|Year : 2017 | Volume
| Issue : 9 | Page : 1100-1112
Usefulness of Positron Emission Tomography in Patients with Syphilis: A Systematic Review of Observational Studies
Jian-Hua Chen1, Xin Zheng2, Xiu-Qin Liu1
1 Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
2 Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
|Date of Submission||18-Jan-2017|
|Date of Web Publication||21-Apr-2017|
Dr. Jian-Hua Chen
Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730
Source of Support: None, Conflict of Interest: None
Background: Diagnosis of syphilis is difficult. Follow-up and therapy evaluation of syphilitic patients are poor. Little is known about positron emission tomography (PET) in syphilis. This review was to systematically review usefulness of PET for diagnosis, disease extent evaluation, follow-up, and treatment response assessment in patients with syphilis.
Methods: We searched PubMed, EMBASE, SCOPUS, Cochrane Library, Web of Science, ClinicalTrials.gov, and three Chinese databases (SinoMed, Wanfang, and CNKI) for English and Chinese language articles from inception to September 2016. We also collected potentially relevant studies and reviews using a manual search. The search keywords included the combined text and MeSH terms “syphilis” and “positron emission tomography”. We included studies that reporting syphilis with a PET scan before and/or after antibiotic treatment. The diagnosis of syphilis was based on serological criteria or dark field microscopy. Outcomes include pre- and post-treatment PET scan, pre- and post-treatment computed tomography, and pre- and post-treatment magnetic resonance imaging. We excluded the articles not published in English or Chinese or not involving humans.
Results: Of 258 identified articles, 34 observational studies were included. Thirty-three studies were single-patient case reports and one study was a small case series. All patients were adults. The mean age of patients was 48.3 ± 12.1 years. In primary syphilis, increased fluorodeoxyglucose (FDG) accumulation could be seen at the site of inoculation or in the regional lymph nodes. In secondary syphilis with lung, bone, gastrointestinal involvement, or generalized lymphadenopathy, increased FDG uptake was the most commonly detected changes. In tertiary syphilis, increased glucose metabolic activity, hypometabolic lesions, or normal glucose uptake might be seen on PET. There were five types of PET scans in neurosyphilis. A repeated PET scan after treatment revealed apparent or complete resolution of the asymmetry of radiotracer uptake.
Conclusion: PET is helpful in targeting diagnostic interventions, characterizing disease extent, assessing nodal involvement, and treatment efficacy for syphilis.
Keywords: Diagnosis; Positron Emission Tomography; Syphilis; Therapeutics
|How to cite this article:|
Chen JH, Zheng X, Liu XQ. Usefulness of Positron Emission Tomography in Patients with Syphilis: A Systematic Review of Observational Studies. Chin Med J 2017;130:1100-12
|How to cite this URL:|
Chen JH, Zheng X, Liu XQ. Usefulness of Positron Emission Tomography in Patients with Syphilis: A Systematic Review of Observational Studies. Chin Med J [serial online] 2017 [cited 2017 Dec 15];130:1100-12. Available from: http://www.cmj.org/text.asp?2017/130/9/1100/204940
| Introduction|| |
Syphilis is a systemic sexually transmitted disease caused by the spirochete Treponema pallidum. The World Health Organization estimated that 5.6 million new cases of syphilis occurred among adolescents and adults aged 15–49 years worldwide in 2012, with a global incidence rate of 1.5 cases per 1000 females and 1.5 cases per 1000 males. The estimated 18 million prevalent cases of syphilis in 2012 translated to a global prevalence of 0.5% among females and 0.5% among males aged 15–49 years. Left untreated, syphilis can progress through four stages: primary syphilis, secondary syphilis, latent syphilis, and tertiary syphilis. Primary syphilis is characterized by a chancre (sore or ulcer) at the site of inoculation and painless regional lymphadenopathy. Secondary syphilis can present with variable manifestations of skin lesions as well as systemic expression. Latent syphilis is characterized by positive syphilis serology with no clinical symptoms or signs. The tertiary stage is subdivided into three general categories: gummatous syphilis, followed by cardiovascular syphilis and finally neurosyphilis. In particular, tertiary syphilis often mimics cancer, because it frequently presents as a space-occupying lesion in visceral organs.,
Fluorine-18-fluorodeoxyglucose (18 F-FDG) uptake on positron emission tomography (PET) is one of the most valuable imaging methods for establishing tumor extent and size, assessing nodal disease, and detecting distant metastases in head and neck cancer.18 F-FDG accumulation in tissues is proportional to the amount of glucose utilization, and thus increased glucose absorption is observed in most cancers, infections, and inflammatory disorders.,
Syphilis has often been called “the great imitator”. The signs and symptoms may be difficult to distinguish from other diseases. Secondary syphilis can be present without any symptoms, but with generalized lymphadenopathy. Most patients with uncomplicated aortitis are asymptomatic. Diagnosis of neurosyphilis can be difficult, as many patients are asymptomatic or present with nonspecific symptoms. Currently, follow-up and therapy efficacy evaluation of syphilis are poor. Considering that PET is a promising new imaging technique for infectious and inflammatory disorders, the aim of this systematic review was to evaluate PET for diagnosis, disease extent evaluation, follow-up, and treatment response assessment in patients with syphilis.
