Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. HMPAO SPECT or SPECT/CT Brain Single-photon-emission computed tomography (SPECT) studies can be used to assess perfusion in patients with moyamoya and can be augmented with acetazolamide challenge to assess perfusion instability and vascular reserve. Perfusion imaging is also used to assess functional improvement after treatment [39]. Arteriography Cervicocerebral Catheter angiography is required for definitive diagnosis of moyamoya and is typically obtained as part of a preoperative assessment prior to surgical revascularization or following revascularization to assess the development of surgically created collaterals. US Duplex Doppler Transcranial Head US does not typically play a role in the management of children with moyamoya. Variant 4: Child. Known or suspected cervicocranial arterial dissection based on clinical or imaging findings. Next imaging study. Cervicocranial artery dissection occurs in 2.5/100,000 children per year and is up to 4 times more common in children than in adults [50-52]. Purely intracranial dissections are also more common in children than adults [50]. Patients with cervical artery dissection can present with headache, neck pain, or ischemic infarction due to emboli, whereas patients with intracranial artery dissection can present with ischemic infarction, subarachnoid hemorrhage (SAH), or symptoms due to local mass effect [50,52]. A history of antecedent trauma may or may not be present. CT Head CT can show areas of infarction or SAH although the sensitivity of CT is less than that of MRI with DWI for demonstrating acute infarction [43]. A crescent-shaped hyperattenuating area in a cranial or cervical artery is consistent with an intramural hematoma and is highly suggestive of dissection [52]. CTA Head and Neck CTA can demonstrate vessel narrowing, pseudoaneurysm, or an intimal flap in dissection [50,52]. MRI Head and Neck MRI is the preferred study for the demonstration of infarction due to cervicocranial arterial dissection [50,52,53].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. DWI and perfusion-weighted MRI provide information on regions of infarction. SWI can demonstrate emboli, and increased oxygen extraction leads to prominence of the veins in infarcted regions. T1-weighted imaging with fat suppression or T2-weighted imaging may demonstrate an intramural hematoma in 76% to 91% of patients with dissection [50,52]. MRA Head and Neck MRA without or with IV contrast may be used to assess for cervicocranial artery dissection to demonstrate an intimal flap, vessel narrowing, or pseudoaneurysm formation [52,53]. Arteriography Cervicocerebral Catheter angiography remains the gold standard for the radiologic evaluation of dissection but is typically reserved for patients in whom dissection is suspected but not confirmed on noninvasive imaging [52,53]. Angiography may reveal vessel narrowing, pseudoaneurysm formation, or an intimal flap in regions of dissection and distal vessel occlusions due to emboli. US Duplex Doppler Transcranial and Carotid Artery Doppler US may be used to evaluate the cervical internal carotid arteries for dissection. The technique is of limited utility for carotid dissections at or above the skull base and in the evaluation of the vertebral arteries because of a lack of a good acoustic window [52]. Variant 5: Child. Clinical presentation suggestive of acute stroke, known or suspected central nervous system vasculitis. Initial imaging. Childhood vasculitis is as an inflammatory process only affecting the intracranial vessels and can result in stroke. It can present as childhood primary angiitis of the central nervous system or as a secondary phenomenon in systemic rheumatologic infections and neoplastic conditions [54]. Childhood primary angiitis of the central nervous system is subcategorized into large-medium vessel vasculitis (angiography positive) or small vessel (vessel abnormality too small to be demonstrated on MRA, CTA, or conventional angiography) best diagnosed by brain biopsy [55].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. The diagnosis of childhood primary angiitis of the central nervous system requires an acquired neurologic deficit, angiographic or histologic features of central nervous system vasculitis, and no evidence of a systemic condition associated with the central nervous system findings. CT Head Evaluation of central nervous system vasculitis by CT is typically negative [56]. CTA Head CTA can provide a noninvasive assessment of intracranial vessels in arteriopathies as an alternative to catheter angiography in some patients but is typically negative in small-vessel vasculitis (eg, childhood primary angiitis of the central nervous system) [17]. MRI Head MRI typically shows progressive multifocal parenchymal lesions on T2-weighted imaging. Gadolinium enhancement of lesions is inconsistent. MRA Head MRA can provide a noninvasive assessment of intracranial vessels in arteriopathies as an alternative to catheter angiography in some patients but is typically negative in small vessel-vasculitis (eg, childhood primary angiitis of the central nervous system) [17]. Arteriography Cervicocerebral Catheter angiography is the most sensitive imaging method in the assessment of cerebral vasculitis but is typically negative in small-vessel vasculitis (eg, childhood primary angiitis of the central nervous system) [17]. US Duplex Doppler Transcranial Head US in not usually indicated in the evaluation of cerebral vasculitis. Variant 6: Child. Nontraumatic intraparenchymal hemorrhage (hematoma) found on CT or MRI. Unknown etiology. Next imaging study. Approximately half of all strokes beyond the perinatal period are hemorrhagic, whereas only 6.5% to 13% of strokes in adults are hemorrhagic [57,58]. Hemorrhagic strokes are associated with a variety of etiologies, including arteriovenous fistula or arteriovenous malformation (48%), brain tumors (15%), genetic or acquired coagulopathy (9%), thrombocytopenia (6%), cavernous malformation (5%), and coagulopathy and aneurysm (2%) [58].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Presenting symptoms of hemorrhagic stroke differ with respect to the age of the child but may include mental status changes, seizures, or focal neurologic deficit. CT Head Unenhanced head CT is useful to assess the location and size of hemorrhage, evidence of mass effect, and hydrocephalus [59]. IV contrast may be helpful in demonstrating an underlying cause for the hemorrhage, such as vascular malformation, aneurysm, or tumor. CTA Head CTA may be used to delineate the vascular anatomy and may be used to demonstrate a vascular malformation or aneurysm but lacks the temporal information available from catheter angiography. MRI Head Unenhanced MRI can delineate the location and size of hemorrhage, evidence of mass effect, and hydrocephalus and may show evidence of an underlying structural lesion, such as vascular malformation, aneurysm, or tumor. SWI and arterial spin-labeling imaging may improve the delineation of the draining veins and arteriovenous shunting, respectively, compared with conventional MR sequences [24]. Contrast may be required to demonstrate small malformations, such as those that may occur in hereditary hemorrhagic telangiectasia, or other causes of parenchymal hematoma, such as tumor. MRA Head MRA may be used to delineate the vascular anatomy and may be used to demonstrate a vascular malformation or aneurysm but lacks the temporal information available from catheter angiography. Arteriography Cervicocerebral Catheter angiography is the gold standard for imaging of high-flow vascular malformations and aneurysms [60]. Although developmental venous anomalies (DVAs) can be demonstrated on catheter angiography, cavernoma and capillary telangiectasia are angiographically occult [61]. Variant 7: Child. Nontraumatic subarachnoid hemorrhage (SAH) detected by noncontrast CT. Next imaging study. Fifty-seven percent of SAH in children is due to aneurysm; however, only 2% to 15% of hemorrhagic strokes in children are due to aneurysm [58,62].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Aneurysms in children account for <1% of SAH due to aneurysms in all age groups [62]. The mortality in pediatric aneurysm has been reported to be 1.3%, with morbidity including infarction (8%) and seizures (4%) [63]. Only 0.6% of ruptured aneurysms occur in patients <19 years of age [51,60]. Aneurysms in children are idiopathic (45%), post-traumatic (20%), or due to a variety of conditions causing abnormal vessel-wall hemodynamic stress [62]. In contrast to adults, aneurysms in children are more likely to be giant (>25 mm) or fusiform [62]. Children with a positive family history of aneurysm account for <5% of pediatric aneurysms, and fewer than 2% of patients with a positive family history of aneurysm develop an aneurysm in the first two decades of life [62]. Fusiform aneurysms are more likely to increase in size over time than are saccular aneurysms [64]. CT Head The initial imaging study in suspected SAH is a noncontrast head CT. If the CT is negative for SAH, lumbar puncture may be performed. Unenhanced head CT is useful in ruptured aneurysms to assess the location and size of hemorrhage, evidence of mass effect, and hydrocephalus [59]. Small aneurysms are difficult to evaluate with unenhanced CT whereas a giant aneurysm, if present, appears as a hyperdense mass. CTA Head CTA is a noninvasive alternative to catheter angiography to show an underlying vascular cause of SAH with reported sensitivity (96.5%) and specificity (88%) for aneurysms of all sizes with sensitivity (98.4%) and specificity (100%) for aneurysms >3 mm [65]. CTA is used to confirm the presence of aneurysm and may be used as an adjunct to catheter angiography in the pretreatment assessment of aneurysm. CTA provides an alternative to catheter angiography for assessing residual or recurrent aneurysm but may be limited by streak artifact from the treatment device.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Using digital subtraction angiography as the gold standard, CTA has a reported sensitivity of 74% and specificity of 96% for the demonstration of residual aneurysm post-treatment [66]. MRI Head MRI is not typically an initial imaging study in patients with suspected SAH. However, SWI is sensitive to the presence of subarachnoid blood. MRI may be useful in classifying the aneurysms into saccular, dissecting, giant, and infectious [60]. MRI may be used to evaluate potential complications of treatment, including cerebral infarction or hemorrhage [63]. Only patients with MRI-safe aneurysm clips should be imaged with MR. MRA Head MRA is a noninvasive alternative to catheter angiography to show an underlying vascular cause of SAH. MRA of the brain is the examination of choice for children with unruptured aneurysms being followed prior to treatment [51]. A meta-analysis of the literature shows the sensitivity and specificity of MRA for the detection of intracranial aneurysm to be 95% and 89%, respectively [67]. Given the limited number of children who will develop an aneurysm under the age of 20, routine screening with MRA of children with a positive family history of aneurysm is not supported in the literature [68]. Arteriography Cervicocerebral Catheter angiography remains the gold standard for the demonstration of high-flow vascular anomalies and aneurysms as a cause of SAH. Catheter angiography can be performed for pretreatment planning and for post- treatment assessment. Catheter angiography is associated with a low incidence of procedural complications in children [51,60]. Catheter angiography is the gold standard for the diagnosis and pretreatment evaluation of intracranial aneurysm and may also be required for post-treatment follow-up in some patients [60]. US Duplex Doppler Transcranial Head US is not sensitive for the presence of subarachnoid blood or vascular causes of intracranial hemorrhage.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Head US provides limited information on intracranial aneurysm, but Doppler US may be used to confirm the vascular nature of a mass seen on head US performed in neonates and young infants with open fontanels. CT Head Unenhanced head CT is useful in hemorrhagic high-flow vascular anomalies to assess the location and size of hemorrhage, evidence of mass effect, and hydrocephalus [59]. High-flow vascular malformations that have not bled are slightly hyperdense relative to brain on unenhanced head CT. The detection of a high-flow vascular anomaly that has not bled may be improved with the use of IV contrast. CTA Head CTA is often used to delineate the anatomy of a high-flow vascular anomaly but lacks the temporal information available from catheter angiography. CTA may be used to monitor the lesion prior to treatment or to assess for growth or recurrence after treatment. MRI Head MRI is used to determine the location and size of high-flow vascular anomalies and is often preferred to CT for use in children. SWI and arterial spin-labeling imaging may improve the delineation of the draining veins and arteriovenous shunting, respectively, compared with conventional MRI sequences [24]. Contrast may be required to demonstrate small malformations. MRA Head MRA, like CTA, can be used to delineate the anatomy of a high-flow vascular anomaly but lacks the temporal information available from catheter angiography. MRA is often preferable to CTA in children for following vascular anomalies serially. The use of IV contrast may be required to assess the venous outflow of the anomaly. MRA may be used to monitor the anomaly prior to treatment or to assess for growth or recurrence after treatment. Arteriography Cervicocerebral With the increased accuracy of the noninvasive imaging studies CTA and MRA, catheter angiography is not typically used as the initial diagnostic imaging for suspected high-flow vascular anomaly.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Catheter angiography can be used for pretreatment evaluation and post-treatment assessment of any residual anomaly [59,71]. US Duplex Doppler Transcranial Head US with Doppler may be used to show the presence of large high-flow vascular malformations, such as vein of Galen malformation and dural arteriovenous fistula or malformation in neonates and young infants. US is useful in very young children because it can be performed without sedation or anesthesia, which may be required for MRI examinations. Variant 9: Child. Clinical presentation suggestive of acute stroke, known or suspected low-flow vascular anomaly. Initial imaging. Low-flow vascular anomalies include cavernous malformation, DVA, and capillary telangiectasia. Cavernomas are comprised of endothelial spaces containing venous blood and account for 17% of hemorrhagic stroke in children [18]. In a large series, 62% of children with cavernomas presented with hemorrhage, 35% with seizures with or without hemorrhage, and 26% had cavernomas discovered incidentally [72]. Patients with cavernoma (15%) have multiple lesions and 10% have a family history of cavernoma and may have mutations in CCM1, CCM2, and CCM3 genes [72-74]. Although 9% are associated with prior cranial irradiation [72], 86% are supratentorial and 14% infratentorial in location. Cavernomas have an annual hemorrhage rate of 3.3% to 4.5% [72,75]. DVA is an anomalous vein draining normal brain parenchyma, and 20% of DVA are associated with cavernoma [72]. Most hemorrhage in patients with DVA is believed to be due to bleeding from an associated cavernoma [61,72]. CT Head Noncontrast CT can show acute hemorrhage with cavernoma. Nonhemorrhagic cavernomas and DVA may be faintly hyperdense on noncontrast imaging [61]. IV contrast increases the conspicuity of DVA. CTA Head CTA plays a limited role in the assessment of cavernoma but may be used to demonstrate a DVA. MRI Head MRI is the imaging study of choice for cavernoma. Various stages of hemorrhage may be evident.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. T2-weighted gradient-echo imaging or SWI may show additional cavernomas not seen on spin-echo imaging. The presence of acute and subacute blood products increases the likelihood of future hemorrhage [75]. DVAs are visible on both spin-echo and gradient-echo imaging and are occasionally associated with gliosis or cortical malformation. Contrast may increase the conspicuity of DVA. MRA Head MRA is not usually helpful in the assessment of cavernoma, capillary telangiectasia, and DVA. Arteriography Cervicocerebral Catheter angiography is rarely required for the evaluation of incidentally discovered DVA but may be used to exclude the possibility of an associated high-flow vascular malformation. An isolated DVA appears as an abnormal cluster of veins draining into a single collector and appears only on the venous phase of the arteriogram [61]. Cavernomas and capillary telangiectasia are usually angiographically occult. US Duplex Doppler Transcranial Head US is not usually helpful in the assessment of cavernoma or capillary telangiectasia. Head US may occasionally be used to demonstrate large DVA in neonates and young infants with open fontanels. Variant 10: Child. Clinical presentation suggestive of acute stroke, known or suspected cortical vein or dural venous sinus thrombosis. Initial imaging. Cerebral sinovenous thrombosis has an incidence of 1/200,000 children per year. It is less common in children than is arterial ischemic or hemorrhagic stroke and is most often associated with infection, trauma, dehydration, cancer, oral contraceptives, and prothrombotic disorders [76,77]. The risk is highest in the first year of life, with neonates accounting for 61% of cerebral sinovenous thrombosis [76-78]. Prothrombotic disorders are present in more than half of children, and multiple risk factors are commonly present. An acute illness with sepsis and dehydration is present in up to one-third of patients. Trauma is more common in older children.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Cerebral sinovenous thrombosis can cause elevation in venous pressure, increased intracranial pressure, and venous infarction. Hemorrhagic infarction (40%) and hydrocephalus (10%) may complicate cerebral sinovenous thrombosis [77]. Infarctions are more frequently hemorrhagic in neonates (72%) than in older children (48%) [79]. The lateral dural venous sinuses (73%) and superior sagittal sinus (35%) are most commonly affected [76- 78]. CT Head CT Head Unenhanced CT shows increased density, often accompanied by distension, of the thrombosed sinus or vein [77,80]. CT is less sensitive than MRI for the demonstration of early ischemic infarction but readily shows areas of brain hemorrhage [77,79]. MRV Head MRV is used to diagnose and follow cortical vein and dural venous sinus thrombosis and is typically performed in conjunction with anatomic MRI without and with IV contrast for a comprehensive assessment of the intracranial venous drainage. MRV without IV contrast is commonly used to confirm absence of flow in a thrombosed dural venous sinus. MRV with IV contrast is less susceptible to the flow artifacts that may occur because of turbulent flow in the dural venous sinuses with noncontrast MRV [80]. Arteriography Cervicocerebral Catheter angiography is not routinely used for the diagnosis of cortical venous or dural venous sinus thrombosis but is used when endovascular treatment is required. US Duplex Doppler Transcranial Head US with Doppler may be used to assess patency of the dural venous sinuses in the neonate. Following closure of the fontanels, CT and MRI are more commonly used. Variant 11: Child. Clinical presentation suggestive of acute stroke, sickle cell disease. New focal fixed or worsening neurologic defect. Initial imaging. SCD constitutes one of the main etiologies of pediatric stroke. Eleven percent of children with SCD not receiving primary stroke prevention therapy will have a stroke by 20 years of age [36,82,83].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Most infarctions are due to vasculopathy involving the supraclinoid portion of the internal carotid artery or branches of the circle of Willis and occurring in a watershed distribution. Clinically silent infarctions are known to occur in 17% of children with SCD [84]. The National Heart Lung and Blood institute recommends that children with SCD between 2 and 16 years of age undergo transcranial Doppler US screening every 6 months. The treatment of acute stroke symptoms in children with SCD is transfusion. CT Head CT is relatively insensitive compared with MRI for the demonstration of infarction and is typically only used in the acute setting if MRI is unavailable or to document hemorrhage or evaluate for mass effect [26]. CTA Head CTA is not used in routine neurovascular screening in children with SCD. CTA can be used in children with contraindication to MRA. MRI Head MRI can show T2 prolongation in watershed vascular territories or cortex in patients with SCD. MRA Head MRA is the study of choice to screen for vessel stenosis in children with SCD with elevated transcranial Doppler US velocities in the intracranial vessels [39,44]. Although MRA can accurately show vessel stenosis, it is susceptible to false-positive results when long echo times are used or when severe anemia is present, resulting in turbulent blood flow and localized artefactual signal loss resembling focal stenosis [26,84,85]. Although gadolinium-enhanced MRA can be used, it is generally not required and is often avoided because of concerns that it may potentiate hemolysis in patients with SCD [26]. MRI of the brain without IV contrast is typically performed during the same examination as the MRA to assess the brain parenchyma for ischemic injury. Arteriography Cervicocerebral Catheter angiography is generally not indicated except in uncommon circumstances, including preoperative assessment for revascularization for moyamoya syndrome and suspected aneurysm complicating SCD [26].


