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Posttransplantation Lympho­proliferative Disease: Proposed Imaging Classification1

Posttransplantation lymphoproliferative disease (PTLD) is the second most common tumor in adult transplant recipients. Most cases of PTLD are attributed to Epstein-Barr virus. Decreased levels of immunosurveillance against this tumor virus as a result of immunosuppressive regimens are thought to account for most cases of PTLD. Histologically, PTLD ranges from relatively benign lymphoid hyperplasia to poorly differentiated lymphoma, and tis-sue sampling is required to establish the subtype. The frequency of PTLD varies depending on the type of allograft and immunosup-pressive regimen. PTLD has a bimodal manifestation, with most cases occurring within the first year after transplantation and a second peak occurring 4–5 years after transplantation. Patients are often asymptomatic or present with nonspecific symptoms, and a mass visible at imaging may be the first clue to the diagnosis. Imaging plays an important role in identifying the presence of dis-ease, guiding tissue sampling, and evaluating response to treatment. The appearance of PTLD at imaging can vary. It may be nodal or extranodal. Extranodal disease may involve the gastrointestinal tract, solid organs, or central nervous system. Solid organ lesions may be solitary or multiple, infiltrate beyond the organ margins, and obstruct organ outflow. Suggestive imaging findings should prompt tissue sampling, because knowledge of the PTLD subtype is imperative for appropriate treatment. Treatment options include reducing immunosuppression, chemotherapy, radiation therapy, and surgical resection of isolated lesions.

©RSNA, 2014 • radiographics.rsna.org

Juan C. Camacho, MD Courtney Coursey Moreno, MD Peter A. Harri, MD Diego A. Aguirre, MD William E. Torres, MD Pardeep K. Mittal, MD

Abbreviations: EBV = Epstein-Barr virus, FDG = fluorodeoxyglucose, PTLD = posttrans-plantation lymphoproliferative disease

RadioGraphics 2014; 34:2025–2038

Published online 10.1148/rg.347130130

Content Code: 1From the Abdominal Imaging Division, Depart-ment of Radiology and Imaging Sciences, Emory University School of Medicine, 1365 Clifton Rd NE, Suite AT-627, Atlanta, GA 30322 (J.C.C., C.C.M., P.A.H., W.E.T., P.K.M.); and Abdomi-nal Imaging Division, Department of Imaging, Fundación Santa Fe de Bogotá University Hos-pital, Bogotá, Colombia (D.A.A.). Presented as an education exhibit at the 2012 RSNA An-nual Meeting. Received May 27, 2013; revision requested July 13 and received May 18, 2014; final version accepted June 3. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relation-ships. Address correspondence to P.K.M. (e-mail: pmittal@emory.edu).

After completing this journal-based SA-CME activity, participants will be able to: ■ Describe the basic pathophysiologic and

epidemiologic characteristics of PTLD.

■ List the imaging findings of the differ-ent patterns of PTLD.

■ Discuss the current therapeutic options for patients with PTLD.

See www.rsna.org/education/search/RG.

SA­CME LEARNING OBJECTIVES

IntroductionSurvival after transplantation has greatly improved over the past several decades due, in large part, to improvements in immunosup-pressive regimens (1). As a consequence of these immunosuppressive regimens, transplant recipients experience a three- to eightfold in-crease in rates of malignancy compared with the general population (2–5). Many such malignancies are mediated by oncoviruses such as Epstein-Barr virus (EBV) (6). Depressed immunosurveillance

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ment of the BCL2 gene—can result in PTLD (17). In some patients, EBV is thought to play a role in the development of genetic mutations, whereas in others, the cause is uncertain. These genes are involved in regulating cell division, pro-liferation, and death (apoptosis). Overproduction of interleukin-6 (a cytokine) is another mecha-nism that can result in PTLD (17). In addition to EBV, cytomegalovirus has been associated with the development of PTLD; specifically, patients who are cytomegalovirus seronegative have a higher risk for developing PTLD after solid organ transplantation (18–20).

PTLD comprises a spectrum of lympho-proliferative diseases that range from relatively benign lymphoid hyperplasia to poorly dif-ferentiated lymphoma. The most recent World Health Organization classification of PTLD was released in 2008 (Table 1) (21). The different forms of PTLD cannot be distinguished at imag-ing, and tissue sampling is required to establish a diagnosis.

