Rak z komórek merkla – Etiologia i przyczyny

Rak z komórek merkla
Etiologia i przyczyny

Rak z komórek Merkla (MCC) to agresywny nowotwór neuroendokrynny skóry, którego etiologia jest wieloczynnikowa. Około 80% przypadków wiąże się z infekcją wirusem polioma komórek Merkla (MCPyV), który integruje swój genom z genomem gospodarza i indukuje ekspresję onkogennych białek hamujących funkcję genów supresorowych. Pozostałe 20% przypadków jest związane z uszkodzeniami DNA spowodowanymi promieniowaniem ultrafioletowym (UV), które indukuje charakterystyczne mutacje w genach TP53 i RB1. Czynniki ryzyka obejmują wiek powyżej 50 lat (mediana 75-79 lat), płeć męską, jasną karnację oraz immunosupresję, która zwiększa ryzyko MCC około 15-krotnie. Immunosupresja może wynikać z chorób autoimmunologicznych, zakażenia HIV, nowotworów hematologicznych (np. CLL) oraz stosowania leków immunosupresyjnych, w tym inhibitorów mTOR i TNF.

Etiologia raka z komórek Merkla

Poliomawirus komórek Merkla (MCPyV)
Ekspozycja na promieniowanie UV
Immunosupresja
Czynniki demograficzne i genetyczne
Inne czynniki ryzyka
Różnice geograficzne i etiologiczne
Pochodzenie komórkowe MCC

Implikacje kliniczne
Podsumowanie etiologii

Kolejne rozdziały

Etiologia raka z komórek Merkla

Rak z komórek Merkla (MCC) to rzadki, ale wysoce agresywny nowotwór skóry o neuroendokrynnym charakterze, charakteryzujący się szybkim wzrostem i wysokim ryzykiem nawrotów oraz przerzutów. Mimo rzadkiego występowania, częstość zachorowań na ten typ nowotworu wzrosła w ostatnich dekadach, szczególnie wśród osób starszych i z osłabionym układem odpornościowym. Etiologia raka z komórek Merkla nie jest w pełni poznana, jednak badania wskazują na kilka głównych czynników przyczyniających się do jego rozwoju¹².

Poliomawirus komórek Merkla (MCPyV)

Najbardziej znaczącym odkryciem w etiologii raka z komórek Merkla było zidentyfikowanie w 2008 roku wirusa polioma komórek Merkla (MCPyV). Wirus ten jest wykrywany w ok. 80% przypadków MCC, co sugeruje jego kluczową rolę w patogenezie³⁴. MCPyV to powszechny wirus, z którym większość populacji ma kontakt we wczesnym dzieciństwie, jednak sam wirus rzadko prowadzi do rozwoju nowotworu⁵⁶.

Mechanizm onkogenezy związanej z MCPyV obejmuje dwa kluczowe etapy: integrację genomu wirusa z genomem gospodarza oraz mutacje prowadzące do ekspresji skróconych antygenów T wirusa, które nie pozwalają na replikację wirusa, ale stymulują wzrost komórek⁷. Białka wirusowe mogą hamować funkcję genów supresorowych nowotworów, co prowadzi do niekontrolowanego wzrostu komórek⁸. U osób z prawidłowo funkcjonującym układem odpornościowym wirus pozostaje pod kontrolą immunologiczną, natomiast u osób z osłabionym układem odpornościowym może dochodzić do jego aktywacji i transformacji nowotworowej⁹.

Ekspozycja na promieniowanie UV

Drugim istotnym czynnikiem w etiologii MCC jest ekspozycja na promieniowanie ultrafioletowe (UV). Około 20% przypadków MCC wiąże się bezpośrednio z uszkodzeniami DNA spowodowanymi przez promieniowanie UV¹⁰. Promieniowanie UV, zarówno z naturalnych źródeł (słońce), jak i sztucznych (łóżka opalające, fotochemioterapia PUVA), powoduje charakterystyczne mutacje w DNA (tzw. sygnatura UV), szczególnie w genach supresorowych nowotworów i genach odpowiedzialnych za naprawę DNA¹¹¹².

Związek między MCC a promieniowaniem UV jest dobrze udokumentowany. Indeks promieniowania słonecznego UV jest pozytywnie skorelowany z częstością występowania MCC. Nowotwór ten często pojawia się na skórze chronicznie eksponowanej na słońce u osób starszych. Ponadto, zwiększona częstość występowania MCC obserwowana jest u osób poddawanych fotochemioterapii UVA¹³.

Co ciekawe, promieniowanie UV może odgrywać rolę zarówno w MCC związanym z wirusem, jak i w przypadkach niezwiązanych z wirusem. W MCC związanym z MCPyV, ekspozycja na UV może przyczyniać się do lokalnej immunosupresji, natomiast w przypadkach niezwiązanych z wirusem, UV bezpośrednio powoduje uszkodzenia DNA¹⁴.

Immunosupresja

Osłabiony układ odpornościowy stanowi istotny czynnik ryzyka rozwoju raka z komórek Merkla. Osoby z obniżoną odpornością mają około 15-krotnie wyższe ryzyko rozwoju MCC w porównaniu do osób z prawidłowo funkcjonującym układem odpornościowym¹⁵¹⁶. Stan immunosupresji może być spowodowany przez:

Choroby autoimmunologiczne jak reumatoidalne zapalenie stawów¹⁷
Zakażenie HIV lub AIDS¹⁸
Choroby nowotworowe układu krwiotwórczego, szczególnie przewlekłą białaczkę limfocytową (CLL)¹⁹
Leki immunosupresyjne stosowane po przeszczepach narządów (azatiopryna, cyklosporyna, cyklofosfamid, inhibitory mTOR)²⁰
Leki biologiczne o działaniu immunosupresyjnym, w tym inhibitory TNF stosowane w chorobach autoimmunologicznych²¹

Obserwacje te sugerują, że sprawny układ odpornościowy odgrywa kluczową rolę w kontroli zarówno infekcji MCPyV, jak i w rozpoznawaniu oraz eliminowaniu komórek nowotworowych²².

