Mycosis fungoides C84.0

Most common (about 50% of all cutaneous T-cell lymphomas/CTCL), chronic progressive, phasic, primary cutaneous T -cell lymphoma (low-malignant T-cell lymphoma) originating from CD4-positive, small to medium-sized T-cells (T-helper lymphocytes).

Functionally, neoplastic T helper cells are associated with a TH2 pattern characterized by a corresponding cytokine profile(IL-4, IL-5, IL-10) with possible consecutive eosinophilia and a potential immunoglobulin increase (IgE, IgA).

See clinical picture.

• Special forms and (partly controversial) clinical and histological variants of Mycosis fungoides:
  • Elastolytic T-cell lymphoma (is assessed differently as an entity)
  • Folliculotropic Mycosis fungoides (synonym: Follicular Mycosis fungoides; MF with follicular mucinosis; Alopecia mucinosa; Mucinosis follicularis s.there)
  • Syringotropic Mycosis fungoides (see below folliculotropic Mycosis fungoides)
  • Granulomatous mycosis fungoides (see also lymphoma, cutaneous T-cell lymphoma, elastolytic = granulomatous slack skin)
  • Pagetoid reticulosis
  • Erythrodermal mycosis fungoides (synonym: Sézary syndrome).
• descriptions of individual cases:
  • Mycosis fungoides with dermal mucin deposits
  • Bullous/dyshidrotic mycosis fungoides
  • Pustulous Mycosis fungoides
  • Hyper- and hypopigmented (poikilodermatic) mycosis fungoides
  • Ichthyosiform Mycosis fungoides
  • Purpura pigmentosa-like mycosis fungoides
  • Perioral dermatitis-like mycosis fungoides
  • Hyperkeratotic-caused Mycosis fungoides
  • Vegetative/papillomatous Mycosis fungoides

Incidence: 0.4-0.5/100,000/inhabitant/year.

Unknown so far. Excessive proliferation mostly of T-helper cells (see below peripheral T-cell lymphomas). Whereas in the context of immunological homeostasis there is a constant immigration and emigration of lymphocytes into the skin organ, this balance is disturbed in MF.

There is a pathological accumulation of CD4-positive T lymphocytes, a "skin-homing" in the uppermost layer of the skin. In some cases, patients show an increased allergic reaction of type IV, which suggests an increased activity of T-helper cells. Here, the production of chemokines by keratinocytes plays a decisive role.

In the early phase of the disease, T-lymphocytes accumulate around the epidermal Langerhans cells and form abscess-like clusters, which appear as Pautrier's microabscesses under the light microscope. In addition to the "skin-homing" properties, activated T cells can also become secretorially active and thus intervene immunomodulatory in the inflammatory process. Furthermore, neoplastic T cells show a reduction of apoptosis, which delays their degradation.

An increased colonization rate with Staphylococcus aureus also appears to be of pathogenetic significance (see also atopic eczema). Their toxins belonging to the superantigens are able to stimulate T-cells in a special way. An eradication is recommended from this point of view.

Onset in the 5th-7th decade of life (mean age of onset 55-60 years).

Rarely in childhood (age range 20-90 years).

Progression over several years (decades).

Men are affected 1.5-2 times more frequently than women.

Torso and flexor-sided thighs, flexor-sided upper arms, especially proximal third. In late stages, the entire integument is affected.

Clinically diverse and variable picture (mean time interval from first symptoms to diagnosis: 4.2 years!). Skin symptoms are initially in the foreground, systemic involvement is only detectable after a longer clinical course. The clinical course of mycosis fungoides is roughly divided into 3 stages, which can generally occur one after the other, but can also occur side by side:

• Initial stage (pre-mycosis stage) ("patch-stage"):
  • Usually few (< 10), rarely solitary, stationary patches occurring in areas not exposed to the sun (chest, flexor side of the upper arms and thighs, other parts of the trunk e.g. flanks). The face is rarely affected in the early stages!
  • Sharply defined, extensive (length > 5.0 cm; width > 3.0 cm), aligned in the lines of cleavage of the skin, either homogeneous red or red-brown spots/erythema with a wrinkled surface (like cigarette paper). A colorful surface pattern (poikilodermatic) with intralesional, alternating brown, brown-red and white patches and telangiectasias is also possible.
  • Clinically uncharacteristic, eczema-like picture, moderate or absent itching. Minor to absent, mostly small-spotted scaling. The skin lesions remain stable in number and size for years. Exposure to sunlight and local glucocorticoid therapy often leads to significant improvement, but not to healing.
    
