Computed Tomography in the Management of Hodgkin’s Disease and Non-Hodgkin’s Lymphoma

Positron Emission Tomography/Computed Tomography in the Management of Hodgkin’s Disease and Non-Hodgkin’s Lymphoma Beatriz Rodríguez-Vigil, MD,a Nieves Gómez-León, MD, PhD,a Inmaculada Pinilla, MD, PhD,a Dolores Hernández-Maraver, MD,b Juan Coya, MD,c and Luis Martín-Curto, MD, PhDc

The incidence of Hodgkin’s disease (HD) and NonHodgkin’s lymphoma (NHL) is around 8% of all malignancies. Fortunately, HD and NHL are among the few malignancies that are potentially curable with current existing treatment modalities, even in advanced or recurrent disease. Accurate staging, early therapy monitoring, and posttreatment evaluation of lymphomas are important for optimum management of these patients. We reviewed the imaging findings of patients with histologically proved lymphoma who underwent staging positron emission tomography/computed tomography (PET/CT), early monitoring therapy PET/CT (after 3 cycles of chemotherapy), and posttreatment PET/CT. PET/CT imaging findings are shown. Utility of PET/CT in recognizing false-positive and falsenegative cases of CT and PET alone is addressed. Pitfalls and diagnostic difficulties are analyzed. PET/CT is a new imaging technology that improves the evaluation of lymphoma. This review will help the reader to better understand the imaging findings and applications of PET/CT in the management of lymphoma.

Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) are lymphoproliferative malignant neoplasms with an incidence of less than 8% of all malignancies, but that has been rising by 3 to 5% per year in the last years.1 Fortunately, these malignancies

From the aDepartment of Radiology, University hospital “La Paz”, Madrid, Spain; bDepartment of Haematology, University hospital “La Paz”, Madrid, Spain; and cDepartment of Nuclear Medicine, University hospital “La Paz”, Madrid, Spain Reprint requests: Beatriz Rodríguez-Vigil, MD, Department of Radiology, University hospital “La Paz”, Paseo de la Castellana, 261, 28046 Madrid, Spain. E-mail: [email protected]. Curr Probl Diagn Radiol 2006;35:151-63. © 2006 Mosby, Inc. All rights reserved. 0363-0188/2006/$32.00 ⫹ 0 doi:10.1067/j.cpradiol.2006.02.001

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are potentially curable with current treatment modalities, even in advanced or recurrent disease. Prognosis and survival of patients with lymphoma depend on three key points: histological grade and clinical stage, determined at the moment of diagnosis, and response to treatment.2 Hence, precise staging, accurate monitoring of therapy, and early detection of relapse are important for the proper selection of therapy and for predicting prognosis. The ultimate aim of the oncologist is to improve the management of patients with lymphoma by identifying equally those patients who can be cured with minimal treatment and those in whom conventional treatment is doomed to failure and in whom more intensive strategies should be employed from the outset.

Computed Tomography (CT) or Positron Emission Tomography (PET)? CT has been the main imaging technique used for staging and follow-up of patients with lymphoma. Its sensitivity in evaluating nodal and extranodal disease ranges between 60 and 90%.3 CT criteria to assess disease are based on abnormal anatomy and abnormal contrast enhancement (Table 1). These criteria imply limitations in depiction of pathologic changes, which result in a reduced sensitivity of lesion detection (Table 2). PET with 2-deoxy-2-fluorine-18-fluoro-D-glucose (18FDG) provides functional information, because it detects elevated glucose metabolism in cells with malignant transformation. The main drawback of PET is that it provides only a small number of anatomic landmarks, which impedes precise location of lesions

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TABLE 1. CT criteria for malignancy in lymphomas Abnormal lymph nodes Cervical and thoracic (⬎10 mm) Organomegaly Abnormal mass or structural changes in a normal-sized organ Abnormal contrast enhancement

Abdominal (⬎5 mm)

Pelvic (⬎10 mm)

Inguinal (⬎15 mm)

TABLE 2. Limitations of CT in evaluation of lymphomas 1. 2. 3. 4.

Depiction of pathologic changes in normal-sized structures Lesions without good contrast with the surrounding tissues Sites of extranodal disease, such as bone marrow Tumoral cells activity within a posttreatment residual mass

TABLE 3. Limitations of PET in evaluation of lymphomas 1. 2. 3. 4.

