FDG-PET/CT in the evaluation of paraneoplastic neurologic syndromes

Steven J Sherry¹, Abdel K Tahari², Sahar Mirpour², Andrew Colucci¹ & Rathan M Subramaniam^*,1,2,3,4

¹Department of Radiology, Boston University School of Medicine, Boston, MA, USA

²Russell H Morgan Department of Radiology & Radiologic Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

³Russell H Morgan Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

⁴Russell H Morgan Department of Otolaryngology & Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Corresponding Author:

M Subramaniam
Department of Radiology
Boston University School of Medicine
Boston, MA, USA
Tel: +1 410 502 3956
Fax: +1 443 287 2933
E-mail: rsubram4@jhmi.edu

Abstract

Paraneoplastic neurologic syndromes (PNS) are a rare, heterogeneous group of complications associated with malignancy, unrelated to direct tumor invasion or metastasis, that may be immune-mediated. The aim of this article is to provide an overview of PNS and outline the value of 2-deoxy-2-[18F]fluoro-D-glucose PET/CT in the evaluation of patients with a PNS. 2-deoxy-2-18F-fluoro-D-glucose PET/CT is valuable to identify or exclude an occult malignancy in patients with suspected paraneoplastic syndromes.

Keywords

occult malignancy • paraneoplastic syndromes • PET/CT

Paraneoplastic neurological syndromes (PNS) are a rare, heterogeneous group of complications associated with malignancy, unrelated to direct tumor invasion or metastasis, that may be immune-mediated [1]. The development of PNS may antedate the diagnosis of cancer by several months or years [2,3]. Therefore, early localization of the initiating cancer can play a crucial role in establishing a prompt and accurate diagnosis. The aim of this article is to provide an overview of PNS and outline the value of imaging with a focus on 2-deoxy-2-18F-fluoro-dglucose (FDG) PET/CT in the management of PNS.

Overview of PNS

Pathogenesis

PNS are a collection of secondary disorders that are hypothesized to occur in patients with various forms of cancer. PNS have been documented to affect the CNS (e.g., limbic encephalitis, cerebellar degeneration, opsoclonus myoclonus and optic neuritis, among others), the peripheral nervous system (e.g., Guillain–Barré syndrome and autonomic neuropathy, among others), and the neuromuscular junction and muscle (e.g., Lambert–Eaton myasthenic syndrome, dermatomyositis and polymyositis, among others) [4].

The specific pathophysiology underlying the various subtypes of PNS is varied and poorly understood; however, autoimmune phenomena appear to be common. More specifically, antibodies [5] and T cells [6,7] responding to a cancer (often early stage or occult) are thought to develop crossreactivity. This crossreactivity can lead to an attack on homologous ectopic antigens, exclusively expressed by the central and peripheral nervous systems [8,9]. It is believed that an autoimmune response to normal self-antigens occurs because cancer cells process autoantigens in a different fashion, thereby making them reactive targets [10].

Conventional diagnostics

Owing to the heterogeneity of PNS presentations and the mild nature of early symptoms, quick and accurate diagnosis is often difficult. With this difficulty in mind, an international panel of neurologists proposed a rigorous set of clinically diagnostic criteria in 2004 [11]. By utilizing a patient’s clinical presentation, cancer workup data, and response to both immunologic and cancer therapies, these criteria try to risk-stratify patients into PNS ‘definite’ or ‘possible’ diagnostic categories.

To augment the clinical diagnosis, serum antibodies associated with PNS are routinely screened in suspected patients. Of these antibodies, some are fully characterized, and others are only partially characterized, requiring further investigation (e.g., PCA2 and antibipolar cells of the retina, among others). Antibodies that are well characterized attack antigens whose molecular identity is already known and understood. These well-characterized antibodies are specifically pathologic, and are rarely found in patients without cancer and/or PNS [12,13].

