Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. CT Area of Interest Without and With IV Contrast There is no relevant literature to support the use of CT area of interest without and with IV contrast as the initial imaging modality in infants with infantile hemangiomas. In the study by Koplewitz et al [20], noncontrast and contrast-enhanced CT scans were performed. It was found that the lesions appeared larger after IV contrast was given and that the complete extent and localization of the lesion could be best defined. Soft Tissue Vascular Anomalies-Child CT Area of Interest Without IV Contrast There is no relevant literature to support the use of CT area of interest without IV contrast as the initial imaging modality in infants with infantile hemangiomas. CTA and CTV Area of Interest With IV Contrast There is no relevant literature to support the use of CT angiography (CTA) or CT venography (CTV) area of interest with IV contrast as the initial imaging modality in infants with infantile hemangiomas. MRA and MRV Area of Interest Without and With IV Contrast Dynamic MR angiography (MRA) and MR venography (MRV) with IV contrast of untreated infantile hemangiomas is capable of showing supplying arterial and draining venous vessels [15]. MRI Area of Interest Without and With IV Contrast MRI of the area of interest without and with IV contrast in patients with infantile hemangiomas may be useful when clinically determining the complete extent of the lesion is not possible, such as when the infantile hemangiomas of the face and deep facial structures or periorbital and intraorbital extent must be defined, when lumbosacral region infantile hemangiomas are present and underlying tethering or other spinal cord anomaly may be present, and there are beard-type infantile hemangiomas that occupy the pharyngeal region and may affect the oropharyngeal airway.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. MRI may also be useful in patients with infantile hemangiomas in anatomic locations, when the presence or growth of the lesion may be disfiguring or interfere with sight or hearing, the face, airway, ears, or breast [17]. MRI Area of Interest Without IV Contrast There is no relevant literature to support the use of MRI of the area of interest without IV contrast as the initial imaging modality for infants with infantile hemangiomas. Radiography Area of Interest There is no relevant literature to support the use of radiography area of interest as the initial imaging modality in infants with infantile hemangiomas. US Area of Interest Ultrasound (US) of the area of interest is useful to distinguish imaging features of infantile hemangiomas from VMs. Paltiel et al [21] studied 49 lesions and Ding et al [14] studied 66 lesions, describing US imaging characteristics of superficial and deep infantile hemangiomas from well-circumscribed mixed echogenicity solid masses with central and peripheral vessels on grayscale US. Both groups showed that US is useful in distinguishing infantile hemangiomas from VMs and for identifying infantile hemangiomas, which may be combined with other VA components [14,21]. US Area of Interest With IV Contrast There is no relevant literature to support the use of US area of interest with IV contrast as the initial imaging modality in infants with infantile hemangiomas. US Duplex Doppler Area of Interest US with duplex Doppler is most useful to assess and confirm diagnosis of infantile hemangiomas. Paltiel et al [21] studied 49 lesions and Ding et al [14] studied 66 lesions, showing that a combination of arterial and venous waveforms on US duplex Doppler enables distinguishing infantile hemangiomas from low-flow VMs.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. A multicenter prospective study of 1,656 infants with infantile hemangiomas confirmed that patients with higher numbers of cutaneous infantile hemangiomas have a greater incidence of infantile hepatic hemangioma, 8.3% in patients with 5 to 9 lesions compared with 0.4% in patients with <5 cutaneous lesions. Based on the results of this study, screening liver imaging examination is indicated in patients with 5 cutaneous infantile hemangiomas and for patients up to 9 months of age [23]. Soft Tissue Vascular Anomalies-Child In an analysis of 121 children with hepatic hemangioma in the Liver Hemangioma Registry, Kulungowski et al [24] found that 88 children had multiple cutaneous infantile hemangiomas lesions, 68 (77%) of which were multifocal and 20 (23%) of which were diffuse type infantile hepatic hemangioma. Arteriography Abdomen There is no relevant literature to support the use of arteriography of the abdomen as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. CT Abdomen With IV Contrast There is no relevant literature to support the use of CT of the abdomen with IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. CT Abdomen Without and With IV Contrast There is no relevant literature to support the use of CT of the abdomen without and with IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. CT Abdomen Without IV Contrast There is no relevant literature to support the use of CT of the abdomen without IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. CTA and CTV Abdomen With IV Contrast There is no relevant literature to support the use of CTA and CTV of the abdomen with IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. MRA and MRV Abdomen Without and With IV Contrast There is no relevant literature to support the use of MRA and MRV of the abdomen without and with IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. MRI Abdomen Without and With IV Contrast There is no relevant literature to support the use of MRI of the abdomen without and with IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. A recent guidance document of the American Society of Pediatric Hematology Oncology Vascular Anomalies Special Interest Group recommends contrast-enhanced MRI of the liver including dynamic sequences if the diagnosis is unclear following Doppler US [25]. MRI Abdomen and Pelvis Without IV Contrast There is no relevant literature to support the use of MRI of the abdomen and pelvis without IV contrast as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. Radiography Abdomen There is no relevant literature to support the use of radiography of the abdomen as the initial imaging modality when screening for hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. US Abdomen With IV Contrast US of the abdomen with IV contrast, specifically for evaluation of the liver, for the presence of hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas may be used to increase the sensitivity and diagnostic confidence, particularly for focal lesions that are seen in congenital hepatic hemangiomas rather than the diffuse and multifocal hepatic hemangiomas seen in infantile hemangiomas [26,27]. The addition of IV contrast for Soft Tissue Vascular Anomalies-Child US of the abdomen has been shown by El-Ali et al [27] to differentiate infantile hepatic hemangioma in infants from congenital hemangioma of the liver in 5 infants based on the pattern of early and late arterial phase and delayed washout of IV contrast (P = . 0016). The IV contrast enhancement pattern on US was similar to the manner in which the lesions are known to enhance with IV contrast on CT and MRI examinations [28]. US Duplex Doppler Abdomen A recent guidance document of the American Society of Pediatric Hematology Oncology Vascular Anomalies Special Interest Group recommends Doppler US of the liver as the preferred initial imaging study. On US examination imaging features such as multifocal and diffuse patterns are more specific to infantile hepatic hemangiomas and may be used to help differentiate them from congenital hemangiomas of the liver [25]. Solitary lesions may be larger in diameter and of heterogeneous echogenicity, with more prominent peripheral vascular components [26]. Variant 3: Child. Clinical signs or symptoms of vascular anomaly (tumor or malformation) not suggesting infantile hemangioma. Initial imaging. VAs are a diverse group of lesions including tumors with benign, locally aggressive, or malignant behaviors and malformations, which may involve low-flow (venous or lymphatic) or fast-flow (arterial) blood flow [4] (see Appendix 1).


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Many VAs are fully formed before birth and do not clinically present in a fashion typical of infantile hemangiomas. Imaging characterization of the lesion and delineation of its extent are warranted. Arteriography Area of Interest There is no relevant literature to support the use of arteriography area of interest as the initial imaging modality for vascular lesion such as tumor or malformation. CT Area of Interest With IV Contrast There is no relevant literature to support the use of CT area of interest with IV contrast as the initial imaging modality for vascular lesion such as tumor or malformation. CT Area of Interest Without and With IV Contrast There is no relevant literature to support the use of CT area of interest without and with IV contrast as the initial imaging modality for vascular lesion such as tumor or malformation. CT Area of Interest Without IV Contrast There is no relevant literature to support the use of CT area of interest without IV contrast as the initial imaging modality for vascular lesion such as tumor or malformation. CTA and CTV Area of Interest With IV Contrast There is no relevant literature to support the use of CTA and CTV area of interest with IV contrast as the initial imaging modality for vascular lesion such as tumor or malformation. MRA and MRV Area of Interest Without and With IV Contrast Using contrast-enhanced MRA and MRV patterns of high or low signal intensity can help distinguish between low- flow and fast-flow VMs. In a study by van Rijswijk et al [29], they describe a 95% specificity and 83% sensitivity in differentiating venous and nonvenous malformations using dynamic contrast-enhanced MRA. Dynamic 4-D MRA with IV contrast may be used to detect the presence of arteriovenous microshunts in VMs, which have been found to be associated with the presence of phleboliths [30].


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Subtraction MRA techniques subtract MR signal from noncontrast-enhanced MR images from a contrast-enhanced MRA, resulting in improved visualization of vascular structures as soft tissue signal is removed [31]. There may also be value in the use of noncontrast MRA as an anatomic survey before performing contrast-enhanced MRA to facilitate planning of field of view and contrast bolus timing [32]. MRA Area of Interest Without IV Contrast Numerous noncontrast-enhanced MRA sequences are also available, relying on the speed of blood flow (flow- dependent) and subject to signal loss in vessels with slow blood flow. Flow-independent noncontrast-enhanced MRA sequences produce bright blood or dark blood pool images and enable imaging a larger field of view. Noncontrast MRA images may incorporate longer scan times and therefore produce higher spatial resolution images Soft Tissue Vascular Anomalies-Child [33]. Noncontrast MRA does not provide dynamic flow information provided by contrast-enhanced MRA. Furthermore, although time-of-flight cannot be used to characterize soft tissue components, it does show the feeding and draining vessels of a fast-flow VM [34]. MRI Area of Interest Without and With IV Contrast MRI area of interest without and with IV contrast as the initial imaging modality for vascular lesion such as tumor or malformation may be helpful as the initial imaging examination and may be performed contemporaneously with US to investigate a soft tissue mass or skin discoloration. MRI findings typically show a lobulated and often infiltrative soft tissue mass with T1 hypointense and T2 hyperintense signal, variable vascular flow voids, variable patterns of enhancement, and possibly phleboliths, depending upon the type of lesion. The addition of MRA may be beneficial to making a definitive diagnosis [31].