Absence of precise anatomic landmarks Physiologic uptake Nontumoral pathologic uptake Lymphomas without uptake or with low 18FDG uptake

with pathologic 18FDG uptake. In addition, there are some issues regarding specificity, because 18FDG is not only taken by many malignant tumors but also by sites of active inflammation and physiologically by some organs (Table 3). FIG 1. Steps in the management of lymphomas with PET/CT. (Color version of figure is available online.)

PET/CT PET/CT is a scanner that precisely coregisters functional and anatomic images by performing a PET study and a CT on the same scanner without moving the patient. It consists of a PET/CT in-line system that combines a PET scanner with multi-detector-row helical CT scanner in one system.4,5 The axes of both systems are mechanically aligned to coincide perfectly and allow for hardware image coregistration of the same patient in one session. Some studies have demonstrated the usefulness of PET/CT compared with that of PET or CT alone in the diagnosis of different tumors, as well as in the management of lymphomas.6-13 At our institution, patients with biopsy-proved and untreated lymphoma, and without a previous CT, have undergone PET/CT examinations for initial staging, early treatment response (after three or four chemotherapy cycles), restaging after treatment completion (six or eight cycles), and post-treatment reevaluations.

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Scanning Protocol Patient Preparation The patient is required to fast for at least 4 hours before PET/CT, to permit the tumor’s 18FDG uptake and minimize cardiac uptake.14 After this, glucose level is measured. If the glycemia is over 150 mg/dL, the study is postponed until the glucose level goes down, because the uptake of 18FDG into cells is competitively inhibited by glucose, as both of them use a common transport mechanism (glucose transporters).14 The next step is to inject 18FDG intravenously, typically a dose of 10 to 15 mCi (370 to 555 MBq), 45 to 60 minutes before the scanning. The patient’s activity and speech are limited from immediately following injection of the radioisotope to the acquisition of data, to minimize physiologic uptake by muscles of the pharynx, larynx, ocular globe, and skeleton, although with the anatomic correlation provided by CT, this physiological uptake is easily

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TABLE 4. Ann Arbor classification with Costwolds’ modification Stage I Stage II Stage III III1 III2 Stage IV A B X E

Involvement of a single lymph node region of lymphoid structure Involvement of two or more lymph node regions on the same side of the diaphragm (the mediastinum is considered as a single site, whereas hilar lymph nodes are considered bilaterally), number of anatomic sites should be indicated by a subscript (eg, II3) Involvement of lymph node regions or structures on both sides of the diaphragm With or without involvement of the spleen, splenic, hilar, celiac, or portal nodes With involvement of paraaortic, iliac, and mesenteric nodes Involvement of one of more extranodal sites in addition to a site for which the designation E has been used Designations applicable to any disease stage No symptoms Fever ⬎38°C, drenching night sweats, unexplained loss of ⬎10% body weight within the preceding 6 months Bulky disease (widening of the mediastinum by more than one-third or the presence of a nodal mass with a maximal dimension of ⬎10 cm) Involvement of a single extranodal site that is contiguous or proximal to the known nodal site

localized and differentiated from pathological uptake on the PET/CT fused images. An oral contrast agent (1800 mL, Gastrographin, 3%) is administered orally during the uptake time of the radiotracer, and another 200 mL to distend the stomach immediately before the patient is transferred onto the PET/CT table.

Patient Position An important aspect of PET/CT imaging is the position of the patient, who must lie in the supine position with the arms raised above the head to reduce beam-hardening artifacts in the thorax and abdomen on the fused PET/CT images.15,16 The overall radiation exposure to the subject would need to be increased if the arms are left next to the patient’s body.16,17 However, arms to the side is an alternative if necessary.

Data Acquisition The CT study begins with the acquisition of a scout scan, from the base of the skull to the upper thigh. This scout scan is then used to plan the PET study with four to six bed positions depending on the height of the patient, which will cover the same axial examination range as the CT. After this, the image acquisition begins: the helical CT is performed with the patient breathing quietly, in a craniocaudal direction. Initially, a low-dose CT to correct attenuation is performed, which takes approximately 30 seconds. Immediately after the CT acquisition, the PET emission images are obtained starting with the upper thigh and pelvis in a caudocranial direction, to avoid the repletion of the urinary bladder by 18FDG and to avoid difficulties in evaluating pathological uptake.

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Each table position lasts 4 minutes, and the whole PET study takes between 16 and 24 minutes. Finally, another CT study is performed, in this case used as a diagnostic CT, if the patient did not have a previous one, with automatic current (at a maximum of 300 mA) and following injection of 140 mL of a low-osmolarity iodinated contrast medium with a scan delay of 45 seconds. PET, CT, and PET/CT image interpretation is performed in a workstation equipped with fusion software that enables multiplanar reconstruction.

