List of Abbreviations
HIV – human immunodeficiency virus
LDH - lactate dehydrogenase
CTCL – cutaneous T-cell lymphomas
PUVA (Psoralen + UltraViolet A) – psoralen-ultraviolet A
PCR – polymerase chain reaction
TFD – total focal dose
TCR – T-cell receptor
TBI – total skin electron beam irradiation
US – ultrasound examination
Terms and Definitions
Mycosis fungoides (MF) – primary epidermotropic cutaneous T-cell lymphoma (CTCL), characterized by the proliferation of small to medium-sized T-lymphocytes with cerebriform nuclei.
ISCL – International Society for Cutaneous Lymphomas
EORTC – European Organisation for Research and Treatment of Cancer
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Mycosis fungoides (MF) – primary epidermotropic cutaneous T-cell lymphoma (CTCL), characterized by the proliferation of small to medium-sized T-lymphocytes with cerebriform nuclei.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The etiology of the disease is unknown. It is believed that cutaneous lymphomas develop as a result of chronic antigenic stimulation, leading to uncontrolled clonal proliferation and the accumulation of neoplastic T cells in the skin. Staphylococcus aureus is hypothesized to play a role in the pathogenesis of cutaneous lymphomas. Some researchers report the significance of Epstein-Barr virus and cytomegalovirus in the etiology of the disease. There is evidence of cutaneous lymphoma development in individuals receiving immunosuppressive therapy following organ transplantation and in HIV-infected patients.
1.3 Epidemiology of the Disease or Condition
Mycosis fungoides is the most common form of cutaneous T-cell lymphoma, accounting for 1% of all non-Hodgkin lymphomas, 50% of primary cutaneous lymphomas, and 65% of cutaneous T-cell lymphomas. The global incidence of mycosis fungoides is 6–7 cases per 10^6 per year, with a steady increase in recent decades. This rate varies significantly across geographic regions: in the USA, the incidence of mycosis fungoides is 0.46 cases per 100,000 population, while in European countries it ranges from 0.26 to 1.0 per 100,000 population per year (55% men and 45% women). More than 75% of mycosis fungoides cases are observed in patients older than 50 years, with the mean age of disease onset being 55–60 years. Mycosis fungoides can also affect children and adolescents (1% of cases). The male-to-female ratio is 2.0:1.0, with a predominance of patients with darker skin tones (1.7:1) [1,2].
1.4 Features of Coding the Disease or Condition
C84.0 – Mycosis fungoides.
1.5 Classification of the disease or condition
1. Mycosis fungoides (classic three-stage variant)
2. Other forms of mycosis fungoides:
a. included in the WHO classification of skin tumors:
- folliculotropic mycosis fungoides;
- pagetoid reticulosis;
- granulomatous slack skin syndrome.
b. rare variants:
- erythrodermic;
- follicular;
- syringotropic;
- bullous/vesicular;
- granulomatous;
- poikilodermatous;
- hyperpigmented;
- hypopigmented;
- unilesional;
- palmoplantar;
- hyperkeratotic/verrucous;
- vegetating/papillomatous;
- ichthyosiform;
- pigmented purpuric;
- pustular.
1.6 Clinical presentation of the disease or condition
In the classic variant of mycosis fungoides, the disease progresses through stages with an increasing extent of involvement and is divided into 3 clinical stages: patch (erythematous), plaque, and tumor.
The disease begins with macules (patches) of various sizes with well-defined borders, which are distributed asymmetrically and most commonly localize on the buttocks and sun-protected areas of the skin – the breasts, lower abdomen, axillary and inguinal folds, and the inner thighs and arms. The color of the patches ranges from pinkish-red to yellowish-orange and brown. The surface of the patches may be wrinkled (pseudoatrophic) and slightly lichenified; in the case of telangiectasia and pigmented areas, poikiloderma develops. In the erythematous stage, the disease may manifest as diverse and atypical erythema, urticarial, psoriasis- and parapsoriasis-like, or eczematoid rashes.
The plaque stage is characterized by the formation of infiltrated plaques of various sizes, yellowish-red or bluish in color. Their surface may be smooth, slightly scaling, or lichenified. Plaque formation is asymptomatic or accompanied by severe pruritus; sometimes their growth is uneven due to the peripheral portion, resulting in annular lesions. Plaques resolve slowly and unevenly, acquiring a annular shape as they clear in the center.
Clinical symptoms characteristic of the early stages of mycosis fungoides include:
- variability in the shape, size, and color of the rashes;
- phenomenon of simultaneous progression and regression of individual rashes;
- poikiloderma (patchy pigmentation, telangiectasia, skin atrophy);
- multiple rashes, multiple involvement zones;
- characteristic localization of rashes on skin areas not exposed to sunlight;
- pruritus accompanying the rashes [3–5].
In the tumor stage, the patient typically presents with a combination of patches, plaques, and tumors (nodules). Nodules may form both within existing plaques and on previously uninvolved skin. Their localization and number can vary from single to multiple. In the tumor stage, lymph nodes and internal organs may be affected [3,4].
