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Paraneoplastic Syndrome of Inappropriate Antidiuretic Hormone Mimicking Limbic Encephalitis FREE

Nicholas A. Blondin, MD; Alexander O. Vortmeyer, MD, PhD; Noam Y. Harel, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Neurology (Drs Blondin and Harel) and Pathology (Dr Vortmeyer), Yale University School of Medicine, New Haven, Connecticut.


Arch Neurol. 2011;68(12):1591-1594. doi:10.1001/archneurol.2011.876.
Text Size: A A A
Published online

ABSTRACT

Objective To compare the features of paraneoplastic syndrome of inappropriate antidiuretic hormone with those of limbic encephalitis.

Design Case study.

Setting Academic medical center.

Patient A 46-year-old woman with progressive memory impairment, hyponatremia, and seizures.

Interventions Magnetic resonance imaging of the brain, fluoro-2-deoxyglucose positron emission tomography of the body, and immunohistochemical analysis of a resected tumor.

Results Though the patient presented with clinical features of classic limbic encephalitis, magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid analysis findings were unremarkable. Her chronic hyponatremia was ultimately found to be due to ectopic secretion of antidiuretic hormone by a neuroendocrine tumor with Merkel cell carcinoma phenotype.

Conclusions Patients presenting with memory impairment, seizures, and hyponatremia should undergo a thorough workup for occult malignancy. In addition to considering classic immune-mediated paraneoplastic limbic encephalitis, the ectopic secretion of antidiuretic hormone should be included in the differential diagnosis.

Figures in this Article

Limbic encephalitis (LE) should be considered in the differential diagnosis of any patient who develops subacute memory loss, psychiatric symptoms, and seizures.1 Limbic encephalitis may occur through paraneoplastic or autoimmune mechanisms, leading to an inflammatory response against neuronal antigens in the medial temporal lobe and limbic structures.2

Among the conditions that can mimic LE, chronic hyponatremia should also be considered. Chronic hyponatremia is associated with encephalopathy, recurrent falls, attention deficits, and seizures.35 The syndrome of inappropriate antidiuretic hormone (SIADH) causes most cases of chronic hyponatremia. Common causes of SIADH include malignancy, pulmonary disorders, traumatic brain injury and other central nervous system disorders, and medications. The syndrome of inappropriate antidiuretic hormone has been reported in conjunction with many types of cancer, most frequently in association with small cell lung carcinoma.68

Because of the common linkage between LE, SIADH, and cancer, a thorough workup for malignancy needs to be initiated in any patient with subacute memory impairment, seizures, and hyponatremia. We discuss the case of a patient with this type of presentation who was ultimately found to have SIADH due to ectopic antidiuretic hormone (ADH) production by a neuroendocrine tumor with a Merkel cell carcinoma (MCC) immunophenotype.

REPORT OF A CASE

A 46-year-old right-handed white woman with an unremarkable medical history presented with progressive memory loss for 9 months, along with generalized seizures for 4 months. She took no medications. During 2 admissions at a local hospital, she was found to have a serum sodium level as low as 110 mEq/L (to convert this to millimoles per liter, multiply by 1). Lumbar puncture and magnetic resonance imaging (MRI) of the brain did not reveal any evident infection, inflammation, ischemia, hemorrhage, or tumor. Levetiracetam was initiated for seizure prophylaxis. She was discharged home but was no longer able to work and had difficulty driving. She was subsequently referred to our medical center for further evaluation and treatment.

On review of systems, she reported an 18-kg weight loss in the past year, hair thinning for the past 2 years, and no menstrual period for the past 6 months. On neurological examination, she was awake and oriented to place but had difficulty with dates. She could not recount any details of personal events over the previous several months. Her speech was fluent, and she could name, repeat, and follow complex commands. Calculation was intact. Her short-term recall was 1 of 3 objects at 3 minutes. Her reflexes were symmetric but diminished throughout. Her cranial nerve, motor, sensory, and coordination examinations were normal.

