Author’s Accepted Manuscript
Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A single center cohort description with two cases of histological validation
Philippe Beauchemin, Raffaele Iorio, Anthony L. Traboulsee, Thalia Field, Anna V. Tinker, Robert L. Carruthers
ELSEVIER
MULTIPLE SCLEROSIS AND RELATED DISORDERS
IN THIS ISSUE
| PII: | S2211-0348(17)30352-8 |
| DOI: | https://doi.org/10.1016/j.msard.2017.12.012 |
| Reference: | MSARD726 |
| To appear in: | Multiple Sclerosis and Related Disorders |
| Received date: | 14 November 2017 |
| Revised date: | 16 December 2017 |
| Accepted date: | 19 December 2017 |
Cite this article as: Philippe Beauchemin, Raffaele Iorio, Anthony L. Traboulsee, Thalia Field, Anna V. Tinker and Robert L. Carruthers, Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A single center cohort description with two cases of histological validation, Multiple Sclerosis and Related Disorders, https://doi.org/10.1016/j.msard.2017.12.012
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Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A single center cohort description with two cases of histological validation.
Philippe Beauchemin MD, MHSc1,2*, Raffaele Iorio MD3 , Anthony L Traboulsee MD1 , Thalia Field1, Anna V Tinker4, Robert L Carruthers MD1
1Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, Canada
2 Département de Médecine, Division Neurologie, Université Laval, ville de Québec, Canada
3Institute of Neurology, Fondazione Policlinico Universitario ‘A. Gemelli’, Catholic University Rome, Rome, Italy
4Department of Medicine, Division of Medical Oncology, University of British Columbia, Vancouver, Canada
*Corresponding Author: Philippe Beauchemin MD, 2211 Wesbrook Mall, Vancouver BC V6T 2B5. phone 418-951-3623; fax 604 822 7703. Canada. philippe.beauchemin.1@ulaval.ca
Keywords: Neuromyelitis Optica; Paraneoplastic Syndrome; Immunology.
Abstract:
Background
Paraneoplastic syndromes are remote effects of cancer caused by an autoimmune response triggered by tumor cells. Paraneoplastic neuromyelitis optica spectrum disorders (NMOSD) has been previously described, but the underlying mechanism for these rare cases is not well characterized. This paper presents a newly described case series of paraneoplastic NMOSD, including 2 new histological types of cancer and histological validation.
Methods
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The UBC NMO clinic database was surveyed and identified 6 patients with paraneoplastic NMOSD. In 2 cases, aquaporin-4 (AQP4) immunoreactivity was assessed on patients’ tumor specimens.
Results
The mean age at NMOSD diagnosis was 56 years old and 5/6 patients were older than 50 years old. 4/6 patients with paraneoplastic NMOSD have positive AQP4 antibodies. The median time between NMOSD and cancer was 12 months. Two new cancer types- serous ovarian carcinoma and adrenocortical carcinoma - were found in paraneoplastic NMOSD cases. A serous ovarian carcinoma and a thymoma, found in patients with AQP4 serological evidence, showed a positive reactivity to AQP4 immunostaining.
Conclusions
Our findings will increase the recognition of NMOSD as a paraneoplastic syndrome. Cancer cells can express AQP4, increasing the likelihood of a direct mechanism between cancer cells and the development of NMOSD in paraneoplastic cases.
Keywords: Neuromyelitis Optica; Paraneoplastic Syndrome; Immunology.
INTRODUCTION:
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory central nervous system (CNS) syndrome distinct from multiple sclerosis (MS) [1]. NMOSD is frequently associated with aquaporin-4 (AQP4) immunoglobulins (IgG) [2], which are found in 60- 70% of patients. NMOSD frequently overlaps with other auto-immune disorders [3].
