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Diagnostic Imaging Modalities for Assessment of Lymphoma with Special Emphasis on CT, MRI, and Ultrasound
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POSITRON EMISSION TOMOGRAPHY PET Clin 1 (2006) 219–230
Diagnostic Imaging Modalities for Assessment of Lymphoma with Special Emphasis on CT, MRI, and Ultrasound Ju¨rgen Rademaker, -
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Clinical features Hodgkin’s disease Non-Hodgkin’s lymphoma Immunocompromised patients Staging classification Imaging techniques Assessment of response to therapy Residual masses Spectrum of imaging findings Head and neck Head and sinonasal cavity Neck Thyroid Skin Thorax Breast Mediastinum
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This article reviews the clinical features of Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) and provides a short introduction to the staging system and radiologic evaluation of the response to treatment, all of which are important for the imaging evaluation of lymphoma. The second part of this article presents common imaging findings of the involvement of different organs.
Thymus Lung Pleural and pericardial disease Chest wall Abdomen and pelvis Liver Gallbladder and adrenal glands Spleen Gastrointestinal tract Pancreas Peritoneum, omentum, and retroperitoneum Kidneys Genitourinary system Central nervous system Musculoskeletal system Summary References
Clinical features HD and NHL may present as the involvement of one or multiple lymph node groups, of an isolated organ, or as widely disseminated disease. In general, there is a displacement of structures by enlarged lymph nodes but not invasion. This imaging feature distinguishes lymphoma from carcinoma. Only large-cell high-grade NHL may be
Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA E-mail address: [email protected] 1556-8598/06/$ – see front matter ª 2006 Elsevier Inc. All rights reserved.
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locally invasive. Although HD and NHL share similar radiologic features, there are some significant differences in their radiographic features.
Hodgkin’s disease In HD, the most common site of involvement is the cervical lymph nodes (60%–80%). Two thirds of patients with newly diagnosed HD have radiologic evidence of intrathoracic involvement. Isolated infradiaphragmatic lymphadenopathy occurs in less than 10% of patients at diagnosis. Nodular sclerosing HD may be associated with normal-sized or only moderately enlarged lymph nodes. HD spreads in a contiguous fashion from one lymph node group to the adjacent lymph nodes. Adjacent structures may be invaded like chest wall, lung, or bone. Extranodal involvement is less common in HD than in NHL.
Non-Hodgkin’s lymphoma In NHL, involved lymph nodes tend to be larger as compared with HD. Although commonly involving lymph node groups, involvement of extranodal sites is also fairly typical. This includes extranodal lymphatic tissue (eg, Waldeyer ring, Peyer patches, spleen) and nonlymphatic organs, such as the liver, bone marrow, bone, and central nervous system (CNS). The clinical and radiographic presentation of NHL is dependent on the histology. Low-grade lymphoma is often associated with large-volume nodal disease. Intermediate-grade lymphoma (includes follicular and diffuse forms) is often associated with rapidly enlarging lymph nodes and extranodal disease. High-grade lymphoma is the most aggressive subtype, but most patients have localized disease at the time of diagnosis.
Immunocompromised patients An increased incidence of NHL was identified in patients with HIV infection or secondary to organ transplantation. In particular, cyclosporine therapy may be associated with NHL or posttransplantation lymphoproliferative disorders (PTLD) (Fig. 1) [1,2]. Unlike lymphoma in the general population, immune deficiency–related lymphoma is often of extranodal origin, with the CNS, bone marrow, gastrointestinal tract (GIT), lung, and liver being the most common sites of disease [2–4].
Staging classification Treatment of lymphoma categorizes disease into early limited disease (stages I and II) when lymphadenopathy is confined to one or a few sites on one side of the diaphragm or an extranodal site, and advanced disease (stages III and IV) with widespread lymphadenopathy on both sides of the diaphragm
Fig. 1. Renal transplant and PTLD. Coronal T1weighted MRI scan of the pelvis reveals an intrarenal mass (arrow) and associated obstruction of the superior calyx (arrowhead). US performed 3 months before MRI depicted only early dilation of the superior calyx but showed no mass, probably because of the often encountered poor contrast between PTLD and the renal transplant. B, bladder.
or involvement of organs, such as the lung, liver, and bone marrow [5]. The initial Ann Arbour staging system for HD was established in 1970, and the introduction of CT and MRI led to the development of the revised Cotswolds classification in 1989. This classification is also applied to NHL, but is of less value, because the prognosis of NHL depends more on the histologic grade and parameters like bulky disease and specific organ involvement. Pediatric patients with NHL more often reveal extranodal involvement, such as that of the GIT or solid organs, and this was incorporated into the staging system of Murphy [7].
Imaging techniques Most clinical management decisions are currently based on either CT or PET, and CT is currently the most used imaging modality for the detection, staging, and follow-up of lymphoma. Nevertheless, other imaging modalities add important information. MRI is irreplaceable for the evaluation of meningeal or spinal cord involvement, infiltration of the bone marrow, and, to a lesser degree, evaluation of chest wall involvement. Although MRI and CT are equally effective in detecting focal brain lesions, it is probably easier to detect small lesions with MRI. MRI with out-of-phase images might help to differentiate unilateral or bilateral adrenal lymphoma from lipid-rich adenoma. The accuracy of MRI in detecting lymph node involvement is similar to that of CT, with most centers preferentially
Diagnostic Imaging of Lymphoma
using CT for a variety of reasons, including costs and availability. Ultrasound (US) is useful for the evaluation of the genitourinary tract, including possible testicular involvement, and for the evaluation of superficial lymph nodes. US-guided biopsies of focal lesions, for example, in the liver and spleen, are useful for tissue sampling [8]. US is also useful for the initial evaluation of symptoms in the abdomen (eg, gallbladder, kidney). Plain films remain important for the evaluation of lymphoma-associated complications, such as pleural effusion, fractures, osteolytic lesions, or small bowel obstruction. Lymphography does not significantly contribute to staging. Some authors consider lymphangiography and CT as complementary [9], but significant disadvantages of lymphangiography include not only a decline in the availability of technical expertise and experience in interpreting the images but the inability to demonstrate lymph nodes in the upper abdomen and outside the retroperitoneum and to assess the true extent of extranodal extension. In addition, the use of a combination of chemotherapy and radiation therapy has increased, diminishing the need for detecting subtle nodal changes [10].
Assessment of response to therapy Patients require routine follow-up to assess tumor shrinkage in response to therapy and to decide on treatment modification if required. Measurements of lesions should be bidimensional (biperpendicular measurement in the axial plane, longest axial dimension X perpendicular dimension). Most of these measurements are relatively easy but might be difficult in cases of irregular edges or rare infiltrating lesions. Pulmonary lymphatic spread or peritoneal infiltrations are difficult to measure, and there is no true consensus on whether necrosis or cystic changes should be included in the measurements [11]. The Cotswold meeting and the National Cancer Institute (NCI) International Working Group defined criteria for response in HD and NHL [6,12,13]. Recommendations of these two consensus meetings include separate definitions for complete remission, partial response, and progressive disease in both diseases. For example, in HD, progressive disease implies a 25% increase in the size of at least one measurable lesion. In NHL, the criteria are more detailed and progressive disease includes the appearance of new lesions or an increase of more than 50% in known lesions. An increase of more than 50% in the greatest diameter of any previously identified node that was greater than 1 cm also represents progressive disease in NHL [6]. For NHL, there is the additional definition
of ‘‘stable disease, ’’ which is less than partial response but not progressive disease.
