Conventional radiographs (x-rays) are still commonly obtained as the initial imaging study in patients with disorders of the lymphoid system. Despite the emergence of sophisticated cross-sectional and functional imaging techniques, radiographs remain attractive for the initial evaluation, and they are inexpensive, rapid, and relatively easy to perform. They can be done without sedation and can be accomplished at far lower radiation doses than computed tomography (CT). Although many disorders will not be evident radiographically, the presence of primary intrathoracic tumors, mediastinal and/or paraspinal masses, intra-abdominal masses and destructive bone lesions can all be detected radiographically. The presence of calcifications in lymphoid masses may be helpful in establishing a differential diagnosis. For the evaluation of children with suspected abdominal conditions, radiographs of the abdomen should be the initial examination of choice to assess for acute obstruction or bowel perforation.

Historically, fluoroscopy was the primary modality used to evaluate the gastrointestinal tract and the upper airway. With the emergence of cross-sectional imaging, fluoroscopy is now rarely used for the primary evaluation of suspected lymphoid lesions. However, children with poorly characterized symptoms and physical exam findings may undergo fluoroscopic evaluation to assess the intestinal tract, and the radiologist should be aware of the imaging findings associated with lymphoid lesions involving the GI tract. Mucosa-based processes such as esophagitis, gastritis, or duodenitis are diagnosed almost exclusively by endoscopy nowadays. However, esophageal and intestinal strictures may benefit from further delineation by fluoroscopy, which can be performed safely and effectively. Current fluoroscopic techniques generally employ very low radiation doses due to advances in pulsed fluoroscopy, image intensifier sensitivity, and improved automatic dose rate controls [1]. Both water-soluble contrast or barium enteric contrast agents used in conjunction with fluoroscopy are considered safe even in immunocompromised children. While there are few contraindications to fluoroscopic evaluation of the intestinal tract, contrast enemas are generally avoided in neutropenic patients and barium enteric contrast should be avoided when bowel stricture or perforation are suspected.

Ultrasound is an excellent technique for evaluating the child with a lymphoid system disease. With the availability of an array of high and low frequency transducers, ultrasound can be used to evaluate both superficial and deeper structures and is particularly useful in evaluating lymph nodes in the neck and axilla as well as the abdominal visceral organs [2]. Diagnostic ultrasound is relatively quick, inexpensive, and does not utilize ionizing radiation. In the hands of a skilled operator, ultrasound can also be used to evaluate even the most anxious child and does not usually require sedation. In contrast to adults, ultrasound images in children are usually of very high quality due to the relative paucity of intra-abdominal fat and other attenuating soft tissues seen in older patients and adults.

Color and pulse wave Doppler as well as the increasing availability of three-dimensional imaging techniques allow dynamic flow and vascularity to be assessed. This can be helpful in distinguishing between hyperemic/inflamed lymphoid tissue and normal tissue. The use of microbubble ultrasound contrast agents is still experimental and not routinely available for use in children [3]. The use of sonoelastography to measure the compressibility and elasticity of tissues—initially used in the evaluation of the liver—is presently under evaluation to determine tissue characteristics of superficial lymphoid structures in an effort to discriminate benign from neoplastic nodal enlargement [4].

Since its emergence in the 1970s, the use of CT has become routine in the evaluation of patients with suspected abnormalities of the lymphoid system. With the development of multiple detector row and ultrafast CT imaging techniques, examinations of the entire body can now be performed in under one minute and, depending on the area of interest, even young children may be evaluated without the need for sedation.