Pancreatic Cyst

Pancreatic Cyst.  Introduction/Background Incidental pancreatic cysts are now increasingly detected on imaging studies performed for unrelated indications. [1-3]. Both increased imaging utilization and improved cross-sectional technique are responsible for the more frequent detection of progressively smaller cysts [4-6]. The most commonly encountered pancreatic cysts include intraductal papillary mucinous neoplasms (IPMNs), serous cystadenoma, mucinous cystic neoplasm (MCN), and pseudocysts [6,7]. There is a very small risk that an incidental pancreatic cyst may be malignant [8]. For instance, an incidental pancreatic cyst on MRI has a 10 in 100,000 chance of being a mucinous invasive malignancy and a 17 in 100,000 chance of being a ductal carcinoma [8]. The risk of malignant transformation in pancreatic cysts is estimated to be 0.24% per year [9], varying according to histologic subtype [7,10]. Yet there is considerable overlap in the imaging appearance of histologically distinct pancreatic cysts, particularly those <3 cm in size, with over 60% of cysts lacking a specific radiologic appearance on CT or MRI [6]. Another important feature in the natural history of pancreatic cysts is the small risk of pancreatic adenocarcinoma developing at a separate site within the pancreas [4,7,11-13]. Although the risk of cyst-related or concomitant pancreatic malignancy is small, there is a need to characterize incidental pancreatic cysts effectively at initial imaging in order to guide management. Appropriate imaging evaluation of incidental pancreatic cysts is critical because morphology determines management. As an example, surveillance is generally recommended for cysts <3 cm in size without worrisome features or high-risk stigmata [7,13]. Cysts with worrisome features undergo sampling with endoscopic ultrasound fine-needle aspiration (EUS-FNA) [8-10] and those with high-risk stigmata are typically resected [8-10].