Residual masses Residual masses seen on CT or MRI after treatment represent a mixture of fibrosis and necrotic tumor in most patients but may sometimes represent viable tumor. The size of residual abnormalities may vary between subcentimeter lesions and much larger residual masses. Depending on the criteria used for their definition, residual masses occur in up to 50% to 70% of patients treated for HD and in up to 20% to 40% of patients with NHL after treatment. In the author’s experience, neither the initial size of the mass nor the size of the residual mass after treatment correlates with the rate of disease relapse. Recurrence may occur within the residual mass as well as outside it in new sites. Residual masses in the chest are not unusual in HD, whereas residual abdominal masses are seen mainly in NHL, especially large-cell subtypes. Serial CT, initially performed at 2- to 3-month intervals, is the most widely used method for following residual masses.
Spectrum of imaging findings Lymphoma can affect any region of the body, and the following sections summarize the most common and important imaging findings of different organs and anatomic regions.
Head and neck Head and sinonasal cavity Extranodal involvement of the region of the head and neck is rare. Waldeyer’s ring is the most common site of head and neck lymphoma. Paranasal sinus involvement often spreads in a contiguous fashion. Parotid gland involvement is the most frequent site of involvement in the salivary glands and is best evaluated by MRI and US.
Neck Lymph nodes greater than 1 cm in diameter are generally considered enlarged and suspicious for disease involvement on CT. Although calcified lymph nodes are rare before therapy (1%), diseased lymph nodes in the neck and at other locations may show irregular calcifications after treatment. Calcifications before treatment occur more often in the mediastinum in patients with NHL and in patients with aggressive HD, such as the nodular sclerosing subtype (Fig. 2) [14].
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Fig. 2. Enlarged lymph nodes in chronic lymphocytic leukemia. PET revealed low-grade fluorodeoxyglucose (FDG) activity with standard uptake values (SUVs) between 2 and 3.6 in most nodes. A CT scan from the PET/CT study reveals four enlarged nodes in the neck (arrows) with coarse calcifications (arrowheads). These particular nodes had SUVs between 8.6 and 10.4 measured on the PET component of the study. A biopsy revealed new nodular sclerosing HD.
Thyroid Primary HD of the thyroid is extremely rare, with only a few sporadic cases having been reported. Secondary involvement occurs in 2% of cases [15]. Most cases of thyroid NHL arise in the background of Hashimoto’s thyroiditis. Involvement of the thyroid might present as diffuse enlargement or as a focal lesion. Fine-needle aspiration is required to establish the diagnosis (Fig. 3).
Fig. 3. Lymphoma involving the thyroid. Initial CT shows a normal-sized thyroid (A), whereas repeat CT performed 3 months later (B) shows significant enlargement of the thyroid. These nonspecific findings may also be seen in thyroiditis. (A) Small nodule is also seen in the right lobe of the thyroid.
the breast. Diagnosis of primary breast lymphoma is based on the exclusion of concurrent lymphoma (with the exception of ipsilateral axillary nodes). Mammographic features of NHL include solitary uncalcified (69%) or multiple (9%) masses or a diffusely increased opacity with skin thickening (9%) (Fig. 4) [19–21].
Skin Cutaneous lesions, including plaques or erythroderma, show no abnormalities on CT. In the stage of tumor formation, thickening of the skin or the presence of cutaneous nodules may be found. These imaging features are nonspecific. The differential diagnosis includes inflammatory panniculitis, cutaneous metastases from melanoma or breast cancer, or subcutaneus nodules of infectious origin (eg, fungal infection) [16,17].
Thorax
Mediastinum More than 80% of patients with HD present with intrathoracic involvement. Lymph nodes in the anterior mediastinum are suspicious, even if they are smaller than 1 cm in diameter. Minimal enlargement of internal mammary or diaphragmatic lymph nodes can be easily overlooked on CT. Diagnosis of lymphomatous involvement of these nodal groups can affect radiation therapy planning, and recurrent disease is common in internal mammary and pericardial lymph nodes, particularly when they are not included in the radiation field [22].
Breast Breast lymphoma accounts for approximately 0.15% of all malignant breast tumors [18]. Less than 0.5% of all malignant lymphomas and approximately 2% of extranodal lymphomas involve
Thymus Current staging considers the thymus as a nodal site. It is often impossible to distinguish the enlarged thymus on CT or MRI from adjacent
Diagnostic Imaging of Lymphoma
or without cavitation), reticular nodular infiltrates, or irregular consolidations have been described as potential patterns in HD and NHL. For correct staging, it is important to distinguish between contiguous extension of disease into the lungs from adjacent sites of lymphoma and parenchymal involvement. Primary pulmonary lymphoma is rare and is encountered with NHL. Most primary lymphomas of the lung represent mucosa-associated lymphoid tissue (MALT) lymphoma [23,24]. Peripheral consolidations without visible connection to hilar nodes may occur in HD and NHL. Recurrences in the lung may be seen in the absence of associated lymphadenopathy (Fig. 5).
Pleural and pericardial disease Fig. 4. Lymphoma of the left breast. MRI (subtraction maximum intensity projection [MIP]) after administration of gadolinium shows a large heterogeneous mass measuring at least 8.7 cm with persistent delayed enhancement (arrow). The previously described MRI appearance of breast lymphoma includes ill-defined masses with rapid and strong enhancement in dynamic sequences. Rim enhancement may also be observed. Veins (arrowhead ).
lymphadenopathy. In adult patients, the thymus is enlarged if the largest diameter is larger than 15 mm. Between 30% and 50% of patients with HD have thymic enlargement at presentation. Current imaging techniques like CT or MRI fail to differentiate between enlargement of the thymus and actual involvement of the thymus. Thymic cysts may occur in HD at initial presentation as well as after therapy, and they may persist or enlarge, but these changes do not indicate residual or recurrent disease or an increased risk of relapse. If hemorrhage occurs, the thymus may undergo calcification [13]. Posttherapeutic enlargement of the thymus may represent recurrent disease, thymic rebound (hyperplastic thymus), or development of thymic cysts. Thymic hyperplasia is usually triangular in shape and may be seen for several months after the completion of treatment, whereas an infiltrated thymus is often quadrilateral in shape. If the thymus was not the original site of disease, posttherapeutic thymic enlargement should be related to hyperplasia rather than to tumor infiltration [13,15].
Pleural effusions are usually associated with mediastinal lymph nodes and, occasionally, with pulmonary involvement. Effusions result from venous or lymphatic obstruction by enlarged lymph nodes rather than from direct lymphomatous involvement. Most effusions are unilateral exudates. Although pleural effusions associated with HD only rarely have positive findings on cytology, this is more common with effusions in NHL. Focal pleural masses are rare but represent an often overlooked location of lymphoma [25]. Pericardial effusions, by contrast, are presumed to represent lymphomatous invasion of the pericardium. They may arise from lymphatic or hematogenous spread or from direct extension of mediastinal lymphoma.
Chest wall Chest wall involvement is not uncommon and may represent an initial manifestation of disease or a site of recurrence (Fig. 6).
Lung Pulmonary parenchymal involvement is more common with HD than with NHL. The lungs are more frequently involved in secondary or recurrent disease than in primary lymphoma. Involvement of the lung is commonly due to direct extension from hilar and mediastinal adenopathy. Nodules (with
Fig. 5. Pulmonary lymphoma. CT reveals mass-like lesions (arrow) in the right lower lung and hazy ground-glass opacities (arrowhead) in an asymptomatic patient with follicular NHL.
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Fig. 6. Lymphoma involving the chest wall. CT shows a mass (arrowheads) extending from the spine to the lateral aspect of the left chest wall. This represents advanced disease and requires chemotherapy. Radiotherapy is only used if it is possible to cover the complete lymphatic station and in this case it would not be possible to cover the complete leftsided pleura with radiotherapy.
Abdomen and pelvis Liver Large focal lesions are seen in only 5% to 10% of patients with hepatic involvement of lymphoma and have similar imaging features to metastatic disease. Despite advances in imaging techniques, the sensitivity of US, CT, or MRI for the detection of diffuse hepatic disease remains low. Hepatomegaly is highly suggestive of disease infiltration, mainly in patients with NHL. In pediatric patients as well as in adult patients, periportal low-density soft tissue infiltration is a more subtle CT or MRI finding and should not be overlooked.
