• View in gallery

    Flowchart of the selection of patients with visceral leishmaniasis.

  • View in gallery

    Coronal and cross-cut sections of computerized tomography (CT) (left), Positron emission tomography (PET)/CT (middle), and PET (on right) showing enhanced uptake in the spleen (standardized uptake value 6,8) with a diffuse and homogeneous pattern.

  • View in gallery

    Coronal section of Positron emission tomography (PET) (left) and PET/computed tomography (right) showing uptake in the spleen (standardized uptake value [SUV 5]) with a diffuse and heterogeneous distribution and splenomegaly (18 cm), compared with the liver (SUV 3.9).

  • View in gallery

    Cross-cut sections and coronal sections of computerized tomography (CT) (left), Positron emission tomography (PET)/CT (middle), and PET (right) showing enhanced splenic uptake (standardized uptake value [SUVmax] 14.9), with a diffuse and heterogenic pattern, as compared with liver uptake (SUVmax 6).

  • View in gallery

    Coronal section of diagnostic Positron emission tomography (PET) and PET/computed tomography showing enhanced uptake in the spleen with a homogeneous pattern (standardized uptake value [SUV] 4.9) as compared with the liver (SUV 3.4). Enhanced uptake is also seen in the bone marrow in a generalized pattern.

  • View in gallery

    Flowchart showing the steps of the search and selection process of the systematic review.

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Utility of Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Patients with Visceral Leishmaniasis: Case Report and Literature Review

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  • 1 Department of Infectious Diseases, Vall d’Hebron University Hospital, PROSICS Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain;
  • | 2 Grupo de Estudios de Infecciones por Micobacterias (GEIM), SEIMC, Madrid, Spain;
  • | 3 Department of Nuclear Medicine, Vall d’Hebron University Hospital, Barcelona, Spain

ABSTRACT

The diagnosis of visceral leishmaniasis (VL) is complicated and often unsuspected. Little is known of the usefulness of nuclear imaging in VL. Our objective was to describe findings seen in fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in cases of VL. We retrospectively reviewed VL cases diagnosed at Vall d’Hebron University Hospital from May 2012 to May 2018 and selected those that had an FDG-PET/CT performed. Information on procedures and details of the FDG-PET/CT features and follow-up were collected. We then systematically reviewed the literature on VL and FDG-PET/CT. Four of 43 patients diagnosed with VL had an FDG-PET/CT performed. All four patients presented diffuse splenic uptake of FDG-PET/CT. Adenopathy was not always present, and bone marrow uptake was found in two patients. A posttreatment FDG-PET/CT in one patient revealed normalization of initial findings. In the literature review, 43 of 50 cases presented similar splenic uptake in the PET/CT, being described as different patterns: “increased metabolism,” “homogeneous,” “diffuse,” “diffuse and multifocal,” “nodular,” “patchy and granular,” “subcortical,” and “compatible with lymphoma.” Other frequent findings were bone marrow uptake and adenopathies. We, therefore, conclude that FDG-PET/CT could become a useful tool for the diagnosis and follow-up of VL and that VL should be taken into account in patients with fever of unknown origin with enhanced splenic uptake in FDG-PET/CT. Differential diagnosis in these cases should be made with splenic primary lymphoma, virus infections, chemotherapy, and colony-stimulating factor therapy. Further structured studies with more cases are needed to define its diagnostic and prognostic value.

INTRODUCTION

Leishmaniasis is a parasitic disease caused by flagellated protozoa of the Leishmania family. Visceral leishmaniasis (VL) causes a very unspecific clinical spectrum that usually manifests with fever, malaise, analytic alterations, and hepatosplenomegaly.1 Nonetheless, these symptoms are not always present, especially in immunosuppressed (IS) patients, which complicates diagnosis.2

It is estimated that every year around 50,000–90,000 cases of VL occur worldwide. Untreated VL is lethal in more than 95% of cases.1 The WHO considers VL endemic in Spain and other Mediterranean countries.3

The diagnosis of VL is based on the direct visualization of amastigotes in tissue samples or the visualization of promastigotes after culture in specific means. Another technique currently accepted is DNA detection through the PCR method in tissue samples.4 Imaging modalities are rarely used in the diagnosis of VL, and there are experiences with findings in ultrasonography, computerized tomography (CT), and magnetic resonance imaging,5,6 but there is little information regarding fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in VL, especially in IS patients.7 The aim of our study was to describe the FDG-PET/CT findings in patients with VL in our institution and those found in a systematic literature review.

