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Imaging in Differentiating Cerebral Toxoplasmosis and Primary
CNS Lymphoma With Special Focus on FDG PET/CT
Charles Marcus, MBBS1, Parissa Feizi, MD2, Jeffery Hogg, MD2, Haley Summerfield, MPAS3, Rudolph Castellani, MD 4,
Shitiz Sriwastava, MD5, Gary D. Marano, MD1
Nuclear Medicine · Review
Keywords
cerebral toxoplasmosis, CNS lymphoma,
HIV infection, PET/CT
Submitted: Nov 26, 2019
Revision requested: Jan 15, 2020
Revision received: Feb 19, 2020
Accepted: Apr 9, 2020
First published online: Oct 28, 2020
The authors declare that they have no
disclosures relevant to the subject matter of
this article.
Marcus et al.
PET/CT of Cerebral Toxoplasmosis and CNS Lymphoma
Nuclear Medicine
Review
Marcus C, Feizi P, Hogg J, et al.
This article is available for credit.
doi.org/10.2214/AJR.19.22629
AJR 2021; 216:157–164
ISSN-L 0361–803X/21/2161–157
© American Roentgen Ray Society
AJR:216, January 2021
OBJECTIVE. The purpose of this article is to present a brief review of literature eval-
uating different imaging modalities with special focus on 18F-FDG PET/CT in differenti-
ating cerebral toxoplasmosis and primary CNS lymphoma.
CONCLUSION. Differentiating cerebral toxoplasmosis and primary CNS lympho-
ma is crucial in the care of patients with HIV infection. Delayed diagnosis can lead to
considerable morbidity and mortality. The reference standard for diagnosis is biopsy
and histopathologic examination. Biopsy has disadvantages due to its invasive nature
and associated complications. Noninvasive imaging can be an alternative to biopsy for
differentiation of toxoplasmosis and primary CNS lymphoma. Despite advances in MRI
techniques, prophylaxis of opportunistic infection, and treatment of HIV infection, clin-
ical situations continue to arise in which the diagnosis is not clear. In these instances,
molecular imaging can be helpful.
In the United States as of 2016, an estimated 1.1 million individuals older than 13 years
were living with HIV infection. The number of individuals with a diagnosis of HIV infec-
tion ever classified as stage III or AIDS by the end of 2017 was 1,281,787. Among individu-
als with a diagnosis of HIV infection made in 2016, 15,807 died. Globally, HIV infection re-
mains one of the most serious infectious diseases: an estimated 36.9 million people were
living with the disease in 2016 [1].
Cerebral toxoplasmosis and primary CNS lymphoma are AIDS-defining illnesses and
in the United States are the two most common diagnoses in a patient with HIV infection
who presents with CNS mass lesions. Differentiating these two entities with conventional
imaging can be a diagnostic challenge because they have overlapping imaging charac-
teristics. Other AIDS-defining illnesses that can present as space-occupying lesions, such
as CNS cryptococcosis and CNS tuberculosis, often have additional imaging features that
can help narrow the differential diagnosis. With widespread use of highly active antiret-
roviral therapy (HAART), the frequency of HIV-associated lymphoma and cerebral toxo-
plasmosis has decreased substantially. Because the prognosis is poor, and these entities
be fatal if left untreated [2], timely diagnosis is crucial, and appropriate treatment can im-
prove long-term survival [3]. This review focuses on imaging evaluation and techniques
that would be helpful for optimal clinical management in differentiating CNS lymphoma
from CNS toxoplasmosis. The overlapping features shared by these distinct disease pro-
cesses make differentiating them a special challenge.
Cerebral Toxoplasmosis in Patients With HIV Infection
Worldwide, an estimated 13,138,600 cases of Toxoplasma gondii infection have oc-
curred in patients with HIV infection; the pooled prevalence among these patients is ap-
proximately 35.8%. In high-income countries, this prevalence has been estimated to be
