¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis of suspected paraneoplastic syndromes: A retrospective analysis

Abstract

Paraneoplastic syndromes are a rare clinical presentation of tumor thought to affect 0.01% of patients with cancer. Paraneoplastic syndromes present a diagnostic challenge as a wide variety of signs and symptoms may appear. This study examines the use of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) as a diagnostic imaging tool for detecting tumor in suspected paraneoplastic syndrome cases. This single-center retrospective study included patients with suspected paraneoplastic syndrome who underwent whole-body ¹⁸F-FDG PET/CT scan between December 2005 and December 2016. Associated clinical data were gathered via electronic chart review. Patient records were reviewed for age, sex, clinical signs and symptoms, ancillary diagnostic procedures, date of diagnosis, and follow-up time. Ninety-nine patients met inclusion criteria for this study. Mean follow-up period was 1.8 years. Cancer prevalence was 12.1%. The ¹⁸F-FDG PET/CT results are as follows: 10 true positives, 5 false positives, 82 true negatives, and 2 false negatives. The diagnostic values are as follows: sensitivity 83.3%, specificity 94.3%, positive predictive value 66.7%, and negative predictive value (NPV) 97.6%. The high NPV in our study supports the effectiveness of ¹⁸F-FDG PET/CT to rule out tumor in suspected paraneoplastic syndrome. Future research aims to analyze which patients with suspected paraneoplastic syndrome would benefit most from ¹⁸F-FDG PET/CT.

Keywords

Oncology - paraneoplastic syndrome - positron emission tomography/computed tomography

Introduction

Paraneoplastic Syndromes Encompass a Variety of Signs and Symptoms That Are Often Present for Months to Years Before Detecting an Underlying Tumor, Arising at a Distance from the Occult Primary Tumor or Metastasis. These Clinical Manifestations Are Thought to Be Caused by an Immunological Response or by a Biochemical Substance, the Former a Result of Ectopic Antigen Expression Normally Found in the Nervous System.[1] Paraneoplastic Syndromes Can Be Caused by Malignant, and Less Frequently Benign, Primary Neoplasms. the Clinical Presentation of Paraneoplastic Syndromes Can Be Divided Into Neurological and Nonneurological Syndromes. the Nonneurological Syndromes Can Be Further Subdivided Into Those Affecting the Dermatologic, Gastrointestinal, Endocrine, Hematologic, and Musculoskeletal Systems. Biochemical Abnormalities May Be Present. in Many Cases Where an Underlying Etiology Cannot Be Found, Paraneoplastic Syndromes Are Often Included in the Differential Diagnosis, Necessitating Workup for Tumor. the Search for Tumor Is Often Hindered by the Small Size of Culprit Neoplasms.[2] While Computed Tomography (Ct) Scan Is Oftenfirst Line in Diagnostic Assessment, Ct Relies on Structural Abnormalities and Changes, Characteristics Which May not Be Seen With a Small Neoplasm. Moreover, Evaluation of Sites Such as the Cerebellum, Spinal Cord, and Oral Cavity Is Limited by Poor Soft Tissue Contrast of Ct, and Visualization of the Oral Cavity Can Be Further Limited by Dental Streak Artifact.[3]

As a result, a whole-body positron emission tomography (PET) scan is a useful imaging tool in addition to a whole-body CT scan. PET involves injecting ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG), a glucose analog labeled with the radioactive isotope fluorine-18. Intense ¹⁸F-FDG uptake in localized areas signifies high metabolic activity, an indication of tumor, inflammation, and/or infection and therefore can play a role in assessing for a culprit neoplasm.[4] The European Federation of Neurological Societies recommends ¹⁸F-FDG PET/CT when morphological imaging tests are negative.[5] This retrospective study assesses the use of ¹⁸F-FDG PET/CT as a diagnostic tool in a group of suspected paraneoplastic syndrome patients in a North American tertiary care center.