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Association of cancer and NMOSD was previously described. Thirty-four paraneoplastic NMOSD cases were reported in a recent review, with one-third of cases associated with breast cancer [4]. The prevalence of cancer in patients with NMOSD associated with positive AQP4-IgG antibodies has been reported to be between 3.2-12% [5-7]. In patients screened for paraneoplastic antibodies, AQP4-IgG were found incidentally in 0.02% and most of these patients had a CNS disorder consistent with NMOSD [5].
In humans, AQP4 is normally expressed on astrocytes, retinal Muller cells, lacrimal gland, salivary duct, inner ear cells, olfactory epithelium, gastric parietal cells, airway cells, renal collecting duct, placenta, fast twitch fibers of the muscle and epithelial cells of the intestine [8]. AQP4 staining of tumor cells has been previously demonstrated [7, 9- 11], supporting a causal link between cancer and NMOSD in paraneoplastic cases.
Paraneoplastic neurological syndromes (PNS) are remote effects of cancer caused by an autoimmune response initiated by neural self-antigens expressed by tumor cells [12]. A definitive PNS is diagnosed if: 1) a cancer is detected within 5 years of a classical neurological syndrome; 2) a clinical improvement is seen after cancer treatment; 3) a non-classical syndrome is associated with a cancer and a well characterized antibody; and/or 4) any neurological syndrome is associated with a well characterised antibody but no cancer is found [12]. When a classical syndrome is diagnosed without a cancer nor a well characterized antibody or when a cancer is present within 2 years of a non-classical syndrome, a possible PNS is diagnosed [12].
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Here, we report 6 newly described cases of paraneoplastic NMOSD, coming from a single large clinic. Moreover, two new types of NMOSD-associated cancer are described. AQP4 staining was performed in some cases to support the hypothesis that a direct pathologic link between cancer and NMOSD is more likely than co-occurrence.
METHODS:
The UBC NMO Clinic and Research program, based in Vancouver, British Columbia, is the only referral center for NMOSD in the province of British Columbia, Canada. Patients with NMOSD and cancer were identified through a local database which started in May 2008. All newly diagnosed patients were met to collect clinical and demographic information, based on self-report. Co-morbidities, including cancer, are recorded into the database. AQP4 serum antibodies were all tested at the same laboratory, who used a cell- based assay (CBA). The pathology reports were used to confirm the cancer diagnosis. To satisfy inclusion criteria, patients would fulfill the 2015 NMOSD diagnostic criteria [1] and have at least 1 confirmed cancer.
All patients signed a written consent form allowing to be contacted or to use their medical information for research. A retrospective chart review was performed in December 2016. This paper is mainly descriptive and hypothesis-generating. The goal is to expand the body of evidence on paraneoplastic NMOSD and raise the awareness about this condition.
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As shown in the flow chart (Figure 1), 11 patients with cancer were identified from our NMOSD cohort (155 patients). 6 of them fulfilled the criteria for a paraneoplastic syndrome. In two cases, AQP4 immunoreactivity was assessed on patients’ tumor specimens. As the other cases came from remote locations across British Columbia, samples were not available for AQP4 staining.
at
155 NMOSD patients in the UBC database
144 NMOSD cases: no cancer identified
11 NMOSD patients with cancer
5 cases not fulfilling possible para- neoplastic definition
6 paraneoplastic NMOSD cases
4 cases without readily available pathologic samples
2 cases with histological validation
Figure 1 Legend: From the 155 NMOSD patients registered in the UBC NMO database, 11 were identified with a cancer prior or after the NMOSD diagnosis. Six patients fulfilled the definition of a paraneoplastic syndrome and, in two cases, the tumor samples were analyzed with AQP4 immuno-staining. < NO COLOR>
In the cases where the tumor biopsy samples were available, indirect immuno- fluorescence staining with a commercial rabbit IgG specific to human AQP4 was performed, using the same technique previously described by Iorio et al [9]. Briefly, paraffin-embedded tissue was deparaffinised. After blocking with 10% normal goat
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serum for 1 hour, tissue sections were incubated with rabbit AQP4-IgG (AbNova, PAB20767, dilution 1:250) for 16 hours at 4 ℃. After extensive washing with phosphate- buffered saline (PBS), sections were incubated with Dylight 550-conjugated anti-rabbit IgG (1:250), washed and mounted with anti-fade medium with DAPI. Results were analyzed using a Zeiss fluorescence microscope.