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. MRI Area of Interest Without IV Contrast MRI area of interest without IV contrast as the initial imaging modality for vascular lesion such as tumor or malformation may be helpful as the initial imaging examination and may be performed contemporaneously with US to investigate a soft tissue mass or skin discoloration. MRI without IV contrast typically shows a lobulated and often infiltrative soft tissue mass with T1 hypointense and T2 hyperintense signal, variable vascular flow voids, and possibly phleboliths, depending upon the type of lesion. The lack of contrast will limit the ability to characterize the type of vessel and characterization of flow through the lesion (high- versus low-flow) and, therefore, the type of VM being evaluated. The addition of IV contrast and possibly MRA may be beneficial to making a more definitive, accurate characterization of the lesion and eventually the diagnosis [31]. Radiography Area of Interest There is no relevant literature to support the use of radiography area of interest as the initial imaging modality for vascular lesions such as tumor or malformation [35]. Radiographs may reveal calcifications within a soft tissue mass, indicating the diagnosis of VM, but is not typically the initial imaging study when a VA is suspected. Phleboliths occur at the site of microshunts in VMs. US Area of Interest US may be used to distinguish characteristic features of VTs and to differentiate between low-flow and fast-flow VMs. Aside from infantile hemangioma, VTs reveal well-defined solid tissue components with variable echotexture [21]. Venous VMs can be partially characterized with grayscale US, and certain features such as multiple anechoic spaces, echogenic phleboliths, and expanded soft tissue spaces that are compressible (muscle, subcutaneous fat, dermis layers) can be diagnostic.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Lymphatic VMs are also able to be at least partially characterized by grayscale US when multiple anechoic spaces with cysts, which may contain fluid-fluid levels in the event there has been prior infection or hemorrhage into the lesion, that are noncompressible are visualized. Venolymphatic VMs show a combination of the above features. Fast-flow VM-AVMs and AVFs show a cluster of vessels without an associated solid tissue mass [36,37] in contradistinction to hemangiomas. Congenital hepatic hemangiomas are focal lesions of the liver associated with multiple cutaneous infantile hemangiomas. US Area of Interest With IV Contrast US of the abdomen and pelvis with IV contrast, specifically for evaluation of the liver, for the presence of hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas may be used to increase sensitivity and diagnostic confidence, particularly for focal lesions, which are seen in congenital hepatic hemangiomas rather than the diffuse and multifocal hepatic hemangiomas seen in infantile hemangiomas [26,27]. The addition of IV contrast for US of the abdomen and pelvis has been shown by El-Ali et al [27] to differentiate infantile hepatic hemangioma in infants from congenital hemangioma of the liver in 5 infants based on the pattern of early and late arterial phase and delayed washout of IV contrast (P = . 0016). The IV contrast enhancement pattern on US was similar to the manner in which the lesions are known to enhance with IV contrast on CT and MRI examinations [28]. US Duplex Doppler Area of Interest US with duplex Doppler may be used to distinguish characteristic features of VTs, verify arterial waveforms in fast- flow VMs (arterialization of draining veins), and differentiate between low-flow and fast-flow VMs. Aside from Soft Tissue Vascular Anomalies-Child infantile hemangioma, VTs typically demonstrate both arterial and venous waveforms.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Venous malformations show multiple anechoic spaces, but the flow in venous VMs may be so slow that it is difficult to perceive on Doppler. Lymphatic VMs are also composed of multiple anechoic spaces with cysts, which may contain fluid-fluid levels in the event there has been prior infection or hemorrhage but will not have Doppler signal. Venolymphatic malformations show a combination of these features. Fast-flow VM-AVMs and AVFs show a cluster of vessels without an associated solid tissue mass [36] with fast-flow on Doppler US. Variant 4: Child. Ultrasound features raise suspicion for vascular malformation. Next imaging study. If initial US imaging raises suspicion for the diagnosis of VM, further imaging is often helpful to visualize the entire extent of the lesion, assess for the presence of multiple lesions, and evaluate possible involvement of adjacent tissues and organs (including sensitive anatomic regions such as deep facial structures, the airway, orbits, and the spine). Arteriography Area of Interest Digital subtraction angiography provides an excellent definition of AVM anatomy, in particular the AVM nidus and the number and definition of feeding arteries and fistulas in fast-flow (arterial) lesions, with greater sensitivity than MRA [38]. Before an invasive procedure such as digital subtraction angiography is performed, it is best to have a narrowed differential diagnosis (usually requires prior MRI/MRA to suggest the diagnosis of a fast-flow VM). Diagnostic angiography may confirm the suspicion of a fast-flow VM if this remains in question following MRI/MRA but is typically reserved for symptomatic patients when simultaneous treatment is a leading consideration.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. CT Area of Interest With IV Contrast Contrast-enhanced CT may provide further anatomic definition of a VM after US in other anatomies, aiding in visualizing phleboliths, thrombus, osseous changes such as erosion or findings related to overgrowth syndromes, and soft tissue involvement, especially in defining the deep or infiltrative extent of a VA [39-41]. CT Area of Interest Without and With IV Contrast There is insufficient literature reviewing the efficacy of CT area of interest without and with IV contrast in this clinical scenario. CT of the chest without and with IV contrast has been used for diagnosis in patients with pulmonary arteriovenous malformations (PAVMs), which are seen in children with hereditary hemorrhagic telangiectasia (HHT), as a follow- up examination for the depiction of precise anatomy of simple and some complex lesions, after initial screening, which may be performed using transthoracic contrast echocardiography, which confirms the presence of a suspected shunt [42]. Both phases of the CT examination may provide important information in the diagnosis of PAVM [42]. Contrast-enhanced CT may provide further anatomic definition of a VM after US in other anatomies, aiding in visualizing phleboliths, thrombus, osseous changes such as erosion or findings related to overgrowth syndromes, and soft tissue involvement, especially in defining the deep or infiltrative extent of a VA [39-41]. CT Area of Interest Without IV Contrast There is no relevant literature reviewing the efficacy of noncontrast enhanced CT evaluation of VM. CT without IV contrast is limited in diagnosis of soft tissue and solid organ VMs and VTs because all structures and tissues show homogenous and similar attenuation, which obscures findings or does not allow characterization of the extent of abnormalities.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. CTA and CTV Area of Interest With IV Contrast CTA and CTV of the upper extremity was shown by Henzler et al [44] to be the superior imaging modality compared with MRI and US because it provides images with high spatial resolution for excellent delineation of the anatomy and extent of VTs and VMs, providing a vascular map of the lesion for use in treatment planning. Soft Tissue Vascular Anomalies-Child CTA of the chest, using a modified pulmonary CTA and CTV protocol, is used to optimally show the feeding artery, nidus, and draining vein components of the PAVM [42]. CTA and CTV may provide further anatomic definition of a VM after US in other anatomies, aiding in visualizing phleboliths, thrombus, osseous changes such as erosion or findings related to overgrowth syndromes, and soft tissue involvement, especially in defining the deep or infiltrative extent of a VA [39-41,45]. MRA and MRV Area of Interest Without and With IV Contrast MRA of the area of interest without and with IV contrast may be used to define venous and arterial anatomy, as well as better differentiate the tissue types involved in the VM. MRA and MRV of the area of interest without IV contrast, using flow-dependent or flow-independent techniques, can be used as well. For example, Relaxation- Enhanced Angiography without Contrast and Triggering, a flow-independent T2-weighted noncontrast-enhanced MRA sequence, has been shown to be effective for defining the anatomy of major feeding arteries and draining veins and correlation with contrast-enhanced MRA and MRV [32,46]. Contrast-enhanced 3-D and 4-D dynamic MRA acquisitions are helpful in distinguishing whether flow through the lesion is slow or fast, arterial and venous anatomy, the location of a nidus in an AVM, and the site of vascular fistula in an AVF.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Dynamic MRA combined with contrast-enhanced MRI has been shown to have excellent sensitivity (83%) and specificity (95%) in differentiating low-flow from fast-flow VMs [29,47]. Dynamic 4-D MRA with IV contrast may be used to detect presence of arteriovenous microshunts in VMs, which have been found to be associated with presence of phleboliths [30]. MRI Area of Interest Without and With IV Contrast MRI of the area of interest without and with IV contrast may be used to define the deep and superficial extent of VM using T1-weighted sequences, and T2-weighted images reveal vascular flow voids as well as fluid filled spaces. Areas of signal loss or flow voids are important to document and can help drive the diagnosis (phleboliths versus fast-flow vessels). A well-defined soft tissue mass is not typically identified in AVM. IV contrast shows intense enhancement of involved soft tissues, cyst walls, and/or vascular structures [31]. MRI Area of Interest Without IV Contrast There is no relevant literature to support the use of MRI area of interest without IV contrast as the next imaging modality for vascular lesion such as tumor or malformation. Radiography Area of Interest There is no relevant literature to support the use of radiography area of interest as the next imaging modality for VMs [35]. US Area of Interest With IV Contrast There is no relevant literature to support the use of US area of interest with IV contrast as the initial imaging modality for patients with vascular lesions such as tumor or malformation [48]. Variant 5: Child. Established diagnosis of vascular malformation presenting with new or persistent signs or symptoms. Initial imaging. VMs are a diverse group of lesions, which are difficult to treat, requiring multiple episodes of interventional embolization/sclerotherapy and or surgical intervention over years of treatment.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Before and throughout the treatment course, interval imaging may help for monitoring regression of the lesion and planning approach to the next treatment session. Arteriography Area of Interest There is no relevant literature to support the use of arteriography as the initial diagnostic imaging modality for patients with an established diagnosis of a low-flow VM. In patients with a fast-flow VM, angiography is useful to characterize new or persistent signs or symptoms (recurrent bleeding events, ischemic changes to normal tissues, etc) when simultaneous treatment is planned [49]. CT Area of Interest With IV Contrast Although contrast-enhanced CT may provide anatomic definition of a VM if there are persistent anatomical questions after MRI/MRA, there is no relevant literature to support the use of CT area of interest with IV contrast Soft Tissue Vascular Anomalies-Child as the initial imaging modality for patients with an established diagnosis of VM presenting with new or persistent signs and symptoms [39]. CT Area of Interest Without and With IV Contrast There is no relevant literature to support the use of CT area of interest without and with IV contrast as the initial imaging modality for patients with an established diagnosis of VM presenting with new or persistent signs and symptoms. CT Area of Interest Without IV Contrast There is no relevant literature to support the use of CT area of interest without IV contrast a as the initial imaging modality for patients with an established diagnosis of VM presenting with new or persistent signs and symptoms. CTA and CTV Area of Interest With IV Contrast There is no relevant literature to support the use of CTA and CTV area of interest with IV contrast as the initial imaging modality for patients with an established diagnosis of VM presenting with new or persistent signs and symptoms.