Materials and Methods

This single-center retrospective study included patients with suspected paraneoplastic syndrome who underwent a whole-body ¹⁸F-FDG PET/CT scan between December 2005 and December 2016. The institutional electronic database was searched for the key terms “paraneoplastic” and “PET/CT,” yielding 352 files. Duplicate files were removed, and patients were excluded if they had previously diagnosed tumor before the PET/CT scan. Each referral was reviewed manually by R. B. for inclusion in the study. Paraneoplastic syndromes were diagnosed by the referring physicians on the foundation of recommendation criteria[6] and following exclusion of other possible causes. Both neurological and nonneurological paraneoplastic syndromes were included. Patients who did not meet the recommendation criteria for paraneoplastic syndrome or were deemed by the referring physician to have a low likelihood of paraneoplastic syndrome were excluded. In a given patient with more than one relevant referral during the inclusion period, only data from thefirst PET/CT scan were used. No uniform paraneoplastic antibody markers or imaging studies were performed before the ¹⁸F-FDG PET/CT scan. Associated clinical data were gathered via electronic chart review. Patient records were reviewed for age, sex, clinical signs and symptoms, further diagnostic procedures, date of confirmed diagnosis, and follow-up time. ¹⁸F-FDG PET/CT findings were noted and compared to the presence of tumor at the last follow-up date.

A ¹⁸F-FDG PET/CT scan was true positive if the suspected tumor was confirmed histologically. A false-negative occurred when the PET/CT scan did not indicate tumor, yet a tumor was confirmed histologically in the subsequent follow-up period. The ¹⁸F-FDG PET/CT scan was false-positive when the scan was suspicious of tumor, yet further diagnostic procedures and follow-up period did not identify the presence of tumor. A scan was considered true-negative if the PET/CT was not suspicious of tumor and no tumor was identified in the subsequent follow-up period. The diagnostic values – sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were then calculated to evaluate the diagnostic ability of ¹⁸F-FDG-PET/CT to assess tumor in suspected paraneoplastic syndrome. The study was approved by the Institutional Review Board vide their letter number 2017P000117/PHS dated January 25, 2017.

Results

A total of 99 patients (55.6% male, average age 57.4 years) were included in this retrospective study. The mean follow-up period was 1.8 years. Patients were divided into subgroups based on clinical signs and symptoms [Table 1]: neurological (n = 87), neurological and abnormal biochemistry (n = 7), hematological (n = 2), dermatological (n = 2), and gastrointestinal (n = 1). These findings are listed in [Table 1] along with the detailed signs and symptoms at presentation.

Table 1 Paraneoplastic syndrome signs and symptoms

The cancer prevalence in our study was 12.1%. ¹⁸F-FDG PET/CT was suspicious for tumor in 15 out of 99 cases (15.2%). Of the 15 cases, 10 had tumor confirmed by biopsy. ¹⁸F-FDG PET/CT did not find tumor in 84 of 99 cases (84.8%). Of the 84 cases, 2 were found to have tumor during the follow-up period. These results culminated in 10 true positives, 82 true negatives, 5 false positives, and 2 false negatives. Therefore, the diagnostic values are as follows: sensitivity 83.3%, specificity 94.3%, PPV 66.7%, and NPV 97.6%.

¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography-diagnosis of tumor

¹⁸F-FDG PET/CT correctly identified 10 of 12 patients with tumor. Patients presented with neurological (n = 7), neurological + abnormal biochemistry (n = 1), hematological (n = 1), and gastrointestinal (n = 1) symptoms. The tumors found include squamous cell carcinoma of lung (n = 1), squamous cell carcinoma of unknown origin (n = 1), ovarian teratoma (n = 1), serous adenocarcinoma (n = 1), papillary thyroid carcinoma (n = 1), invasive ductal carcinoma of the breast (n = 1) [Figure 1], small cell carcinoma of lung (n = 1) [Figure 2] atypical mesothelioma (n = 1) [Figure 3], neuroendocrine carcinoma (n = 1), and transitional cell carcinoma of the bladder (n = 1). Two cases, the squamous cell carcinoma of lung and transitional cell carcinoma of the bladder, were determined not to be causing paraneoplastic syndrome, as symptoms failed to improve after treatment of the tumor. These findings are shown in [Table 2].

Figure 1 A 55-year-old woman with chronic intestinal pseudo-obstructions, fever, nausea, vomiting, and diarrhea. ¹⁸F-FDG PET/CT scan shows (a) nodular opacity in the medial left breast on CT, with (b-d) intense ¹⁸F-FDG uptake (arrow). Gastrointestinal symptoms gradually resolved after patient underwent surgery, chemotherapy, and radiation therapy for invasive ductal breast carcinoma

Figure 2 A 76-year-old man with new-onset nystagmus, altered mental status, and unsteady gait. Brain magnetic resonance imaging (not shown) was without acute abnormality. (a) CT scan shows a small right upper lobe nodule (open arrow), and (b) lymphadenopathy in the right hilum and mediastinum (arrows). (c and d) ¹⁸F-FDG PET/CT scan shows moderate uptake in the lung nodule (open arrow) and intense uptake in the hilar and mediastinal lymph nodes (arrows). Biopsy of lymph node revealed metastatic small cell lung carcinoma