Gallbladder and adrenal glands The CT and sonographic features of lymphoma of the gallbladder are different from the sonographic features of cholecystitis. In lymphoma, there is usually homogeneous thickening of the gallbladder wall without a hypoechoic edematous middle layer within the gallbladder wall (eg, no ’’halo sign‘‘) (Fig. 7). Adrenal involvement is often (50%) bilateral.
Fig. 7. Gallbladder T-cell lymphoma. (A) US shows hyperechoic thickening of the gallbladder wall (arrows). (B) CT reveals homogeneous thickening and enhancement of the gallbladder wall (arrow) and ascites.
spleen is difficult to detect with US, CT, and MRI. Marked splenomegaly or splenic hilar lymphadenopathy suggests splenic infiltration. Splenic infarctions, which may occur in association with lymphoma, display mass-like features on CT and MRI but have a characteristic wedge shape and peripheral location. Contrast-enhanced US may improve the detectability of splenic abnormalities [26]. Failure to detect splenic involvement is not associated with significantly poorer patient outcome, because relapse caused by untreated splenic infiltration can be easily treated with multiagent chemotherapy. More centers are now using imaging-guided needle biopsies of splenic lesions for tissue sampling and the procedure is often ultrasound-guided. Subcapsular or intraperitoneal hemorrhage occurs in 8% of these biopsies [8].
Gastrointestinal tract Spleen The spleen is frequently involved in lymphoma, and focal nodules are the most common pattern of involvement. The size of the spleen is not an indicator of disease, because diffuse infiltration may be present in spleens of normal size and reactive splenomegaly may often occur in the absence of lymphoma deposits. Diffuse involvement of the
The GIT is the most common site of primary extranodal lymphoma, most commonly NHL of B-cell origin. HD involving the GIT is extremely rare. The stomach is the most commonly involved organ (50%) in primary and secondary lymphoma, followed by the small bowel (33%). Primary gastric lymphoma accounts for 1% to 5% of all malignant disorders of the stomach, with most cases being
Diagnostic Imaging of Lymphoma
B-cell NHL, including low-grade MALT lymphoma, which is associated with Helicobacter pylori infection [27]. Gastric lymphoma may present with three predominant growth patterns on CT and US: nodular, carcinoma-like ulcerative lesions, and infiltrating tumor masses that frequently invade the adjacent mesentery and lymph nodes. Radiographic findings observed in low-grade gastric lymphoma are similar to those in gastric carcinoma or gastritis. Common findings at upper gastrointestinal examination include mucosal nodularity, ulcer, rugal thickening, and masses. Disorganized convergent rugae, vague ulcer margins, and multiplicity of lesions may be helpful in differentiating gastric lymphoma from carcinoma or gastritis [28,29]. CT is useful to assess the presence of lymph nodes above and below the diaphragm, but it has a relatively low sensitivity for detection of perigastric nodes. Endoscopic US has established itself as the procedure of choice for the staging of gastric lymphoma [27]. Lymphoma represents 50% of all primary tumors of the small bowel, occurring most frequently in the terminal ileum. Small-bowel lymphoma is often depicted on CT as a segmental area of circumferential thickening with homogeneous attenuation and enhancement [30]. Disease is often multifocal, and intussusception, predominantly in the terminal ileum, is a classic mode of presentation.
Pancreas Secondary involvement of the pancreas occurs in more than 30% of patients with NHL. Secondary pancreatic involvement is most likely attributable to direct infiltration from adjacent lymphadenopathy. In HIV patients, the GIT is most commonly affected by extranodal NHL, and a significant number of primary manifestations (5%) arise in the pancreas. In patients with primary pancreatic lymphoma, a rare manifestation, pancreatic ductal dilation may be absent, even with ductal invasion [31]. Diffuse infiltration of the pancreas without signs of pancreatitis is also suspicious for pancreatic lymphoma [31].
Fig. 8. Abdominal lymphoma. CT shows a homogeneous mass (arrow) formed by a conglomerate of mesenteric and retroperitoneal lymphadenopathy. The mass surrounds but does not occlude the mesenteric vessels (arrowhead).
Adjacent anatomic spaces are often affected because of the continuous spread of the disease (Fig. 9) [32]. Primary lymphoma of the peritoneum has an increased incidence in AIDS patients. These masses may be extremely hypoechoic on US and can be mistaken for fluid collections.
Kidneys NHL may often involve the kidneys, whereas renal involvement with HD is rare and represents advanced or recurrent disease in most cases. Patterns of renal involvement with lymphoma include multiple or solitary masses, renal invasion from retroperitoneal disease, perirenal disease, and diffuse
Peritoneum, omentum, and retroperitoneum Lymphoma is the most common malignancy resulting in mesenteric lymphadenopathy. Mesenteric or peritoneal infiltration by lymphoma is seen almost exclusively in NHL. Imaging findings may mimic peritoneal carcinomatosis, with peritoneal nodules, ascites, and mesenteric infiltration. Early in the course of the disease, lymph nodes may be small. As the disease progresses, the nodes may form conglomerates and soft tissue masses (Fig. 8). The tumor tends to grow around and displace normal anatomic structures, such as blood vessels or bowel.
Fig. 9. Retroperitoneal lymphoma. CT demonstrates retroperitoneal lymphadenopathy (arrows). Generalized stranding (arrowheads) is seen in the perirenal space as well as in the mesentery and subcutaneous tissue. The differential diagnosis includes malignant infiltration or congestion of lymphatic vessels.
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Fig. 10. Relapsed anaplastic large-cell testicular lymphoma. (A) US demonstrates a heterogeneous right testicle with scattered hypoechoic regions (arrow) and moderate hypervascularity. (B) Large heterogenous extratesticular hypervascular mass fills the right upper scrotal sac (arrowheads). (C) After treatment, there is a new thinwalled, septated, cystic intratesticular mass likely to be necrosis. T, testis.
infiltration. On CT, lymphomatous renal masses often demonstrate homogeneous attenuation, unlike the usually heterogeneous renal cell carcinoma. Renal lymphoma is usually hypoechoic on US, a finding that reflects tissue homogeneity. No correlation between the histologic type of lymphoma, the pattern of renal involvement, and imaging findings has been demonstrated [25,33,34]. A solitary mass
arising in the renal transplant pedicle, hilum, or pelvis and spreading into the adjacent renal parenchyma or perinephric space is highly suggestive of a PTLD (see Fig. 1).
Genitourinary system Testicular lymphoma constitutes 1% to 9% of all testicular tumors and 1% of NHL, and it is the most
Fig. 11. Diffuse large B-cell lymphoma of the uterus. The sagittal (A) and coronal (B) T2-weighted MRI scans reveal a large cervical mass (arrow in A and B), small masses in the myometrium (arrowheads in A), and additional tumor in the enlarged left ovary (small arrow in B). Surgery revealed additional infiltration of the left fallopian tube.
Diagnostic Imaging of Lymphoma
common testicular tumor in men older than the age of 60 years (Fig. 10). Unlike inflammation, testicular lymphoma is usually painless, the testes are not tender on palpation, and these findings limit the differential diagnosis. Testicular lymphoma is locally aggressive and can infiltrate the epidymis, spermatic cord, and scrotal skin. The lesions typically demonstrate increased blood flow and reveal infiltrative but nondestructive US features. Testicular lymphoma has a predilection for widespread dissemination to unusual sites, including the CNS, Waldeyer’s ring, skin, and lungs. Involvement of the bladder, uterus, ovaries, or especially the prostate is extremely rare [35]. Primary lymphoma of the cervix uteri arises from the cervical stroma rather than from the mucosa. Cytology is not a sensitive diagnostic tool, and deep cervical biopsies are required. Cervical lymphoma usually presents as a bulky mass with homogeneous enhancement (Fig. 11).