MATERIALS AND METHODS

A retrospective study was performed using data from patients diagnosed with VL in Vall d’Hebron University Hospital in Barcelona (Spain) over the period of May 2012–May 2018. Adult patients who were diagnosed with VL and had an FDG-PET/CT performed were included. We excluded patients younger than 18 years and other types of presentation of Leishmania. We retrieved clinical data and FDG-PET/CT data from all selected patients using an electronic medical record.

Literature review.

We performed a systematic review of the literature to identify articles with information regarding patients with VL and FDG-PET/CT. The following search strategy (keywords and Boolean operators) without language restriction was conducted in various databases (Medline, ScienceDirect, Web Of Science, Cochrane, and Google Scholar): (“Leishmaniasis, Visceral”) AND (“Positron-Emission Tomography”).

Evidence summary tools such as UpToDate and Trip databases were reviewed for records. We also performed a manual search strategy of the references of selected articles and searched the gray literature for additional information. We selected relevant studies that reported on the use of FDG-PET/CT in patients with VL and were peer-reviewed with the full text available.

Fluorodeoxyglucose positron emission tomography/computed tomography.

All patients from our cohort fasted for 6 hours before PET/CT scanning to achieve blood glucose concentrations < 150 mg/dL. Images were obtained from the skull base to the proximal third thigh 1 hour after fludeoxyglucose intravenous administration of about 3.7 MBq/kg. An iodine-based intravenous contrast agent was also used. All images were evaluated by two medical experts in nuclear medicine who were blinded to clinical information.

Ethical consideration.

The study was approved by our Ethical Review Board. We followed ethical standards detailed in the Declaration of Helsinki 2013. An informed consent waiver was granted by our review board because of the retrospective nature and the absence of intervention.

RESULTS

During the study period, 43 patients were diagnosed with Leishmania spp. infection, and four patients had VL and an FDG-PET/CT performed. A flowchart is shown in Figure 1.

Figure 1.
Figure 1.

Flowchart of the selection of patients with visceral leishmaniasis.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 3; 10.4269/ajtmh.19-0858

Cases presentation.

Table 1 shows comparative diagnostic data of the four cases of VL in our institution. Table 2 depicts FDG-PET/CT characteristics of the four cases.

Table 1

Comparative data and clinical presentation of patients in our cohort

Patient informationCase 1Case 2Case 3Case 4
ImmunodepressedYesNoNoYes
Biopsy locationBone marrowBone marrowLiver biopsy and bone marrowBone marrow
Biopsy resultsLeishmania spp. amastigotesLeishmania spp. amastigotesLiver biopsy: Leishmania spp. amastigotesLeishmania spp. amastigotes
Bone marrow: 50% hemophagocytosis, without evidence of Leishmania spp.
PCR for Leishmania spp.NDBone marrow aspiration: L. infantumBone marrow aspiration: L. infantumBone marrow aspiration: L. infantum
Blood: L. infantumBlood: L. infantumBlood: L. infantum
PancytopeniaYesNo (only leukopenia and anemia)YesYes
Serology for Leishmania spp.NDAntibodies against L. infantumAntibodies against L. infantumND
Other imaging techniques and findingsCT scan: splenomegaly and enlargement of mediastinal adenopathyCT scan: homogeneous hepatomegaly and heterogeneous splenomegaly with hypodense pseudonodular images suggestive of lymphoma; retroperitoneal adenopathyAbdominal ultrasound: hepatic steatosisChest CT scan: upper abdomen without significant alterations, bilateral pleural effusion, peribronchial pulmonary opacities of possible infectious inflammatory origin
CT scan: global cardiomegaly, mild bilateral pleural effusion, small intrapulmonary cystic lesions in both lower lobes, homogeneous hepatic parenchyma, splenomegaly of 130 mm; a mesenteric panniculitis

CT = computerized tomography; L. infantum = Leishmania infantum; ND = not done; spp. = species pluralis.