approximately 26.3%. These statistics emphasize the importance of routine screening
for this opportunistic infection, prompt diagnosis, and prompt treatment [4]. The clinical
presentation of cerebral toxoplasmosis is nonspecific but usually is subacute neurologic
symptoms and signs. However, rapidly progressing and diffuse encephalitis, ventriculitis,
and a cerebrovascular accident–like presentation have been described [5–7]. The most
1
Department of Radiology, West Virginia University, 1 Medical Center Dr, Morgantown, WV 26505. Address
correspondence to C. Marcus (charlesmarcus1986@gmail.com).
Department of Neuroradiology, West Virginia University, Morgantown, WV.
2
Department of Infectious Diseases, West Virginia University, Morgantown, WV.
3
4
Department of Pathology, West Virginia University, Morgantown, WV.
Department of Neurology, West Virginia University, Morgantown, WV.
5
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common presentations include headache, fever, seizures, fo-
cal neurologic deficits, cranial nerve palsies, visual disturbances,
confusion, and psychomotor or behavioral changes [8–10]. With
delayed treatment, the disease can progress to stupor, coma, and
death. Prompt diagnosis and treatment improve survival, even in
severe forms of the disease [11].
Primary CNS Lymphoma in Patients With HIV Infection
The risk of primary CNS lymphoma among patients living with
HIV infection is 250- to 500-fold that of the average population
in the United States. Primary CNS lymphoma in patients with HIV
infection is primarily non-Hodgkin lymphoma, which in patients
living with HIV infection is linked to immunosuppression and HIV
viremia [12]. This disease process has been found to be associated
with Epstein-Barr virus (EBV) infection. The clinical presentation
includes headache, focal neurologic deficit, seizures, and cogni-
tive dysfunction. These symptoms overlap with the presenting
clinical features of cerebral toxoplasmosis and can be extreme-
ly difficult to differentiate clinically. Definitive diagnosis is based
on histopathologic examination, which requires an invasive neu-
rosurgical procedure that is associated with morbidity and in-
troduces sampling errors. The prognosis remains poor (survival
time, 2–4 months) but can be improved with prompt initiation of
chemotherapy (median survival time, 1.5 years) [13].
Differentiating Cerebral Toxoplasmosis and Primary
CNS Lymphoma in Patients With HIV Infection
Clinical differentiation of cerebral toxoplasmosis and primary
CNS lymphoma can be extremely difficult because they commonly
present with overlapping signs and symptoms. Laboratory markers
such as the presence of Epstein-Barr virus DNA in the CSF and a neg-
ative serologic result for toxoplasmosis are helpful in making the
diagnosis of CNS lymphoma [13] but in certain cases cannot com-
pletely exclude it [10]. Furthermore, CNS lymphoma and cerebral
toxoplasmosis are often indistinguishable from each other on im-
ages obtained with conventional cross-sectional techniques [14].
Advances in treatment and prophylaxis have resulted in a
marked decrease in the incidence of CNS lymphoma and cerebral
toxoplasmosis, which has made the clinical dilemma of differen-
tiating them less common. In addition, recent literature on this
topic is scarce. Physicians who are part of the multidisciplinary
teams caring for these patients may be asked to use imaging to
differentiate CNS lymphoma from cerebral toxoplasmosis. Al-
though these requests may not be common, familiarity with the
imaging evaluation and available techniques can help radiol-
ogists and nuclear physicians direct clinicians toward the most
likely diagnosis. This article reviews the literature with special fo-
cus on 18F-FDG PET/CT to help differentiate these two diseases
by use of imaging. In as many as 20% of patients with HIV infec-
tion, clinical and imaging findings may be inconclusive, and biop-