While serum antibody screens can add important clinical data to the diagnosis of PNS, there are multiple well-established caveats. First, it has been established that cancer patients without PNS may still demonstrate a positive serum antibody screen for specific PNS-involved antibodies [14,15]. Furthermore, certain antibodies are associated with multiple PNS subtypes, and certain PNS subtypes are associated with multiples types of antibodies. In addition, several PNS antibodies may occur simultaneously in the same patient (e.g., in patients with small-cell lung cancer) [16,17]. Finally, it has been shown that positive antibody screens do not always differentiate between the paraneoplastic and the nonparaneoplastic causes of their associated syndromes. For example, patients with antiamphiphysin antibodies typically have the associated stiff-person syndrome, but frequently do not have an associated cancer (and hence do not have PNS) [18,19].

In light of these various shortcomings with serum antibody screens, it is imperative to look for other, more precise methods for diagnosing patients with PNS. Lumbar puncture with the intent of screening the cerebrospinal fluid for paraneoplastic antibodies has been suggested, but in most cases, these antibodies are found in the serum as well [20]. Other efforts have looked into utilizing electrophysiology for further diagnostic characterization of PNS. However, while certain syndromes (e.g., myasthenia gravis) are associated with characteristic electrophysiological findings, this modality does not allow one to differentiate between the PNS-associated syndromes and their non-PNS counterparts.

Finally, brain MRI can aid in the diagnosis of specific PNS subtypes, such as limbic encephalitis and cerebellar degeneration [21,22]. In the majority of PNS subtypes, however, brain MRI demonstrates normal or nonspecific radiologic changes. Previous studies demonstrated that morphological cross-sectional imaging modalities, such as CT or MRI, have a low yield in the localization of cancer in cases of PNS, since lesions may be small or limited to metastatic lymph nodes [23].

Role of FDG-PET & PET/CT in PNS

In many patients, PNS is diagnosed before the discovery of a primary cancer. In these patients, PET/CT can evaluate patients with suspected PNS to detect an occult malignancy and identify metabolic brain abnormalities confirming PNS. FDG-PET/CT is useful in the diagnosis, therapy assessment and follow-up of patients with many human solid tumors [24–30]. A number of retrospective and prospective trials have agreed on the utility of FDG-PET in the setting of PNS (Table 1), and especially in the event of an unknown primary tumor [31,32] or inflammatory etiology (Figures 1–4). However, differing results have resulted in two recommendations for the application of FDG-PET in PNS: imaging when PNS is clinically suspected, or imaging only in cases of antibody-proven PNS.

Rees et al. [31] retrospectively reviewed the records of 43 unselected patients with suspected PNS referred for FDG-PET scanning to determine the value of this technique when conventional imaging was negative. Of these, 16 patients had PET scans consistent with malignancy (37%) and 27 had negative scans. All but one of the patients with a negative PET result remained free of malignancy on prolonged followup. They concluded specifically that FDG-PET was useful for detecting small lesions in the setting of suspected PNS, and that false-positive or -negative studies do not occur at a clinically problematic rate.

Berner et al. found a high specificity and negativepredictive value (NPV) and determined that FDG-PET is helpful in the diagnosis of patients with suspected PNS (Figures 5 & 6) [35]. In this study, out of 30 patients with suspected PNS, seven showed malignancy (23%). Six out of the seven were positive by PET (sensitivity: 86%). PET correctly ruled out underlying malignancy in 21 out of 23 patients (specificity: 91%). McKeon et al. [36] studied 56 patients with clinically suspected PNS who underwent PET/CT after negative standard evaluations. These investigators demonstrated that the use of PET/CT increased the diagnostic yield for cancer by 18% in patients with suspected PNS for whom results of standard oncologic tests were negative.

Linke et al. [37] showed that the integration of PET and CT scanning increases sensitivity and accuracy of tumor diagnosis. In this study, CT was positive for malignancy in three of ten patients (sensitivity of 30%), which FDG-PET detected in nine of ten (sensitivity of 90%), and the difference between the two techniques was significant (p < 0.01). The combination of both methods demonstrated a sensitivity of 100%. Nevertheless, Titulaer et al. stated a negative PET/CT does not rule out underlying cancer and repeat PET/CT scanning after a 3–6-month interval can be fruitful [38].

