Paraneoplastic brainstem encephalitis in a patient with exceptionally long course of a metastasized neuroendocrine rectum neoplasm
- Michael Boch†1,
- Anja Rinke†1,
- Peter Rexin2,
- Maria Seipelt3,
- Dörte Brödje4,
- Marvin Schober1,
- Thomas M Gress1,
- Patrick Michl1 and
- Sebastian Krug1Email author
© Boch et al.; licensee BioMed Central Ltd. 2014
Received: 30 March 2014
Accepted: 17 September 2014
Published: 22 September 2014
Paraneoplastic neurological syndromes (PNS) have frequently been described in patients with lung or breast cancer. However, some reports also described a correlation to carcinoid tumors, probably triggered via the excessive release of hormones.
We report the case of a 40-year-old woman that was diagnosed with a neuroendocrine neoplasm (NEN) of the rectum and multiple synchronous liver metastases ten years ago. She initially responded well to transarterial chemoembolization (TACE), resulting in prolonged disease stabilization. However, ten years after initial diagnosis the patient developed unspecific neurological symptoms that could not be classified by standard neurological diagnostic work-up. Special laboratory analysis revealed a high titer of anti-Ri (ANNA-2), a well-characterized antibody that is associated with paraneoplastic neurologic syndromes. The patient’s symptoms improved markedly after a 5-day-course of high-dose glucocorticoid therapy. To our knowledge, this is the first report of a Ri-positive PNS in a patient with hormone-negative rectal NEN.
PNS can complicate the patient’s clinical course, response to treatment, impact prognosis and even be interpreted as metastatic spread. However, owing to their rarity, the knowledge of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches.
KeywordsNeuroendocrine rectum neoplasm TACE Paraneoplastic syndrome Anti-Ri-antibody ANNA-2
Neuroendocrine Neoplasms (NENs) of the rectum have been increasing in incidence over the last decades and now comprise 16% of all NENs . Most rectal NENs are localized at diagnosis with acceptable 5-year overall survival rates of approximately 90%. However, regional and distant disease is associated with a dramatically impaired outcome. Factors influencing survival included tumor size, histology, proliferation index, depth of invasion and lymphvascular invasion . Localized tumors that are small (T1 and <1-2 cm of size) can be managed with endoscopic resection. For advanced disease the benefit of radical surgery remains to be elucidated . So far, no published data on treatment outcomes for the metastatic situation are existing, therefore, multidisciplinary treatment options should be included into considerations .
Paraneoplastic neurological syndromes (PNS) are mainly associated with lung cancer, gynecological tumors and hematological diseases. The expression of antigens by various neoplasms lead to antibody formation that may induce an intrathecal inflammatory process leading to distinct neurological symptoms [4, 5]. Moreover, specific antigen recognition of antibodies in neuronal tissue induces characteristic neurological symptoms. There are few cases describing concomitant neurological symptoms in patients with neuroendocrine neoplasms, however, mostly due to excessive hormone release and seldomly correlated to positive antibodies . This report represents the first case of an anti-Ri positive paraneoplastic brainstem encephalitis in a patient with exceptionally long course of a metastasized neuroendocrine rectum neoplasm.
Factors predicting malignant behavior (8, 11)
> than 20 mm
>2/10 high power fields
Muscularis layer invasion
Epidemiologic data (6)
Neuroendocrine tumor of the rectum
General data (our patient)
Age diagnosis years
Disease stage at diagnosis (%)
Survival rate (months)
Paraneoplastic neurological syndromes
Paraneoplastic syndromes form a heterogeneous group of complications associated with malignancy that are caused neither by local effects of the tumor mass or its metastases, nor by vascular, infectious, or nutritional impairments. In several literature reports, paraneoplastic syndromes are estimated to occur in approximately 0.01 to 8% of cancer patients [16, 17]. The most frequent cancer entity associated with paraneoplastic syndromes is small cell lung cancer  followed by breast cancer, gynecologic tumors and hematologic malignancies such as lymphoma . A paraneoplastic syndrome can affect various organs and has been proposed to be caused by two main pathophysiological mechanisms. First, tumors are capable of producing a variety of functionally active peptides that imitate hormone function and lead to a metabolic disturbance (as in endocrine paraneoplastic syndromes) . In neurologic paraneoplastic syndromes it has been described that tumors ectopically express antigens that are normally expressed in the nervous system which leads to an immune-mediated cross-reactivity [19, 20]. Neurologic PNS may involve any part of the nervous system (central, peripheral or the neuromuscular junction) . The production of antibodies against tumorous antigens is an autoimmune process . The similarity of tumor antigens to elements of the nervous system leads to an attack of tumor-directed antibodies against nerval epitopes. These antibodies are known as onconeural antibodies and are commonly used in the diagnostic work-up to diagnose paraneoplastic neurological syndromes . The diagnostic criteria for a PNS include the presence of cancer within the next 5 years, the definition of a classical or non-classical syndrome and the presence of well-defined onconeural antibodies . Based on the classification in classic and non-classic PNS, brainsteam encephalitis is affiliated to the non-classic forms.