CT scanning is routinely performed in transaxial cross-sections with multiplanar reconstructions being rapidly generated from the axial image data. With the use of multidetector helical CT scanners and isotropic imaging acquisition techniques, the reconstructed images have no discernible loss of resolution or contrast as compared to source transaxial data. The use of contrast agents (both intravenous and enteric) in pediatric CT scanning depends on the condition being evaluated. For assessment of the mediastinum and lymphoid tissues, the presence of contrast is considered helpful, if not essential, to better characterize lymph nodes relative to adjacent vascular structures. In addition, the use of contrast-enhanced CT scanning remains the standard of care to accurately measure the size of lymphoid tumors to determine response to therapy [5, 6]. Although concerns regarding reactions to iodinated intravenous contrast agents are frequently raised, the rate of adverse reactions, including acute allergic or anaphylactoid reactions, asthmatic reactions, and vasovagal reactions, are exceedingly rare [7]. The presence of a prior contrast reaction does, however, predict subsequent recall-type allergic reactions, and clinicians and radiologists should be aware of the increased potential for adverse events in these patients and provide appropriate premedication as indicated. Awareness by radiologists and clinicians of guidelines for the use of iodinated contrast agents is important so that imaging protocols can be modified as needed [8].

Over the past 10 years, there has been a heightened awareness of the potential risk posed by CT scanning from ionizing radiation doses used [9]. When comparing the effective dose for a pediatric chest CT to a chest radiograph, some estimates indicate the CT scan is the equivalent of tens to hundreds of chest radiographs [10]. While it is clear that the use of multiple CT scanning phases and the need for multiple sequential CT examinations increases the relative radiation risk, a more extensive discussion of the radiation risk estimates associated with CT scanning in pediatric patients is beyond the scope of this chapter and can be reviewed in a number of recent publications [11–14]. It is reasonable to conclude that opinions vary widely and uncertainty about the absolute risk of cancers associated with ionizing radiation in the diagnostic CT dose range remains [15]. Nonetheless, the principle that guides the use of CT scanning in pediatric patients is adherence to the ALARA (as low as reasonably achievable) guidelines, which seek to balance the relative risk of exposure to ionizing radiation against the potential benefit from the diagnostic information obtained. Namely, every effort should be made to adjust the CT doses to the patient’s body size and clinical indications and to minimize scanning of body regions that are not involved or not suspected as harboring disease.

Most major manufacturers now have new dose-reducing automatic tube current modulation technologies as well as iterative image reconstruction algorithms that allow scans to be performed at much lower doses and for the doses to be adjusted dynamically, accounting for the differing tissue densities being imaged [16]. While the technical parameters used in CT scanning are ultimately the responsibility of the radiologist, clinicians ordering CT scans should be aware of these considerations in determining the need for CT and whether the clinical indications warrant the particular examination being ordered.

Magnetic resonance imaging (MRI), in contrast to the transmission technologies such as conventional radiography, fluoroscopy, and CT, belongs to the group of emission technologies. MRI consists of dynamic interactions between a strong external magnetic field, the application of radiofrequency waves, and subsequent reception of low level radiofrequency (RF) emissions from hydrogen nuclei within the body [17]. Once the patient is placed in a magnetic field, the hydrogen nuclei become aligned in the orientation of the magnetic field. When they are bombarded with radiofrequency pulses, the hydrogen nuclei absorb the RF energy. Once the RF waves are turned off, the hydrogen nuclei begin to release the absorbed energy (“decay”) in a manner that is related to the tissue characteristics within which the nuclei are residing. This allows exquisitely detailed images of the body’s soft tissues to be acquired. There are a number of factors that can influence the signal and image quality obtained during MRI, but these are beyond the scope of this review. In general, in order to acquire a diagnostically useful image, contrast between normal tissues and diseased tissues is needed. Such contrast differences are an inherent reflection of the different tissue environments within which the protons live. Depending on the clinical indication, the MRI pulse sequences can be tailored to address specific clinical questions.

For evaluating the patient with abnormalities of the lymphoid system, characterization of normal and diseased lymph nodes can usually be accomplished well using standard T1- and T2-weighted imaging techniques in axial and at least one orthogonal (coronal or sagittal) imaging plane. The use of gadolinium-based contrast agents can be helpful in further characterizing tissue abnormalities. In some instances, the presence of iron or hemosiderin deposition may be helpful in rendering a differential diagnosis and gradient echo or T2-weighted images, which are sensitive to the local magnetic field inhomogeneities induced by the presence of paramagnetic compounds such as iron, can be utilized [18, 19].

