Keywords
2-deoxy-2-(Fluorine-18) fluoro-D-glucose positron emission tomography/computed tomography - active granulomatous diseases - benign lesions of the thorax - infective lesions - inflammatory or proliferative conditions
Introduction
Positron emission tomography/computed tomography (PET/CT) imaging with 2-deoxy-2-(Fluorine-18) fluoro-D-glucose (18F-FDG) is a combined functional and anatomic imaging modality widely used to evaluate, stage, and monitor malignancy.[1] The abnormal areas of 18F-FDG accumulation are identified by qualitatively comparing the tracer uptake with normal background activity. However,18F-FDG affinity is not malignancy specific and during the PET/CT oncologic evaluation, imagers may encounter incidental and/or co-existing 18F-FDG avid findings, which are not related to the investigated malignant processes. This may lead to false-positive results and incorrect diagnostic predicaments, which may significantly impact the care and welfare of patients. Accurate diagnosis can reduce unnecessary invasive procedures such as biopsy and thoracotomy in patients with benign disease,[2] and therefore, familiarity with the different causes of increased 18F-FDG uptake in the thorax mimicking cancer is imperative. This imaging review encompasses inflammation, infection, physiologic variants, trauma, iatrogenic processes, posttherapeutic changes and benign diseases of the lung parenchyma, pleura, and different components of the mediastinum and chest walls based on etiology for optimized diagnosis based on its thoracic location [Table 1].
Table 1 Diagnostic benign lesions of thorax with corresponding median SUVmax values
Physiologic Variants
Muscle tracer uptake is related to voluntary or involuntary exertion, increased insulin level, or postprocedural changes. Exertion up to 48 h before PET/CT imaging may result in muscle uptake.[3] Positive uptake features are mostly demonstrated in the head and neck, trunk, extremities, and diffusely throughout the body from different causes such as neck strain lying on stretcher, chewing gum, talking, finger tapping, cough, labored breathing, muscle spasms, jerking movements from seizure, and more. Familiarity with muscle uptake features (anatomic locations and symmetrical patterns) and knowledge of recent voluntary or involuntary exertion prior to PET/CT imaging are helpful to avoid false-positive diagnosis of cancer [Figure 1].
Figure 1 Whole body maximum intensity projection image demonstrating increased radiotracer uptake at the musculature of the right neck, right shoulder girdle predominantly at the pectoralis major and subscapularis muscles, and entire right upper extremity due to involuntary dyskinetic muscular exertion from recent seizure occurring < 48 h before the positron emission tomography/computed tomography imaging
Brown adipose tissue is a well-known cause of false-positive uptake on PET/CT due to the hypermetabolic nature of the tissue.[4],[5] Brown fat may be detected in 4%–5% of all PET/CT cases more frequently in women than in men.[6] The frequently encountered patterns of brown adipose tissue are bilateral and symmetrical at sites of CT-depicted fat tissue attenuation of sub-occipital, cervical, supraclavicular, axillary, paraspinal, and intercostal regions [Figure 2]. Intermittently, brown fat deposit may be at less common and asymmetrical locations potentially leading to an interpretation error, specifically along the sternum mimicking mammary lymph nodes.
Figure 2 Whole body positron emission tomography maximum intensity projection image demonstrating classic bilateral and symmetrical pattern of hypermetabolic brown adipose tissue at the sub-occipital, cervical, supraclavicular (arrows), axillary, and paraspinal regions
Myocardial metabolism may be from free fatty acid or glucose substrates depending on the fasting or nonfasting status of the patient. During oncologic imaging, the required patient's fasting forces the heart to use free fatty acid as substrate and should result in low and uniformed cardiac uptake features.[7] In real practice, the cardiac uptake patterns are variable even in serial PET/CT exams of the same patient. 18F-FDG uptake by atrial appendages or atria is related to atrial fibrillation or overload physiology. The less frequent tracer uptake by ventricles or simultaneously to all chambers of the heart may be secondary to pressure overload or underlying valvular heart diseases.[8] Correlation with additional cardiac imaging (CT, echocardiography, and magnetic resonance imaging [MRI]) may be useful to distinguish benign cardiac uptake from metastatic tumor and mediastinal lymphadenopathy[9]
[Figure 3].
