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Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 27 of 40

CUTANEOUS T-CELL LYMPHOMA
Cutaneous T-cell lymphoma (CTCL) is a type of T-cell mediated dermatologic neoplasm which falls under
non-Hodgkin’s lymphoma [193] . Mycosis fungoides (MF) and Sézary syndrome (SS), the most frequently
diagnosed forms of CTCL, have become some of the most researched forms of non-melanoma skin
cancers. CTCLs are often misdiagnosed as benign skin conditions, such as atopic dermatitis or psoriasis [194] .
Understanding the various signaling pathways of CTCL is conducive to forming proper treatment plans
and prognoses. The goal of this section is to discuss the pathways in which CTCL arises and the treatment
options utilized for this form of non-melanoma skin cancer.

There are various theorized and studied pathways in which CTCL arises. The majority of these cases do
not progress to systemic malignancy, rather, it remains a mostly cutaneous cancer. Clinical features of
CTCL can be fairly variable. From erythrodermic exanthems to flesh colored papules, CTCL can present
in a number of cutaneous manifestations. There are a few exogenous factors to note that have been studied
to have an antigen induced CTCL reaction. A common pathway in which CTCL evades the body is via
the antigen-antibody mechanism. In the antigen-antibody mechanism, T-cells are consistently exposed
to specific antigens resulting in proliferation and failure to induce cellular apoptosis [195] . Not only are
medications thought to be provoking factors in antigens causing T-cell proliferation, but viral, bacterial,
and fungal antigens are also factors causing uncontrolled T-cell proliferation [195] . Some of these viral
antigens include human T-cell lymphoma virus, Epstein-Barr virus, and herpes simplex virus. In addition,
methicillin resistant Staphylococcus aureus (MRSA), Mycobacterium leprae, Chlamydia pneumoniae,
and even fungal dermatophytes can be inducing factors causing CTCL [196,197] . Furthermore, there is an
association between vitamin D deficiency, and even vitamin D receptor single nucleotide polymorphisms,
causing deficiencies within the system. Vitamin D is important for the function of many immune cells
including those of T cells. Paracrine communication between B and T lymphocytes, Cathledicin gene
regulation and innate immunity all function with the use of Vitamin D. Without properly regulated innate
and adaptive immunity, Staphylococcus aureus and other bacteria and viruses have a higher probability
of colonizing the skin while continuously priming and activating T lymphocytes. As mentioned earlier,
Staphylococcus aureus has a known association with CTCL meaning that Vitamin D and polymorphisms in
[198]
the VDR can indirectly have an association with CTCL .

Some studies have found association between atopy and CTCL with an IgE increase found in biopsies.
However, there is a need for further research in the subject of atopy and allergen-induced CTCL.

Extrinsic exposures
Various studies have determined that if the antigen producing agent is removed, then the CTCL
response will eventually eliminate itself. When comparing patients with CTCL and hypertension taking
hydrochlorothiazide to those with CTCL that are not taking hydrochlorothiazide, complete clearance
or improvement of their CTCL cutaneous lesions has been observed when hydrochlorothiazide is
withdrawn [195] . What is most important is that it is understood the different ways in which CTCL can
be treated. Disruption of specific pathways via monoclonal antibody addition, as well as removing an
antagonizing antigen, are just a couple examples in how this research has allowed for the elimination of this
cutaneous neoplasm.

MRSA has also been found to be an insult leading to CTCL. Moreover, the treatment of MRSA can lead
to improvement of CTCL. Patients with erythrodermic CTCL were discovered to have a decreased body
surface area affected when being treated for a MRSA infection [196] . This finding leads to the conclusion
that patients with erythrodermic CTCL have obtained a coinfection MRSA. Once treated, the cutaneous
manifestations dramatically decrease, thus, it is recommended that patients with CTCL be empirically
treated for a MRSA infection [196] .