Table 2

Fluorodeoxyglucose positron emission tomography/computerized tomography details in cases of visceral leishmaniasis in our cohort

CaseCase 1Case 2Case 3Case 4
Details (uptake)SUVmaxSize (mm)Details (uptake)SUVmaxSize (mm)Details (uptake)SUVmaxSize (mm)Details (uptake)SUVmaxSize (mm)
OrganSpleenDiffuse and homogeneous6.8120Diffuse and discreetly heterogeneous5180Diffuse and heterogeneous14.9140Diffuse and homogeneous4.9110
LiverNormal6.1Hepatomegaly3.9Normal6Normal3.6
AdenopathyParatracheal (×2)*6.1/7.112 × 17/17 × 18Hepatic hilum5.6ConglomerateRight axillary (×5)17.5–18.68 × 12No alterationsNo uptake
Para-aortic3.412 × 13
Retroperitoneal3.6Conglomerate
Internal mammary node4.311 × 7
Bone marrowNo alterationsGloballyNot measuredNo alterationsLight uptake globallyNot measured
LungBase of the right lung (fibrosis)8.5Irregular

SUV = standardized uptake value.

More likely related to respiratory infection.

The general uptake in the bone marrow depends on the visual pattern and not on the SUVmax, unless there is a focal lesion.

Case 1 is a 63-year-old woman from Tarragona (Spain) with a medical history of a left lung transplant due to idiopathic pulmonary fibrosis. The patient came to the emergency department a year after the transplant because of fever, dyspnea on exertion, and diarrhea. Initial blood analyses revealed pancytopenia and worsened renal function. A CT scan showed an enlarged spleen, and FDG-PET/CT revealed discrete and diffuse splenic uptake of FDG, without any focal lesions (Figure 2). Bone marrow biopsy showed abundant intra- and extracellular amastigotes of Leishmania spp. Liposomal amphotericin B therapy was administered, and low doses of immunosuppressant drugs were maintained. Despite treatment, the patient died 2 days later because of refractory respiratory failure and sepsis by Enterococcus faecalis.

Figure 2.
Figure 2.

Coronal and cross-cut sections of computerized tomography (CT) (left), Positron emission tomography (PET)/CT (middle), and PET (on right) showing enhanced uptake in the spleen (standardized uptake value 6,8) with a diffuse and homogeneous pattern.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 3; 10.4269/ajtmh.19-0858

Case 2 is an 18-year-old man from Lérida (Spain) with daily nocturnal fever, weight loss, and abdominal pain for 2 months. A CT scan revealed hepatomegaly and heterogeneous splenomegaly with hypodense pseudonodular images suggestive of lymphoma. Blood analyses revealed anemia, leukopenia, and elevated reactive C protein (RCP). An FDG-PET/CT study was requested showing splenomegaly, with diffuse and heterogeneous increase in FDG uptake, also a diffuse uptake in the bone marrow (Figure 3). Bone marrow biopsy was taken showing macrophages with Leishmania spp. amastigotes and even some extracellular Leishmania spp. amastigotes. The patient was treated with liposomal B amphotericin, and after 6 months, the patient had recovered and the PCR for Leishmania spp. in peripheral blood was negative and a CT scan showed a homogenous and normal sized spleen.

Figure 3.
Figure 3.

Coronal section of Positron emission tomography (PET) (left) and PET/computed tomography (right) showing uptake in the spleen (standardized uptake value [SUV 5]) with a diffuse and heterogeneous distribution and splenomegaly (18 cm), compared with the liver (SUV 3.9).

Citation: The American Journal of Tropical Medicine and Hygiene 104, 3; 10.4269/ajtmh.19-0858

Case 3 is a 73-year-old man who came to the emergency department at our hospital suffering from fever, anorexia, and fatigue for 3 weeks. A blood test revealed pancytopenia, elevated RCP and lactate dehydrogenase, and elevation of liver enzymes. Microbiological results retrieved were negative. A CT scan revealed splenomegaly and mesenteric panniculitis. To further investigate the fever of unknown origin, an FDG-PET/CT was performed that revealed slight splenomegaly with intense and diffuse hypermetabolism of pathological characteristics (Figure 4). Also, a infracentimetric adenopathy in the right axillary region was reported. Bone marrow biopsy revealed the mononuclear phagocyte system with hemophagocytosis in 50% of cells. No organisms compatible with parasites were identified. So, with this result and progressive pancytopenia and affected liver enzymes, a transjugular liver biopsy was performed. While waiting for histological results, PCR results on bone marrow came back positive for Leishmania infantum, so liposomal amphotericin B was administered. Steroid treatment was added because of the diagnosis of secondary hemophagocytic syndrome. An FDG-PET/CT was requested 3 weeks after beginning treatment with a normalization of the splenic uptake, with reduction of uptake of the right axillary adenopathy, but the appearance of mesenteric and left para-aortic adenopathy was considered secondary to the already known mesenteric panniculitis. Eleven months later, the patient was asymptomatic, and PCR for L. infantum in peripheral blood remained negative.