Czynniki demograficzne i genetyczne

Istnieje kilka czynników demograficznych, które zwiększają ryzyko rozwoju raka z komórek Merkla²³:

Wiek – MCC występuje najczęściej u osób powyżej 50. roku życia, a mediana wieku w momencie diagnozy wynosi 75-79 lat. Około 80% pacjentów ma ponad 70 lat²⁴²⁵
Płeć – Mężczyźni chorują około dwukrotnie częściej niż kobiety, co może być związane z większą ekspozycją na promieniowanie słoneczne²⁶
Kolor skóry – Osoby o jasnej karnacji są znacznie bardziej narażone na rozwój MCC. Ponad 90% przypadków diagnozowanych jest u osób rasy białej, co prawdopodobnie wynika z mniejszej ochrony przed promieniowaniem UV u osób o jasnej skórze²⁷

Badania genetyczne wykazały, że w komórkach MCC często występują aberracje chromosomalne, w tym delecja krótkiego ramienia chromosomu 1 (1p36), jednak dokładne znaczenie tych zmian w rozwoju nowotworu pozostaje niejasne²⁸. Ponadto, w MCC niezwiązanym z wirusem obserwuje się mutacje w genach supresorowych nowotworów, takich jak TP53 i RB1²⁹³⁰.

Inne czynniki ryzyka

Istnieją dodatkowe czynniki, które mogą zwiększać ryzyko rozwoju raka z komórek Merkla:

Historia innych nowotworów skóry – Osoby z historią raka podstawnokomórkowego, kolczystokomórkowego lub czerniaka mają zwiększone ryzyko rozwoju MCC³¹
Ekspozycja na arsen – Długotrwała ekspozycja na wysokie stężenia arsenu może zwiększać ryzyko MCC³²³³
Ekspozycja na promieniowanie podczerwone – Narażenie na światło podczerwone z laserów lub lamp grzewczych może stanowić dodatkowy czynnik ryzyka³⁴
Przewlekłe choroby zapalne – Choroby powodujące przewlekły stan zapalny, takie jak łuszczyca, mogą przyczyniać się do rozwoju MCC³⁵

Różnice geograficzne i etiologiczne

Ciekawe jest to, że istnieją znaczące różnice geograficzne w etiologii MCC. W północnej półkuli większość przypadków MCC ma etiologię wirusową (związaną z MCPyV), natomiast w regionach o wysokiej ekspozycji na promieniowanie UV dominuje karcinogeneza związana z uszkodzeniami UV³⁶. Te obserwacje wskazują na złożoną interakcję między czynnikami środowiskowymi a biologicznymi w rozwoju tego nowotworu.

Pochodzenie komórkowe MCC

Wbrew swojej nazwie, rak z komórek Merkla prawdopodobnie nie wywodzi się bezpośrednio z komórek Merkla. Najnowsze badania sugerują, że MCC może powstawać z wczesnych komórek B (limfocytów) na podstawie morfologii komórkowej, ekspresji markerów wczesnych komórek B i klonalnego przegrupowania łańcuchów immunoglobulinowych³⁷. Inna hipoteza sugeruje, że MCC może pochodzić z pluripotencjalnych komórek macierzystych, co tłumaczyłoby jego związek z innymi nowotworami i możliwość różnicowania w kierunku różnych linii komórkowych (neuroendokrynnej, płaskonabłonkowej, przydatkowej i melanocytarnej)³⁸.

Implikacje kliniczne

Zrozumienie złożonej etiologii raka z komórek Merkla ma istotne implikacje kliniczne. Świadomość czynników ryzyka pozwala na identyfikację osób wymagających wzmożonej czujności i regularnych badań dermatologicznych. Ponadto, rozpoznanie różnic między MCC związanym z wirusem a MCC niezwiązanym z wirusem może prowadzić do opracowania bardziej spersonalizowanych strategii terapeutycznych³⁹.

Odkrycie roli układ odpornościowego w kontroli MCC doprowadziło do rozwoju immunoterapii, która zmienia podejście do leczenia tego nowotworu⁴⁰. Z kolei zrozumienie mechanizmów molekularnych związanych z infekcją MCPyV i transformacją nowotworową może prowadzić do opracowania nowych celowanych terapii⁴¹.

Podsumowanie etiologii

Etiologia raka z komórek Merkla jest złożona i obejmuje interakcję między czynnikami wirusowymi (MCPyV), środowiskowymi (ekspozycja na promieniowanie UV) oraz immunologicznymi (osłabiony układ odpornościowy). Około 80% przypadków MCC jest związanych z infekcją MCPyV, natomiast pozostałe 20% wynika głównie z uszkodzeń DNA spowodowanych przez promieniowanie UV⁴².

Rozumienie złożoności czynników przyczynowych MCC podkreśla znaczenie wielokierunkowego podejścia do zapobiegania i leczenia tego rzadkiego, ale agresywnego nowotworu skóry. Obejmuje to ochronę przed promieniowaniem UV, regularne badania dermatologiczne dla osób z grup ryzyka oraz odpowiednie monitorowanie osób z obniżoną odpornością⁴³.

Dalsze badania nad etiologią MCC są niezbędne do pełnego zrozumienia patogenezy tego nowotworu i opracowania skuteczniejszych strategii prewencyjnych i terapeutycznych⁴⁴.

