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March 11, 2020

Co-occurrence of Merkel Cell Carcinoma and Chronic Inflammatory Demyelinating Polyneuropathy

Author Affiliations
  • 1Multidisciplinary Skin Cancer Management Program, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Dermatol. Published online March 11, 2020. doi:10.1001/jamadermatol.2020.0055

Merkel cell carcinoma (MCC) is a rare type of neuroendocrine skin cancer with an annual incidence rate of about 0.7 cases per 100 000 persons.1 Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nerves and nerve roots, with an annual incidence rate of 0.33 cases per 100 000 persons.2 We describe 3 patients diagnosed as having both MCC and CIDP and discuss the possible association between these 2 diseases.

Report of Cases

Patient 1

A 67-year-old man with an 8-year history of CIDP treated with intravenous immunoglobulin and 1 year of treatment with rituximab presented with multifocal tumors on the leg. Biopsy results demonstrated MCC, and positron emission tomography revealed groin lymphadenopathy, resulting in a stage of cT2N2M0 according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, eighth edition. The MCC was unresectable and was therefore treated with avelumab and radiotherapy. After a partial response, the patient sustained an unrelated cerebral infarction and heart failure. Avelumab, radiotherapy, and intravenous immunoglobulin were discontinued, and new tumors emerged after 4 months of stopping these treatments. He resumed taking avelumab 2 months later with no response, and the patient died of MCC 1.5 years after diagnosis.

Patient 2

A 69-year-old man with an 8-year history of CIDP treated with corticosteroids presented with a tumor on the left forearm. Biopsy results demonstrated MCC; wide excision of the primary tumor and sentinel node biopsy findings revealed a stage of pT1N0M0R0 according to the AJCC staging system. Two years later, he was diagnosed as having another primary MCC on the right hand, stage pT1N0M0R0, which was treated with wide excision. The patient received no adjuvant therapy for either tumor, and his metachronous MCCs have not recurred in 2 and 0.5 years, respectively.

Patient 3

A 70-year-old man presented with a tumor on the left side of his chin. Biopsy results demonstrated MCC with imaging studies showing cervical lymphadenopathy. He underwent wide excision of the primary tumor, therapeutic cervical lymphadenectomy, and adjuvant radiotherapy for MCC at stage pT1N1bM0R0 according to the AJCC staging system. Thirty-three months after completing treatment for MCC, the patient was diagnosed as having CIDP not yet requiring therapy. He remains free of MCC since completing treatment 4 years ago.

Discussion

Based on the incidence of CIDP and MCC independently, the estimated annual incidence rate of having both conditions is 0.23 cases per 10 billion persons. Nonetheless, between 2015 and 2019, 3 patients with a diagnosis of MCC and CIDP were treated at our center. To our knowledge, no direct associations between CIDP and MCC have been reported to date. However, MCC has been reported to occur with chronic inflammatory disorders3 and, likewise, CIDP with other types of cancer.4

The possible association between MCC and CIDP may be due to cross-reactivity of antibodies to MCC and neural antigens. Melanocytes and Schwann cells both derive from the neural crest and may share antigens, such as GM2 gangliosides, yielding cross-reactive antibodies that lead to both melanoma and CIDP.4 Since Merkel cells also derive from the neural crest, similar mechanisms may lead to CIDP and MCC co-occurrence. Moreover, MCC shares a neuroendocrine origin with small cell lung carcinoma, which may harbor the Hu and collapsin response-mediator protein 5 (CRMP5) antigens associated with neurological syndromes such as CIDP.4 Direct cross-reactivity of anti-Hu antibodies to small cell lung carcinoma and neurons is established in subacute sensory neuropathy, but the reactivity with the peripheral nervous system may be more complex. Although antibody titers were not measured in our patients, a previous case report5 described a patient with MCC, progressive sensorimotor neuropathy, autonomic neuropathy, and encephalopathy as well as anti-Hu antibodies in serum samples and Hu protein expression in the tumor. Another case report from 20186 described a patient with MCC, cerebellar ataxia, and encephalopathy who had anti-CRMP5 antibodies in the peripheral blood and cerebrospinal fluid.

Considering the rarity of MCC and CIDP independently, the simultaneity of both conditions in these patients was probably not a coincidence. Understanding the shared pathophysiologic mechanisms between MCC and CIDP and reporting new cases of co-occurrence may inform immunologically based treatment strategies for these diseases.

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Article Information

Corresponding Author: Christopher Andrew Barker, MD, Multidisciplinary Skin Cancer Management Program, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (barkerc@mskcc.org).

Published Online: March 11, 2020. doi:10.1001/jamadermatol.2020.0055

Conflict of Interest Disclosures: Dr Barker reports grants from Amgen, Merck, and Elekta, personal fees from Regeneron Pharmaceuticals and Pfizer, and nonfinancial support from AlphaTau Medical.

Additional Contributions: We thank the patients for granting permission to publish this information.

References
1.
Paulson  KG, Park  SY, Vandeven  NA,  et al.  Merkel cell carcinoma: current US incidence and projected increases based on changing demographics.  J Am Acad Dermatol. 2018;78(3):457-463.e2. doi:10.1016/j.jaad.2017.10.028PubMedGoogle ScholarCrossref
2.
Broers  MC, Bunschoten  C, Nieboer  D, Lingsma  HF, Jacobs  BC.  Incidence and prevalence of chronic inflammatory demyelinating polyradiculoneuropathy: a systematic review and meta-analysis.  Neuroepidemiology. 2019;52(3-4):161-172. doi:10.1159/000494291PubMedGoogle ScholarCrossref
3.
Sahi  H, Sihto  H, Artama  M, Koljonen  V, Böhling  T, Pukkala  E.  History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection.  Br J Cancer. 2017;116(2):260-264. doi:10.1038/bjc.2016.391PubMedGoogle ScholarCrossref
4.
Rajabally  YA, Attarian  S.  Chronic inflammatory demyelinating polyneuropathy and malignancy: a systematic review.  Muscle Nerve. 2018;57(6):875-883. doi:10.1002/mus.26028PubMedGoogle ScholarCrossref
5.
Greenlee  JE, Steffens  JD, Clawson  SA, Hill  K, Dalmau  J.  Anti-Hu antibodies in Merkel cell carcinoma.  Ann Neurol. 2002;52(1):111-115. doi:10.1002/ana.10225PubMedGoogle ScholarCrossref
6.
Santomasso  B, D’Angelo  S.  Anti–CRMP5-associated paraneoplastic neurologic syndrome developing in a patient with metastatic Merkel cell carcinoma during immune checkpoint inhibitor treatment.  Neurology. 2018;90(15 suppl):P5.409.Google Scholar
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