Figure 4.
Figure 4.

Cross-cut sections and coronal sections of computerized tomography (CT) (left), Positron emission tomography (PET)/CT (middle), and PET (right) showing enhanced splenic uptake (standardized uptake value [SUVmax] 14.9), with a diffuse and heterogenic pattern, as compared with liver uptake (SUVmax 6).

Citation: The American Journal of Tropical Medicine and Hygiene 104, 3; 10.4269/ajtmh.19-0858

Case 4 is a 60-year-old man from Tarragona (Spain) with a bilateral lung transplant due to severe chronic obstructive pulmonary disease. Ten months after the transplant, he presented anemia that progressed to pancytopenia that was initially attributed to the prophylactic antiviral treatment for cytomegalovirus infection, so the medication was modified. The patient subsequently presented fever and slight dyspnea. An FDG-PET/CT revealed an increased uptake of FDG in the spleen with a diffuse and homogeneous pattern and global uptake in the bone marrow (Figure 5). Bone marrow biopsy revealed amastigotes in bone marrow macrophages. Treatment with liposomal amphotericin B was administered. After 6 months of follow-up, the patient did not show any sign of recurrence.

Figure 5.
Figure 5.

Coronal section of diagnostic Positron emission tomography (PET) and PET/computed tomography showing enhanced uptake in the spleen with a homogeneous pattern (standardized uptake value [SUV] 4.9) as compared with the liver (SUV 3.4). Enhanced uptake is also seen in the bone marrow in a generalized pattern.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 3; 10.4269/ajtmh.19-0858

Details of FDG-PET/CT in our cohort.

In all four clinical cases, the FDG-PET/CT showed FDG uptake in the spleen with a maximum standardized uptake value (SUVmax): case 1 = 6.8, case 2 = 5, case 3 = 14.9, and case 4 = 4.9. The average SUVmax was 7.9. In all four cases, the uptake was diffuse and mostly homogeneous (except in case 2 that presented a discretely heterogeneous uptake). In three of the four cases, abnormal uptake in various lymph nodes was seen.

The main difference between IS and immunocompetent patients was the uptake in the spleen. In the immunocompetent patients, it was more heterogeneous than that in the IS patients, but both had a diffuse pattern. Two of the four patients had increased and generalized FDG uptake in the bone marrow. The details of the FDG-PET/CT are summarized in Table 2.

Literature review.

Our search retrieved a total of 1,049 articles. After reading the title/abstract and following exclusion criteria, we selected 26 articles with 50 clinical cases. Search in UpToDate and Trip databases did not reveal any additional information on the use of FDG-PET/CT in VL patients. The manual search and gray literature search did not add any relevant articles. We did not find any prospective studies or clinical trials. Figure 6 depicts the flowchart of the systematic review, detailing the steps of the search and selection process. Table 3 summarizes the extracted data from the selected articles.

Figure 6.
Figure 6.

Flowchart showing the steps of the search and selection process of the systematic review.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 3; 10.4269/ajtmh.19-0858