Less aggressive forms of PTLD generally arise from different B cells and are pathologically re-ferred to as polymorphic. Further environmental influences and mutations can produce dominant subclones, which progressively become more ma-lignant and result in oligoclonal and, sometimes, monomorphic lymphocyte populations (22). Normal cell proliferation–control mechanisms may be limited, leading to formation of a highly malignant monoclonal PTLD neoplasm.

Epidemiologic FeaturesThe frequency of PTLD ranges from 1%–20% and varies depending on the type of allograft used (23). PTLD occurs in 1%–3% of renal transplant recipients and in as many as 20% of non–renal allograft recipients (24–30). The highest rates of PTLD are in small intestine transplant recipients, as many as 20% of whom develop PTLD (24–30). PTLD develops in 1%–11% of heart transplant recipients, 2%–10% of lung transplant recipients, and 1%–3% of liver transplant recipients (24–32). These

against oncoviruses is thought to account for higher malignancy rates in the posttransplanta-tion population compared with the general popu-lation (6).

Malignancy is the third most common cause of death after cardiovascular events and infec-tion among adult transplant recipients (2–4,6). As a cause of death among posttransplantation patients, cancer rates dramatically increased from 1.2% between 1970 and 1979 to 13.2% between 1990 and 1999, findings that are probably related to increased survival after transplantation, nor-mal aging of the posttransplantation population, and improved immunosuppressive regimens (2). Posttransplantation lymphoproliferative disease (PTLD) is the second most common tumor in adult transplant recipients after nonmelanoma-tous skin cancer (7–10). PTLD comprises a spec-trum of diseases that range from lymphoid hyper-plasia to poorly differentiated lymphoma (9).

Imaging plays an important role in identifying disease, guiding tissue sampling, and monitoring re-sponse to treatment. Patients may be asymptomatic, and clinical symptoms, if present, are often nonspe-cific (11). A soft-tissue mass that is visible at imag-ing may be the first clue to the diagnosis. Because effective treatments are available for many forms of PTLD, accurate and timely diagnosis is important. In this article, we discuss the pathogenesis, epi-demiologic characteristics, and treatment options of PTLD, as well as a new classification system developed on the basis of imaging findings.

PathogenesisIn most cases, PTLD is thought to result from T-cell suppression in patients with latent EBV in-fection (12). EBV is a common infection, and as many as 90%–95% of adults are EBV seropositive (13). In immunocompetent hosts, T cells fight the initial EBV infection by eradicating B cells that display EBV antigens. However, even in immuno-competent hosts, a small number of EBV-infected B cells escape immunosurveillance and survive, harboring a latent EBV infection (13).

After solid-organ transplantation, EBV-specific cytotoxic T cells may be completely lost within 6 months of transplantation, a result of immuno-suppressive medications (14). In such a T-cell–de-pleted environment, latently infected B cells can proliferate and result in PTLD (15). In addition, when an EBV-seronegative recipient receives an organ from an EBV-seropositive donor, de novo EBV infection can lead to early-onset PTLD, a scenario that is more common in children, who are often EBV naive (16).

A variety of genetic mutations—including those that involve the NRAS, c-myc, and p53 genes, deletion of the IMP1 gene, and rearrange-

Table 1: World Health Organization 2008 Pathologic Classification of Posttransplanta­tion Lymphoproliferative Disease

Early lesions: plasmacytic hyperplasia, infectious mononucleosis–like

PolymorphicMonomorphic: B-cell, T-cell, natural killer cellClassic Hodgkin lymphoma

Source.—Reference 21.

RG • Volume 34 Number 7 Camacho et al 2027

than late-onset PTLD and usually has a posi-tive response to treatment, which often entails reducing the level of immunosuppression (16). By comparison, late-onset PTLD is less com-monly associated with EBV, more commonly has a monomorphic cell population, and has an aggressive and sometimes chemotherapy-refrac-tory course with a higher mortality rate (39,40). In general, mortality from PTLD ranges from 22% to 70% (41–44). In a study published in 2007, a higher mortality rate was reported in the late-onset group (63%) compared with the early-onset group (50%) (45).