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Materiały źródłowe

#1 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
Merkel cell carcinoma (MCC) pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. […] Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. […] In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. […] MCC carcinogenesis can be initiated by the clonal integration of the MCPyV genome or UV-mediated DNA damage caused by chronic exposure to sunlight. Of note, UV exposure could also play a part in viral carcinogenesis by causing local immunosuppression.
#2 Merkel Cell Carcinoma of the Skin – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK482329/
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with increasing incidence. Specific risk factors include ultraviolet (UV) exposure, advancing age, and immunosuppression, and its development is associated with Merkel cell polyomavirus (MCPyV) infection. […] Studies have established the presence of MCPyV in the majority (80%) of MCC, suggesting its role as an etiologic agent in carcinogenesis. […] UV exposure, advancing age, and immunosuppression are known risk factors for the development of MCC.
#3 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
Merkel cell carcinoma (MCC) pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. […] Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. […] In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. […] MCC carcinogenesis can be initiated by the clonal integration of the MCPyV genome or UV-mediated DNA damage caused by chronic exposure to sunlight. Of note, UV exposure could also play a part in viral carcinogenesis by causing local immunosuppression.
#4 Facts About Merkel Cell Carcinoma | Fred Hutchinson Cancer Center
https://www.fredhutch.org/en/diseases/merkel-cell-carcinoma/facts-resources.html
Merkel cell carcinoma is usually caused in part by an extremely common and typically harmless virus that was discovered in 2008, the Merkel cell polyomavirus. […] Another very important cause is extensive exposure to sunlight, possibly many years earlier, especially in white people with fairer skin. […] About 80% of MCC cases are caused by the virus, and about 20% are caused by extensive sun damage. […] People who have significant, prolonged suppression of their immune system (such as after a kidney or heart transplant or due to infection with human immunodeficiency virus, HIV) are at high risk of MCC, but over 90% of MCC patients have no known problem with their immune system. […] MCC is more common after age 65.
#5 Merkel Cell Carcinoma Risk Factors | American Cancer Society
https://www.cancer.org/cancer/types/merkel-cell-skin-cancer/causes-risks-prevention/risk-factors.html
Having a risk factor for Merkel cell carcinoma (MCC), or even many risk factors, doesn’t mean that you will get it. Most people with risk factors never get MCC, while others with this disease may have few or no known risk factors. […] The Merkel cell polyomavirus (MCV) is found in the cancer cells of about 8 out of 10 people with Merkel cell carcinoma. MCV is a common virus. Most people are infected with it at some point (often as children). But the infection doesn’t cause symptoms, and it rarely leads to MCC. Because of this, there are no recommended screening tests or treatments for MCV infection. […] For example, it’s not clear how exactly how it might cause MCC, or why there are so few cases of MCC when infection with MCV is very common. […] Exposure to ultraviolet (UV) rays is thought to be a major risk factor for most skin cancers, including MCC. UV rays damage the DNA inside skin cells. When ongoing damage affects the DNA of genes that control skin cell growth, skin cancer can develop.
#6 Merkel Cell Carcinoma: Symptoms, Treatment, and More
https://www.verywellhealth.com/merkel-cell-carcinoma-overview-and-more-5199239
Biological sex: Men are more likely to develop MCC than women. […] History of skin cancer: Other skin cancers, such as melanoma, basal cell carcinoma, or squamous cell carcinoma, are associated with an increased risk for Merkel cell carcinoma. […] Researchers have recently discovered that a common virus, called Merkel cell polyomavirus, plays a role in the development of many Merkel cell carcinoma cases. This virus lives on the skin and doesnt cause symptoms. Because the virus is common and Merkel cell carcinoma is rare, experts say these other factors must contribute to the development of this cancer. […] Merkel cell polyomavirus, which was discovered in 2008, lives in the skin of most people without developing into cancer. Between 60% and 80% of Americans carry this virus. Researchers are still unsure how or why the virus causes Merkel cell carcinoma in some people.
#7 The biology and treatment of Merkel cell carcinoma: current understanding and research priorities | Nature Reviews Clinical Oncology
https://www.nature.com/articles/s41571-018-0103-2
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. […] In most parts of the world, the majority of MCCs are caused by the monoclonal integration of Merkel cell polyomavirus (MCPyV), and the remainder are associated with exposure to ultraviolet light. […] Oncogenic transformation by MCPyV is hypothesized to require two events: integration of the viral genome into the host genome and truncation of LT to render the viral genome incapable of replication. […] By contrast, VP-MCCs tend to have a low mutational burden, no definitive mutational signature and an absence of TP53 and RB1 mutations. […] The genomic changes observed in MCC have implications for the relative contributions of the major intracellular signalling cascades to tumorigenesis. […] The fact that MCC is either polyomavirus-positive (VP-MCC) or negative (VN-MCC) presents both unique opportunities and a therapeutic conundrum.
#8 Merkel Cell Carcinoma: Symptoms, Causes, Stages & Treatment
https://my.clevelandclinic.org/health/diseases/17971-merkel-cell-carcinoma
UV light exposure, a weak immune system, age and viral infection may cause this cancer. […] Exposure to ultraviolet (UV) light and other risk factors can cause these cells to become cancerous and grow uncontrollably. […] UV rays from sun exposure or artificial light sources like tanning beds cause most types of skin cancer, including Merkel cell carcinoma. UV radiation can damage the genetic makeup, or DNA, of skin cells. […] Eight in 10 people with Merkel cell carcinoma have the Merkel cell polyomavirus (MCP). But most people infected with MCP don’t develop Merkel cell carcinoma. […] Research suggests a weakened immune system may not be able to suppress the virus. As a result, the virus causes skin cells to make a protein that turns off the genes that normally suppress the growth of tumors.