Pediatric whole-body MRI techniques with rapid scanning sequences can now be accomplished typically in 30 min or less and have been advocated for staging and screening patients with abnormalities of the lymphoid system [20, 21]. The use of parallel imaging techniques and the ability to simultaneously receive RF information using multiple receiver coils allows for more rapid imaging and improved temporal and spatial resolution. The increased ability to perform rapid MRI studies for a wide variety of pediatric indications is particularly important for young children in whom an MRI examination of 30 min or more may require sedation in order to minimize patient motion.

The use of diffusion-weighted imaging has recently gained attention for body imaging techniques [22–24]. Diffusion-weighted imaging was initially developed for characterizing sites of brain ischemia in neuroradiologic applications. For oncologic purposes, the ability to evaluate tissue density and tumor cellularity based on changes in the restricted diffusion of water molecules within a particular region, has been helpful in characterizing and evaluating effects of therapy [24]. While diffusion-weighted imaging may aid in detecting small lymph nodes, it has not yet been able to reliably distinguish between neoplastic and non-neoplastic lymph node processes [25, 26].

The use of MR contrast agents includes both positive and negative contrast agents. Gadolinium (Gd)-based agents rely on the paramagnetic effects of Gd, which causes both T1 and T2 relaxation time shortening. The Gd ion itself is toxic and is only provided in the form of a gadolinium chelate. The pattern of tissue uptake and excretion may vary depending on the chelate used, but most commercially available Gd-based MR contrast agents are administered intravenously and are primarily excreted through the genitourinary tract. Iron- and iron oxide-based contrast agents have been specifically advocated for evaluation of the lymphoid system [19]. These agents rely on the T2 shortening effects of iron. Normal cells of the macrophage and reticuloendothelial cell lineage will typically scavenge the iron-based nanoparticles, and the use of these contrast agents has been shown in several pilot studies to be helpful in distinguishing lymph nodes involved by tumor from normal lymph nodes. Despite the potential appeal of this class of contrast agents, they have not received universal clinical acceptance.

The use of Gd-based chelates is relatively safe, although patients with underlying acute or chronic renal insufficiency have been shown to be at risk of developing nephrogenic systemic fibrosis (NSF) [27]. NSF is characterized by progressive tissue fibrosis that may be limited. On occasion, NSF may be progressive with involvement of other tissues such as the heart, lungs, and esophagus resulting in significant pathology and potentially death. Although the risk of developing NSF seems to relate to the doses of Gd chelate used and the degree of renal insufficiency, the majority of patients with renal insufficiency do not develop NSF. Nonetheless, the evaluation of renal function prior to the intended use of Gd-based contrast agents is needed in order to minimize this potential risk.

Functional imaging techniques in nuclear medicine are commonly used in evaluating patients with abnormalities of the lymphoid system. Although these techniques provide less anatomic and morphologic information than either CT or MRI, there is often valuable metabolic and functional information to be gathered from specific nuclear medicine techniques. As with MRI, nuclear medicine imaging relies on emission data following injection with a radiopharmaceutical agent to generate an image [28]. Depending on the pharmaceutical and isotope utilized, the agent localizes to target organs and tissues and is visualized using highly specialized detector cameras used to acquire and display images of the whole body or selected body regions. Cameras are configured to acquire both 2-D planar as well as multiplanar tomographic images and can be placed at various angles and positions to optimize image quality and lesion conspicuity.

Positron emission tomography (PET) utilizes positron-emitting radiopharmaceuticals. Following radionuclide decay in situ, emitted positrons annihilate upon contact with electrons near the point of tissue localization releasing two 511 keV photons traveling in opposite directions. These high-energy photons can be imaged using coincidence detection techniques to permit precise identification of the initial site of radiopharmaceutical localization and positron decay. Similarly, single photon emission computed tomography (SPECT) applies tomographic rather than planar imaging techniques to gamma particle emitting radiopharmaceuticals allowing multiplanar acquisition and projection images to be generated. These can be fused to CT and/or MRI images, which in some instances may be simultaneously acquired to allow anatomical and functional co-localization.