Controversy about Imaging Protocol On the basis of the literature, we appreciate that using CT contrast agents in PET/CT imaging is still subject to controversy. However, the standard-of-care CT scan generally dictates the use of either intravenous or oral contrast, or both as in the case of lymphoma studies, as well as the use of diagnostic current dose, to provide a high-quality diagnostic CT study. The first prototype PET/CT scanner was built in 1998, installed at the University of Pittsburgh Medical Center, and used until August 2001, when it was replaced with a commercial PET/CT scanner.4,5,18 The original thought was that CT would just be an enhancement for attenuation correction, providing accuracy in lesion location and reducing acquisition times.19 Currently, some authors believe that CT image data should be used only for attenuation correction of PET and for locating hypermetabolic lesions, whereas others advocate the need of performing contrast and high-resolution CT to have diagnosticquality CT scans at the same session.19-21 Thus, some

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FIG 2. Initial staging PET/CT scan in a 43-year-old woman with NHL who had negative bilateral posterior iliac crest bone marrow biopsy. (A) Coronal CT, PET, and PET/CT show mediastinal and mesenteric adenopathy, and a focal uptake in the 5th lumbar vertebra. (B) Axial PET shows uptake of L5 (arrowhead). (C) CT demonstrates a subtle sclerosis of part of the vertebral body (arrows). It is uncertain whether it represents lymphomatous involvement. (D) PET/CT clearly depicts focal bone marrow involvement and results in upstaging (stage III to stage IV). This lesion disappeared after chemotherapy. (Color version of figure is available online.)

authors begin the PET/CT study with the acquisition of contrast-enhanced and full-dose diagnostic CT and secondarily acquire PET images covering the same axial extent, using the CT data for both attenuation correction and fused PET/CT images.18,19,22,23 Others prefer to perform two CT scans, a low- or intermediate-dose, unenhanced CT for attenuation correction and, a diagnostic IV-contrast-enhanced CT if required, subsequently performed at the end of the study.16,19 It has been referred in the literature that IV contrast produces regions of high density on CT that may lead

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to artifactual hot spots in the attenuation corrected image or to quantitative overestimation of 18FDG activity if they are applied as transmission images.15,24 Nevertheless, recent results22,25 have shown that the presence of IV contrast at normal concentrations actually has little effect on the CT-based attenuation correction factors. Some studies have also shown a small effect of oral contrast on the SUV and its clinically insignificant effect.26,27 Various scanning PET/CT protocols must be further studied to achieve the most convenient and standardized protocol.

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FIG 3. Seventy-nine-year-old woman with NHL referred for initial staging. (A) CT of the upper abdomen shows no pathologic findings. (B) PET at the same level shows focal uptake next to the left hepatic lobe, but the precise location of the lesion was unclear. (C) PET/CT clearly localizes the abnormal 18FDG uptake to the gastric wall. Biopsy demonstrated gastric infiltration by NHL. PET/CT was superior to PET or CT alone. (Color version of figure is available online.)

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FIG 4. Initial staging PET/CT scan in a 49-year-old man with follicular NHL with a bulky mediastinal mass, mesenteric, and retroperitoneal adenopathy. (A) PET shows FDG uptake in the posterior right thoracic wall, but is unable to determine its exact localization. (B) CT demonstrates right pleural focal thickness, with bilateral pleural effusion and passive atelectasis. (C) PET/CT reveals that the 18FDG uptake corresponds to the thickened pleura. Although a biopsy of the lesion was not performed, it resolved with chemotherapy and probably corresponded to pleural involvement by NHL. (Color version of figure is available online.)

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FIG 5. (A) PET shows bilateral uptake at the level of the mandible. (B) Normal CT at the level of the epiglottis. (C) PET/CT shows masseteral physiologic uptake. (Color version of figure is available online.)

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Management of Lymphomas with PET/CT There are multiple steps where PET/CT may be of use to the oncologist, and where it can change decisions in the management of lymphomas.2 These points are summarized in Fig 1.