| Methods|| |
Databases and search strategy
The present protocol was registered online at the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/RPOSPERO, registration number: CRD42016047471). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed.
We first searched the existing literature for systematic reviews and meta-analyses involving studies on PET scans in syphilis. However, no reviews or meta-analyses were found. We then used the combined text and MeSH terms “syphilis” and “positron emission tomography”. Two authors (Jian-Hua Chen and Xin Zheng) searched the following electronic bibliographic databases: PubMed, EMBASE, SCOPUS, Cochrane Library, Web of Science, ClinicalTrials.gov, and three Chinese databases (SinoMed, Wanfang, and CNKI). The period for research was from establishment of each database to September 2016. We also collected potentially relevant studies and reviews using a manual search. We assessed both English and Chinese language articles for eligibility.
Study selection and data extraction
The inclusion criteria for studies were that the diagnosis of syphilis was based on serological criteria or dark field microscopy and that syphilitic patients must have undergone a PET scan before and/or after antibiotic treatment. The exclusion criteria were articles not published in English or Chinese or not involving humans.
Two independent investigators (Jian-Hua Chen and Xin Zheng) reviewed the study titles and abstracts, and studies that satisfied the inclusion criteria were retrieved for full-text assessment. Consensus was reached through discussion with all of the authors.
We extracted the following data from each selected study: first author, publication year, age, gender, symptoms, cerebrospinal fluid examinations, pre- and post-treatment serum rapid plasma regain (RPR) or venereal disease research laboratory test (VDRL) titers, type of syphilis, pre- and post-treatment PET scans, and pre- and post-treatment computed tomography (CT) and magnetic resonance imaging (MRI) examinations.
| Results|| |
Our initial database search retrieved 258 articles, of which 224 were excluded for not meeting the inclusion criteria [Figure 1]. All 34 observational studies included in the systematic review were published in English. Thirty-three studies were single-patient case reports and one study was a small case series [Table 1]. All patients were adults, 28 (80.0%) were male, 6 (17.1%) were female, and one patient's gender was not reported. The mean age was 48.3 ± 12.1 years. Hoffman et al. reported the first syphilitic patient with a PET scan after antibiotic treatment in 1993, and Heald et al. reported another case with a PET scan before antibiotic treatment in 1996. All PET scans in the studies were 18 F-FDG PET, except for the study by Mimura et al., in which oxygen-15-labeled tracers were used for the PET scan [Table 2] and [Table 3]. There were three cases of syphilis with HIV coinfection. Five studies provided the maximum standardized uptake value (SUVmax), and the mean pretreatment SUVmax was 6.99 ± 2.47 (range: 3.60–10.30).
|Figure 1: Flow diagram of search strategy for this systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PET: Positron emission tomography.|
Click here to view
Positron emission tomography in primary and secondary syphilis
In one patient with anal and rectal syphilis, PET demonstrated increased FDG uptake in the distal rectum, anus, and regional lymphadenopathy. In another case with oropharyngeal and gastric syphilis, PET showed increased FDG accumulation in the oropharynx and lymph nodes of the cervical regions. Two cases of secondary syphilis presented with generalized lymphadenopathy, and one of them also had asymptomatic neurosyphilis., Three cases were syphilis with pulmonary involvement,,, one was syphilitic osteomyelitis, one was syphilitic aortitis, and one was syphilitic hepatitis.
