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Clinically Inapparent Gallbladder Cancer presenting with Paraneoplastic Cranial Neuropathies

Aunali S Khaku, MD; Lisa Aenlle MD, Irene A Malaty, MD University of Florida Department of Neurology Abstract
We report the occurrence of multiple bilateral cranial nerve palsies as a paraneoplastic phenomena due to gallbladder carcinoma. Neuropathology confirmed the lack of direct invasion by malignant cells and, rather, the presence of immune cell infiltrate. The cancer was not clinically detectable at the time of symptom onset, but was advanced in spread by the time of post-mortem analysis one year later.

Diagnostic Tests
Initial Cerebrospinal fluid (CSF): Protein- 70, WBC- 38 (91% lymphocytes), RBC- 30, Glucose- 55. Repeat CSF: Protein- 60, WBC- 4, RBC-0, Glucose- 56. Repeated CSF cytology and flow cytometry were negative. CSF FISH and cytogenetic studies were negative for lymphoma. CSF ACE, AFB, Lyme, CMV, EBV, and VDRL were negative. A commercially available paraneoplastic antibody (Ab) panel, ganglioside and thyroid peroxidase Ab were negative. AST, ALT, TSH, T3, T4, HIV, SPEP, UPEP, P-ANCA, C-ANCA, cryoglobulins, SCL-70 Ab, NDNA Ab , Anti-Smith Ab, SSA, SSB, Acetylcholinesterase Ab, RPR, TPPA were all negative. CRP- 7.6, and ESR-55

Clinical Course
Over the course of her illness, the patient was treated with high-dose Solu-Medrol (1 Gram for 5 days), plasma exchange (1 cycle), and IVIG (Two 5-day courses) with only mild relief of her symptoms. Repeat MRI did show improvement in the enlargement and enhancement of the cranial nerves. The patient passed away one year later and autopsy revealed a poorly differentiated hepatobilliary cancer.

Discussion
This is a very unusual case of progressive onset of multiple bilateral cranial nerve palsies in a 69 year old woman who, despite normal systemic imaging including PET scanning, was found to have gross evidence of hepatobiliary/gallbladder carcinoma at autopsy, 1year and 7months after initial presentation. Pathologic evaluation did not reveal any evidence of nervous system metastasis or direct invasion of malignancy, confirming paraneoplastic etiology.

Background
Paraneoplastic disease occurs as an autoimmune phenomena triggered by a malignancy, and may occur prior to the presence of a detectable tumor. Typical paraneoplastic syndromes include limbic encephalitis, cerebellar ataxia, sensory neuronopathy, and LambertEaton syndrome, among others. Cranial nerve palsies are less commonly seen as a paraneoplastic phenomena, but have been reported to occur in association with antiHu antibodies, and with testicular carcinoma (3,4). There have not been any reports to date associated with gallbladder carcinoma. Gallbladder cancer has been reported to cause paraneoplastic encephalomyelitis and peripheral sensory neuropathy associated with anti-Hu antibodies (5).

Pathology:

Imaging
Contrasted MRI of the head, neck, & orbits revealed enlargement and post-contrast enhancement of the cranial nerves III, VI, & VIII. A contrasted CT of the chest, abdomen, & pelvis and whole body PET scan did not detect a malignancy.

Although less common, paraneoplastic syndromes have been shown to involve cranial nerves. We report the first Brain, conjunctival, and eyelid biopsies were unremarkable and case to our knowledge of paraneoplastic cranial without evidence of sarcoidosis. neuropathies associated with a clinically inapparent primary carcinoma of the gall bladder. Autopsy revealed poorly differentiated adenocarcinoma of the hepatobiliary tract originating in the gallbladder but infiltrating This case highlights the need to consider paraneoplastic the common bile duct, liver, and pancreas, with regional lymph syndromes in cryptogenic cases of multiple cranial node metastasis. Cranial nerves 3, 6 and 7 were neuropathies, and to continue surveillance for occult hypertrophied and histology revealed extensive infiltration of malignancy. the endoneurium by mature lymphocytes, primarily CD3reactive T-lymphocytes with a few CD20-reactive B-cells.

