Keywords [
18 F]-2'-fluoro-2'-deoxy-D-glucose - [
18 F]-fluorocholine - choriocarcinoma - gestational trophoblastic neoplasia - positron
emission tomography/computed tomography
Introduction
Gestational trophoblastic neoplasia (GTN) is a rare pregnancy-related neoplasm. The
incidence of GTN in South East Asia, including Thailand, is 3–16 times higher than
in Western countries.[1 ] Metastases have been reported in 19% of GTN, most commonly to the lung, followed
by brain and liver.[2 ]
Molecular imaging can be helpful in diagnosis and staging of GTN, by more accurately
determining the sites and number of metastatic lesions, monitoring treatment responses,
and predicting the resistance to chemotherapy. [18 F]-2'-fluoro-2'-deoxy-D-glucose ([18 F]-FDG) positron emission tomography/computed
tomography (PET/CT) can localize glycolytically active lesions; however, false interpretations,
indeterminate lesions, and limitations in hyperglycemic patients have been reported.[3 ],[4 ] Many cancers have also increased choline metabolism associated with increased cell
membrane turnover.[5 ] Increased choline uptake in GTN cells is mediated by overexpression of high- and
low-affinity choline transporters.[6 ],[7 ] Choline PET imaging has been used in other gynecologic malignancies,[8 ] but not in GTN. We present the results of PET/CT studies with [18 F]-FDG and [18 F]-fluorocholine (FCH) in three patients with different types of GTN in comparison
with histopathological findings, treatment responses, and the overall outcome.
Case Reports
This study was approved by the institutional review board (COA No. Si 744/2017) and
all subjects signed informed consent form. PET/CT imaging studies were conducted in
three patients, who had fulfilled the criteria for the diagnosis of GTN. Both [18 F]-FDG and [18 F]-FCH PET/CT were manufactured in accordance with CGMP at our hospital, using a fully
automated radiosynthesis system (Sumitomo Heavy Industries, Japan). Imaging studies
were performed using Discovery STE PET/CT scanner (GE Healthcare, Milwaukee, WI, USA).
First, static PET/CT images from skull vertex to the mid-thigh were obtained at 60
min after intravenous administration of [18 F]-FDG (5.18–7.4 MBq/kgBW). On the next day, dynamic PET/CT images of pelvic region
were obtained during 0–10 min postadministration of [18 F]-FCH (370 MBq/patient), followed by static whole-body PET/CT imaging, starting at
60 min postadministration. Each lesion was characterized by visual and quantitative
analyses, and the levels of radioactivity accumulation were expressed as standard
uptake values.
Case 1
A 47-year-old woman was diagnosed with molar pregnancy postcurettage with initial
serum βHCG of 300,000 mIU/ml, which decreased to 10,000 mIU/ml after the first cycle
of chemotherapy. However, the symptoms of vaginal bleeding persisted, with persistently
high serum βHCG. Preoperative PET/CT with [18 F]-FDG and [18 F]-FCH both demonstrated mild hypermetabolism in the peripheral rim of the primary
tumor [Figure 1 ] and [Table 1 ].
Figure 1 [18 F]-2ʼ-fluoro-2ʼ-deoxy-D-glucose positron emission tomography/computed tomography images
of a 47-year-old woman with gestational trophoblastic neoplasia for preoperative staging
found a small hypermetabolic lesion with modest enhancement on computed tomographyin
the upper endometrial wall, but without the evidence of active metastasis. The [18 F]-2ʼ-fluoro-2ʼ-deoxy-D-glucose positron emission tomography/computed tomography study
(a and c) revealed similar findings as [18 F]-fluorocholine (b and d), but the magnitude of [18 F]-fluorocholine accumulation was much lower than that of [18 F]-2ʼ-fluoro-2ʼ-deoxy-D-glucose
Table 1 Comparison of quantitative analysis results for each lesion detected by both positron
emission tomography/computed tomography studies in three patients
The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy. Pathological
examination confirmed the invasive hydatidiform mole with invasion to myometrium and
left adnexal vessels, resulted in GTN Stage II, Score 6. Serum βHCG fell to normal
level after eight cycles of chemotherapy. The patient is still free from the disease
clinically and biochemically for 18 months after chemotherapy withdrawal.
