Diagnostic role of whole-body [18F]-FDG positronemission tomography in patients with symptomssuspicious for malignancy after heart transplantationVera Graute, MD,a Nathalie Jansen, MD,a Hae-Young Sohn, MD,b Alexander Becker, MD,c
Barbara Klein, MD,d Irene Schmid, MD,d Sabine Greil, MD,e Sebastian Lehner, MD,a
Peter Bartenstein, MD,a Thomas Pfluger, MD,a and Marcus Hacker, MDa
From the Departments of aNuclear Medicine, bCardiology (Innenstadt), cCardiology (Grosshadern), dPaediatric Oncology and
ePaediatric Cardiology, University of Munich, Munich, Germany.
The yearly number of heart transplant recipients reportedto the transplant registry of the International Society forHeart and Lung Transplantation (ISHLT) peaked in themid-1990s at �4,000 patients annually, and remains at thislevel to the present day.1 Advances in immunosuppression
Reprint requests: Marcus Hacker, MD, Department of Nuclear Medi-cine, University of Munich, Marchioninistrasse 15, 81377 München, Ger-many. Telephone: ��49-89-7095-4650. Fax: ��49-89-7095-7646.
and peri-operative care had led to steadily improving me-dian survival after heart transplantation,2 which increasedfrom 8.3 years in the 1980s to 10.4 years in the 1990s, andcontinues to improve further1; the mortality rate 1 year aftertransplantation is now only 3% to 4% per year.1 Althoughthe main complication within the first 30 days after hearttransplantation remains graft failure, malignancy is themost common long-term complication, followed by late graftfailure, cardiac allograft vasculopathy3 and infections, all of
which contribute significantly to mortality in the years after
959Graute et al. PET for the Detection of Complications After HTX
heart transplantation.4 During long-term treatment immuno-suppressive medications impart a significant risk of complica-tions, such as malignancies, notably post-transplant lym-phoproliferative disorders (PTLDs) as well as infections.PTLDs have a particularly high incidence in transplant recip-ients relative to the general population.5 Their reported inci-dence ranges from 0.8% in adult renal transplant recipients, to1.8% in heart, 2.2% in liver, 4.6% in heart–lung and 20% inlung transplant recipients, which probably reflects the particu-lar immunosuppressive doses required for the different proce-dures.6–9
Clinical symptoms arising in patients undergoing pro-longed immunosuppression are often vague, and laboratoryfindings can be difficult to interpret. The clinical presenta-tion of PTLD, for example, can range from an isolatedabnormal lymphadenopathy to fulminant systemic dis-ease.10 Most such patients present with lymphadenopathy,fever or non-specific symptoms, such as tonsillitis andweight loss.10 Furthermore, the clinical presentation of in-fections can likewise extend from an isolated lymphadenop-athy to fulminant systemic disease. In addition, it is oftendifficult to differentiate PTLD from infection or allograftrejection on the basis of clinical manifestations alone.11
The timely and accurate diagnosis of complications arisingfrom immunosuppression is essential for early and appropriateintervention. Positron emission tomography (PET) with theglucose analog [18F]-fluorodeoxyglucose ([18F]-FDG) has be-come indispensible for diagnosing tumors and infections,when investigations by other imaging modalities haveproven inconclusive. The clinical benefits of [18F]-FDGPET specifically for PTLD have been reported in a num-ber of studies.11–14 In addition to detecting tumors, [18F]-FDG PET can help identify microbial infections, autoim-mune inflammations, non-infectious granulomatousdiseases and immunologic disorders.15 Thus, [18F]-FDGPET seems likely to deliver incremental diagnostic value inorthotopic heart transplantation (OHT) patients with non-specific suspicion of complications, which were inconclu-sive with conventional diagnostic procedures. Therefore, weaimed to test the fitness of whole-body [18F]-FDG PET fordetecting malignancies or infections in a consecutive seriesof heart transplant patients with non-specific symptoms andinconclusive conventional diagnostic evaluation.