Pancreatic Cyst

Pancreatic Cyst. For management recommendations please refer to the ACR White Paper on Management of Incidental Pancreatic Cysts [7]. The following recommendations refer to the initial imaging evaluation of pancreatic cysts incidentally detected and incompletely evaluated on imaging studies performed for unrelated indications. The recommendations below apply Reprint requests to: publications@acr.org Pancreatic Cyst irrespective of the imaging modality in which the cyst was initially detected. CT abdomen, MRI abdomen with MRCP, and US abdomen endoscopic are included in the discussion. These are the three conventional imaging modalities used in the workup of pancreatic cysts. Although we acknowledge the added value of US (especially contrast-enhanced US) in select cases in which workup with conventional imaging is inconclusive or incomplete, US has been omitted from the discussion because it is not routinely used in this setting. Discussion of Procedures by Variant Variant 1: Incidentally detected pancreatic cyst less than or equal to 2.5 cm in size. Initial evaluation. CT Abdomen MRI is preferred over contrast-enhanced CT in this setting. The sensitivity and specificity of CT for distinguishing IPMN from other cystic pancreatic lesions is 80.6% and 86.4% compared with 96.8% and 90.8% for MRI [3,18]. Advantages of CT include its ease of implementation and excellent spatial resolution. Multidetector CT provides critical diagnostic information pertaining to the presence or absence of calcifications (both in the background parenchyma and in the cyst proper), ductal dilation, intralesional septations, mural nodules, and pancreatic duct communication [6,15]. MRI Abdomen with MRCP Contrast-enhanced MRI with MR cholangiopancreatography (MRCP) is considered the procedure of choice in this setting because of its superior soft-tissue contrast and superior ability to demonstrate ductal communication [6-10].


Pancreatic Cyst

Pancreatic Cyst. The reported sensitivity of thin-slice 3-D MRCP acquisitions for demonstrating communication of a cyst with the pancreatic duct is as high as 100% [6,22]. Communication with the main pancreatic duct is suggestive of IPMN, although this may also be seen in the setting of pseudocysts [6]. The sensitivity of MRI for detection of internal septations is 91% [6,22], and its diagnostic accuracy for distinguishing between malignant and nonmalignant lesions ranges between 73.2% and 91% [6,23,24]. In distinguishing IPMN from other cystic lesions, studies have reported a sensitivity of 96.8% and a specificity of 90.8% [3,18]. Pancreatic Cyst MRI Abdomen with MRCP Because of its superior soft-tissue resolution and noninvasive approach, contrast-enhanced MRI with MRCP is generally favored over CT or EUS-FNA in this setting [6-10]. The diagnostic accuracy of MRI for distinguishing between malignant and nonmalignant lesions ranges from 73.2% to 91% [6,23,24]. Its accuracy at diagnosing the specific type of cyst is slightly lower at 50% [23]. However, an exception may be the distinction of IPMN from other cystic lesions, in which studies have reported a sensitivity of 96.8% and specificity of 90.8% [3,18]. In a study of over 300 patients with pancreatic cysts, the addition of EUS-FNA to the diagnostic workup significantly altered the management strategy in nearly 72% of patients [28]. Management algorithms integrating clinical data, imaging, and fluid analysis have reported cyst classification sensitivities of 90% to 100% and specificities of 92% to 98% [7,25]. The addition of EUS-FNA to management algorithms combining clinical history and imaging may also reduce unnecessary surgeries by 91% [7]. Variant 3: Incidentally detected pancreatic cyst greater than 2.5 cm in size. High-risk stigmata or worrisome features. Initial evaluation.


Pancreatic Cyst

Pancreatic Cyst. CT Abdomen The presence of high-risk stigmata or worrisome features significantly increases the risk of malignancy, and therefore EUS-FNA is favored over CT in this setting [8,9,14]. In cases in which EUS-FNA cannot be performed and the patient is not a candidate for MRI with MRCP, a dual-phase contrast-enhanced pancreatic protocol CT may still be of value for cyst characterization or presurgical planning [1,7-10,13,19-21]. The use of IV contrast improves detection of worrisome features and high-risk stigmata and the assessment of surrounding anatomy [1,7-10,13,19- 21]. Pancreatic Cyst US Abdomen Endoscopic When high-risk stigmata or worrisome features are present, the appropriate initial imaging study is EUS-FNA [7- 10]. The unique advantage of EUS-FNA is its ability to distinguish mucinous from nonmucinous lesions by means of biochemical markers assayed from cyst fluid samples. This facilitates a specific diagnosis in many cases [25,28- 30]. For instance, the presence of nongut mucin supports a diagnosis of mucinous neoplasm. Carcinoembryonic antigen levels <5 ng/mL suggest pseudocyst or serous cystadenoma. A carcinoembryonic antigen threshold level in the range of 192 to 200 ng/mL is 80% accurate for diagnosis of a mucinous cyst [13,29]. Amylase levels of >250 IU/L suggest a pseudocyst. Molecular assays for markers such as K-ras, GNAS, PTEN, VHL, TP53, and PIK3CA may also assist in differentiating neoplastic cystic lesions and predicting cyst behavior. When performed in centers with expertise in EUS-FNA, cytological evaluation can identify atypia, dysplasia, or neoplasia [7,13,25]. Studies have demonstrated that the presence of high-grade epithelial atypia in IPMN detects approximately 30% more cancers than the presence of worrisome imaging features alone [13]. Pancreatic Cyst Variant 5: Follow-up imaging of pancreatic cyst. CT Abdomen The risk of malignant transformation of a pancreatic cyst is approximately 0.24% per year [9].


Pancreatic Cyst

Pancreatic Cyst. Once a pancreatic cyst has been characterized on a dedicated baseline examination, subsequent follow-up may be performed with either CT or MRI. There is no evidence to suggest that MRI is superior to CT for detection of new or developing worrisome features or pancreatic ductal adenocarcinoma, and cysts that change at follow up typically do so by increasing size, which is well assessed by either modality [7], although modality concordance between baseline and follow-up examinations may facilitate comparison. For CT follow-up, a dual-phase contrast-enhanced pancreatic protocol CT, including late arterial and portal venous phases, should be performed [7,8]. The frequency and duration of follow-up is controversial and depends on multiple factors, including patient age, family history of pancreatic ductal adenocarcinoma, cyst size, and whether or not there has been prior surgical resection of a pancreatic cyst. For patients with a nonspecific pancreatic cyst without a history of prior surgery, the surveillance plan will depend upon patient age and the cyst size. Follow-up intervals are generally in the range of 6 months to every 2 years for a minimum of 5 to 10 years [7-9]. Development of high-risk stigmata or worrisome features during the surveillance period should prompt EUS-FNA or surgical evaluation. For patients with a previous history of surgery for IPMN or invasive MCN without residual disease, continued surveillance is recommended, in view of the small yearly risk of pancreatic ductal adenocarcinoma of 0.7% to 0.9% [8]. For patients with known IPMN in the remnant pancreas, residual IPMN at the surgical margins, or new postoperative recurrence of IPMN, surveillance recommendations are less well defined [8]. To date, there is no evidence basis for the recommended size threshold to follow-up cysts. Based on limited clinical and published experience, a cyst <5 mm may require one follow-up CT or MRI at 2 years. Demonstrating stability at 2 years is sufficient to stop surveillance.


Pancreatic Cyst

Pancreatic Cyst. MRI Abdomen with MRCP The risk of malignant transformation of a pancreatic cyst is approximately 0.24% per year [9]. Once a pancreatic cyst has been characterized on a dedicated baseline examination, subsequent follow-up may be performed with either CT or MRI. There is no evidence to suggest that MRI is superior to CT for detection of new or developing worrisome features or pancreatic ductal adenocarcinoma [7], although modality concordance between baseline and follow-up examinations may facilitate comparison. The issue of whether IV contrast is necessary for MRI follow-up of pancreatic cysts remains controversial. Noncontrast MRI is associated with shorter scan times, with some sources citing little difference in the ability to detect evolving dysplastic changes compared with a contrast-enhanced study [7,33,34]. However, the use of IV contrast may permit detection of high-risk stigmata such as enhancing mural nodules. An abbreviated protocol MRI, including T2-weighted sequences and dual-phase (late arterial and portal venous phase) contrast-enhanced acquisitions, has been shown to be equivalent to standard pancreatic protocol MRI for detection of evolving dysplasia [7,34]. The frequency and duration of follow-up is controversial and depends on multiple factors, including patient age, family history of pancreatic ductal adenocarcinoma, cyst size, and whether or not there has been prior surgical resection of a pancreatic cyst. For patients with a nonspecific pancreatic cyst without a history of prior surgery, the surveillance plan will depend upon patient age and the cyst size. Follow-up intervals are generally in the range of 6 months to every 2 years for a minimum of 5 to 10 years [7-9]. Development of high-risk stigmata or worrisome features during the surveillance period should prompt EUS-FNA or surgical evaluation [8,9,14,26].


Supplemental Breast Cancer Screening Based on Breast Density.  Although overall sensitivity of mammography is in the range of 70% to 85%, the sensitivity can vary significantly with breast density [5-7]. The mammographic sensitivity is higher in women with fatty breast parenchyma; however, the sensitivity may decrease to as low as 30% in women with dense breast tissue [5-9]. Although the overall performance of digital mammography is similar to film screen mammography, digital mammography has better performance in specific subgroups, such as in women with dense breasts [8,9]. In addition, even with regular mammographic screening, the interval cancer rate may be as high as 30% [10-13]. Given the limitations of mammography, supplemental screening has been advocated for women with dense breast tissue. In order to bring uniformity to the language, a federal law passed in February 2019, enables the FDA to develop a statement that the effect of breast density on mammographic sensitivity be included in all mammography report. aPerelman School of Medicine of the University of Pennsylvania, Philadelphia, PennsylvaniabPanel Chair, Boston University School of Medicine, Boston, Massachusetts. cPanel Vice-Chair, New York University School of Medicine, New York, New York. dBoston University Schools of Medicine and Public Health, Boston, Massachusetts. eYale School of Medicine, New Haven, Connecticut; Society of Surgical Oncology. fThomas Jefferson University Hospital, Robbinsville, New Jersey; American College of Obstetricians and Gynecologists. gAlpert Medical School of Brown University, Providence, Rhode Island. hFeinberg School of Medicine, Northwestern University, Chicago, Illinois; American College of Physicians. iUniversity of California San Francisco, San Francisco, California. jSutter Medical Group and Sutter Cancer Center, Roseville, California. kThe University of Texas MD Anderson Cancer Center, Houston, Texas. lEmory University Hospital, Atlanta, Georgia. mSanford Health of Northern Minnesota, Bemidji, Minnesota.