Initial Staging Accurate staging of lymphomas is important for optimum selection of treatment options and results in improved treatment outcomes. The Ann Arbor system is used for staging the disease and is based on the anatomic extension and presence or absence of symptoms (Table 4).3 Along with the histological grade, it has been the most extensive system used to make an adequate treatment decision. In addition to clinical and analytical findings, the staging of the disease is based on imaging techniques, bone marrow biopsy, and laparotomy. However, these methods have limitations. Bone marrow biopsy allows categorization in stage IV, but can be false negative in cases with scattered infiltration28 (Fig 2). PET/CT can play a major role in the accurate staging of lymphoma, because it may help precisely locate pathologic lymphadenopathy seen on PET alone and other sites of disease29-34 (Figs 3 and 4). PET/CT also aids in distinguishing between tumoral and physiologic or nontumoral pathologic uptake that PET alone may misdiagnose as lymphomatous involvement (Figs 5 to 7). Other pathologies (incidental findings) apart from lymphoma may also be found thanks to evaluation of CT images (Fig 8). Overall, PET/CT can change the disease stages in some cases compared with PET and CT alone. Possible pitfalls may occur in cases of lymphomas with low uptake of 18FDG. There is evidence that indolent lymphoma and some histologic types of lymphoma are not always detectable by PET alone, because they can sometimes show minimal or no uptake at all of 18FDG.35,36 In these cases, the CT component of PET/CT is of great importance for staging and follow-up (Fig 9). Although PET/CT helps in avoiding pitfalls of PET alone, such as physiologic uptake or false location of disease, infectious or inflammatory diseases can also lead to misdiagnosis of lymphoma even with PET/CT.15 This is a possible pitfall of PET/CT, so the radiologist and nuclear physician must be aware and correlate the imaging

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FIG 6. (A) PET shows bilateral uptake in the thoracic wall. (B) CT shows no anomalies. (C) PET/CT demonstrates bilateral uptake of serratus and intercostal muscles, probably related to the position (arms above head) of the patient during the examination. (Color version of figure is available online.)

findings with the clinical and analytical data of the patient.

Early Response to Treatment Most patients will have initial treatment with a course of chemotherapy. The standard principle of chemo-

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FIG 7. PET/CT staging study in a 61-year-old man diagnosed with HD who presented with mediastinal, hilar, retroperitoneal, and iliac adenopathy, without known extranodal involvement. (A) PET shows a focal moderate uptake around the right shoulder (arrows). Lymphomatous involvement was suspected. (B) CT demonstrates degenerative disease of the acromioclavicular articulation. (C) PET/CT locates the increased uptake in this joint, related to benign disease, resulting in downstaging compared to PET alone. (Color version of figure is available online.)

therapy used in lymphoma is to administer it until a clinical complete remission is achieved and then to give two further cycles of treatment. Patients who fail to achieve complete remission after six or eight conventional cycles of treatment will be unlikely cured by standard dose chemotherapy alone and will either move to more intensive chemotherapy or have locoregional consolidation with radiotherapy. A small number of patients do not respond to primary chemotherapy and move much earlier into more intensive therapy. Overall, around 85% of pa-

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FIG 8. Fifteen-year-old woman with NHL in cervical, thoracic, and abdominal lymphadenopathy referred for staging. (A) PET of the pelvis shows low-to-moderate diffuse uptake. (B) CT shows a left ovarian mass with a fat-fluid level that corresponds to a teratoma. (C) PET/CT shows no pathologic uptake of the mass. (Color version of figure is available online.)

tients will respond satisfactorily to their primary chemotherapy.2 Early identification (after three or four cycles of conventional chemotherapy) of those patients who will not be cured with primary chemotherapy would, however, be a major advance in the management of this disease, because other effective, albeit more toxic, salvage schedules utilizing high-dose chemotherapy

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with stem cell harvest and marrow rescue can be employed. CT cannot determinate if a residual mass still has tumoral active cells, so PET/CT is necessary to assess whether disease is satisfactorily responding to treatment, which is evaluated as a decrease in 18FDG uptake37-40 (Fig 10). Limitations of PET/CT to assess tumoral activity of residual masses may be found in cases of hypermetabolic brown fat15,41 (Fig 11).