Regarding pulmonary involvement, hypermetabolic activity nodules in the lung could be detected by PET., Kim et al. described that there was no significant hypermetabolism in small pulmonary nodules, while hypermetabolic enlarged nodes were only present in the inguinal regions. In syphilitic bone destruction, PET images demonstrated multiple foci of increased FDG uptake in all extremities, corresponding to the osseous destruction observed on the concurrent CT images. In secondary syphilis presenting with generalized lymphadenopathy, PET showed intensely increased FDG uptake with enlarged lymph nodes in the submandibular areas, neck levels, axillary and inguinal regions, and retroperitoneal, hilar, mediastinal, internal, and external iliac areas.,
Positron emission tomography in latent syphilis
Joseph Davey et al. reported one case with latent syphilis presenting as generalized lymphadenopathy and probable aortitis. In that case, the PET scan confirmed increased glucose metabolism in the inguinal regions and along the ascending aorta and aortic arch, being compatible with aortitis.
Positron emission tomography in tertiary syphilis
Six cases were diagnosed as cardiovascular syphilis and presented with aortitis and thoracic aneurysm.,,,,, Two patients were diagnosed as gummatous syphilis of the adrenal gland, and hepatic gummas and syphilitic episcleritis. Twelve patients were diagnosed as neurosyphilis.,,,,,,,,,, One was diagnosed as tertiary syphilis with bone, adrenal gland, liver, and skin involvement.
In syphilitic aortitis, PET showed marked radiotracer enhancement along the ascending aortic wall or in the thoracoabdominal aorta with involvement of the brachiocephalic and left carotid arteries.,,, In syphilitic thoracic aneurysm, PET showed increased glucose metabolic activity, or no enhanced uptake., PET in gummatous syphilis with adrenal gland involvement showed high uptake of FDG in lesions. Scheurkogel et al. reported a case of syphilis with liver involvement as a lesion with photopenia at the center of the mass, indicating an area of central necrosis. In tertiary syphilis with bone involvement, PET showed increased uptake of FDG at the bone.
There were five types of PET scans in neurosyphilis. The first type of PET revealed a focus of intensely increased FDG uptake with or without a background of globally decreased FDG uptake., The second type of PET showed a focal hypometabolic mass., The third type of PET produced patchy severe hypometabolism, usually involving the medial frontal cortex, temporal parietal area, inferior temporal gyrus, anterior temporal lobe, orbitofrontal lobe, posterior gyrus cingulum/precuneus, medial temporal lobe, intraparietal sulcus, or occipital lobe.,,, The fourth type of PET in neurosyphilis only presented as generalized lymphadenopathy and demonstrated hypermetabolic enlarged lymph nodes in the symmetric bilateral cervical, axillary, hilar, tracheobronchial, protocaval, iliac, or inguinal regions, without abnormal FDG uptake in the brain.,, The fifth type of PET in neurosyphilis revealed no pathological glucose uptake anywhere in the whole body scan. In neurosyphilitic gumma, PET may demonstrate an intensely FDG avid lesion or a hypometabolic lesion.,
Positron emission tomography in targeting diagnostic interventions
Three cases with syphilitic aortitis and one case with anal and rectal syphilis were incidentally diagnosed by PET.,,, There were three cases, in which PET was used to rule out paraneoplastic limbic encephalitis or malignancy.,, In one case with aortic aneurysm, PET was carried out to exclude active vasculitis. In ten case reports, other diseases such as malignancy or Alzheimer's disease were first considered, until the PET findings of intensely hypermetabolic lesions, indicative of inflammatory processes, led to the suspicion of syphilis, which was then confirmed by a biopsy or serological tests.,,,,,,,,,,,,,,
There were 32 patients with positive PET findings and positive VDRL and/or RPR results, one patient with positive PET findings and negative VDRL/RPR results, and two patients with negative PET findings and positive VDRL/RPR results. Compared with nontreponemal tests for VDRL/RPR, the sensitivity of PET in identifying syphilis was 94.3% versus 97.1%.
Positron emission tomography in characterizing disease extent
The majority of the case reports found that a PET scan was useful for characterizing the disease extent, especially in generalized lymphadenopathy, syphilitic aortitis, and neurosyphilis with dementia,,,,,,,,,,,,,,, with the exception being cases in which the PET scan showed no pathological glucose uptake.,
Positron emission tomography in follow-up and treatment response assessment
Eleven case reports described that a repeated PET scan after antibiotic therapy revealed apparent or complete resolution of the asymmetry of radiotracer uptake, in accordance with decreased RPR titer and/or disappearance of clinical symptoms and signs.,,,,,,,,,,, Two cases of neurosyphilis with dementia showing no clinical improvement after treatment were not reexamined by a PET scan.,
| Discussion|| |
Little is known about PET scans in syphilitic patients. This study was a comprehensive systematic review on PET in syphilis worldwide. We found that PET is prospective for diagnosis, follow-up, and therapy evaluation in disseminated syphilis.