Supplemental Breast Cancer Screening Based on Breast Density. nUniversity of Washington, Seattle, Washington. oDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York. pNorthShore University HealthSystem, Evanston, Illinois; American College of Surgeons. qSpecialty Chair, NYU Clinical Cancer Center, New York, New York. The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through representation of such organizations on expert panels. Participation on the expert panel does not necessarily imply endorsement of the final document by individual contributors or their respective organization. Reprint requests to: publications@acr.org Supplemental Screening Based on Breast Density Discussion of Procedures by Variant Variant 1: Supplemental breast cancer screening. Average-risk females with nondense breasts. Mammography remains the only validated screening tool for breast cancer screening. Despite widespread mammographic screening, breast cancer represents the leading cause of cancer mortality in women. Although multiple studies have demonstrated improved survival and reduction in breast cancer mortality by up to 30% with regular mammographic screening, there continues to be approximately 40,000 breast cancer deaths annually [10- 13]. Women who have <15% lifetime risk are considered to be at average risk [15]. In women with nondense breast tissue, the sensitivity of mammography is high [5]. In addition to the increase in the CDR, another benefit of adding DBT to 2-D mammography is the reduction in the recall rate [16-19]. In a single-center screening program, Sharpe et al [18] reported a reduction in the recall rate by 18.8%. In the prospective Oslo Tomosynthesis Screening Trial, the recall rate was reduced from 6.7/1,000 to 3.6/1,000 [19]. There is also evidence that the reduction in the recall rate is maintained over consecutive screening episodes [18].


Supplemental Breast Cancer Screening Based on Breast Density. Mammography With IV Contrast CEDM combines the techniques of conventional mammography with administration of IV contrast, thus leveraging functional imaging by assessing for lesion vascularity. A dual-energy technique is utilized to acquire the images in the conventional craniocaudal and mediolateral oblique projections. The acquired data are processed and produce a low-energy image and a diagnostic recombined image. There is limited but emerging literature regarding the use of CEDM in the screening setting [26,27]. However, in the diagnostic setting, CEDM has been shown to demonstrate improved sensitivity and specificity over 2-D mammography [28-31]. The greatest improvement in the sensitivity and specificity is seen in women with dense breast tissue [29,30]. However, at this time there is no relevant literature regarding the use of mammography with IV contrast for supplemental screening in average-risk women with nondense breasts. MRI Breast Without IV Contrast There is no relevant literature regarding the use of MRI breast without IV contrast for supplemental screening in average-risk women with nondense breasts. MRI Breast Without IV Contrast Abbreviated There is no relevant literature regarding the use of AB-MRI breast without IV contrast for supplemental screening in average-risk women with nondense breasts. MRI Breast Without and With IV Contrast There are limited data regarding screening average-risk women with breast MRI with and without IV contrast. In a prospective observational trial, after negative mammographic screening, Kuhl et al [33] reported an additional CDR of 15.5/1,000 with MRI screening in average-risk women across all densities. However, the authors did not analyze the added CDR by breast density. FDG-PET Breast Dedicated There is limited relevant literature regarding the use of FDG-PET breast dedicated for supplemental screening in average-risk women with nondense breasts. This is not currently widely used in clinical practice.


Supplemental Breast Cancer Screening Based on Breast Density. Sestamibi MBI There is limited relevant literature regarding the use of Tc-99m sestamibi MBI for supplemental screening in average-risk women with nondense breasts. This is not currently widely used in clinical practice. Variant 2: Supplemental breast cancer screening. Intermediate-risk females with nondense breasts. Women at intermediate risk for breast cancer are defined as having a 15% to 20% lifetime risk [15]. Although there are clear screening guidelines for women with >20% lifetime risk, the screening guidelines have not clearly been defined for women who are at intermediate risk. Women in this category may include patients who have been diagnosed with lobular neoplasia, atypical ductal hyperplasia, previous history of breast cancer, or have a family history of breast cancer without known genetic mutations such as breast cancer gene (BRCA)1/2. In addition to the increase in the CDR, another benefit of adding DBT to 2-D mammography is the reduction in the recall rate [16-19]. In a single-center screening program, Sharpe et al [18] reported a reduction in the recall rate by 18.8%. In the prospective Oslo Tomosynthesis Screening Trial, the recall rate was reduced from 6.7/1,000 to 3.6/1,000 [19]. There is also evidence that the reduction in the recall rate is maintained over consecutive screening episodes [18]. Supplemental Screening Based on Breast Density In women with a personal history of breast cancer, the supplemental CDR of screening ultrasound (US) has been reported to be 2.88/1,000 [34]. There was no difference in the CDR based on breast density or age. However, the authors reported an interval cancer rate of 1.5/1,000, which was higher in women who were <50 years of age and in those with dense breast tissue, indicating the failure of screening US in these 2 subgroups.


Supplemental Breast Cancer Screening Based on Breast Density. Cortesi et al [35] evaluated the efficacy of biennial screening US examination in women who were BRCA mutation carriers, high-risk (non-BRCA1/2), and intermediate-risk patients. Overall, MRI had sensitivity of 93.7%, followed by mammography with sensitivity of 55.0% and US with 29.4% sensitivity. In the nondense breast, the sensitivity of mammography was 82.5% versus 10% for US. In the dense breast, the sensitivity of mammography was 50% versus 42.6% for US. Sensitivity analysis by risk level was also performed. The US sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and intermediate-risk patients were 22.7%, 24.5%, and 33.6%, respectively. The mammographic sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and intermediate-risk patients were 25.0%, 66.4%, and 56.6%, respectively. Only the BRCA1/2 mutation carriers underwent MRI screening, which demonstrated a sensitivity of 93.7%. The authors did not analyze the efficacy of US screening based on both density and risk. Mammography With IV Contrast CEDM combines the techniques of conventional mammography with administration of IV contrast, thus leveraging functional imaging by assessing for lesion vascularity. A dual-energy technique is used to acquire the images in the conventional craniocaudal and mediolateral oblique projections. The acquired data are processed, producing a low- energy image and a diagnostic recombined image. There is limited but emerging literature regarding the use of CEDM in the screening setting. However, in the diagnostic setting, CEDM has been shown to demonstrate improved sensitivity and specificity over 2-D mammography [28-31]. The greatest improvement in the sensitivity and specificity is seen in women with dense breast tissue [29,30]. However, at this time, there is no relevant literature regarding the use of mammography with IV contrast for supplemental screening in intermediate-risk women with nondense breasts.


Supplemental Breast Cancer Screening Based on Breast Density. MRI Breast Without IV Contrast Abbreviated There is no relevant literature regarding the use of AB-MRI breast without IV contrast for supplemental screening in intermediate-risk women with nondense breasts. MRI Breast Without and With IV Contrast Abbreviated AB-MRI performed with IV contrast is an abbreviated breast MRI examination. It is similar to a full MRI examination yet does not have a standard protocol; however, at minimum, it must include a precontrast and one postcontrast sequence. A T2-weighted sequence may also be included. There are currently limited data on screening women with nondense breasts at intermediate lifetime risk with AB-MRI. In 2 retrospective reader studies, in women recently diagnosed with unifocal breast cancer, the sensitivity of AB-MRI was comparable with the full protocol [36,37]. When the performance of AB-MRI was compared with screening US and mammography, there were 12 cancers in 12 women (CDR 15/1,000), 7 of which were not detected on WBUS and mammography [38]. In a prospective observational study of 443 women with mild to moderately elevated lifetime risk for breast cancer, AB-MRI had a similar diagnostic accuracy as the full MRI protocol [39]. MRI Breast Without IV Contrast There is no relevant literature regarding the use of MRI breast without IV contrast for supplemental screening in intermediate-risk women with nondense breasts. MRI Breast Without and With IV Contrast There is some relevant literature supporting the use of MRI breast without and with IV contrast for supplemental screening in intermediate-risk women, specifically in women with a history of lobular carcinoma in situ or a personal history of breast cancer, although these studies included all breast densities [40-42].


Supplemental Breast Cancer Screening Based on Breast Density. At the time of this writing, the American Cancer Society is currently re-reviewing the literature regarding intermediate-risk women; however, its current stance, last updated in 2007, states there is insufficient evidence to formulate a recommendation in this group [15]. As of 2018, ACR recommends annual surveillance MRI in women with dense breasts and a personal history of breast cancer as well as in women who were diagnosed before age 50 [43]. The ACR suggests that MRI should be considered in the following categories: in women with personal histories of breast cancer and who do not fit the 2 previously stated categories and in women with atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ [43]. Supplemental Screening Based on Breast Density FDG-PET Breast Dedicated There is limited relevant literature regarding the use of FDG-PET breast dedicated for supplemental screening in intermediate-risk women with nondense breasts. This is not currently widely used in clinical practice. Sestamibi MBI There is limited relevant literature regarding the use of Tc-99m sestamibi MBI for supplemental screening in intermediate-risk women with nondense breasts. This is not currently widely used in clinical practice. In addition to the increase in the CDR, another benefit of adding DBT to 2-D mammography is the reduction in the recall rate [16-19]. In a single-center screening program, Sharpe et al [18] reported a reduction in the recall rate by 18.8%. In the prospective Oslo Tomosynthesis Screening Trial, the recall rate was reduced from 6.7/1,000 to 3.6/1,000 [19]. There is also evidence that the reduction in the recall rate is maintained over consecutive screening episodes [18]. Cortesi et al [35] evaluated the efficacy of biannual screening US examination in women who were BRCA mutation carriers, high-risk (non-BRCA1/2), and intermediate-risk patients.


Supplemental Breast Cancer Screening Based on Breast Density. Overall, MRI had sensitivity of 93.7%, which was followed by mammography (55.0%), and US (29.4%). In the nondense breast, the sensitivity of mammography was 82.5% versus 10% for US. In the dense breast, the sensitivity of mammography was 50% versus 42.6% for US. Sensitivity analysis by risk level was also performed. The US sensitivitities for BRCA1/2, high-risk (non- BRCA1/2), and intermediate-risk patients were 22.7%, 24.5%, and 33.6%, respectively. The mammographic sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and intermediate-risk patients were 25.0%, 66.4%, and 56.6%, respectively. Only the BRCA1/2 mutation carriers underwent MRI screening, which demonstrated a sensitivity of 93.7%. The authors did not analyze the efficacy of US screening based on both density and risk. The addition of WBUS to mammography increases the CDR in high-risk women. In a surveillance cohort study of 529 women with elevated lifetime risk, the sensitivity of mammography, WBUS, and the 2 modalities combined was 33%, 40%, and 49%, respectively [44]. However, subgroup analysis was not performed by breast density. In the same population, MRI had a sensitivity of 91% [44]. In the ACRIN 6666 trial, after 3 rounds of screening mammography and screening WBUS in women with dense breast tissue at intermediate to elevated lifetime risk, the sensitivity, specificity, and positive predictive value (PPV3) of mammography was 0.52, 0.91, and 0.38, Supplemental Screening Based on Breast Density respectively. The addition of US to mammography increased the sensitivity (0.76) but decreased the specificity (0.84) and the PPV3 (0.38) [45]. In a prospective cohort trial of 687 high-risk women, the cancer yield of mammography alone was 5.4/1,000 and increased to 7.7/1,000 with the addition of US [46].