Figure 3 Composite positron emission tomography/computed tomography images demonstrating tracer uptake at the right atrium/atrial appendage and left atrium (arrows, left image) and left atrial appendage (arrow, right image), which could mimic hypermetabolic mediastinal nodal disease
Lipomatous hypertrophy of the interatrial septum (LHIS) is a benign fat accumulation in the interatrial septum with a prevalence of 2%–3%. CT at the level of the fossa ovalis shows a “dumb-bell” shape due to sparing of the fossa in 78% of patients with LHIS. LHIS demonstrates a greater mean standardized uptake value (SUV) on PET/CT when compared to chest wall fat.[10] This is due to the increased amount of brown fat in LHIS, making it more metabolically active and thus 18F-FDG avid. These features will help differentiate LHIS from malignant cardiac processes. Fat accumulation in the interatrial septum increases with patient's age and obesity.[11] The thicker and bulkier the fat infiltration of the interatrial septum, the more prominent 18F-FDG uptake is seen. The diagnosis of LHIS rests on the fat attenuation characteristics demonstrated by the transmission CT [Figure 4].
Figure 4 Composite positron emission tomography/computed tomography images demonstrating hypermetabolic lipomatous hypertrophy of the inter-atrial septum with corresponding tissue with adipose attenuation characteristics on transmission computed tomography (arrows). A right peri-hilar hypermetabolic lung malignancy is seen on axial images (small arrow)
Inflammation
Lung inflammatory pseudotumor, also known as inflammatory myofibroblastic tumor, represents a spectrum of myofibroblastic proliferations containing a varying infiltrate of chronic inflammatory cells.[12] Radiographically, it is nonspecific featuring round/oval lung nodule or mass with possible speculations and variable degrees of contrast enhancement. Due to infiltrating inflammatory cell composition, it exhibits 18F-FDG uptake simulating malignancy [Figure 5].
Figure 5 Composite positron emission tomography/computed tomography images demonstrating a spiculated right upper pulmonary lobe lesion with prominent tracer uptake (cross-hair) suspicious for lung malignancy. Histology of the resected lesion shows an inflammatory pseudotumor
Resection of the lesion is the treatment of choice. However, nonsurgical treatments such as radiotherapy (RT) and steroids have been employed in the setting of incomplete surgical resection, tumor recurrence, and patients being unfit for surgery. PET/CT can play a role in monitoring postradiation changes attempting to decrease surgical and further radiation treatments.[13] The definitive identification of lung inflammatory pseudotumor is histological.
Systemic IgG4-related sclerosing disease is characterized by lesions with lymphoplasmacytic infiltrative fibrosis. Also known as autoimmune pancreatitis due to the originally reported involvement of the pancreas, this disorder also features lesions of different organ systems of the body such as the orbits, salivary glands, thyroid, gallbladder, biliary ducts, retroperitoneum, aorta, kidneys, prostate, lymphatic system, airways and lungs [Figure 6]. Lung involvement is related to IgG4-positive plasma cell and lymphocyte infiltrating the parenchyma with immunohistochemically evident fibrous interstitial proliferation in the background. Correct diagnosis of this condition is crucial because steroid therapy can be curative. Unfortunately, malignancy cannot be differentiated from the imaging findings, and tissue sampling is necessary to confirm the diagnosis of IgG4-related lung disease.[14] Within the mediastinum, it can present with nonspecific bronchial wall thickening [Figure 7]. Recognizing additional areas of involvement, especially the bilateral and symmetrical orbital and salivary gland 18F-FDG avid features, is helpful in differentiating the correct diagnosis from malignancy.
