NORD gratefully acknowledges Neha Singh, BS, Research Scientist, Song Park, MD, and Paul Nghiem, MD, PhD, Professor & Head, University of Washington Dermatology, for assistance in the preparation of this report.
Merkel cell carcinoma (MCC) is a rare form of skin cancer. It is an aggressive type of cancer that can spread (metastasize) to other areas of the body. The exact, underlying cause of the disease is not known, but there are several factors, including environmental and immunologic ones, that contribute to the development of the disease. For many years, this form of cancer was thought to arise from Merkel cells. These cells are found in the outermost layer of the skin called the epidermis. Merkel cells are located very close to nerve endings that receive touch sensations and may act as nerve receptors. Recent research suggests that the MCC might not arise from Merkel cells. It is possible that this cancer arises from immature cells that eventually become Merkel cells (these are Merkel cell precursors).
Endocrine tissue is specialized tissue that contains hormone-secreting cells. These cells secrete several different hormones into the blood (endocrine) or to local cells (paracrine, autocrine). These hormones have a variety of functions within the body. Merkel cell carcinoma is characterized as a neuroendocrine carcinoma because it has features of nerves and endocrine (hormone-secreting) cells. There are also several other types of cancers that look similar under the microscope, but these tumors often behave quite differently from each other.
Merkel cell carcinoma most commonly affects regions of the skin that are exposed to the sun including the head/neck and arms, but it can also develop on other areas of the body that are not typically sun-exposed.
In most people, the first sign of Merkel cell carcinoma is a small bump (nodule) on the skin. This bump is usually firm and appears either skin-colored or red-purple. It also tends to grow rapidly. Often, there no symptoms associated with the nodule. Sometimes, the nodule can have a shiny surface or be covered with small widened (dilated) vessels. Although uncommon for MCC, the abnormal growth can rip open (ulcerate) to form an open sore with crusting. The acronym ‘AEIOU’ can be used to note characteristic clinical findings. The acronym stands for: asymptomatic (no noticeable symptoms); expanding rapidly (within 3 months’ times); immune suppression; older than 50 years of age; and ultraviolet light-exposed area affecting a fair-skinned individual (Health 2008).
In some instances, lymph node(s) to which the primary lesion drains can become enlarged (lymphadenopathy). This is a clinical indication (via palpation and/or imaging) that the disease has spread to the patient’s nearby (regional) lymph node bed. This can occur in patients who present with a primary skin lesion and also with those who do not. Individuals affected by MCC without a primary tumor (no original skin lesion) tend to do better because it is likely that their immune systems were able to eliminate the primary lesion and is thus more likely to be able to eliminate small numbers of undetected MCC cells that may be present elsewhere in the body.
Larger MCC tumors are associated with moderately higher risk of recurrence and spreading to lymph nodes. However, even small MCC tumors carry at least a 15% risk of spreading to nearby (regional) lymph nodes. Merkel cell carcinoma can also spread to other areas of the body, like the liver, bones, pancreas, and other skin/body wall locations.
Several risk factors have been established for MCC. Risk factors include being over the age of 50, having fair-skin, experiencing extensive sun exposure (ultraviolet light), or having an immune system that is either weakened or compromised. Individuals with conditions such as HIV/AIDS, kidney or heart transplantation, and autoimmune diseases that require medications that suppress the immune system, chronic lymphocytic leukemia (CLL), and certain forms of blood cancer (hematologic cancer) such as leukemia or lymphoma are commonly associated with weakened immunity. Although such persons are at elevated risk of developing MCC, over 90% of people with MCC do not have any known problem with their immune system.
Researchers have determined that Merkel cell carcinoma is frequently associated (~80%) with a virus called Merkel cell polyomavirus (MCPyV). It is now clear that the majority of people become infected with MCPyV by adulthood, but it appears that the virus does not cause any symptoms except in the very rare situations in which it much later leads to MCC (Martel-Jantin 2013, Becker 2017, others). In addition, some individuals develop Merkel cell carcinoma without the presence of the Merkel cell polyomavirus (~20%), and such cases are usually associated with extensive UV exposure.