Folliculotropic mycosis fungoides is an independent variant of mycosis fungoides characterized by the presence of folliculotropic infiltrates, often with sparing of the interfollicular epidermis and predominant involvement of the head and neck. Folliculotropic mycosis fungoides develops mainly in adults, but has also been described in children and adolescents. Males are affected more frequently than females. Skin lesions are located predominantly on the face and neck, where they are most pronounced. The disease may manifest as grouped follicular papules, patch-associated follicular lesions, dense plaques, or tumors. Other clinical manifestations include acneiform eruptions (comedones, cysts) and keratosis pilaris-like eruptions, which are localized mainly on the trunk and limbs. Skin involvement in folliculotropic mycosis fungoides is often associated with alopecia. In children, the disease most frequently manifests as hypopigmented, hair follicle-oriented patches and associated alopecia. A frequent and very characteristic sign of the disease is infiltrated plaques in the eyebrow area accompanied by hair loss. Pruritus is often very intense. Secondary bacterial infections are common. In rare cases, folliculotropic mycosis fungoides may present as solitary lesions (solitary or unilesional folliculotropic mycosis fungoides) or erythroderma [5].
Syringotropic mycosis fungoides is a rare variant of the disease that shares many features with folliculotropic mycosis fungoides. It is characterized by prominent involvement of eccrine glands, often associated with pilotropism. Skin lesions may be solitary or, more commonly, generalized [4].
Pagetoid reticulosis is a rare variant of mycosis fungoides characterized by localized patches or plaques with intraepidermal proliferation of neoplastic T-lymphocytes. The term pagetoid reticulosis should be used only for the localized type of the disease (Woringer-Kolopp type) and not for the disseminated type (Ketron-Goodman type), since currently in most patients with generalized eruptions the disease is considered a primary cutaneous CD8+ aggressive epidermotropic cytotoxic lymphoma, primary cutaneous gamma/delta T-cell lymphoma, or the tumor stage of mycosis fungoides [5]. Skin lesions in patients typically present as solitary, slowly progressing psoriasiform or hyperkeratotic plaques, usually localized on the extremities, most commonly on the hands and feet [5].
Granulomatous slack skin syndrome is an extremely rare variant of mycosis fungoides characterized by the slow formation of pendulous folds of lax skin and a granulomatous infiltrate with clonal T-lymphocytes. The initial manifestation of skin involvement in granulomatous slack skin syndrome, as in classic mycosis fungoides, consists of patches and plaques that transform into large, hanging folds of atrophic skin in flexural areas (axillae and groin), resembling cutis laxa. Extracutaneous dissemination of the pathological process develops extremely rarely, and in most patients the disease has an indolent course [5].
Hypopigmented mycosis fungoides is frequently found in individuals with darker skin and is common in children and adolescents. In white patients, hypopigmented lesions usually coexist with erythematous eruptions typical of classic mycosis fungoides. The disease manifests as hypopigmented patches localized predominantly on the trunk and extremities, unaccompanied by subjective sensations [5].
In addition to the variants discussed in detail above, several other clinical variants of mycosis fungoides have been described. Variants such as hyperpigmented, bullous/vesicular, poikilodermatous, pigmented purpuric, pustular, ichthyosiform, and palmoplantar mycosis fungoides were named according to their characteristic clinical manifestations. Nevertheless, they generally exhibit the same histological features and clinical course as classic mycosis fungoides and are therefore not included in the latest classification of cutaneous lymphomas as independent diseases [5].
2. Diagnostics, medical indications and contraindications for diagnostic methods
- Criteria for establishing the diagnosis/condition: The diagnosis of mycosis fungoides is based on a comprehensive assessment of the clinical presentation (presence of patches, plaques, tumors, skin pigmentation changes, and rashes atypical for classic mycosis fungoides, such as blisters and pustules), histopathological examination of skin biopsy (surgical) material (presence of small-to-medium-sized pleomorphic ["cerebriform"] lymphoid cells in the infiltrate;
- presence of lymphoid cells arranged in chains along the basal layer of the epidermis (3 or more);
- presence of intraepidermal lymphocytes surrounded by a clear perinuclear halo;
- increased number of intraepidermal lymphocytes in the absence of spongiosis ("disproportionate epidermotropism");
- epidermal lymphocytes larger in size than dermal lymphocytes;
- intraepidermal accumulations of lymphocytes (Pautrier microabscesses);
- fibrosis and/or edema of the papillary dermis.)
Morphological features characteristic of various stages and forms of mycosis fungoides are described in detail in the comments, including the use of immunohistochemistry with antibodies against CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD56, TIA1, granzyme B, TCR (βF1), TCR-γ, and CD45RO [3–5].
Immunohistochemical criteria for the diagnosis of mycosis fungoides:
- infiltrating cells consist of α/β T-helper cells – mature memory cells with the immunophenotype: βF1+ CD2+ CD3+ CD4+ CD5+ CD7+ CD8- CD45RO+ [3–5];
- loss of CD7 marker expression by lymphocytes by more than 10% [6,16].
- complete or partial loss of expression of pan-T-cell antigens CD2, CD3, CD5, and CD7 in late stages [3–5];
- dissociation of the immunophenotype of intraepidermal and dermal lymphoid components (with weak expression and loss of expression of some antigens such as CD2, CD3, CD4, CD5, CD7)
- Increased CD4/CD8 ratio (greater than 8/1) [33],
determination of T-cell receptor gene rearrangement ( : PCR testing to determine T-cell receptor [TCR] gene rearrangement is an auxiliary method, since infiltration monoclonality is detected in 90% of cases of plaque and tumor stages of mycosis fungoides and only in 50–60% of the patch stage. The results of molecular genetic studies must be evaluated in conjunction with other diagnostic methods, since a dominant T-lymphocyte clone can be detected in the group of so-called "clonal" dermatoses [3,8–14])
according to the recommendations of the International Society for Cutaneous Lymphomas and the European Organisation for Research and Treatment of Cancer for mycosis fungoides and Sézary syndrome (Appendix G1) [3,6,7].