There are various cases in the literature describing patients with neuroendocrine carcinoid tumors and neurological symptomes with the tumors being localized in the stomach  or the bronchial system [25, 26]. In the majority of these cases the neurological affections were due to the hormones produced by the carcinoid or by the metastases . Only a minority of single cases accomplish the diagnostic criteria of a PNS (e.g. positive antibodies). One case of PNS in neuroendocrine tumor of the rectum has been reported in association with anti-Hu antibodies . To our knowledge, our case represents the first describing a non-functional neuroendocrine tumor leading to a paraneoplastic neurological syndrome due to anti-Ri antibodies. The Anti-Ri antibody which was found in our case belongs to the group of antibodies whose strong association to cancer has been proven. Most commonly this antibody is associated with breast cancer and small cell lung cancer [6, 29]. Typically, jaw dystonia and laryngospasm which were predominant symptoms of our patient are strongly associated with brainstem encephalitis due to Ri antibodies . There are reports about Anti-Ri associated PNS in neuroendocrine tumors [25, 31] but to the best of our knowledge none was associated with nonfunctional rectal neuroendocrine tumors. Most effective treatment of the PNS is tumor specific treatment that is in accordance to the existing treatment guidelines of the tumor entity . As described in other publications , immunomodulatory or –suppressive treatment leads to improvements of the functional ability of the patient but does not represent causal therapy. Our patient received high-dose immunmodulatory therapy and fortunately showed positive response. After being free from neurological symptomes the therapy was gradually reduced. Until now, there was no relapse of symptomes. Since the patient is still stable on follow-up according to imaging and biochemical means 6 months after the occurrence of the PNS, so far we have no indication that the PNS represents an early sign of disease recurrence.
In summary, this report represents the first case of an anti-Ri positive PNS occurring in a non-functional rectal NEN. Neurological symptoms in a patient with NEN should always trigger further work-up to rule out a PNS also in patients who are long-term clinically stable.
Materials and methods
We retrospectively analyzed a patient with metastasized neuroendocrine rectum neoplasm treated in our institution since 2003. This case presentation was conducted in accordance with the Declaration of Helsinki and with the approval of the local ethics committee at the University of Marburg. The evaluation of the patient-related information was done with patient informed consent. Tumor tissue was explored immunohistochemically concerning expression of Chromogranin, Synaptophysin, Ki-67. Analyses were performed according to a standardized protocol using Leica-Bond-Max-Autostainer and the antibodies in the following dilutions: Chromogranin: Dako 1:2000; Synaptophysin: Dako 1:50; Ki-67: Dako 1:1000. For indirect immunofluorescence technique (IIFT) patient serum in various dilutions (1:10-1:5120) was incubated with tissue sections of primate cerebellum, nerve and gut (Neurology Mosaik1, Fa. Euroimmun, Lübeck). Fluorescein-tagged goat-anti-human-IgAGM detected bound anti-Ri antibodies. The IIFT was corroborated via immunoblotting. 1.5 ml of serum (dilution 1:101) was incubated with the following antigen fragments: Amphiphysin, CV2, PNMA2 (Ma2/Ta), Ri, Yo and Hu (Euroline Profil 2, Fa. Euroimmun Lübeck). Alkaline phosphatase-labelled goat-anti-human-IgG served as the enzyme conjugate.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Patrick Michl and Sebastian Krug shared last authorship.
We gratefully acknowledge the patient for collaboration.
Address all correspondence and requests for reprints to: Dr. med. Sebastian Krug, Dept. of Gastroenterology, Endocrinology and Metabolism Philipps-University of Marburg, Baldingerstrasse, 35043 Marburg, Germany. E-mail: email@example.com.
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