Figure 6 Whole body maximum intensity projection images of a patient with IgG4-related sclerosing disease before and after corticotherapy demonstrate resolution of tracer uptake at the bilateral salivary glands (top arrows), right hilar node, right lower pulmonary lobe (midlevel arrows) and pancreas (bottom arrow)
Figure 7 Composite positron emission tomography/computed tomography images demonstrating IgG4-related sclerosing lesions of bilateral bronchi with narrowing of the airways (arrows)
Sarcoidosis is a chronic systemic inflammatory disease of unknown origin involving preferentially lungs often with associated hilar and mediastinal adenopathy. Characteristic radiologic and PET/CT features of thoracic sarcoidosis are well recognized by clinicians and imagers and are actually used to follow the status of patients undergoing treatment.[15],[16] Since the PET/CT features are frequently indistinguishable from other advanced neoplasms with mediastinal lymphadenopathy, histologic proof is typically necessary for the correct diagnosis of systemic inflammatory disease [Figure 8].
Figure 8 Composite positron emission tomography/computed tomography images demonstrating clustered hypermetabolic nodal disease in the mediastinum and bilateral hilar regions from sarcoidosis
The false-positive PET/CT findings from reactive process to foreign material mimic nodal metastasis from lung malignancy. Mediastinal node staging with PET/CT in coal workers has been rendered insufficient due to the high false-positive rates given the presence of pneumoconiosis with positive predicted values as low as 66%.[17],[18] Therefore, more invasive methods of nodal sampling are necessary in differentiating anthracosis from malignancy in patients with PET/CT positive lymph nodes and known pneumoconiosis exposure [Figure 9].
Figure 9 Composite positron emission tomography/computed tomography images in axial and coronal projections (left) and maximum intensity projection image (right) demonstrating hypermetabolic adenopathy in the subcarinal and bilateral hilar regions from histologically proven anthracosis
Thyroid uptake in PET/CT imaging poses a common conundrum among imagers. Diffuse uptake is typically associated with a benign pathology such as thyroiditis and focal nodular uptake may be related to hyperfunctioning nodules or malignancy.[19] Occasionally, a substernal thyroid is present and can present as a focal hypermetabolic mediastinal mass on PET/CT [Figure 10]. Three-dimensional PET/CT evaluation of the thoracic inlet is helpful to ascertain the origin of this potential lesion.
Figure 10 Composite positron emission tomography/computed tomography images demonstrating uptake features of thyroiditis with substernal component (crosshair). The diffuse pattern of F-18 FDG distribution in the thyroid gland is in favor of benign or inflammatory processes
Infections
Thoracic infectious diseases may target the lung parenchyma, mediastinum, or chest wall. The high concentration of macrophages and inflammatory cells and consequently high 18F-FDG avidity at sites of infection and abscess formation may mimic cancer especially at prior sites of resected/treated malignancy and the existence of cavitation reminiscent of malignant central necrosis [Figure 11].[20] Coccidioidomycosis is an endemic fungal disease of the arid and semi-arid regions of the North, Central, and South American continent and is secondary to inhalation of the arthroconidia form of Coccidioides immitis. This disease, primarily a regional public health concern, may be encountered worldwide due to the large population migration, and seasonal and recreational transit through the endemic areas. Risk factors are pregnancy, extreme stages of life, diabetes, corticosteroid use, immunocompromised health conditions and dark-skinned ethnics. Although the pulmonary manifestations of this infection vary and resemble those seen in mycobacterial infections,[21] the acute phase of the disease may present with nonspecific infectious findings such as infiltrates, consolidation, adenopathy, and pleural effusion[22] giving the appearance of a primary lung malignancy [Figure 12].