Supplemental Breast Cancer Screening Based on Breast Density. Mammography With IV Contrast CEDM combines the techniques of conventional mammography with administration of IV contrast, thus leveraging functional imaging by assessing for lesion vascularity. A dual-energy technique is utilized to acquire the images in the conventional craniocaudal and mediolateral oblique projections. The acquired data are processed, producing a low-energy image and a diagnostic recombined image. There is limited literature regarding the use of CEDM in the screening setting. However, in the diagnostic setting, CEDM has been shown to demonstrate improved sensitivity and specificity over 2-D mammography [28-31]. The greatest improvement in the sensitivity and specificity is seen in women with dense breast tissue [29,30]. At this time, there is limited but emerging literature regarding the use of mammography with IV contrast for supplemental screening in high-risk women with nondense breasts. Jochelson et al [47] screened 318 high-risk women using both CEDM and MRI [47]. Both techniques detected carcinomas not visualized on mammography, 2 using CEDM and 3 using MRI. MRI Breast Without IV Contrast Abbreviated There is no relevant literature regarding the use of AB-MRI breast without IV contrast for supplemental screening in high-risk women with nondense breasts. MRI Breast Without and With IV Contrast Abbreviated AB-MRI performed with IV contrast is an abbreviated breast MRI examination. It is similar to a full MRI examination yet does not have a standard protocol; however, at minimum, it must include a precontrast and one postcontrast sequence. A T2-weighted sequence may also be included. There is limited relevant literature regarding the use of AB-MRI breast without and with IV contrast in high-risk women with nondense breasts. In 2 retrospective studies comparing the full diagnostic protocol with an abbreviated protocol in high-risk women, the authors found both protocols to have similar sensitivity [48,49].


Supplemental Breast Cancer Screening Based on Breast Density. However, neither study evaluated the CDR by breast density. MRI Breast Without IV Contrast There is no relevant literature regarding the use of MRI breast without IV contrast for supplemental screening in high-risk women with nondense breasts. FDG-PET Breast Dedicated There is limited relevant literature regarding the use of FDG-PET breast dedicated for supplemental screening in high-risk women with nondense breasts. This is not currently widely used in clinical practice. Sestamibi MBI There is limited relevant literature regarding the use of Tc-99m sestamibi MBI for supplemental screening in high- risk women with nondense breasts. This is not currently widely used in clinical practice. Variant 4: Supplemental breast cancer screening. Average-risk females with dense breasts. Mammography remains the only validated screening tool for breast cancer screening. Despite widespread mammographic screening, breast cancer represents the leading cause of cancer mortality in women. Although multiple studies have demonstrated improved survival and reduction in breast cancer mortality by up to 30% with regular mammographic screening, there continues to be approximately 40,000 breast cancer deaths annually [10- 13]. Women who have <15% lifetime risk are considered to be at average risk [15]. The greatest improvement in the CDR with DBT is seen in women with dense breast tissue [21,22,57,58]. Although the TOMMY trial did not reach statistical significance across all breast densities, in women with >50% breast density, statistical significance was achieved with the sensitivity of 2-D mammography plus DBT reaching 93% versus 86% for 2-D mammography alone [21,22]. In a meta-analysis of 16 studies evaluating women with dense breasts, addition of DBT improved the CDR, compared with 2-D mammography alone, in both diagnostic (relative risk [RR]: 1.16) and the screening (RR: 1.33) settings [58].


Supplemental Breast Cancer Screening Based on Breast Density. In addition to the increase in the CDR, another benefit of adding DBT to 2-D mammography is the reduction in the recall rate [16-19]. In a single-center screening program, Sharpe et al [18] reported a reduction in the recall rate by 18.8%. In the prospective Oslo Tomosynthesis Screening Trial, the recall rate was reduced from 6.7/1,000 to 3.6/1,000 [19]. There is also evidence that the reduction in the recall rate is maintained over consecutive screening episodes [18]. At a high-volume screening center, when women with heterogeneously or extremely dense breast tissue were offered automated 3-D US screening in addition to full-field digital mammography (FFDM), the added CDR rose by 2.4/1,000 screened (6.6/1,000 automated 3-D US screening plus FFDM versus 4.2/1,000 for FFDM alone) [59]. However, the risk level of the population was not defined other than patients with a personal history of breast cancer were excluded, and 3.5% of the patients reported a family history of breast cancer. Buchberger et al [60] compared the performance of screening mammography with and without screening US in average-risk women. In the subgroup of women with dense breasts, the CDR increased from 1.8/1,000 to 2.4/1,000, with the addition of screening US. However, the PPV2 decreased from 52.7/1,000 with mammography alone to 37.7/1,000 with mammography plus US. For the entire population, there were 28 interval cancer rates within a 12- month period after screening (0.42/1,000): 18 in women with dense breasts and 10 in women with nondense breasts. In the Japan Strategic Anti-cancer Randomized Trial, 72,998 asymptomatic women 40 to 49 years of age were randomized to mammographic screening alone or mammographic plus US screening [61]. The sensitivity and specificity in the mammogram arm were 77.0% and 91.4%, respectively. In comparison, the mammogram plus US arm had a higher sensitivity (91.1%) but lower specificity (87.7%).


Supplemental Breast Cancer Screening Based on Breast Density. The interval cancer rate was halved in the arm that received US screening, from the baseline level of 0.10% to 0.05%. Using Breast Cancer Surveillance Consortium data, Lee et al [62] assessed the performance of the addition of screening US in women with dense breasts in the community. The CDR of mammography plus US was 5.4/1,000 versus 5.5/1,000 for mammography alone. The false-positive biopsy rate and PPV of biopsy recommendations for Supplemental Screening Based on Breast Density mammography plus US were 52.0/1,000 and 9.5%, respectively, compared with 22.2/1,000 and 21.4%, respectively, for mammography alone. The interval cancer rate did not differ significantly in the 2 arms: the mammography plus US arm was 1.5/1,000 versus 1.9/1,000 for mammography alone. Utilizing the registry data and data from the literature, Sprague et al [63] used simulation models to assess the outcomes of supplemental US screening after negative screening mammography in women with dense breasts. Per 1,000 women screened, the authors concluded there would be 0.36 breast cancer deaths averted, 354 additional biopsy recommendations, and 1.7 quality-adjusted life-years gained at a cost $325,000 for each quality-adjusted life-year gained [63]. Although the supplemental screening debate was initiated partly because of the limitations of screening mammography in women with dense breast tissue, there is some evidence to suggest that breast density alone may not be sufficient reason to recommend supplemental screening. One way to assess the failure of mammography is by determining the interval cancer rate in the study population. Using the Breast Cancer Surveillance Consortium data, the women most likely to present with interval cancers were women with an elevated 5-year risk for breast cancer >1.67% and with dense breast tissue, representing approximately 24% of all women with dense breasts [64].


Supplemental Breast Cancer Screening Based on Breast Density. Mammography With IV Contrast CEDM combines the techniques of conventional mammography with administration of IV contrast, thus leveraging functional imaging by assessing for lesion vascularity. A dual-energy technique is used to acquire the images in the conventional craniocaudal and mediolateral oblique projections. The acquired data are processed, producing a low- energy image and a diagnostic recombined image. There is limited but emerging literature regarding the use of CEDM in the screening setting. However, in the diagnostic setting, CEDM has been shown to demonstrate improved sensitivity and specificity over 2-D mammography [28-31]. The greatest improvement in the sensitivity and specificity is seen in women with dense breast tissue [29,30]. At this time, there is limited literature regarding the use of mammography with IV contrast for supplemental screening in average-risk women with dense breasts. MRI Breast Without IV Contrast Abbreviated There is no relevant literature regarding the use of AB-MRI breast without IV contrast for supplemental screening in average-risk women with dense breasts. MRI Breast Without IV Contrast There is no relevant literature regarding the use of MRI breast without IV contrast for supplemental screening in average-risk women with dense breasts. MRI Breast Without and With IV Contrast There are limited data regarding screening average-risk women with breast MRI with and without IV contrast. In a prospective observational trial, after negative mammographic screening, Kuhl et al [33] reported an additional CDR of 15.5/1,000 with MRI screening in average-risk women across all densities. However, the authors did not analyze the added CDR by breast density. FDG-PET Breast Dedicated There is limited relevant literature regarding the use of FDG-PET breast dedicated for supplemental screening in average-risk women with dense breasts [67]. This is not currently widely used in clinical practice.


Supplemental Breast Cancer Screening Based on Breast Density. Supplemental Screening Based on Breast Density Sestamibi MBI There is limited relevant literature regarding the use of Tc-99m sestamibi MBI for supplemental screening in average-risk women with dense breasts. This is not currently widely used in clinical practice. Variant 5: Supplemental breast cancer screening. Intermediate-risk females with dense breasts. Women at intermediate risk for breast cancer are defined as having a 15% to 20% lifetime risk [15]. Although there are clear screening guidelines for women with >20% lifetime risk, the screening guidelines have not been clearly defined for women who are at intermediate risk. Women in this category may include patients who have been diagnosed with lobular neoplasia, atypical ductal hyperplasia, previous history of breast cancer, or have a family history of breast cancer without known genetic mutations such as BRCA1/2. The greatest improvement in the CDR with DBT is seen in women with dense breast tissue [21,22,57,58]. Although the TOMMY trial did not reach statistical significance across all breast densities, in women with >50% breast density, statistical significance was achieved with the sensitivity of 2-D mammography plus DBT reaching 93% versus 86% for 2-D mammography alone [21,22]. In a meta-analysis of 16 studies evaluating women with dense breasts, DBT improved the CDR compared with 2-D mammography alone, in both the diagnostic (RR: 1.16) and the screening (RR: 1.33) settings [58]. In addition to the increase in the CDR, another benefit of adding DBT to 2-D mammography is the reduction in the recall rate [16-19]. In a single-center screening program, Sharpe et al [18] reported a reduction in the recall rate by 18.8%. In the prospective Oslo Tomosynthesis Screening Trial, the recall rate was reduced from 6.7/1,000 to 3.6/1,000 [19]. There is also evidence that the reduction in the recall rate is maintained over consecutive screening episodes [18].