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. MRA and MRV Area of Interest Without and With IV Contrast MRA and MRV of the area of interest without and with IV contrast may be used to update venous and arterial anatomy as well as better differentiate the tissue types involved in the VM. As embolization and sclerotherapy treatments change the vascular channels, MRA can provide updated information. Contrast-enhanced 3-D and 4-D dynamic MRA acquisitions are helpful in assessing flow through the lesion before and after treatment, the location of a new nidus in an AVM, and a new vascular fistula in an AVF. Dynamic MRA and MRV combined with contrast-enhanced MRI has been shown to have excellent sensitivity (83%) and specificity (95%) in differentiating low-flow from fast-flow VMs [29,47]. Embolization and sclerotherapy are expected to change the shunting within these low-flow VMs. MRI Area of Interest Without and With IV Contrast MRI of the area of interest without and with IV contrast may be used to define the deep and superficial extent of VM with expected treatment changes. IV contrast shows intense enhancement of involved soft tissues, cyst walls, and/or vascular structures [31]. Particular attention may need to be paid to imaging findings that may suggest treatment complications (abscess, tissue necrosis, cellulitis, deep vein thrombosis, etc). MRI Area of Interest Without IV Contrast There is no relevant literature to support the use of MRI area of interest without IV contrast as the initial imaging modality for patients with an established diagnosis of VM presenting with new or persistent signs and symptoms. Radiography Area of Interest Radiographs of the area of interest may reveal calcified phleboliths and embolization material within a previously treated VM; these findings may be helpful in choosing a follow-up imaging study (ie, US for suspected occluded deep vein after sclerotherapy).


Soft Tissue Vascular Anomalies Vascular Malformations and Infantile Vascular Tumors Non CNS Child. Radiographs may also better characterize imaging artifacts (embolization coils), which may limit the evaluation of residual VM on MRI/US [35]. US Area of Interest US area of interest may be useful as an initial imaging modality in patients with an established diagnosis of VM when presenting with new or persistent signs or symptoms. However, US may be limited if there is extensive embolization material present. VM occlusions directly due to embolization versus associated soft tissue swelling from treatment changes can be visualized on grayscale US. US Area of Interest With IV Contrast There is no relevant literature to support the use of US area of interest with IV contrast as the initial imaging modality for patients with an established diagnosis of VM presenting with new or persistent signs and symptoms. It has been shown that the dynamics of blood flow through VM can be determined using contrast-enhanced US, and that differences in blood flow dynamics as measured using time intensity curve analysis can be shown by comparing pretreatment and post-treatment examinations [50]. US Duplex Doppler Area of Interest US with duplex Doppler may be helpful as an initial imaging modality in patients with an established diagnosis of VM when presenting with new or persistent signs or symptoms. Doppler US can help distinguish changes following Soft Tissue Vascular Anomalies-Child enhanced US and that differences in blood flow dynamics as measured using time intensity curve analysis can be shown by comparing pretreatment and post-treatment examinations. Supporting Documents The evidence table, literature search, and appendix for this topic are available at https://acsearch. acr.org/list. The appendix includes the strength of evidence assessment and the final rating round tabulations for each recommendation. For additional information on the Appropriateness Criteria methodology and other supporting documents go to www. acr.org/ac.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer.  Introduction/Background Neoadjuvant chemotherapy (NAC) is often given before definitive surgical intervention for locally advanced breast cancer, which is defined as a tumor >5 cm with regional and/or metastatic lymph nodes, skin, or chest wall involvement. NAC is also indicated in T2 tumors (2-5 cm) in which lumpectomy might result in substantial cosmetic defect, triple-negative tumors 2 to 5 cm in size even if node-negative, and human epidermal growth factor receptor 2 (HER2)/neu-positive tumors 2 to 5 cm in size even if node-negative. The primary aims of this approach are to 1) reduce tumor burden, thereby permitting breast conservation rather than mastectomy; 2) promptly treat possible metastatic disease, whether or not it is detectable on preoperative staging; and 3) potentially tailor future chemotherapeutic decisions by monitoring in vivo tumor response [1,2]. Although the overall and disease-free survival for women receiving neoadjuvant versus adjuvant chemotherapy are not substantially different, women who do receive neoadjuvant therapy are less likely to undergo mastectomy and are more likely to be treated with breast conservation [1]. Imaging plays a vital role in managing patients undergoing NAC as treatment decisions rely heavily on accurate assessment of response to therapy. Beyond assessing the primary lesion, imaging is used to stage and monitor patients before, during, and after completion of initial therapy, including the axilla and potential distant metastatic sites. Accurate assessment of tumor burden is critical in determining the best management. Imaging plays an important role as clinical breast examination is challenging for primary tumors that are <2 cm in size, have an irregular shape or ill-defined margins, and show necrosis, fibrosis, or fragmentation with treatment [3]. Axillary imaging is increasingly used before, during, and after therapy to monitor response to treatment and help guide surgical management [4].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Most practices define response per Response Evaluation Criteria in Solid Tumors (RECIST) or RECIST 1, which defines complete response (CR) as disappearance of the tumor in its entirety, partial response (PR) as at least 30% decrease in the longest diameter of the tumor compared with pretreatment baseline, progression of disease as at least 20% increase in longest diameter, and stable disease as no change in the tumor size that would qualify as PR or progression of disease on the basis of longest diameter [5]. Pathologic complete response (pCR) is defined as a surgical specimen free of carcinoma following therapy and represents a surrogate endpoint for treatment with pCR predicting improved disease-free survival [1,6]. Although there is a paucity of published data in men and transgender patients diagnosed with breast cancer, in practice, these patients are managed similarly to women. Special Imaging Considerations There are several single-institution studies that demonstrate contrast-enhanced mammography has comparable sensitivity and specificity to contrast-enhanced MRI in evaluating for residual disease after NAC [7-10]. Therefore, although not widely used in clinical practice, this may be an option for patients who are unable to undergo MRI [7- 10]. aUniversity of California San Francisco, San Francisco, California. bResearch Author, University of California San Francisco, San Francisco, California. cPanel Chair, New York University Grossman School of Medicine, New York, New York. dPanel Vice-Chair, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. eBoston Medical Center, Boston, Massachusetts, Primary care physician. fHackensack University Medical Center, Hackensack, New Jersey; American College of Surgeons. gUniversity of North Carolina Hospital, Chapel Hill, North Carolina. hElizabeth Wende Breast Care, Rochester, New York.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. iUniversity of Wisconsin School of Medicine & Public Health, Madison, Wisconsin. jSanford Health of Northern Minnesota, Bemidji, Minnesota. kUniversity of Washington, Seattle, Washington. lMayo Clinic, Phoenix, Arizona. mLoyola University Chicago, Stritch School of Medicine, Department of Radiation Oncology, Cardinal Bernardin Cancer Center, Maywood, Illinois. nHoag Family Cancer Institute, Newport Beach, California and University of Southern California, Los Angeles, California; Commission on Nuclear Medicine and Molecular Imaging. oSpecialty Chair, Boston University School of Medicine, Boston, Massachusetts. 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 OR Discussion of Procedures by Variant Variant 1: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer. Initial determination of tumor size and extent within the breast prior to neoadjuvant chemotherapy. Initial imaging. Digital Breast Tomosynthesis Diagnostic Mammography, ultrasound (US), and MRI are complementary modalities for assessing primary tumor size before treatment because they are reliable tools to determine tumor size at diagnosis [1,11-15]. Mammography and US are the two main modalities for assessing primary tumor size before treatment because they are reliable tools to determine tumor size at diagnosis [11-15]. Mammography is most accurate for ductal and low-grade malignancies and less accurate for invasive lobular cancers and higher-grade lesions [11-16].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Digital breast tomosynthesis (DBT) addresses some of the limitations encountered with standard mammographic views. In addition to planar images, DBT creates thin-section reconstructed images, which decreases the lesion- masking effect of overlapping normal tissue. In the screening setting, some authors found the advantages of DBT to be especially pronounced in patients <50 years of age [17,18], in patients with dense breasts [17,19], and with lesion types including spiculated masses, [20] asymmetries [21], and architectural distortion [22]. DBT is also useful in the diagnostic setting, improving lesion characterization [22-25] in noncalcified lesions compared with conventional mammography. A prospective study of 166 patients with breast cancer compared digital mammography (DM) to combined DM plus DBT for accuracy of local tumor staging. They demonstrated better accuracy of DM plus DBT for detecting additional ipsilateral and contralateral disease in patients with nondense breasts [26]. A retrospective study of 222 cancers demonstrated that pathologic response to NAC was less likely with the baseline mammographic finding of spiculation [27]. Because of the presence of dense tissue in up to 50% of patients, obscured margins may limit evaluation of the extent of disease [28]. Therefore, mammography or DBT is most often combined with other modalities, such as US or MRI, to guide clinical management. FDG-PET/CT Skull Base to Mid-Thigh Fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT has a low sensitivity for detection of primary breast cancer because of the low spatial resolution of the scanners and the relatively low FDG uptake of both invasive lobular cancers and low-grade malignancies [29,30]. As a result, this modality is not routinely used for pretreatment imaging of the primary breast tumor.