Rates of PTLD-associated lymphoma are higher in children than adults (35). For example, the relative risk of a heart transplant recipient younger than 10 years old developing lymphoma during the 5-year posttransplantation period is 1240 times that of the general population com-pared with 16 times that of the general popula-tion for adults older than 60 years (35). This higher relative risk in the pediatric population is attributed to relatively low rates of lymphoma in the comparable general pediatric population and to relatively low rates of EBV seropositivity among pediatric recipients compared with adult recipients (35).

Imaging Pattern– based Approach for

Accurate Diagnosis of PTLDPTLD can be extremely varied in its manifesta-tion and cell type. Given these challenges, making a diagnosis of PTLD on the basis of radiologic studies, especially early in the disease course, can be challenging. However, several common pat-terns of involvement have been identified that facilitate radiologic suspicion and direct final di-agnosis and therapeutic courses.

PTLD can be divided into categories or pat-terns to aid in diagnosis. In this section, PTLD is divided into two major categories on the basis of its primary location: nodal and extranodal. The nodal category is defined by lymphadenopa-thy and is subdivided according to the primary location of nodal disease burden into two sub-categories: mediastinal and retroperitoneal. The extranodal category is defined by disease located in organs other than the lymph nodes and is sub-divided according to the primary location into three subcategories: gastrointestinal tract, solid organ, and central nervous system. The solid or-gan subcategory is organized into four patterns: obstructive, hilar or solitary mass, parenchymal, and infiltrative. Use of this classification system with imaging characteristics can help establish a differential diagnosis, which can be narrowed on the basis of clinical features (Table 2) (Fig 1).

different rates are thought to be related to dif-ferent degrees of immunosuppression, which vary depending on the type of transplantation performed (23,32). For example, higher levels of immunosuppression are generally used for transplants for which rejection is immediately dire (ie, heart and lung), and relatively lower levels of immunosuppression are used for renal transplants because dialysis is an option if the transplant fails. In addition, higher numbers of lymphoid aggregates are found in intestinal and lung transplants compared with renal trans-plants; these lymphoid aggregates may contrib-ute to the development of PTLD (33).

Rates of PTLD also vary depending on the immunosuppressive regimen being followed. In general, immunosuppressive agents that suppress T-cell activity (ie, antithymocyte globulin) are associated with relatively higher rates of PTLD than those that do not suppress T-cell activity (eg, interleukin-2 receptor antagonists) (34,35). Furthermore, a larger total number of immu-nosuppressant agents, including induction and maintenance therapies, are associated with an increased risk for PTLD (34,35).

The location of PTLD-related tumors also varies depending on the type of transplanted organ. In general, for nonrenal allografts, PTLD most commonly involves the allograft itself or the region of the allograft, possibly because of chronic antigenic stimulation by the allograft (35). The liver is the most common site of disease when lymphoma occurs after liver transplanta-tion, and the lungs are the most common site of disease when lymphoma occurs after lung or heart-lung transplantation (35). In comparison, when lymphoma occurs after renal transplanta-tion, the gastrointestinal tract, followed by the central nervous system and kidneys, is the most common site of disease (35). It is uncertain why the kidney is not the most common PTLD tumor location in renal allograft recipients.

PTLD has a bimodal manifestation, with an early peak within the first year after transplanta-tion and a later peak 4–5 years after transplanta-tion (23,35). Rates of PTLD are highest within the first year after transplantation, although cases that occurred within the first month after transplantation have been reported (36). That immunosuppression is usually greatest during the first year after transplantation is thought to account for this early peak (23). There is a di-rect relationship between EBV and early-onset PTLD. The risk for developing early-onset PTLD is especially increased in recipients who are EBV seronegative and who receive an organ from a donor who is EBV seropositive (37,38). Early-onset PTLD is more often polymorphic

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Nodal PTLD Imaging PatternPTLD may appear as lymphadenopathy. However, isolated nodal disease occurs in a minority of cases of PTLD (Fig 2) (46). In the chest, PTLD may appear as mediastinal lymphadenopathy or as an infiltrative and hy-poenhancing anterior mediastinal mass. The retroperitoneum is the most common location for PTLD-related lymphadenopathy below the level of the diaphragm (46). Lymph nodes are typically homogeneously enlarged and hypoen-hancing, and they may demonstrate loss of their usual fatty hilum (Figs 3, 4) (46).