References

1.Corcia P, De Toffoi B, Hommet C, Saudeau D, Autret A. J Neurol Neurosurg Psychiatry. 1997 Mar;62(3):293. Paraneoplastic opsoclonus associated with cancer of the gall bladder. 2.Braik T, Evans AT, Teifer M, McDunn S. Am J Med Sci. 2010 Oct;340(4):301-8. Paraneoplastic neurological syndromes: unusual presentations of cancer. A practical review. 3.Fujimoto S, Kumamoto T, Ito T, Sannomiya K, Inuzuka T, Tsuda T. Clin Neurol Neurosurg. 2002 May;104(2):98-102. A clinicopathological study of a patient with anti-Hu-associated paraneoplastic sensory neuronopathy with multiple cranial nerve palsies. 4.Morelli N, Mancuso M, Frittelli C, Falorni M, Gallerini S, Paolo de S, Orlandi G, Murri L. Neurologist. 2007 Jul;13(4):222-4. Multiple cranial nerve palsies in testicular lymphoma: report of a case. 5.Graus F, Keime-Guibert F, Rene R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:113848. 6.Tans RJ, Koudstall J, Koehler PJ, Clin Neurol Neurosurg. 1993 Sep;95(3):253-6. Meningeal carcinomatosis as presenting symptom of a gallbladder carcinoma. 7.Antoine JC, Mosnier JF, Lapras J, et al. Chronic inflammatory demyelinating polyneuropathy associated with carcinoma. J Neurol Neurosurg Psychiatry 1996;60:188-190. 8.Gaumann A, Marx J, Bohl J, Kommoss F, Khler H, Tews DS. Pathol Res Pract. 1999;195(7):495-9. Leptomeningeal carcinomatosis and cranial nerve palsy as presenting symptoms of a clinically inapparent gallbladder carcinoma. 9.Nakashima A, Kawai M, Tofuku Y, Takeda R, Katsuda S, Ookada Y. Painful ophthalmoplegia caused by metastasis of cholangiocarcinoma of the liver. Ala J Med Sci 1987 Jan ;24(1):29-30 10.Gaumann A, Marx J, Bohl J, Kommoss F, Khler H, Tews DS. Leptomeningeal carcinomatosis and cranial nerve palsy as presenting symptoms of a clinically inapparent gallbladder carcinoma. Pathol Res Pract. 1999;195(7):495-9.

Case Report
A 69-year-old female smoker with a past medical history significant only for hypothyroidism presented with a four month history of multiple cranial nerve palsies initially beginning with unilateral ptosis but progressing to involve cranial nerves 3, 6 and 7 bilaterally.

Physical Exam
Physical exam was significant for bilateral severe ptosis requiring manual assistance to open eyes, bilateral dilated pupils, ophthalmoplegia with sparing of intorsion (CN IV), bilateral upper and lower facial weakness with inability to smile, bilateral brisk reflexes in all four extremities, and mildly unsteady gait.

Fig 5. Cranial Neuritis- H&E stain showing lymphocytic infiltrate Fig 6. Cranial Neuritis- CD3 stain depicting primarily CD3-reactive T lymphocytes

11.Hammam T, McFadzean RM, Ironside JW. J Neuroophthalmol. 2005 Jun;25(2):101-4. . Anti-hu paraneoplastic syndrome presenting as bilateral sixth cranial nerve palsies.

Figures 1- 4 : Pre & post contrasted MRI images showing enlargement & post contrast enhancement of CNs III & VII.

Fig 7. Cranial Neuritis- Immunohistochemistry staining showing most of We would like to thank neuropathologist Dr Yachnis for his the T cells are CD 8 positive contribution and the Malcolm Randall VA Library staff. Fig 8. Brainstem Encephalitis- H&E Stain of the Pons demonstrating lymphocyte infiltration

Acknowledgments

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