Paraneoplastic Merkel cell carcinoma: Searchin’ for my lost shaker of salt

By Warren R. Heymann, MD, FAAD
Sept. 6, 2023
Vol. 5, No. 35

By pure coincidence, Jimmy Buffett passed away from Merkel cell carcinoma (MCC) as I researched the topic of paraneoplastic MCC. Although I am no parrothead, every time I’d hear Margaritaville, I’d smile and fantasize about a lifestyle that is counter to my reality. I chose the topic of paraneoplastic MCC for this commentary because of an intriguing case report of the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) in an 86-year-old woman with recurrent MCC. (1) I would wager that there are many Google searches about MCC today. I do not know any details about Jimmy Buffett’s case. Regardless, dermatologists should recognize that MCC patients may rarely exhibit paraneoplastic phenomena.  

MCC is a highly aggressive primary neuroendocrine skin cancer. According to Akaike and Ngheim, although MCC is rare, its incidence is increasing rapidly; during 2000-2013, the number of MCC cases increased by 95% — faster than all solid tumors (15%) or melanoma (56%). MCC usually appears as a firm, non-tender, red, or skin-colored nodule. Clinical features of MCC are summarized in the acronym: AEIOU (Asymptomatic, Expanding rapidly, Immune suppression [chronic T cell immunosuppression such as HIV, chronic lymphocytic leukemia, and solid organ transplant], Older than 50 years, and Ultraviolet (UV)-exposed site on a person with fair skin. The most frequent sites of primary MCC tumors are the head and neck (43%), upper limbs and shoulder (24%), lower limbs and hip (15%), trunk (11%), and others (9%). “Merkel cell polyomavirus (MCPyV) and ultraviolet (UV)-induced mutations are two major causative factors of MCC. Virus-positive MCCs express polyomavirus oncoproteins that are highly immunogenic yet are required for ongoing tumor growth. Virus-negative MCCs have a high burden of UV-DNA mutations that encode tumor-specific UV-neoantigens.” (2) 

Paraneoplastic syndromes are rare disorders with complex systemic clinical manifestations from an occult malignancy. Malignant cells do not directly manifest symptoms of metastasis but instead generate autoantibodies, cytokines, hormones, or peptides that affect multiple organ systems such as neurological, dermatological, gastrointestinal, endocrine, hematologic, and cardiovascular systems. (3)  

Early detection and management of paraneoplastic syndromes can improve morbidity and mortality; definitive treatment remains effective surgical or anti-tumor therapies. The following are the criteria for defining ectopic hormonal paraneoplastic syndromes: a) the presence of an endocrine or metabolic abnormality in a patient with a neoplasm; b) symptomatic remission after effective treatment; c) endocrine syndrome recurrence with disease relapse; d) abnormally regulated elevated hormone concentration; e) a significant gradient between hormone concentration in the venous effluent from the tumor and arterial hormone levels; f) tumor samples exhibiting bio-and/or immunoreactive hormone; g) relevant hormone mRNA that can be identified in tumor tissue; and h) synthesis and secretion of relevant hormone by tumor cells in vitro. (4) 

The most common endocrine paraneoplastic syndrome is hypercalcemia of malignancy (tumor-induced hypercalcemia), in which 80% of cases are due to parathyroid hormone- related peptide (PTHrP) secretion. SIADH is the next most common and is characterized by the secretion of ADH in the absence of osmotic or non-osmotic stimuli without any other cause of hyponatremia. Ectopic Cushing syndrome is mostly caused by tumors that produce proopiomelanocortin, a precursor molecule of ACTH. (4,5) 

Donovan et al state that squamous cell carcinoma is the most common cause of PTHrP-mediated hypercalcemia. In their review of 138 patients with elevated PTHrP and hypercalcemia neuroendocrine (MCC) was associated in 3 (2.2%). (6) Ishay et al reported the case of an 82-year-old man with a 2-year history of metastatic MCC with uncontrolled hypertension, hypokalemia, and new onset hyperkalemia. Strikingly elevated levels of cortisol and ACTH confirmed the diagnosis of ectopic Cushing syndrome. (7) Anzai et al detailed an 85-year-old Japanese woman with a MCC with Bowen's disease on her right cheek. The lesion was excised under general anesthesia; 3 days post-operatively, hyponatremia was observed. Although an increased level of ACTH was found both in the tumor and in the peripheral blood, the postoperative hyponatremia was presumed to be caused by the stress of the operation and indapamide (a thiazide-like diuretic) administration. (8) 

SIADH may present with nausea, anorexia, fatigue, and lethargy to severe symptoms like confusion, seizures, respiratory depression, and coma. Laboratory findings include hyponatremia, hyperosmolality, and increased urine osmolality. (3) As in other paraneoplastic disorders, the optimal treatment is directed to the underlying malignancy. Acute, severe hyponatremia is a life-threatening emergency requiring hypertonic saline. (4) Blondin et al presented the case of a 46-year-old woman with progressive memory impairment, hyponatremia, and seizures. Her chronic hyponatremia was ultimately found to be due to ectopic secretion of anti-diuretic hormone by a neuroendocrine tumor with Merkel cell carcinoma phenotype. (9) Iyer et al reviewed 211 patients with hyponatremia from the Kaiser-Permanente data base, finding that 9 patients (4.3%) had severe hyponatremia that met the criteria for being MCC-associated. Additionally, in their review of the Seattle MCC repository, 8 paraneoplastic cases were observed — hyponatremia in 5, Lambert-Eaton myasthenic syndrome in 2, and 1 case of cerebellar degeneration. (10) 

In conclusion, paraneoplastic syndromes may accompany MCC, despite their rarity, possibly with hyponatremia and/or SIADH being most common. Like millions, I am saddened by the death of Jimmy Buffett. Perhaps people will become more aware of MCC and be more vigilant about sunscreen when enjoying their cheeseburger in paradise. I will always associate the search for the lost shaker of salt with Margaritaville, but now, I will also be reminded of SIADH in MCC.  