Initial laboratory test results were notable for a serum sodium level of 118 mEq/L and serum osmolality level of 244 mOsm/kg (to convert to millimoles per kilogram, multiply by 1), with elevated urine sodium and osmolality levels (Table 1). She appeared euvolemic, and thyroid study results and cortisol level were normal. These findings were consistent with a diagnosis of SIADH. Along with fluid restriction and ongoing anticonvulsant treatment, she was initially treated with 1 g of intravenous methylprednisolone daily for 5 days for presumed LE, with no improvement in her symptoms.

Table Graphic Jump LocationTable 1. Serum, Urine, and CSF Findings

Results of cerebrospinal fluid analysis were unremarkable (Table 1). Standard awake and asleep electroencephalogram demonstrated mild generalized slowing, no epileptiform discharges, and no pathological response to photic stimulation. Contrast-enhanced MRI of the brain was normal. Results of serum and cerebrospinal fluid examination for paraneoplastic antibodies associated with LE were negative (Table 2). Notably, she was found to have a modestly elevated anti–N-type calcium channel antibody titer, of unclear significance (see “Comment” section).

Table Graphic Jump LocationTable 2. Serum and CSF Paraneoplastic Panel Resultsa

To further evaluate for malignancy, we obtained computed tomography scans of her chest, abdomen, and pelvis, as well as a full-body fluoro-2-deoxyglucose positron emission tomography study. The fluoro-2-deoxyglucose positron emission tomography scan demonstrated an area of focal uptake in the anterior right thigh (Figure 1A). Magnetic resonance imaging of the right inguinal region confirmed a heterogeneously enhancing mass, concerning for malignancy (Figure 1B).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Radiological and pathological features of the neuroendocrine tumor with Merkel cell carcinoma phenotype. A, Whole-body fluoro-2-deoxyglucose positron emission tomography scan, demonstrating focal abnormal metabolic activity in the right thigh (arrow). B, T1-weighted magnetic resonance imaging of the thigh with contrast, demonstrating a heterogeneously enhancing subcutaneous mass (arrow). C, Hematoxylin-eosin stain of the resected tumor (original magnification ×10).

On histological analysis of the openly resected mass, the tissue comprised sheets and clusters of intermediate-sized cells with a neuroendocrine-type nuclear chromatin pattern (Figure 1C). Results of immunohistochemical analysis were positive for CK20, pankeratin, synaptophysin, chromogranin, and neurofilament and negative for CK7, TTF1, S-100, and HMB45. Notably, the tumor stained positive with anti-ADH antibody, indicating ectopic ADH secretion (Figure 2).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Ectopic antidiuretic hormone (ADH) secretion, immunohistochemical analysis with anti-ADH antibody (original magnification ×10). A, Hypothalamic positive control tissue revealing positive cytoplasmic immunoreactivity in neurons. B, Resected tumor, negative control. C, Resected tumor, with positive cytoplasmic immunoreactivity for ADH in numerous tumor cells.

The pathological appearance of the mass was consistent with a neuroendocrine tumor involving the lymph node, with an immunophenotype of MCC. Based on these findings, we believe she had a metastatic MCC. No primary tumor was found on extensive further investigation.

Following tumor resection, the patient underwent local radiation therapy followed by systemic chemotherapy with etoposide and carboplatin. Her seizures remitted and serum sodium level normalized over a 2-week period. Fluid restriction was discontinued on hospital discharge, followed by gradual improvement in her cognition over the next 3 months. She had no further seizures, and her anticonvulsant treatment was tapered and discontinued. At 6 months after hospital discharge, she had returned to living independently and working full-time. At 1 year following diagnosis, she remained in complete remission. She has very subtle residual deficits in attention and long-term memory.

COMMENT

Limbic encephalitis commonly manifests with subacute memory loss and seizures. The co-occurrence of LE and SIADH should raise concern for malignancy, especially small cell lung carcinoma. Appropriate screening includes computed tomography scan of the chest, abdomen, and pelvis. Should computed tomography scan be unrevealing, a whole-body fluoro-2-deoxyglucose positron emission tomography scan should be performed.9,10 Vaginal or testicular ultrasonography should also be performed to fully evaluate for a gonadal or germ cell tumor.11

Antibodies known to be associated with paraneoplastic LE include anti-Hu,12 anti-Ma2,13 anti- N-methyl-D-aspartate receptor,14 anti–collapsin response-mediator protein type 5,15 anti-amphiphysin,16 and anti-GABAB receptor.17 Limbic encephalitis causes medial temporal lobe hyperintensity on MRI in 70% to 80% of cases.1 Other supporting findings for paraneoplastic LE include inflammatory changes in the cerebrospinal fluid and focal slowing or epileptiform activity on electroencephalogram.18 In patients without supporting MRI, cerebrospinal fluid, and electroencephalogram findings, paraneoplastic LE is less likely, and alternative diagnoses should be strongly considered.