Table 3

Details of the cases found in the literature

ArticleGender and age (years)IMDClassical symptomsDiagnosis and speciesSplenomegalyUptake by spleenUptake by other partsOther imaging techniques and findings
CDC17*(USA)M NDNoCachexiaBM and liver biopsy and culture −YesFindings suggestive of lymphomaNot mentionedND
FeverPCR BM −
PancytopeniaRetrospective liver biopsy Leishmania spp. +
Hepatosplenomegaly
Lupi27 (Italy)M 48Not mentionedFeverBM biopsy Leishmania spp.NoVery marked patchy and granular aspectDiffuse BM and increased uptake in the liverND
CachexiaHypermetabolism in the spleen
Casadevall25 (France)M 19Yes (HIV)FeverSerology L. infantum +NDIncreased isolated uptake (pseudonodular and heterogeneous)Diffuse BMND
PancytopeniaBM biopsy −
BM PCR + for Leishmania spp., Western blot +
Yapar19 (Turkey)F 51Not mentionedSplenomegalyHistology of splenectomy Leishmania spp. BM biopsy −Yes (exact size ND)Diffuse uptakeSplenic hilar, lymph nodes, hypermetabolic lymph node on poles of kidneys and diffuse BMND
Other not mentioned
Vase30 (Denmark)M 60Yes (steroids)FeverBM biopsy 2004/2007 hyperplastic (Second review: + for Leishmania spp.)Yes (exact size ND)CT scan: moderate splenomegaly
CachexiaBM biopsy 2010 Leishmania spp.
Leukopenia and thrombocytopeniaRetrospective review of the spleen + for Leishmania spp., kidney biopsy + for Leishmania spp.
PCR L. infantum + in cultures
Ravaglia 20129 (Italy)F 42Yes (steroids and immunosuppressive drugs)FeverBM biopsy Leishmania spp.Yes (exact size ND)Increased metabolismLiver, thoracic, and abdominal lymph nodes and D3 vertebra and bilateral nodular infiltratesCT scan: bilateral nodules of variable sizes in upper lung fields
Hepatosplenomegaly
Lymphopenia and anemia
Kyrtatos24 (France)M 44Yes (HIV)FeverBM biopsy −Yes (exact size ND)First PET/CT multifocal areaFirst PET/CT retroperitoneal lymph nodes, diffuse BMCT scan: hypertrophic multinodular spleen
PancytopeniaPeripheral blood PCR and serology Leishmania spp. +Second PET/CT decreased uptakeSecond PET/CT decreased uptake in retroperitoneal nodal lesions
BM PCR +
Berry13 (Australia)F 69Yes (immunosuppressive drugs)FeverFirst BM biopsy − (Second review: + for Leishmania spp.)Yes (exact size ND)Increased metabolismNoneCT scan: unchanged pulmonary nodularity and new splenomegaly
PancytopeniaHistology and PCR splenic tissue L. infantum +
Second BM biopsy Leishmania spp.
Martin8 (Belgium)NDYes (HIV)FeverBM biopsy +NDNot specifiedCervical adenopathyND
Other not mentioned
Evers12 (Germany)M 57NoFeverFirst BM aspiration −Yes (209 × 67 mm)Increased metabolismNot mentionedND
HepatosplenomegalySecond BM aspiration L. infantum
PancytopeniaSerology Leishmania spp.
Peripheral blood PCR Leishmania spp. +
Spleen biopsy L. infantum
Fuertes28 (Spain)F NDNoFeverSpleen and liver histology Leishmania spp. +NDIncreased metabolism (subcortical uptake)First PET/CT visceral and parietal left pleura, inflammatory/infectious pleuritis, left internal mammal artery lymph node, ascending colonND
Second PET/CT multiple subcortical hypodense images in the spleen
Chianura20 (case 1) (Italy)F 53Yes (renal transplant)FeverSerology −Yes (150 mm)Diffuse increased metabolismNot mentionedAbdominal US: splenomegaly
PancytopeniaBM biopsy Leishmania spp. +CT scan: splenomegaly
Chianura20 (case 2) (Italy)M 45Yes (HIV)CachexiaSerology −Yes (150 mm)Diffuse increased metabolismDiffuse in the spineAbdominal US: splenomegaly
PancytopeniaBM biopsy Leishmania spp. +CT scan: splenomegaly
Gallina15 (Italy/Austria)M 72NoFeverSerology IgG Leishmania spp. +Yes (141 mm)Increased metabolismBM mild and homogeneousUS: splenomegaly
PancytopeniaBM biopsy Leishmania spp. +
Gibson26 (Australia)M 48NoFeverSpleen histology Leishmania spp. +YesIncreased metabolism with multiple nodulesDiffuse BMND
Hepatosplenomegaly