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Mammography Diagnostic Mammography, US, and MRI are complementary modalities for assessing primary tumor size before treatment because they are reliable tools to determine tumor size at diagnosis [1,11-15]. Mammography is most accurate for ductal and low-grade malignancies and less accurate for invasive lobular cancers and higher-grade lesions [11-16]. DBT addresses some of the limitations encountered with standard mammographic views. In addition to planar images, DBT creates thin-section reconstructed images, which decreases the lesion-masking effect of overlapping normal tissue. In the screening setting, some authors found the advantages of DBT to be especially pronounced in patients <50 years of age [17,18], in patients with dense breasts [17,19], and with lesion types including spiculated masses [20] and asymmetries [21]. DBT can also be useful in the diagnostic setting, improving lesion characterization [22-25] in noncalcified lesions compared with conventional mammography. Monitoring Response to Neoadjuvant Chemotherapy A prospective study of 166 patients with breast cancer compared DM to combined DM plus DBT for accuracy of local tumor staging. They demonstrated better accuracy of DM plus DBT for detecting additional ipsilateral and contralateral disease in patients with nondense breasts [26]. A retrospective study of 222 cancers demonstrated that pathologic response to NAC was less likely with the baseline mammographic finding of spiculation [27]. Because of the presence of dense tissue in up to 50% of patients, obscured margins may limit evaluation of the extent of disease [28]. Therefore, mammography or DBT is most often combined with other modalities, such as US or MRI, to guide clinical management. MRI Breast Without and With IV Contrast MRI is complementary to mammography and US for assessing tumor size before treatment. MRI permits evaluation of a viable tumor before and after NAC by detecting changes in tumor vascularity [31].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. There is substantial evidence to support the routine use of contrast-enhanced MRI to stage, monitor early response, and assess for residual and recurrent disease given the overall high sensitivity and relatively high specificity of this technique [1]. Dynamic contrast-enhanced MRI is a sensitive tool to determine extent of disease in the breast, especially in young patients (<50 years of age), with sensitivity approaching 90% and specificity ranging between 50% and 97% [1,32]. To accurately evaluate for response to NAC, a pretreatment MRI must be obtained to serve as a baseline for comparison. MRI is particularly useful in the assessment of multifocal and multicentric disease, which is often underestimated on both mammography and US [28]. In fact, multifocal and multicentric disease are detected in up to 16% of patients on staging MRI according to a study by Houssami et al [33]. A prospective study of 216 patients demonstrated that size determination on MRI was superior to clinical examination in predicting pathologic response both before, during, and after completion of NAC [31]. The enhancement pattern on the pretreatment MRI also indicates how reliable this technique will be in evaluating response. Nonmass enhancement on the pretreatment MRI has been shown to reveal a scattered cell pattern more commonly on posttreatment imaging, thereby making assessment of residual disease more difficult [34]. However, when a mass with well-defined margins is seen, MRI can more accurately predict the amount of residual disease on posttreatment imaging [34]. In addition, several studies have shown that MRI is more accurate than mammography and US in defining disease extent for invasive lobular cancer [32,35,36]. MRI can reliably assess the chest wall because pectoral or intercostal muscle enhancement correlates well with invasion [37].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Finally, several studies have shown that up to 3% of patients have unsuspected contralateral disease at the time of initial diagnosis and MRI has been proven effective in detecting such contralateral disease [38]. MRI Breast Without IV Contrast A small study of 71 patients with MRI before and after treatment found no significant difference in lesion size interpretation on unenhanced versus enhanced MRI sequences [39]. However, there is insufficient literature to support the use of MRI without intravenous (IV) contrast in initial imaging evaluation of tumor size and extent in the breast before NAC. Sestamibi MBI A few institutions routinely image newly diagnosed breast cancer with molecular breast imaging (MBI) using Tc- 99m sestamibi, which is also sometimes referred to as scintimammography. This functional imaging technique reflects cell metabolism by accumulating in active mitochondrial cells. A prospective study of 90 patients found the longest dimension of the cancer measured on MRI was within 1 cm of that on MBI in 72% of cases and concluded that MBI may be an option for patients with contraindication to MRI [40,41]. However, there is insufficient literature to support the routine use of sestamibi MBI in initial imaging evaluation of tumor size and extent in the breast before NAC. US Breast Mammography, US, and MRI are complementary modalities for assessing primary tumor size before treatment because they are reliable tools to determine tumor size at diagnosis [1,11-15]. US is more accurate in measuring tumor size than clinical breast examination or mammography. It is most often performed in conjunction with mammography and is more accurate in assessing tumor size [16,42]. Monitoring Response to Neoadjuvant Chemotherapy Variant 2: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer. Imaging of the breast after initiation or completion of neoadjuvant chemotherapy. Initial imaging.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Digital Breast Tomosynthesis Diagnostic Although mammography, DBT, and US are reliable for determining tumor size at diagnosis [11-15], changes within the tumor secondary to NAC may be difficult to evaluate after treatment is initiated. It is well known that tumoral changes related to necrosis, fragmentation, and fibrosis make it difficult for mammography, DBT, and US to accurately determine residual tumor burden [43,44]. In a retrospective study of 445 patients who underwent NAC, mammography was 94% sensitive and 50% specific for predicting residual disease in the breast. In cases presenting as mass lesions, 95% of masses decreased in mammographic size with treatment. However, there was correlation between mammographic size and surgical pathology in only 60% of cases [45]. One study found that if >50% of the margin of the primary lesion was mammographically visible at baseline, posttreatment mammographic imaging was a reliable tool for determining lesion size [28,46]. In a study of 56 patients, mammography was 79% sensitive and 77% specific in predicting residual disease after therapy, performing better than clinical breast examination [47]. The extent of calcifications on mammography after therapy does not correlate well with residual tumor burden and is overestimated in up to 45% of patients [48-50]. Therefore, it is not a reliable marker of remaining viable tumor. In a study including 139 patients with baseline mammographic calcifications, residual calcifications were present on all posttreatment mammograms [45]. Estrogen receptor (ER)-positive tumors are more likely than ER-negative tumors to have residual malignant calcifications on mammography after treatment, whereas triple-negative tumors are the least likely to have residual malignant calcifications after therapy, suggesting that different tumor subtypes may warrant different approaches [48,51].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. There is no relevant literature specifically comparing the performance of DBT to mammography after initiation or completion of NAC. FDG-PET/CT Skull Base to Mid-Thigh Because of its relatively low specificity, PET/CT is not routinely used for posttreatment imaging of the primary breast tumor and is typically only used in combination with other imaging modalities to monitor treatment response [52-54]. Two meta-analyses found posttreatment PET/CT sensitivities of 77% to 84% and specificities of 66% to 78% for predicting response to therapy [52,54]. In a study by Bassa et al [55], PET was able to accurately predict residual disease in only 75% of cases, compared with 88% for US. However, PET may have use in assessing early response to therapy, with a study in 47 patients showing that a >50% to 60% reduction in FDG uptake after one cycle of therapy correlated with a pCR [56]. PET imaging may be more helpful for certain tumor subtypes. Three studies showed that PET/CT can reliably detect early response and predict residual disease in HER2/neu-positive tumors [57-59], and a <42% decrease in radioisotope uptake in triple-negative tumors correlates with poor response and outcome [60]. Lobular cancers are less FDG avid, making assessment challenging [61,62]. Mammography Diagnostic Although mammography and US are reliable for determining tumor size at diagnosis [11-15], changes within the tumor, secondary to NAC, may be difficult to evaluate after treatment is initiated. It is well known that tumoral changes related to necrosis, fragmentation, and fibrosis make it difficult for mammography, DBT, and US to accurately determine residual tumor burden [43,44]. In a retrospective study of 445 patients who underwent NAC, mammography was 94% sensitive and 50% specific for predicting residual disease in the breast. In cases presenting as mass lesions, most masses (95%) decreased in mammographic size with treatment.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. However, there was correlation between mammographic size and surgical pathology in only 60% of cases [45]. One study found that if >50% of the margin of the primary lesion was mammographically visible at baseline, posttreatment mammographic imaging was a reliable tool for determining lesion size [28,46]. In a study of 56 patients, mammography was 79% sensitive and 77% specific in predicting residual disease after therapy, performing better than clinical breast examination [47]. The extent of calcifications on mammography after therapy does not correlate well with residual tumor burden and is overestimated in up to 45% of patients [48-50]. Therefore, it is not a reliable marker of remaining viable tumor. In a study including 139 patients with baseline mammographic calcifications, residual calcifications were present 7 Monitoring Response to Neoadjuvant Chemotherapy on all posttreatment mammograms [45]. ER-positive tumors are more likely than ER-negative tumors to have residual malignant calcifications on mammography after treatment, whereas triple-negative tumors are the least likely to have residual malignant calcifications after therapy, suggesting that different tumor subtypes may warrant different approaches [48,51]. There is no relevant literature specifically comparing the performance of DBT to mammography after initiation of completion of NAC. MRI Breast Without and With IV Contrast MRI is a functional imaging technique that permits evaluation of a viable tumor before and after NAC by detecting changes in tumor vascularity [31]. There is substantial evidence to support the routine use of MRI to stage, monitor early response, and assess for residual and recurrent disease, given the overall high sensitivity and relatively high specificity of this technique [1]. However, MRI can overestimate as well as underestimate the amount of residual tumor after completion of therapy.