A wide variety of radiopharmaceuticals is available, although the main agents used in routine evaluation of children with lymphoid disorders include ^99mTc labeled methylene diphosphonate (MDP), 67Ga, and ¹⁸F-fluorodeoxyglucose (FDG). ^99mTc-MDP localizes to areas of bone turnover and is useful in assessing osteoblastic metastatic disease as well as sites of lytic bony disease. Historically, ⁶⁷Ga, whic binds to transferrin receptors expressed on lymphoid cells, was used to evaluate patients with lymphoma. The use of gallium scanning has been essentially replaced by FDG PET imaging, and the latter has become standard of care in the evaluation of patients with lymphoma [29, 30] as well as a variety of other non-neoplastic lymphoid disorders [31]. FDG PET imaging relies on the presence of ¹⁸F-fluorine as a positron-emitting radiotracer that is incorporated into the glucose analog fluorodeoxyglucose. FDG accumulates at relatively high levels in metabolically active lesions including lymphoid malignancies and inflammatory disorders, providing a very sensitive means of evaluating patients with abnormalities of the lymphoid system. Nearly all PET imaging is currently performed with integrated PET/CT scanners. This allows areas of FDG uptake at sites of concern to be fused to simultaneously acquired CT images to afford better anatomic correlation and coregistration of uptake sites. In addition, areas of background or physiologic uptake such as brown fat can be accurately identified using co-registered PET/CT images.

Other nuclear medicine imaging techniques include the use of ^99mTc-HMPAO or ¹¹¹In-oxine labeled leukocytes for inflammatory imaging, although this technique is now less frequently used with the advent of FDG PET imaging. Nuclear medicine plays an important complimentary role in providing a functional characterization of patients with disorders of the lymphoid system. In many diseases, functional imaging is crucial for disease staging, response assessment, and in certain instances disease surveillance. Increasingly, however, the use of nuclear medicine techniques is closely integrated with simultaneously acquired cross-sectional imaging examinations (e.g., CT or MRI), requiring careful assessment of both the functional and anatomic imaging data for diagnostic evaluation [29, 30, 32].

Primary immunodeficiencies (PID) are a rare and heterogeneous group of diseases caused by congenital defects affecting the innate and/or adaptive immunity, with impact on the humoral and/or cell-mediated immunity. The most updated classification for PID provided by the International Union of Immunodeficiencies Studies recognizes eight categories [37]: (1) combined immunodeficiencies: e.g., severe common immunodeficiency (SCID); (2) predominantly antibody deficiencies: e.g., X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID); (3) well-defined syndromes with immunodeficiency: e.g., Wiskott-Aldrich syndrome, DNA repair defects; (4) diseases of immune dysregulation: e.g., autoimmune lymphoproliferative syndrome (ALPS), familial hemophagocytic lymphohistiocytosis; (5) congenital defects of phagocyte number, function or both: e.g., chronic granulomatous disease, severe congenital neutropenia; (6) defects in innate immunity: e.g., deficiencies impairing the interferon gamma/interleukin 12 axis; (7) autoinflammatory disorders: e.g., familial Mediterranean fever; and (8) complement deficiencies. More than 120 distinct genes have been identified, with abnormalities that account for more than 150 different forms of PID [38].

Patients with PID have a higher than usual risk of developing lymphoid malignancies, and these represent the second leading cause of death in this group [39]. The incidence of lymphoproliferative disease ranges from 1.4 to 24 % depending of the type of the PID. The diseases commonly associated with lymphoproliferative disorders or neoplasms include ataxia-telangiectasia, Wiscott-Aldrich syndrome, Nijmegen breakage syndrome, CVID, XLA, and autoimmune lymphoproliferative syndrome. In these patients, lymphoma is diagnosed at a median age of 7.1 years [39].

