Delisha Doppa 1

BIOL-110-04- Biology Of Human Cancer

Merkel Cell Carcinoma

1) Epidemiology:

Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine skin cancer

heavily associated with UV Exposure. Consequently, individuals who live in regions of

the world closer to the equator (experience more sunlight) are more likely to develop

MCC. Therefore, MCC varies from location to location, like any other cancer does.

Infection related cancers are often more common in the Eastern World, while in the

Western World where infection is more controlled, hormonal/reproductive cancers are

common. (e.g prostate or breast cancer)

Merkel cells are very rare, neuroendocrine cells found at the base of the epidermis. They

are at the end of nerve endings and are associated with neural development and tactile

sensation (the sense of touch). (1) MCC is most prominently seen in older caucasian

males in southwestern US as skin cancer is very common there. (2) This also relates to

how with age, mutations accumulate. In addition, cancer strikes when the immune system

is weak– whether that be in infants or seniors. In the case of MCC, it is mostly seen in

seniors. “MCC incidence increased exponentially with age, from 0.1 to 1.0 to 9.8 (per

100,000 person-years) between age groups 40–44, 60–64, 85+ years, respectively. Due to

aging of the “baby-boom” generation, US MCC incidence is predicted to climb to 2,835

cases in 2020 and 3,284 cases in 2025.”(3) Perhaps with the development of new medical

technologies to help combat MCC, or cancer in general, MCC incidence can be lowered.

These technologies should put a stop to the causation of tumorigenicity through UV

exposure. Often, UV rays cause cells to mutate and transform into malignant, unstable
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cells. Thus, UV exposure is seen as a human skin carcinogen, and must highly be

avoided. Although scientists can’t say that UV exposure causes cancer, they can only

correlate.

The first and most prominent risk factor of MCC is UV/sun exposure. As said earlier, UV

exposure causes cells to mutate, and genetic changes to DNA occur. This sets off a set of

events that can possibly lead to cancer. The sun is a very common UV light source, as it

emits UV rays. Other UV rays can come from tanning beds, or anything artificial similar

to that. UV exposure has been linked to the concept of persistent irritation before. The

concept of persistent irritation was created by a scientist Rudolf Virchow in 1850 after

observing the work of an english scientist named Potts. During that time, young boys

would get in chimneys to clean them while being naked. Soot is very carcinogenic, but no

one knew at the time. The boys ended up getting scrotal (skin) cancer. Virchow later

explained this as persistent irritation. What happened was that their cells became very

irritated which caused damage to their body. It caused their cells to divide more, which

led to higher mutation rates. This theory can relate to UV exposure too. UV rays can

cause a lot of damage to cells and to DNA. (4)

Another risk factor of MCC includes immunosuppression. Immunosuppression is heavily

associated with old age, as said earlier. With old age, comes a weakened immune system.

Poor survival of MCC is heavily corresponded with a weak immune system, and vice

versa. In addition, UV exposure can induce immunosuppressive effects. MCC in

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younger patients can occur, but if it does, usually those patients are immunosuppressed

(can be organ transplant recipients or even have HIV/AIDS) (5).

Another significant risk factor is old age. Age is one of the most significant risk factors of

the majority of cancers. Age is very connected to cancer as with age, mutations

accumulate. Compared to a younger patient, an older patient is more likely to have a

more severe/developed case of MCC as they have been exposed to more sunlight than a

younger patient.

2) Types Of Cancer:

Merkel Cell Carcinoma is a non-melanoma skin cancer. “Non-melanoma skin

cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC)

and Merkel cell carcinoma (MCC).” (6) In all non-melanoma skin cancers physical

exposure to deadly carcinogens are common. Unique to MCC, the presence of Merkel

Cell Polyomavirus Infection (MCPyV) in the genome will inevitably lead to MCC. For

BCC and SCC “Other risk factors for the development of BCC and SCC include

concurrent diseases and dedicated treatments (i.e., psoriasis), chronic exposure to human

papilloma virus, drug-induced immune suppression in transplanted patients and targeted

agents for the treatment of other cancer types (notably, melanoma).” (6) These differ

greatly when compared to MCC.

Merkel Cell Polyomavirus Infection (MCPyV) is a crucial component of MCC.