sy may be required for diagnosis. Histopathologic confirmation,
however, may not be required when clinical, serologic, and imag-
ing findings are consistent with the diagnosis [15].
CT and MRI in Differentiating Cerebral Toxoplasmosis
and Primary CNS Lymphoma
In a contrast-enhanced CT or MRI examination, cerebral toxo-
plasmosis often is visualized as multiple nodular or ring-en-
158
hancing lesions with associated vasogenic edema often dispro-
portionate to lesion size and resultant mass effect. The most
common locations of these lesions are the basal ganglia and fron-
tal and parietal lobes [10, 16, 17].
In CT examinations, primary CNS lymphoma commonly exhib-
its isoattenuating or hyperattenuating mass lesions owing to its
high cellularity. After contrast administration, CT or MRI of these
lesions may show round or oval homogeneous contrast enhance-
ment and a varying extent of edema in a multifocal or periven-
tricular distribution [18].
The pattern of MRI signal-intensity characteristics has been de-
scribed as a tool for differentiating cerebral toxoplasmosis and
primary CNS lymphoma. The “eccentric target” sign, which con-
sists of an innermost enhancing eccentric core, an intermediate
hypointense zone, and a peripheral hyperintense enhancing rim,
is associated with cerebral toxoplasmosis in comparison with oth-
er parenchymal lesions on contrast-enhanced T1-weighted im-
ages. This sign, however, has been observed in only one-third of
cases [19, 20]. On T2-weighted MR images, a pattern of concentric
zones of hypointensity and hyperintensity, called the “concen-
tric target” sign, has been described in cerebral toxoplasmosis
but needs further validation [21]. In a small case series of 14 pa-
tients with cerebral toxoplasmosis [22], a target sign visualized on
T2-weighted or FLAIR images consisted of a hypointense core, an
intermediate hyperintense region, and a peripheral hypointense
rim, which is the inverse appearance of the previously described
target sign on contrast-enhanced T1-weighted images. The au-
thors observed that most of the patients (71%) in the series had a
contrast-enhanced T1-weighted target sign, a T2-weighted FLAIR
target sign, or both.
A study of 13 patients [23] who underwent dynamic suscepti-
bility contrast-enhanced MRI showed that lymphomas had sta-
tistically significantly higher (p = 0.0013) relative cerebral blood
volume (rCBV) than toxoplasmosis lesions. The mean rCBV for all
toxoplasmosis lesions was 0.98 compared with 2.07 for all lym-
phoma lesions. The authors suggested an rCBV threshold of 1.5
for differentiating the two lesions. For image-based lesion seg-
mentation, manual definition of lesion enhancement, exclud-
ing regions of hemorrhage, macrovessel, and necrosis, was per-
formed. The difference in rCBV is attributed to lack of vasculature
in cerebral toxoplasmosis and hypervascularity in foci of active
tumor growth in lymphoma [24].
Conventional DWI and apparent diffusion coefficient (ADC)
maps and values have had mixed results for differentiating pri-
mary CNS lymphoma and cerebral toxoplasmosis. At least one
study [25] showed considerable overlap between these two en-
tities. However, a study of 21 patients [26] showed significantly
greater diffusion (i.e., lesser degree of restricted diffusion) in ce-
rebral toxoplasmosis (p = 0.004). The ADC ratios had 1.0–1.6 over-
lap. The authors suggested that ADC ratios greater than 1.6 are
associated with toxoplasmosis.
In terms of contrast enhancement dynamics, primary CNS lym-
phoma and cerebral toxoplasmosis appear to have different char-
acteristics, primary CNS lymphoma exhibiting delayed contrast
enhancement [27] (Fig. 1).
MR spectroscopy can be helpful for differentiating toxoplas-
mosis from lymphoma. Toxoplasmosis lesions typically have de-
creased levels of choline (a marker of cellular turnover), whereas
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A B C