The pathogenesis of lymphoproliferative diseases in PIDs involves multiple mechanisms rooted in defects in DNA damage response (e.g., ataxia-telangiectasia and Wiscott-Aldrich syndrome) and immune deregulation that characteristically results in abnormal response to viral infections such as Epstein-Barr virus (EBV), hepatitis B or C viruses, and human papillomavirus [40]. The inability to eliminate infection is speculated to create an inflammatory environment that can eventually promote tumor development and growth by promoting and sustaining the acquisition of oncogenic somatic mutations [39].

Lymphoid proliferations associated with PID are heterogeneous and range in spectrum from reactive hyperplasia to non-Hodgkin and Hodgkin lymphoma. The most common presentation is at extranodal sites; namely, the gastrointestinal tract, lungs, and central nervous system. In patients with XLA and SCID, non-neoplastic lesions include a polymorphous lymphoid proliferation with plasmablasts, immunoblasts and Reed-Sternberg-like cells that result from primary EBV infection. Patients with CVID can present with lymphoid hyperplasia in the gastrointestinal tract or with lymph node follicular hyperplasia and expansion of paracortical areas by immunoblasts infected by EBV. In patients with ALPS, lymphadenopathy results from follicular hyperplasia with or without progressive transformation of germinal centers. Overt lymphomas generally have clonal IgH rearrangement whereas non-neoplastic or polymorphous lymphocytic proliferations may show either oligoclonal or monoclonal IgH rearrangements. The presence of clonality in patients with PID does not always indicate the presence of lymphoma and correlation with clinical and imaging findings is particularly important.

The lymphomas that can occur in patients with PID are generally classified like those that arise in non-immunosuppressed patients. Diffuse large B-cell lymphoma is the most common type, followed by Burkitt lymphoma. Lymphomatoid granulomatosis involving the lungs shows T-cell background infiltrate and neoplastic B-cells, and is most commonly seen in patients with Wiscott-Aldrich syndrome. Classical Hodgkin lymphoma is less common than diffuse large B-cell lymphoma in PID patients and has been reported in patients with ataxia-telangiectasia syndrome and Wiscott-Aldrich syndrome. Peripheral T-cell lymphoma is rare and has been described in patients with ALPS. The EBV virus has been demonstrated to be present in most of the cases [41]. A summary of the most common PID types associated with lymphoproliferative disorders and neoplasms is listed in Table 5.3.

Imaging features associated with PID vary by the type and severity of the immunodeficiency. Patients with XLA do not produce immunoglobulin but do have normal T-cell function and normal thymic development. Radiographically, this disorder is most frequently associated with the sequelae of recurrent pulmonary infections such as bronchiectasis, pulmonary parenchymal scarring and heterogeneous or mosaic patterns of lung aeration and attenuation (Fig. 5.2). Bacterial infection can also occur at other sites such as the sinuses and genitourinary tract; however, these are not as commonly encountered as pulmonary infections [42]. Patients with IgA deficiency develop pulmonary and GI infections and may have underlying allergic and autoimmune disorders. In comparison to XLA, the imaging findings are less severe and bronchiectasis, for example, is less common. Patients with CVID, as with XLA, may also have recurrent infections, bronchiectasis, and bronchial wall thickening. In contrast to the other PID, patients with CVID may also develop lymphadenopathy and splenomegaly in addition to a more generalized lymphoproliferative process (Fig. 5.3), presumably because of varying degrees of associated T-cell functional abnormalities [42, 43].

DiGeorge syndrome (DGS) and SCID are the most severe of the PID syndromes. DiGeorge syndrome, also known as thymic hypoplasia, results in primary T-cell deficiency secondary to abnormal thymic development [42]. Patients with DGS have other findings including hypertelorism and micrognathia, which may be apparent radiologically. Other associated anomalies include a host of cardiovascular anomalies such as abnormalities of the aortic arch and tetralogy of Fallot. Apart from the narrow mediastinum resulting from absent thymic tissue, there are no other specific imaging findings to indicate the diagnosis of DGS. Severe combined immunodeficiency syndrome results from absent T- and B-cell function, as well as diminished natural killer cell function. As with DGS, the combination of deficiencies in both humoral and cellular immunity in patients with SCID leads to recurrent and severe opportunistic infections [43].