Definitive Response to Primary Chemotherapy Course Definitive response to primary chemotherapy after completion of six or eight conventional cycles is also of great importance. There is often uncertainty as to whether a true complete remission has been achieved or not, especially when a residual mass is still visible on CT or MR imaging, or when normal-sized lymph nodes are present at a site where there was previous obvious pathological lymphadenopathy, with uncertainty on radiological grounds as to whether there is still active disease. It is in this setting of the residual mass evaluation that PET/CT has been shown to have the greatest utility.34,37,40,42,43 Recognition of the presence of active disease can make these patients undergo a short course of radiotherapy following an intensive period of chemotherapy. In those cases where absence of active cells within the residual radiological abnormality is assessed, radiotherapy will be unnecessary, saving its additional morbidity. After chemotherapy, bone marrow rebound may be seen as a homogeneous low-to-moderate uptake of the bone marrow, which must not be confused with lymphomatous infiltration15,41 (Fig 12). A thymic rebound may also be seen as a nontumoral enlargement with moderate FDG uptake.44

Follow-Up

FIG 9. Initial staging PET/CT scan in a 64-year-old man with biopsy-proven low-grade NHL. (A) PET of the upper abdomen shows no increased focal uptake, only diffuse low uptake of both liver and spleen that may be physiologic. (B) CT demonstrates splenomegaly and hepatic hilar adenopathy. (C) No pathologic FDG uptake is seen in adenopathy nor in the spleen, although these organs were affected by lymphoma. Therefore, follow-up evaluations must unavoidably include a diagnostic CT. (Color version of figure is available online.)

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Most protocols nowadays include a follow-up CT scan at 3 to 6 months after completion of treatment to document complete remission; when such remission has not been achieved, patients will be further investigated and embark on additional treatment.2 For the patients who have achieved complete remission at the end of their treatment scheme, regular outpatient visits will be undertaken at 3- to 4-month intervals for the first 2 to 3 years, every 6 months for

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FIG 11. PET/CT reevaluation scan in a 32-year-old woman diagnosed with NHL who had cervical and thoracic adenopathy before treatment. (A) CT after four cycles of chemotherapy shows small supraclavicular adenopathy. (B) PET/CT shows increased FDG uptake in the brown adipose tissue of the supraclavicular regions, which makes it difficult to determine if the adenopathy has residual tumoral activity. (Color version of figure is available online.)

FIG 10. PET/CT mid-treatment reevaluation study in a 20-year-old woman who had HD with a bulky hypermetabolic mediastinal at diagnosis. (A) CT after four cycles of chemotherapy shows a residual mediastinal mass. (B) PET shows no evidence of pathologic FDG uptake in the mediastinum, but there is increased bilateral axillary uptake. (C) PET/CT confirms the response of the mass to chemotherapy and clearly shows that the axillary uptake corresponds to brown fat. The mass was even smaller at the end of the treatment and remained negative for FDG uptake. (Color version of figure is available online.)

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5 years, and then annually. Early identification of patients who have low probability of relapse compared with those who are prone to relapse would again be of considerable value. The role of PET/CT has not been widely investigated as a prognostic factor, and although some studies affirm its accuracy in the prediction of early recurrence,34 more studies are needed to demonstrate if an early negative PET/CT scan after completion of treatment is a predictor for patients who will be cured and in whom follow-up could be minimized.

Specific Artifacts and Pitfalls of PET/CT One of the problems of PET/CT is related to differences in breathing patterns between the CT and the PET scans, because PET acquisitions are always

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performed during tidal breathing due to the duration of the study. On the other hand, CT images are usually acquired during a breath-hold. Thus, misregistration of pulmonary nodules between both modalities, particularly in the periphery and at the bases of the lungs, and mispositioning of abdominal activity into the chest, may occur when the PET and CT images are fused together. Differences in position may approach 15 mm. This misregistration can be minimized by performing the CT scan during normal expiration.45-48 Another possible problem is the use of IV or oral contrast, because they can lead to artifactual hot spots in the attenuation corrected images or quantitative overestimation of FDG activity. This aspect has been previously referred to in this article. Also, the arms next to the side position, when the above-the-head position is not possible, can lead to beam-hardening artifacts on the CT scan that may translate to incorrect attenuation correction.15,16 Differences in the field-of-view diameter between the larger PET and smaller CT parts of combined scanners can lead to truncation artifacts at the edge of the CT image, but these are generally small and can be minimized by the use of iterative image reconstruction methods.15

Summary Coregistration of PET scans with CT scans using a combined PET/CT scanner can improve the overall sensitivity and specificity of information provided by PET or CT alone. PET/CT may be useful not only in staging, but also in assessment of early response to therapy, restaging, and follow-up of HD and NHL, improving the clinical management of these patients.

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FIG 12. Sixty-nine-year-old woman with thyroid gland NHL. (A) CT of evaluation after chemotherapy completion shows some small infracarinal lymph nodes. (B) PET/CT confirms increased uptake of this adenopathy, due to incomplete response to treatment. (C) Sagittal images also show increased FDG uptake of bone marrow related to bone marrow rebound after chemotherapy treatment. (Color version of figure is available online.)

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