D E F

Fig. 1—51-year-old man with few-day history of

altered mental status, expressive aphasia, and right-
sided weakness. Initial clinical evaluation showed
positive result of HIV screen and CD4 count of 5 cells/
μL. Contrast-enhanced MRI of brain was performed
for further evaluation.
A–H, Axial T1-weighted contrast-enhanced (A
and E), axial T2-weighted FLAIR (B and F), axial
DWI (C and G), and axial relative cerebral blood
volume overlay (D and H) MR images show nodular
peripherally enhancing lesions centered within
left basal ganglia (arrow, A–D) and posterior left
frontal centrum semiovale (arrow, E–H). T2-weighted
FLAIR images (B and F) show associated vasogenic
edema and mass effect. Regional cerebral volume
evaluation showed no clinically significant increase
corresponding to regions of enhancement. Similarly,
no clinically significant restricted diffusion was seen.
These findings favor cerebral toxoplasmosis over
primary CNS lymphoma.
G H

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CNS lymphomas generally have elevated choline levels. Howev-
er, this difference has not been found reliable for differentiating
cerebral toxoplasmosis from primary CNS lymphoma, because
these two conditions can have overlapping characteristics [28].
Peripheral enhancement and restricted diffusion both can be
seen these disease processes. CNS lymphoma can exhibit periph-
eral enhancement with central necrosis in immunocompromised
patients as opposed to more homogeneous enhancement in im-
munocompetent patients. Other AIDS-defining illnesses, such
as cryptococcosis, can also present with peripherally enhancing
cryptococcomas, but they can be differentiated through identifi-
cation of dilated perivascular spaces with pseudocyst formation
and superimposed leptomeningeal enhancement [29]. CNS tu-
berculosis may also present with ring-enhancing tuberculomas,
although features such as leptomeningeal enhancement, espe-
cially in the basal cisterns, and, in rare instances, pachymeningeal
enhancement typically are seen [30].
Molecular Imaging in Differentiating Cerebral
Toxoplasmosis and Primary CNS Lymphoma
Thallium-201-Labeled SPECT
Thallium-201, a potassium analogue once commonly used as a
cardiac perfusion agent, is known to accumulate in many tumors
[31, 32]. During initial evaluation in this context, 201Tl SPECT had
promising diagnostic accuracy (100% sensitivity, 90% specificity)
and higher radiotracer retention in patients with lymphoma than
in patients with nonmalignant lesions (retention index, 1.35 vs
0.56). A study of 32 patients with HIV infection who had focal CNS
lesions [33] showed that single lesions with focal accumulation of
201
Tl were strongly suggestive of lymphoma. The uptake ratios of
the lesions in comparison with the normal contralateral side were
calculated, and ratios of 2.9 or greater were suggestive of lympho-
ma. Similar findings were supported in a study [34] in which semi-
quantitative analysis of these lesions showed that a large lesion to
large background ratio of 2.9 or greater was 71% accurate in sug-
gesting the presence of lymphoma. In addition to these findings,
calculating retention index increased the specificity (76–100%) of
differentiating nonmalignant lesions from lymphoma. The reten-
tion index was calculated between two time points (10 minutes
and 3 hours) after injection of radiotracer and was defined as the
ratio of the delayed-to-early target-to-background mean count
ratio [35]. Detection appears to be related to the size of the lesion.
Lesions larger than 2 cm are associated with higher diagnostic ac-
curacy (100% sensitivity, 89% specificity) [36].
Technetium-99m-labeled sestamibi SPECT has been evaluated
for differentiating primary CNS lymphoma from other intracrani-
al lesions. In a study that included 17 patients [37], the ratio be-
tween radiotracer uptake of the lesion and uptake on the con-
tralateral side was estimated, and a value greater than 1.5 was
considered suggestive of lymphoma. The study showed specific-
ity of 69% for 99mTc-sestamibi SPECT and specificity of 54% for 201Tl
SPECT, suggesting that 99mTc-sestamibi SPECT may perform bet-
ter. However, the number of patients was small, and further stud-
ies are needed to support the conclusion. A subsequent study
[38] showed poor performance of SPECT with accuracy of 57%,
sensitivity of 60%, and specificity of 55%. These later findings
have been linked to advances in HAART. The diagnostic value of
201
Tl SPECT in differentiating cerebral toxoplasmosis and primary
160
CNS lymphoma has significantly decreased, more than one-half
of patients with cerebral toxoplasmosis having increased radio-
tracer uptake while undergoing HAART [39]. These findings com-
bined with greatly decreased or even discontinued routine use of
201
Tl in clinical molecular imaging have caused this technique to
fall out of favor.
FDG PET/CT of the Brain
With the increase in clinical use of FDG PET/CT for evaluating a
multitude of disease processes, this modality has also been used
to differentiate cerebral toxoplasmosis and CNS lymphoma. For 10