CachexiaSpleen PCR L. donovani +
Pancytopenia
Mao11 (southeast China)M 45NoFeverSerology Leishmania spp. +YesIncreased metabolismNot mentionedAbdominal US: splenomegaly with heterogeneous parenchyma due to multiple hypoechoic nodules.
CachexiaBM aspirate +CT scan: splenomegaly with contrast multiple hypodense nodules with mild ring-like enhancement
PancytopeniaMagnetic resonance imaging: splenomegaly and multiple inhomogeneous parenchymal lesions and infarction in anterior aspect of the spleen
Van Raalte14* (Netherlands)M 69NoFeverBM biopsy and PCR + L. infantumYesIncreased uptakeBM
Cachexia
Pancytopenia
Splenomegaly
Prajapati29* (India)M 52NoFeverBM biopsy −YesDiffuse BM uptake and chronic disease of liverAbdominal US: Grade 1 fatty liver, mild splenomegaly with minimal ascites
HepatosplenomegalySerology IgG Leishmania spp. +CT scan: splenomegaly early chronic liver disease and mild ascites
PancytopeniaLiver biopsy Leishmania spp. +
Eichenberger10 (Switzerland)M 80Yes (steroids, immunosuppressive drugs)FeverPeripheral blood PCR L. donovani +Yes (180 mm)Increased metabolismEnhancement throughout the colon, liver, lymph nodes, and basal compartments of the lungsND
Hepatosplenomegaly
Leukopenia
Colon biopsy and PCR Leishmania spp. +
Liver biopsy
L. donovani +
BM biopsy L. donovani +
Schwertz18 (Austria)M 60NoFeverPeripheral blood PCR L. donovani +Yes (164 mm)Homogeneous uptakeBM central and peripheralAbdominal US: Splenomegaly
Cachexia
Anemia and thrombocytopeniaBM biopsy and PCR Leishmania spp. +
Tatarelli21* (Italy)M 24YesFeverBM aspiration Leishmania spp. +Yes (165 mm)Diffuse splenic uptakeFirst PET/CT: abdominal lymph node enlargementND
Diffuse BM uptake
Peripheral blood PCR
Second PET/CT −
Leishmania spp. +
Hemopoietic cell transplant
Pancytopenia
Serology Leishmania spp. +
Sayin22 (case 1) (Turkey)M 49Yes (steroid treatmentFeverFirst BM biopsy −YesDiffusely increased uptakeNot mentionedNot specified
Hepatosplenomegaly
Second BM biopsy +
Cachexia
Splenic tissue −
PancytopeniaSerology Leishmania spp. +
 Sayin22 (CASE 2) (Turkey)F 75NoFeverBM biopsy −YesDiffuse splenic uptake, superimposed areas of multifocal hypodense nodulesBM all areasNot specified
Hepatosplenomegaly
Splenic tissue −
Pancytopenia
Serology Leishmania spp. +
Machelart16* (France)M 76NoFeverSecond BM aspirate − (Second review: PCR + for Leishmania spp.)YesIncreased uptakeInguinal glandsCT scan: hepatosplenomegaly
Pancytopenia
Hepatomegaly
BM biopsy − splenic tissue + L. infantum
Serology Leishmania spp. +
PCR serum, BM and spleen Leishmania spp. +
Rinaldi5 (Italy)M 32NoFeverSerology Leishmania spp. −Yes (200 mm)Diffuse and superimposed multifocal uptakeNot mentionedAbdominal US: splenomegaly with multiple hypoechoic lesions
SplenomegalyCT scan: splenomegaly with multiple hypointense splenic lesions
Pancytopenia
PCR Leishmania spp. + in BM biopsy and serum
Martinez de Narvajas23 (Spain)M 55NoFeverIgG serology Leishmania spp. +Yes (150 mm)Diffuse high uptake in the spleenLiver and BMAbdominal US: hypoechoic lesion suggestive of subcapsular infarction
PancytopeniaIgM serology Leishmania spp. −CT scan: splenomegaly and several splenic infarctions
BM aspiration 2212
Liver biopsy Leishmania spp. +
PCR liver tissue + L. infantum
Zanoni7 (Italy) Study with 23 casesM: 22 patientsIMD: two patientsNot mentionedNot mentionedNDSplenic uptake: 21 patientsBM diffuse uptake: 13 patientsNot mentioned
F: one patientDiffuse pattern: 13 patientsLymph nodes: six patients (two abdominal, two mediastinal, two supra- and subdiaphragmatic localization)
Median age: 60 yearsFocal over diffuse: seven patientsLung uptake: one patient
Zhang31* (China)M 25NoFeverFirst BM biopsy and aspirationYesNo pathological uptakeNot mentionedND
Second BM biopsy + L. donovani
HepatosplenomegalySerology + L. donovani
Pancytopenia

