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Last updated: 06/23/2023
Years published: 2018, 2023
NORD gratefully acknowledges Neha Singh, BS, Clinical Research Fellow, Song Park, MD, Acting Instructor, and Paul Nghiem, MD, PhD, Professor & Head, University of Washington Dermatology, for assistance in the preparation of this report.
Summary
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. Treatment guidelines are rapidly evolving with new studies and treatment options. Clinical features, tests for diagnosis and treatment options are discussed below. MCC is characterized as a neuroendocrine carcinoma because it involves interaction between the nervous system and the endocrine system.
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. Sometimes, the nodule can have a shiny surface or be covered with small widened (dilated) vessels. It also tends to grow rapidly. Often, there are no symptoms associated with the nodule. Although uncommon for MCC, the abnormal growth can rip open (ulcerate) to form an open sore with crusting. The acronym โAEIOUโ can be used to note characteristic clinical findings. The acronym stands for: asymptomatic (no noticeable symptoms); expanding rapidly (within 3 monthsโ times); immune suppression; older than 50 years of age; and ultraviolet light-exposed area affecting a fair-skinned individual.
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 patientโs nearby (regional) lymph node bed. This can occur in patients who present with a primary skin lesion as well as in those who do not. Individuals affected by MCC without a primary tumor (no original skin lesion) tend to do better compared to patients with primary tumor as well aslymph node involvement because it is likely that their immune system was able to eliminate the primary lesion and are 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 about a 25% risk of spreading to nearby 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. These 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 that suppress the immune system are at elevated risk of developing MCC. However, 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. 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 2020, approximately 3,000 persons per year are diagnosed with this cancer in the United States. The projected incidence is 3,200 cases by the year 2025.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 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.
Diagnosis
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 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 positron emission tomography (PET), computed tomography (CT) and occasionally magnetic resonance imaging (MRI) are used to see whether the cancer has spread. Doctors often 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). PET/CT has higher sensitivity compared to CT scans alone and is often the favored imaging modality for scans to determine the stage of the cancer.
MCC has a higher propensity to have metastasized at diagnosis compared to other skin cancers. Nearly 1 in every 6 MCC patients are upstaged by baseline imaging, compared to <1% of melanoma patients. Staging
When an individual is diagnosed with Merkel cell carcinoma, additional studies are required to determine the extent or โstageโ 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) as noted above. Merkel cell carcinoma has an established, worldwide consensus staging system. This staging system is summarized at:
https://www.merkelcell.org/testing-and-diagnosis/staging/
Treatment
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 or tumor histopathologic features; an individualโs 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
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.
Most people with recurrent or metastatic disease are recommended to undergo immunotherapy. This type of treatment aims to enhance the bodyโs innate ability to fight cancer using the immune system. For example, avelumab is a type of immunotherapy called PD-L1 blockade, which releases the โbrakesโ 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. Based on the data from clinical trials, the U.S. Food and Drug Administration (FDA) approved the immunotherapy, avelumab (Bavencio) in 2017 and pembrolizumab (Keytruda) in 2018 for the treatment of adults and children over the age of 12 who have metastatic Merkel cell carcinoma.
Historically, chemotherapy was the preferred systemic treatment option for recurrent or metastatic disease. However, chemotherapy only offers limited benefit with an average period of disease control of approximately 90 days from the start of therapy. There are also concerns about the use of chemotherapy because it typically suppresses activity of the immune system. As a consequence, chemotherapy is no longer recommended as a first-line agent for patients with metastatic MCC who are eligible for immunotherapy. It is generally reserved for patients whose disease does not respond to immunotherapy or for patients with particularly advanced tumors (palliative intent).
Options for patients who do not respond to first-line anti-PD-(L)1 therapy are limited. The combination of ipilimumab, a CTLA-4 inhibitor, and nivolumab, a PD-1 inhibitor, has been explored in this setting and has shown ~30% response rate.
Pazopanib or imatinib, which are vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, have shown some benefit in treating 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.
Sandostatin is a somatostatin peptide analogue that has also demonstrated efficacy in treating select neuroendocrine cancers, including MCC. Uniquely, up to 85% of advanced MCC tumors express somatostatin receptors (SSTR) compared to ~15% expressed in other high-grade neuroendocrine cancers. Somatostatin works by turning off cancer growth signals.
Palliative RT involves treating tumors with radiation therapy without curative intent. This modality can be used to shrink larger tumors or in combination with immunotherapy.
Several trials have also investigated the efficacy of intralesional therapies and shown encouraging results. A clinically available agent (approved for melanoma) which has shown efficacy based on multiple case reports of MCC is talimogene laherparepvec (T-VEC; a modified oncolytic virus).
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:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Kim S, Wuthrick E, Blakaj D, et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet. 2022 Sep 24;400(10357):1008-1019. https://www.ncbi.nlm.nih.gov/pubmed/36108657
Saiag P, Blom A. Combined nivolumab and ipilimumab in non-resectable Merkel cell carcinoma. Lancet. 2022 Sep 24;400(10357):976-977. https://www.ncbi.nlm.nih/gov/pubmed/36108656
Akaike T, Qazi J, Anderson A, et al. High somatostatin receptor expression and efficacy of somatostatin analogues in patients with metastatic Merkel cell carcinoma. Br J Dermatol. 2021 Feb;184(2):319-327. https://ncbi.nlm.nih.gov/pubmed/32320473
Singh N, Alexander NA, Lachance K, et al. Clinical benefit of baseline imaging in Merkel cell carcinoma: Analysis of 584 patients. J Am Acad Dermatol. 2021 Feb;84(2):330-339. https://www.ncbi.nlm.nih.gov/pubmed/32707254
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
DโAngelo 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/
OโBrien 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
INTERNET
American Cancer Society. Merkel Cell Skin Cancer. Available at: https://www.cancer.org/cancer/merkel-cell-skin-cancer.html Accessed December 8, 2022.
National Cancer Institute. Merkel Cell Carcinoma Treatment (PDQยฎ) โ Patient Version. May 2, 2018. Available at: https://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq Accessed December 8, 2022.
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 December 8, 2022.
Tai P, Nghiem PT, Park SY. Pathogenesis, clinical features, and diagnosis of Merkel cell carcinoma. UpToDate, Inc.Nov 23, 2022. Available at: https://www.uptodate.com/contents/pathogenesis-clinical-features-and-diagnosis-of-merkel-cell-neuroendocrine-carcinoma Accessed June 14, 2023.
Tai P, Nghiem PT, Park SY. Staging and treatment of Merkel cell carcinoma. UpToDate, Inc.Feb 27, 2023. Available at: https://www.uptodate.com/contents/staging-and-treatment-of-merkel-cell-carcinoma Accessed June 16, 2023.
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-carcihnoma Accessed June 16, 2023.
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