According to the recommendations of the International Society for Cutaneous Lymphomas and the European Organisation for Research and Treatment of Cancer, there are 4 stages of mycosis fungoides – stage I, subdivided into stages IA and IB, as well as stages II, III, and IV.
The evaluation plan varies depending on the stage of mycosis fungoides:
- in stages IA and IB, a physical examination with skin mapping, targeted chest radiography, and ultrasound of (peripheral) lymph nodes are required [3,7].
- Patients with stages II, III, and IV must be evaluated in accordance with standard diagnostic guidelines for patients with nodal lymphomas. In addition, in the presence of patches/plaques, the body surface area of skin involvement must be determined; in the presence of tumors, their total number, the size of the largest tumor, and involved skin areas must be assessed.
Staging is an important factor in treatment planning and prognosis determination. For most patients with early stages, the median survival is 12 years. In late stages, for patients with tumors, erythroderma, lymph node and blood involvement, but without visceral involvement, the median survival is 5 years. Patients with tumors (T3) have a worse prognosis than those with erythroderma (T4). Visceral involvement is rare, with a median survival of less than 2.5 years. Patients with stages IB/IIA who have follicular mycosis fungoides or patients with very "thick" plaques have a worse prognosis due to reduced sensitivity to topical therapies, which must be considered when prescribing treatment. In late stages, the presence of multiple tumors, large-cell transformation, and a decreased number of CD8+ T cells in the dermal infiltrate and/or blood are also associated with reduced survival.
2.1 Complaints and Anamnesis
Mycosis fungoides is characterized by an insidious onset and slow progression. Rashes often resolve spontaneously without leaving scars. Patients complain of skin rashes, which are frequently accompanied by pruritus [3–5].
2.2 Physical Examination
Clinical examination of the patient remains a fundamental method in diagnosing early mycosis fungoides, as it allows not only for the suspicion of mycosis fungoides, but also for determining the variant and stage of the disease, as well as identifying the optimal site for a skin biopsy. The clinical examination should evaluate the type of skin lesions (patches, plaques, tumors, or a combination thereof) and the affected body surface area. Criteria for the clinical diagnosis of early-stage mycosis fungoides are provided in Section 1.6 "Clinical presentation of the disease or condition (group of diseases or conditions)"
To establish the disease stage according to ISCL-EORTC recommendations, in the presence of patches/plaques, it is necessary to determine the body surface area of skin involvement; in the presence of tumors, their total number, the size of the largest tumor, and involved skin areas must be determined. Palpation of lymph nodes is also required to assess their size, consistency, mobility, adherence to surrounding tissues, and tenderness [6].
2.3 Laboratory Diagnostics
A complete blood count (CBC) with differential is recommended to detect potential abnormalities [6] and conditions that are contraindications to systemic therapy for mycosis fungoides, as well as to monitor the safety of ongoing systemic therapy or phototherapy [15–17].
GRS CLOE 5Grade of Recommendation Strength C (Level of Evidence – 5)
Comments: drugs used for systemic therapy of mycosis fungoides have adverse effects manifested as changes in blood parameters, the detection of which requires a complete blood count [15]. Thrombocytopenia, anemia, neutropenia, and changes in other parameters may develop during systemic therapy [18–21].
It is recommended to perform a routine blood chemistry panel including lactate dehydrogenase and uric acid levels [3,22], as well as to detect potential abnormalities [6] and conditions that are contraindications to systemic therapy for mycosis fungoides, and to monitor the safety of ongoing systemic therapy or skin phototherapy [15–17].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: an elevated blood level of lactate dehydrogenase and uric acid indicates progression and an aggressive course of mycosis fungoides [3,7]. Drugs used for systemic therapy of mycosis fungoides have adverse effects manifested as changes in blood chemistry parameters, the detection of which requires a blood chemistry panel [15]. During systemic therapy, increases in creatinine [20], triglycerides [21], and elevated liver transaminases may be observed[23].
2.4 Instrumental Diagnostics
It is recommended that all patients with mycosis fungoides undergo ultrasound examination of (peripheral) lymph nodes to determine the extent of their involvement in the pathological process and the stage of the disease [3,6,7].
Let Level 5Recommendation Grade C (Level of Evidence 5)
Comments: this imaging method is used to confirm or detect lymphadenopathy and/or monitor the condition of patients with early-stage mycosis fungoides (T1N0B0, T2N0B0). Detection of lymph node changes caused by pathological proliferation of T lymphocytes indicates progression of mycosis fungoides and the need for additional investigations [6].
It is recommended that all patients with mycosis fungoides undergo targeted chest radiography [3,6,7].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
Comments: this imaging method is used to confirm the absence or presence of lymphadenopathy and/or monitor the condition of patients with early-stage mycosis fungoides (T1N0B0, T2N0B0). Detection of lymph node changes caused by pathological proliferation of T lymphocytes indicates progression of mycosis fungoides and the need for additional investigations [6].
It is recommended to perform magnetic resonance imaging or positron emission tomography combined with computed tomography (PET/CT) of the chest, abdomen, and pelvis to detect potential involvement of lymph nodes and internal organs in patients with advanced mycosis fungoides and/or upon detection of altered peripheral lymph nodes during examination [3,6,7].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: detection of changes in lymph nodes or internal organs caused by the pathological proliferation of T-lymphocytes indicates the development of advanced stages of mycosis fungoides.
2.5 Other Procedures
It is recommended for all patients with suspected mycosis fungoides to undergo pathological anatomy examination of skin biopsy (surgical) material from the lesion site to verify the diagnosis [6,24–27].