Methods
Patients
We retrospectively identified 17 patients (9 women, 8 women),mean age 48 � 22 (range 5 to 71) years, who had undergonewhole-body [18F]-FDG PET. In all these patients, routine diagnos-tics, which included physical examination, chest X-ray, laboratorytests and abdominal ultrasonography, were ambiguous, resulting inthe decision to also perform a PET scan. Patients were followed inaccordance with the appropriate international guidelines.16 Thefollow-up data (abdominal ultrasonography, blood test, X-ray ex-
diography, myocardial biopsy, virology, bacteriology, mycology,histology or bone marrow biopsy) were assembled by chart review.
Whole-body [18F]-FDG PET and PET/CT
For this retrospective study, we queried our PET database for hearttransplant patients and then retrieved the patients’ charts for re-view. [18F]-FDG PET and PET/CT scans were evaluated as towhether they were diagnostically useful.
Whole-body PET scans were acquired in 3-dimensional (3D)mode extending from the proximal femur to the base of theskull in 9 patients and from the proximal femur including theskull in 4 patients. In another 4 patients, total-body scans wereperformed. In 10 of the 17 patients we performed a PET/CTscan (with either a Biograph 64 TruePoint PET/CT from Sie-mens Medical Solutions, or a GE Discovery 690 from GEHealthcare, Pollards Wood, UK). In the other 7 cases we per-formed PET without CT using a Philips Allegro scanner(Philips Medical Systems, Hamburg, Germany); 3 of thesepatients had a separate CT, and 4 patients had magnetic reso-nance imaging (MRI) within the week of the PET scan.
After patients had fasted for at least 6 hours, and blood glucoselevels were measured, a diuretic and an anti-spasmodic medicationwere administered intravenously, followed by bolus administrationof [18F]-FDG (mean 228 MBq). Just prior to the scan, patientswere asked to void their bladder, and then recline on the scanningbed. The emission sequence was initiated at approximately 60minutes after intravenous injection of the [18F]-FDG. Attenuationscanning was obtained either by CT or an external source. Twonuclear medicine physicians working side-by-side made a consen-sus evaluation of the final PET/CT or PET images using a dedi-cated software package (Hermes Hybrid Viewer, version 1.4;Hermes Medical Solutions, Stockholm, Sweden).
Results
Patients’ characteristics
For the 17 patients retrospectively included in our study, themean time between OHT and PET(/CT) was 8 � 6 (range0.1 to 21) years. Pre-transplant diagnoses necessitatingOHT were non-ischemic dilated cardiomyopathy (7 pa-tients), ischemic cardiomyopathy (6), congenital heart dis-ease (2) and retransplantation (1). At the time of PET, thepatients presented with non-specific symptoms including:lymphadenopathy (5 cases); persistent recurrent fever ofunknown origin (6); weight loss (5); abdominal pain, nightsweating or cough (1); or generally reduced physical con-dition (4). Fourteen of 17 patients presented with an unex-plained elevation of C-reactive protein (CRP) levels.Throughout the post-transplant interval, patients weretreated with immunosuppressive medication in accordancewith international guidelines,16 namely cyclosporine, myco-phenolate mofetil, tacrolimus, sirolimus and/or everolimus.Five patients (Patients 1, 3, 4, 5 and 6) received antibiotic,virustatic or anti-mycotic agents in addition to the immu-nosuppressive medication. Details of patient demographics
are presented in Table 1.
960 The Journal of Heart and Lung Transplantation, Vol 31, No 9, September 2012
Results of whole-body [18F]-FDG PET
The PET scan was rated positive in 13 of 17 patients (6 PETpatients vs 7 PET/CT patients) and negative in 4 cases (1PET patient vs 3 PET/CT patients). The diagnostic accuracyof [18F] FDG is presented in Table 2.