patients with HIV infection and contrast-enhancing lesions on MRI
[40], subsequent FDG PET/CT of the brain was performed 1 hour af-
ter radiotracer administration. High metabolic activity correspond-
ing to the enhancing lesions on MRI was considered suggestive of
primary CNS lymphoma. Six of the 10 patients had no clinically
significant associated increase in metabolic activity, and cerebral
toxoplasmosis was diagnosed. Two patients with increased meta-
bolic activity were confirmed to have CNS lymphoma. One of the
other two patients had progressive multifocal leukoencephalop-
athy with equivocal metabolic activity, and the other had hemor-
rhagic brain metastasis with normal metabolic activity.
Another study [41] showed increased metabolic activity of
primary CNS lymphoma in comparison with nonmalignant dis-
ease processes. For qualitative assessment, a scoring system was
proposed in which 1 indicated less metabolic activity than con-
tralateral white matter; 2, equal to contralateral white matter; 3,
between contralateral white matter and gray matter; 4, equal to
contralateral gray matter; and 5, greater than contralateral gray
matter. For semiquantitative analysis, an ROI was drawn on the
lesion and contralaterally in the corresponding homologous
brain region. A count ratio of lesion to contralateral homologous
brain was estimated. Both qualitative (score 1 or 5 in lymphoma)
and semiquantitative analyses (1.8 vs 0.65, 0.70, and 1.3) showed
higher scores and values in lymphoma in comparison with toxo-
plasmosis, syphilis, and progressive multifocal leukoencephalop-
athy (p = 0.006) [41]. These findings were supported by a study
[42] in which the standardized uptake value (SUV) ratio of the le-
sion to the contralateral brain was significantly lower in cerebral
toxoplasmosis or tuberculoma than in primary CNS lymphoma
(p < 0.04; SUV ratio, 0.3–0.7 vs 1.7–3.1). A similar semiquantita-
tive assessment [43] showed decreased lesional uptake in cere-
bral toxoplasmosis in comparison with the normal brain cortex
(mean maximum SUV [SUVmax], 3.5; range, 1.9–5.8), whereas pa-
tients with primary CNS lymphoma had lesional radiotracer up-
take greater than that of normal brain cortex (mean SUVmax, 18.8;
range, 12.4–29.9). The presence of normal contralateral increased
metabolic activity associated with normal structures such as the
basal ganglia can impede estimation of SUV ratios and compari-
son with contralateral normal brain metabolic activity.
Delayed FDG PET/CT has been found to be reliable for differ-
entiating infection or inflammation from malignancy. Malignant
tumors exhibit a progressive increase in metabolic activity over
time in comparison with normal tissues, which either have sta-
ble or decreased metabolic activity, resulting in high lesion to
background contrast in malignant lesions [44]. Other studies in
adult patient populations [45, 46] have shown that at delayed
imaging malignant lesions have higher metabolic activity than
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benign disease processes like infection and also have improved
contrast (1 hour vs 2 hours after radiotracer administration) with
lesion-based sensitivity as high as 98%. Tumor to background
contrast was also significantly improved in delayed acquisitions
in comparison with routine 1-hour imaging.
In CNS neoplasms, delayed FDG PET/CT examinations have
shown higher radiotracer uptake in tumors than in adjacent nor-
mal gray matter, adjacent normal gray and adjacent normal white
matter, and white matter. In comparison with routine imaging (0–
90 minutes), delayed imaging (180–480 minutes) shows greater
lesion contrast. The improved contrast is attributed to a greater
effect of FDG-6-phosphate degradation on normal brain relative
to malignant disease processes [47]. Delayed FDG PET/CT can be
a reliable tool for problem solving in differentiating a malignant
disease process such as CNS lymphoma from other infectious
diseases (Fig. 2). In comparison, as found in the previously cited
studies, infectious disease processes such as cerebral toxoplas-
mosis are associated with decreased metabolic activity in com-
parison with the contralateral normal brain matter (Fig. 3).
Some patients may not have classic CT or MRI findings of lym-
phoma, and the initial clinical examination findings can be incon-
clusive, as shown in Figures 1–3. An FDG PET/CT brain examination
may be requested when the diagnosis is unclear. Results of a rou-
tine FDG PET/CT brain examination performed 60 minutes after
radiotracer injection can be equivocal. The challenge in evaluat-
ing these lesions and applying semiquantitative analyses similar
to the methods described in the literature arises when the corre-
sponding normal structures in the contralateral brain exhibit nor-
mal, physiologic increased metabolic activity. However, delayed
images obtained more than the conventional 60 minutes after
radiotracer administration can be helpful and can show progres-
sive increases in metabolic activity in malignant disease p
­ rocesses