• Plaque stage:
  • Suspicious sign of impending progression of the lymphoma is an increasing, stronger "inflammation" of the patches and emphasized poikilodermatic aspect as well as an increasing increase in consistency.
  • Increasing itching.
  • Increasing scaling.
  • Large-area plaques with significantly increased consistency. The previously "eczema-like" foci, which are more noticeable in untanned skin and can disappear completely in summer, increasingly increase their clinical presence with constant localization. They spread, with a tendency to confluence and an increasing increase in consistency.
  • Color: bright red.
  • Lymphadenopathy is possible and usually non-specific.
  • Infestation of the capillitium may cause alopecia.
  • Diagnosis can now be confirmed both clinically and histologically.
  • At this stage of the disease, mycosis fungoides is increasingly perceived by the patient as a threatening "disease".
    
• Tumor stage:
  • Red, mushroom-shaped or lobulated, bulging nodules in plate-like, thickened, arcuately configured, lesional skin; tendency to ulceration.
  • Therapeutically hardly controllable itching, severe in affected skin.
  • Specific lymph node infestation.
  • Infestation of internal organs (liver, spleen) is possible.
  • Increasingly marked disturbance of the general condition with febrile episodes.
  • Tendency to septic bacterial and viral infections (frequent cause of death).
    
    

Concomitant symptoms of mycosis fungoides:

• Mucosal involvement: Possible in any phase; in particular of the oral mucosa, tongue, tonsils, nasal cavities, pharynx.
• Organ involvement: Involvement of the spleen, liver, lungs, gastrointestinal tract or CNS in later stages of the disease. Note: Organ involvement is an indication of a change in the "homing behavior" of the tumor cells.

Variants of mycosis fungoides:

• Pagetoid reticulosis: Misnomer for a localized, low-malignant cutaneous T-cell lymphoma with unusually pronounced epidermotropy. Clinically, a distinction is made between a localized and a disseminated type.
• Folliculotropic mycosis fungoides: Rare variant of mycosis fungoides with follicularly accentuated, grater-like surface texture
• Syringotropic mycosis fungoides: Rare variant with preferential infiltration of the eccrine sweat glands.
• Granulomatous slack skin: Very rare granulomatous variant (< 100 cases in the world literature) of a usually CD4-positive, cutaneous T-cell lymphoma, which is characterized by granulomatous tissue formations and loss of elastic fibres. The prognosis for this variant is worse than for the classic form (5-year survival rate around 60%).

• Hypopigmented mycosis fungoides: Rare poikilodermatic variant with a good prognosis, which is mainly observed in children (skin type IV-VI according to Fitzpatrick).

• Erythrodermic mycosis fungoides: Erythroderma can occur in the advanced stage of mycosis fungoides. More rarely, it is a primary erythrodermic onset of mycosis fungoides. In this case, differentiation from Sezary syndrome would be difficult.

• Unilesional and palmoplantar forms of mycosis fungoides. They are difficult to diagnose both clinically and histologically. They are usually only suspected due to their resistance to therapy and the later appearance of plate-like infiltration of the lesions.

Discontinuation of local or systemic glucocorticoid therapy is important for histopathological evaluation!

Initial or patch stage: Variable density, band-like or lichenoid, subepidermal infiltrate of small, epidermotropic, neoplastic CD4+ lymphocytes, a mixture of non-neoplastic CD4- and CD8+ lymphocytes and dendritic cells. Eosinophilic granulocytes and histiocytes are present in varying densities. Plasma cells are usually absent! Typical: Pearl cord-like accumulation of lymphocytes at the dermo-epidermal junction zone(lining-up phenomenon). Moderate epidermotropy of atypical lymphoid and monocytoid cells into the epidermis. The invaded cells often appear enlarged in the epidermis and are surrounded by an optically empty halo (halo cells). Typical spongiosis is absent; so is marked parakeratosis (distinguishing it from eczema). Pautrier's microabscesses are detectable, but rather rare at this stage.

Plaque stage: Dense, dermal (papillary and reticular dermis) infiltrate of atypical, small but also medium-sized lymphocytic cells. Eosinophilic granulocytes and histiocytes are present in varying densities. Marked epidermotropy with formation of Pautrier's microabscesses (characteristic of this phase). The epidermis is not infrequently acanthotic with parakeratotic keratinization. Frequent adnexotropia (follicles and sweat glands) with destruction of the adnexa.