True positive results
PET detected the cause of non-specific symptoms in 9 of 17patients. In particular, in the subgroup analysis comparingPET vs PET/CT, 3 of 7 scans were rated positive in the PETgroup (43%) and 6 of 10 scans were rated positive in thePET/CT group (60%). Among these 9 true positive findingswe diagnosed lymphoproliferative diseases in 5 patients. In4 patients, the diagnosis of PTLD was histologically proven.We assessed tumor stage according to the Ann Arbor clas-sification of PTLD. In Patient 3, the lymphoma manifesta-tion was restricted to the small intestine only (tumor stageIE). Patient 6 had tumor manifestation only in the lymphnodes, in particular the cervical, axillary and hilar lymph
Table 1 Characteristics and Clinical Data of 17 Patients With
Pat. no.Gender/age(years)
Time betweenPET and HTx(years) Pathologic laboratory
sented with extranodal and nodal manifestation affectingliver, spleen and lymph nodes on both sides of the dia-phragm (tumor stage IIIS). Patient 8 (Figure 2) had mani-festation in the inguinal and iliac lymph nodes (tumor stageII1), which was diagnosed histologically as B-cell non-Hodgkin lymphoma. In 2 of the 9 patients with true positivefindings (Patients 9 and 15), we found tumor-characteristichigh [18F]-FDG uptake in the liver, with histologically ver-ified cholangiocellular carcinoma.
[18F]-FDG PET gave 2 correct diagnoses of infection. InPatient 14 (Figure 3), we diagnosed an infection at the site ofa hip prosthesis; joint aspirate was positive for coagulase-negative Staphylococcus and the prosthesis was removed. InPatient 13, we correctly detected a paraspinal abscess, whichwas cured after antibiotic treatment, as verified by subsequentMRI.
True negative results
In 3 patients (Patients 1, 10 and 11), we correctly could notdetect pathologic [18F]-FDG findings. All 3 patients underwent
ecific Symptoms After Heart Transplantation
icrobiology, virology PET findings
yte2, EBV negative Inconspicuous
yte2, thrombocyte2,ive
Pathologic uptake of mediastinal andabdominal lymph nodes, liver andspleen
Pathologic uptake of the smallintestine
300 and 10,000 Pathologic uptake of the aortic valve
yte1 Inconspicuous
ve titer indicative ofa
Pathologic uptake of lymph nodes,cervical, axillary, hilar
Pathologic uptake of the liverPathologic uptake of lymph nodes,
iliac and inguinalPathologic uptake of the liverInconspicuousInconspicuousPathologic uptake of ileum and
metatarsalsPathologic uptake paraspinalPathologic uptake of hip prosthesisPathologic uptake of the liverPathologic uptake of liver, spleen
dicative of a past Pathologic uptake of lymph nodes onboth sides of the diaphragm, liver,spleen
a PET/CT scan. During a mean follow-up of 10.6 (range 5.4 to
961Graute et al. PET for the Detection of Complications After HTX
17.8) months there was no clinical evidence of infection, tumormanifestation or any other pathologic finding.
False positive results
We evaluated 4 scans incorrectly as positive: 3 in the PETgroup and 1 in the PET/CT group. In Patient 4 we attributeda focal uptake of the aortic valve to endocarditis. However,no pathologic findings were documented on twice-repeatedtransoesophageal echocardiography. This patient was foundto have a high cytomegalovirus load, and underwent appro-priate therapy. In Patient 7 (Figure 4), we detected a focalhigh [18F]-FDG uptake in segment IV of the liver, whichappeared to be a tumorous lesion. However, biopsy was notsuspicious for malignancy, and the patient remained symp-tom-free during the follow-up of 4.5 years. In Patient 12, weconsidered focal uptakes in the ileum and in the metatarsalbone as local infections. However, an infection could not beproven in the follow-up and the patient has remained symp-tom-free for 4.6 years. In Patient 16, we incorrectly re-
Table 1 Continued from page 960.
