiration breath-hold for pediatric patients with mediastinal lymphoma.

INTRODUCTION: The prospective TEDDI protocol investigates the feasibility of radiotherapy delivery in deep inspiration breath-hold (DIBH) for pediatric patients. To secure optimal radiotherapy planning, a diagnostic baseline FDG PET/CT in free breathing (FB) and DIBH was acquired. The anatomical changes in the mediastinum and the effect on PET metrics between the two breathing conditions were assessed for pediatric patients with mediastinal lymphoma. MATERIAL AND METHODS: Ten patients aged 5-17 were included and had a PET/CT in FB and DIBH. Metabolic active lymphoma volumes were manually delineated with a visually based segmentation method and the PET metrics were extracted. The anatomical lymphoma, lung and heart volumes were delineated on CT. RESULTS: The lung volume increased while the heart was displaced caudally and separated from the lymphoma in DIBH compared to FB. Both the anatomical and the metabolically active lymphoma volumes appeared different regarding shape and configuration in the two breathing conditions. The image quality of the DIBH PET was equal to the FB PET regarding interpretation and delineation of lymphoma lesions. All PET metrics increased on the DIBH PET compared to the FB PET with the highest increase observed for the maximum standardized uptake value (33%, range 7-56%). CONCLUSION: Diminished respiratory motion together with anatomical changes within the lymphoma increased all PET metrics in DIBH compared to FB. The anatomical changes observed in DIBH compared to FB are expected to reduce radiation doses to the heart and lungs in pediatric patients with mediastinal lymphoma referred for radiotherapy delivery in DIBH and, thereby, reduce their risk of late effects. TRIAL REGISTRATION: The Danish Ethical Committee (H-16035870, approved November 24th 2016), the Danish Data Protection Agency (2012-58-0004, approved 1 January 2017). Registered retrospectively at clinicaltrials.gov (NCT03315546, 20 October 2017).

Rare Presentation of Late Complications After Undiagnosed Perforated Appendicitis Mimicking Recurrent Endometrial Carcinoma on 18F-FDG PET/CT.

ABSTRACT: Acute appendicitis is one of the most common causes of acute abdominal pain. Undiagnosed or untreated appendicitis can lead to serious complications. The most frequent complication of acute appendicitis is perforation with subsequent formation of a localized periappendiceal abscess or diffuse bacterial peritonitis. Late occurring complications following undiagnosed appendix perforation can pose a diagnostic challenge due to uncharacteristic clinical and imaging presentation. Herein, we describe late findings of undiagnosed perforated appendicitis that on 18F-FDG PET/CT mimicked recurrent endometrial carcinoma disease in a 67-year-old woman.

PET/CT Variants and Pitfalls in Gynecological Cancers.

The role of hybrid imaging with 2-[18F] flourodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) is continuously evolving and now considered standard practice in evaluation of disease stage, treatment response, recurrent disease and follow-up for numerous primary malignancies. In gynecological malignancies FDG PET/CT plays an important role, not only in the assessment of disease in the pre-and post-therapy setting, but also in radiation therapy (RT) planning by defining the metabolically active gross tumor volume (GTV. The glucose analogue radiotracer, FDG, is by far the most utilized radiotracer in PET/CT and is typically seen with high uptake in malignant cells. The radiotracer FDG has a high sensitivity but low specificity for malignancy, as benign processes with an inflammatory response for example infection, are also FDG-avid. In the evaluation of the female pelvic region an awareness of potential confounding factors in the interpretation of FDG is essential as variations of FDG uptake occur in accordance with the menstrual cycle and the menopausal state. Incidental imaging findings in the female genital can pose differential diagnostic challenges as false-positive and false-negative findings in benign and malignant processes are not uncommon. Gynecological malignancies continue to pose major public health problems with cervical cancer as the fourth most common cancer in women ranking after breast cancer, colorectal cancer and lung cancer. Familiarity with frequently encountered benign and malignant variants and pitfalls in FDG PET/CT in the female pelvic region can aid the reader in differential diagnostic considerations.

Relapse localization in Danish pediatric patients with Hodgkin lymphoma.