Tumor stage: Dense, diffuse or nodular, dermal or even subcutaneous infiltrate of atypical, medium-sized, lymphocytic cells. Eosinophilic granulocytes and histiocytes in varying density. High mitotic activity (MIB 1). Sporadically also immunoblasts or large anaplastic CD30+ cells. Mostly still marked epidermotropy. Pautric microabscesses may occur but are never obligate. Epidermotropism may be completely absent at this stage of development! The epidermis is acanthotic but also atrophic. Parakeratotic keratinization. The follicles are often destroyed. In the infiltrate, epithelial regenerates of the follicles are not infrequently detectable.

In about 25% of cases, transformation into diffuse large cell lymphoma occurs at the tumor stage, which may be either CD30- or CD30+. The prognosis is then significantly worse. The histological picture is then identical to primary cutaneous T-cell lymphomas, which occur without precursor stages.

Recent studies show that CD4-CD8-negative lymphocytes can immunohistochemically indicate an early form of mycosis fungoides.

The diagnosis is made clinically. Accurate tumor staging is necessary for disease definition (see table). In addition to routine laboratory and organ analysis, diagnosis confirmation and tumor staging is performed by histologic, immunohistologic, molecular biologic, and imaging radiologic (CT/nuclear spin studies) and sonographic examinations.

• Immunophenotyping: This allows differentiation between T and B cell series; also detection of T cell subpopulations using CD4, CD8 and CD30 antibodies. Antibodies to CD45RO+ memory T lymphocytes are frequently detected in the early form of mycosis fungoides.
• T-cell receptor gene rearrangement: Diagnostically important (although not conclusive); detection of monoclonality of T-cell infiltrates possible by this method.
• FACS analysis: diagnostically important: in cases of v.a. leukemic course (always in Sézary syndrome).
• Lymph node diagnostics: Sonographic examination of lymph nodes close to the skin; if necessary, lymph node biopsy and fine tissue diagnostics.
• Bone marrow biopsy: Since bone marrow involvement is rare in the early forms of CTCL (T1-3, N0-1, M0), this diagnostic procedure can generally be omitted.

The clinical differential diagnosis of mycosis fungoides depends on the clinical stage of the disease and also its clinical variants (see classification below). Therefore, this chapter will not contain a generally valid differential diagnosis.

Initial stage: Very different clinical pictures appear depending on the stage of development and spread of the spots. An important indicator sign is the longitudinal alignment of the spots in the cleavage lines (tension lines) of the skin. This macro-pattern is common to only a few diseases(see there).

• Parapsoriasis en plaques: Few (on average up to 6) usually only discrete inflammatory, larger (usually more than 10 cm in diameter), roundish or oval, sharply demarcated, little scaling spots or plaques. Longitudinal axes usually aligned with the cleavage lines. Frequently precursors of mycosis fungoides. Histologic workup.
• Microbial eczema: Initially usually small, reddish-brownish, pruritic, red scaly or crusty papules or papulo-vesicles. Gradual growth in size to sharply or indistinctly circumscribed, 1.0-6.0 cm, red coin-like ("nummular eczema") plaques with yellowish crusts or scaly crusts. No nodule formation. The clear "eczema character" speaks against the diagnosis "mycosis fungoides". Further histological clarification!
• Psoriasis vulgaris: The classic extension pattern of distribution speaks against mycosis fungoides. Also the typical psoriasis phenomena like Auspitz- and Köbner-phenomenon are always missing.
• Eczema, atopic: Important here is the history with the typical type I allergies; in the eczematoid form there are scaly, partly eroded, scratched and crusted different red plaques. Marked pruritus is always present. Histology: typical eczema morph.
• Pityriasis rosea: truncal, relapsing exanthema lasting 1-2 weeks; oriented along the cleavage lines (Christmas tree pattern), foci: 0.2-1.0 cm, oval or elongated, little raised, scaly plaque. Acuity of the manifestations argues against mycosis fungoides.

Plaque stage: A plaque stage will always be combined with premycotic (eczema-like) changes in the classic course. In this respect, this picture is characterized by a diversity of manifestations. Histological and immunohistological confirmation will always be necessary to clinically confirm the diagnosis.