PET normally depicts increased FDG up-take, with a median maximum standardized uptake value of 8.2 (range, 3–30) (47) and 17.4 (range, 2.6–26.4) (48), according to two stud-ies. Postoperative changes and scar tissue may also demonstrate increased FDG uptake, but their standardized uptake value is usually not as high as with PTLD. In a recent study, PET was found to have an overall sensitivity of 89%, specificity of 89%, positive predictive value of 91%, and negative predictive value of 87% for depicting PTLD (48). False-positive results were a result of infectious or inflammatory

Table 2: Key Imaging Features of PTLD

Imaging Pattern Location Imaging Characteristics Differential Diagnosis

Nodal Mediastinal Mediastinal

lymph nodesHypoenhancing lymph nodes with

loss of normal morphologic charac-teristics and fatty hilum, FDG avid

Infectious or inflamma-tory lymphadenopathy, granulomatous disease, metastases

Retroperitoneal Retroperitoneal lymph nodes

Hypoenhancing lymph nodes with loss of normal morphologic charac-teristics and fatty hilum, FDG avid

Infectious or inflamma-tory lymphadenopathy, granulomatous disease, metastases

Extranodal Gastrointestinal

tractGastrointestinal

tractWall thickening or an eccentric mass

that may ulcerate, hypoenhancing, can manifest as an intussusception, FDG avid

Infection, recurrence, new malignancy, Kaposi sarcoma

Solid organ: obstructive (liver)

Periportal or liver hilum

Hypoenhancing mass with low SI on T1W and T2W images, secondary biliary duct dilatation, and potential vascular encasement; FDG avid

Infection, recurrence, or new malignancy

Solid organ: obstructive (kidney)

Renal hilum Hypoenhancing hilar mass with low SI on T1W and T2W images, secondary hydronephrosis, and ± vascular encasement; FDG avid

Recurrence; new malig-nancy; hydronephrosis from a secondary source (eg, stone, stricture, clot, or transitional cell carci-noma)

Solid organ: hilar or solitary mass

Kidney, liver spleen, lung

Hypoenhancing mass with low SI on T1W and T2W images; possible obstruc tion (biliary or hydronephro-sis); FDG avid

Cholangiocarcinoma, in-flammatory pseudotumor, metastases

Solid organ: parenchyma (scattered)

Kidney, liver, spleen, lung

Multiple hypoenhancing masses with low SI on T1W and T2W images; FDG avid

Infection, new or recurrent malignancy, metastases, Kaposi sarcoma

Solid organ: infiltrative

Solid organ, ab-dominal wall

Hypoenhancing mass extending from the allograft through abdominal fas-cial planes with low SI on T1W and T2W images; FDG avid

Infection, sarcoma, cellulitis

Central nervous system

Basal ganglia and subcortical white matter

Ring enhancement; bright SI on T2W images with vasogenic edema; restricted diffusion, increased cho-line and lactate, and substantially reduced N-acetylaspartate at MR spectroscopy

Lymphoma, new or recur-rent primary malignancy, infection, hematoma

Note.—FDG = fluorodeoxyglucose, SI = signal intensity, T1W = T1-weighted, T2W = T2-weighted.

RG • Volume 34 Number 7 Camacho et al 2029

Figure 2. Flowchart shows an overview of nodal PTLD imaging patterns.

causes, whereas false-negative results were most commonly a result of limited or early lesions (48).

Patients with PTLD may be asymptomatic or present with nonspecific symptoms, including fever and night sweats. The differential diagnosis for the nodal disease pattern includes infectious or inflammatory lymphadenopathy, granuloma-tous disease, and metastases.

Extranodal PTLD Imaging Patterns

Gastrointestinal Location.—This subcategory is defined by peritoneal and gastrointestinal involvement (Fig 5). Peritoneal PTLD may be seen as nodules or diffuse infiltrating soft tis-sues (46) (Fig 6). A variety of gastrointestinal PTLD appearances have been described, includ-ing circumferential wall thickening, aneurysmal dilatation, ulceration, and polypoid masses (46). Much like lymphomas that are not associated with PTLD, mechanical obstruction resulting from the tumor itself is uncommon, even with large tumors (46).

At MR imaging, PTLD typically appears solid and may have low signal intensity on T1- and T2-

weighted images (Fig 6). At contrast-enhanced CT or MR imaging, tumors related to PTLD are typically hypoenhancing. PET normally depicts increased FDG uptake.