BACKGROUND: Pediatric Hodgkin lymphoma (pHL) is highly curable. However, a minority experience relapse and are subjected to toxic salvage regimens. Investigating the patterns of relapse could help to select the patients and/or the involved sites that would benefit from consolidating radiotherapy. MATERIAL AND METHODS: The Danish Childhood Cancer Registry was used to identify children <18 years with relapsed pHL from 1990-2018. The lymphoma volumes involved at diagnosis and at relapse were contoured on the patients' original scans. Rigid image co-registration was used to merge the scans enabling a visual assessment of the anatomical relapse localization relative to the initially involved lymph nodes, and if irradiated, to the radiotherapy field. RESULTS: From 185 patients with pHL, 24 patients with relapse were available for analysis. All patients received combination chemotherapy and seven had consolidating radiotherapy. Relapses exclusively in initially involved sites occurred in 14 patients. Relapses exclusively in new sites were rare and only observed in three irradiated patients. Seven patients relapsed in both initially involved and new sites. The median time to relapse was 6 months (range 2-59 months), however, in-field relapses in irradiated patients occurred later (54 months, range 10-59 months). Neither risk group, initial bulky disease, early response, or metabolic activity seemed to be associated with the site of a later relapse. CONCLUSION: The number of relapses were small, and conclusions regarding the selection of patients for radiotherapy could not be drawn. Relapse exclusively in initially involved sites were the most common, most often in the exact same initially involved lymph nodes. Hence, modern involved site radiotherapy, focusing on the initially involved lymphoma volume and minimizing the radiation doses to normal tissues, should be applied when consolidating radiotherapy is used in patients with pHL.

Imaging for Target Delineation in Head and Neck Cancer Radiotherapy.

The definition of tumor involved volumes in patients with head and neck cancer poses great challenges with the increasing use of highly conformal radiotherapy techniques eg, volumetric modulated arc therapy and intensity modulated proton therapy. The risk of underdosing the tumor might increase unless great care is taken in the process. The information gained from imaging is increasing with both PET and MRI becoming readily available for the definition of targets. The information gained from these techniques is indeed multidimensional as one often acquire data on eg, metabolism, diffusion, and hypoxia together with anatomical and structural information. Nevertheless, much work remains to fully exploit the available information on a patient-specific level. Multimodality target definition in radiotherapy is a chain of processes that must be individually scrutinized, optimized and quality assured. Any uncertainties or errors in image acquisition, reconstruction, interpretation, and delineation are systematic errors and hence will potentially have a detrimental effect on the entire radiotherapy treatment and hence; the chance of cure or the risk of unnecessary side effects. Common guidelines and procedures create a common minimum standard and ground for evaluation and development. In Denmark, the treatment of head and neck cancer is organized within the multidisciplinary Danish Head and Neck Cancer Group (DAHANCA). The radiotherapy quality assurance group of DAHANCA organized a workshop in January 2020 with participants from oncology, radiology, and nuclear medicine from all centers in Denmark, treating patients with head and neck cancer. The participants agreed on a national guideline on imaging for target delineation in head and neck cancer radiotherapy, which has been approved by the DAHANCA group. The guidelines are available in the Supplementary. The use of multimodality imaging is being recommended for the planning of all radical treatments with a macroscopic tumor. 2-[18F]FDG-PET/CT should be available, preferable in the treatment position. The recommended MRI sequences are T1, T2 with and without fat suppression, and T1 with contrast enhancement, preferable in the treatment position. The interpretation of clinical information, including thorough physical examination as well as imaging, should be done in a multidisciplinary setting with an oncologist, radiologist, and nuclear medicine specialist.

Extensive Subcutaneous Foreign Body Granulomas Associated With "Skin Popping" Demonstrated on 18F-FDG PET/CT.

In illicit drug use, "skin popping" refers to the method of administering drugs by injecting it into the subcutaneous tissue. "Skin popping" can lead to acute and chronic skin manifestations caused by the drug itself and/or by the various adulterants and fillers commonly added to drug substances. Chronic skin manifestations include a foreign-body reaction with formation of granulomas at the site of injection. We present the F-FDG PET/CT findings of extensive subcutaneous granulomas in a 58-year-old woman with a heroin addiction undergoing treatment for infective endocarditis of the mitral valve.

18F-FDG PET/CT Findings in Disseminated Genital Herpes in an Immunocompetent Patient With Anaplastic Lymphoma Kinase Rearranged Advanced Nonsmall Cell Lung Cancer.

We present the PET/CT findings of extensive disseminated genital herpes simplex virus infection in a 29-year-old woman known with disseminated anaplastic lymphoma kinase-mutated nonsmall lung cancer. PET/CT revealed extensive involvement of the outer and inner genitalia, multiple lymph nodes extending from the porta hepatis to the groins, and involvement of the liver. Disseminated herpes simplex virus infection is well described in neonates and immunocompromised individuals but very rare in immunocompetent adults as was the case with this patient.

18 F-FDG PET/CT in Extensive Graft-Versus-Host Disease of the Gastrointestinal Tract Following Autologous Stem Cell Transplantation.