Central nervous system Primary CNS lymphoma represents 1% of all lymphomas and accounts for up to 16% of all brain tumors. Primary CNS lymphoma may arise from different parts of the brain, including the corpus callosum, cerebellum, orbits, and cranial nerves. Most lesions enhance homogeneously, but nonenhancing lesions are also encountered. Highly packed cells are thought to be responsible for the high attenuation of lesions in unenhanced CT. Most primary CNS lymphomas are of non-Hodgkin’s B-cell type, and the leptomeninges are also involved in 12% of cases [36,37]. In primary CNS lymphoma, it is useful to distinguish between presentations in immunocompetent and immunocompromised patients. Immunocompromised patients have a higher frequency of multiple lesions, which are often heterogeneous, with ring enhancement or irregular margins (Fig. 12). Most lesions in immunocompetent patients reveal homogeneous enhancement (Fig. 13). CT and MRI findings of intracranial lymphoma are nonspecific, and the definitive diagnosis requires histologic confirmation. The differential diagnosis includes other neoplasms, toxoplasmosis, tuberculosis, and sarcoidosis. Primary leptomeningeal lymphoma without additional solitary lesions is rare and represents less than 8% of all primary CNS lymphomas. Neuroimaging assessment is often unremarkable with nonspecific findings, such as hydrocephalus. Occasionally, meningeal calcifications, discrete densities, or faint meningeal enhancement may be seen. Proton density (PD) or fluid attenuation inversion recovery (FLAIR) sequences in MRI showing
Fig. 12. Primary large B-cell CNS lymphoma in an immunocompromised patient. Coronal T1-weighted MRI after administration of gadolinium reveals multifocal brain parenchymal enhancement, including the basal ganglia and the right caudate body (arrows). There is also extensive tumor-associated vasogenic edema (arrowheads) of the left hemisphere (which may be better appreciated on T2-weighted sequences, although they are not shown here).
the presence of high signal intensity in the subarachnoidal space may support the diagnosis of leptomeningeal lymphoma [36,37]. Neurolymphomatosis is an entity defined by infiltration of peripheral or cranial nerves (Fig. 14) and should not be confused with leptomeningeal
Fig. 13. Primary large B-cell CNS lymphoma in an immunocompetent patient. Coronal T1-weighted MRI scan after administration of gadolinium reveals patchy infiltrative enhancement within the body of the corpus callosum extending into bilateral frontal white matter. The lesion crosses the corpus callosum in a classic butterfly pattern (arrow).
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Fig. 15. Large-cell lymphoma with bone involvement. Axial MRI of the femur (short tau inversion recovery [STIR]) reveals an intramedullary tumor with a large circumferential soft tissue mass (arrow) in the left femur.
Fig. 14. Neurolymphomatosis. A patient with diffuse large B-cell lymphoma developed progressive arm and foot pain and weakness after completion of four cycles of chemotherapy. CT (A) and corresponding fluorodeoxyglucose (FDG) PET/CT (B) reveal thickening of the sacral (arrows in A) and brachial (not shown) nerves.
lymphoma. Neurolymphomatosis is a unique subtype, mainly of extranodal large B-cell NHL, which usually appears during or immediately after systemic chemotherapy. The clinical differential diagnosis includes herpes zoster, radiation- or chemotherapyassociated neuropathy, and lymphoma-associated vasculitis. Secondary cerebral lymphoma occurs in 10% to 15% of patients with NHL and is rare in HD. It has the tendency to involve the epidural, subdural, and subarachnoid spaces in the cerebellum and the epidural and subarachnoidal spaces in the spine. Extension through the intervertebral neural foramina and spinal cord compression are not uncommon. In these cases, the tumor compresses the dura, which acts as an effective barrier to further intrathecal spread of tumor, however [36,37].
Musculoskeletal system Bone and bone marrow involvement may occur in NHL and HD. A permeative metadiaphyseal lesion with periosteal reaction on plain radiographs and a soft tissue mass on MRI is highly suggestive of lymphoma, especially in a patient older than the age of 30 years. The wide spectrum of radiographic findings includes near–normal-appearing bone and
focal lytic or mixed sclerotic-lytic lesions. Cortical breakthrough, pathologic fractures, and soft tissue masses represent a more aggressive type of involvement and have a poorer prognosis. Periosteal reaction has been reported in approximately 60% of cases [38]. In HD, bony structures like the sternum or vertebrae may be infiltrated from adjacent soft tissue masses. The sclerotic ’’ivory vertebrae‘‘ with no abnormality of its contour or adjacent disks is a rare but classic finding [39]. Primary lymphoma of the bone is almost exclusively attributable to NHL, usually involving a single bone. MRI shows the extent of bone marrow and soft tissue invasion but is inferior to CT in predicting bone destruction. In successfully treated primary lymphoma of bone, MRI shows a rapid decrease in tumor volume with complete disappearance of the soft tissue component. Minor signal abnormalities of bone marrow may persist for up to 2 years [40]. Bone marrow infiltration may be the site of primary disease (stage IE) but occurs more often with disseminated disease (stage IV). It is rare at presentation in HD but is found in 20% to 40% of patients with newly diagnosed NHL. MRI is the most sensitive technique to demonstrate bone marrow involvement. On T1-weighted images, tumor infiltration is of low signal intensity. Depiction of bone marrow involvement might be useful to guide biopsy (Figs. 15 and 16) [38,39].
Summary Imaging plays a major role in the noninvasive assessment of patients with lymphoma. The diagnostic capabilities, characteristic patterns, and efficiency of various imaging modalities presently
Diagnostic Imaging of Lymphoma
Fig. 16. Primary NHL of the distal femur. The patient had chronic pain, nonspecific findings at radiography and MRI, and several nondiagnostic biopsies over a period of several years. (A) Radiographs performed 3 years before the diagnosis show a poorly defined area of patchy sclerosis (arrows) in the distal right femoral metaphysis. (B) MRI performed 3 months before a repeat biopsy established the diagnosis shows areas of low signal intensity (arrows) and prior biopsy canals (arrowhead). (C) MRI performed after treatment shows that the areas of low signal intensity have completely resolved. The biopsy canals are evident (arrowhead). (D) MRI 2 months after completion of treatment shows a new well-defined lesion (arrow) in the right distal femur.
used for the assessment of nodal and extranodal manifestations of HD and NHL, including CT, MRI, and US, have been discussed.