Patel et al. note that FDG-PET was more sensitive than CT for detecting an unknown primary tumor for patients with suspected PNS [32]. Vaidyanathan et al. showed that PET/CT is a highly sensitive and specific imaging technique in the assessment of PNS and adds confidence to clinical possibility [23]. In that retrospective study, they showed that PET/CT had 100% sensitivity, 82% specificity, 42% positivepredictive value (PPV) and 100% NPV in detecting malignant involvement of the PNS. On the other hand, clinical risk scoring on its own was 50% sensitive, 70% specific, 18% PPV and 91% NPV. On combining the two methods, the additive sensitivity was 100%, specificity was 84%, PPV was 36% and NPV was 100%.

FDG-PET useful for clinically suspected PNS for antibody-proven PNS

Younes-Mhenni et al. recommend a more restricted role for FDG-PET. Finding only moderate sensitivity and PPV, with poor specificity and NPV, they concluded that FDG-PET for PNS is only indicated for patients with well-defined PNS antibodies, in specific settings (e.g., unknown primary or difficult-tobiopsy lesions). They stated PET should be reserved for patients with well-characterized paraneoplastic antibodies when conventional imaging fails to detect primary malignancy [34].

On the contrary, Hadjivassiliou et al. found a high specificity and NPV and agreed with the utility of FDG-PET for clinically suspected PNS, without a need for positive PNS antibodies before imaging [33]. In this study, the prevalence of abnormal PET in 80 patients clinically suspected for PNS was 18 out of 80 (23%). Biopsy-proven cancer was confirmed in 44% of patients with abnormal PET as opposed to less than 2% of patients with a normal PET. According to their results, the presence of PNS antibodies should not be a prerequisite for performing a PET scan; however, the presence of PNS antibodies increases the chances of the PET scan detecting a tumor. Additionally, Matsuhisa et al. showed that PET/CT was a useful screening method for patients with clinically suspected PNS who do not demonstrate well-characterized paraneoplastic antibodies. They retrospectively studied the utility of FDGPET/ CT in 27 patients with suspected PNS and found that FDG-PET/CT detected malignancy in 19% of the cases [39].

FDG-PET & altered brain glucose metabolism:

The metabolic abnormalities depicted on PET/CT typically correlate with clinical symptoms. Both qualitative and quantitative analysis of brain glucose metabolism may be helpful in evaluating PNS, especially in patients with a normal MRI. In many patients with para neoplastic limbic encephalitis, FDG-PET shows hypermetabolism in the temporal lobes with negative findings on MRI or T2-hyperintense mesiotemporal lesions. In the literature, focal hypermetabolism on PET was attributed to seizure activity [40,41], or an underlying inflammatory process [42–44]. Patients with PNS may demonstrate abnormal hypometabolism on brain FDG-PET/CT before MRI demonstrates cerebellar atrophy [45].

Conclusion

In conclusion, FDG-PET/CT offers value in investigating suspected PNS to identify or exclude occult malignancy, with a greater likelihood of cancer detection in cases of antibody-proven PNS.

Future perspective

FDG-PET/CT is valuable in excluding occult malignancy in patients with suspected PNS. It may help in identifying the malignancy in antibody-proven PNS. The value of novel radiophramaceuticals, such as ¹¹C-choline and ⁶⁸Ga-DOTA, in identifying the occult malignancies is currently unknown in patients suspected or antibody-proven PNS and further studies will be conducted in the next few years. In addition, future novel radiopharmaceuticals targeting the immune system will help elucidate the biologic mechanisms of PNS.

Financial & competing interests disclosure

RM Subramaniam is a speaker for Eli-Lilly Amyloid Imaging and receives research support from MimVista Inc. He also received a research grant from RSNA/GE. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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