Patients with Wiskott-Aldrich syndrome and ataxia telangiectasia have a high incidence of developing malignancy, particularly leukemia and lymphoma [44, 45] (Fig. 5.4). In addition, patients with ataxia telangiectasia are at an increased risk of radiation-induced malignancy, which creates unique challenges for surveillance imaging studies. Because imaging examinations in these populations of patients are aimed at screening for malignancy or characterizing active or chronic sites of infection, the results are often nonspecific, prompting multiple follow-up imaging evaluations. As such, techniques that require repeated exposure to ionizing radiation (i.e., CT) should be used judiciously [46].

Human immunodeficiency virus (HIV) infection and the associated acquired immune deficiency syndrome (AIDS) occur infrequently in children and often as the result of in utero transmission. A distinct group of lymphoid neoplasms arise in the setting of HIV infection. These include lymphomas that are seen in HIV-negative patients such as Burkitt lymphoma, diffuse large B-cell lymphoma, and Hodgkin lymphoma. In addition, HIV patients are affected by lymphomas that are only rarely seen outside the setting of HIV: primary effusion lymphoma and plasmablastic lymphoma. The introduction of highly active antiretroviral therapy (HAART) has resulted in a dramatic decrease in the incidence of high grade lymphomas in HIV patients.

Most patients present with advanced stage disease and extranodal involvement. Extranodal sites usually include the gastrointestinal tract, central nervous system (CNS), liver and bone marrow, as well as more unusual sites such as oral mucosa and body cavities. Lymph nodes can also be involved. Epstein-Barr virus is identified in approximately 40 % of HIV-associated lymphomas, but this percentage varies significantly between the different types of lymphomas. Distinction between neoplasia and infection on imaging studies may be difficult occasionally; for example, CNS involvement by toxoplasmosis is a rare complication in pediatric HIV patients and can be difficult to distinguish from lymphoma [47].

Post-transplant lymphoproliferative disorders (PTLD) are lymphoid or plasma cell disorders that develop in a recipient of a solid organ or allogeneic stem cell transplant as a result of iatrogenic immunosuppression. The spectrum of PTLD is clinically and histologically variable. Three broad categories of PTLD are recognized: (1) early lesions (infectious mononucleosis-like and plasmacytic hyperplasia); (2) polymorphic PTLD; and (3) monomorphic PTLD. The latter includes lymphomas that also occur in non-immunosuppressed patients such as Hodgkin lymphoma and plasma cell myeloma. When compared to the adult population, the incidence of PTLD in children is higher, especially following solid organ transplant. The risk for development of PTLD is significantly associated with the occurrence of primary EBV infection after transplantation [48, 49].

Imaging of PTLD patients is directed at establishing the extent of involvement and should include cross-sectional imaging, either CT or MRI, of the entire torso as well as FDG PET imaging to establish the overall extent of disease [50]. Both CT and PET can be used to monitor response to therapy and/or immunomodulation. FDG PET has been shown to be superior to conventional imaging techniques in the early evaluation of PTLD response to therapy [50].

Routine screening for PTLD (e.g., EBV serologic studies or quantitative assessment of viral RNA) facilitates early diagnosis and treatment by reduction of immunosuppression. Lymph nodes as well as extranodal sites (tonsil, gastrointestinal tract, lungs, spleen and liver can be involved (Fig. 5.5). In solid organ transplant recipients, PTLD may affect the allograft itself and needs to be differentiated from rejection or infection. Detection of EBV-encoded RNA in the lesion generally favors PTLD. Early lesions, including infectious mononucleosis-like PTLD are more frequent in children and usually involve tonsils and adenoids. They have a good prognosis and respond to reduction of immunosuppressive treatment. However, the polymorphous PTLD is the most common type affecting pediatric transplant recipients. Some cases of polymorphic PTLD and most cases of monomorphic PTLD require additional treatment that includes monoclonal antibodies against B-cell antigens (e.g., rituximab), chemotherapy, and more recently cellular immunotherapy (EBV-specific cytotoxic T-cell immunity).