Clinically, patients may present with vague abdominal pain or vomiting. Fever may also be present. The differential diagnosis for a gastroin-testinal location includes infection, gastrointesti-nal malignancy, and Kaposi sarcoma.

Solid Organ Location: Obstructive Pattern.—This subcategory includes either an infiltrative mass or multiple masses located outside the organ hilum, which results in extrinsic compres-sion and causes secondary vascular compromise, or it may obstruct the nonvascular outflow of the affected organ (ie, bile ducts). When the liver is affected, the primary location is the periportal space, which leads to obstruction of blood flow and bile ducts. Primary imaging characteristics are biliary ductal dilatation with or without vascular encasement from a hypoen-hancing mass (Fig 7). PET normally depicts increased FDG uptake. Clinical features may include fever, pain, and jaundice. The differen-tial diagnosis includes infection and a recurrent or new malignancy.

When the kidney is affected, the primary loca-tion is outside the renal pelvis, causing obstruc-tion of blood vessels and the renal collecting system. The primary imaging characteristics are urinary obstruction with hydronephrosis, with or without vascular encasement (Fig 8). At CT and MR imaging, this obstruction results from a hy-poenhancing hilar mass. At MR imaging, PTLD usually has low signal intensity on T1- and T2-weighted images. PET normally depicts increased FDG uptake. Clinical features include poor urine output, pain over the allograft site, and elevated creatinine levels. The differential diagnosis in-cludes hydronephrosis from a secondary source

Figure 1. Flowchart shows an overview of the different imaging categories, locations, and patterns of PTLD.

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Figure 4. Retroperitoneal, mesenteric, and porta hepatis nodal pattern in a 28-year-old woman who underwent kidney transplantation. (a) Coronal T2-weighted MR image shows multiple enlarged mesenteric and retroperitoneal lymph nodes (arrow) with intermediate to dark signal intensity and the renal transplant (arrowhead) in the left lower quadrant. (b) Coronal fused PET/CT image shows intense hypermetabolic activity in abnormally enlarged mesenteric lymph nodes (ar-row) and the renal transplant (arrowhead) in the left lower quadrant.

(eg, stone or postoperative changes) and a recur-rent or new malignancy. If a surgical stricture is encountered, additional stent placement should be considered to avoid graft failure.

Solid Organ Location: Parenchymal (Scattered) Pattern.—This pattern is defined by multiple scattered lesions throughout the parenchyma of

Figure 3. Mediastinal nodal pat-tern in a 34-year-old patient who underwent orthotopic liver trans-plantation. Oblique FDG-enhanced three-dimensional positron emission tomographic (PET) (a) and coronal fused PET/CT (b) images show multiple hypermetabolic paratracheal and superior mediastinal lymph nodes (arrow) secondary to tissue-proved PTLD.

the affected organ (Figs 9–11). Primary imaging characteristics include multiple hypoenhancing nodules or masses throughout the affected al-lograft at cross-sectional imaging. In the lung, nodules are usually solid with a random distribu-tion and, rarely, cavitations (Fig 10) (11,49–51). Multifocal ill-defined alveolar infiltrates may also be seen (11,49–51). At MR imaging, nodules

RG • Volume 34 Number 7 Camacho et al 2031

Figure 5. Flowchart shows an over-view of the imaging patterns of extra-nodal PTLD. GI = gastroiintestinal.

may have decreased signal intensity on T1- and T2-weighted images. PET normally depicts in-creased FDG uptake.

Clinical features may include fever; allograft dysfunction (eg, elevated creatinine levels, jaun-dice, cough, and dyspnea); and pain, including vague abdominal or pleuritic chest pain. Patients may also be relatively asymptomatic. The differ-

Figure 6. Gastrointestinal extranodal pattern (with peri-toneal and intestinal involvement) in a 52-year-old man who underwent orthotopic liver transplantation. (a) Axial T2-weighted MR image shows material with intermedi-ate signal intensity (arrow) in the greater omentum and extending along the antimesenteric border of the hepatic flexure of the colon. (b) Axial fused PET/CT image shows hypermetabolic activity in the greater omentum (arrow). (c) Coronal contrast-enhanced CT image shows a colo-colonic intussusception involving the hepatic flexure of the colon (arrow). Post-stenotic dilatation of the portal vein (arrowhead) is also seen. A diagnosis of PTLD was made on the basis of histologic analysis.

ential diagnosis includes infection and recurrent or new malignancy. In the case of lung involve-ment, Kaposi sarcoma is also a differential diag-nostic consideration.

