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Original Investigation |

Abnormal Neurons in Teratomas in NMDAR Encephalitis

Gregory S. Day, MD, MSc, BScH1,2; Simin Laiq, MD3,4; David F. Tang-Wai, MD, FRCPC1,2; David G. Munoz, MD, FRCPC3,4
[+] Author Affiliations
1Division of Neurology, University of Toronto, Toronto, Ontario, Canada
2University Health Network Memory Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
3Division of Pathology, Department of Laboratory Medicine, Saint Michael’s Hospital, Toronto, Ontario, Canada
4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
JAMA Neurol. 2014;71(6):717-724. doi:10.1001/jamaneurol.2014.488.
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Importance  Ovarian teratomas are frequently described in patients with N-methyl-d-aspartate receptor (NMDAR) encephalitis, yet NMDAR encephalitis is rarely described in patients with ovarian teratomas. Understanding why a minority of patients with teratomas are seen with autoimmune encephalitis may improve the management of NMDAR encephalitis and other teratoma-associated autoimmune diseases.

Objective  To characterize the unique organization of neuroglial elements within ovarian teratomas resected from patients with NMDAR encephalitis.

Design  Case-control study comparing the pathological features of ovarian teratomas resected from consecutively accrued cases with NMDAR encephalitis between January 1, 2009, and December 15, 2013, and ovarian teratomas resected from controls between June 1, 2012, and June 30, 2013.

Setting  Pathology tissue database at a tertiary academic care center.

Participants  Five cases with teratoma-associated NMDAR encephalitis and serum or cerebrospinal fluid autoantibodies against central nervous system (CNS) NMDAR and 38 controls (39 ovarian teratomas) without neurological symptoms or signs.

Exposures  Formalin-fixed, paraffin-embedded ovarian teratomas were examined for the presence of CNS tissue and inflammatory infiltrates using direct microscopy, enhanced with standard histopathological and immunological stains.

Main Outcomes and Measures  Frequency of detection of atypical (dysplastic) CNS neuronal elements in ovarian teratomas resected from cases vs controls, as well as characterization of the relationship between atypical neurons and immune infiltrates.

Results  Central nervous system neuronal elements were detected in 4 of 5 teratomas resected from cases with NMDAR encephalitis and in 20 of 39 controls (P = .36). Atypical neurons were seen within teratomas resected from 4 of 5 cases but not in 39 controls, reliably distinguishing teratomas associated with NMDAR encephalitis (P < .001). If found within the CNS, these histological abnormalities would have received the diagnosis of gangliogliomas (n = 3) and ganglioneuroblastoma (n = 1). Reactive changes were present in teratomas from controls, including ferruginated neurons and Rosenthal fibers. Abnormal neuroglial elements were closely related to immune infiltrates in teratomas resected from 4 of 4 cases. Inflammatory infiltrates were not associated with neuroglial tissue in 20 controls, further differentiating these populations (P < .001).

Conclusions and Relevance  Abnormal neurons within teratomas distinguish cases with NMDAR encephalitis from controls and may promote the development of autoimmunity.

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Figure 1.
Pathological Findings in Teratomas Resected From Cases

A-D, Case A. A, Mature cystic ovarian teratoma (low power, hematoxylin-eosin) showing a small focus of neuroglial tissue (N) surrounded by chronic inflammation (black arrowheads). B, On higher power, clusters of dysplastic ganglion cells (black arrowheads) with binucleated forms (yellow arrowheads) are seen surrounded by chronic inflammation (white arrowhead). C and D, Neurons were labeled by antibodies to Hu (C) and neuron-specific enolase (D) (yellow arrowheads and insets delineate binucleated forms). E-H, Case B. E, Immature cystic ovarian teratoma (low power, hematoxylin-eosin) showing neuroglial tissue (N) surrounded by inflammation with lymphoid follicles (black arrowheads). F, On higher power, primitive neuronal elements were detected concentrated around small blood vessels (black arrowheads). G and H, Immunohistochemistry showed graded expression of Hu (G) and neuron-specific enolase (H) moving outward from the central blood vessels, labeling more mature neurons (black arrowheads). I-L, Case C. I, Mature cystic ovarian teratoma (low power, hematoxylin-eosin) showing skin (upper half) and neural tissue (lower half). J, Higher power revealed neoplastic neuroglial tissue with primitive neurons and abnormal mitotic figures (black arrowheads). K, CD163 immunostain on low power revealed a bandlike distribution of CD163-positive histiocytic infiltrates (black arrowheads) within the segment of neuroglial tissue. L, Neuron-specific enolase staining confirmed that neurons were closely approximated by the inflammatory infiltrates (black arrowheads). Higher-power view (inset) showing abnormal, primitive neurons with dendrites closely approximating one another. M-P, Case D. M, Mature cystic ovarian teratoma (medium power, hematoxylin-eosin) showing neuroglial tissue containing ganglion cells (white arrowhead and bottom inset), neurocytes, and mitotic figures (black arrowhead). The top inset shows astrocytes (white arrowhead) and mitotic figures (black arrowhead). N, On medium power, neuron-specific enolase staining identified neuropil (black arrowhead) and individual neurons (white arrowhead). The inset shows multinucleated neuronal cells labeled by Hu. O and P, On low power, comparison of glial fibrillary acidic protein immunostain (O) and CD3 immunostain (P) demonstrated the intimate association between the neuropil and the lymphocytic infiltrate. A rim of neuropil was observed surrounding the inflammatory infiltrates (black arrowheads in O and P).

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Figure 2.
Selected Pathological Findings in Teratomas Resected From Controls (High Power, Hematoxylin-eosin)

A, Ferruginated neurons with calcifications (black arrowheads). B, Neuroglial tissue with gliosis and Rosenthal fibers (black arrowheads). C, Neuroglial tissue (N) with unremarkable neurons (black arrowheads). D, Neuroglial tissue (N) with Rosenthal fibers (black arrowheads) and pigmented epithelium (white arrowheads). No inflammatory infiltrates were observed in association with neuroglial tissue in teratomas resected from controls.

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