Follow-Up Classific
Negative follow-up True neg
Positive histology for PTLD True pos
Positive histology for lymphoma True pos
Transesophageal echocardiography negative,treatment for CMV
False po
Blood culture positive for Actinomyces False ne
Positive histology for PTLD True pos
Negative histology and follow-up False poPositive histology for follicular B-cell non-Hodgkin
lymphomaTrue pos
Positive histology for CCC True posNegative follow-up True negNegative follow-up True negNegative follow-up False po
Antibiotic treatmentof the abscess True posExplantation of hip prosthesis, Staphylococcus True posPositive histology for CCC True posTreatment of panarteritis nodosa False poPositive histology for PTLD True pos
garded high uptake of the liver and the spleen as being
pathologic, but this was not confirmed by clinical follow-up,and the patient was treated for polyarteritis nodosa.
False negative results
The PET scan of Patient 5 was considered unsuspicious, butActinomyces was detected in the blood culture.
PET accuracy
[18F]-FDG PET yielded true positive findings in 9 patients,true negative in 3 patients, false positive in 4 patients andfalse negative in 1 patient, indicating sensitivity, specificityand positive and negative predictive values of 0.90, 0.43,0.69 and 0.75, respectively, and an overall diagnostic accu-racy of 0.71.
Discussion
To our knowledge, the present study is the first evaluation of
Medication: immunosuppressive agent, antibiotics, anti-mycotics, virustatica only
962 The Journal of Heart and Lung Transplantation, Vol 31, No 9, September 2012
heart transplant patients with symptoms suspicious for ma-lignancy. Revealing the cause of non-specific symptomsafter OHT poses a significant diagnostic challenge, partic-ularly given that routine laboratory tests, blood cultures,
Figure 1 A 70-year-old male patient who presented with abdominaand elevated CRP (3.1 mg/dl) at 8.3 years after heart transplantation. Win liver and spleen as well as in the mediastinal and abdominal lympof the PET scan confirmed the hepatomegaly and showed multiple inh
Table 2 Diagnostic Accuracy of Whole-body [18F]-FDG PETin Patients After HTx With Suspected OncologicDisease/Infections
the patient died 13 months after PET examination due to progressive liver
chest X-ray or abdominal ultrasound can be inadequate forunambiguous diagnosis. Morphologic changes may be ab-sent or minor in this setting, or may be too non-specific inthe initial phase of infection or neoplasm to permit a cleardiagnosis.
To date, there are minimal data on the utility of PETscanning in heart transplant patients, with the majority ofsuch studies being in other transplant populations. Even so,there have been only a few instances reported of using PETfor evaluation of PTLD in solid-organ transplantation. vonFalck et al17 evaluated the role of [18F]-FDG PET in bothinitial staging and therapy monitoring of 7 pediatric patientswho had PTLD after solid-organ transplantation. The trans-planted organs included the heart (n � 2), combined heartand lungs (n � 1) and the kidneys (n � 4). They showedthat [18F]-FDG PET was able to correctly identify all sitesof PTLD involvement as shown by CT/MRI. These findingsare in line with our present results, demonstrating reliablediagnostic accuracy in identification of PTLD using [18F]-FDG PET. Furthermore, von Falck et al reported that [18F]-FDG PET was able to demonstrate remission after therapyearlier than morphologic imaging modalities. However, toour knowledge, there has been, until now, no report focus-ing exclusively on heart transplant patients in a setting ofelucidating the cause of non-specific symptoms.
The main finding of the present study is that [18F]-FDGPET examinations served to determine correctly the cause
night sweating, weight loss, fever, leukocytopenia, thrombocytopeniaody [18F]-PET/FDG PET showed pathologic, inhomogeneous uptakes. Histology was positive for lymphoma. MRI performed at the timeneous pathologic lesions of the spleen. Despite aggressive treatment,
l pain,hole-b
h nodeomoge
failure and terminal renal insufficiency.
itive fo
963Graute et al. PET for the Detection of Complications After HTX
of non-specific symptoms in 12 of 17 patients (71%), ofwhom 9 were correctly rated as positive for disease and 3were correctly rated as having a negative [18F]-FDG PETscan. Of the 9 patients with disease plausibly accounting fortheir symptoms, we diagnosed lymphoproliferative dis-eases in 5 patients (4 PTLD, and 1 B-cell non-Hodgkinlymphoma), carcinoma in 2 and infections in 2. In theremaining 3 patients, we could correctly exclude malig-nancy or infection, giving an overall sensitivity of 90%and specificity of 43%.