Approximately 60% of MCC tumors arise in men. In the past 15 years, the incidence has tripled in the United States, and it can be lethal for about one-third of the people affected. As of 2015, approximately 2,500 persons per year are diagnosed with this cancer in the United States. The incidence (number of people who develop a disorder over a given period of time such as one year) is approximately 0.7 people per 100,000 people in the general population of the United States. It dramatically increases to approximately to 9.8 people per 100,000 in individuals more than 85 years of age. There is a 100,000-fold difference between the risk of developing MCC for patients under the age of 30 compared to those who are greater than 85 years old (Paulson 2018).
A diagnosis of Merkel cell carcinoma is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
A doctor may remove a small sample of affected skin that to be studied under a microscope, also known as a biopsy. The most common types of biopsies include a shave biopsy (part of the top of the abnormal tissue is removed with a scalpel) or a punch biopsy (a small cylinder of tissue is removed). The sample is then examined by a pathologist, who is a specialist trained in examining tissues and cells to understand the basis of the disease.
To ensure proper care for MCC, doctors typically perform a sentinel lymph node biopsy (SLNB) to determine whether the cancer has spread to draining lymph nodes. A sentinel lymph node biopsy is used to determine the first lymph nodes to which the cancer may have spread. This technique is used to identify the sentinel lymph node (draining lymph node basin). This procedure is carried out in the operating room. During this procedure, a doctor will inject radioactive dye into the site of the primary lesion. The dye will then travel to and collect in the sentinel lymph node. Doctors will be able to see this through a special probe that can view the radioactive dye. The sentinel lymph node is then removed and examined carefully under a microscope for even a small number of MCC tumor cells.
Imaging techniques including computerized tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) are used to see whether the cancer has spread.
Sometimes, doctors will recommend a combined PET/CT scan. This scan gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has at the same time as mapping the adjacent body structures (CT).
When an individual is diagnosed with Merkel cell carcinoma, additional studies are required to determine the extent or “stage” of the disease. Staging is important to help characterize the potential disease course and determine appropriate treatment approaches. A variety of diagnostic tests may be used in staging Merkel cell carcinoma (e.g., blood tests, SLNB, CT scan). Merkel cell carcinoma has an established, worldwide consensus staging system. This staging system is summarized at:
The diagnosis and therapeutic management of Merkel cell carcinoma requires the coordinated efforts of a team of medical professionals who are focused on diagnosing and treating skin disorders (dermatologists); diagnosing and treating cancer (medical oncologists); cancer treatment through surgery (surgical oncologists); cancer treatment through radiation (radiation oncologists); oncology nurses; dietitians; psychiatrists; and/or other healthcare professionals. Psychosocial support for the entire family is also often indicated because of the rarity and relatively high risk of this cancer.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; location of the tumor; the presence or absence of certain symptoms; an individual’s age and general health; and/or other factors such as immune health. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
In general, for individuals who have localized disease without involvement of the lymph nodes and without (distant) spread of the cancer, surgery is recommended to remove the primary Merkel cell carcinoma. Usually, the tumor is removed along with some of the healthy skin that surrounds it (wide local excision). If nearby lymph nodes are also affected, but the cancer has not spread (metastasized) further, then the affected lymph nodes are typically treated by surgery (and/or radiation treatment). The surgical removal of lymph nodes may be referred to as a lymph node dissection or lymphadenectomy.
A specific type of surgery called Mohs micrographic surgery may be appropriate for some individuals with Merkel cell carcinoma. In this approach, a surgeon uses a precise technique to remove diseased tissue while leaving as much normal tissue as possible. Studies suggest that in order to optimize control of MCC, radiation therapy needs to be done following Mohs surgery.