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[25] Metser U, Goor O, Lerman H, et al. PET-CT of extranodal lymphoma. AJR Am J Roentgenol 2004; 182:1579–86. [26] Catalano O, Sandomenico F, Matarazzo I, et al. Contrast-enhanced sonography of the spleen. AJR Am J Roentgenol 2005;184:1150–6. [27] Ahmad A, Govil Y, Frank BB. Gastric mucosaassociated lymphoid tissue lymphoma. Am J Gastroenterol 2003;98:975–86. [28] Kim YH, Lim HK, Han JK, et al. Low-grade gastric mucosa-associated lymphoid tissue lymphoma: correlation of radiographic and pathologic findings. Radiology 1999;212:241–8. [29] An SK, Han JK, Kim YH, et al. Gastric mucosaassociated lymphoid tissue lymphoma: spectrum of findings at double-contrast gastrointestinal examination with pathologic correlation. Radiographics 2001;21:1491–504. [30] Macari M, Balthazar EJ. CT of bowel wall thickening: significance and pitfalls of interpretation. AJR Am J Roentgenol 2001;176:1105–16. [31] Merkle EM, Bender GN, Brambs HJ. Imaging findings in pancreatic lymphoma: differential aspects. AJR Am J Roentgenol 2000;174:671–5. [32] Lucey BC, Stuhlfaut JW, Soto JA. Mesenteric lymph nodes seen at imaging: causes and significance. Radiographics 2005;25:351–65. [33] Urban BA, Fishman EK. Renal lymphoma: CT patterns with emphasis on helical CT. Radiographics 2000;20:197–212. [34] Chepuri NB, Strouse PJ, Yanik GA. CT of renal lymphoma in children. AJR Am J Roentgenol 2003;180:429–31. [35] Zicherman JM, Weissman D, Gribbin C, et al. Primary diffuse large B-cell lymphoma of the epididymis and testis. Radiographics 2005; 25:243–8. [36] Slone HW, Blake JJ, Shah R, et al. CT and MRI findings of intracranial lymphoma. AJR Am J Roentgenol 2005;184:1679–85. [37] Erdag N, Bhorade RM, Alberico RA, et al. Primary lymphoma of the central nervous system: typical and atypical CT and MR imaging appearances. AJR Am J Roentgenol 2001;176:1319–26. [38] Krishnan A, Shirkhoda A, Tehranzadeh J, et al. Primary bone lymphoma: radiographic-MR imaging correlation. Radiographics 2003;23: 1371–87. [39] Ochsner HC, Moser RH. Ivory vertebra. AJR Am J Roentgenol 1933;29:635–7. [40] Mengiardi B, Honegger H, Hodler J, et al. Primary lymphoma of bone: MRI and CT characteristics during and after successful treatment. AJR Am J Roentgenol 2005;184:185–92.
POSITRON EMISSION TOMOGRAPHY PET Clin 1 (2006) 219–230
Diagnostic Imaging Modalities for Assessment of Lymphoma with Special Emphasis on CT, MRI, and Ultrasound Ju¨rgen Rademaker, -
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Clinical features Hodgkin’s disease Non-Hodgkin’s lymphoma Immunocompromised patients Staging classification Imaging techniques Assessment of response to therapy Residual masses Spectrum of imaging findings Head and neck Head and sinonasal cavity Neck Thyroid Skin Thorax Breast Mediastinum
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This article reviews the clinical features of Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) and provides a short introduction to the staging system and radiologic evaluation of the response to treatment, all of which are important for the imaging evaluation of lymphoma. The second part of this article presents common imaging findings of the involvement of different organs.
Thymus Lung Pleural and pericardial disease Chest wall Abdomen and pelvis Liver Gallbladder and adrenal glands Spleen Gastrointestinal tract Pancreas Peritoneum, omentum, and retroperitoneum Kidneys Genitourinary system Central nervous system Musculoskeletal system Summary References
Clinical features HD and NHL may present as the involvement of one or multiple lymph node groups, of an isolated organ, or as widely disseminated disease. In general, there is a displacement of structures by enlarged lymph nodes but not invasion. This imaging feature distinguishes lymphoma from carcinoma. Only large-cell high-grade NHL may be
Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA E-mail address: [email protected] 1556-8598/06/$ – see front matter ª 2006 Elsevier Inc. All rights reserved.
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locally invasive. Although HD and NHL share similar radiologic features, there are some significant differences in their radiographic features.
Hodgkin’s disease In HD, the most common site of involvement is the cervical lymph nodes (60%–80%). Two thirds of patients with newly diagnosed HD have radiologic evidence of intrathoracic involvement. Isolated infradiaphragmatic lymphadenopathy occurs in less than 10% of patients at diagnosis. Nodular sclerosing HD may be associated with normal-sized or only moderately enlarged lymph nodes. HD spreads in a contiguous fashion from one lymph node group to the adjacent lymph nodes. Adjacent structures may be invaded like chest wall, lung, or bone. Extranodal involvement is less common in HD than in NHL.
Non-Hodgkin’s lymphoma In NHL, involved lymph nodes tend to be larger as compared with HD. Although commonly involving lymph node groups, involvement of extranodal sites is also fairly typical. This includes extranodal lymphatic tissue (eg, Waldeyer ring, Peyer patches, spleen) and nonlymphatic organs, such as the liver, bone marrow, bone, and central nervous system (CNS). The clinical and radiographic presentation of NHL is dependent on the histology. Low-grade lymphoma is often associated with large-volume nodal disease. Intermediate-grade lymphoma (includes follicular and diffuse forms) is often associated with rapidly enlarging lymph nodes and extranodal disease. High-grade lymphoma is the most aggressive subtype, but most patients have localized disease at the time of diagnosis.
Immunocompromised patients An increased incidence of NHL was identified in patients with HIV infection or secondary to organ transplantation. In particular, cyclosporine therapy may be associated with NHL or posttransplantation lymphoproliferative disorders (PTLD) (Fig. 1) [1,2]. Unlike lymphoma in the general population, immune deficiency–related lymphoma is often of extranodal origin, with the CNS, bone marrow, gastrointestinal tract (GIT), lung, and liver being the most common sites of disease [2–4].
Staging classification Treatment of lymphoma categorizes disease into early limited disease (stages I and II) when lymphadenopathy is confined to one or a few sites on one side of the diaphragm or an extranodal site, and advanced disease (stages III and IV) with widespread lymphadenopathy on both sides of the diaphragm
Fig. 1. Renal transplant and PTLD. Coronal T1weighted MRI scan of the pelvis reveals an intrarenal mass (arrow) and associated obstruction of the superior calyx (arrowhead). US performed 3 months before MRI depicted only early dilation of the superior calyx but showed no mass, probably because of the often encountered poor contrast between PTLD and the renal transplant. B, bladder.
or involvement of organs, such as the lung, liver, and bone marrow [5]. The initial Ann Arbour staging system for HD was established in 1970, and the introduction of CT and MRI led to the development of the revised Cotswolds classification in 1989. This classification is also applied to NHL, but is of less value, because the prognosis of NHL depends more on the histologic grade and parameters like bulky disease and specific organ involvement. Pediatric patients with NHL more often reveal extranodal involvement, such as that of the GIT or solid organs, and this was incorporated into the staging system of Murphy [7].
Imaging techniques Most clinical management decisions are currently based on either CT or PET, and CT is currently the most used imaging modality for the detection, staging, and follow-up of lymphoma. Nevertheless, other imaging modalities add important information. MRI is irreplaceable for the evaluation of meningeal or spinal cord involvement, infiltration of the bone marrow, and, to a lesser degree, evaluation of chest wall involvement. Although MRI and CT are equally effective in detecting focal brain lesions, it is probably easier to detect small lesions with MRI. MRI with out-of-phase images might help to differentiate unilateral or bilateral adrenal lymphoma from lipid-rich adenoma. The accuracy of MRI in detecting lymph node involvement is similar to that of CT, with most centers preferentially
Diagnostic Imaging of Lymphoma
using CT for a variety of reasons, including costs and availability. Ultrasound (US) is useful for the evaluation of the genitourinary tract, including possible testicular involvement, and for the evaluation of superficial lymph nodes. US-guided biopsies of focal lesions, for example, in the liver and spleen, are useful for tissue sampling [8]. US is also useful for the initial evaluation of symptoms in the abdomen (eg, gallbladder, kidney). Plain films remain important for the evaluation of lymphoma-associated complications, such as pleural effusion, fractures, osteolytic lesions, or small bowel obstruction. Lymphography does not significantly contribute to staging. Some authors consider lymphangiography and CT as complementary [9], but significant disadvantages of lymphangiography include not only a decline in the availability of technical expertise and experience in interpreting the images but the inability to demonstrate lymph nodes in the upper abdomen and outside the retroperitoneum and to assess the true extent of extranodal extension. In addition, the use of a combination of chemotherapy and radiation therapy has increased, diminishing the need for detecting subtle nodal changes [10].