Paraneoplastic SIADH due to ectopic ADH production by neoplastic cells has been demonstrated in small cell lung carcinoma19 and non-Hodgkin lymphoma.20 Thus, the co-occurrence of paraneoplastic LE due to antitumor antibodies with SIADH due to ectopic ADH secretion by tumor cells may occur in rare cases.

Merkel cell carcinoma, or primary neuroendocrine carcinoma of the skin, is a rare and aggressive cutaneous tumor.21 In normal tissue, Merkel cells function as mechanoreceptors.22 They also function as neuroendocrine cells, secreting metenkephalin, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide to transmit or transduce chemical information.23 The histological appearance of MCC is similar to other neuroendocrine tumors, and immunohistochemical analysis is essential for diagnosis.24

Treatment of MCC is based on excision of the tumor with wide margins and adjuvant radiation therapy.25 The role of systemic chemotherapy is currently experimental, with treatment based on regimens for small cell lung carcinoma.26 Following excision, our patient underwent both radiation and chemotherapy for presumed metastatic MCC. Cases of spontaneous tumor regression have been reported,27 and we believe that our patient had a spontaneous regression of the primary lesion prior to diagnosis.

Merkel cell carcinoma has been associated with paraneoplastic syndromes in case reports. It has been found in the anti-Hu antibody syndrome, causing paraneoplastic LE.28,29 Merkel cell carcinoma has also been found in cases of Lambert-Eaton myasthenic syndrome, in association with anti–P/Q-type calcium channel antibodies.30 However, our patient was not found to have anti-Hu antibodies or any other antibodies known to be associated with LE.

In our patient, the only antibody detected was anti–N-type calcium channel antibody (at a titer of 0.13 nmol/L). While N-type calcium channel antibodies were found (at a titer of 0.42 nmol/L) in a single case report of a patient with LE,31 we do not believe there is evidence that these antibodies had clinical significance in our patient.

We hypothesize that chronic hyponatremia due to ectopic ADH secretion by a neuroendocrine tumor with MCC phenotype was the underlying cause of our patient's cognitive impairment and seizures, resulting in a presentation mimicking LE. Fluid restriction and tumor resection followed by radiotherapy and chemotherapy have resulted in complete remission of her symptoms and malignancy.

ARTICLE INFORMATION

Correspondence: Nicholas A. Blondin, MD, Department of Neurology, Yale University School of Medicine, PO Box 208018, 15 York St, LCI-9, New Haven, CT 06520-8018 (nicholas.blondin@yale.edu).

Accepted for Publication: May 18, 2011.

Author Contributions: The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Blondin and Harel. Acquisition of data: Blondin, Vortmeyer, and Harel. Analysis and interpretation of data: Blondin, Vortmeyer, and Harel. Drafting of the manuscript: Blondin and Harel. Critical revision of the manuscript for important intellectual content: Vortmeyer and Harel. Administrative, technical, and material support: Blondin and Vortmeyer. Study supervision: Harel.

Financial Disclosure: None reported.