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Multiple studies show that dynamic contrast-enhanced MRI is the optimal imaging tool to determine disease response, with sensitivity approaching 90%, specificity ranging from 60 to 100%, and an accuracy of approximately 91% [31,32,35,36,43,63-66]. MRI is particularly helpful in patients with documented multifocal and multicentric tumors on the pretreatment study, despite the fact that MRI underestimates disease extent in up to 18% of cases [67,68]. However, there is a lack of consensus in the literature on the optimal imaging interval to assess response to therapy. Tumor measurements on MRI more accurately predict residual tumor and pathologic response than clinical assessment, a finding corroborated in several studies [69-71], with volume measurements performing better than tumor diameter early in treatment after the first cycle of chemotherapy [31]. In a prospective clinical trial of 138 patients, longest diameter on posttreatment MRI was superior to both mammography and clinical breast examination in detecting residual disease. MRI tumor volume was also shown to predict recurrence free survival in a trial of 162 patients [72]. The ability of MRI to evaluate disease response is variable on the basis of tumor subtype, being more effective for invasive lobular carcinoma, triple-negative, and HER2/neu-positive tumors and less accurate for luminal subtypes (ER and/or progesterone receptor positive, HER2/neu-positive or negative), with an overall accuracy of approximately 75% [73-81]. A study of 208 patients suggested that patients who can safely consider breast conservation therapy after NAC have tumors <3 cm in maximal size on pretreatment MRI, reduction in tumor size on posttreatment MRI, and more often have HER2/neu-positive or triple-negative tumors [67,82]. When the tumor presents as diffuse nonmass enhancement on the pretreatment MRI or is of low nuclear grade, MRI is less helpful in assessing response to therapy [83].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. In addition, tumors presenting initially as nonmass enhancement more likely presented as scattered foci within an area of fibrosis on posttreatment MRI, making prediction of residual disease challenging [34,84]. Finally, there is some evidence that certain chemotherapeutic agents, such as ER modulators, antiangiogenic agents, and taxane-based therapies, may alter perfusion to the breasts, limiting the ability of MRI to accurately predict residual tumor after chemotherapy, most often leading to disease underestimation [85,86]. MRI Breast Without IV Contrast A small study of 71 patients with MRI before and after treatment found no significant difference in lesion size interpretation on unenhanced versus enhanced MRI sequences [39]. However, there is insufficient literature to support the use of MRI without IV contrast of the breast in initial imaging evaluation of tumor size and extent in the breast after initiation or completion of chemotherapy. Sestamibi MBI In a study of 20 patients who underwent imaging with Tc-99m sestamibi, reduction in tumor size correlated reliably with size on MRI, but tumor to background ratio after chemotherapy did not correlate with treatment response [95]. Monitoring Response to Neoadjuvant Chemotherapy A small study of 62 patients also showed that high uptake after chemotherapy predicts poor survival [96]. In one study of 122 patients, breast-specific gamma imaging had sensitivity of 74% and specificity of 72% for detection of residual tumor after chemotherapy, but it underestimated the amount of residual disease for tumors of luminal subtype [97]. In a small study of 49 patients with locally advanced breast cancer, MBI did not accurately predict response to therapy [98]. In a prospective study of 90 patients, posttreatment MBI had a higher false-negative rate than MRI (41% versus 18%) for predicting pathologic response [41].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. A retrospective study of 114 patients demonstrated that posttreatment MBI had a lower sensitivity than MRI for detecting residual tumor (70% versus 83%). However, MBI was more specific than MRI in determining CR (90% versus 60%) [99]. At present, there is insufficient literature to support the routine use of Sestamibi MBI in imaging of the breast after initiation or completion of NAC. US Breast US is a reliable modality for determining tumor size, especially if the residual tumor measures >7 mm [100,101]. A decrease in tumor vascularity does appear to correlate with response [28]. In 2 studies, US predicted residual tumor size accurately in 60% to 80% of patients, compared with 32% to 71% for mammography [102,103]. In a study by Keune et al [104], the absence of residual disease on both mammography and US correlated with a pCR in 80% of patients. Although pretreatment tumor stiffness as determined by shear-wave elastography has shown strong correlation with response to therapy, there is insufficient data to support its routine use at this time [105,106]. In addition, there is insufficient data to support the routine use of contrast-enhanced US, although some early research suggests that changes in the time-intensity curves may reliably predict response to therapy [107,108]. Variant 3: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer, clinically node-negative. Axillary evaluation prior to neoadjuvant chemotherapy. Initial imaging. Digital Breast Tomosynthesis Diagnostic There is no relevant literature to support the use of DBT in the initial imaging evaluation of the axilla before NAC. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. FDG-PET/CT Skull Base to Mid-Thigh FDG-PET/CT is not routinely used for initial imaging of the clinically node-negative axilla before NAC because of its low sensitivity and specificity for detecting nodal disease [4]. In several studies on detection of nodal disease, including a multicenter study of 360 patients, PET had disparate sensitivities (43%-79%) and specificities (66%-93%), possibly related to differences in tumor size in patient populations [109,110]. Given these limitations, surgical sampling of the axillary nodes remains the standard of care. However, when an FDG-avid axillary node is seen on a pretreatment PET/CT scan, this is highly predictive of metastasis [111]. Mammography Diagnostic There is no relevant literature to support the use of diagnostic mammography in initial imaging evaluation of the axilla before NAC. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections. MRI Breast Without and With IV Contrast There is robust evidence to support MRI for determining the extent of disease in the breast, both before and after NAC [1,4,31,32,35,36,43,63-66]. Although the axillary lymph nodes are included on MRI, it is only moderately sensitive for the detection of axillary nodal metastasis before and after therapy [4,112,113]. Therefore, MRI is not typically obtained solely for the purpose of staging the clinically node-negative axilla before NAC [4]. MRI Breast Without IV Contrast There is no relevant literature to support the use of MRI breast without IV contrast in initial imaging evaluation of the axilla before NAC. US Axilla Current National Comprehensive Cancer Network practice guidelines recommend considering axillary US and possible biopsy before starting NAC, even in clinically node-negative patients [115,116].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Assessment of the axilla before and after NAC with US can help guide surgical management. US permits routine visualization of stage I and II nodes. By identifying subclinical metastases in clinically node-negative patients, US-guided fine-needle aspiration (FNA) or core needle biopsy (CNB) may select patients who require axillary lymph node dissection [116]. However, a study of 402 patients with a clinically negative axilla demonstrated that half of patients with abnormal lymph nodes on pretreatment imaging did not require axillary lymph node dissection [116]. Therefore, pretreatment imaging of the axilla in clinically node-negative patients remains controversial [4]. US-Guided Core Biopsy Axillary Node There is no evidence to support US-guided sampling as the initial imaging test for axillary lymph node evaluation. However, US-guided axillary lymph node sampling is typically the next study performed when axillary imaging is suspicious for metastatic disease. Overall, US-guided biopsy offers a minimally invasive option to obtain histopathologic proof of axillary nodal involvement for suspicious findings, although a negative biopsy does not reliably exclude metastatic disease, and therefore surgical pathology remains the reference standard. When US- guided biopsy confirms metastatic disease in pathologic-appearing nodes, it can obviate the need for pretreatment sentinel node biopsy, because the completion of axillary surgery is typically performed after therapy [2,117]. US-Guided Fine Needle Aspiration Biopsy Axillary Node There is no evidence to support US-guided sampling as the initial imaging test for axillary lymph node evaluation. However, US-guided axillary lymph node sampling is typically the next study performed when axillary imaging is suspicious for metastatic disease.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Overall, US-guided FNA offers a minimally invasive option to obtain histopathologic proof of axillary nodal involvement for suspicious findings, although a negative biopsy does not reliably exclude metastatic disease, and therefore surgical pathology remains the reference standard. When US- guided biopsy confirms metastatic disease in pathologic-appearing nodes, it can obviate the need for pretreatment sentinel node biopsy, because the completion of axillary surgery is typically performed after therapy [2,117]. Variant 4: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer, clinically node-positive. Axillary evaluation prior to neoadjuvant chemotherapy. Initial imaging. Digital Breast Tomosynthesis Diagnostic There is no relevant literature to support the use of DBT in the initial imaging evaluation of the axilla before NAC. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections. FDG-PET/CT Skull Base to Mid-Thigh FDG-PET/CT may be useful for staging and restaging clinically node-positive patients undergoing NAC [4]. In node-positive patients, the decrease in standardize uptake value from pre- to posttreatment scans can be used to monitor response and help predict pCR [116]. This possibly may lead to less aggressive axillary surgery upon completion of chemotherapy rather than complete lymph node dissection [118]. In several studies on detection of nodal disease, including a multicenter study of 360 patients, PET had disparate sensitivities (43%-79%) and specificities (66%-93%), possibly related to differences in tumor size in patient populations [109,110]. Given these limitations, surgical sampling of the axillary nodes remains the standard of care.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. However, when an FDG-avid axillary node is seen on a pretreatment PET/CT scan, this is highly predictive of metastasis [111]. Monitoring Response to Neoadjuvant Chemotherapy Mammography Diagnostic There is no relevant literature to support the use of diagnostic mammography in initial imaging evaluation of the axilla before NAC. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections. MRI Breast Without and With IV Contrast MRI does not always include the entire axilla and is not routinely used solely for evaluation of axillary lymph nodes. However, contrast-enhanced MRI may be useful for monitoring the breast and axillary response in clinically node- positive patients [4]. MRI Breast Without IV Contrast There is no relevant literature to support the use of MRI breast without IV contrast in initial imaging evaluation of the axilla before NAC. US Axilla Axillary US is routinely performed for pretreatment evaluation of a clinically positive axilla [4]. Current National Comprehensive Cancer Network practice guidelines recommend axillary US and possible biopsy before starting systemic therapy [115]. US-guided FNA or CNB can confirm and mark metastatic disease. When US-guided biopsy confirms metastatic disease in pathologic-appearing nodes, it can obviate the need for pretreatment sentinel node biopsy because the completion of axillary surgery is typically performed after therapy [2,117]. Placing a biopsy clip to mark the metastatic lymph node before therapy can also help guide the type of axillary restaging surgery following NAC [119]. US-Guided Core Biopsy Axillary Node There is no evidence to support US-guided sampling as the initial imaging test for axillary lymph node evaluation.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. However, US-guided axillary lymph node sampling is typically the next study performed when axillary imaging is suspicious for metastatic disease. Overall, US-guided biopsy offers a minimally invasive option to obtain histopathologic proof of axillary nodal involvement for suspicious findings, although a negative biopsy does not reliably exclude metastatic disease, and therefore surgical pathology remains the reference standard. When US- guided biopsy confirms metastatic disease in pathologic-appearing nodes, it can obviate the need for pretreatment sentinel node biopsy, because the completion of axillary surgery is typically performed after therapy [2,117]. US-Guided Fine Needle Aspiration Biopsy Axillary Node There is no evidence to support US-guided sampling as the initial imaging test for axillary lymph node evaluation. However, US-guided axillary lymph node sampling is typically the next study performed when axillary imaging is suspicious for metastatic disease. Overall, US-guided FNA offers a minimally invasive option to obtain histopathologic proof of axillary nodal involvement for suspicious findings, although a negative biopsy does not reliably exclude metastatic disease, and therefore surgical pathology remains the reference standard. When US- guided biopsy confirms metastatic disease in pathologic-appearing nodes, it can obviate the need for pretreatment sentinel node biopsy, because the completion of axillary surgery is typically performed after therapy [2,117]. Variant 5: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer, clinically node-negative. Axillary evaluation after completion of neoadjuvant chemotherapy, axilla not previously evaluated. Initial imaging. Digital Breast Tomosynthesis Diagnostic There is no relevant literature to support the use of DBT in initial imaging of the axilla after NAC [4].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Monitoring Response to Neoadjuvant Chemotherapy Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections. FDG-PET/CT Skull Base to Mid-Thigh PET/CT is not routinely used for evaluation of the axilla after NAC as data are limited [4]. In several studies on detection of nodal disease, including a multicenter study of 360 patients, PET had disparate sensitivities (43%-79%) and specificities (66%-93%), possibly related to differences in tumor size in patient populations [109,110]. Given these limitations, this modality is not particularly useful to evaluate the axilla, and surgical sampling of the axillary nodes remains the standard of care. However, when an FDG-avid axillary node is seen on a pretreatment PET/CT scan, this is highly predictive of metastasis [111]. In addition, in node-positive tumors, PET/CT can be used to monitor response and possibly lead to sentinel node biopsy upon completion of chemotherapy rather than full axillary dissection [118]. Mammography Diagnostic There is no relevant literature to support the use of diagnostic mammography in initial imaging of the axilla after NAC [4]. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections. MRI Breast Without and With IV Contrast The current literature evaluates performance of posttreatment MRI evaluation of the axilla only in the setting of baseline pretreatment imaging and/or clinically node-positive patients, as described below. These data cannot necessarily be extrapolated to initial imaging after completion of therapy in the absence of pretreatment axillary evaluation.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. MRI of the axilla is only 38% to 61% sensitive for detection of residual disease after NAC [112,113]; therefore, surgical sampling is the standard of care [114,120-122]. In a retrospective study of 135 clinically node-positive patients after NAC, MRI had a low negative predictive value (NPV) of 26% for predicting axillary disease when a positive MRI was defined by node >1 cm, cortex >3 mm, loss of hilum, or irregular contour [121]. In a retrospective study of 269 node-positive patients, posttreatment MRI was only 38% sensitive, 76% specific, and 58% accurate in predicting the pathology of the sentinel lymph node (SLN). In a prospective study of 45 patients, 35 of whom were node-positive, there was no association between posttreatment axillary MRI and surgical pathology; MRI had a high false negative rate (46%), low sensitivity (55%), and specificity (63%) [114]. MRI Breast Without IV Contrast There is no relevant literature to support the use of MRI breast without IV contrast in initial imaging of the axilla after NAC. US Axilla US is not typically performed for initial evaluation of the axilla after initiation of NAC, and the current literature does not specifically evaluate this scenario. The literature on posttreatment axillary US predicting residual nodal disease evaluates patients with established node-positive disease before therapy, as described below. These data cannot necessarily be extrapolated to initial imaging after therapy in the absence of pretreatment axillary evaluation. No imaging test can reliably detect residual nodal disease after NAC, and therefore surgical sampling is the standard of care. In established node-positive patients after therapy, axillary US only demonstrates moderate sensitivity (53%-86%) and specificity (78%) for detecting residual disease with an NPV ranging from 46% to 90% [112,123,124]. Therefore, surgical sampling of axillary lymph nodes after therapy remains the standard of care.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. In a retrospective study of 408 clinically node-positive breast cancer patients treated with NAC, the strongest predictor for residual axillary disease was preoperative US showing axillary lymphadenopathy, defined as axial cortical thickness >3.5 mm or loss of the hilum [125]. The prospective clinical Z1071 trial included 611 patients with US after NAC; US features associated with residual disease included increased cortical thickness (mean 3.5 mm), absent hilum, and longer lymph node diameter [126]. Monitoring Response to Neoadjuvant Chemotherapy US-Guided Core Biopsy Axillary Node There is no relevant literature to support the use of US-guided core biopsy of axillary nodes in initial imaging of the axilla after completion of NAC. US-Guided Fine Needle Aspiration Biopsy Axillary Node There is no relevant literature to support the use of US-guided FNA of axillary nodes in initial imaging of the axilla after completion of NAC. Variant 6: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer with clinical suspicion of metastatic disease. Staging or assessment of response to neoadjuvant chemotherapy. Initial imaging. Bone Scan Whole Body Staging of patients before and after treatment typically entails either 1) FDG-PET/CT skull base to mid-thigh only or 2) bone scan in conjunction with CT chest, abdomen, and pelvis with IV contrast, depending upon institutional preference. There is no evidence to support performing all 3 studies. Bone scan represents one of the standard imaging tests to stage a patient with newly diagnosed breast cancer, allowing assessment of bony metastasis. PET/CT combines cross-sectional imaging with tumor metabolism and has been shown to be more sensitive and accurate than conventional staging with combined CT and bone scan [127].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. CT Chest, Abdomen, and Pelvis With IV Contrast Staging of patients before and after treatment typically entails either 1) FDG-PET/CT skull base to mid-thigh only or 2) bone scan in conjunction with CT chest, abdomen, and pelvis with IV contrast, depending upon institutional preference. There is no evidence to support performing all 3 studies. CT with IV contrast is commonly used to stage patients with newly diagnosed, locally advanced, or recurrent breast cancer [128]. PET/CT combines cross-sectional imaging with tumor metabolism and has been shown to be more sensitive and accurate than conventional staging with combined CT and bone scan [127]. CT Chest, Abdomen, and Pelvis Without and With IV Contrast There is no relevant literature to support the use of CT chest, abdomen, and pelvis without and with IV contrast in the initial evaluation of metastatic disease. CT Chest, Abdomen, and Pelvis Without IV Contrast There is no relevant literature to support the use of CT chest, abdomen, and pelvis without IV contrast in the initial evaluation of metastatic disease. FDG-PET/CT Skull Base to Mid-Thigh Staging of patients before and after treatment typically entails either 1) FDG-PET/CT skull base to mid-thigh only or 2) bone scan in conjunction with CT chest, abdomen, and pelvis with IV contrast, depending upon institutional preference. There is no evidence to support performing all 3 studies. PET/CT combines cross-sectional imaging with tumor metabolism and has been shown to be more sensitive and accurate than conventional staging with combined CT and bone scan [127]. Staging with PET/CT detects distant metastases with a sensitivity of 50% to 100% and a specificity of 50% to 97% in patients with advanced breast cancers, some of which were occult on conventional CT imaging. In one study by Lee et al, the detection of distant metastases occult on conventional CT imaging led to changes in clinical stage for 52% of women [129].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Given that 8% to 14% of women with locally advanced breast cancer have distant metastatic disease at diagnosis (beyond the axillary nodes), FDG-PET/CT skull base to mid-thigh may be preferred over conventional CT imaging [130]. In addition, several studies have shown FDG-PET/CT to be superior in detecting internal mammary and mediastinal lymphadenopathy [129] but inferior to contrast-enhanced chest CT at detecting pulmonary metastases [130]. Multiple studies show that PET/CT staging is more useful for stage IIIB and operable stage IIIA tumors and specific tumor subtypes including invasive ductal cancers, ER-negative and triple-negative tumors, high-grade malignancies, and those with p53 mutations [131-133]. PET/CT staging is not as useful for low-grade malignancies or invasive lobular cancers because of the overall low isotope uptake [134]. MRI Chest, Abdomen, Pelvis Without and With IV Contrast There is no relevant literature to support the use of MRI chest, abdomen, and pelvis without and with IV contrast in the initial evaluation of metastatic disease. 13 Monitoring Response to Neoadjuvant Chemotherapy MRI Chest, Abdomen, Pelvis Without IV Contrast There is no relevant literature to support the use of MRI chest, abdomen, and pelvis without IV contrast in the initial evaluation of metastatic disease. Variant 7: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known axillary lymph node-positive breast cancer on prior mammography, US, or MRI. Axillary evaluation after completion of neoadjuvant chemotherapy, axilla previously evaluated. Next imaging study. Digital Breast Tomosynthesis Diagnostic Although many patients undergo mammography or DBT after NAC, there is no specific evidence supporting its use in the imaging of known axillary lymph node-positive breast cancer after completion of therapy.