#9 Merkel Cell Carcinoma: Symptoms, Treatment and Prognosis
https://www.cancercenter.com/cancer-types/skin-cancer/types/merkel-cell-carcinoma
About 80 percent of Merkel cell carcinoma cases are caused by a skin virus called Merkel cell polyomavirus (MCPyV), and the rest likely by extensive UV damage. […] Although MCPyV infection is common among adults, not every individual infected with MCPyV develops Merkel cell carcinoma. Most healthy people can control MCPyV. However, immunocompromised individuals such as seniors or patients with human immunodeficiency virus (HIV) or other diseases affecting the immune system may lose control of the virus. A weakened immune system may lead to virus activation, which in turn may transform normal skin cells into cancerous ones. […] Seniors are more susceptible to development of Merkel cell carcinoma. The median age at diagnosis is 75 to 79 years old. In addition, increased sun exposure due to a depleted ozone layer may also drive the Merkel cell carcinoma rates up.
#10 Merkel Cell Carcinoma (MCC) > Fact Sheets > Yale Medicine
https://www.yalemedicine.org/conditions/merkel-cell-carcinoma-mcc
Merkel cell carcinoma is a rare type of skin cancer associated with the Merkel cell polyomavirus that usually develops on areas of skin that are exposed to the sun. […] Doctors dont yet know the exact cause of Merkel cell carcinoma. Researchers have identified two causes of the condition: […] Around 80% of cases of Merkel cell cancer in the U.S. are caused by infection by a virus called Merkel cell polyomavirus (MCPyV). […] In the U.S., around 20% of cases are attributed to exposure to ultraviolet radiation. Ultraviolet radiation damages DNA, resulting in mutations in certain genes involved in suppressing tumor formation and DNA repair. These mutations disrupt the function of these genes and lead to the development of Merkel cell carcinoma.
#11 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
Merkel cell carcinoma (MCC) pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. […] Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. […] In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. […] MCC carcinogenesis can be initiated by the clonal integration of the MCPyV genome or UV-mediated DNA damage caused by chronic exposure to sunlight. Of note, UV exposure could also play a part in viral carcinogenesis by causing local immunosuppression.
#12 Merkel Cell Carcinoma (MCC) > Fact Sheets > Yale Medicine
https://www.yalemedicine.org/conditions/merkel-cell-carcinoma-mcc
Merkel cell carcinoma is a rare type of skin cancer associated with the Merkel cell polyomavirus that usually develops on areas of skin that are exposed to the sun. […] Doctors dont yet know the exact cause of Merkel cell carcinoma. Researchers have identified two causes of the condition: […] Around 80% of cases of Merkel cell cancer in the U.S. are caused by infection by a virus called Merkel cell polyomavirus (MCPyV). […] In the U.S., around 20% of cases are attributed to exposure to ultraviolet radiation. Ultraviolet radiation damages DNA, resulting in mutations in certain genes involved in suppressing tumor formation and DNA repair. These mutations disrupt the function of these genes and lead to the development of Merkel cell carcinoma.
#13 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
The correlation between MCC and UV radiation is well documented: the solar UV index was positively associated with the incidence of MCC in the United States in 19861994 and 19861999. […] Additional evidence arises from the frequent occurrence of MCC in elderly patients on chronically sun-exposed skin, the increased MCC incidence in individuals treated with UVA photochemotherapy and the observation that many patients with MCC have a history of other skin cancers associated with sun exposure. […] However, a molecular UV signature (DNA mutations that are typically caused by UV damage, such as C to T transitions that occur in the context of di-pyrimidines) has been demonstrated only in a subset of cases of MCPyV MCCs; thus, the association with UV exposure in MCPyV+ MCC might be related to other factors, such as UV-induced immune suppression. […] Chronic inflammatory disorders such as rheumatoid arthritis are also associated with higher incidence of MCC. […] An association between MCC and chronic arsenic exposure has also been noted.
#14 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
Merkel cell carcinoma (MCC) pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. […] Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. […] In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. […] MCC carcinogenesis can be initiated by the clonal integration of the MCPyV genome or UV-mediated DNA damage caused by chronic exposure to sunlight. Of note, UV exposure could also play a part in viral carcinogenesis by causing local immunosuppression.
#15 Merkel Cell Carcinoma Risk Factors
https://www.skincancer.org/skin-cancer-information/merkel-cell-carcinoma/mcc-risk-factors/
Anything that increases your likelihood of developing a disease like Merkel cell carcinoma (MCC) is called a risk factor. […] Cancers are caused by DNA changes in cells. While scientists and researchers know the risk factors behind Merkel cell carcinoma, they are still working to gain a comprehensive understanding of precisely how these factors lead to the DNA changes that result in the disease. Since MCC does not seem to run in families, these DNA changes most likely happen during the course of a personâs life. […] Not only does UV exposure cause damage that increases your skin cancer risk; it also suppresses your immune system. This reduces its ability to repair damage and fight skin cancers and other diseases. […] If your immune system is persistently weakened or suppressed, you are about 15 times more likely to develop MCC than people with healthy immune systems.
#16 What Is Merkel Cell Carcinoma? Symptoms, Causes, Diagnosis, Treatment, and Prevention
https://www.everydayhealth.com/skin-cancer/what-is-merkel-cell-carcinoma-symptoms-causes-diagnosis-treatment-and-prevention/
A Weakened Immune System If your immune system is suppressed (as a result of HIV infection, chronic leukemia, or immunosuppressive drugs), you are about 15 times more likely to develop MCC than people with healthy immune function. […] Light Skin Color More than 9 out of 10 cases of MCC in the United States are diagnosed in whites.
#17 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