Case 2
A 52-year-old woman, who was diagnosed with an intermediate trophoblastic tumor and
had undergone a total hysterectomy with bilateral salpingo-oophorectomy 7 years ago,
presented with recurrent bleeding. She underwent exploratory laparotomy with tumor
resection and postoperative chemotherapy but had to withdraw after the fourth cycle
due to renal impairment. The serum βHCG was continuously rising: from 3.36 mIU/ml
to 28.31 mIU/ml over 9 months postsurgery. Contrast-enhanced CT demonstrated tumor
recurrence in the mid-left side of the vaginal stump and several pulmonary nodules,
which showed progression in the follow-up CT study.
The patient refused radiation therapy, so preoperative chemotherapy was initiated
but then discontinued due to complications. Then, a laparoscopic examination and adhesion
lysis were performed, revealing a 2 cm × 3 cm mass located on the left side above
the vaginal stump, adherent to the left ureter. Because serum βHCG levels continued
to rise up to 1110 mIU/ml and the patient developed severe headaches, CT scan of the
brain was performed and revealed a small ill-defined hyperdense lesion in the left
posterior aspect of the parietal lobe with perifocal edema but no contrast enhancement
which could not exclude a metastasis-associated hemorrhage. Both [18 F]-FDG and [18 F]-FCH PET/CT studies obtained 2 months later demonstrated low uptake of both tracers
in the primary tumor and in the brain lesion. In contrast, all metastatic lesions
in the lungs were hypermetabolic, especially with [18 F]-FDG [Figure 2 ], [Figure 3 ] and [Table 1 ].
Figure 2 Whole-body positron emission tomography/computed tomography images of a 52-year-old
woman with recurrent gestational trophoblastic neoplasia, posttotal hysterectomy with
bilateral salpingo-oophorectomy. No hypermetabolic lesions were detectable at the
residual calcified mass after chemotherapy in either [18 F]-2´-fluoro-2´-deoxy-D-glucose positron emission tomography/computed tomography (a
and b) or [18 F]-fluorocholine positron emission tomography/computed tomography (c and d). Contrast
material was not used due to severely impaired renal function
Figure 3 Whole-body [18 F]-2ʼ-fluoro-2ʼ-deoxy-D-glucose positron emission tomography/computed tomography study
(without contrast) in the same patient (Case 2) revealed multiple hypermetabolic pulmonary
nodules in both lungs, suggestive of pulmonary metastases (a-c), which on the [18 F]-fluorocholine positron emission tomography/noncontrast computed tomography study
showed less uptake intensity in the corresponding lesions (d-f)
The patient was diagnosed with GTN Stage III, Score 11. Consistent with this bad prognosis,
the patient's serum βHCG level continued to rise up to 1765 mIU/ml during 16 months
after PET/CT studies, even during aggressive chemotherapy. The fate of this patient
at present is unknown because contact with this patient was lost.
Case 3
A 36-year-old woman was diagnosed with choriocarcinoma with lung metastasis and 3-year
history of seizures of unknown etiology. The patient was initially treated with chemotherapy
and effective anti-epileptic therapy. Patient's serum βHCG level had risen from 0.88
to 81.66 mIU/ml during 5 months of chemotherapy. The patient underwent total hysterectomy
and the residual tumor was not detectable. The serum βHCG level kept rising during
the 8 months of postsurgical chemotherapy. Diagnostic CT scan revealed a few new pulmonary
nodules (0.2–0.3 cm in size) without an evidence of local recurrence. [18 F]-FDG and [18 F]-FCH PET/CT studies revealed a hypermetabolic pulmonary nodule in the left lower
lobe, suggestive of pulmonary metastasis [Figure 4 ] and [Table 1 ]. The patient was diagnosed with GTN Stage III, Score 14. Two months after the PET/CT
studies, the patient suddenly developed a disturbance of consciousness, left hemiparesis,
and symptoms of left oculomotor nerve palsy. An emergency CT scan of the brain revealed
an acute subdural hemorrhage originating from the bleeding metastatic tumor lesion
in the left temporal lobe and the presence of several other brain metastatic lesions.
Patient's neurological symptoms improved after tumor excision, followed by palliative
whole-brain 3D conformal radiation therapy and chemotherapy, but high levels of βHCG
in the serum still persisted. The patient died 3 months later due to progression of
brain metastasis, acute decompensation of chronic kidney disease, pancytopenia, and
urinary tract and pulmonary tract infection-induced sepsis.