BM = bone marrow; CT = computerized tomography; F = female; 18F-FDG = fludeoxyglucose; IMD = immunodeficiency; L. donovani = Leishmania donovani; L. infantum = Leishmania infantum; M = male; spp. = species pluralis; ND = no data; PET/CT = Positron Emission Tomography/Computed Tomography; US = ultrasound.

All PET/CT use 18 FDG tracer, except eight (Myles,17 Ravaglia,9 Van Raalte14, Vase30, Prajapati29, Tatarelli21, Machelart16 and Zhang31) that did not mention the tracer in the article.

We found FDG uptake in the spleen in 43 of the 50 cases in the literature. In the article by Martin et al.,8 the description of FDG-PET/CT was not detailed. The uptake pattern was described specifically in 34 of the 43 cases. The remaining nine cases were simply described as an increased metabolism in the spleen916 or an uptake compatible with lymphoma.17 In the other cases, the FDG uptake in the spleen was described as “homogeneous” in one case,18 “diffuse” in 19 cases,7,1923 “diffuse and multifocal” in 10 cases,5,7,22,24 “nodular” in two cases,25,26 “patchy and granular” in one case,27 and “with subcortical uptake” in one case.28

The pattern of the uptake was variable, and information was not always available in the cases reported in literature. We classified the patterns in two groups: “homogeneous and diffuse” and “multifocal” pattern were included in the diffuse group and the “patchy and granular,” “subcortical uptake,” and “pseudonodular pattern” were considered as focal/nodular.

In 27 cases, enhanced uptake was seen in the bone marrow. Of these, five cases were IS patients,9,20,21,24,25 20 cases were in immunocompetent patients,7,14,15,18,22,23,26,29 and in two cases, the immune state was unknown.19,27 Bone marrow biopsy revealed Leishmania spp. amastigotes in three of the IS patients,9,20,21 with PCR for Leishmania spp. being positive in the remaining two.24,25 Biopsy was positive for Leishmania spp. in three non-IS patients.14,15,18 Of the remaining cases with enhanced bone marrow uptake, three biopsies were negative22,23,29 and 14 cases did not undergo bone marrow biopsy or had no information available.7,26

Lymph node involvement was only mentioned in 13 cases (five IS810,21,24 and eight non-IS7,16,28). The other cases did not present enough information or did not specify other findings and, therefore, remained as unknown FDG uptake status.

The species of Leishmania was specified in 10 patients, showing L. infantum in six cases1214,23,25,30 and Leishmania donovani in the remaining four patients.10,18,26,31 Splenectomy was performed in seven patients because of initial suspicion of malignancy.12,13,16,19,26,28,30

DISCUSSION

Fluorodeoxyglucose positron emission tomography/computed tomography is widely used in oncology to diagnose, stage, and evaluate response to treatment32 and in the diagnosis of fevers of unknown origin.33 Little is known about the diagnostic potential of FDG-PET/CT in VL, especially in IS patients.7

We include 54 cases of VL with PET/CT undertaken, 15 IS cases, 37 immunocompetent cases, and two unknown immune status cases. Enhanced splenic uptake in FDG-PET/CT was seen in 47 patients diagnosed with VL. The predominant pattern was a “diffuse” pattern, detected in 55.3% (26 cases),5,7,1823 followed by “focal/nodular” pattern in 25.5% (12 cases).7,24,25,27,28 There was no uptake in the spleen in seven cases.7,2931 There was a “diffuse” uptake in 51.3% of immunocompetent patients and 40% of IS patients, and a “focal/nodular” pattern was found in 24.3% of immunocompetent patients and 13.3% of IS patients.

Enhanced lymph node uptake was seen in 17 cases (six cases, IS patients810,21,24; 10 patients, non-IS patients7,16,28; and one case immune status unknown19). However, information on nodal uptake was not always available or clear, so the remaining cases cannot be assumed as negative.

Enhanced bone marrow metabolism was seen in 29 cases (six IS cases, 21 non-IS, and two immune status unknown).7,9,14,15,1827,29 Of these, four resulted in a negative biopsy for Leishmania spp.,19,22,23,29 one was not biopsied,26 and 11 cases were positive,9,14,15,18,20,21,24,25,27 with six cases being IS, four cases non-IS, and one unknown. In the remaining 13 cases, biopsy was not specified.7 Interestingly, 13 cases showed no bone marrow uptake but had a positive bone marrow aspiration.5,1013,16,17,20,22,30,31

In oncology, studies have shown that the extent of FDG uptake in neoplasms is positively correlated with the number of malignant cells, and there is a higher biopsy yield in the most enhanced areas.34 We therefore infer that enhanced bone marrow uptake could correlate with a higher parasitic replication rate and increase the diagnostic yield of bone marrow biopsies.

It seems that the diagnostic yield of bone marrow biopsy was higher in IS patients than immunocompetent patients. In addition, lymph node involvement and enhanced bone marrow uptake were more frequent in immunocompetent patients. Of note, the most predominant pattern in both groups was a “diffuse pattern.”