Point to Remember: Merkel cell carcinoma may be associated with several paraneoplastic phenomena, including the syndrome of inappropriate anti-diuretic hormone secretion, ectopic Cushing syndrome, and others. 

Our expert’s viewpoint

Paul Nghiem, MD, PhD, FAAD
Professor & Head, University of Washington Dermatology
George F. Odland Endowed Chair
Director, Skin Oncology Clinical Program, Fred Hutchinson Cancer Center
Seattle, Washington

Jimmy Buffett’s passing from Merkel cell carcinoma reminds us that even with the best possible care, our current treatments remain insufficient for many people. Yes, progress has been remarkable in that the chance of being alive several years after developing advanced MCC is now (in the immunotherapy era) about 10-fold higher than it used to be (in the chemotherapy era). Specifically, about 50% of patients survive advanced MCC for multiple years, versus 5% in the recent past. Indeed, the public statements regarding Jimmy Buffett’s MCC course indicate that he survived for 4 years. It is now a major goal in the MCC field to find options for patients with PD1 immunotherapy-refractory MCC. Several trials are now designed to address this challenge, by targeting the p53 pathway, the ATR pathway, or adding additional immune stimulating agents. 

Regarding paraneoplastic syndromes and MCC, they are certainly well known to happen, but occur in well under 10% of cases. The single most likely is hyponatremia due to SIADH, which typically improves quickly if the cancer is controlled. A fascinating aspect is that patients with auto-immune mediated paraneoplastic syndromes (for example, cerebellar ataxia, mediated by immune attack of proteins present in this ‘neuroendocrine’ carcinoma and in the brain) are significantly more likely to survive their cancer. This is likely another indicator of the importance of anti-cancer immunity in fighting MCC. (10) 

1. Mercadé-Torras JM, Samaniego C, Sáez A, Yebenes M, Mazarico I. Paraneoplastic secretion of antidiuretic hormone in Merkel cell carcinoma: A case report. J Dermatol. 2023 Aug;50(8):e247-e248. doi: 10.1111/1346-8138.16774. Epub 2023 Mar 21. PMID: 36942530.

2. Akaike T, Nghiem P. Scientific and clinical developments in Merkel cell carcinoma: A polyomavirus-driven, often-lethal skin cancer. J Dermatol Sci. 2022 Jan;105(1):2-10. doi: 10.1016/j.jdermsci.2021.10.004. Epub 2021 Oct 18. PMID: 34836718; PMCID: PMC8810602.

3. Thapa B, Mahendraker N, Ramphul K. Paraneoplastic Syndromes. 2023 Mar 31. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 29939667.

4. Onyema MC, Drakou EE, Dimitriadis GK. Endocrine abnormality in paraneoplastic syndrome. Best Pract Res Clin Endocrinol Metab. 2022 May;36(3):101621. doi: 10.1016/j.beem.2022.101621. Epub 2022 Feb 4. PMID: 35153144.

5. Sardiña González C, Martínez Vivero C, López Castro J. Paraneoplastic syndromes review: The great forgotten ones. Crit Rev Oncol Hematol. 2022 Jun;174:103676. doi: 10.1016/j.critrevonc.2022.103676. Epub 2022 Apr 2. PMID: 35378267.

6. Donovan PJ, Achong N, Griffin K, Galligan J, Pretorius CJ, McLeod DS. PTHrP-mediated hypercalcemia: causes and survival in 138 patients. J Clin Endocrinol Metab. 2015 May;100(5):2024-9. doi: 10.1210/jc.2014-4250. Epub 2015 Feb 26. Erratum in: J Clin Endocrinol Metab. 2019 Jul 1;104(7):2614. PMID: 25719931.

7. Ishay A, Touma E, Vornicova O, Dodiuk-Gad R, Goldman T, Bisharat N. Ectopic Cushing's syndrome in a patient with metastatic Merkel cell carcinoma: A case report. World J Clin Cases. 2022 Aug 6;10(22):7989-7993. doi: 10.12998/wjcc.v10.i22.7989. PMID: 36158508; PMCID: PMC9372868.

8. Anzai S, Sato T, Takayasu S, Asada Y, Terashi H, Takasaki S. Postoperative hyponatremia in a patient with ACTH-producing Merkel cell carcinoma. J Dermatol. 2000 Jun;27(6):397-400. doi: 10.1111/j.1346-8138.2000.tb02190.x. PMID: 10920586.

9. Blondin NA, Vortmeyer AO, Harel NY. Paraneoplastic syndrome of inappropriate antidiuretic hormone mimicking limbic encephalitis. Arch Neurol. 2011 Dec;68(12):1591-4. doi: 10.1001/archneurol.2011.876. PMID: 22159058.

10. Iyer JG, Parvathaneni K, Bhatia S, Tarabadkar ES, Blom A, Doumani R, McKenzie J, Asgari MM, Nghiem P. Paraneoplastic syndromes (PNS) associated with Merkel cell carcinoma (MCC): A case series of 8 patients highlighting different clinical manifestations. J Am Acad Dermatol. 2016 Sep;75(3):541-547. doi: 10.1016/j.jaad.2016.04.040. Epub 2016 May 11. PMID: 27177440; PMCID: PMC4992627.

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