RESULTS:
From the 11 patients identified with both cancer and NMOSD, 6 fulfilled the criteria of possible paraneoplastic syndrome. A summary table of the main findings of these patients is provided in Table 1.
Table 1: Clinical information from the cohort of patients diagnosed with paraneoplastic NMOSD.
Age at NMOS Initial D
Initial AQ MRI
Timin Tumo g of r cancer
Cas Se e ☒ x
presentati
finding statu
P4 Comorbidit ies
Tumor type AQP4 relativ Treatment e to staini
Evoluti on
diagno on sis
s
s
ng NMO SD
| 1 F | 54 | Intractabl e nausea + bulbar weakness | Expansi ve spine lesion from C5 to medulla Normal Brain MRI | + | Hypothyroid ism | Ovarian serous carcinoma (BRCA1 mutation) | + 18 + month s | Acute: IVMP, PLEX and Mitoxanthr one Chronic: Azathioprin e | Partial recover y. No recurren ce over 2 years. |
|---|---|---|---|---|---|---|---|---|---|
| 41 | Normal | Acute: | Partial | ||||||
| 2 F | Right severe | Brain and | + | Hepatitis B, Sjogren's | Thymoma | - 4 | IVMP Chronic: | recover y. 1 TM 6 | |
| + month | |||||||||
| ON | Orbits MRI | disease | s | Azathioprin e | years later |
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| 3 | M | 61 | LETM | 1 thoracic cord lesion (T9- | - | Type 2 Diabetes, COPD, CAD | Prostate adenocarcin oma | n/a | + 3 month s | Acute: IVMP Chronic: None | Partial recover y. No recurren |
|---|---|---|---|---|---|---|---|---|---|---|---|
| T11) | ce over 8 years. | ||||||||||
| 1 | Rectal | ||||||||||
| cervical cord | adenocarcin oma | - 14 | Complet | ||||||||
| lesion | Endometrial | years | Acute: | e | |||||||
| 4 | F | 54 | LETM | (C2- | None | - 4 | IVMP | recover | |||
| C7) | - | adenocarcin | n/a | years | Chronic: | y. 1 TM 3 | |||||
| Non- | oma | - 1 | None | ||||||||
| specific Brain | Urothelial papillary | year | months later. | ||||||||
| lesions | carcinoma | ||||||||||
| Chronic | Non- | - 4 | Acute: IVMP | Partial | |||||||
| 5 | F | 62 | Bilateral ON | Normal Brain MRI | + | kidney failure, Raynaud, Scleroderma | Hodgkin Lymphoma Non-small | n/a | years + 6 | Chronic: Azathioprin e, | recover y. 1 TM |
| cell lung | years | then | over 5 | ||||||||
| cancer | Mycopheno | years. | |||||||||
| late | |||||||||||
| Complet | |||||||||||
| 2 | e | ||||||||||
| F | thoracic | Acute: | recover | ||||||||
| 6 | 65 | cord | Osteoporosis | Adrenocorti | + 6 | IVMP, | y. | ||||
| LETM | lesions (T4- | + | , Hypertensio | cal carcinoma | n/a | month s | PLEX Chronic: | 2 TM and 1 | |||
| T10 and | n | Enrolled RCT | right ON | ||||||||
| T3-T4) | |||||||||||
| over 5 | |||||||||||
| years. |
legend: Six paraneoplastic NMOSD cases are presented with demographic information, key aspects related to their NMOSD diagnosis and their cancer diagnosis. AQP4: aquaporin-4. BRCA: Breast cancer susceptible gene. CAD: coronary artery disease. COPD: chronic obstructive pulmonary disease. IVMP: intravenous methylprednisolone. LETM: longitudinally extensive transverse myelitis. MRI: Magnetic Resonance Imaging. n/a: not available. NMOSD: Neuromyelitis Optica Spectrum Disorder. ON: Optic Neuritis. PLEX: Plasmapheresis. RCT: Randomized controlled trial. TM: Transverse Myelitis.