During the pathological anatomy examination, it is necessary to consider the cellular composition of the dermal infiltrate and its location. The main diagnostic criteria are [6,24–27]:
- presence in the infiltrate of pleomorphic ("cerebriform") small and medium-sized lymphoid cells;
- presence of lymphoid cells arranged in chains along the basal layer of the epidermis (3 or more);
- presence of intraepidermal lymphocytes surrounded by a clear perinuclear halo;
- increased number of intraepidermal lymphocytes in the absence of spongiosis ("disproportionate epidermotropism");
- epidermal lymphocytes larger in size than dermal lymphocytes;
- intraepidermal accumulations of lymphocytes (Pautrier microabscesses);
- fibrosis and/or edema of the papillary dermis.
Morphological features characteristic of different stages and forms of mycosis fungoides are described in detail in the comments
LOC 4Level of Clinical Recommendation C (Level of Evidence – 4)
Comments: to increase the reliability of the pathological anatomy examination, it is necessary to discontinue treatment with any topical agents, especially those containing corticosteroids, as well as systemic corticosteroids and immunosuppressants 2 weeks before the biopsy. In unclear cases, performing multiple biopsies from different lesions and repeat biopsies after 2–4 weeks (without topical therapy) is recommended [3,4].
In the patch (erythematous) stage, the pathological anatomy examination reveals epidermotropic superficial microfocal perivascular infiltrates; in the plaque stage, an epidermotropic dense band-like infiltrate in the upper dermis; in the tumor stage, a dense focal or diffuse infiltrate occupying the entire dermis and penetrating into the subcutaneous adipose tissue, while epidermotropism may be absent [3,4,24–31].
Folliculotropic mycosis fungoides is morphologically characterized by a perifollicular or diffuse lymphocytic infiltrate of the dermis with varying degrees of infiltration of the follicular epithelium by small, medium-sized, and sometimes large T-cells with cerebriform hyperchromic nuclei. In many cases, mucinous degeneration of the follicular epithelium (follicular mucinosis) is detected, which can be visualized by alcian blue or colloidal iron staining, although cases without follicular mucinosis have also been described. Infiltration of the follicular epithelium may be accompanied by infiltration of eccrine sweat glands (syringotropism), a combination often referred to as adnexotropic mycosis fungoides [32]. Nevertheless, simultaneous infiltration of the interfollicular epidermis (epidermotropism), which characterizes early stages of classical mycosis fungoides, is rare. In early lesions clinically characterized by follicle-centered patches, acneiform eruptions, or keratosis pilaris-like eruptions, the perifollicular infiltrate is usually scanty and contains, besides atypical T-cells, a varying number of small reactive T-cells, histiocytes, and sometimes eosinophils. As skin lesions progress to more infiltrated plaques or tumors, dermal infiltrates become more diffuse and may contain a larger number of large cells or medium-sized cells with finely dispersed chromatin. A significant admixture of eosinophils and, especially in cases of secondary bacterial infection, plasma cells is frequently observed. In some cases, clusters of small B-lymphocytes may be present. In cases of destruction of hair follicle epithelium, a granulomatous reaction may be observed. In cases with diffuse dermal infiltrates with partial or even complete destruction of epithelial structures, differential diagnosis between follicular mycosis fungoides and other types of CTCL can be challenging.
Large-cell transformation, defined by the presence of more than 25% blast cells or the presence of clusters of blast cells, has been described in more than 20% of folliculotropic mycosis fungoides cases and is observed more frequently than in classical mycosis fungoides [5].
The typical histological picture is represented by epidermal hyperplasia with marked infiltration by small and medium-sized atypical cells located singly or in nests or clusters. Atypical cells have medium-sized or large cerebriform nuclei and abundant vacuolated cytoplasm. An infiltrate consisting predominantly of small lymphocytes may be present in the superficial dermis, but occasionally it contains neoplastic T-lymphocytes [5].
Histologically, granulomatous slack skin syndrome is characterized by a dense infiltrate throughout the entire thickness of the dermis composed of small and medium-sized T-lymphocytes admixed with numerous macrophages and multiple scattered multinucleated giant cells. The presence of multinucleated giant cells containing more than 10 nuclei per cell is considered a hallmark of the disease, but has also been observed in cases of granulomatous mycosis fungoides. Loss of elastic fibers, elastophagocytosis, and emperipolesis ( engulfment of lymphocytes) by multinucleated cells are commonly observed. The epidermis may be infiltrated by small atypical T-lymphocytes with cerebriform nuclei, as in classical mycosis fungoides [5].
In hypopigmented mycosis fungoides, a typical histological picture of the early patch stage of mycosis fungoides is found. Variants of mycosis fungoides such as hyperpigmented, bullous/vesicular, poikilodermic, pigmented purpuric, pustular, ichthyosiform, and palmoplantar are characterized by the same histological features as classical mycosis fungoides [5].
It is recommended in the presence of histological signs of mycosis fungoides (lymphoproliferative disease) in the morphological picture to apply the immunohistochemical method using antibodies against CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, CD56, TIA1, granzyme B, TCR (ßF1), TCR-γ, CD45RO [3–5].
Immunohistochemical criteria for the diagnosis of mycosis fungoides:
- infiltrating cells consist of α/β T-helper cells – mature memory cells with the immunophenotype: βF1+ CD2+ CD3+ CD4+ CD5+ CD7+ CD8- CD45RO+ [3–5];
- loss of CD7 marker expression by lymphocytes by more than 10% [6,16].