For some individuals, radiation therapy may be recommended after surgery. This is called adjuvant radiation and is given after primary therapy (in this instance surgery) to help lower the risk that the cancer will come back. The adjuvant radiation therapy means radiotherapy is used to destroy cancerous cells that remain after surgery has removed all clinically detectable tumor (visible tumor). Radiation therapy uses x-rays or similar forms of radiation to directly destroy cancer cells. Radiation therapy can also be used as a primary therapy in people for whom surgical removal of cancer is not possible.
Sometimes, doctors may recommend anti-cancer drugs as an adjuvant therapy to surgery. Chemotherapy and radiation therapy can be used together as an adjuvant therapy. There are concerns about the use of chemotherapy because some chemotherapy regimens may suppress the activity of the immune system.
Chemotherapy has also been tried for recurrent or metastatic disease. However, it only offers limited benefit with an average period of disease control of only approximately 90 days. [Iyer J 2016, Cowey 2017]. As a consequence, chemotherapy is generally reserved for patients whose disease did not respond to immunotherapy (see below), or to diminish symptoms (palliative care) of patients with advanced MCC who are no longer candidates for curative therapies.
Most people with recurrent or metastatic disease are recommended to undergo immunotherapy. This type of treatment aims to enhance the body’s innate ability to fight cancer using the immune system. For example, avelumab is a type of immunotherapy called PD-L1 blockade, which releases the “brakes” on the immune system that some cancers use to try to evade the immune cells.
Recent clinical trials of PD-1 or PD-L1 blockade agents (e.g. avelumab, pembrolizumab, and nivolumab) in advanced MCC have demonstrated durable response of approximately 60% for patients who have not been previously treated with chemotherapy. The response rate is approximately 32% for patients who have been previously treated with chemotherapy. Because these immunotherapy responses are very durable (often lasting years), as compared to chemotherapy (typically lasting months), these findings have quickly led to a preference for immunotherapy over chemotherapy for MCC. [Kaufman 2016, Nghiem 2016, D’Angelo 2018]. Based on the data from clinical trials, in 2017, the U.S. Food and Drug Administration (FDA) approved the immunotherapy, avelumab (Bavencio®), for the treatment of adults and children over the age of 12 who have metastatic Merkel cell carcinoma. The data also led to changes in National Comprehensive Cancer Network guidelines for advanced MCC. In 2016, these guidelines listed only chemotherapy as an option, in 2017 pembrolizumab was included, and in 2018, avelumab, nivolumab, and pembrolizumab were all included with a preference that such immunotherapy be given prior to possible chemotherapy. [Bichakjian 2018].
Pazopanib or imatinib, which are tyrosine kinase inhibitors, have shown some activity against Merkel cell carcinoma. More research is necessary to determine the long-term safety and effectiveness of these therapies for Merkel cell carcinoma and what role, if any, they may have in a treatment plan.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Bichakjian CK, Olencki T, Aasi SZ, et al. Merkel cell carcinoma, version 1.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2018;16:742-774. https://www.ncbi.nlm.nih.gov/pubmed/29891526
D’Angelo SP, Russell J, Lebbe C, et al. Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol. 2018;4:e180077. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885245/
O’Brien T, Power DG. Metastatic Merkel-cell carcinoma: the dawn of a new era. BMJ Case Rep. 2018;2018. https://www.ncbi.nlm.nih.gov/pubmed/30002209
Paulson K, Park S, Vandeven N, et al. Merkel cell carcinoma: Current S incidence and projected increases based on changing demographics. J Am Acad Dermatol. 2018;78;457-63. https://www.merkelcell.org/wp-content/uploads/2018/02/paulsonfinal.pdf