REFERENCES

Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment.  Neurologist. 2007;13(5):261-271
PubMed   |  Link to Article
Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS.  Lancet Neurol. 2008;7(4):327-340
PubMed   |  Link to Article
Miyazaki T, Ohmoto K, Hirose T, Fujiki H. Chronic hyponatremia impairs memory in rats: effects of vasopressin antagonist tolvaptan.  J Endocrinol. 2010;206(1):105-111
PubMed   |  Link to Article
Halawa I, Andersson T, Tomson T. Hyponatremia and risk of seizures: a retrospective cross-sectional study.  Epilepsia. 2011;52(2):410-413
PubMed
Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.  Am J Med. 2006;119(1):71- e1-e8
PubMed   |  Link to Article
Ma AT, Lei KI. Small cell neuroendocrine carcinoma of the ethmoid sinuses presenting with generalized seizure and syndrome of inappropriate antidiuretic hormone secretion: a case report and review of literature.  Am J Otolaryngol. 2009;30(1):54-57
PubMed   |  Link to Article
Tai P, Yu E, Jones K, Sadikov E, Mahmood S, Tonita J. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with limited stage small cell lung cancer.  Lung Cancer. 2006;53(2):211-215
PubMed   |  Link to Article
Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease.  J Intern Med. 1995;238(2):97-110
PubMed   |  Link to Article
Younes-Mhenni S, Janier MF, Cinotti L,  et al.  FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes.  Brain. 2004;127(pt 10):2331-2338
PubMed   |  Link to Article
Basu S, Alavi A. Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PET-MRI correlates.  Mol Imaging Biol. 2008;10(3):131-137
PubMed   |  Link to Article
Mathew RM, Vandenberghe R, Garcia-Merino A,  et al.  Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.  Neurology. 2007;68(12):900-905
PubMed   |  Link to Article
Graus F, Keime-Guibert F, Reñe R,  et al.  Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.  Brain. 2001;124(pt 6):1138-1148
PubMed   |  Link to Article
Dalmau J, Graus F, Villarejo A,  et al.  Clinical analysis of anti-Ma2-associated encephalitis.  Brain. 2004;127(pt 8):1831-1844
PubMed   |  Link to Article
Zandi MS, Irani SR, Follows G, Moody AM, Molyneux P, Vincent A. Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin lymphoma.  Neurology. 2009;73(23):2039-2040
PubMed   |  Link to Article
Honnorat J, Cartalat-Carel S, Ricard D,  et al.  Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.  J Neurol Neurosurg Psychiatry. 2009;80(4):412-416
PubMed   |  Link to Article
Dorresteijn LD, Kappelle AC, Renier WO, Gijtenbeek JM. Anti-amphiphysin associated limbic encephalitis: a paraneoplastic presentation of small-cell lung carcinoma.  J Neurol. 2002;249(9):1307-1308
PubMed   |  Link to Article
Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.  Neurology. 2011;76(9):795-800
PubMed   |  Link to Article
Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis.  Mayo Clin Proc. 2003;78(11):1363-1368
PubMed   |  Link to Article
Müssig K, Horger M, Häring HU, Wehrmann M. Syndrome of inappropriate antidiuretic hormone secretion and ectopic ACTH production in small cell lung carcinoma.  Lung Cancer. 2007;57(1):120-122