Assessment of response to therapy Patients require routine follow-up to assess tumor shrinkage in response to therapy and to decide on treatment modification if required. Measurements of lesions should be bidimensional (biperpendicular measurement in the axial plane, longest axial dimension X perpendicular dimension). Most of these measurements are relatively easy but might be difficult in cases of irregular edges or rare infiltrating lesions. Pulmonary lymphatic spread or peritoneal infiltrations are difficult to measure, and there is no true consensus on whether necrosis or cystic changes should be included in the measurements [11]. The Cotswold meeting and the National Cancer Institute (NCI) International Working Group defined criteria for response in HD and NHL [6,12,13]. Recommendations of these two consensus meetings include separate definitions for complete remission, partial response, and progressive disease in both diseases. For example, in HD, progressive disease implies a 25% increase in the size of at least one measurable lesion. In NHL, the criteria are more detailed and progressive disease includes the appearance of new lesions or an increase of more than 50% in known lesions. An increase of more than 50% in the greatest diameter of any previously identified node that was greater than 1 cm also represents progressive disease in NHL [6]. For NHL, there is the additional definition
of ‘‘stable disease, ’’ which is less than partial response but not progressive disease.
Residual masses Residual masses seen on CT or MRI after treatment represent a mixture of fibrosis and necrotic tumor in most patients but may sometimes represent viable tumor. The size of residual abnormalities may vary between subcentimeter lesions and much larger residual masses. Depending on the criteria used for their definition, residual masses occur in up to 50% to 70% of patients treated for HD and in up to 20% to 40% of patients with NHL after treatment. In the author’s experience, neither the initial size of the mass nor the size of the residual mass after treatment correlates with the rate of disease relapse. Recurrence may occur within the residual mass as well as outside it in new sites. Residual masses in the chest are not unusual in HD, whereas residual abdominal masses are seen mainly in NHL, especially large-cell subtypes. Serial CT, initially performed at 2- to 3-month intervals, is the most widely used method for following residual masses.
Spectrum of imaging findings Lymphoma can affect any region of the body, and the following sections summarize the most common and important imaging findings of different organs and anatomic regions.
Head and neck Head and sinonasal cavity Extranodal involvement of the region of the head and neck is rare. Waldeyer’s ring is the most common site of head and neck lymphoma. Paranasal sinus involvement often spreads in a contiguous fashion. Parotid gland involvement is the most frequent site of involvement in the salivary glands and is best evaluated by MRI and US.
Neck Lymph nodes greater than 1 cm in diameter are generally considered enlarged and suspicious for disease involvement on CT. Although calcified lymph nodes are rare before therapy (1%), diseased lymph nodes in the neck and at other locations may show irregular calcifications after treatment. Calcifications before treatment occur more often in the mediastinum in patients with NHL and in patients with aggressive HD, such as the nodular sclerosing subtype (Fig. 2) [14].
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Fig. 2. Enlarged lymph nodes in chronic lymphocytic leukemia. PET revealed low-grade fluorodeoxyglucose (FDG) activity with standard uptake values (SUVs) between 2 and 3.6 in most nodes. A CT scan from the PET/CT study reveals four enlarged nodes in the neck (arrows) with coarse calcifications (arrowheads). These particular nodes had SUVs between 8.6 and 10.4 measured on the PET component of the study. A biopsy revealed new nodular sclerosing HD.
Thyroid Primary HD of the thyroid is extremely rare, with only a few sporadic cases having been reported. Secondary involvement occurs in 2% of cases [15]. Most cases of thyroid NHL arise in the background of Hashimoto’s thyroiditis. Involvement of the thyroid might present as diffuse enlargement or as a focal lesion. Fine-needle aspiration is required to establish the diagnosis (Fig. 3).
Fig. 3. Lymphoma involving the thyroid. Initial CT shows a normal-sized thyroid (A), whereas repeat CT performed 3 months later (B) shows significant enlargement of the thyroid. These nonspecific findings may also be seen in thyroiditis. (A) Small nodule is also seen in the right lobe of the thyroid.
the breast. Diagnosis of primary breast lymphoma is based on the exclusion of concurrent lymphoma (with the exception of ipsilateral axillary nodes). Mammographic features of NHL include solitary uncalcified (69%) or multiple (9%) masses or a diffusely increased opacity with skin thickening (9%) (Fig. 4) [19–21].
Skin Cutaneous lesions, including plaques or erythroderma, show no abnormalities on CT. In the stage of tumor formation, thickening of the skin or the presence of cutaneous nodules may be found. These imaging features are nonspecific. The differential diagnosis includes inflammatory panniculitis, cutaneous metastases from melanoma or breast cancer, or subcutaneus nodules of infectious origin (eg, fungal infection) [16,17].
Thorax
Mediastinum More than 80% of patients with HD present with intrathoracic involvement. Lymph nodes in the anterior mediastinum are suspicious, even if they are smaller than 1 cm in diameter. Minimal enlargement of internal mammary or diaphragmatic lymph nodes can be easily overlooked on CT. Diagnosis of lymphomatous involvement of these nodal groups can affect radiation therapy planning, and recurrent disease is common in internal mammary and pericardial lymph nodes, particularly when they are not included in the radiation field [22].
Breast Breast lymphoma accounts for approximately 0.15% of all malignant breast tumors [18]. Less than 0.5% of all malignant lymphomas and approximately 2% of extranodal lymphomas involve
Thymus Current staging considers the thymus as a nodal site. It is often impossible to distinguish the enlarged thymus on CT or MRI from adjacent
Diagnostic Imaging of Lymphoma
or without cavitation), reticular nodular infiltrates, or irregular consolidations have been described as potential patterns in HD and NHL. For correct staging, it is important to distinguish between contiguous extension of disease into the lungs from adjacent sites of lymphoma and parenchymal involvement. Primary pulmonary lymphoma is rare and is encountered with NHL. Most primary lymphomas of the lung represent mucosa-associated lymphoid tissue (MALT) lymphoma [23,24]. Peripheral consolidations without visible connection to hilar nodes may occur in HD and NHL. Recurrences in the lung may be seen in the absence of associated lymphadenopathy (Fig. 5).
Pleural and pericardial disease Fig. 4. Lymphoma of the left breast. MRI (subtraction maximum intensity projection [MIP]) after administration of gadolinium shows a large heterogeneous mass measuring at least 8.7 cm with persistent delayed enhancement (arrow). The previously described MRI appearance of breast lymphoma includes ill-defined masses with rapid and strong enhancement in dynamic sequences. Rim enhancement may also be observed. Veins (arrowhead ).
lymphadenopathy. In adult patients, the thymus is enlarged if the largest diameter is larger than 15 mm. Between 30% and 50% of patients with HD have thymic enlargement at presentation. Current imaging techniques like CT or MRI fail to differentiate between enlargement of the thymus and actual involvement of the thymus. Thymic cysts may occur in HD at initial presentation as well as after therapy, and they may persist or enlarge, but these changes do not indicate residual or recurrent disease or an increased risk of relapse. If hemorrhage occurs, the thymus may undergo calcification [13]. Posttherapeutic enlargement of the thymus may represent recurrent disease, thymic rebound (hyperplastic thymus), or development of thymic cysts. Thymic hyperplasia is usually triangular in shape and may be seen for several months after the completion of treatment, whereas an infiltrated thymus is often quadrilateral in shape. If the thymus was not the original site of disease, posttherapeutic thymic enlargement should be related to hyperplasia rather than to tumor infiltration [13,15].
Pleural effusions are usually associated with mediastinal lymph nodes and, occasionally, with pulmonary involvement. Effusions result from venous or lymphatic obstruction by enlarged lymph nodes rather than from direct lymphomatous involvement. Most effusions are unilateral exudates. Although pleural effusions associated with HD only rarely have positive findings on cytology, this is more common with effusions in NHL. Focal pleural masses are rare but represent an often overlooked location of lymphoma [25]. Pericardial effusions, by contrast, are presumed to represent lymphomatous invasion of the pericardium. They may arise from lymphatic or hematogenous spread or from direct extension of mediastinal lymphoma.