The correlation between MCC and UV radiation is well documented: the solar UV index was positively associated with the incidence of MCC in the United States in 19861994 and 19861999. […] Additional evidence arises from the frequent occurrence of MCC in elderly patients on chronically sun-exposed skin, the increased MCC incidence in individuals treated with UVA photochemotherapy and the observation that many patients with MCC have a history of other skin cancers associated with sun exposure. […] However, a molecular UV signature (DNA mutations that are typically caused by UV damage, such as C to T transitions that occur in the context of di-pyrimidines) has been demonstrated only in a subset of cases of MCPyV MCCs; thus, the association with UV exposure in MCPyV+ MCC might be related to other factors, such as UV-induced immune suppression. […] Chronic inflammatory disorders such as rheumatoid arthritis are also associated with higher incidence of MCC. […] An association between MCC and chronic arsenic exposure has also been noted.
#18 Update on Merkel Cell Carcinoma: Epidemiology, Etiopathogenesis, Clinical Features, Diagnosis, and Staging | Actas Dermo-SifiliogrÃ¡ficas
https://www.actasdermo.org/en-update-on-merkel-cell-carcinoma-articulo-S1578219016303407
The frequency is higher in immunocompromised individuals, especially after heart or kidney transplants; during immunosuppressant treatment with azathioprine, ciclosporin, cyclophosphamide, and mTOR (target of rapamycin) inhibitors; and in persons living with human immunodeficiency virus (HIV) infection. […] Risk for MCC is 13-fold higher in HIV-infected individuals than in the general population. […] The incidence of MCC has risen 3-fold in recent decades in the United States, from 0.15 per 100000 population in 1981 to 1.44 per 100000 population in 2011. […] The increase is attributable to greater awareness of the disease among dermatologists and pathologists; greater ease of diagnosis thanks to immunohistochemical techniques; and increased population risk due to UV light exposure, aging, and immunosuppression.
#19 Merkel cell cancer causes – wikidoc
https://www.wikidoc.org/index.php/Merkel_cell_cancer_causes
Common causes of merkel cell carcinoma include merkel cell polyomavirus, age, skin tone, exposure to sunlight and history of immunosuppression. […] Common causes of merkel cell carcinoma may include: Merkel cell polyomavirus […] Ultraviolet radiation especially UVB plays an important role in the developing merkel cell carcinoma. […] Fair skin people are more prone to merkel cell carcinoma. […] Especially patients with HIV positive patients, Organ transplant patients, Chronic lymphocytic leukemia (CLL), Lymphoproliferative disorders. […] The risk increases with the age and the median age is around 65 years or above. […] Merkel cell carcinoma is caused most commonly by mutation in TP53 gene mutations, Retinoblastoma (RB1) gene mutations.
#20 Update on Merkel Cell Carcinoma: Epidemiology, Etiopathogenesis, Clinical Features, Diagnosis, and Staging | Actas Dermo-SifiliogrÃ¡ficas
https://www.actasdermo.org/en-update-on-merkel-cell-carcinoma-articulo-S1578219016303407
The frequency is higher in immunocompromised individuals, especially after heart or kidney transplants; during immunosuppressant treatment with azathioprine, ciclosporin, cyclophosphamide, and mTOR (target of rapamycin) inhibitors; and in persons living with human immunodeficiency virus (HIV) infection. […] Risk for MCC is 13-fold higher in HIV-infected individuals than in the general population. […] The incidence of MCC has risen 3-fold in recent decades in the United States, from 0.15 per 100000 population in 1981 to 1.44 per 100000 population in 2011. […] The increase is attributable to greater awareness of the disease among dermatologists and pathologists; greater ease of diagnosis thanks to immunohistochemical techniques; and increased population risk due to UV light exposure, aging, and immunosuppression.
#21 Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel | Journal for ImmunoTherapy of Cancer
https://jitc.bmj.com/content/10/6/e004742
Patients affected by autoimmune diseases and treated with biologic immunosuppressives, including anti-tumor necrosis factor, are thought to have an increased risk of MCC development; taking into account a possible cause-effect relationship, after MCC diagnosis immediate discontinuation, at least for a limited time interval, or dose reduction or eventually replacement medication with less immunosuppressive burden should be considered.
#22 Merkel Cell Carcinoma Causes, Symptoms, and Treatments | UPMC
https://www.upmc.com/services/endocrinology/conditions/merkel-cell-carcinoma
Merkel cell tumors happen when the Merkel cell grows out of control. […] A healthy immune system can often recognize and destroy these abnormal Merkel cells. Weaker immune systems are less able to hunt down and destroy them. […] Some scientists think that a virus called Merkel cell polyomavirus (MCPyV) can lead to Merkel cell cancer. It may cause the tumor or increase the risk of getting it. […] Most people get MCPyV at some point. It usually causes no symptoms. Only a small number of people who get the virus get cancer.
#23 Merkel Cell Carcinoma Treatment – NCI
https://www.cancer.gov/types/skin/patient/merkel-cell-treatment-pdq
Merkel cell carcinoma is a very rare type of cancer that forms in the skin. […] Sun exposure and having a weak immune system affects the risk of developing Merkel cell carcinoma. […] Risk factors for Merkel cell carcinoma include: being exposed to a lot of natural sunlight, being exposed to artificial sunlight, such as from tanning beds or psoralen and ultraviolet A (PUVA) therapy for psoriasis, having an immune system weakened by disease, such as chronic lymphocytic leukemia or HIV infection, taking medicine that makes the immune system less active, such as after an organ transplant, having a history of other types of cancer, being older than 50 years, male, or White.
#24 Merkel Cell Carcinoma Risk Factors | American Cancer Society
https://www.cancer.org/cancer/types/merkel-cell-skin-cancer/causes-risks-prevention/risk-factors.html
The risk of Merkel cell cancer is much higher for White people than for Black or Hispanic people. Nearly all (more than 9 out of 10) MCCs are diagnosed in White people. This is probably because darker skin has a protective effect against the damaging effects of UV rays. […] The risk of Merkel cell carcinoma goes up as people get older. In fact, this cancer is very rare in people under the age of 50. About 8 out of 10 people with MCC are over age 70. […] Men are about twice as likely as women to develop Merkel cell carcinoma. The reason for this isn’t clear, but it might be because men tend to get more sun exposure. […] People with weakened immune systems (from certain diseases or medical treatments) are more likely to develop some types of cancer, including Merkel cell carcinoma. […] Some studies have suggested that long-term exposure to high levels of arsenic might increase the risk of Merkel cell cancer.