In our patient cohort PET scans were the method of lastoption because the routine diagnostic results were difficultto interpret or inconclusive. The patient in this study cohortwas highly selective because the referring physicians se-lected patients in whom diagnosis was not already made byroutine methods and who likely have benefited from PET.At this point, we suspect that the selection bias influencedthe pre-test probability of PET and, consequently, sensitiv-ity and specificity.
The incremental diagnostic value of [18F]-FDG PET inpatients with fever of unknown origin (FUO) and carcinomaof unknown primary (CUP) has been examined in severalprevious studies, in one of which [18F]-FDG PET orPET/CT contributed to the correct final diagnosis in 16% to89% of the FUO cases.18 A recently published meta-anal-ysis of such studies showed that, overall, 32% of the [18F]-FDG PET examinations and 62% of the [18F]-FDG PET/CTexaminations contributed to obtaining a correct diagnosis in
Figure 2 A 47-year-old female patient who presented with exhashowed clearly pathologic tracer uptake in the external iliac lympthe inguinal lymph nodes. Histology of the lymph nodes was pos
the patients19; as in the earlier report, they also described a
considerable range in the contribution between studies,which they attributed to methodologic differences, includ-ing [18F]-FDG dose, time interval between [18F]-FDG ad-ministration and scanning, acquisition time for emissionscans, number and experience of interpreters, referencestandard used and the reference interpretation method. Inaddition, it must be considered that the particular diseasescausing FUO can depend on geographic/climatic factors andthe socioeconomic status of the patients, and that an earlydiagnosis depends on the extent of the physician’s experi-ence.18
In general, the most common reason for FUO amongnon-transplanted patient cohorts is infection (21% to 54%),followed by non-infectious inflammatory diseases (13% to24%) and neoplasm (6% to 31%).18 In contrast, we foundthat tumor manifestations were the leading cause of unclearsymptoms in heart transplant patients, accounting for 41%of our cases, whereas only 12% were attributable to infec-tion (1 prosthesis infection and 1 paraspinal abscess). In-deed, malignancy, especially PTLD, is the most commonlong-term complication in heart transplant patients,4 clearlyarising from prolonged immunosuppression.
For the case of CUP in non-transplant patients, recourseto [18F]-FDG PET has also improved diagnostic accuracy,and facilitated the identification of more tumor manifesta-tions than was possible using conventional modalities alone.A recently published systematic review of [18F]-FDG PETin patients with CUP syndromes20 reported sensitivity for
21 years after heart transplantation. Whole-body [18F]-FDG PETs on the right side, as well as less markedly pathologic uptake inr follicular B-cell non-Hodgkin lymphoma (Stage 1a).
ustionh node
primary tumor detection in the range 55% to 100%, and
964 The Journal of Heart and Lung Transplantation, Vol 31, No 9, September 2012
specificity in the range 73% to 100%, with pooled sensitiv-ity and specificity estimates of 84%. In that study, theprimary tumor detection rate was in the range 22% to 73%,with an overall detection rate of 37%. In general, CUPrepresents a heterogeneous group of metastatic tumors forwhich the primary site can be difficult or impossible to
Figure 3 A 54-year-old male patient who presented at 4.6 years awith CRP 4.7 mg/dl and creatinine 2.1 mg/dl. Whole-body [18F]-PX-ray examination of the prosthesis 2 weeks later showed a discrof loosening, but did not detect the infection. Diagnosis of anStaphylococcus was isolated, such that the PET result was ratedfollow-up.
ascertain. The most commonly detected locations of the
primary CUP tumor are lung (33%), oropharynx (16%) andpancreas (5%).20 Again, our finding of predominantly lym-phoproliferative diseases stands in contrast to these resultsin CUP patients, stressing the characteristic manifestation oftumors arising due to immunosuppression.