- complete or partial loss of expression of pan-T-cell antigens CD2, CD3, CD5, and CD7 in late stages [3–5];
- dissociation of the immunophenotype of intraepidermal and dermal lymphoid components (with weak expression and loss of expression of some antigens such as CD2, CD3, CD4, CD5, CD7)
- Increase in the CD4/CD8 ratio (greater than 8/1) [33].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
Comments: the presented diagnostic criteria are the most common in the classical variant of mycosis fungoides, characterized by an infiltrate of mature memory cells (α/β T-helper cells). Other phenotypes are less common: the T-cytotoxic (βF1+ CD3+ CD4- CD5+ CD8+) and γ/δ (βF1- CD3+ CD4- CD5+ CD8+) phenotypes. In these cases, clinico-morphological correlation is necessary—comparing the clinical manifestations of the disease with the histological picture to rule out CD8+ aggressive epidermotropic T-cell lymphoma and γ/δ T-cell lymphoma. In advanced stages of mycosis fungoides, complete or partial loss of expression of pan-T-cell antigens CD2, CD3, CD5, and CD7, the appearance of expression of cytotoxic proteins TIA-1, granzyme B, and perforin, as well as an aberrant CD4+/CD8+ or CD4-/CD8- phenotype, may be observed. The absence of expression of the pan-T-cell antigen CD7 on tumor cells is not informative, as it can also be found in inflammatory dermatoses [3–5]. In almost all cases of folliculotropic mycosis fungoides, neoplastic cells have the CD3+/CD4+/CD8− phenotype, similar to classical mycosis fungoides [22]. An admixture of large lymphoid cells with nuclear atypia, frequently with CD30 expression, is noted.
In pagetoid reticulosis, the phenotype of neoplastic T-lymphocytes can be characterized either as CD3+/CD4−/CD8+ or, less commonly, as CD3+/CD4+/CD8− or CD3+/CD4−/CD8−. In cases with CD8+ or CD4−/CD8− phenotypes, cytotoxic proteins are expressed (e.g., T-cell intracellular antigen [TIA]-1, granzyme A/B, and perforin). CD30 is frequently expressed [34].
In the majority of cases of granulomatous slack skin syndrome, a CD3+/CD4+/CD8– T-lymphocyte phenotype is noted [5].
The description of the immunohistochemical study and the pathomorphological conclusion must indicate the presence of CD30-positive cells in the lymphoid infiltrate, including cells of the reactive microenvironment, using a semiquantitative assessment taking into account grading: <10%, 10-30%, >30%, >50%. If CD30-positive cells are present in the infiltrate (regardless of their number), the diagnosis must be formulated as follows: mycosis fungoides (CD30-positive).
It is recommended to perform a pathomorphological examination of a lymph node biopsy (surgical) specimen if signs of lymph node involvement are detected (enlargement > 1.5 cm in diameter and/or with a dense, irregular structure) based on ultrasound examination and/or targeted chest radiography and/or MRI and/or positron emission tomography combined with computed tomography (PET/CT) [6].
GRS CLOE 5Grade of Recommendation Strength C (Level of Evidence – 5)
Comments: For biopsy, lymph nodes measuring > 1.5 cm and more and/or with a dense, irregular structure are selected. The biopsy is performed by medical specialists with surgical training, including an oncologist/hematologist. The purpose of the pathomorphological examination of the lymph node biopsy (surgical) specimen is to rule out or verify the presence of specific lymph node involvement and to perform differential diagnosis with dermatopathic lymphadenitis. If specific lymph node involvement is detected, the patient is referred to a hematologist or oncologist for further management and treatment.
It is recommended to perform molecular biological testing of hematopoietic tissue punctate (lymph node) if a tumor substrate is detected during the pathomorphological examination of the lymph node biopsy (surgical) specimen using immunohistochemical methods [6, 35].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
Comments: PCR testing makes it possible to determine the clonality of the lymph node substrate. If specific lymph node involvement is detected, the patient is referred to a hematologist or oncologist for further management and treatment.
It is recommended to use pathomorphological examination of the biopsy (surgical) specimen using immunohistochemical methods if a lymph node tumor substrate is detected [6, 35].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
Comments: immunohistochemical examination makes it possible to determine the phenotype of lymphocytes in the lymph node substrate. If specific lymph node involvement is detected, the patient is referred to a hematologist or oncologist for further management and treatment.
It is recommended to perform a pathomorphological examination of a bone marrow biopsy (surgical) specimen in patients with advanced stages of mycosis fungoides and/or suspected bone marrow involvement [36]. If pathological changes are detected in the bone marrow substrate, it is recommended to perform PCR testing, immunohistochemical examination, and/or flow cytometry of the biological material [36].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: bone marrow involvement occurs in approximately 20% of patients with mycosis fungoides and is most often associated with an aggressive disease course and low survival rates [36]. Bone marrow trephine biopsy is performed by medical specialists skilled in bone marrow core biopsy techniques (surgeons, hematologists, or oncologists). Pathomorphological examination of the bone marrow biopsy (surgical) specimen makes it possible to determine the presence of specific bone marrow involvement. If specific bone marrow involvement is detected, the patient is referred to a hematologist or oncologist for further management and treatment.
Pathomorphological examination of a bone marrow biopsy (surgical) specimen using immunohistochemical staining makes it possible to determine the nature of proliferating cells in the bone marrow.
It is recommended to perform molecular genetic testing for T-cell receptor gene rearrangement [3, 4, 8–14].
LoE 4Level of Recommendation C (Level of Evidence – 4)
Comments: PCR testing to determine T-cell receptor (TCR) chain gene rearrangement is an auxiliary method, since infiltrate monoclonality is detected in 90% of cases of plaque and tumor stages of mycosis fungoides and in only 50–60% of the patch stage. The results of molecular genetic testing must be evaluated in combination with other diagnostic methods, since a dominant T-lymphocyte clone can be detected in the group of so-called “clonal” dermatoses [3, 8–14].
