Mycosis fungoides
Template:Short description Template:Cs1 config Template:Infobox medical condition Mycosis fungoides, also known as Alibert-Bazin syndrome or granuloma fungoides,<ref>Template:WhoNamedIt</ref> is the most common form of cutaneous T-cell lymphoma. It generally affects the skin, but may progress internally over time. Symptoms include rash, tumors, skin lesions, and itchy skin.
While the cause remains unclear, most cases are not hereditary. Most cases are in people over 20 years of age, and it is more common in men than women. Treatment options include sunlight exposure, ultraviolet light, topical corticosteroids, chemotherapy, and radiotherapy.
Signs and symptoms
The symptoms of mycosis fungoides are categorized into three clinical stages: the patch stage, the plaque stage, and the tumour stage.<ref name="Harvey_2015">Template:Cite journal</ref> The patch stage is defined by flat, reddish patches of varying sizes that may have a wrinkled appearance. They can also look yellowish in people with darker skin.<ref name="Harvey_2015" /> The plaque stage follows the patch stage of mycosis fungoides.<ref name="Hristov_2019">Template:Cite journal</ref> It is characterized by the presence of raised lesions that appear reddish-brown; in darker skin tones, plaques may have a greyish or silver appearance.<ref name="Cerroni_2018">Template:Cite journal</ref> Both patch and plaque stages are considered early-stage mycosis fungoides.<ref name="Hristov_2019" /> The tumour stage typically shows large irregular lumps. Tumours can develop from plaques or normal skin in any region of the body, including the face and head regions.<ref name="Valipour_2020">Template:Cite journal</ref>
The symptoms displayed are progressive, with early stages consisting of lesions presented as scaly patches. Lesions often initially develop on the trunk of the body in places that are rarely exposed to the sun, such as the buttocks.<ref name="Harvey_2015" /> These lesions can start as insignificant patches and may remain undiagnosed for up to a decade.<ref>Template:Citation</ref> Hypopigmentation (when the skin is lighter than normal) of lesions are less common but can be found in children, adolescents and/or dark-skinned individuals.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
The advanced stage of mycosis fungoides is characterized by generalized erythroderma (red rash covering most of the body) with severe pruritus (itching) and scaling.<ref name="Cerroni_2018"/> Itching (pruritus) is the most commonly reported symptom of people experiencing mycosis fungoides with up to 88% of people reporting varying intensities of pruritus that typically worsens as the disease progresses.<ref>Template:Cite journal</ref> Those that experience intense pruritus commonly indicate that it negatively affects their quality of life emotionally, functionally and physically.<ref>Template:Citation</ref>
Mycosis fungoides (MF) and Sézary syndrome (SS) are related conditions, with the same type of cancer T-lymphocytes, that initially grow in different body compartments. SS cells are found mainly in the blood, whereas MF typically involves the skin. In advanced stages of MF, the cancer cells move from the skin into other organs and the bloodstream; this progression is referred to as "leukemic mycosis fungoides", "Sézary syndrome preceded by mycosis fungoides", or "secondary mycosis fungoides".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Cause
Mycosis fungoides is caused by abnormal white blood cells (T-lymphocytes). These abnormal cells have a preference for localizing and proliferating uncontrolled in the outer layer of the skin (epidermis). The abnormal cells may later involve other organs such as the lymph nodes. It is hypothesized that the genetic mutations in these cancer cells lead to increased growth and escape from programmed cell death.<ref>Template:Cite journal</ref>
Additionally, the disease is an unusual expression of CD4 T cells, a part of the immune system. These T cells are skin-associated, meaning they are biochemically and biologically most related to the skin, in a dynamic manner. Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL), but there are many other types of CTCL that have nothing to do with mycosis fungoides and these disorders are treated differently.<ref>Template:Cite journal</ref>