Chest wall Chest wall involvement is not uncommon and may represent an initial manifestation of disease or a site of recurrence (Fig. 6).
Lung Pulmonary parenchymal involvement is more common with HD than with NHL. The lungs are more frequently involved in secondary or recurrent disease than in primary lymphoma. Involvement of the lung is commonly due to direct extension from hilar and mediastinal adenopathy. Nodules (with
Fig. 5. Pulmonary lymphoma. CT reveals mass-like lesions (arrow) in the right lower lung and hazy ground-glass opacities (arrowhead) in an asymptomatic patient with follicular NHL.
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Fig. 6. Lymphoma involving the chest wall. CT shows a mass (arrowheads) extending from the spine to the lateral aspect of the left chest wall. This represents advanced disease and requires chemotherapy. Radiotherapy is only used if it is possible to cover the complete lymphatic station and in this case it would not be possible to cover the complete leftsided pleura with radiotherapy.
Abdomen and pelvis Liver Large focal lesions are seen in only 5% to 10% of patients with hepatic involvement of lymphoma and have similar imaging features to metastatic disease. Despite advances in imaging techniques, the sensitivity of US, CT, or MRI for the detection of diffuse hepatic disease remains low. Hepatomegaly is highly suggestive of disease infiltration, mainly in patients with NHL. In pediatric patients as well as in adult patients, periportal low-density soft tissue infiltration is a more subtle CT or MRI finding and should not be overlooked.
Gallbladder and adrenal glands The CT and sonographic features of lymphoma of the gallbladder are different from the sonographic features of cholecystitis. In lymphoma, there is usually homogeneous thickening of the gallbladder wall without a hypoechoic edematous middle layer within the gallbladder wall (eg, no ’’halo sign‘‘) (Fig. 7). Adrenal involvement is often (50%) bilateral.
Fig. 7. Gallbladder T-cell lymphoma. (A) US shows hyperechoic thickening of the gallbladder wall (arrows). (B) CT reveals homogeneous thickening and enhancement of the gallbladder wall (arrow) and ascites.
spleen is difficult to detect with US, CT, and MRI. Marked splenomegaly or splenic hilar lymphadenopathy suggests splenic infiltration. Splenic infarctions, which may occur in association with lymphoma, display mass-like features on CT and MRI but have a characteristic wedge shape and peripheral location. Contrast-enhanced US may improve the detectability of splenic abnormalities [26]. Failure to detect splenic involvement is not associated with significantly poorer patient outcome, because relapse caused by untreated splenic infiltration can be easily treated with multiagent chemotherapy. More centers are now using imaging-guided needle biopsies of splenic lesions for tissue sampling and the procedure is often ultrasound-guided. Subcapsular or intraperitoneal hemorrhage occurs in 8% of these biopsies [8].
Gastrointestinal tract Spleen The spleen is frequently involved in lymphoma, and focal nodules are the most common pattern of involvement. The size of the spleen is not an indicator of disease, because diffuse infiltration may be present in spleens of normal size and reactive splenomegaly may often occur in the absence of lymphoma deposits. Diffuse involvement of the
The GIT is the most common site of primary extranodal lymphoma, most commonly NHL of B-cell origin. HD involving the GIT is extremely rare. The stomach is the most commonly involved organ (50%) in primary and secondary lymphoma, followed by the small bowel (33%). Primary gastric lymphoma accounts for 1% to 5% of all malignant disorders of the stomach, with most cases being
Diagnostic Imaging of Lymphoma
B-cell NHL, including low-grade MALT lymphoma, which is associated with Helicobacter pylori infection [27]. Gastric lymphoma may present with three predominant growth patterns on CT and US: nodular, carcinoma-like ulcerative lesions, and infiltrating tumor masses that frequently invade the adjacent mesentery and lymph nodes. Radiographic findings observed in low-grade gastric lymphoma are similar to those in gastric carcinoma or gastritis. Common findings at upper gastrointestinal examination include mucosal nodularity, ulcer, rugal thickening, and masses. Disorganized convergent rugae, vague ulcer margins, and multiplicity of lesions may be helpful in differentiating gastric lymphoma from carcinoma or gastritis [28,29]. CT is useful to assess the presence of lymph nodes above and below the diaphragm, but it has a relatively low sensitivity for detection of perigastric nodes. Endoscopic US has established itself as the procedure of choice for the staging of gastric lymphoma [27]. Lymphoma represents 50% of all primary tumors of the small bowel, occurring most frequently in the terminal ileum. Small-bowel lymphoma is often depicted on CT as a segmental area of circumferential thickening with homogeneous attenuation and enhancement [30]. Disease is often multifocal, and intussusception, predominantly in the terminal ileum, is a classic mode of presentation.
Pancreas Secondary involvement of the pancreas occurs in more than 30% of patients with NHL. Secondary pancreatic involvement is most likely attributable to direct infiltration from adjacent lymphadenopathy. In HIV patients, the GIT is most commonly affected by extranodal NHL, and a significant number of primary manifestations (5%) arise in the pancreas. In patients with primary pancreatic lymphoma, a rare manifestation, pancreatic ductal dilation may be absent, even with ductal invasion [31]. Diffuse infiltration of the pancreas without signs of pancreatitis is also suspicious for pancreatic lymphoma [31].
Fig. 8. Abdominal lymphoma. CT shows a homogeneous mass (arrow) formed by a conglomerate of mesenteric and retroperitoneal lymphadenopathy. The mass surrounds but does not occlude the mesenteric vessels (arrowhead).
Adjacent anatomic spaces are often affected because of the continuous spread of the disease (Fig. 9) [32]. Primary lymphoma of the peritoneum has an increased incidence in AIDS patients. These masses may be extremely hypoechoic on US and can be mistaken for fluid collections.
Kidneys NHL may often involve the kidneys, whereas renal involvement with HD is rare and represents advanced or recurrent disease in most cases. Patterns of renal involvement with lymphoma include multiple or solitary masses, renal invasion from retroperitoneal disease, perirenal disease, and diffuse
Peritoneum, omentum, and retroperitoneum Lymphoma is the most common malignancy resulting in mesenteric lymphadenopathy. Mesenteric or peritoneal infiltration by lymphoma is seen almost exclusively in NHL. Imaging findings may mimic peritoneal carcinomatosis, with peritoneal nodules, ascites, and mesenteric infiltration. Early in the course of the disease, lymph nodes may be small. As the disease progresses, the nodes may form conglomerates and soft tissue masses (Fig. 8). The tumor tends to grow around and displace normal anatomic structures, such as blood vessels or bowel.
Fig. 9. Retroperitoneal lymphoma. CT demonstrates retroperitoneal lymphadenopathy (arrows). Generalized stranding (arrowheads) is seen in the perirenal space as well as in the mesentery and subcutaneous tissue. The differential diagnosis includes malignant infiltration or congestion of lymphatic vessels.
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Fig. 10. Relapsed anaplastic large-cell testicular lymphoma. (A) US demonstrates a heterogeneous right testicle with scattered hypoechoic regions (arrow) and moderate hypervascularity. (B) Large heterogenous extratesticular hypervascular mass fills the right upper scrotal sac (arrowheads). (C) After treatment, there is a new thinwalled, septated, cystic intratesticular mass likely to be necrosis. T, testis.
infiltration. On CT, lymphomatous renal masses often demonstrate homogeneous attenuation, unlike the usually heterogeneous renal cell carcinoma. Renal lymphoma is usually hypoechoic on US, a finding that reflects tissue homogeneity. No correlation between the histologic type of lymphoma, the pattern of renal involvement, and imaging findings has been demonstrated [25,33,34]. A solitary mass
arising in the renal transplant pedicle, hilum, or pelvis and spreading into the adjacent renal parenchyma or perinephric space is highly suggestive of a PTLD (see Fig. 1).