In general, [18F]-FDG trapping in tissue is an indicator of
art transplantation with a persistently elevated infection parameter,revealed focal tracer accumulation at the femoral head prosthesis.reased transparency around the head of the prosthesis, indicativetion was verified by needle aspiration of the hip, from which
positive for infection. The hip prosthesis was explanted during
fter heET/CTete inc
infecas true
cellular glucose metabolism, such that elevated trapping is
ed 3 w
965Graute et al. PET for the Detection of Complications After HTX
not specific for tumors or infections. Indeed, [18F]-FDG canalso accumulate in inflammatory lesions, in benign tumors,or in brown fat or other normal tissues. The main reason forthe false positive results in the present study was non-specific tracer uptake. In 1 such case, we misclassified afocal uptake of the aortic valve, reflecting the [18F]-FDGuptake in myocardium, which can be unaffected by fasting.Another source of false positive findings arises from thephysiologically high and frequently inhomogeneous [18F]-FDG uptake of liver, spleen and bowel, which was presentin 2 of our patients. Finally, focal uptake in the metatarsusof 1 patient was incorrectly assigned to a local infection, butwas later revealed by X-ray examination to be associatedwith a stress fracture.
In 1 of our patients, [18F]-FDG PET failed to revealany lesion accounting for the non-specific symptoms,despite the presence of Actinomyces in blood culture. Thepatient was being treated with vancomycin and cotri-moxazol at the time of the PET scan, which may havemasked focal organ manifestations of the infection. Inany event, chronic and sub-acute infections tend to haveonly slightly elevated glucose consumption relative tohealthy tissue, resulting in only marginally enhanced[18F]-FDG uptake.
For historic reasons, only 10 of 17 of the present caseswere examined with PET/CT, whereas the other 7 patientswere examined with a stand-alone PET scanner, with sub-sequent CT (3 patients) or MRI (4 patients). Using twoscanners was not only time-consuming, but in some casesalso made it difficult to allocate pathologic uptake to ana-tomic structures, due to the patients’ different bedding anddifferent in-/expiratory positions. In prospective studies, thesimultaneous acquisition of both imaging modalities shouldlikely reduce the incidence of false positive and false neg-ative results, given the ability of PET/CT to provide supe-rior anatomic assignment of suspected [18F]-FDG avid re-gions. Although [18F]-FDG uptake was the main parameterof interest in all 17 patients, the additional CT informationproved to be instrumental in allocating the pathologic up-take to an anatomic structure more precisely in 3 patients
Figure 4 Routine diagnostic abdominal ultrasonography of a 6hypoechoic lesion of the liver. Subsequent CT showed a correspon[18F]-FDG PET was performed for further clarification. The examas malignant, but for which a CT-controlled core biopsy perform
(Patients 3, 4 and 13). In Patient 3, focal [18F]-FDG uptake
could be attributed to the small intestine, in Patient 4 to thefemoral part of his hip prosthesis, and in Patient 13 to aparaspinal abscess.
Limitations
In this retrospective evaluation, we included patientsconsecutively. Thus, a potential selection bias affectingthe results of our study cannot be excluded. Furthermore,in this retrospective setting we included consecutive pa-tients with non-specific symptoms after OHT. In all pa-tients, PET scans were the method of last option becausethe routine diagnostic results were difficult to interpret orwere inconclusive. Consequently, the patient cohort washighly selective and necessarily biased; those patientswith unspecific symptoms in whom diagnosis was al-ready made by routine methods had no need for PETexamination. From this standpoint, we suspect that selec-tion bias has likely falsely decreased the utility of PET,and we would expect even higher values for sensitivityand specificity had PET been used prospectively in aroutine setting.
In conclusion, in this investigation we found that a non-invasive strategy of using whole-body [18F]-FDG PET orPET/CT in immunosuppressed heart transplant recipientswith non-specific, unexplained symptoms may provide di-agnostic stratification for malignancy and infections with ahigh sensitivity and modest diagnostic accuracy. Thesefindings require prospective confirmation. (Table 2).
Disclosure statementThe authors have no conflicts of interest to disclose. We thank DrPaul Cumming for a critical reading of the manuscript.
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