Diagnosis
Diagnosis often requires a combination of clinical and pathological studies. Diagnosis is sometimes difficult because the early phases of the disease often resemble inflammatory dermatoses (such as eczema, psoriasis, lichenoid dermatoses including lichen planus, vitiligo, and chronic cutaneous lupus erythematosus), as well as other cutaneous lymphomas.<ref name="Cerroni_2018"/> Several biopsies are recommended, as the key microscopic features are often absent in early MF, and a complete diagnosis requires a combination of clinical and histological study.<ref>Template:Cite journal</ref> It is important to note that misdiagnosis is common for this condition and dermatologists who mistakenly identify early-stage MF as common inflammatory skin conditions, such as psoriasis, may administer prolonged treatment with topical steroids or immunosuppressive drugs without obtaining a biopsy or proper follow-up, which can obscure the underlying disease.<ref name="Real-Life Barriers to Diagnosis of">Template:Cite journal</ref> Similarly, general practitioners, who manage skin conditions, may incorrectly treat non-classical MF lesions with antifungal creams, further complicating the diagnosis when the lesions fail to respond to the treatment.<ref name="Real-Life Barriers to Diagnosis of"/> Furthermore, long periods of treatment can alter the biopsy findings, making it difficult to distinguish from other inflammatory dermatoses.<ref name="Cerroni_2018" />
Childhood Mycosis fungoides makes up 0.5% to 7.0% of cases.<ref name="Jung_2021a">Template:Cite journal</ref> Although data on childhood MF is limited, a 2021 systematic review observed that there is a significant delay in the diagnosis of childhood MF which may negatively affect a child's prognosis. Notably, most pediatric persons with MF present with early-stage disease.<ref name="Jung_2021a"/> Moreover, the initial signs of MF in women are often seen on areas like the buttocks, thighs, and breasts, where the lesions may be easily overlooked due to their subtle appearance and placement.<ref name="Beigi_2017a" /><ref name="Real-Life Barriers to Diagnosis of"/> Interestingly, MF is less common in women than in men, and women tend to present with earlier-stage disease.<ref name="Assessing Health-Related Quality of">Template:Cite journal</ref> A review of the National Cancer Database revealed that women with MF have higher 5- and 10-year survival rates compared to men.<ref name="Assessing Health-Related Quality of"/> Even after accounting for age and disease stage, women still show a survival advantage.<ref name="Assessing Health-Related Quality of"/> This suggests that biological differences in women may provide a protective effect, though further research is needed to understand the mechanisms behind this gender-related prognosis difference.<ref name="Assessing Health-Related Quality of"/>
Histology
The criteria for the disease are established on the skin biopsy by the presence of the following:<ref>Template:Cite book</ref>
- Presence of cancer cells with twisted contours (cerebriform nuclei)
- In the patch and plaque stages, the cancer cells are seen in the epidermis (the most superficial layer of skin).<ref name="Vaidya_2021">Template:Cite book</ref> This is referred to as epidermotropism.
- Pautrier's microabcesses, aggregates of four or more atypical lymphocytes arranged in the epidermis. Pautrier microabcesses are characteristic of mycosis fungoides but are generally absent.
- In the tumour stage, the cancer cells move into the dermis (the deeper layer of skin)<ref name="Vaidya_2021" />
- Large cell transformation, where clonally identical lymphocytes in the lesion exhibit hypertrophy. In transformed cells, presence of the CD30 receptor is associated with improved survival<ref>Template:Cite journal</ref>
To stage the disease, various tests may be ordered, to assess nodes, blood and internal organs, but most patients present with disease apparently confined to the skin, as patches (flat spots) and plaques (slightly raised or 'wrinkled' spots).