Figure 4 [18 F]-2ʼ-fluoro-2ʼ-deoxy-D-glucose positron emission tomography/computed tomography images
of a 36-year-old patient with choriocarcinoma and lung metastases, acquired 5 months
postchemotherapy, revealed a hypermetabolic pulmonary nodule located in the left lower
lobe, suggestive of pulmonary metastasis (a and c), which on the [18 F]-fluorocholine positron emission tomography/computed tomography study showed similar
but less uptake intensity (b and d). The surgical bed and regions elsewhere were unremarkable
Discussion
This case series has demonstrated the potential utility of PET/CT imaging with [18 F]-FDG and [18 F]-FCH in GTN. To the best of our knowledge, this is the first report describing the
results of PET/CT with [18 F]-FCH in this particular tumor type. The uptake of [18 F]-FDG was higher than [18 F]-FCH in all detectable lesions. In the first patient, PET/CT studies performed before
the surgical resection demonstrated significant intratumoral heterogeneity, with only
a small region of increased glucose and choline metabolism within the primary tumor
lesion, but not in other active disease sites, which were associated with good treatment
response. In the other two cases, in which primary tumors were already treated, both
PET/CT studies confirmed the absence of active loco-regional disease. The most common
site of demonstrable metastatic disease in these patients was in the lungs, with higher
uptake of [18 F]-FDG. Both PET/CT studies were more sensitive in detecting tiny subpleural metastatic
nodules as compared to CT studies. However, due to lower resolution of PET and low-dose
CT used in hybrid PET/CT, very small metastatic GTN lesions may demonstrate false-negative
results.
The second most common metastatic site in these patients was the brain. We expected
that [18 F]-FCH will have higher specificity than [18 F]-FDG for detection of brain metastasis. However, both studies failed to detect the
intracranial lesion in one patient with an indeterminate lesion seen in a preceding
CT study (Case 2). This patient is still free from neurological symptom during 18
months of follow-up, so brain metastases might possibly be ruled out. However, in
another patient, who exhibited rapidly worsening clinical symptoms and had imaging
findings of hemorrhagic brain metastasis, both PET/CT studies also cannot be used
for detection of brain metastases of GTN or for prognosis. Rapid progression of brain
metastasis of choriocarcinoma has been reported previously.[9 ] Therefore, screening and close monitoring of potential metastatic GTN lesions in
the brain using MRI are still recommended in high-risk patients (e.g., extremely high
serum βHCG level), even if the [18 F]-FDG and [18 F]-FCH studies show negative results.
None of the patients in our series had a hepatic metastasis. Therefore, the roles
of [18 F]-FDG and/or [18 F]-FCH in this situation should be investigated. Furthermore, all these patients had
undergone treatment before the PET/CT studies; thus, untreated patients may produce
different imaging results.
One limitation of [18 F]-FCH is its significant bladder activity. In contrast, [11 C]-choline is eliminated
predominantly by hepatobiliary excretion and may have an advantage over the [18 F]-FCH for detection of lesions in the pelvis. However, the short half-life of [11
C] limits its wide use in routine clinical studies. We used early dynamic images of
pelvic region followed by delayed whole-body imaging after voiding, which showed no
significant bladder activity that could complicate the detection of primary tumors
or postsurgical recurrence. Other interventions, such as retained urinary catheter
or diuretic administration together with volume loading, are not generally acceptable
because these procedures cause unnecessary discomfort and also increase the risk of
infection.
Conclusion
PET/CT studies, with either [18 F]-FDG or [18 F]-FCH, could play an important role in the accurate staging and scoring of GTN and
may improve the understanding of roles that glucose and choline metabolic pathways
play in aggressiveness and treatment response. Even though, in our series, the [18 F]-FCH uptake was lower than [18 F]-FDG, it may be an alternative option in patients with potentially limited efficacy
of [18 F]-FDG. Rapid progression of brain metastasis may not be predictable by the baseline
PET/CT studies; thus, additional neuroimaging studies with MRI are recommended.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms.
In the form, the patients have given their consent for their images and other clinical
information to be reported in the journal. The patients understand that their names
and initials will not be published and due efforts will be made to conceal their identity,
but anonymity cannot be guaranteed.