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. The axilla is incompletely visualized on the mediolateral and lateral projections, thereby limiting the use of these modalities to reliably detect residual disease. FDG-PET/CT Skull Base to Mid-Thigh PET/CT is not routinely used to evaluate the axilla after completion of NAC. Although a few studies suggest that PET can reliably predict the response of axillary nodes early in treatment, a majority of studies show that PET has low sensitivity (63%) for detection of residual disease after NAC [112,135]. No imaging test can reliably detect residual nodal disease after NAC, and therefore surgical sampling is the standard of care. Mammography Diagnostic Although many patients undergo mammography or DBT after NAC, there is no specific evidence supporting its use in the imaging of known axillary lymph node-positive breast cancer after completion of therapy [4]. The axilla is incompletely visualized on the mediolateral and lateral projections, thereby limiting the use of these modalities to reliably detect residual disease. MRI Breast Without and With IV Contrast MRI is not routinely used for evaluation of the axilla after completion of NAC because it is only 38% to 61% sensitive for detecting residual axillary disease [112-114,120-122]. No imaging test can reliably detect residual nodal disease after NAC, and therefore surgical sampling is the standard of care. Use of MRI for restaging the axilla in clinically node-positive patients is questionable [4]. In a retrospective study of 135 clinically node-positive patients who underwent NAC, MRI evaluation of the axilla after treatment had a low NPV (26%) and therefore could not predict residual axillary disease when a positive MRI of the axilla was defined as node >1 cm, cortex >3 mm, loss of hilum, or irregular contour [121]. In a retrospective study of 269 node-positive patients, postchemotherapy MRI was only 38% sensitive, 76% specific, and 58% accurate in predicting the pathology result of the SLN.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. In a prospective study of 45 patients, 35 of whom were node-positive, there was no association between posttreatment axillary MRI findings and surgical pathology; MRI had a high false negative rate (46%), low sensitivity (55%), and specificity (63%) [114]. MRI Breast Without IV Contrast There is no relevant literature to support the use of MRI breast without IV contrast in the imaging of known axillary lymph node-positive breast cancer after completion of NAC. US Axilla If the axilla is imaged after NAC, US is the most useful imaging modality, although it only demonstrates moderate sensitivity (53%-86%) and specificity (78%) for detecting residual disease [112,124]. Therefore, surgical sampling of axillary lymph nodes after therapy remains the standard of care. US permits image-guided localization of the clipped metastatic axillary lymph node if the patient is undergoing sentinel node biopsy with surgical excision of the clipped node. The axilla is most commonly imaged after NAC in patients with a clinically positive axilla before therapy [4]. In a retrospective study of 408 clinically node-positive breast cancer patients treated with NAC, the strongest predictor of residual axillary disease was posttreatment US showing axillary lymphadenopathy, defined as axial cortical thickness >3.5 mm or loss of the hilum [125]. The prospective clinical Z1071 trial included 611 patients with US after NAC, 238 of whom had axillary CR. US features associated with residual disease included increased cortical thickness (mean 3.5 mm), absent hilum, and longer lymph node diameter [126]. Monitoring Response to Neoadjuvant Chemotherapy US Breast There is no relevant literature to support the use of breast US alone in the evaluation of known axillary lymph node- positive disease after completion of NAC. However, some studies have shown a correlation between pCR in the breast and the axilla [136].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. US-Guided Core Biopsy Axillary Node There is no relevant literature to support the use of US-guided core biopsy of the axillary node in imaging of known axillary lymph node-positive breast cancer after completion of NAC. No imaging test can reliably detect residual nodal disease after NAC; therefore, surgical intervention (either sentinel node biopsy or axillary dissection) is necessary after completion of treatment, provided the patient demonstrated a PR or CR warranting surgery and did not undergo axillary surgery before treatment [112,137]. Some centers place a clip in the biopsied positive axillary node before treatment so that it can be surgically excised along with the sentinel node(s) after completion of the NAC; this procedure is sometimes referred to as targeted axillary dissection [138]. US-guided localization of the clipped lymph node can be performed preoperatively [139]. Excising the clipped lymph node and SLN(s) decreases the false-negative rate of SLN biopsy (SLNB) [140]. In a study of 31 patients, 11 patients had residual axillary disease, and, in all cases, the clipped lymph node was positive [141]. In a prospective study of 23 patients with clipped axillary metastases before NAC, the surgeon retrieved the clipped node in 22 cases, and the SLN was retrieved in only 19. The clipped node was the SLN in only 14 cases (61%). The NPV was 100% for removal of clipped and sentinel node but only 85% for SLN removal alone [119]. US-Guided Fine Needle Aspiration Biopsy Axillary Node There is no relevant literature to support the use of US-guided FNA of the axillary node in imaging of known axillary lymph node-positive breast cancer after completion of NAC.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. No imaging test can reliably detect residual nodal disease after NAC; therefore, surgical intervention (either sentinel node biopsy or axillary dissection) is necessary after completion of neoadjuvant treatment, provided the patient demonstrated a PR or CR warranting surgery and did not undergo axillary surgery before treatment [112,137]. Some centers place a clip in the biopsied positive axillary node before treatment so that it can be surgically excised along with the sentinel node(s) after completion of the NAC; this procedure is sometimes referred to as targeted axillary dissection [138]. US-guided localization of the clipped lymph node can be performed preoperatively [139]. Excising the clipped lymph node and SLN(s) decreases the false-negative rate of SLNB [140]. In a study of 31 patients, 11 patients had residual axillary disease, and, in all cases, the clipped lymph node was positive [141]. In a prospective study of 23 patients with clipped axillary metastases before NAC, the surgeon retrieved the clipped node in 22 cases, and the SLN was retrieved in only 19. The clipped node was the SLN in only 14 cases (61%). The NPV was 100% for removal of clipped and sentinel node but only 85% for SLN removal alone [119]. Variant 8: Adult female or male or transfeminine (male-to-female) or transmasculine (female-to-male). Known breast cancer. Axillary imaging suspicious for metastatic disease on mammography, US, or MRI during initial evaluation. Next imaging study. Digital Breast Tomosynthesis Diagnostic There is no relevant literature to support the use of DBT in further evaluation of axillary imaging suspicious for metastatic disease. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Mammography Diagnostic There is no relevant literature to support the use of diagnostic mammography in further evaluation of axillary imaging suspicious for metastatic disease. Mammography or DBT is performed for initial diagnosis of the primary breast cancer. This procedure incompletely images the axilla, although pathologically enlarged stage I and II nodes may be included on the lateral and mediolateral oblique projections. MRI Breast Without and With IV Contrast There is no relevant literature to support the use of MRI breast with IV contrast in the further evaluation of axillary imaging suspicious for metastatic disease. Monitoring Response to Neoadjuvant Chemotherapy There is robust evidence to support MRI for determining extent of disease in the breast, both before and after NAC [1,4,31,32,35,36,43,63-66]. Although the axillary lymph nodes are included on MRI, it is only moderately sensitive for detection of axillary nodal metastasis before and after therapy [4,112,113]. MRI Breast Without IV Contrast There is no relevant literature to support the use of MRI breast without IV contrast in the further evaluation of imaging suspicious for metastatic disease. US-Guided Core Biopsy Axillary Node US-guided axillary lymph node sampling is the most useful next study performed when axillary imaging is suspicious for metastatic disease [4]. Sampling of abnormal-appearing nodes by CNB is typically performed using a 14- to 18-gauge device. Some centers place a clip in the biopsied node to facilitate future image-guided localization of the lymph node at surgical excision after completion of NAC. US-guided CNB has proven high specificity, with a moderate to high sensitivity in the detection of metastatic lymph nodes. Houssami et al [33] published a meta-analysis of 2,874 FNA and CNB procedures and found a pooled sensitivity of 80%, a specificity of 98%, and a positive predictive value of 97%.


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. Another meta-analysis of 1,353 patients undergoing axillary lymph node biopsy to detect metastases showed that both CNB and FNA procedures performed well, with sensitivities of 74% and 88%, respectively, and a specificity of 100% for both procedures. Complication rates with US-guided biopsies were low, although slightly higher for CNB when compared with FNA (7% versus 1%, respectively), and most commonly included pain, hematoma, and bruising [142]. Some centers place a clip in the biopsied positive axillary node before treatment so that it can be surgically excised along with the sentinel node(s) after completion of the NAC; this procedure is sometimes referred to as targeted axillary dissection [138]. US-guided localization of the clipped lymph node can be performed preoperatively [139]. Excising the clipped lymph node and SLNs decreases the false-negative rate of SLNB [26]. In a study of 31 patients, 11 patients had residual axillary disease, and, in all cases, the clipped lymph node was positive [141]. In a prospective study of 23 patients with clipped axillary metastases before NAC, the surgeon retrieved the clipped node in 22 cases, and the SLN was retrieved in only 19. The clipped node was the SLN in only 14 cases (61%). The NPV was 100% for removal of clipped and sentinel nodes but only 85% for SLN removal alone [119]. Overall, US-guided biopsy offers a minimally invasive option to obtain histopathologic proof of axillary nodal involvement for suspicious findings, although a negative biopsy does not reliably exclude metastatic disease, and therefore surgical pathology remains the reference standard. When US-guided biopsy confirms metastatic disease in pathologic-appearing nodes, it can obviate the need for pretreatment sentinel node biopsy because the completion of axillary surgery is typically performed after therapy [2,117].


Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. US-Guided Fine Needle Aspiration Biopsy Axillary Node US-guided axillary lymph node sampling is the most useful next study performed when axillary imaging is suspicious for metastatic disease [4]. Sampling of abnormal-appearing lymph nodes by US-guided FNA is frequently performed with a 22- or 25-gauge needle and also requires the availability of skilled cytopathologists. False-negative rates are low (< 2%) in experienced hands but may occur, especially with smaller metastatic deposits [143]. Some centers place a clip in the biopsied node to facilitate future image-guided localization of the lymph node at surgical excision after completion of NAC. US-guided axillary FNA has proven high specificity, with a moderate to high sensitivity in the detection of metastatic lymph nodes. A retrospective study of 65 patients compared US-guided FNA results to final surgical pathology in patients with radiographically suspicious lymph nodes and demonstrated high sensitivity, specificity, and positive predicative value (89%, 100% and 100%, respectively) for FNA [144]. A larger meta-analysis of 1,353 patients undergoing axillary lymph node biopsy to detect metastases showed that both FNA and CNB performed well, with sensitivities of 74% and 88%, respectively, and a specificity of 100% for both procedures. Complication rates for FNA were lower than CNB (1% versus 7%, respectively) and were most commonly pain, hematoma, and bruising [142]. Additionally, one prospective study of combined axillary US and FNA in 315 patients with sonographically positive lymph nodes again demonstrated high sensitivity (81%), specificity (100%), and positive predictive value (100%). However, the NPV was low (50%), supporting the need for definitive surgical sampling [145].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs.  Perinatal stroke (<6 months of age), although the most common acute stroke in children (20 to 62.5/100,000 live births), will not be discussed in this topic. As in many cases, the diagnosis is retrospective when the child presents later in life with new onset seizure, asymmetric motor function, or failure of developmental milestones [8]. The majority of perinatal stroke is likely to be caused by thromboembolism from the placenta through a patent foramen ovale or fetal heart defect [8]. The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document. Reprint requests to: publications@acr.org and 25% presented outside of the therapeutic window [2]. The study was closed by the NIH for lack of patient accrual [2]. To date, there is insufficient information about acute pediatric stroke to confirm the appropriate window for initiation of thrombolytic therapy in children [12]. A window of 24 hours from stroke onset to initiation of treatment is used in this clinical scenario. This treatment is considered in children >2 years of age [13]. The risk of symptomatic hemorrhage into an ischemic infarction in adults treated with IV tissue-type plasminogen activator is 6.4% and is unknown in children [2]. Recently, interest in the use of intra-arterial treatment for stroke in children has developed because of the documented success of this type of therapy in adults. However, currently, no systematic study of such therapy in children has been performed, and only case reports exist [14]. Adult studies have shown good results with mechanical thrombectomy up to 6 hours or longer on a case-by-case basis from acute stroke symptom onset [15].


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. CT Head CT of the head is frequently the front-line imaging study for the assessment of a child with a suspected acute stroke. Although CT is less sensitive than MRI for the early depiction of acute ischemic infarction, the technique is rapid, usually does not require the child to be sedated, and can be useful in evaluating for hemorrhage or in excluding other treatable pathologies [16]. CTA Head CT angiography (CTA) can provide a useful assessment of intracranial vessels in arteriopathies and thromboembolic disease [17]. MRA Head MR angiography (MRA) can provide information on the intracranial vasculature and is particularly helpful in noninvasive assessment of arteriopathies [17]. MRA is susceptible to flow-related artifacts that may simulate regions of stenosis, especially in the setting of turbulence that may occur with anemia at vessel branch points [26]. MRI and MRA of the cervical vessels in cases of unexplained stroke should be considered, with attention paid to the time constraints of the window of therapeutic intervention [27]. MRA can be performed with IV contrast to improve vessel delineation, although contrast is not typically required to produce diagnostic imaging in acute stroke. CT Head Perfusion Perfusion CT in children is feasible but requires repetitive imaging of the brain [28]. MR Head Perfusion Perfusion-weighted MR can be performed with either dynamic susceptibility contrast administration or arterial spin-label techniques without IV contrast and can provide information on the adequacy of cerebral blood flow [17,19,29]. Perfusion MR is not necessary to proceed to emergent acute stroke thrombolysis. CT Head CT of the head is frequently the initial imaging study for the assessment of a child with a suspected acute stroke.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Although CT is less sensitive than MRI for the early depiction of acute ischemic infarction, the technique is rapid, usually does not require the child to be sedated, and can be useful in evaluating for hemorrhage or in excluding other treatable pathologies [16]. CTA Head CTA can provide a useful assessment of intracranial vessels in arteriopathies and thromboembolic disease [17]. MRA Head MRA can provide information on the intracranial vasculature and is particularly helpful in noninvasive assessment of arteriopathies [17]. MRA is susceptible to flow-related artifacts that may simulate regions of stenosis, especially in the setting of turbulence that may occur with anemia at vessel branch points [26]. MRI and MRA should include the cervical vessels in cases of unexplained stroke because cerebral arterial abnormalities are found in 25% of patients [27]. CT Head Perfusion Perfusion CT in children is feasible but requires repetitive imaging of the brain [28]. MR Head Perfusion Perfusion-weighted MR can be performed with either dynamic susceptibility contrast administration or arterial spin-label techniques without IV contrast and can provide information on the adequacy of cerebral blood flow [17,19,29]. US Duplex Doppler Transcranial Using an open fontanel as an acoustic window, ultrasound (US) can be used to diagnose infarction in the neonate but MRI, as in the older child, is more definitive. US shows 68% of infarctions in the first 3 days of life and 87% within the first 2 weeks [34]. Detailed evaluation of the brain parenchyma is generally not possible with US following the closure of the fontanels, but Doppler US can be used to interrogate flow in the intracranial vessels [35]. Variant 3: Child. Clinical presentation suggestive of acute stroke, known or suspected arteriopathy, or moyamoya. Not a candidate for emergent treatment. Initial imaging.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. Arteriopathies, defined as intrinsic vessel stenosis, irregularity, pseudoaneurysm, banding, or dissection flap, account for 18% to 64% of pediatric ischemic stroke cases [36]. Common causes of arteriopathy include moyamoya (22%), arterial dissection (15% to 20%), vasculitis (12%), and sickle cell disease (SCD) arteriopathy (8%) [27,36]. Genetic mutation constitutes an increasingly represented etiology of cerebral arteriopathy as demonstrated by mutations in the ACTA2 or CERC 1 genes. Arteriopathies are a strong indicator of recurrent stroke risk (66%) [36-38]. Moyamoya refers to the angiographic appearance of a progressive stenosis or occlusion of the internal carotid artery apex and proximal branches of the circle of Willis with the development of stereotypical collaterals. Moyamoya occurs in approximately one in every 1 million children in the United States and accounts for 6% of all pediatric strokes [39]. The underlying cause is unclear, but it is likely that many different factors, both genetic and environmental, contribute to developing the arteriopathy. The moyamoya syndrome may be idiopathic (moyamoya disease) or occur in association with other conditions (moyamoya syndrome). Up to 40% of children with SCD may show moyamoya-like changes on imaging [39]. Moyamoya disease is, by definition, bilateral but may be asymmetric in severity [39]. Unilateral involvement is considered moyamoya syndrome. As many as 12% of patients with sickle cell anemia will have a clinically detected stroke by the age of 20 [40,41]. Importantly, at a minimum, 85% of patients with sickle cell anemia who present with frank stroke will have evidence of cerebral arteriopathy on neuroimaging [41,42]. Most strokes in moyamoya in children are ischemic and most frequently occur in the vascular border zone territories, but cortical infarctions can occur as well.


Cerebrovascular Disease Child PCAs

Cerebrovascular Disease Child PCAs. CT Head CT is less sensitive than MRI for demonstrating acute infarctions but can be useful in evaluating rare instances of intracranial hemorrhage in moyamoya [43]. CTA Head CTA, including multiphase CTA, is an alternative to MRA and catheter angiography in the initial diagnosis and follow-up of children with moyamoya. MRI Head Proposed screening guidelines for moyamoya include diagnostic imaging using MRI/MRA in at-risk populations, particularly if there are symptoms of cerebral ischemia. Screening of first-degree relatives of patients with moyamoya is probably not warranted in the absence of symptoms or unless multiple family members are already known to be affected. T2-weighted fluid-attenuated inversion-recovery imaging may show high signal in the sulci (ivy sign), indicative of slow flow in affected vascular territories. A similar appearance may be evident on T1- weighted contrast-enhanced studies. SWI may be used to demonstrate microhemorrhage that has been reported in up to 52% of patients [44]. Arteriopathy can also be further evaluated with the technique of vessel-wall imaging [15,45]. MRA Head MRA is an alternative to CTA in the initial and follow-up imaging evaluation of children with moyamoya and is the preferred noninvasive vascular imaging modality. MRA is typically performed together with brain MRI to evaluate both the cerebral vasculature and the brain parenchyma. CT Head Perfusion The use of perfusion CT, including xenon-enhanced CT, in children with moyamoya is feasible but requires repetitive imaging of the brain [28]. MR Head Perfusion MR cerebral blood flow evaluation includes perfusion-weighted MR, either using arterial spin-labeling techniques without IV contrast or dynamic susceptibility contrast techniques with IV contrast. Perfusion imaging is also used to assess functional improvement after treatment [39,46-49].