#25 Merkel Cell Carcinoma: Symptoms, Treatment and Prognosis
https://www.cancercenter.com/cancer-types/skin-cancer/types/merkel-cell-carcinoma
About 80 percent of Merkel cell carcinoma cases are caused by a skin virus called Merkel cell polyomavirus (MCPyV), and the rest likely by extensive UV damage. […] Although MCPyV infection is common among adults, not every individual infected with MCPyV develops Merkel cell carcinoma. Most healthy people can control MCPyV. However, immunocompromised individuals such as seniors or patients with human immunodeficiency virus (HIV) or other diseases affecting the immune system may lose control of the virus. A weakened immune system may lead to virus activation, which in turn may transform normal skin cells into cancerous ones. […] Seniors are more susceptible to development of Merkel cell carcinoma. The median age at diagnosis is 75 to 79 years old. In addition, increased sun exposure due to a depleted ozone layer may also drive the Merkel cell carcinoma rates up.
#26 Merkel Cell Carcinoma Risk Factors | American Cancer Society
https://www.cancer.org/cancer/types/merkel-cell-skin-cancer/causes-risks-prevention/risk-factors.html
The risk of Merkel cell cancer is much higher for White people than for Black or Hispanic people. Nearly all (more than 9 out of 10) MCCs are diagnosed in White people. This is probably because darker skin has a protective effect against the damaging effects of UV rays. […] The risk of Merkel cell carcinoma goes up as people get older. In fact, this cancer is very rare in people under the age of 50. About 8 out of 10 people with MCC are over age 70. […] Men are about twice as likely as women to develop Merkel cell carcinoma. The reason for this isn’t clear, but it might be because men tend to get more sun exposure. […] People with weakened immune systems (from certain diseases or medical treatments) are more likely to develop some types of cancer, including Merkel cell carcinoma. […] Some studies have suggested that long-term exposure to high levels of arsenic might increase the risk of Merkel cell cancer.
#27 Merkel Cell Carcinoma Risk Factors | American Cancer Society
https://www.cancer.org/cancer/types/merkel-cell-skin-cancer/causes-risks-prevention/risk-factors.html
The risk of Merkel cell cancer is much higher for White people than for Black or Hispanic people. Nearly all (more than 9 out of 10) MCCs are diagnosed in White people. This is probably because darker skin has a protective effect against the damaging effects of UV rays. […] The risk of Merkel cell carcinoma goes up as people get older. In fact, this cancer is very rare in people under the age of 50. About 8 out of 10 people with MCC are over age 70. […] Men are about twice as likely as women to develop Merkel cell carcinoma. The reason for this isn’t clear, but it might be because men tend to get more sun exposure. […] People with weakened immune systems (from certain diseases or medical treatments) are more likely to develop some types of cancer, including Merkel cell carcinoma. […] Some studies have suggested that long-term exposure to high levels of arsenic might increase the risk of Merkel cell cancer.
#28 Merkel Cell Tumors of the Head and Neck: Overview, Pathophysiology and Etiology, Clinical Features
https://emedicine.medscape.com/article/853565-overview
Although evidence suggests a causative link between MCV and MCC, further research is needed to evaluate the absolute risk of cancer. […] Risk factors for MCC include exposure to sun and UV light. MCC appears to be correlated with the UV-B index. […] Immunosuppression appears to be a significant risk factor for MCC. […] MCC has a notable genetic component. […] The most common abnormality is deletion of the short arm of chromosome 1 (1p36). […] The relevance of these chromosomal changes and their effect on cancer development remains unclear.
#29 Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel | Journal for ImmunoTherapy of Cancer
https://jitc.bmj.com/content/10/6/e004742
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine carcinoma with disputed origin, high risk of recurrence and aggressive behavior. […] Moreover, a special correlation between MCC and the Merkel cell polyomavirus (MCPyV) was discovered in 2008. This virus is an enveloped double-stranded DNA polyomavirus that infects most of the human population asymptomatically. However, it has been speculated that in the elderly and/or immunocompromised subjects it can cause MCC. The integrated viral genomes express mutant MCPyV tumor antigens that are crucial for driving the oncogenic development of MCC. […] The virus-related MCC is well distinguished from the non-virus-related MCC, whose pathogenesis is mainly driven by ultraviolet (UV) radiation and whose most frequent mutations are in tumor-suppressor genes such as RB1, TP53 and genes encoding member of Notch family.
#30 Merkel cell cancer causes – wikidoc
https://www.wikidoc.org/index.php/Merkel_cell_cancer_causes
Common causes of merkel cell carcinoma include merkel cell polyomavirus, age, skin tone, exposure to sunlight and history of immunosuppression. […] Common causes of merkel cell carcinoma may include: Merkel cell polyomavirus […] Ultraviolet radiation especially UVB plays an important role in the developing merkel cell carcinoma. […] Fair skin people are more prone to merkel cell carcinoma. […] Especially patients with HIV positive patients, Organ transplant patients, Chronic lymphocytic leukemia (CLL), Lymphoproliferative disorders. […] The risk increases with the age and the median age is around 65 years or above. […] Merkel cell carcinoma is caused most commonly by mutation in TP53 gene mutations, Retinoblastoma (RB1) gene mutations.
#31 Merkel Cell Carcinoma – Symptoms | Causes | Diagnosis | Treatment | prevention
https://www.icliniq.com/articles/cancer/merkel-cell-carcinoma