A B C

D E F
Fig. 2—51-year-old man with few-day history of altered mental status, expressive aphasia, and right-sided weakness (same patient as in Fig. 1). FDG PET/CT brain
examination was performed because CSF examination was negative for Epstein-Barr virus and CSF polymerase chain reaction result was negative for Toxoplasma
gondii organisms.
A–F, Axial 1-hour (A and D) and 5-hour (B and E) FDG PET/CT images show progressive increase in metabolic activity over time in left basal ganglia (arrow, A
and B) and left centrum semiovale (arrow, D and E). These findings were highly suggestive of lymphoma. Patient underwent stereotactic biopsy of brain lesions.
Photomicrographs show infiltrate composed of large malignant lymphoid cells (H and E, ×120) (C) and diffusely positive expression of pan B-cell marker CD20 (F),
indicative of diffuse large B-cell lymphoma (scale bar = 100 µm).

AJR:216, January 2021 161

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A B C

D E F
Fig. 3—68-year-old man with 1-week history of lower extremity weakness and ataxia.
A–C, Axial DWI (A), coronal T1-weighted contrast-enhanced (B), and axial T2-weighted FLAIR (C) MR images show single right cerebellar lesion (arrow, A and B) that
exhibits peripheral restricted diffusion, peripheral enhancement, and lack of central enhancement and is surrounded by vasogenic edema. Imaging features are not
conclusive. HIV screen result was positive, and CD4 count was 5 cells/μL. Empirical antibiotic therapy was started, and patient’s clinical condition worsened. Serologic
result for Toxoplasma organisms was negative.
D and E, Axial FDG PET (D) and fused FDG PET/CT (E) images show decreased metabolic activity (arrow) in comparison with contralateral cerebellar hemisphere
suggestive of infectious disease process.
F, Photomicrograph (H and E, ×120) of cerebellar lesion obtained at stereotactic biopsy shows toxoplasma bradyzoite (arrow).

(Fig. 2). It is well known that malignant disease processes exhibit
progressive radiotracer accumulation over time in comparison with
infectious or inflammatory disease processes. Dual-time-point FDG
PET/CT can be a valuable tool in differentiating these two disease
processes, especially when the diagnosis is unclear, and can have
great impact on clinical management. A working algorithm for dif-
ferentiating cerebral toxoplasmosis and primary CNS lymphoma in
patients with HIV infection is presented in Figure 4.
Conclusion
Differentiating cerebral toxoplasmosis and primary CNS lym-
phoma on clinical grounds in patients with HIV infection is ex-
tremely difficult but is crucial. Delayed diagnosis results in poor
prognosis, including death. Improved treatment of HIV infection
with more effective prophylaxis against opportunistic infection
in the last 2 decades has resulted in fewer cases of HIV infection
presenting as advanced disease. Clinical presentation of HIV in-
fection with neurologic decline due to a cerebral mass and the
need to differentiate CNS lymphoma from cerebral toxoplasmo-
sis arises less often than in the past. However, in cases that do
present as advanced as HIV disease in this manner, accurately dif-
ferentiating CNS lymphoma from cerebral toxoplasmosis remains
critical to patient care. In the era of HAART for HIV infection, some
of the imaging used in the past may not be useful. FDG PET/CT

162 AJR:216, January 2021

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