INTERESTING IMAGE

AIDS-Related Central Nervous System Toxoplasmosis With
Increased 18F-Fluoroethyl-L-Tyrosine Amino Acid PET Uptake
Due to LAT1/2 Expression of Inflammatory Cells
Markus Hutterer, MD,*†‡ Elisabeth Bumes, MD,†‡ Markus J. Riemenschneider, MD,‡§
Jirka Grosse, MD,‡|| Dirk Hellwig, MD,‡|| Norbert Galldiks, MD,¶**††
Karl-Josef Langen, MD,¶‡‡ and Peter Hau, MD†‡
Abstract: We report the case of a 40-year-old woman with a progressive
right-sided hemiparesis. Standard MRI revealed a contrast-enhancing brain
lesion within the left basal ganglia. 18Ffluoroethyl-L-tyrosine (18F-FET) PET
showed a distinct tracer uptake (lesion-to-brain ratio [LBR]: LBRmax = 2.03,
LBRmean = 1.68) with a significant larger metabolic lesion volume than
contrast-enhancement in MRI, indicating cerebral glioma. Surprisingly, histopathologic analysis demonstrated central nervous system toxoplasmosis
with pronounced inflammatory reaction (reactive astrogliosis, microglia activation, macrophage, and T-lymphocyte infiltration), which was associated
with strong LAT1/LAT2/CD98 expression. In conclusion, inflammatory
brain lesions, such as cerebral toxoplasmosis, represent a potential pitfall
of 18F-FET PET mimicking a brain tumor.
Key Words: 18F-FET PET, brain tumor, CNS toxoplasmosis,
MRI, LAT1/LAT2/CD98 expression
(Clin Nucl Med 2017;00: e00–e00)

Received for publication March 9, 2017; revision accepted September 20, 2017.
From the *Department of Neurology 1, NeuroMed Campus, Kepler University
Hospital, Linz, Austria; †Department of Neurology, ‡Wilhelm Sander
Neurooncology Unit, and Departments of §Neuropathology and ||Nuclear
Medicine, University of Regensburg Medical School, Regensburg; ¶Institute
of Neuroscience and Medicine, Forschungszentrum Jülich, Jülich; **Department of Neurology, University of Cologne, Cologne; ††Center of Integrated
Oncology, Universities of Cologne and Bonn, Cologne; and ‡‡Department of
Nuclear Medicine, University of Aachen, Aachen, Germany.
Conflicts of interest and sources of funding: none declared.
18
F-fluoroethyl-L-tyrosine was used as an unapproved radiopharmaceutical after
individual prescription by a nuclear medicine physician according to §13(2b)
German Drug Act (AMG) with prior notification of the drug and its indication
to the relevant supervisory authority (§67 AMG).
Correspondence to: Markus Hutterer, MD, Department of Neurology 1, NeuroMed
Campus, Kepler University Hospital; Wagner-Jauregg Weg 15, A-4020 Linz,
Austria. E-mail: markus.hutterer@gmx.at.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0363-9762/17/0000–0e00
DOI: 10.1097/RLU.0000000000001873

ACKNOWLEDGMENT
The authors thank Maria Hirblinger for excellent technical assistance.
REFERENCES
1. Hutterer M, Ebner Y, Riemenschneider MJ, et al. Epileptic activity increases
cerebral amino acid transport assessed by 18F-fluoroethyl-L-tyrosine amino
acid PET: a potential brain tumor mimic. J Nucl Med. 2017;58:129–137.
2. Bowen LN, Smith B, Reich D, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nat Rev Neurol. 2016;12:
662–674.
3. Floeth FW, Pauleit D, Sabel M, et al. 18F-FET PET differentiation of ringenhancing brain lesions. J Nucl Med. 2006;47:776–782.
4. Hutterer M, Nowosielski M, Putzer D, et al. [18F]-fluoro-ethyl-L-tyrosine PET:
a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma.
Neuro Oncol. 2013;15:341–351.
5. Pichler R, Dunzinger A, Wurm G, et al. Is there a place for FET PET in the
initial evaluation of brain lesions with unknown significance? Eur J Nucl
Med Mol Imaging. 2010;37:1521–1528.
6. Salber D, Stoffels G, Pauleit D, et al. Differential uptake of O-(2-18Ffluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain
abscesses. J Nucl Med. 2007;48:2056–2062.
7. Spaeth N, Wyss MT, Weber B, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl18
L-tyrosine, and F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence. J Nucl
Med. 2004;45:1931–1938.
8. Salber D, Stoffels G, Pauleit D, et al. Differential uptake of [ 18F]FET and
[3H]L-methionine in focal cortical ischemia. Nucl Med Biol. 2006;33:
1029–1035.
9. Salber D, Stoffels G, Oros-Peusquens AM, et al. Comparison of O-(2-18Ffluoroethyl)-L-tyrosine and L-3H-methionine uptake in cerebral hematomas.
J Nucl Med. 2010;51:790–797.