Solid Organ Location: Solitary Mass.—This pattern is defined by a solitary mass at ultraso-nography (US), CT, or MR imaging (Fig 12). At US, the mass tends to be hypoechoic with no mi-crocalcifications or color Doppler signal. At MR

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Figure 8. Perirenal obstructive solid organ extranodal pattern in a 32-year-old patient who underwent en bloc renal transplantation. Axial contrast-enhanced CT images show mild caliectasis (arrow in a) secondary to ill-defined infiltrative soft tissue in the renal hila (arrow in b). A diagnosis of PTLD was made on the basis of histologic analysis.

Figure 7. Periportal obstructive solid organ extranodal pattern in a 54-year-old patient who underwent orthotopic liver transplantation. (a) Axial T2-weighted MR image shows infiltrative, ill-defined material with intermediate to bright signal intensity (arrow) in the liver hilum and periportal region and moderate upstream intrahepatic biliary ductal dilatation (arrowhead). (b) Unenhanced T1-weighted MR image shows an area of intermediate signal inten-sity in the liver hilum and periportal region. Percutaneous biopsy results revealed PTLD.

imaging, PTLD nodules tend to have decreased signal intensity on both T1- and T2-weighted im-ages, with no significant contrast enhancement (Fig 12).

Patients are often asymptomatic. However, fever, anemia, decreasing liver function, jaundice, elevated creatinine levels, and scleral icterus may be present. The differential diagnosis includes cholangiocarcinoma, inflammatory pseudotumor, and metastases to the liver or spleen.

Solid Organ Location: Infiltrative Pattern.—This pattern is defined by a lesion that extends from the affected organ and involves surrounding struc-

tures, including the chest, abdominal wall, and ad-jacent organs. Its primary imaging characteristics are a hypoenhancing mass extending from its pri-mary site, possibly through the fascial planes and into the subcutaneous fat (Fig 13). This invasion often causes secondary edema of the subcutaneous tissues. If the mass grows into an adjacent organ, loss of the normal fat planes occurs.

Clinical features include fever, pain over the allograft, allograft dysfunction, and skin ery-thema. If another organ is affected, dysfunction of the infiltrated organ may occur. The differen-tial diagnosis includes infection, sarcoma, pri-mary malignancy, and cellulitis.

RG • Volume 34 Number 7 Camacho et al 2033

Figure 9. Parenchymal and scattered solid organ extranodal pattern in a 65-year-old patient who underwent renal transplantation. (a) Axial T2-weighted MR image shows several round areas of low signal intensity (arrows) in the parenchyma of the renal transplant in the left lower quadrant. (b) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation shows that the masses are hypoenhancing (arrows). A diagnosis of PTLD was made on the basis of histologic analysis.

Central Nervous System.—Although any portion of the central nervous system may be affected, the most commonly reported locations are the basal ganglia and subcortical white matter (52). Lesions are typically multifocal and may demon-strate homogeneous or rim enhancement (52). At MR imaging, the primary imaging characteristics include decreased signal intensity on T1-weighted images with avid enhancement after adminis-tration of gadolinium-based contrast material. Increased signal intensity on T2-weighted images with surrounding vasogenic edema may be seen, along with restricted diffusion (Fig 14). At MR spectroscopy, increased choline and lactate peaks are common, as well as a significant reduction in N-acetylaspartate.

Clinical features include headache and neuro-logic symptoms that result from mass effect. The differential diagnosis includes a new or recurrent malignancy, hematoma, and infection.

Treatment Overview of PTLDTissue sampling is required to establish the sub-type of PTLD, and treatment varies depending on the subtype, its distribution, and the type of organ that was transplanted. Treatment options include reducing immunosuppression, chemo-therapy, radiation therapy, rituximab (a monoclo-nal antibody) therapy, and surgical resection of isolated lesions (53–55).

The goals of treatment are both to treat PTLD and preserve graft function. For organs (such as the kidney) for which alternatives (eg, hemodi-alysis and peritoneal dialysis) to transplant func-tion exist, treatment of PTLD can take priority. However, for other organs, such as the lung and heart, graft survival is the priority.