Supplemental Breast Cancer Screening Based on Breast Density. In women with a personal history of breast cancer, the supplemental CDR of screening US has been reported to be 2.88/1,000 [34]. There was no difference in the CDR based on breast density or age. However, the authors reported an interval cancer rate of 1.5/1,000, which was higher in women who were <50 years of age and in those with dense breast tissue, indicating the failure of screening US in the 2 subgroups. Cortesi et al [35] evaluated the efficacy of biannual screening US examination in women who were BRCA mutation carriers, high-risk (non-BRCA1/2), and intermediate-risk patients. Overall, MRI had sensitivity of 93.7%, followed by mammography (55.0%) and US (29.4%). In the nondense breast, the sensitivity of mammography was 82.5% versus 10% for US. In the dense breast, the sensitivity of mammography was 50% versus 42.6% for US. Sensitivity analysis by risk level was also performed. The US sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and 12 Supplemental Screening Based on Breast Density intermediate-risk patients were 22.7%, 24.5%, and 33.6%, respectively. The mammographic sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and intermediate-risk patients were 25.0%, 66.4%, and 56.6%, respectively. Only the BRCA1/2 mutation carriers underwent MRI screening, which demonstrated a sensitivity of 93.7%. The authors did not analyze the efficacy of US screening based on both density and risk. Although the supplemental screening debate was initiated partly because of the limitations of screening mammography in women with dense breast tissue, there is some evidence to suggest that breast density alone may not be sufficient reason to recommend supplemental screening. One way to assess the failure of mammography is by determining the interval cancer rate in the study population.


Supplemental Breast Cancer Screening Based on Breast Density. Using Breast Cancer Surveillance Consortium data, the women most likely to present with interval cancers were women with an elevated 5-year risk for breast cancer >1.67% and with dense breast tissue, representing approximately 24% of all women with dense breasts [64]. Mammography With IV Contrast CEDM combines the techniques of conventional mammography with administration of IV contrast, thus leveraging functional imaging by assessing for lesion vascularity. A dual-energy technique is utilized to acquire the images in the conventional craniocaudal and mediolateral oblique projections. The acquired data are processed, producing a low-energy image and a diagnostic recombined image. There is limited literature regarding the use of CEDM in the screening setting. However, in the diagnostic setting, CEDM has been shown to demonstrate improved sensitivity and specificity over 2-D mammography [28-31]. The greatest improvement in the sensitivity and specificity is seen in women with dense breast tissue [29,30]. At this time, there is limited but emerging literature regarding the use of mammography with IV contrast for supplemental screening in intermediate-risk women with dense breasts. However, in women with dense breast tissue and given the limited sensitivity of mammography and the need for supplemental screening, CEDM may have a potential role; however, more data on CEDM in the screening setting in intermediate-risk women with dense breast tissue are needed. MRI Breast Without IV Contrast Abbreviated There is no relevant literature regarding the use of AB-MRI breast without IV contrast for supplemental screening in intermediate-risk women with dense breasts. MRI Breast Without and With IV Contrast Abbreviated AB-MRI performed with IV contrast is an abbreviated breast MRI examination. It is similar to a full MRI examination yet does not have a standard protocol; however, at minimum, it must include a precontrast and one postcontrast sequence.


Supplemental Breast Cancer Screening Based on Breast Density. A T2-weighted sequence may also be included. There are currently limited data on screening women with dense breasts at intermediate lifetime risk with AB-MRI. In 2 retrospective reader studies, in women recently diagnosed with unifocal breast cancer, the sensitivity of AB-MRI was comparable with the full protocol [36,37]. When the performance of AB-MRI was compared with screening US and mammography, 12 cancers in 12 women (CDR 15/1,000) were detected, 7 of which were not detected on WBUS and mammography [38]. In a prospective observational study of 443 women with mild to moderately elevated lifetime risk for breast cancer, AB- MRI had a similar diagnostic accuracy as the full MRI protocol [39]. MRI Breast Without IV Contrast There is no relevant literature regarding the use of MRI breast without IV contrast for supplemental screening in intermediate-risk women with dense breasts. MRI Breast Without and With IV Contrast There is some relevant literature supporting the use of MRI breast without and with IV contrast for supplemental screening in intermediate-risk women, specifically in women with a history of lobular carcinoma in situ or a personal history of breast cancer, although these studies included all breast densities [40-42]. At the time of this writing, the American Cancer Society was re-reviewing the literature regarding intermediate-risk women; however, its current stance, last updated in 2007, states there is insufficient evidence to formulate a recommendation in this group [15]. As of 2018, the ACR recommends annual surveillance MRI in women with dense breasts and with a personal history of breast cancer, as well as in women who were diagnosed before age 50 [43].


Supplemental Breast Cancer Screening Based on Breast Density. The ACR suggests that MRI should be considered in the following categories: in women with personal histories of breast cancer and who do not fit the 2 previously stated categories as well as in women with atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ [43]. FDG-PET Breast Dedicated There is limited relevant literature regarding the use of FDG-PET breast dedicated for supplemental screening in intermediate-risk women with dense breasts. This is not currently widely used in clinical practice. Supplemental Screening Based on Breast Density Sestamibi MBI There is limited relevant literature regarding the use of Tc-99m sestamibi MBI for supplemental screening in intermediate-risk women with dense breasts. This is not currently widely used in clinical practice. The greatest improvement in the CDR with DBT is seen in women with dense breast tissue [21,22,57,58]. Although the TOMMY trial did not reach statistical significance across all breast densities, in women with >50% breast density, statistical significance was achieved, with the sensitivity of 2-D mammography plus DBT reaching 93% versus 86% for 2-D mammography alone [21,22]. In a meta-analysis of 16 studies evaluating women with dense breasts, DBT improved the CDR compared with 2-D mammography alone in both the diagnostic (RR: 1.16) and the screening (RR: 1.33) settings [58]. In addition to the increase in the CDR, another benefit of adding DBT to 2-D mammography is the reduction in the recall rate [16-19]. In a single-center screening program, Sharpe et al [18] reported a reduction in the recall rate by 18.8%. In the prospective Oslo Tomosynthesis Screening Trial, the recall rate was reduced from 6.7/1,000 to 3.6/1,000 [19]. There is also evidence that the reduction in the recall rate is maintained over consecutive screening episodes [18].


Supplemental Breast Cancer Screening Based on Breast Density. Cortesi et al [35] evaluated the efficacy of biannual screening US examination in women who were BRCA mutation carriers, high-risk (non-BRCA1/2), and intermediate-risk patients. Overall, MRI had sensitivity of (93.7%), followed by mammography (55.0%), then US (29.4%). In the nondense breast, the sensitivity of mammography was 82.5% versus 10% for US. In the dense breast, the sensitivity of mammography was 50% versus 42.6% for US. Sensitivity analysis by risk level was also performed. The US sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and intermediate-risk patients were 22.7%, 24.5%, and 33.6%, respectively. The mammographic sensitivities for BRCA1/2, high-risk (non-BRCA1/2), and intermediate-risk patients were 25.0%, 66.4%, and 56.6%, respectively. Only the BRCA1/2 mutation carriers underwent MRI screening, which demonstrated a sensitivity of 93.7%. The authors did not analyze the efficacy of US screening based on both density and risk. The addition of WBUS to mammography increases the CDR in high-risk women. In a surveillance cohort study of 529 women with elevated lifetime risk, the sensitivity of mammography, WBUS, and the 2 modalities combined was 33%, 40%, and 49%, respectively [44]. However, subgroup analysis was not performed by breast density. In Supplemental Screening Based on Breast Density the same population, MRI had a sensitivity of 91% [44]. In the ACRIN 6666 trial, after 3 rounds of screening mammography and screening WBUS in women with dense breast tissue at intermediate to elevated lifetime risk, the sensitivity, specificity, and PPV3 of mammography was 0.52, 0.91, and 0.38, respectively. The addition of US to mammography increased the sensitivity (0.76) but decreased the specificity (0.84) and PPV3 (0.38) [45]. In a prospective cohort trial of 687 high-risk women, the cancer yield of mammography alone was 5.4/1,000 and increased to 7.7/1,000 with the addition of US [46].


Supplemental Breast Cancer Screening Based on Breast Density. MRI Breast Without IV Contrast Abbreviated There is no relevant literature regarding the use of AB-MRI breast without IV contrast for supplemental screening in high-risk women with dense breasts. MRI Breast Without and With IV Contrast Abbreviated AB-MRI performed with IV contrast is an abbreviated breast MRI examination. It is similar to a full MRI examination yet does not have a standard protocol; however, at minimum, it must include a precontrast and one postcontrast sequence. A T2-weighted sequence may also be included. There is limited relevant literature regarding the use of AB-MRI breast without and with IV contrast in high-risk women with dense breasts. In 2 retrospective studies comparing the full diagnostic protocol to an abbreviated protocol in high-risk women, the authors found both protocols to have similar sensitivity [48,49]. However, neither study evaluated the CDR by breast density. MRI Breast Without IV Contrast There is no relevant literature regarding the use of MRI breast without IV contrast for supplemental screening in high-risk women with dense breasts. MRI Breast Without and With IV Contrast The American Cancer Society advocates MRI screening in high-risk women regardless of breast density [15]. There is ample evidence in the literature supporting this recommendation [46,50-54]. In the high-risk population, sensitivity of mammography alone is approximately 31% to 33%, compared with the sensitivity of MRI alone which is 87% to 96% [45,46,55]. The combination of mammography and MRI yields 100% sensitivity compared with the 44% to 48% sensitivity of combined mammography and US [45,46]. In addition, the types of carcinoma detected on MRI compared with mammography may differ. Cancers detected on MRI are more likely to be invasive carcinomas (71%), whereas cancers detected on mammography were are likely to be ductal carcinoma in situ (65%), or associated with calcifications (88%) [56].