Peripheral smear will often show buttock cells.<ref name="O'Connell2013">Template:Cite book</ref>
Laboratory Tests
The laboratory diagnosis of MF includes a comprehensive metabolic panel (CMP) and complete blood count (CBC) with differential, with a manual slide review to detect Sézary cells, which show characteristic cerebriform nuclei.<ref name="Beigi_2017a">Template:Cite book</ref> Liver function tests assess potential extracutaneous involvement, while uric acid and lactate dehydrogenase (LDH) levels serve as markers for aggressive disease.<ref name="Beigi_2017a" /><ref name="Diagnostics in mycosis fungoides an">Template:Cite journal</ref> Flow cytometry identifies malignant T-cell clones, and T-cell receptor (TCR) gene rearrangement testing confirms clonal expansion if blood involvement is suspected.<ref name="Beigi_2017a" /><ref name="Diagnostics in mycosis fungoides an"/> Additional tests, such as HIV and HTLV-1 screening, should be considered in patients from endemic regions, as HTLV-1 has been linked to some MF cases.<ref name="Beigi_2017a" />
Imaging
- In the early stages of mycosis fungoides, imaging includes posteroanterior (PA) and lateral chest X-rays, along with ultrasound to examine peripheral lymph nodes.<ref name="Beigi_2017a" />
- For cases progressing beyond stage IIA, contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis should be performed for further assessment.<ref name="Beigi_2017a" /><ref name="Multidisciplinary Approach to the D">Template:Cite journal</ref>
- Positron emission tomography-computed tomography (PET-CT) may be used for additional disease monitoring.<ref name="Beigi_2017a" /><ref name="Multidisciplinary Approach to the D"/>
Staging
Traditionally, mycosis fungoides has been divided into three stages: premycotic, mycotic and tumorous. The premycotic stage clinically presents as an erythematous (red), itchy, scaly lesion. Microscopic appearance is non-diagnostic and represented by chronic nonspecific dermatosis associated with psoriasiform changes in epidermis.Template:Medical citation needed
In the mycotic stage, infiltrative plaques appear and biopsy shows a polymorphous inflammatory infiltrate in the dermis that contains small numbers of frankly atypical lymphoid cells. These cells may line up individually along the epidermal basal layer. The latter finding if unaccompanied by spongiosis is highly suggestive of mycosis fungoides. At this stage, biopsies can reveal medium to large lymphocytes with convoluted, cerebriform nuclei in the epidermis, which are larger than the lymphocytes typically seen in inflammatory dermatoses. These atypical lymphocytes are mature skin-homing CD4+ T cells, and their presence in the epidermis is a key feature of early MF. Additionally, the cells may form microabscesses in the epidermis, known as Pautrier's microabscesses.<ref name="Beigi_2017a" /> In the tumorous stage a dense infiltrate of medium-sized lymphocytes with cerebriform nuclei expands the dermis.Template:Cn
Accurate staging of mycosis fungoides is essential to determine appropriate treatment and prognosis.<ref name="Jawed_2014">Template:Cite journal</ref> Staging is based on the tumor, node, metastasis, blood (TNMB) classification proposed by the Mycosis Fungoides Cooperative Group and revised by the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer.<ref name="Jawed_2014" /> This staging system examines the extent of skin involvement (T), presence of lymph node (N), visceral disease (M), and presence of Sezary cells in the peripheral blood (B).<ref name="Jawed_2014" />
Most patients with mycosis fungoides have early-stage disease (Stage IA-IIA) at the time of their initial diagnosis.<ref name="Jawed_2014" /> People with early stage disease that is primarily confined to the skin have a favorable prognosis.<ref name="Jawed_2014" /> People with advanced stage (Stage IIB-IVB) are often refractory to treatment and have an unfavorable prognosis.<ref name="Jawed_2014" /> Treatment options for people with advanced stage disease are designed to reduce tumor burden, delay disease progression, and preserve quality of life.<ref name="Jawed_2014" />
French dermatologist, Vidal and Barocq introduced and used the term "MF d'emblée" for cases of MF that were presenting with tumours without the usual preceding plaques or patches.<ref>Template:Cite journal</ref><ref name="Khan Mohammad Beigi_2017" /> This was believed to have represented other cases of Cutaneous T-cell Lymphomas (CTCLs) rather than MF.