No complete consensus for treatment of PTLD has been established, and multiple treat-ment strategies exist. For patients with early le-sions, reducing immunosuppression may be ad-equate and is considered the first-line treatment. Approximately 25%–50% of patients respond to reduction or withdrawal of immunosuppression therapy (56–58). For example, for kidney trans-plant recipients, low-level immunosuppression with prednisone alone may be adequate anti-rejection therapy. However, recipients of other

Figure 10. Parenchymal and scattered solid organ extranodal pattern in a 56-year-old patient who underwent bilateral lung trans-plantation. Axial contrast-enhanced CT im-age shows innumerable randomly distributed soft-tissue parenchymal nodules (arrows). A diagnosis of PTLD was made on the basis of histologic analysis.

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Figure 11. Parenchymal and scattered solid organ extranodal pattern in a 75-year-old man who underwent liver transplantation 3 months earlier and presented with newly abnormal liver function test results. (a) Transverse US image shows innumerable subcentimeter hypoechoic liver lesions. (b) Axial T2-weighted MR image shows the inter-mediate-to-high-signal-intensity lesions. (c) Axial T1-weighted MR image shows the lesions, which have low signal intensity. (d) Contrast-enhanced MR image shows the lesions, which demonstrate hypoenhancement. The patient underwent US-guided liver biopsy, results of which revealed monomorphic large B-cell lymphoma.

types of solid organ transplants may require stronger immunosuppression than, or in addi-tion to, prednisone, and complete withdrawal of immunosuppression therapy may not be possi-ble. Administering antiviral agents, such as acy-clovir and gancyclovir, may be useful in patients with early disease, when active EBV replication occurs (58).

Rituximab is an antibody that is di-rected against CD20, which is expressed on B-lymphocytes and can be used as a mono-therapy or in combination with chemotherapy for B-cell PTLD (25,59,60). Combination che-motherapy is used in advanced cases and cases in which immunosuppression and rituximab therapy have not caused remission. Rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy may be admin-istered (24,61). Radiation therapy may also be

used, especially in patients with central nervous system disease (62).

SummaryThe imaging appearances of PTLD can vary and include nodal and extranodal disease. Extranodal disease may involve the gastrointestinal tract, solid organs, or the central nervous system. Lesions may be solitary or multiple, infiltrate across tissue planes, and result in obstruction of organ outflow. Suggestive imaging findings should prompt tissue sampling, because knowl-edge of the subtype of PTLD is imperative for appropriate treatment.

Acknowledgments.—The education exhibit “Post-Transplant Lymphoproliferative Disease (PTLD): Imaging Findings of a Poorly Recognized and Not So Rare Malignant Entity” was conducted without funding

RG • Volume 34 Number 7 Camacho et al 2035

and was presented at the 98th Scientific Assembly and Annual Meeting of the Radiological Society of North America. No financial support was received. The loca-tion of the study, the facilities, and the study subjects were recruited at Emory University Affiliated Hospitals, Atlanta, Georgia, and at Fundación Santa Fe de Bogotá University Hospital, Bogotá, Colombia. We want to thank Mauricio Moreno, MD, and Daniel Russell, MD, for their help in the selection of cases and in the initial preparation of the education exhibit. Additionally, we want to recognize Deborah Baumgarten, MD, MPH, FSAR, and Aarti Sekhar, MD, for providing additional cases and for editing help during the preparation of the initial education exhibit.

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the 20th century. N Engl J Med 2004;351(26): 2678–2680.

2. Howard RJ, Patton PR, Reed AI, et al. The chang-ing causes of graft loss and death after kidney transplantation. Transplantation 2002;73(12): 1923–1928.

3. Collins AJ, Kasiske B, Herzog C, et al. Excerpts from the United States Renal Data System 2003 Annual Data Report: atlas of end-stage renal disease in the United States. Am J Kidney Dis 2003; 42(6 suppl 5):A5–A7, S1–S230.

4. Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant 2001;16(8):1545–1549.

5. Apel H, Walschburger-Zorn K, Häberle L, Wach S, Engehausen DG, Wullich B. De novo malignancies in renal transplant recipients: experience at a single center with 1882 transplant patients over 39 yr. Clin Transplant 2013;27(1):E30–E36.