PubMed   |  Link to Article
Kobayashi K, Yokote T, Akioka T, Takubo T, Tsuji M, Hanafusa T. Inappropriate antidiuretic hormone production in diffuse large B-cell lymphoma.  Br J Haematol. 2008;143(1):2
PubMed   |  Link to Article
Swann MH, Yoon J. Merkel cell carcinoma.  Semin Oncol. 2007;34(1):51-56
PubMed   |  Link to Article
Halata Z, Grim M, Bauman KI. Friedrich Sigmund Merkel and his “Merkel cell”, morphology, development, and physiology: review and new results.  Anat Rec A Discov Mol Cell Evol Biol. 2003;271(1):225-239
PubMed   |  Link to Article
Tachibana T, Nawa T. Recent progress in studies on Merkel cell biology.  Anat Sci Int. 2002;77(1):26-33
PubMed   |  Link to Article
Poulsen M. Merkel-cell carcinoma of the skin.  Lancet Oncol. 2004;5(10):593-599
PubMed   |  Link to Article
Smith DF, Messina JL, Perrott R,  et al.  Clinical approach to neuroendocrine carcinoma of the skin (Merkel cell carcinoma).  Cancer Control. 2000;7(1):72-83
PubMed
Eng TY, Boersma MG, Fuller CD,  et al.  A comprehensive review of the treatment of Merkel cell carcinoma.  Am J Clin Oncol. 2007;30(6):624-636
PubMed   |  Link to Article
Connelly TJ, Cribier B, Brown TJ, Yanguas I. Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases.  Dermatol Surg. 2000;26(9):853-856
PubMed   |  Link to Article
Lopez MC, Pericay C, Agustí M, Martinez-Gallo M, Bordes R, Gelpí C. Merkel cell carcinoma associated with a paraneoplastic neurological syndrome.  Histopathology. 2004;44(6):628-629
PubMed   |  Link to Article
Greenlee JE, Steffens JD, Clawson SA, Hill K, Dalmau J. Anti-Hu antibodies in Merkel cell carcinoma.  Ann Neurol. 2002;52(1):111-115
PubMed   |  Link to Article
Eggers SD, Salomao DR, Dinapoli RP, Vernino S. Paraneoplastic and metastatic neurologic complications of Merkel cell carcinoma.  Mayo Clin Proc. 2001;76(3):327-330
PubMed   |  Link to Article
Xia Z, Mehta BP, Ropper AH, Kesari S. Paraneoplastic limbic encephalitis presenting as a neurological emergency: a case report.  J Med Case Reports. 2010;4:95
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Radiological and pathological features of the neuroendocrine tumor with Merkel cell carcinoma phenotype. A, Whole-body fluoro-2-deoxyglucose positron emission tomography scan, demonstrating focal abnormal metabolic activity in the right thigh (arrow). B, T1-weighted magnetic resonance imaging of the thigh with contrast, demonstrating a heterogeneously enhancing subcutaneous mass (arrow). C, Hematoxylin-eosin stain of the resected tumor (original magnification ×10).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Ectopic antidiuretic hormone (ADH) secretion, immunohistochemical analysis with anti-ADH antibody (original magnification ×10). A, Hypothalamic positive control tissue revealing positive cytoplasmic immunoreactivity in neurons. B, Resected tumor, negative control. C, Resected tumor, with positive cytoplasmic immunoreactivity for ADH in numerous tumor cells.