Tarabadkar ES, Thomas H, Blom A, et al. Clinical benefit from tyrosine kinase inhibitors in metastatic Merkel cell carcinoma: a case series of 5 patients. Am J Case Rep. 2018;19:505-511. https://www.ncbi.nlm.nih.gov/pubmed/29706615
Voelker R. Why Merkel cell cancer is garnering more attention. JAMA. 2018;320:18-20. https://www.ncbi.nlm.nih.gov/pubmed/29898204
Becker JC, Stang A, DeCaprio JA, et al. Merkel cell carcinoma. Nat Rev Dis Primers. 2017;3:17077. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054450/
Cowey CL, Mahnke L, Espirito J, et al. Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future Oncol. 2017;13:1699-1710. https://www.ncbi.nlm.nih.gov/pubmed/28605939
Muller-Richter UDA, Gesierich A, Kubler AC, Hartmann S, Brands RC. Merkel cell carcinoma of the head and neck: recommendations for diagnostics and treatment. Ann Surg Oncol. 2017;24:3430-3437. https://www.ncbi.nlm.nih.gov/pubmed/28762116
Banks PD, Sandhu S, Gyorki DE, Johnston ML, Rischin D. Recent insights and advances in the management of Merkel cell carcinoma. J Oncol Pract. 2016;12:637-646. https://www.ncbi.nlm.nih.gov/pubmed/27407160
Harms KL, Healy MA, Nghiem P, et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC Staging System. Ann Surg Oncol. 2016;23:3564-2571. https://www.ncbi.nlm.nih.gov/pubmed/27198511
Iyer JG, Blom A, Doumani R, et al. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med. 2016;5:2294-2301. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055152/
Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374-1385. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587154/
Kline L, Coldiron B. Mohs micrographic surgery for the treatment of Merkel cell carcinoma. Dermatol Surg. 2016;42:945-954. https://www.ncbi.nlm.nih.gov/pubmed/27467228
Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374:2542-2552. https://www.ncbi.nlm.nih.gov/pubmed/27093365
Cimino PJ, Robirds DH, Tripp SR, et al. Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma. Mod Pathol. 2014;27:1073-1087. https://www.ncbi.nlm.nih.gov/pubmed/24406863
Ramahi E, Choi J, Fuller CD, Eng TY. Merkel cell carcinoma. Am J Clin Oncol. 2013;36:299-309. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121923/
Wang TS, Byrne PJ, Jacobs LK, Taube JM. Merkel cell carcinoma: update and review. Semin Cutan Med Surg. 2011;30:48-56. https://www.ncbi.nlm.nih.gov/pubmed/21540020
Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. JAAD. 2008 Mar;58(3):375-81. https://www.ncbi.nlm.nih.gov/pubmed/18280333
American Cancer Society. Merkel Cell Skin Cancer. Available at: https://www.cancer.org/cancer/merkel-cell-skin-cancer.html Accessed August 15, 2018.
Cutaneous neuroendocrine carcinoma. Orphanet Encyclopedia, July 2007. Available at: https://www.orpha.net/consor4.01/www/cgi-bin/OC_Exp.php?lng=EN&Expert=79140 Accessed August 15, 2018.
National Cancer Institute. Merkel Cell Carcinoma Treatment (PDQ®) – Patient Version. May 2, 2018. Available at: https://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq Accessed August 15, 2018.
Mayo Clinic for Medical Education and Research. Merkel Cell Carcinoma. March 7, 2018. Available at: https://www.mayoclinic.org/diseases-conditions/merkel-cell-carcinoma/symptoms-causes/syc-20351030 Accessed August 15, 2018.
Tai P, Ngheim PT, Park SY. Pathogenesis, clinical features, and diagnosis of Merkel cell carcinoma. UpToDate, Inc. 2018 Aug 1. Available at: https://www.uptodate.com/contents/pathogenesis-clinical-features-and-diagnosis-of-merkel-cell-neuroendocrine-carcinoma Accessed August 6, 2018.
Tai P, Ngheim PT, Park SY. Staging and treatment of Merkel cell carcinoma. UpToDate, Inc. 2018 Jun 26. Available at: https://www.uptodate.com/contents/staging-and-treatment-of-merkel-cell-carcinoma Accessed August 6, 2018.
Wells GL. Merkel cell carcinoma. Merck Manual Online Professional Version website. Updated February 2017. Available at: https://www.merckmanuals.com/professional/dermatologic-disorders/cancers-of-the-skin/merkel-cell-carcinoma Accessed August 16, 2018.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100