The mean age of patients at NMOSD diagnosis was 56 years (range 41-65; SD 8.7) and 83% were female. Three patients presented with longitudinally extensive transverse myelitis (LETM), one with severe unilateral optic neuritis (ON), one with bilateral ON
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and one with area postrema syndrome. AQP4 seropositivity was found in two-thirds of patients (4/6).
The median time between NMOSD and cancer was 12 months (range 3 to 48) and half had cancers diagnosed after NMOSD (3, 6 and 18 months). One patient (Case 4) had Lynch syndrome with multiple cancers (endometrium, colon and bladder). The other cancer types were lung adenocarcinoma (1), non-Hodgkin lymphoma (1), thymoma (1), adrenocortical carcinoma (1) and ovarian serous carcinoma associated with BRCA1 mutation (1). As it is commonly seen in NMOSD, two patients had concurrent auto- immune diseases. Case 2 has Sjogren’s disease and Case 5 has both Raynaud’s and scleroderma.
Positive staining for AQP4 was found on two available tumor samples. An ovarian serous carcinoma (Case 1) and a thymoma (Case 2), found in patients with serological evidence of AQP4, showed a positive reactivity to AQP4 immunostaining. Description of the two positive cases is provided below.
CASE DESCRIPTION:
Case 1:
A 54 year old woman was hospitalized in December 2014 for hypernatremia following two weeks of nausea and vomiting. After an initial negative gastro-intestinal work-up, including a normal computed tomography (CT) and a normal echography of the abdomen and pelvis, the patient developed dysarthria, dysphagia and tongue weakness. A
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brainstem syndrome was suspected. The magnetic resonance imaging (MRI) showed a lesion in the medulla extending into the cervical spinal cord up to C5 (Figure 2). Serum AQP4-IgG antibodies were positive. A lumbar puncture was performed, showing 96 white blood cells (38% neutrophils, 62% lymphocytes) with an elevation of protein (1.525 g/L, normal: 0.15-0.45 g/L) and no oligoclonal bands.
Figure 2 Legend: In this 54-year-old woman diagnosed with NMOSD and a serous ovarian carcinoma, a longitudinally extensive MRI lesion (large arrow) is present,
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spanning from the upper portion of the medulla (small arrow) to C5. The brain MRI (not shown) did not revealed any other abnormalities. < NO COLOR>
The patient was treated with five consecutive days of intra-venous methylprednisolone (IVMP) without improvement. Five plasma exchanges on consecutive days were done without significant improvement. Finally, she received two doses of Mitoxanthrone, one month apart, and then slowly improved. She was discharged on high-dose steroids and started on azathioprine. MRI imaging was repeated in March 2015 and showed mild improvement. Clinically, she is still symptomatic.
In addition to hypothyroidism, she was assessed in 2008 for an incomplete sensory myelitis with a normal spinal cord MRI, which was done three months following symptom onset. Her symptoms then resolved over a few weeks. She never experienced any ocular symptoms and her visual evoked potentials (VEP) were normal.
In May 2016, she presented a sudden-onset pain in the right pelvic area. An ultra-sound showed a large pelvic mass measuring 7.1 cm x 8.5 cm x 9.1 cm. She underwent hysterectomy with bilateral salpingo-oophrectomy and final pathology revealed a high- grade serous carcinoma, present in both ovaries, the mucosa of the left fallopian tube, the uterine serosa and the cul-de-sac (stage III). AQP4-IgG staining showed a positive reactivity of the cancer cells (Figure 3). Tumor markers (CA125, CEA, CA 19-9 and CA 15-3) were all normal. A germline mutation in the BRCA1 gene was identified. She was treated with adjuvant chemotherapy and has not had a recurrence of neurological symptoms.