Tables

Table Graphic Jump LocationTable 1. Serum, Urine, and CSF Findings
Table Graphic Jump LocationTable 2. Serum and CSF Paraneoplastic Panel Resultsa

References

Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment.  Neurologist. 2007;13(5):261-271
PubMed   |  Link to Article
Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS.  Lancet Neurol. 2008;7(4):327-340
PubMed   |  Link to Article
Miyazaki T, Ohmoto K, Hirose T, Fujiki H. Chronic hyponatremia impairs memory in rats: effects of vasopressin antagonist tolvaptan.  J Endocrinol. 2010;206(1):105-111
PubMed   |  Link to Article
Halawa I, Andersson T, Tomson T. Hyponatremia and risk of seizures: a retrospective cross-sectional study.  Epilepsia. 2011;52(2):410-413
PubMed
Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.  Am J Med. 2006;119(1):71- e1-e8
PubMed   |  Link to Article
Ma AT, Lei KI. Small cell neuroendocrine carcinoma of the ethmoid sinuses presenting with generalized seizure and syndrome of inappropriate antidiuretic hormone secretion: a case report and review of literature.  Am J Otolaryngol. 2009;30(1):54-57
PubMed   |  Link to Article
Tai P, Yu E, Jones K, Sadikov E, Mahmood S, Tonita J. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with limited stage small cell lung cancer.  Lung Cancer. 2006;53(2):211-215
PubMed   |  Link to Article
Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in malignant disease.  J Intern Med. 1995;238(2):97-110
PubMed   |  Link to Article
Younes-Mhenni S, Janier MF, Cinotti L,  et al.  FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes.  Brain. 2004;127(pt 10):2331-2338
PubMed   |  Link to Article
Basu S, Alavi A. Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PET-MRI correlates.  Mol Imaging Biol. 2008;10(3):131-137
PubMed   |  Link to Article
Mathew RM, Vandenberghe R, Garcia-Merino A,  et al.  Orchiectomy for suspected microscopic tumor in patients with anti-Ma2-associated encephalitis.  Neurology. 2007;68(12):900-905
PubMed   |  Link to Article
Graus F, Keime-Guibert F, Reñe R,  et al.  Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients.  Brain. 2001;124(pt 6):1138-1148
PubMed   |  Link to Article
Dalmau J, Graus F, Villarejo A,  et al.  Clinical analysis of anti-Ma2-associated encephalitis.  Brain. 2004;127(pt 8):1831-1844
PubMed   |  Link to Article
Zandi MS, Irani SR, Follows G, Moody AM, Molyneux P, Vincent A. Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin lymphoma.  Neurology. 2009;73(23):2039-2040
PubMed   |  Link to Article
Honnorat J, Cartalat-Carel S, Ricard D,  et al.  Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.  J Neurol Neurosurg Psychiatry. 2009;80(4):412-416
PubMed   |  Link to Article
Dorresteijn LD, Kappelle AC, Renier WO, Gijtenbeek JM. Anti-amphiphysin associated limbic encephalitis: a paraneoplastic presentation of small-cell lung carcinoma.  J Neurol. 2002;249(9):1307-1308
PubMed   |  Link to Article
Boronat A, Sabater L, Saiz A, Dalmau J, Graus F. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders.  Neurology. 2011;76(9):795-800
PubMed   |  Link to Article
Lawn ND, Westmoreland BF, Kiely MJ, Lennon VA, Vernino S. Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis.  Mayo Clin Proc. 2003;78(11):1363-1368
PubMed   |  Link to Article
Müssig K, Horger M, Häring HU, Wehrmann M. Syndrome of inappropriate antidiuretic hormone secretion and ectopic ACTH production in small cell lung carcinoma.  Lung Cancer. 2007;57(1):120-122
PubMed   |  Link to Article
Kobayashi K, Yokote T, Akioka T, Takubo T, Tsuji M, Hanafusa T. Inappropriate antidiuretic hormone production in diffuse large B-cell lymphoma.  Br J Haematol. 2008;143(1):2
PubMed   |  Link to Article
Swann MH, Yoon J. Merkel cell carcinoma.  Semin Oncol. 2007;34(1):51-56
PubMed   |  Link to Article
Halata Z, Grim M, Bauman KI. Friedrich Sigmund Merkel and his “Merkel cell”, morphology, development, and physiology: review and new results.  Anat Rec A Discov Mol Cell Evol Biol. 2003;271(1):225-239
PubMed   |  Link to Article
Tachibana T, Nawa T. Recent progress in studies on Merkel cell biology.  Anat Sci Int. 2002;77(1):26-33
PubMed   |  Link to Article
Poulsen M. Merkel-cell carcinoma of the skin.  Lancet Oncol. 2004;5(10):593-599
PubMed   |  Link to Article
Smith DF, Messina JL, Perrott R,  et al.  Clinical approach to neuroendocrine carcinoma of the skin (Merkel cell carcinoma).  Cancer Control. 2000;7(1):72-83
PubMed
Eng TY, Boersma MG, Fuller CD,  et al.  A comprehensive review of the treatment of Merkel cell carcinoma.  Am J Clin Oncol. 2007;30(6):624-636
PubMed   |  Link to Article
Connelly TJ, Cribier B, Brown TJ, Yanguas I. Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases.  Dermatol Surg. 2000;26(9):853-856
PubMed   |  Link to Article
Lopez MC, Pericay C, Agustí M, Martinez-Gallo M, Bordes R, Gelpí C. Merkel cell carcinoma associated with a paraneoplastic neurological syndrome.  Histopathology. 2004;44(6):628-629
PubMed   |  Link to Article
Greenlee JE, Steffens JD, Clawson SA, Hill K, Dalmau J. Anti-Hu antibodies in Merkel cell carcinoma.  Ann Neurol. 2002;52(1):111-115
PubMed   |  Link to Article
Eggers SD, Salomao DR, Dinapoli RP, Vernino S. Paraneoplastic and metastatic neurologic complications of Merkel cell carcinoma.  Mayo Clin Proc. 2001;76(3):327-330
PubMed   |  Link to Article
Xia Z, Mehta BP, Ropper AH, Kesari S. Paraneoplastic limbic encephalitis presenting as a neurological emergency: a case report.  J Med Case Reports. 2010;4:95
PubMed   |  Link to Article

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