Figure 3 An 88-year-old man with new-onset diplopia, nausea, and unsteady gait. Brain magnetic resonance imaging (not shown) was without acute abnormality. (a) ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography scan maximum intensity projection image demonstrates multiple intensely ¹⁸F-fluorodeoxyglucose-avid right pleural nodules. (b and c) Pleural nodule (arrow) was biopsied, revealing malignant mesothelioma

Table 2 Patients with confirmed tumor

¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography-misdiagnosis of tumor

The ¹⁸F-FDG-PET/CT was false-negative in two patients who both presented with neurological symptoms and abnormal biochemistry. The patients were found to have an ovarian teratoma and renal oncocytoma, respectively, during the follow-up period.

The ¹⁸F-FDG PET scan was classified as being false-positive in 5 cases. Three patients had abnormal ¹⁸F-FDG uptake in the gastrointestinal tract or neighboring lymph nodes. The remaining two patients had suspicion for tumor in the pancreatic head and right kidney, respectively. Further diagnostic tests did not identify a tumor in the follow-up period. [Table 3] conveys the interrelationship between paraneoplastic syndrome symptoms, ¹⁸F-FDG PET/CT findings, and further diagnostic procedures.

Table 3 False-positive ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography results

Discussion

The strengths of this study include a large heterogeneous patient cohort and long follow-up period. The cancer prevalence was 12.1%, which is similar with other studies [Table 4],[7],[8],[9],[10],[11],[12],[13],[14],[15] although slightly higher than Kristensen et al. who also excluded patients with previously diagnosed tumors from their group composition and reported a cancer prevalence of 8.8%.[7] Our prevalence may be in the higher range due to a greater proportion of suspected paraneoplastic syndrome cases (88% vs. 49%) and possibly higher pretest probability as other differentials were extensively investigated before the ¹⁸F-FDG PET/CT scan was used. Our study has a similar composition to Vaidyanathan et al. with a slightly larger neurological subgroup (88% vs. 81%).[8] Our results follow similar trends to previous studies [Table 4], with moderate-high sensitivities, high specificities, very high NPV, and moderate PPV.

Table 4 Similar ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography studies for comparison

The major strength of the ¹⁸F-FDG-PET/CT scan in suspected paraneoplastic syndrome cases lies in its ability to rule out disease, shown by the very high NPV (98%). Schramm et al. found that ¹⁸F-FDG PET/CT is a useful single-combined modality tool for ruling out tumor, especially in sick patients with rapid clinical deterioration. In a per-patient analysis, sensitivity and specificity for neoplastic findings were 100% and 90% for ¹⁸F-FDG PET/CT, compared to 78% and 88% for contrast-enhanced CT alone.[12] Moreover, the ¹⁸F-FDG PET/CT scan can identify patients with incidental tumors that are unrelated to the paraneoplastic syndrome. Two of our patients (one squamous cell carcinoma of the lung and one transitional cell carcinoma) had neoplastic findings unrelated to the paraneoplastic syndrome but still held significant implications for the patients' health.

A major weakness of the ¹⁸F-FDG PET/CT scan in evaluating for tumor in suspected paraneoplastic syndrome is its low sensitivity for certain tumors, particularly those that are small and occur in regions of high physiological ¹⁸F-FDG activity. ¹⁸F-FDG PET/CT is not recommended for primary detection of ovarian cancer, bladder and kidney tumors, hepatocellular carcinomas smaller than 5 cm in diameter, and early-stage lung cancer.[16],[17],[18],[19] The ¹⁸F-FDG PET/CT was not suspicious for two patients in our study who were found to have an ovarian teratoma and renal oncocytoma, respectively, in the subsequent follow-up period. Despite this, ¹⁸F-FDG PET/CT remains a superior diagnostic imaging tool for anatomical localization and lesion characterization compared to the conventional CT scan.[10]

Another drawback of the ¹⁸F-FDG PET/CT scan is the high false-positive rate and low PPV. There is normal physiological uptake of ¹⁸F-FDG in the brain, heart, liver, spleen, gastrointestinal tract, urinary collecting system, and bone marrow that may be confused for pathology (i.e., tumor, inflammation, and infection) and lead to unneeded diagnostic procedures.[20] In our study, there were five false positives which led to a variety of further procedures which may have been superfluous in retrospect. On the other hand, an esophageal ultrasound in one patient led to the diagnosis of esophagitis with ulceration. In future, a larger risk–benefit analysis could be beneficial in determining the need for further testing.