One can even consider it a risk factor. MCPyV has been present in MCC tumors, which

led scientists to believe that MCPyV must be present for MCC to occur. “Persistent

expression of MCPyV T antigens from the integrated viral genome is required for MCC
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tumor cells to survive. Together, these findings provide strong support for a causal role of

MCPyV in the development of MCC skin cancer.” (7) MCPyV and MCC have a strong

connection with one another, and hopefully in the future scientists will examine this

connection, and come up with ways to prevent MCC from developing. Being exposed to

MCPyV isn’t really preventable as it is a virus, but scientists can hopefully prevent MCC

from being induced.

3) Studies:

In a study conducted by McArdle Laboratory for Cancer Research, a 3D tissue

culture was used to study MCPyV’ specific role in causing MCC to arise. They used this

system to replicate MCPyV and MCC on human skin. They looked at biomarkers for

both the polyvirus and the cancer, and looked for keratinocytes and fibroblasts markers as

well. “Although our studies identified several raft setups that developed MCC-like

lesions, we identified one (Setup 6), in which MCPyV+ MCC cells suspended in collagen

between the epithelial and dermal equivalents, which best recapitulated the

histopathology of human MCC, based on the high frequency and large size of the

MCC-like lesions. Our 3D in vitro co-culture studies further illuminate that the

development of MCC-like lesions from MCPyV+ MCC cells in organotypic rafts does

not depend upon the presence of human keratinocytes.” (8)

Another study was conducted on both felines and canines (dogs and cats). It has

been speculated that in canines, MCC becomes more benign, while in felines, MCC is

more aggressive. Risk factors for felines and canine for MCC haven't been identified yet.

They came to the conclusion that, “although feline and canine MCC share histological
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features with their human counterpart, the current findings are not consistent with the

hypothesis that MCCs in dogs and cats derive from early B cells. The

immunohistochemistry panel confirms a neuroendocrine origin.” (9) The difference of

aggressiveness in MCC between both felines and canines can be due to many things. The

main one being, that they are fundamentally and biologically different. Felines might

have specific enzymes that react differently compared to canines. This concept alo varies

to humans as well. All humans have different enzymes, and react differently to different

things.

Therapy Options:

The primary therapy options for MCC are surgery and chemotherapy, like many

other cancers. Usually, if a patient's MCC is treatable, their physician would recommend

chemotherapy, and then surgery. If it is more advanced, then just chemotherapy. Chemo

doesn’t do a lot in these certain cases. In the specific case of surgery, “ A wide local

excision, with sentinel node (SLN) biopsy, is the recommended treatment of choice. If

SLN is involved, nodal dissection should be performed; unless the patient is unfit, then

regional radiotherapy can be given.” (10) If the node comes back positive, the patient

goes to chemo. It's hard to determine if chemo really helps in the particular case of MCC,

as it is already so rare, and there aren’t a lot of studies regarding it. “Surgery is the

mainstay of treatment for MCC. Radiotherapy is an inferior option for cancer control

since the complete response of gross disease of MCC to radiotherapy is only 75%.” (11)

Radiotherapy and chemo are considered inferior, because they are ineffective. MCC is a

very aggressive cancer, and is hard to “cure”. This causes surgeons to be cautious of
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MCC. Mohs micrographic surgery has been created to more accurately excise tumors

developed by MCC, and is being tested.

Another therapy that is starting to come up is “checkpoint inhibitors”(CPI). CPIs

fall under the umbrella of immunotherapy. “​A

​ s treatment options for the loco-regional

form have already been standardized, there are no therapeutic agents specifically

approved for the treatment of the advanced form of MCC, and treatment choice is often

based on data available from retrospective series and prospective randomized controlled

trials [32]. In the metastatic setting, chemotherapy has limited efficacy, but advances in

immunotherapeutics are likely to have a major impact on the management and outcomes

of MCC.” (12) It is predicted that CPIs will help greatly specifically in metastatic cases

of MCC. Essentially, CPIs will block PD-1 and PD-L1 (programmed cell death receptor 1

being PD-1, and programmed cell death ligand 1 being (PD-L1) (12)) With CPIs

blocking these, it is likely to make CPIs in the specific case of MCC more successful in

eroding the tumors.

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