• Pseudolymphoma of the skin: Rather monomorphic appearance. No history of many years. Histology not with the typical changes of mycosidic infiltrate.
• Leukemias of the skin: Very different clinical pictures, mostly exanthematous spread. No staged course as in mycosis fungoides. No poikiloderma.
• Lupus erythematosus tumidus: Mostly disseminated, chronically stationary, 0.5-5.0 cm in size, red, usually not hypersensitive, sharply demarcated papules and plaques with smooth shiny, non-scaling surface. Marked photosensitivity. No stage-like progression as in mycosis fungoides.
• Urticaria pigmentosa: Flat, oval or round, grayish-brown or brown patches of varying size with urticarial reaction (this phenomenon is completely absent in mycosis fungoides). Frequent elevated dermographism.
• Tinea corporis: Only in untreated extensive forms is this differential diagnosis considered. Marginal foci, pruritus, scaling; native and cultural piz detection.

Tumor stage:

• Other cutaneous T-cell lymphomas: In this case, the phasic course is absent. Mostly primary nodule formation. Histology is demonstrative.
• Cutaneous B-cell lymphoma: In this case, the phasic sequence is absent. Mostly primary nodularity. Histology is conclusive.

Therapy depends on the individual clinical stages of mycosis fungoides. Aggressive therapy modalities in the early stages of the disease have not proven successful! There is a risk of tumor enhancement.

Thus, in stage IA, the expectional concept of "watchful waiting" is rightly followed by most dermatologic experts.

A distinction must be made between local and systemic measures, which can be combined. Basically, the following therapeutic modalities can be considered (see also table):

• Glucocorticoids, external or systemic
• Climatic therapy
• Heliotherapy (UVB; SUP)
• PUVA therapy, systemic or as bath PUVA
• Interferon alfa as monotherapy or in combinations
• Retinoids in combination with PUVA therapy
• Chemotherapeutic agents externally or systemically
• Photopheresis (extracorporeal)
• Brentuximab vedotin (Adcetris®): Approved since 2017 for the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy [Wiley, JDDG Supplement No. 8/2018].
• Chloromethine gel (Valchlor® = mechlorethamine) approved since 2019: 1 x / day.
• Experimental: Interleukin-12: Experimental study approaches with first positive results include therapeutic modalities with recombinant interleukin-12 in clinical stage 1A, 1B, IIA (2 times/week 300 ng/kg bw s.c., maintenance dose: 100 ng/kg bw s.c.).

Radiological therapy methods are successful (targeted irradiation with fast electrons) for unilesional or few foci and are rightly used.

In the generalized patch or plaque stage (T2-3), whole-body electron irradiations are an important therapeutic option (ED 1.5-2.0Gy; GD <30Gy). In several studies, complete remissions of 75% were achieved in stage T2 and 47% in stage T3.

"Indolent course". The duration of the premycotic stage can be from 5 years to more than 20 years. Regressions and recurrences are possible.

5-year survival rate: 66.1%

10-year survival rate: 43.2%

Mean survival rate (all stages): 11.4 years

Mean survival rate (stage-dependent):

• T2 patients: 12.1 years
• T3/T4 patients: 3-4 years
• N0 patients: 17,5 years
• N1 patients: 6.5 years
• N2 patients: 1.7 years
• B0 patients: 12.3 years
• B1 patients: 3.0 years.

Staging of mycosis fungoides

Tumour stage Ia and Ib: clinical examination and palpation of the lymph nodes every 6-12 months.

In more advanced stages, closer monitoring with imaging (lymph node sonography, CT thorax/abdomen) and laboratory chemistry (differential blood count, FACS analysis) diagnostics.

The term mycosis fungoides should be used only for the classic "Alibert-Bazin" type. An early form of mycosis fungoides can be evaluated according to an algorithm elaborated by Pimpinelli et al (> 4 points = mycosis fungoides probable):

• Clinic:
  • Persistent or progressive patches or plaques (1 point).
  • Localization not sun-exposed/large area, poikilodermic (1 point).
• Histology:
  • Superficial lymphoid infiltrate, cellular and nuclear atypia, epidermotropism (1 point)
• Molecular Biology:
  • Clonal T-cell pattern (1 point)
• Immunohistology:
  • < 50% of T cells express CD2, Cd3 and/or CD5.
  • < 10% CD7 (1 point)
  • Increased number of lymphocytes (CD2, CD3, CD5, CD7) in the epidermis (disproportionate epidermotropism) (1 point).

The efficacy of pegylated liposomal doxorubicin for the treatment of mycosis fungoides has been described in several studies. Controversy continues to surround the efficacy of the therapy. In 2000, Wollina et al. reported a clinical response of 83% in a case report with 6 patients. Subsequent studies have also published similarly good results. However, the significance of these studies is limited by the small number of subjects.

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