It is recommended to perform peripheral blood flow cytometry to assess the presence and number of T-lymphocytes with an aberrant phenotype (CD4+/CD26- or CD4+/CD7-) in the following cases:
- in the diagnosis of Sézary syndrome
- when peripheral blood involvement is suspected (complete blood count revealing absolute lymphocytosis).
- in case of lymph node and internal organ involvement [37].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
Comments: this test may help verify Sézary syndrome when diagnosis via skin biopsy is not possible (non-diagnostic biopsy, contraindications to biopsy). It also makes it possible to determine the disease stage according to the ISLE-EORTC recommendations (Appendix G2).
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Treatment of Patients with Early Stages of Mycosis Fungoides
It is recommended for the treatment of patients with early stages (IA–IIA) of mycosis fungoides to use topical glucocorticoids used in dermatology [7, 38, 39]:
#betamethasone**, cream, ointment applied topically to lesions 2 times a day until complete resolution of the rash [7, 38, 39, 67, 68].
For adults: Level of Recommendation C (Level of Evidence – 2)
For children: Level of Recommendation C (Level of Evidence – 4)
or
#mometasone** cream, ointment applied topically to lesions 2 times a day until complete resolution of the rash [7, 38, 39, 69, 70].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: for early stages of mycosis fungoides, a conservative approach with topical therapy is the preferred first-line treatment. For patients in stage IA with small skin lesions, a watch-and-wait strategy under close medical supervision is acceptable.
It is recommended to administer ultraviolet skin irradiation to patients with mycosis fungoides in stages IA–IIB [40–43]:
generalized or localized narrow-band ultraviolet B (NBUVB) phototherapy [40–44].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: irradiation is performed 2–3 times a week; the first exposure should not exceed 70% of the previously determined minimum erythemal dose. Subsequent exposures are administered as follows: in the absence of erythema, exposure time is increased by 40%; with mild erythema, by 20%; with pronounced erythema, it remains unchanged. Recommended for patches and thin plaques; no severe side effects are observed.
or
psoralen plus ultraviolet A (PUVA) therapy with systemic administration of psoralens [40, 42, 44].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: 2 hours before irradiation, the patient takes -#methoxsalen orally at a dose of 0.6 mg/kg of body weight; the initial irradiation dose depends on the skin type (0.25–1.0 J/cm2), then with each session the dose is increased by 0.25–0.5 J/cm2 or more depending on the severity of erythema. Treatment is carried out 3–4 times a week until the rash resolves (30–35 sessions). The total dose ranges from 50 to 80 J/cm2, which is sufficient to achieve clinical remission. It is used for widespread and more infiltrated lesions, as well as the follicular form of mycosis fungoides. Side effects include erythema, nausea, photosensitivity, and photocarcinogenesis.
It is recommended to use external beam radiotherapy for soft tissue involvement using a medical electron linear accelerator in patients with mycosis fungoides with localized skin lesions without lymph node and bone marrow involvement [3, 45–47].
GRC CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: for localized stages of MF, it is optimal to use external beam radiotherapy on medical linear accelerators with an energy of 4–8 MeV, depending on the depth of skin lesions. In the presence of a single lesion, the recommended total cumulative radiation dose is 24–30 Gy. In the presence of several separate lesions, the total dose should not exceed 8–12 Gy, while a total dose of 8 Gy can be delivered in 2 fractions.
Total skin electron beam therapy (external beam radiotherapy using medical electron linear accelerators) is used for generalized skin lesions in the absence of lymph node involvement and visceral organ involvement. Total doses range from 12 to 36 Gy, no more than 4–6 Gy per week. The advantages of using low total radiation doses are a reduction in the severity of radiation reactions and the possibility of subsequent repeat courses of radiation therapy.
In case of lymph node and visceral organ involvement, additional external beam gamma therapy at a total dose of 20–30 Gy may be used.
3.2 Treatment of patients with advanced stages of mycosis fungoides and relapsed and refractory forms of mycosis fungoides
Recommended as first-line therapy for patients with stage IIB and III mycosis fungoides, as well as second-line therapy for early-stage mycosis fungoides in the absence or insufficient efficacy of ongoing therapy with #interferon alfa-2b** in moderately high doses: 3–10 million IU daily or 3 times a week [18].
LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)
Comments: treatment is carried out until complete control is achieved (no signs of further progression). It can be combined with PUVA therapy, retinoids, and chemotherapy. Prolonged administration of the drug may cause thyroid dysfunction. In patients with thyroid disorders, the thyroid-stimulating hormone concentration must be determined before starting treatment, and monitoring its level at least once every 6 months is recommended. Diabetes mellitus is very rare. With prolonged use, usually after several months of treatment, visual disorders may occur. An ophthalmological examination is recommended prior to initiation of therapy. If any visual disturbances are reported, an immediate consultation with an ophthalmologist is required. Patients with conditions that may cause retinal changes, such as diabetes mellitus or arterial hypertension, must undergo an ophthalmological examination at least once every 6 months. Patients with cardiovascular diseases and/or progressive malignancies require careful monitoring and ECG surveillance. In case of psychiatric and/or CNS changes, including the development of depression, psychiatric supervision is recommended during treatment and for 6 months after its completion.