Genitourinary system Testicular lymphoma constitutes 1% to 9% of all testicular tumors and 1% of NHL, and it is the most
Fig. 11. Diffuse large B-cell lymphoma of the uterus. The sagittal (A) and coronal (B) T2-weighted MRI scans reveal a large cervical mass (arrow in A and B), small masses in the myometrium (arrowheads in A), and additional tumor in the enlarged left ovary (small arrow in B). Surgery revealed additional infiltration of the left fallopian tube.
Diagnostic Imaging of Lymphoma
common testicular tumor in men older than the age of 60 years (Fig. 10). Unlike inflammation, testicular lymphoma is usually painless, the testes are not tender on palpation, and these findings limit the differential diagnosis. Testicular lymphoma is locally aggressive and can infiltrate the epidymis, spermatic cord, and scrotal skin. The lesions typically demonstrate increased blood flow and reveal infiltrative but nondestructive US features. Testicular lymphoma has a predilection for widespread dissemination to unusual sites, including the CNS, Waldeyer’s ring, skin, and lungs. Involvement of the bladder, uterus, ovaries, or especially the prostate is extremely rare [35]. Primary lymphoma of the cervix uteri arises from the cervical stroma rather than from the mucosa. Cytology is not a sensitive diagnostic tool, and deep cervical biopsies are required. Cervical lymphoma usually presents as a bulky mass with homogeneous enhancement (Fig. 11).
Central nervous system Primary CNS lymphoma represents 1% of all lymphomas and accounts for up to 16% of all brain tumors. Primary CNS lymphoma may arise from different parts of the brain, including the corpus callosum, cerebellum, orbits, and cranial nerves. Most lesions enhance homogeneously, but nonenhancing lesions are also encountered. Highly packed cells are thought to be responsible for the high attenuation of lesions in unenhanced CT. Most primary CNS lymphomas are of non-Hodgkin’s B-cell type, and the leptomeninges are also involved in 12% of cases [36,37]. In primary CNS lymphoma, it is useful to distinguish between presentations in immunocompetent and immunocompromised patients. Immunocompromised patients have a higher frequency of multiple lesions, which are often heterogeneous, with ring enhancement or irregular margins (Fig. 12). Most lesions in immunocompetent patients reveal homogeneous enhancement (Fig. 13). CT and MRI findings of intracranial lymphoma are nonspecific, and the definitive diagnosis requires histologic confirmation. The differential diagnosis includes other neoplasms, toxoplasmosis, tuberculosis, and sarcoidosis. Primary leptomeningeal lymphoma without additional solitary lesions is rare and represents less than 8% of all primary CNS lymphomas. Neuroimaging assessment is often unremarkable with nonspecific findings, such as hydrocephalus. Occasionally, meningeal calcifications, discrete densities, or faint meningeal enhancement may be seen. Proton density (PD) or fluid attenuation inversion recovery (FLAIR) sequences in MRI showing
Fig. 12. Primary large B-cell CNS lymphoma in an immunocompromised patient. Coronal T1-weighted MRI after administration of gadolinium reveals multifocal brain parenchymal enhancement, including the basal ganglia and the right caudate body (arrows). There is also extensive tumor-associated vasogenic edema (arrowheads) of the left hemisphere (which may be better appreciated on T2-weighted sequences, although they are not shown here).
the presence of high signal intensity in the subarachnoidal space may support the diagnosis of leptomeningeal lymphoma [36,37]. Neurolymphomatosis is an entity defined by infiltration of peripheral or cranial nerves (Fig. 14) and should not be confused with leptomeningeal
Fig. 13. Primary large B-cell CNS lymphoma in an immunocompetent patient. Coronal T1-weighted MRI scan after administration of gadolinium reveals patchy infiltrative enhancement within the body of the corpus callosum extending into bilateral frontal white matter. The lesion crosses the corpus callosum in a classic butterfly pattern (arrow).
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Fig. 15. Large-cell lymphoma with bone involvement. Axial MRI of the femur (short tau inversion recovery [STIR]) reveals an intramedullary tumor with a large circumferential soft tissue mass (arrow) in the left femur.
Fig. 14. Neurolymphomatosis. A patient with diffuse large B-cell lymphoma developed progressive arm and foot pain and weakness after completion of four cycles of chemotherapy. CT (A) and corresponding fluorodeoxyglucose (FDG) PET/CT (B) reveal thickening of the sacral (arrows in A) and brachial (not shown) nerves.
lymphoma. Neurolymphomatosis is a unique subtype, mainly of extranodal large B-cell NHL, which usually appears during or immediately after systemic chemotherapy. The clinical differential diagnosis includes herpes zoster, radiation- or chemotherapyassociated neuropathy, and lymphoma-associated vasculitis. Secondary cerebral lymphoma occurs in 10% to 15% of patients with NHL and is rare in HD. It has the tendency to involve the epidural, subdural, and subarachnoid spaces in the cerebellum and the epidural and subarachnoidal spaces in the spine. Extension through the intervertebral neural foramina and spinal cord compression are not uncommon. In these cases, the tumor compresses the dura, which acts as an effective barrier to further intrathecal spread of tumor, however [36,37].
Musculoskeletal system Bone and bone marrow involvement may occur in NHL and HD. A permeative metadiaphyseal lesion with periosteal reaction on plain radiographs and a soft tissue mass on MRI is highly suggestive of lymphoma, especially in a patient older than the age of 30 years. The wide spectrum of radiographic findings includes near–normal-appearing bone and
focal lytic or mixed sclerotic-lytic lesions. Cortical breakthrough, pathologic fractures, and soft tissue masses represent a more aggressive type of involvement and have a poorer prognosis. Periosteal reaction has been reported in approximately 60% of cases [38]. In HD, bony structures like the sternum or vertebrae may be infiltrated from adjacent soft tissue masses. The sclerotic ’’ivory vertebrae‘‘ with no abnormality of its contour or adjacent disks is a rare but classic finding [39]. Primary lymphoma of the bone is almost exclusively attributable to NHL, usually involving a single bone. MRI shows the extent of bone marrow and soft tissue invasion but is inferior to CT in predicting bone destruction. In successfully treated primary lymphoma of bone, MRI shows a rapid decrease in tumor volume with complete disappearance of the soft tissue component. Minor signal abnormalities of bone marrow may persist for up to 2 years [40]. Bone marrow infiltration may be the site of primary disease (stage IE) but occurs more often with disseminated disease (stage IV). It is rare at presentation in HD but is found in 20% to 40% of patients with newly diagnosed NHL. MRI is the most sensitive technique to demonstrate bone marrow involvement. On T1-weighted images, tumor infiltration is of low signal intensity. Depiction of bone marrow involvement might be useful to guide biopsy (Figs. 15 and 16) [38,39].
Summary Imaging plays a major role in the noninvasive assessment of patients with lymphoma. The diagnostic capabilities, characteristic patterns, and efficiency of various imaging modalities presently
Diagnostic Imaging of Lymphoma
Fig. 16. Primary NHL of the distal femur. The patient had chronic pain, nonspecific findings at radiography and MRI, and several nondiagnostic biopsies over a period of several years. (A) Radiographs performed 3 years before the diagnosis show a poorly defined area of patchy sclerosis (arrows) in the distal right femoral metaphysis. (B) MRI performed 3 months before a repeat biopsy established the diagnosis shows areas of low signal intensity (arrows) and prior biopsy canals (arrowhead). (C) MRI performed after treatment shows that the areas of low signal intensity have completely resolved. The biopsy canals are evident (arrowhead). (D) MRI 2 months after completion of treatment shows a new well-defined lesion (arrow) in the right distal femur.
used for the assessment of nodal and extranodal manifestations of HD and NHL, including CT, MRI, and US, have been discussed.
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