Figure 11 Composite positron emission tomography/computed tomography images (left) and maximum intensity projection image (right) of the right chest wall abscess and of right upper pulmonary lobe abscess with cavitation (arrow) in two different patients mimicking malignancy
Figure 12 Composite positron emission tomography/computed tomography and maximum intensity projection images demonstrating coccidiodomycosis of the medial left lung and mediastinal and hilar nodes
Trauma, Iatrogenic and Postprocedural Changes
Benign Tumors
Schwannomas involve frequently spinal nerve roots, and nerves of the head and neck, and flexor surfaces of extremities. They are usually solitary in a patient population of third to fifth decades of life[29] with or without association with neurofibromatosis type 1. Their prominent 18F-FDG uptake, not related to size or tumor proliferation rate characterized by the Ki-67 index may be linked to overexpression of glucose transporter proteins by the tumor cells.[30] Thoracic schwannomas may involve the mediastinum or chest wall [Figure 21]. PET/CT cannot distinguish schwannomas from malignant peripheral nerve sheath tumors or malignant nodal disease based solely on the uptake values. The diagnosis of schwannomas rests on histological identification. Fibromatosis is a group of benign soft tissue tumors with locally aggressive behavior characterized by proliferation of fibroblasts with mature collagen.[31] It is mostly associated with Gardner's syndrome. This syndrome is a rare autosomal dominant inherited disorder characterized by intestinal polyposis, bone and soft-tissue tumors, including osteomas, epidermal inclusion cysts, lipomas, fibromas, gastric and duodenal polyposis, frequently complicated by subsequent desmoid tumors of the mesenteric and abdominal/chest wall [Figure 22]. The PET/CT uptake features are probably related to high cellularity and mitotic activity of fibromatosis. Elastofibromas dorsi are benign soft tissue tumors characterized by fibroblastic proliferation and accumulation of abnormal elastic fibers with a reported prevalence on CT of 2% in the elderly population. These lesions are predominantly encountered in elderly women. They may be bilateral and asymmetrical in size in about 10% of all cases. MRI and CT show elongated soft tissue masses with combined characteristics of muscle and fat tissue. Elastofibromas are located between the ribs and serratus and latissimus dorsi musculature, deep to the inferior angle of the scapula. PET/CT shows mild to moderate degree of 18F-FDG uptake. These cross-sectional and PET/CT features are helpful to avoid unnecessary biopsy during evaluation of primary and secondary malignancies[32]
[Figure 23]. Other benign bones tumors may be 18F-FDG avid. They include osteoblastoma, chondromyxoid fibroma, aneurysmal bone cyst [Figure 24], giant cell and brown tumor.[33],[34] These lesions cannot be distinguished from malignant bone tumors based on SUV and additional imaging methods (MRI, CT, and radiograph) and ultimately tissue sampling may be required for further characterization.[35]{Figure 21}{Figure 22}{Figure 23}{Figure 24}
Figure 21 Composite positron emission tomography/computed tomography images demonstrating two benign schwannomas of the infero-posterior mediastinum at right retrocrural region (top row, arrows) and of the right chest wall at intercostal location (bottom row, arrows)
Figure 22 Axial positron emission tomography/computed tomography image of a patient with Gardner's syndrome demonstrating a hypermetabolic left anterior chest wall desmoid encasing an adjacent rib (arrow)
Figure 23 Composite positron emission tomography/computed tomography images of bilateral hypermetabolic elastofibroma dorsi at the postero-lateral aspect of the chest wall (right side: top image, left side: bottom image) located between the ribs and inferior aspect of the scapula (arrows)
Figure 24 Composite positron emission tomography/computed tomography and computed tomography (upper right corner, arrow) images of an aneurysmal bone cyst of the right aspect of T9 with increased tracer uptake (crosshair)
Conclusion
Significant overlap regarding the appearance of inflammatory, infectious and malignant processes exists causing a potential problem in accurate PET/CT interpretation. Benign processes are more inclined to exhibit symmetrical, curvilinear, geometric, anatomic and diffuse scintigraphic features. Malignant lesions usually show a random distribution with nodular, mass-like and amorphous PET/CT features. Correlation with clinical, radiation and surgical history and also imaging cross-check evaluation of contemporary CT, MR and radiographs for the anatomic location and further imaging remains the mainstay of PET/CT characterization of positive findings. For indeterminate cases, tissue sampling remains the only option to adequately identify these indeterminate lesions. Familiarity of false positive findings improves the PET/CT evaluation accuracy of benign lesions of the thorax.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