Chronic Cough

Chronic Cough.  Introduction/Background Chronic cough is defined by a duration lasting at least 8 weeks [1], often contributing to patient discomfort and altered psychosocial well-being [2]. The most common causes of chronic cough include smoking-related lung disease, upper airway cough syndrome (UACS), asthma, gastroesophageal reflux disease (GERD), and nonasthmatic eosinophilic bronchitis [1-3]. Cough can further be characterized by quality, that is productive or nonproductive. Conditions that may be associated with productive cough include bronchiectasis, chronic bronchitis, asthma, and immunodeficiencies [4-6]. There is varied opinion in the literature regarding the utility of cough productivity in the phenotypic stratification of chronic cough patients [5,7,8]. Cough is a protective reflex mediated by a complex network of afferent and efferent neuronal pathways [9]. Stimuli for cough can occur in the chest wall, airways, esophagus, larynx, and middle ear [10]. It is believed that a significant number of individuals with chronic cough may be suffering from cough hypersensitivity [11,12], in which the threshold for cough is lowered by repeated exposure to stimulus or inflammation [11-13]. There may be similarity in the neuronal hyperstimulation seen in chronic cough with that of chronic pain [14]. The etiology of chronic cough in some patients may be difficult to localize to an isolated source and is often multifactorial [15]. The complex pathophysiology, clinical presentation, and variable manifestations of chronic cough underscore the challenges faced by clinicians in the evaluation and management of these patients. Varying guidelines and algorithms exist for the evaluation and management of chronic cough, driven by a thorough history and physical examination, empiric treatment, and often diagnosis by exclusion [1,15,16]. Standardized clinical algorithms have shown efficacy in the diagnosis and treatment of chronic cough [7,10,16,17].


Chronic Cough

Chronic Cough. Imaging plays a role in the evaluation, although there is lack of high-quality evidence guiding which modalities are useful and at what time point in the clinical evaluation they should be performed. Further research may be needed to evaluate which imaging modalities performed earlier in the clinical assessment are beneficial in long-term outcomes. Special Imaging Considerations Our literature review has identified several studies investigating thoracic ultrasound (US) in the evaluation of the noncardiac chest pain. Noncardiac thoracic US performed better than radiography in small prospective cohorts staged in the postoperative intensive care unit [18] and primary care setting [19], confidently identifying findings such as pneumothorax, pleural effusion, consolidation, and interstitial patterns of lung disease. US was shown to correlate well with high-resolution CT (HRCT) and pulmonary function test (PFT) abnormalities [20], and it performed well in several small studies of patients with known interstitial lung disease [21-23]. US may be prone to diminished specificity. For instance, Moazedi-Fuerst et al [24] showed that up to 12% of patients with normal HRCT studies had sonographic findings of an interstitial pattern based on B-lines and artifacts. Adequate US evaluation is operator dependent and requires experience to perform and interpret examination findings. To our knowledge, there is no relevant literature to support the use of thoracic US in the evaluation of chronic cough; however, it is included in this section for awareness and to promulgate future research into this particular topic. Reprint requests to: publications@acr.org Chronic Cough Low-dose chest CT (LDCT) has been clinically validated in the National Lung Screening Trial Research Team for early detection of lung cancer [25]. LDCT has been investigated for early detection of pulmonary infection in elderly patients with normal or equivocal chest radiographs.


Chronic Cough

Chronic Cough. Park et al [26] showed that 49 out of 166 elderly patients presenting to the emergency room who had normal chest radiographs were subsequently diagnosed with acute respiratory infection from findings on LDCT. In a prospective case comparison, Christe et al [27] showed good correlation between standard dose (150 mAs) and low-dose (40 mAs) CT protocols for evaluating the majority of pulmonary abnormalities, including bronchiectasis, air trapping, and pleural disease. Investigators did identify a drop in sensitivity in low-dose scans for ground-glass nodules, reticulation, and mucus plugging [27]. Ultra-low- dose CT demonstrated 91% sensitivity and 100% specificity in identifying asbestos-related lung abnormalities in a prospective cohort of 55 asymptomatic persons with relevant exposure history [28]. To our knowledge, there is no relevant literature to support the use of LDCT in the evaluation of chronic cough, and further research into this topic may be warranted. OR Discussion of Procedures by Variant Variant 1: Chronic cough lasting more than 8 weeks. No known risk factors for lung cancer. Initial imaging. Radiography Chest Chest radiography is recommended by numerous pulmonary and thoracic societies for the evaluation of chronic cough [1,10,15,29], although the exact timing of imaging has varied between groups. The American College of Chest Physicians (ACCP) includes a recommendation for an initial chest radiograph in their chronic cough algorithm [1]. The evidence supporting chest radiography at initial evaluation of chronic cough is limited to case series, observational studies, and retrospective analysis. Initial evaluation with posteroanterior chest radiography has been included as part of two investigative case series using standardized clinical protocols for chronic cough [7,17].


Chronic Cough

Chronic Cough. Of the 131 patients evaluated, 49 chest radiographs were reported abnormal, with the final diagnosis of primary lung pathology other than asthma made in 29 patients, including 8 patients with bronchiectasis, 8 patients with interstitial lung disease, and 2 patients with neoplasm. The authors did not report the sensitivity or specificity of chest radiography in the setting of chronic cough; however, abnormal radiography was positively associated with underlying primary pulmonary pathology other than asthma (odds ratio 7.7) [7]. Ojoo et al [17] prospectively evaluated 112 patients with chronic cough in a similar standardized clinical investigative protocol. In this study, 7 radiographs (6.3%) were reported contributory to the final diagnosis. Of the 92 patients with diagnosis found at discharge, 12 (13%) patients had pathologies including bronchiectasis, interstitial lung disease, self-limiting cough, and 2 cases of lung cancer. Both of these studies reported clinical efficacy with standardized protocols utilizing initial chest radiography, with diagnosis achieved in 93% in the Kastelik et al study [7] and 82% in the Ojoo et al study [17]. The most commonly reported etiologies were reflux, asthma, postinfective or viral cough, and rhinitis, representing between 61% to 67% of final diagnosis, which were more common than bronchiectasis, interstitial lung disease, and neoplasm, which represents <13% to 18% of final diagnosis [7,17]. Both case series are limited by sample size, and both studies were performed out of referral centers, likely contributing to selection bias. Retrospective analyses have been performed specific to chronic cough and normal chest radiography. Turner et al [16] retrospectively reviewed the medical records of 404 patients with chronic cough referred to specialty care who either had or subsequently were found to have a normal chest radiograph.


Chronic Cough

Chronic Cough. Of the 266 patients who were given a diagnosis, 8 patients were found to have a diagnosis that could be made on imaging (4 with lower respiratory tract infection, 2 with malignancy, 1 with bronchiectasis, and 1 with pulmonary fibrosis). Although made explicit for the 2 cases with malignancy, it is only implied that the other 6 patients had normal chest radiography and that the diagnosis was made by other means (ie, chest CT). Additionally, the cases of malignancy were suspected on the Chronic Cough The diagnostic performance of chest radiography varies among the reviewed literature. In a systematic review of the literature, Piccazzo et al [30] reported a high negative predictive value for chest radiography in the evaluation of active and inactive tuberculosis. Abnormalities on chest radiography did have a lower specificity, and findings, which were equivalent the authors concluded, should prompt consideration for CT as this modality was shown to have better performance for both active and inactive tuberculosis. Colaci et al [31] prospectively evaluated 107 consecutive patients with systemic sclerosis with both radiography and HRCT. Their study showed strong correlation between radiographic and HRCT findings of interstitial lung disease, with strong association between cough symptoms and HRCT findings. Interstitial lung pattern and restrictive PFT was more commonly identified than airway involvement and obstructive disease. The authors, however, did not publish sensitivity or specificity for radiography [31]. The diagnostic performance of radiography for other patterns of lung disease may be worse. In a retrospective analysis of 236 patients with CT-proven bronchiectasis, Altenburg et al [32] reported that up to 34% of chest radiographs were reported unremarkable. As mentioned above, the most common CT findings in those patients with chronic cough with normal radiographs were in fact bronchiectasis (28%) and bronchial wall thickening (21%) [3].


Chronic Cough

Chronic Cough. The sensitivity of chest radiography for airway abnormalities was found to be 69% to 71% when referenced to helical CT in 70 patients with known airway abnormalities and lesions [33]. In a retrospective analysis of elderly emergency room patients who were evaluated for acute respiratory infection, Park et al [26] showed that chest radiographs were normal in 49 out of 166 confirmed cases on LDCT. Chest radiography was more often normal when LDCT identified ground-glass opacity (GGO), bronchial wall thickening, centrilobular nodules, and small and dependent consolidations. Chest radiography was also found to have poor correlation with chest CT for the presence of pulmonary opacities [34,35], with a positive predictive value of only 27% when compared with chest CT in a secondary analysis of a large retrospective cohort of 3,400 patients. Limitations of chest radiography reflect superimposed soft-tissue structures, radiographic findings related to comorbidities, and limited contrast resolution. Unfortunately, there are no high-quality studies evaluating the clinical efficacy of chest radiography in the early evaluation of patients with chronic cough, and this may be an area of future investigation. Based on the available literature, there is a suggestion that initial evaluation of chronic cough with chest radiography is beneficial in the clinical setting. There does remain question regarding the sensitivity of chest radiography in this group [3], which is likely skewed toward early disease and airway abnormalities. This could potentially result in delayed diagnosis for a small percent of patients with chronic cough. CT Chest There is no high-quality evidence to support the use of chest CT in the initial evaluation of patients presenting with chronic cough. No studies have directly compared the utility of contrast-enhanced versus noncontrast-enhanced CT imaging in regard to chronic cough.


Chronic Cough

Chronic Cough. Contrast-enhanced studies offer improved visualization of cardiopulmonary vasculature, mediastinal structures, and soft-tissue abnormalities [35], although MRI is developing a more consistent role for the latter. For the majority of studies, however, the noncontrast technique appears to be adequate. Chest CT is more sensitive than chest radiographs for the evaluation of most pulmonary abnormalities as well as mediastinal, cardiac, and chest wall findings, combining improved soft-tissue contrast and anatomical localization. This was demonstrated in a few small studies included in our literature review [3,32,36]. Chest CT is considered the reference standard for the noninvasive diagnosis of bronchiectasis [37] as well as of interstitial lung disease. CT abnormalities have been described in patients with chronic cough. Truba et al [3] performed a retrospective analysis of patients with chronic cough with negative initial chest radiograph findings, reporting 21 out of 59 patients with CT abnormalities believed to be relevant to chronic cough. The authors identified bronchiectasis and Chronic Cough Other studies showed a lack of association between cough symptoms and chest CT findings. Ooi et al [6] was unable to correlate respiratory symptom exacerbation (including cough symptoms) with HRCT findings of small airways abnormality, mosaic attenuation, and bronchial wall thickening in 60 patients with CT-proven bronchiectasis, although there was association between CT findings and sputum production and PFT abnormality. Wilsher et al [40], in a prospective analysis of 60 consecutive patients newly diagnosed with RA, demonstrated that bronchiectasis was prevalent in up to 48% of patients, despite only 30% of patients presenting with respiratory complaints. There was no association between the cough symptoms and bronchiectasis, although there was a statistically significant association for dyspnea symptoms.