6. Gutierrez-Dalmau A, Campistol JM. Immunosup-pressive therapy and malignancy in organ trans-plant recipients: a systematic review. Drugs 2007; 67(8):1167–1198.

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9. Penn I. The problem of cancer in organ transplant recipients: an overview. Transplant Sci 1994;4(1): 23–32.

10. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spec-trum of cancer risk among US solid organ transplant recipients. JAMA 2011;306(17):1891–1901.

11. Pickhardt PJ, Siegel MJ, Anderson DC, Hayashi R, DeBaun MR. Chest radiography as a predictor of outcome in posttransplantation lymphoprolifera-tive disorder in lung allograft recipients. AJR Am J Roentgenol 1998;171(2):375–382.

12. Parker A, Bowles K, Bradley JA, et al. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients: BCSH and BTS Guide-lines. Br J Haematol 2010;149(5):675–692.

13. Cohen JI. Epstein-Barr virus infection. N Engl J Med 2000;343(7):481–492.

Figure 12. Solitary mass solid organ extranodal pat-tern in a 30-year-old patient who underwent orthotopic liver transplantation. (a) Axial T2-weighted MR image shows a round mass (arrow) with intermediate to bright signal intensity in the caudate lobe. (b) Axial contrast-enhanced T1-weighted MR image obtained with fat saturation shows the mass (arrow), which demonstrates hypoenhancement. (c) Apparent diffusion coefficient map shows restricted diffusion in the region of the mass (arrow), a finding that relates to hypercellularity and suggests malignancy. A diagnosis of PTLD was made on the basis of histologic analysis.

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Figure 14. Central nervous system extranodal pattern in a 52-year-old patient who underwent orthotopic liver transplantation. (a) Axial contrast-enhanced T1-weighted MR image shows an enhancing mass in the left basal ganglia (arrow). (b) Axial fluid-attenuated inversion-recovery (FLAIR) MR image shows an area of corresponding intermediate signal intensity and adjacent vasogenic edema (arrow). Stereotactic biopsy results revealed PTLD.

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Figure 13. Abdominal wall infiltrative extranodal pattern in a 43-year-old pa-tient who underwent renal transplanta-tion. Axial unenhanced CT image shows a hypoattenuating infiltrative mass ex-tending from a left lower quadrant renal transplant into the anterior abdominal wall (arrow). Adjacent edema is also seen. A diagnosis of PTLD was made on the basis of histologic analysis.

RG • Volume 34 Number 7 Camacho et al 2037

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This journal-based SA-CME activity has been approved for AMA PRA Category 1 CreditTM. See www.rsna.org/education/search/RG.

Teaching Points November­December Issue 2014

Posttransplantation Lymphoproliferative Disease: Proposed Imaging Clas­sificationJuan C. Camacho, MD • Courtney Coursey Moreno, MD • Peter A. Harri, MD • Diego A. Aguirre, MD • Wil-liam E. Torres, MD • Pardeep K. Mittal, MD

RadioGraphics 2014; 34:2025–20388 • Published online 10.1148/rg.347130130 • Content Code:

Page 2025As a consequence of these immunosuppressive regimens, transplant recipients experience a three- to eightfold increase in rates of malignancy compared with the general population (2–5).

Page 2026In such a T-cell–depleted environment, latently infected B cells can proliferate and result in PTLD (15).

Page 2027PTLD can be divided into categories or patterns to aid in diagnosis. In this section, PTLD is divided into two major categories on the basis of its primary location: nodal and extranodal. The nodal category is defined by lymphadenopathy and is subdivided according to the primary location of nodal disease burden into two subcategories: mediastinal and retroperitoneal. The extranodal category is defined by disease located in organs other than the lymph nodes and is subdivided according to the primary location into three subcategories: gastrointestinal tract, solid organ, and central nervous system. The solid organ subcategory is organized into four patterns: obstructive, hilar or solitary mass, parenchymal, and infiltra-tive. Use of this classification system with imaging characteristics can help establish a differential diagno-sis, which can be narrowed on the basis of clinical features (Table 2) (Fig 1).

Page 2032At MR imaging, PTLD nodules tend to have decreased signal intensity on both T1- and T2-weighted images, with no significant contrast enhancement (Fig 12).

Page 2033For patients with early lesions, reducing immunosuppression may be adequate and is considered the first-line treatment.