In IS due to HIV, Leishmania amastigotes can be found in atypical locations (gastrointestinal, pulmonary, or laryngeal regions), and clinical presentation can be atypical and hard to suspect.2 Surprisingly, however, only one case of the 15 IS patients showed enhanced uptake in organs other than the spleen, liver, or bone marrow.10

Differential diagnosis of FDG splenic uptake includes conditions such as splenic focal infarcts and abscesses, infectious granulomatous diseases such as tuberculosis or brucellosis, and inflammatory granulomatous diseases such as sarcoidosis and viral infections. Splenic uptake of FDG can also occur in malignancies such as primary splenic lymphoma, metastasis, and other non-Hodgkin lymphomas and can be secondary to chemotherapy and treatment with colony-stimulating factors.35

One of the main patterns that may have a similar uptake is the splenic marginal zone lymphoma (SMZL). The SMZL accounts for 1% of all B-cell lymphomas. Fluorodeoxyglucose positron emission tomography/computed tomography findings in SMZL are unclear, but recent studies show a diffuse or focal uptake pattern in the spleen, with an SUVmax of 2.3 points higher than the liver.36 Lymph node involvement is less frequent in SMZL than that in other non-Hodgkin lymphomas.37 An FDG-PET/CT with enhanced FDG avidity in the spleen, liver, bone marrow, and/or lymph nodes may occur in VL or SMZL, among others. Therefore, Leishmania spp. should be ruled out before splenectomy.4,38 Noninvasive methods such Leishmania spp. peripheral blood PCR should be encouraged, and results should guide the diagnostic approach.

Interestingly, FDG-PET/CT could be used as a noninvasive follow-up tool. In two cases, a posttreatment FGD-PET/CT showed a reduction in splenic and lymph node uptake.24 The FDG-PET/CT could also be useful in the follow-up of HIV patients with recurrent VL.38 In these cases, imaging could be used as a noninvasive diagnostic tool for early detection of recurrences in addition to Leishmania spp. PCR in peripheral blood.38

Our study has some limitations, inherent to its retrospective nature and limited cases reported in the literature. In addition, our review found no reported cases of VL with FDG-PET/CT in children, limiting the generalizability of our results in this population. Moreover, FDG-PET/CT images vary in quality and characteristics depending on the detection machines and protocols used in different hospitals. Narrative description of the uptake pattern does not follow any standardized guidelines, adding extra heterogeneity to stratification of the finding. Despite all these limitations, this study could help increase the limited information concerning VL and FDG-PET/CT.

In conclusion, we deem that the FDG-PET/CT study could become a useful tool in the diagnosis and follow-up of VL. The most frequent finding was enhanced splenic uptake with a diffuse pattern. The differential diagnosis in these cases should include viral infections, chemotherapy and colony-stimulating factors, and lymphomas with splenic activity. Further structured studies with more cases are needed to better define its diagnostic and prognostic value.

ACKNOWLEDGMENTS

We thank the Department of Nuclear Medicine of Vall d’Hebron University Hospital in Barcelona for the opportunity of presenting our cases in the clinical session on February 11, 2019.

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Author Notes

Address correspondence to Adrián Sánchez-Montalvá, Departamento de Enfermedades Infecciosas, Hospital Universitario Vall d’Hebron, Passeig Vall d’Hebron, 119-129, Edificio General, 6a planta, Barcelona 08035, Spain. E-mails: adsanche@vhebron.net or adrian.sanchez.montalva@gmail.com

Disclosure: A. S.-M. is supported by a postdoctoral grant “Juan Rodés” (JE18/00022) from Instituto de Salud Carlos III through the Ministry of Economy and Competitiveness, Spain.

Authors’ addresses: Harriet P. Pinnegar, Adrián Sánchez-Montalvá, Pau Bosch-Nicolau, Fernando Salvador, and Israel Molina, Department of Infectious diseases, Vall d’Hebron University Hospital, PROSICS Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain, E-mails: harrietphyllispinnegar@gmail.com, adsanche@vhebron.net, pau.boschnicolau@gmail.com, medinano@yahoo.es, and israelmolina@ymail.com. Marta Barios Profitos, Department of Nuclear Medicine, Vall d’Hebron University Hospital, Barcelona, Spain, E-mail: mbarios@vhebron.net.

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