Doctors are still not sure what causes Merkel cell carcinoma. This carcinoma begins in the Merkel cells, the cells found in the epidermis (the outermost layer of the skin). […] Recently, a common virus was found to play a role in causing Merkel cell carcinoma. This virus, Merkel cell polyomavirus, lives on the human skin and does not result in any signs or symptoms, and how it causes this carcinoma is not yet determined. As this is a common virus and MCC is so rare, it is most likely that other risk factors play a role in forming MCC. […] The following factors may increase the risk of a person developing Merkel cell carcinoma: […] Excessive Sunlight Exposure – No matter the source of UV (ultraviolet) light, both natural sunlight and artificial light (light from tanning beds) increase the risk of Merkel cell carcinoma. […] Advanced Age – The majority of patients diagnosed with MCC are above the age of 50 years. […] Lighter Skin Tone – Those with a fair skin tone more commonly develop Merkel cell carcinoma than those with a darker skin tone. […] Weak Immunity – People with a weakened immune system, such as those infected with HIV (human immunodeficiency virus), cancer patients, and those taking immunosuppressants, are at more risk of MCC. […] A History of Other Skin Cancers – People with a history of basal cell carcinoma, squamous cell carcinoma, or other skin cancers are more at risk of developing Merkel cell carcinoma. […] Infection With Merkel Cell Polyomavirus – Almost eight out of ten patients diagnosed with MCC have this virus present in the cancerous cells.
#32 Merkel Cell Carcinoma Risk Factors | American Cancer Society
https://www.cancer.org/cancer/types/merkel-cell-skin-cancer/causes-risks-prevention/risk-factors.html
The risk of Merkel cell cancer is much higher for White people than for Black or Hispanic people. Nearly all (more than 9 out of 10) MCCs are diagnosed in White people. This is probably because darker skin has a protective effect against the damaging effects of UV rays. […] The risk of Merkel cell carcinoma goes up as people get older. In fact, this cancer is very rare in people under the age of 50. About 8 out of 10 people with MCC are over age 70. […] Men are about twice as likely as women to develop Merkel cell carcinoma. The reason for this isn’t clear, but it might be because men tend to get more sun exposure. […] People with weakened immune systems (from certain diseases or medical treatments) are more likely to develop some types of cancer, including Merkel cell carcinoma. […] Some studies have suggested that long-term exposure to high levels of arsenic might increase the risk of Merkel cell cancer.
#33 Markel Cell Carcinoma Causes Clear Skin Clinic
https://www.clearskin.london/skin-conditions/markel-cell-carcinoma/causes/
Recently it was discovered that the medicine methoxsalen contributed to the development of cancer in some patients. Methoxsalen has been known to contribute to the slow but definite development of cancer in patients. […] Diseases like AIDS and lymphocytic leukaemia, weaken the immune system, leaving your body vulnerable to serious diseases. […] Infrared light or arsenic exposure increases the risk of having MCC when exposed to it. It could be from the environment or the workplace. In some cases, there have been traces of arsenic in well water that people drink.
#34 Merkel Cell Cancer | Cedars-Sinai
https://www.cedars-sinai.org/health-library/diseases-and-conditions/m/merkel-cell-cancer.html
Not protecting your skin from the sun […] Having light-colored skin […] Being over age 50 […] Being male […] Having a weakened immune system, such as from some types of blood cancer, HIV, or caused by medicines used with an organ transplant […] Arsenic exposure […] Infrared light exposure, such as lasers or heat lamps.
#35 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
The correlation between MCC and UV radiation is well documented: the solar UV index was positively associated with the incidence of MCC in the United States in 19861994 and 19861999. […] Additional evidence arises from the frequent occurrence of MCC in elderly patients on chronically sun-exposed skin, the increased MCC incidence in individuals treated with UVA photochemotherapy and the observation that many patients with MCC have a history of other skin cancers associated with sun exposure. […] However, a molecular UV signature (DNA mutations that are typically caused by UV damage, such as C to T transitions that occur in the context of di-pyrimidines) has been demonstrated only in a subset of cases of MCPyV MCCs; thus, the association with UV exposure in MCPyV+ MCC might be related to other factors, such as UV-induced immune suppression. […] Chronic inflammatory disorders such as rheumatoid arthritis are also associated with higher incidence of MCC. […] An association between MCC and chronic arsenic exposure has also been noted.
#36 Merkel cell carcinoma
https://pmc.ncbi.nlm.nih.gov/articles/PMC6054450/
Merkel cell carcinoma (MCC) pathogenesis is associated with either the presence of Merkel cell polyomavirus or chronic exposure to ultraviolet light (UV), which can cause a characteristic pattern of multiple DNA mutations. […] Notably, in the Northern hemisphere, the majority of MCC cases are of viral aetiology; by contrast, in areas with high UV exposure, UV-mediated carcinogenesis is predominant. […] In fact, UV exposure is probably involved in both viral-mediated and non-viral-mediated carcinogenesis, by contributing to immunosuppression or DNA damage, respectively. […] MCC carcinogenesis can be initiated by the clonal integration of the MCPyV genome or UV-mediated DNA damage caused by chronic exposure to sunlight. Of note, UV exposure could also play a part in viral carcinogenesis by causing local immunosuppression.
#37 Merkel cell carcinoma
https://dermnetnz.org/topics/merkel-cell-carcinoma
Merkel cell polyomavirus (MCPyV) has been detected in about 80% Merkel cell carcinomas tested. […] It is thought that the virus causes gene mutations leading to Merkel cell carcinoma when immune function is defective. […] The virus-negative tumours are associated with high exposure to ultraviolet radiation, due to the occurrence of the tumour on sun-exposed skin. […] Immunosuppression is an important factor for the development of Merkel cell carcinomas. […] Merkel cell carcinoma was previously believed to arise from Merkel cells, which are pressure receptors in the skin. A recent investigation is pointing to their origin being early B-cells (lymphocytes) based on cellular morphology, the expression of early B-cell markers and clonal immunoglobulin chain rearrangement.
#38 Merkel Cell Carcinoma Associated with In situ and Invasive Squamous Cell Carcinoma | HTML | Acta Dermato-Venereologica
https://www.medicaljournals.se/acta/content/html/10.2340/00015555-0563