Recommended for patients with late-stage mycosis fungoides, as well as in cases of inefficacy or insufficient response to prior topical therapy and/or phototherapy and/or interferon alfa-2b therapy, regardless of stage, with #methotrexate** at a dose of no more than 50 mg per week (standard dose: 25 mg once a week orally) [48,76].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: treatment is carried out until complete control is achieved (no signs of further progression) or until signs of unacceptable toxicity appear; it can be combined with interferon alfa-2b (IFN-α).
Before initiating treatment with #methotrexate** or resuming therapy after a break, it is necessary to perform a complete blood count (clinical blood test) with a leukocyte differential and platelet count, and evaluate the activity of "hepatic" enzymes (investigation of blood albumin level, total blood bilirubin, determination of aspartate aminotransferase and alanine aminotransferase activities in the blood), as well as targeted chest X-ray examination and renal function tests. If clinically indicated, examinations to exclude hepatitis and other somatic diseases are prescribed.
During treatment with #methotrexate** (monthly for the first 6 months and at least every 3 months thereafter; when increasing doses, it is advisable to increase the frequency of examinations), the following tests are performed:
1. Examination of the oral cavity and throat to detect mucosal changes.
2. Blood test with determination of leukocyte differential and platelet count. Even when used in standard therapeutic doses, #methotrexate** can cause bone marrow suppression. In case of a significant decrease in leukocyte or platelet counts, #methotrexate** treatment is immediately discontinued and symptomatic supportive therapy is prescribed.
3. Liver function tests. Special attention should be paid to detecting signs of liver damage. #methotrexate** treatment should not be initiated or must be suspended in case of any abnormalities in liver function test results or liver biopsy. Values usually normalize within 2 weeks, after which treatment may be resumed at the physician's discretion.
4. Renal function tests and urinalysis. Since #methotrexate** is excreted primarily by the kidneys, patients with renal impairment may experience elevated blood concentrations of #methotrexate**, which can lead to severe adverse reactions. The condition of patients at risk for renal impairment (e.g., elderly patients) must be closely monitored.
5. Since #methotrexate** affects the immune system, it can alter the response to vaccination and affect the results of immunological tests. Special caution is required when treating patients with inactive, chronic infections (such as herpes zoster, tuberculosis, viral hepatitis B or C) due to the risk of their reactivation. Live vaccines should not be administered during #methotrexate** treatment.
Due to the possibility of chronic infection reactivation, patients scheduled for or undergoing #methotrexate** therapy may require testing for hepatitis B virus surface antigen (HBsAg), antibodies to hepatitis C virus in the blood, and antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1 and HIV-2 in the blood.
Recommended for late stages (IIB–IVB) of mycosis fungoides, as well as second-line therapy for early stages of mycosis fungoides in the absence or insufficient effect of ongoing therapy with #vorinostat 200–400 mg orally daily [49–52].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: Side effects of the histone deacetylase inhibitor #vorinostat include thrombocytopenia, anemia, anorexia, nausea, and muscle cramps. Treatment is continued until there is no evidence of further progression or until unacceptable toxicity occurs. Contraindication: age under 18 years. Administration of #vorinostat may lead to thrombocytopenia and anemia, which may require drug discontinuation or cessation of treatment. Leukopenia and neutropenia may develop, requiring dose reduction. An increase in plasma creatinine concentration has been reported. Hypokalemia and elevated plasma creatinine may also occur, which may require a dose reduction. Hyperglycemia has been reported during #vorinostat therapy, which may necessitate dietary modifications and/or hypoglycemic treatment. Proteinuria may also occur.
The use of combined chemoradiotherapy not only fails to improve the median survival of patients compared to "conservative" therapy, but even increases the relapse rate; therefore, it is preferable to use topical therapy, biological agents, or their combination [49].
Monotherapy with #gemcitabine** according to the regimen of 1200 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for a total of 6 cycles, is recommended as systemic chemotherapy for patients with late-stage mycosis fungoides with an aggressive course and/or inefficacy of other treatment methods [53].
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
or
#gemcitabine** in low doses with prolonged infusion at a dose of 250 mg/m2 over 6 hours once a week [77]
GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)
Recommended brentuximab vedotin** for the treatment of adult patients in the absence or insufficient response after at least one line of prior systemic therapy in the presence of CD30+ antigen expression [21,54].
LoR BLevel of recommendation B (level of evidence
– 2)
Comments: administered at a dose of 1.8 mg/kg intravenously every 21 days. Treatment is carried out for 8 cycles; if a partial response is achieved, another 8 cycles may be administered. If adverse effects occur (most commonly peripheral polyneuropathy), a dose reduction to 1.2 mg/kg and an increase in the interval between cycles is permissible. Treatment with brentuximab vedotin** may cause anemia, thrombocytopenia, and severe prolonged (≥1 week) neutropenia, which may increase the risk of severe infections. Cases of elevated alanine aminotransferase and aspartate aminotransferase levels have been reported. Hyperglycemia has been reported in clinical trials in patients with an increased body mass index, both with and without a history of diabetes mellitus.
For patients with progressive forms of mycosis fungoides refractory to at least 5 lines of systemic therapy (including interferon alfa-2b**, #methotrexate**, brentuximab vedotin**, #gemcitabine**, #vorinostat), off-protocol palliative treatment regimens may be used, such as (in descending order):
- #cyclophosphamide** (50–100 mg orally daily, no more than 1 year of therapy, considering the risk of myelodysplastic syndrome) [55],
- #etoposide** (50 mg orally twice daily) [56],
- #bendamustine** (120 mg/m2 on days 1 and 2 of each 3-week cycle, total of 6 cycles) [57],
- #bortezomib** (1.3 mg/m2 on days 1, 4, 8, 11, total of 6 cycles of therapy) [58].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended for patients with large cell transformation of mycosis fungoides and/or extracutaneous spread of mycosis fungoides to use the CHOP regimen as systemic chemotherapy: Doxorubicin** 50 mg/m2 IV infusion, day 1, Cyclophosphamide** 750 mg/m2 IV infusion, day 1, #Vincristine** 1.4 mg/m2 (total dose not exceeding 2 mg) IV, day 1, #Prednisolone** 100 mg orally, days 1–5, 21-day cycle, 6 cycles in total [59–62, 71–75].