Treatment
The most commonly recommended first-line treatment for mycosis fungoides is psoralen plus ultraviolet A (PUVA therapy).<ref name="Valipour_2020" /> PUVA is a photochemotherapy that involves topical or oral administration of the photosensitizing drug psoralen followed by skin exposure to ultraviolet radiation.<ref>Template:Cite journal</ref> Systemic treatments of mycosis fungoides often lead to resistance; as such, additional treatment options are often necessary in advanced disease.<ref name="Blackmon_2020">Template:Cite journal</ref>
Other treatments have been suggested, however, larger and more extensive research is needed to identify effective treatment strategies for this disease.<ref name="Valipour_2020" /> Suggested treatments include light therapy, ultraviolet light (mainly NB-UVB 312 nm), topical steroids, topical and systemic chemotherapies, local superficial radiotherapy, the histone deacetylase inhibitor vorinostat, total skin electron radiation, photopheresis, systemic therapies (e.g. retinoids, rexinoids), and biological therapies (e.g. interferons). Treatments are often used in combination.<ref name="Valipour_2020" /> Due to the possible adverse effects of treatment options in early disease it is recommended to begin therapy with topical and skin-directed treatments before progressing to more systemic therapies.<ref name="Valipour_2020" /> In 2010, the U.S. Food and Drug Administration granted orphan drug designation for naloxone lotion, a topical opioid receptor competitive antagonist used as a treatment for pruritus in cutaneous T-cell lymphoma.<ref name="CTCL">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Mogamulizumab is a CCR4 monoclonal antibody which has been shown to improve progression-free survival. It was approved by the US FDA in 2018 for use in people with relapsed or refractory mycosis fungoides or Sézary disease.<ref name="Blackmon_2020" />
There is no evidence to support the use of acitretin or extracorporeal photopheresis (ECP: a type of phototherapy) for treating people with mycosis fungoides.<ref name="Valipour_2020" /> There is also no evidence to support the combination treatment of PUVA and intralesional IFN-α or PUVA and bexarotene.<ref name="Valipour_2020" />
Children
Treatment for adults and children with mycosis fungoides often differs because of the safety profiles of modalities.<ref name="Jung_2021a"/> Narrowband UV-B is commonly considered for children, as opposed to Psoralen with UV-A, mechlorethamine hydrochloride, or oral bexarotene, which is often used in adults.<ref name="Jung_2021a" />
Prognosis
A 1999 US-based study of people with CLL's medical records observed a 5-year relative survival rate of 77%, and a 10-year relative survival rate of 69%.<ref name="WeinstockReynes1999" /> After 11 years, the observed relative survival rate remained around 66%.<ref name="WeinstockReynes1999" /> Poorer survival is correlated with advanced age and black race. Superior survival was observed for married women compared with other gender and marital-status groups.<ref name="WeinstockReynes1999">Template:Cite journal</ref> The complete remission rate in children is nearly 30%.<ref name="Jung_2021a" />
Epidemiology
It is rare for mycosis fungoides to appear before age 20; the average age of onset is between 45 and 55 years of age for people with patch and plaque disease only, but is over 60 for people who present with tumours, erythroderma (red skin) or a leukemic form (Sézary syndrome). Mycosis fungoides is more common in males than in females with differences in incidence across various racial groups reported in different studies.<ref>Template:Cite journal</ref> The incidence of mycosis fungoides was seen to be increasing between 2000 and 2020,<ref>Template:Cite journal</ref> although certain regions have demonstrated some stabilization.<ref>Template:Cite journal</ref>
The global age adjusted incidence of Mycosis Fungoides is approximately 6-7 cases for every 1 million people, with rates varying across regions and ethnicities.<ref name="Beigi_2017b">Template:Cite book</ref> Racial disparities amongst Mycosis Fungoides diagnosis have been seen to be higher in African American populations when compared to Caucasian populations in America.<ref name="Beigi_2017b" /> With the mean diagnosis age being 49.3 in African Americans and 60.0 in Caucasians.<ref>Template:Cite journal</ref>
Research indicates that early-onset MF cases are less likely to occur with approximately 0.5% - 5% of all MF cases being diagnosed before the age of 20.<ref>Template:Cite journal</ref><ref name="Beigi_2017c">Template:Cite book</ref> Gender disparities are present in juvenile cases as well, with there being a male-to-female ratio of 2:1, indicating a higher rate amongst males in this age demographic.<ref>Template:Cite journal</ref><ref name="Beigi_2017c" />
History
Mycosis fungoides was first described in 1806 by French dermatologist Jean-Louis-Marc Alibert.<ref name="Bolognia">Template:Cite book</ref><ref>Template:Cite book</ref> The name mycosis fungoides is very misleading—it loosely means "mushroom-like fungal disease". The disease, however, is not a fungal infection but rather a type of non-Hodgkin's lymphoma. It was so named because Alibert described the skin tumors of a severe case as having a mushroom-like appearance.<ref name="Zinzani_2008">Template:Cite journal</ref>
In 1814, Alibert named the disease Pian fungicides because of the visual similarity to the treponemal disease Yaws, also known as Pian.<ref name="Khan Mohammad Beigi_2017">Template:Cite book</ref>
See also
- Cutaneous T-cell lymphoma
- Pagetoid reticulosis
- Premycotic phase
- Sézary's disease
- Secondary cutaneous CD30+ large cell lymphoma
- Angiocentric lymphoma
- List of cutaneous conditions
References
Further reading
External links
Template:Diseases of the skin and appendages by morphology Template:Hematological malignancy histology