Chronic Cough

Chronic Cough. The major pulmonary societies recommend noncontrast chest CT for the evaluation of chronic cough when the more common causes are excluded or empirically treated [1,10,15,29], and this is usually preceded by a chest radiograph. Of the studies evaluating the clinical management of patients with chronic cough, none utilized chest CT in the initial workup [3,7,16,17], and two studies specifically addressed a cohort of patients with normal chest radiography findings [3,16]. Kastelik et al [7] utilized a probability-based clinical algorithm in the prospective treatment of 131 patients presenting with cough lasting >8 weeks. All patients were initially evaluated with chest radiography and empirically treated based on the probability of underlying etiologies. Chest CT was performed in those patients with clinical suspicion of underlying disease (n = 29) as well as in those with indications or negative initial workup otherwise (n = 17). Of these, 26 out of 29 patients (positive predictive value of 90%) suspected of having underlying pulmonary disease were diagnosed and treated as appropriate; however, 17 patients in whom chest CT was performed without cause and as part of the algorithmic evaluation did not have findings relevant to their management. The authors concluded that chest CT should be performed only in selected patients and those with abnormal chest radiographs. In another prospective observational study, Ojoo et al [17] evaluated 112 consecutive patients with chronic cough. All patients were evaluated with chest radiography. Chest CT was performed only based on clinical suspicion. The authors reported that 74 out of 81 patients managed clinically without the need for chest CT examination, suggesting chest CT would not have made a difference in these patients. It should be noted that both studies did identify primary pulmonary etiologies felt to be associated with chronic cough, of which bronchiectasis and interstitial lung disease were the two most common.


Chronic Cough

Chronic Cough. In a retrospective cohort of patients with chronic cough referred to specialty care with normal chest radiographs, Turner et al [16] showed successful clinical management of 266 patients with minimal investigation and empiric treatment, requiring chest CT in 1 patient to diagnose bronchiectasis, 1 patient with pulmonary fibrosis, and 2 patients with malignancy. Future studies may be needed to better validate CT findings with clinical features in order to determine causation/association in the context of chronic cough. Lung patterns of disease and obvious abnormalities identified on CT will still be of clinical value, and an expected number of CT Chronic Cough abnormalities may be noncontributory to management. The role of chest CT in the initial evaluation of chronic cough remains indeterminate. The evidence suggests that wide application in all patients presenting with chronic cough may be of low clinical yield. Appropriate selection would likely improve the specificity of findings. FDG-PET/CT Skull Base to Mid-Thigh There is no relevant literature to support the use of fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET in the initial evaluation of chronic cough. FDG-PET/CT is not listed as an imaging option in the most recent ACCP guidelines on chronic cough [1]. FDG-PET utilizes a radiolabeled glucose analog to evaluate for upregulated metabolism in areas of infection, inflammation, and neoplasm [43]. MRI Chest There is no relevant literature to support the use of thoracic MRI in the initial evaluation of chronic cough. MRI of the chest is not included in the clinical algorithms recommended by various pulmonary and thoracic societies [1,10,15,29]. Thoracic MRI (nonbreast, noncardiac, nonmusculoskeletal) is currently utilized for the evaluation of indeterminate findings on other imaging modalities, most commonly mediastinal and thymic [44], less often utilized for vascular, airway, and pulmonary parenchymal abnormalities.


Chronic Cough

Chronic Cough. MRI offers improved soft-tissue contrast, with advanced sequences able to identify soft-tissue characteristics to the cellular level (ie, diffusion-weighted imaging and spectroscopy). Advanced techniques allow for calculation of total lung water density, which has been shown to correlate with disease severity in adult patients with cystic fibrosis [45]. With the addition of intravenous (IV) contrast, the vascular nature of an abnormality is exquisitely imaged and has been shown to be as accurate as contrast-enhanced CT for the evaluation for pulmonary embolism [35]. IV contrast also offers the evaluation of pulmonary perfusion [46]. Limitations of pulmonary MRI include low signal-to-noise ratio (especially with a normally aerated lung), low spatial resolution, and need for adequate breath-hold technique or respiratory gating [46]. Parenchymal lung abnormalities naturally increase cellular proton density and/or water content while displacing low signal gas, providing contrast for visualization [35]. Despite limitations, pulmonary MRI has been shown to have noninferior diagnostic quality when compared with CT [46,47]. Ohno et al [47] analyzed 85 consecutive patients with high-resolution pulmonary MR using ultrashort time to echo and compared findings with both standard CT and LDCT. The authors found equivalent diagnostic efficacy for all observed findings, noting decreased sensitivity and image quality when evaluating for emphysema, bronchiectasis, and reticular opacity. The authors concluded that based on their assessment, ultrashort time to echo pulmonary MR is equivalent to LDCT imaging [47]. There is no relevant literature evaluating IV contrast versus noncontrast MRI in the setting of chronic cough, and decisions may need to be made on a case-by-case basis. Investigational contrast agents may prove useful in the future. Hyperpolarized gas MRI is an example, which is currently FDA approved for investigational use [44,48].


Chronic Cough

Chronic Cough. Hyperpolarized Xe-129 gas MRI allows for improved contrast of the lung parenchyma with techniques allowing for the evaluation of anatomical and functional data [48]. These techniques are still in their infancy and will likely require future studies to evaluate their role in imaging in chronic cough. In 2014, Ackman et al [44] surveyed thoracic radiologists from the Society of Thoracic Radiology regarding utilization of nonvascular thoracic MRI. Respondents offered an insight into the underutilization of thoracic MRI. Challenges in implementing MRI into clinical practice were described, including ordering health care provider awareness, lack of training, and technical, as well as administration hurdle. Variant 2: Chronic cough lasting more than 8 weeks. Increased risk for lung cancer. Initial imaging. Radiography Chest Chest radiography is often performed early in the investigation of chronic cough and is recommended by the ACCP [1]. There was no literature that addressed this modality in the setting of chronic cough with risk factors for lung cancer. In each of the available prospective case series evaluating standardized clinical protocols for chronic cough, there was a diagnosis of malignancy in 2 of 131 [7] and 2 of 122 [17] patients assessed, all of whom had initial chest radiography. Both studies reported that clinical and radiographic findings led to increased suspicion of malignancy. In a retrospective analysis of patients with chronic cough who had normal chest radiographs, 2 out of 266 diagnosis were determined to be malignant. Both patients had suspicious clinical findings, which prompted further evaluation with chest CT [16]. Cough has been shown to be a prevalent symptom in patients with lung cancer [49,50], with 57% consecutive patients with lung cancer reporting cough as a symptom (n = 223). The exact prevalence of malignancy in a population with chronic cough is not well documented and likely <1% to 2% from the small collection of case series Chronic Cough reviewed.


Chronic Cough

Chronic Cough. Nevertheless, in the setting of elevated risk (ie, smoking and occupational exposure), the prevalence may be more significant. The role of chest radiography in the early evaluation of patients with chronic cough is largely founded in the exclusion of treatable and/or serious underlying pulmonary pathology. When extrapolating from the available evidence, there remains a question regarding the sensitivity of chest radiography for the detection of subclinical disease and early malignancy. In this setting, there may be a population of patients with chronic cough that may benefit from earlier use of advanced imaging. Future research into this topic may elucidate the specific features and clinical qualities that would provide risk stratification and entail appropriate imaging recommendation. CT Chest There is no relevant literature to support the use of chest CT in patients with chronic cough who have one or more high-risk factors for lung cancer. In nonsmoking adults, risk factors vary and include environmental pollutants, genetic variations, underlying chronic pulmonary disease, immunosuppression, and occupational exposures (ie, asbestos and silica) [52]. Cough has been shown to be a prevalent symptom in patients with lung cancer [49,50], 57% of a small cohort of consecutive patients with lung cancer (n = 223). However, the true prevalence of isolated cough (without any additional clinical features) in the setting of malignancy remains unknown. Some authors suggest this combination to be rare in the clinical setting of chronic cough [16]. In a retrospective analysis of patients with chronic cough who have normal chest radiographs, 2 out of 266 diagnoses were determined to be malignancy. Both patients had suspicious clinical findings, which prompted further evaluation with chest CT. It is also worth noting that both patients had a normal chest radiograph [16].


Chronic Cough

Chronic Cough. In prospective case series evaluating standardized clinical protocols for chronic cough, the prevalence of malignancy was found to be between 1% and 2% [7,17]. CT of the chest is recommended for the evaluation of suspected pulmonary neoplasm [15,53] and has been recommended for patients with chronic cough who are smokers or when chronic lung disease is clinically suspected [16,53]. Chest CT has been shown to be more sensitive than chest radiography for the detection of lung cancer in the National Lung Cancer Screening Trial [25], with significant overall mortality benefit. There is limited data regarding the differential imaging evaluation of patients with chronic cough with occupational exposures. In a small sample of male welders (n = 74) with a normal chest radiograph, HRCT identified 27 patients with micronodular disease, 5 patients with emphysematous changes, 3 patients with GGO, and 1 patient with pleural thickening [51], questioning the sensitivity of radiography for occupational disease. Red flags and concerning features are discussed by various authors and larger pulmonary societies [1,13,29], although our literature review did not identify studies directly evaluating CT of the chest in patients with chronic cough with elevated risk. Additionally, red flags in this setting have not been validated and shown to be predictive of malignancy. In the setting of elevated lung cancer risk, there is no high-quality evidence supporting chest CT in patients with chronic cough. It is worth noting that in the few case series evaluating patients with chronic cough, malignancy was diagnosed in 1% to 2% of studied groups. This is a not an insignificant quantity and actually rivals case detection in both lung cancer and breast cancer screening. Furthermore, at least two of these reported malignancies were in the context of a normal chest radiograph. It is likely that the prevalence of malignancy in the setting of chronic cough is far lower, and these studies are likely biased by selection.