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A
B
C
D
Figure 3 legend: On the H&E (A), the ovarian sample shows high cellularity and atypia. Intense AQP4 immunoreactivity (indicated in red) of cancer cells is observed at low (B) and high power field (C). Usually not found in the ovary, AQP4 is detected here at the periphery of the cancer cells and is potentially involved in cell membrane transport. No immunoreactivity is detected when the tumor sections were incubated with the anti-rabbit IgG alone (D). < COLOR>
Case 2: While investigated for cough, a 41-year-old woman of Chinese origin was diagnosed with thymoma. Surgical resection was performed in April 2002, followed by radiation therapy. She was known to have hepatitis B and Sjogren’s disease. She never had any symptoms suggestive of myasthenia gravis and the acetylcholine receptor antibodies were negative. Four months later, she presented with severe right optic neuritis with partial recovery following steroids. Her initial brain MRI was normal and an orbit MRI,
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performed later, did not show any optic nerve abnormality. In 2008, she presented with a partial TM with a normal cervico-thoracic MRI. AQP4-IgG testing was positive and she was treated with azathioprine. She has been clinically stable since. Subsequent AQP4 staining of her thymoma showed positive reactivity (Supplementary Figure 1).
DISCUSSION:
With 6 newly described cases of paraneoplastic NMOSD from a single center, we have described one of the largest series to date. The prevalence of cancer in NMOSD patients followed at our center (7.1%) is consistent with previous reports with a prevalence between 3.2-12% [5-7]. This is possibly an underestimation, as it is based on patient self- report, then confirmed by the pathological report. A more accurate prevalence would be found with data linkage, using provincial registries, which was not possible.
We also reported two new types of NMOSD-associated cancer. Ovarian serous carcinoma and adrenocortical carcinoma have never been associated with paraneoplastic NMOSD. In a previous review of literature [4], cancer types described were breast carcinoma, lymphoma, lung carcinoma, carcinoid tumor, thymoma, ovarian teratoma, uterine cervical cancer, thyroid carcinoma, monoclonal gammopathy, prostate adenocarcinoma, acute myeloid leukemia and pituitary somatotropinoma.
Consistent with known demographics for NMOSD, the majority of patients in our series were female (83%). At NMOSD diagnosis, 5 out of 6 patients were over the age of 50, with a mean age of 56. This is consistent with a review by Cai et al [4]. Most cancers
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increase in incidence with age and this could be considered as a potential confounder. One might also argue that most of these cases are co-occurrence of one rare disease (NMOSD) and a more common disease (cancer) associated with a 40% lifetime prevalence [13].
However, the demonstration of AQP4 immunoreactivity on cancer specimens supports a causative link between the immune response directed at the neoplasm and the development of AQP4 autoantibodies in at least a small proportion of cases. As shown in Figure 3, the AQP4 immunoreactivity is detected at the periphery of the cancer cells and is potentially involved in water transport through the cancer cell membrane. Evidence suggests that aquaporin molecules are critical for tumor growth and metastasis [8]. A limitation of our study is that the AQP4 staining could not be performed for all cases, due to the unavailability of solid tumor samples from referring centers outside our catchment area.
There is mounting evidence in the medical literature that cancer can be linked to some cases of NMOSD [4, 7, 14]. Lacking a well-described paraneoplastic antibody or a classical paraneoplastic syndrome, a definitive paraneoplastic syndrome cannot be diagnosed based on consensus definition [12]. However, as the cancers were discovered within two years in 5/6, we can conclude these patients have a probable PNS. As the number of paraneoplastic NMOSD cases published is increasing, this may lead to a recognition of NMOSD as a classical PNS and lead to clear recommendations about cancer screening, for example.