Our results showed that hypermetabolic activity nodules in the lung could be detected on PET in pulmonary syphilis., Although PET had high overall sensitivity and specificity in pulmonary lesions, it had low accuracy in smaller subcentimeter lung lesions., We should also remember that increased glucose metabolism in lesions on PET occurred in a large variety of primary lung tumors and metastases as well as in inflammatory diseases such as tuberculosis, fungal infection, and sarcoidosis., Our findings further demonstrated that PET could provide positive results in gastrointestinal syphilis with increased FDG accumulation in the infected region and with regional lymphadenopathy.,,
The findings of this systematic review implied that PET could identify syphilitic aortitis at an early asymptomatic stage.,, PET could detect early inflammation of the vessel wall because the activated inflammatory cells were characterized by increased FDG uptake. Large-vessel vasculitis could be diagnosed by 18 F-FDG PET at an earlier stage compared with conventional imaging techniques, such as CT or MRI. PET might also be helpful in the distinction of syphilitic aortitis from large-vessel vasculitis. Giant-cell arteritis usually showed homogeneous/smooth linear or long segmental patterns of FDG uptake in the thoracic aorta and its main branches. Takayasu's arteritis affected the aorta and its branches but might show a more focal and localized inhomogeneous pattern of FDG uptake and had a more aggressive clinical course., The localization of the increased metabolic activity seemed to be present in the ascending aorta in syphilitic aortitis, consistent with postmortem examinations. The ascending aorta and transverse aortic arch were the most commonly affected blood vessels in syphilitic aortitis.
The findings of this systematic review also implied that PET should have some priority over head MRI while central nervous system involved, especially when the latter has demonstrated no focal lesions on fluid-attenuated inversion recovery and diffusion-weighted imaging. Our results demonstrated that PET in neurosyphilis is somewhat complicated. There are five types of PET patterns ranging from hypermetabolic to hypometabolic foci or no significant glucose uptake in the brain.,,,,, The latter is often seen in syphilitic cauda equina radiculitis, syphilitic retinitis, and syphilitic spondylodiscitis.,, Gummatous neurosyphilis may demonstrate intense FDG avidity on PET. A global reduction in glucose consumption particularly in the frontal or temporal areas and precuneus/posterior cingulate with sparing of the basal ganglia and thalamus in neurosyphilis with dementia can usually be found on PET.,,,,
From this systematic review, it appeared that there is no definable influence on PET results of the presence or absence of HIV coinfection. In syphilitic patients with lymph node, lung, anus, and rectum involvement, the SUVmax ranged from about 3.60 to 10.30.,,,, This systematic review told us that metabolic findings on PET should be always interpreted with caution. It was important to suspect inflammatory or infectious diseases even in cancer patients to avoid a false-positive interpretation.
This systematic review indicated that no clinical symptoms or no serologic evidence for active infection were not always equal to no inflammatory pathological processes.,, Follow-up of syphilis was usually achieved by assessing the clinical and serological response to treatment. Globally, however, many studies have confirmed that follow-up was poor., About 15% of patients with early syphilis and no HIV infection did not have a 4-fold decrease in titer at 6 months, and in late syphilis, the serological response was often absent. In some patients, serological tests might remain positive for life following effective treatment, and a positive treponemal test did not distinguish between active infection and infection that has been previously treated., Thus, it was important to have one proper assessment that could prevent unnecessary retreatment. Our results showed that PET is helpful not only for diagnosis, but also in follow-up and assessment of antibiotic treatment response. PET adequately enabled imaging of the therapeutic response and might be superior to morphologic imaging. Utilization of PET in syphilis should be combined with serological tests or dark field microscopy, and its positive effect might be maximized by repeating the examination during follow-up to assess the response to antibiotic therapy.
There were some limitations to this systematic review as follows. The major limitation was the small sample size, which was related to the lack of experience with PET in syphilis among clinicians. It could be difficult to differentiate active inflammation (infectious or not) from cancer when high FDG uptake was observed without serological tests. Our exclusion of non-English or non-Chinese studies might neglect some information that could make our results more concrete.
In conclusion, this systematic review suggested that 18 F-FDG PET is useful for diagnosis, disease extent evaluation, follow-up, and treatment efficacy assessment in patients with disseminated syphilis., PET may shed light on the follow-up of syphilis besides the clinical and serological response to treatment, which currently remains a puzzle. Further prospective cohort studies and clinical trials are warranted.
The authors appreciate the assistance provided by Dr. Hong-Wei Wang.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]