Graft-versus-host-disease (GVHD) following stem cell transplantation (SCT) is a common complication in patients that have undergone allogenic SCT but rare in recipients of autologous SCT. Gastro-intestinal tract (GIT)-GVHD can be difficult to diagnose due to non-specific symptoms such as fever, nausea, diarrhea, and vomiting; a histological confirmation is therefore required. Here, we present the findings of a whole-body 18FDG PET/CT with extensive and multifocal involvement of the GIT in a patient that developed severe acute GVHD 93 days post autologous SCT for Hodgkin's lymphoma. PET and CT findings included characteristic patterns of bowel inflammation with bowel wall thickening, mural stratification and enhancement with high FDG-uptake of the involved regions, as well as typical extra intestinal findings such as ascites, engorgement of the vasa recti and stranding of the mesenteric fat. Although, the above-mentioned findings are not exclusive to GIT-GVHD and can be seen in other settings of inflammatory bowel disease such as enterocolitis or Mb Crohn our findings were used for targeted biopsy that confirmed acute GIT-GVHD. This case demonstrates that 18F-FDG-PET/CT can be a valuable non-invasive tool in mapping the activity and distribution of intestinal GVHD and direct for targeted biopsies of involved regions.

18F-FDG PET/CT Findings Following Repeated Intramuscular Injections of "Site Enhancement Oil" in the Upper Extremities.

We present the findings on F-FDG PET/CT in a 50-year-old man known to self-administer intramuscular injections with site enhancement oil in the upper extremities. PET images show diffuse pathological high FDG uptake in soft tissue of the upper arms and in scanned portions of the forearms. On the CT images, the muscles in the upper arm are swollen with a moth-eaten appearance and surrounding edema. Interspersed in the muscle tissue are several "cystic" lesions interpreted as oil deposits termed oleomas.

Clinical utility of 18F-FDG positron emission tomography/computed tomography scan vs. 99mTc-HMPAO white blood cell single-photon emission computed tomography in extra-cardiac work-up of infective endocarditis.

The extra-cardiac work-up in infective endocarditis (IE) comprises a search for primary and secondary infective foci. Whether 18FDG-PET/CT or WBC-SPECT/CT is superior in detection of clinically relevant extra-cardiac manifestations in IE is unexplored. The objectives of this study were to identify the numbers of positive findings detected by each imaging modality, to evaluate the clinical relevance of these findings and to define the reproducibility for extra-cardiac foci in patients with definite IE. Each modality was evaluated for numbers and location of positive extra-cardiac foci in patients with definite IE. A team of 2 × 2 cardiologists evaluated each finding to determine clinical relevance. Clinical utility was determined by 4 criteria converted into an ordinal scale. Using the manifestation with highest clinical utility rating in each patient, the clinical impact of the two imaging modalities was expressed in a clinical utility score. To evaluate reproducibility for each modality, an imaging core laboratory reviewed all findings. In 55 IE patients, 91 pathological foci were found by FDG-PET/CT and 37 foci were identified by WBC-SPECT/CT (p < 0.001). The clinical utility of FDG-PET/CT was significantly higher than that of WBC-SPECT/CT when comparing clinical utility score (2.06 vs. 1.17; p = 0.01). In assessment of extra-cardiac diagnostics in IE, inter-observer reproducibility was substantial for WBC-SPECT/CT (k 0.69, 95% CI 0.49-0.89) and substantial to excellent for FDG-PET/CT (k 0.79, 95% CI 0.61-0.98). FDG-PET/CT has a significantly higher clinical utility score than WBC SPECT/CT and is potentially superior to WBC-SPECT/CT in detection of extra-cardiac pathology in patients with IE.

A Case of Asymptomatic Venous Air Embolism Demonstrated on 18F FDG PET/CT.

We present the findings on F FDG PET/CT in connection with iatrogenic venous air embolism. The patient was referred for a posttreatment evaluation PET/CT for peripheral T-cell lymphoma. On the PET images, an intense FDG-uptake was seen in the injected vein. Simultaneous non-contrast-enhanced CT showed air bubbles of various sizes within the affected veins. Because no intravenous contrast was administered, we conclude that the source of venous air embolism was either the insertion of the peripheral intravenous cannula and/or the injection of F FDG, via a power injector, 1 hour before the scan.

Pelvic Actinomycosis Associated with an Intrauterine Contraceptive Device Demonstrated on F-18 FDG PET/CT.

A 44-year-old woman with a history of dysmenorrhea, obstipation, and low back pain was investigated for gynecological disorder. Physical examination indicated a "frozen pelvis". Ultrasound examination revealed the ovaries adherent to the uterus, bilateral ovarian cysts, and an intrauterine contraceptive device in situ, which reportedly had been in place for 19 years. Prior to a scheduled laparoscopy, the patient returned with oedema of the lower abdomen and legs, fatigue, and weight loss. Laboratory findings included elevated CA-125, anemia, leucocytosis and high C-reactive protein. Pelvic actinomycosis was subsequently diagnosed. We report the PET/CT appearance of this condition.