Merkel cell carcinoma (MCC) is an uncommon neuroendocrine malignant neoplasm whose origin has not been well documented. […] Suggested causes or risk factors for the association with Bowens disease include chronic exposure to arsenic or other harmful chemicals, and excessive radiation. […] The origin of cutaneous MCC has not yet been elucidated. Although the most commonly accepted hypothesis is an origin from the Merkel cell, a mechanoreceptor located at the basal layer of the epidermis, some authors propose a pluripotential cell as the origin of this type of tumour. […] The possibility of considering MCC arising from a pluripotential stem cell is supported by the association between MCC and other neoplasms and by the divergent differentiation (neuroendocrine, squamous, adnexal and melanocytic) described in some MCC. […] Although the induction of a second neoplasm by the first tumour cannot be excluded, the most probable explanation is that we are dealing with a collision tumour, either coincidental or because they share some common aetiopathogenic agents or risk factors that have not yet been identified.
#39 The biology and treatment of Merkel cell carcinoma: current understanding and research priorities | Nature Reviews Clinical Oncology
https://www.nature.com/articles/s41571-018-0103-2
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. […] In most parts of the world, the majority of MCCs are caused by the monoclonal integration of Merkel cell polyomavirus (MCPyV), and the remainder are associated with exposure to ultraviolet light. […] Oncogenic transformation by MCPyV is hypothesized to require two events: integration of the viral genome into the host genome and truncation of LT to render the viral genome incapable of replication. […] By contrast, VP-MCCs tend to have a low mutational burden, no definitive mutational signature and an absence of TP53 and RB1 mutations. […] The genomic changes observed in MCC have implications for the relative contributions of the major intracellular signalling cascades to tumorigenesis. […] The fact that MCC is either polyomavirus-positive (VP-MCC) or negative (VN-MCC) presents both unique opportunities and a therapeutic conundrum.
#40 Skin cancer types: Merkel cell carcinoma causes
https://www.aad.org/public/diseases/skin-cancer/types/common/merkel-cell/causes
Its believed that a weakening immune system is the reason MCC usually develops after 65 years of age and why the risk of developing this skin cancer continues to increase with age. […] Two scientists discovered this virus in 2008 while studying MCC. What they learned is that people in the United States who develop MCC often have both: A weakened immune system, The MCP virus. […] It may be that the years of UV damage to the skin and a weakened immune system cause the virus to mutate (change). These changes to the virus may cause MCC. More research is needed find out whether this happens. […] While there are still plenty of questions to be answered, the discovery that that the immune system plays a key role in MCC is changing the way this cancer is treated.
#41 Merkel Cell Carcinoma – Causes, Symptoms, Diagnosis, Treatment & Prevention
https://www.medindia.net/health/conditions/merkel-cell-carcinoma.htm
The cause of MCC is still unknown, though long-term sun exposure and infection with Merkel cell polyomavirus (MCV) has been suggested. […] Factors that increase the risk of Merkel cell carcinoma are: Age 50 years, majority of the patients are over 70 years of age, Male gender, UV rays exposure – exposure to excessive and prolonged sunlight and to tanning beds, Light skin colour – the cancer is more common in white people, Low immunity states – e.g. patients who have undergone organ transplant or suffer from AIDS or chronic lymphocytic leukaemia, Psoriatic patients treated with ultraviolet A (PUVA) or psoralen. […] Merkel cell carcinoma may be caused by Merkel cell polyomavirus. […] Merkel cell carcinoma caused by Merkel cell polyomavirus is a rare type of skin cancer which can now be treated with a triple drug immunotherapy.
#42 Facts About Merkel Cell Carcinoma | Fred Hutchinson Cancer Center
https://www.fredhutch.org/en/diseases/merkel-cell-carcinoma/facts-resources.html
Merkel cell carcinoma is usually caused in part by an extremely common and typically harmless virus that was discovered in 2008, the Merkel cell polyomavirus. […] Another very important cause is extensive exposure to sunlight, possibly many years earlier, especially in white people with fairer skin. […] About 80% of MCC cases are caused by the virus, and about 20% are caused by extensive sun damage. […] People who have significant, prolonged suppression of their immune system (such as after a kidney or heart transplant or due to infection with human immunodeficiency virus, HIV) are at high risk of MCC, but over 90% of MCC patients have no known problem with their immune system. […] MCC is more common after age 65.
#43 Merkel Cell Carcinoma of the Skin | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/25006
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with increasing incidence. Specific risk factors include ultraviolet (UV) exposure, advancing age, and immunosuppression, and its development is associated with Merkel cell polyomavirus (MCPyV) infection. […] Studies have established the presence of MCPyV in the majority (80%) of MCC, suggesting its role as an etiologic agent in carcinogenesis. […] UV exposure, advancing age, and immunosuppression are known risk factors for the development of MCC. […] The exact mechanism of carcinogenesis remains unclear. MCPyV infection is present in the majority of tumors, and several studies have demonstrated a causal relationship. Impaired immune surveillance, which may occur through factors such as aging, immunosuppressive medications, or AIDS, may facilitate the tumorigenicity of MCPyV. Integration of the virus into host DNA must be accompanied by specific mutations, which are thought to result from environmental mutagens, such as UV irradiation. These events contribute to the transformation of an asymptomatic viral infection into a tumorigenic infection. The remaining virus-negative tumors are thought to acquire multiple UV-signature mutations and have a much higher mutational burden than MCPyV-positive tumors.
#44 Merkel Cell Carcinoma Causes, Symptoms and Treatment
https://www.netmeds.com/health-library/post/merkel-cell-carcinoma-causes-symptoms-and-treatment?srsltid=AfmBOord8TIObmOnzSOK931Yn3SF0U_Riozjj8jCunEcfrH7WxDR1-5K
Just like any other form of cancer, the exact cause of Merkel cell carcinoma is yet unknown, but reports suggest that they usually begin in the Merkel cells, which are found at the base of the epidermis, the outermost layer of the skin. […] Although there are no solid proofs, in some cases Merkel cell carcinoma has been found associated with people suffering from a type of viral infection, named Merkel cell polyomavirus which usually resides on the skin.