Two recent meta-analyses have been published on the use of ¹⁸F-FDG PET scan in suspected paraneoplastic syndrome.[14],[15] The study published by Sheikhbahaei et al. in recent systematic review and meta-analysis of ¹⁸F-FDG PET and ¹⁸F-FDG PET/CT in patients with paraneoplastic syndrome demonstrated a pooled sensitivity of 0.81, specificity of 0.88, and moderate diagnostic odds ratios (DOR). The area under the curve (AUC) of the summary receiver operating characteristic curve was 0.916. While the studies were heterogeneous, a secondary analysis excluding studies with high degrees of bias yielded an AUC of 0.931. A false-negative rate was seen as 19%, suggesting the need for ongoing screening at 3–6 month intervals following a negative study. Patients with positive paraneoplastic antibodies tended to have more diagnostically accurate scans. However, the presence of onconeural or classic antibodies did not affect the diagnostic performance of PET. Both studies' conclusions indicated that ¹⁸F-FDG PET and ¹⁸F-FDG PET/CT have excellent diagnostic accuracy with moderate sensitivity/specificity.

Comparison of our results to these published meta-analyses is difficult, as the evaluated prior studies comprised of heterogeneous individuals with varying degrees of pretest suspicion of paraneoplastic syndrome. In addition, those studies used varying imaging protocols, some using PET/CT and others PET only. However, the overall sensitivity and specificity of ¹⁸F-FDG PET/CT reported in these meta-analyses of 77%–87.7% and 87%–89%, respectively, are comparable to our results, and the authors of both studies conclude that ¹⁸F-FDG PET/CT has a high diagnostic performance for detection of underlying tumor syndrome. Our study demonstrated a very high NPV not seen in the meta-analysis. Explanation for this could be due to our diagnostic workup before PET scan, which would confer a patient selection bias. The heterogeneity of tumor type may also have played a role. Methodology with respect to pretest suspicion is also highly variable.

Further research is needed to classify patients who would most benefit from a ¹⁸F-FDG PET/CT. Bannas et al. suggest testing for paraneoplastic antibodies (anti-Hu, anti-Yo, anti-CV2/CRMP5, anti-Ri, anti-Ma2, etc.,) before considering paraneoplastic syndrome as a differential diagnosis.[11]

The European Federation of Neurological Sciences published a framework for the use of ¹⁸F-FDG PET/CT in suspected paraneoplastic syndrome, suggesting that other imaging modalities (US, CT) should be performed before the use of PET/CT.[5] However, we feel this could lead to potential delay in diagnosis and definitive management, and a ¹⁸F-FDG PET/CT should be initially considered to rule out tumor.

The major limitation of our study is its retrospective nature. In addition, the ¹⁸F-FDG PET/CT scans were read by a group of radiologists (n = 7) from a single institution that may lead to variability in the interpretation of ¹⁸F-FDG-avid sites. Although the average follow-up period in our study was relatively long compared to previously published studies, the time between paraneoplastic syndrome onset and diagnosis of underlying tumor has been found to be as long as 8 years.[21]

Conclusion

Overall, the very high NPV found in our study supports the role of ¹⁸F-FDG PET/CT as a diagnostic imaging modality to evaluate for the presence or absence of tumor in suspected paraneoplastic syndrome. Note is made however that the duration of follow-up, in this study – 1.5 years, can affect the NPV. Over a longer follow-up period, occult neoplasms can become apparent thus raising the false-negative rate and lowering the NPV. An advantage of ¹⁸F-FDG PET/CT is that it can identify patients with incidental tumors and other abnormalities that are unrelated to the paraneoplastic syndrome. A drawback of ¹⁸F-FDG PET/CT is the relatively low PPV that may lead to unnecessary diagnostic procedures. In future, patients could benefit from larger studies into implementation of cost-benefit analysis when considering further diagnostic procedures. In addition, such an analysis would more clearly identify which patients with suspected paraneoplastic syndrome would most benefit from ¹⁸F-FDG PET/CT.

This work was presented as a scientific poster at the European Society of Radiology 2018 Annual Meeting in Vienna, Austria on March 3, 2018.

Conflict of Interest

There are no conflicts of interest.

Financial support and sponsorship

Nil.

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Publikationsverlauf

Eingereicht: 23. Juni 2019

Angenommen: 04. September 2019

Artikel online veröffentlicht:
19. April 2022