Clinical Nuclear Medicine • Volume 00, Number 00, Month 2017

www.nuclearmed.com

e1

Hutterer et al

Clinical Nuclear Medicine • Volume 00, Number 00, Month 2017

FIGURE 1. We report the case of a 40-year-old woman who presented with progressive right-sided brachiofacial
accentuated hemiparesis. A, Standard MRI revealed a contrast-enhancing brain lesion with central necrosis (T1wCE, DT1wCE-T1)
and perifocal edema (FLAIR) within the left basal ganglia and capsula interna. Diffusion- and perfusion-weighted MRI demonstrated
no significant diffusion restriction (diffusion-weighted imaging [DWI]/apparent diffusion coefficient [ADC]) or hyperperfusion
(perfusion-weighted imaging-time-to-peak/mean transit time/cerebral blood volume/cerebral blood flow [PWI-TTP/MTT/CBV/
CBF]). Additional 18F-FET PET (20–30 minutes post-injectionem) showed a distinct tracer uptake (lesion-to-brain ratio [LBR],
LBRmax 2.03, LBRmean 1.68; LBR calculation was performed as described previously1) with a metabolic lesion volume (MLVFET)
of 13.7 mL. MLVFET was larger than contrast enhancement (VolcT1wCE 5.6 mL, 41%) and smaller than perifocal edema
(VolFLAIR 25.3 mL, 185%), indicating a cerebral glioma. Surprisingly, stereotactic biopsy and histopathologic analysis revealed
central nervous system (CNS) toxoplasmosis with a strong inflammatory reaction (Fig. 2). Further laboratory diagnostics was
consistent with a newly diagnosis of a human immunodeficiency virus (HIV) infection, leading to an opportunistic cerebral
toxoplasmosis as the first symptom and without further signs of AIDS. B, Therapy with clindamycin, pyrimethamine/leucovorin,
folic acid, and dexamethasone for CNS toxoplasmosis, as well as raltegravir and emtricitabine/tenofovir disoproxil for HIV infection,
resulted in continuous clinical improvement. After 12 weeks, MRI and 18F-FET PET showed a treatment response with significant
reduction of contrast enhancement, perifocal edema, and 18F-FET uptake (LBRmax 1.72, LBRmean 1.41; MLVFET 5.4 mL; VolcT1wCE
1.9 mL, VolFLAIR 7.2 mL).

e2

www.nuclearmed.com

© 2017 Wolters Kluwer Health, Inc. All rights reserved.

Clinical Nuclear Medicine • Volume 00, Number 00, Month 2017

18

F-FET PET Uptake in CNS Toxoplasmosis

FIGURE 2. Neuropathological workup led to the diagnosis of CNS infection by Toxoplasma gondii in hematoxylin-eosin
staining (A, Toxoplasma bradyzoites encased in a cyst, green arrow) and immunohistochemistry (B, Toxoplasma tachyzoites,
yellow arrows). Hematoxylin-eosin staining demonstrated a distinct inflammatory process (C) with GFAP+-reactive astrogliosis
(D), CD68+-microglia activation and CD68+-macrophage infiltration (E), CD3+–T-lymphocytic infiltration (F), and less
pronounced CD20+–B-lymphocytic (G) and CD138+-plasma cellular (H) staining. Of note, the system L-amino acid transporter
LAT1/LAT2 (light chain) and CD98 (heavy chain) (I–K), which are known to specifically mediate 18F-FET uptake into cells, were
immunohistochemically strongly expressed in immune-reactive astrocytes, microglia and macrophages, T lymphocytes, and
vascular endothelial cells (I–K, blue arrows). Here we present a novel case of an AIDS/HIV-associated solitary cerebral
toxoplasmosis lesion2 mimicking cerebral glioma in 18F-FET PET because of a strong LAT1/LAT2/CD98 expression of resident
and immigrated inflammatory activated immune cells mediating a nontumoral tracer uptake. 18F-FET uptake by nonneoplastic
tissue is considered as a rare phenomenon. Similar “pitfalls” of 18F-FET PET were reported for various inflammatory and
ischemic brain lesions, intracerebral hematoma, and cortical epileptic activity.1,3–9 As LAT transporters are expressed in the
endothelium, 18F-FET uptake mainly occurs independent of blood-brain barrier disruption, as indicated by contrast
enhancement and perifocal edema in MRI.1 Therefore, 18F-FET PET may show increased uptake in both contrast- and
non–contrast-enhancing inflammatory brain lesions, but not in perifocal edema, which offers important additional
information to standard MRI alone. In conclusion, etiologically distinct brain lesions may induce an increase in cerebral amino
acid transport. In order to avoid misinterpretation and/or overtreatment, these “pitfalls” have to be closely matched with
clinical and additional technical information whenever 18F-FET PET images are available.

© 2017 Wolters Kluwer Health, Inc. All rights reserved.

www.nuclearmed.com

e3