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Cancer may not be clinically evident at the moment of the PNS diagnosis and can be diagnosed in the following years [15]. The same applies for paraneoplastic NMOSD [4]. In our cohort, half were diagnosed with cancer after their NMOSD diagnosis (3, 6 and 18 months), reinforcing the possible implication of the cancer in the cascade leading to NMOSD, possibly by neo-antigens developed by the cancer. Also, as seen in most cases presented the Table 1 and in the two cases described, few relapses are seen after treatment. Indeed, two patients did not present any new neurological relapse (2 and 8 years of follow up) and three presented only 1 other relapse (up to 6 years of follow-up) that was not temporally related to a cancer recurrence.
It is worth mentioning that cancer can benefit from immunotherapy, for example in cancers with high mutational burden [16]. Due to the small number of patients in our cohort, it is not possible to draw a conclusion on the best therapeutic approach for paraneoplastic NMOSD. We acknowledge some drugs received by these patients, such as azathioprine and mitoxantrone, are associated with secondary cancers. Even if it might be a contributing factor in some cases, not all patients in our series receive these drugs. Also, we would have a higher-than-expected frequency of drug-related cancers [17]. For these reasons, this hypothesis cannot be the sole explanation of the cancer in our patients. Furthermore, in case 1, there was a BRCA 1 gene mutation, which suggests that the patient’s predisposition for cancer predated her disease-modifying treatment.
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Other factors could also trigger NMOSD. In a series describing the overlap between Myasthenia Gravis and NMOSD [18], it was shown that thymectomy could contribute to the development of NMOSD, sometimes years after the surgery. This was the case in Patient 2 and suggest cancer surgeries could be involved in the immunological cascade leading to paraneoplastic NMOSD.
CONCLUSION:
We described one of the largest single-center series of paraneoplastic NMOSD. Two new cancer types, an ovarian serous carcinoma associated with BRCA1 mutation and an adrenocortical carcinoma, were described.
Accoglie patient det an .
As shown, pathologic samples from tumours cells can express AQP4, increasing the confidence of a direct involvement of cancer in the development of NMOSD in some paraneoplastic cases. Our findings add up to existing evidence that we hope will raise awareness on paraneoplastic NMOSD.
Supplementary Figure 1: Indirect Immunofluorescence assay on tumor specimen from Case 2.
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ACKNOWLEDGEMENTS
: PB’s fellowship is supported by the Canadian Network of Multiple Sclerosis Clinics. RC gratefully acknowledge salary support from the Milan & Maureen Ilich Foundation. We would like to thank Dr. Blake C Gilks, from the UBC Department of Pathology and Laboratory Medicine, for his contribution to this project.
DECLARATION OF INTERESTS:
Philippe Beauchemin: Consulting fees: Novartis, EMD Serono, Roche Canada, Biogen Canada. Raffaele Iorio: no relevant disclosure to report.
Anthony L Traboulsee: has received grant funding from the MS Society of Canada, Canadian Institute for Health Research, Roche, and Genzyme; received honoraria or travel grants from Teva Canada Innovation, Roche, Merck/EMD Serono, Genzyme, Chugai Pharmaceuticals.
Thalia Field: no relevant disclosures to report.
Anna V Tinker: no relevant disclosures to report.
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Robert Carruthers: is a site principal investigator for studies funded by MedImmune, Teva, and Guthy Jackson. He has received speaking fees for unbranded lectures from Biogen, Genzyme, and Teva. He has received consulting fees for Novartis, EMD Serono, and Genzyme.
FUNDING
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Highlights
· Six new cases of paraneoplastic NMOSD are presented.
. Two new cancer types associated with paraneoplastic NMOSD are identified.
· Our findings add to existing evidence and raise awareness on paraneoplastic NMOSD.
· Increasing evidence suggests AQP4 can be produced by a paraneoplastic response.
. AQP4 antibodies could be produced by an anti-neoplastic immune response.