For adults: Oxford grade of recommendation B (level of evidence – 2)
For children: Oxford grade of recommendation C (level of evidence – 4)
Allogeneic bone marrow transplantation (hematopoietic stem cell transplantation) is recommended for patients under 60 years of age in the absence of response to other therapies, upon early progression to advanced disease stages, in large-cell transformation of mycosis fungoides, and in advanced stages of MF, provided that partial or complete remission is achieved at the pre-transplantation stage [62, 63].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
3.3 Other Treatment
It is recommended to prescribe systemic antihistamines in accordance with their instructions for use to patients presenting with pruritus [64, 65]
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
4. Medical Rehabilitation and Sanatorium-Resort Treatment
There are no special rehabilitation methods for mycosis fungoides.
5. Prevention and Dispensary Observation
There are currently no prevention methods for mycosis fungoides since the etiological factor(s) leading to the development of the disease are unknown. Follow-up care by a hematologist or oncologist is carried out during treatment and after achieving lymphoma remission.
In case of relapse or progression of mycosis fungoides, a repeat skin biopsy and repeat pathomorphological examination of the skin biopsy (surgical) material must be performed, as well as a repeat pathomorphological examination of the skin biopsy (surgical) material using immunohistochemistry to rule out large cell transformation, and a repeat staging procedure if necessary. Treatment tactics for relapses are also based on determining the stage of the disease, taking into account the development of resistance to previous therapies.
It is recommended that patients with early stages undergo annually: physical examination with skin mapping, targeted chest X-ray, and ultrasound of peripheral lymph nodes [3, 6, 7, 65].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
It is recommended that patients with advanced stages undergo every 6 months: physical examination with skin mapping, ultrasound of peripheral lymph nodes, CT scan of the chest, abdomen, and pelvis [3, 6, 7, 65].
Leveled Clinical Recommendation 5Grade of Recommendation C (Level of Evidence – 5)
6. Organization of Medical Care
As part of primary health care, general practitioners, district pediatricians, and family physicians, upon detecting skin rashes, pruritus, or symptoms/signs of mycosis fungoides in patients, refer the patient to a dermatovenereology medical organization or an oncologist/hematologist office for primary specialized health care, and also provide medical care in accordance with the recommendations of the dermatovenereology medical organization and/or oncologist/hematologist, in the absence of medical indications for referral.
If it is impossible to provide medical care within the framework of primary specialized health care and if there are medical indications, the patient is referred to a medical organization providing specialized medical care.
Specialized, including high-tech, medical care is provided by dermatovenereologists and/or a hematologist in inpatient settings.
Specialized medical care is provided to patients at early stages (IA–IIA) by dermatovenereologists.
Specialized, including high-tech, medical care is provided to patients at stages (IIB–IVB) by hematologists/oncologists.
Indications for scheduled hospitalization in a medical organization:
1) Indications for providing medical care in a day hospital setting:
- insufficient efficacy of outpatient treatment in patients with limited skin lesions;
- patient examination, including biopsy and invasive interventions, in cases where it cannot be performed on an outpatient basis;
2) Indications for inpatient medical care:
- lack of response to ongoing outpatient treatment;
- stages of mycosis fungoides requiring phototherapy and/or systemic therapy;
- patient examination, including biopsy and invasive interventions, in cases where it cannot be performed on an outpatient basis;
3) Indications for emergency hospitalization in a hospital of a medical organization providing specialized, including high-tech, medical care in the profile of "hematology" and "oncology":
- Development of a severe infection (hospitalization in a hematology unit is not mandatory).
- development of life-threatening cytopenias (severe anemia, hemorrhagic syndrome, neutropenia);
- development of life-threatening complications of mycosis fungoides;
- development of treatment complications, including tumor lysis syndrome, severe infusion reactions, myelotoxic agranulocytosis with fever, and other life-threatening complications.
Indications for discharging a patient from a medical organization:
- partial or complete regression of rashes.
- completion of a course of treatment or one of the stages of specialized, including high-tech, medical care in a round-the-clock or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in inpatient settings.
7. Additional Information
Repeated skin biopsy and repeated pathomorphological examination of skin biopsy material, including the use of immunohistochemistry, especially when clinical manifestations change, allow timely detection of disease progression and correction of therapy if necessary.
Criteria for Evaluating the Quality of Medical Care
Quality of care evaluation criteria for Mycosis fungoides (outpatient stage)
№ | Quality criteria | Performance evaluation |
|---|---|---|
1 | A complete blood count was performed in a patient with suspected mycosis fungoides (MF) or confirmed MF at the initial or follow-up visit in case of systemic therapy, as well as upon relapse or progression. | Yes\No |
2 | Pathomorphological examination of skin biopsy material was performed in a patient with suspected mycosis fungoides (MF) at the initial visit, upon relapse, or progression. | Yes\No |
3 | Instrumental diagnostic methods were performed in a patient with suspected or confirmed mycosis fungoides (MF) (advanced stages), as well as upon relapse or progression, at diagnosis or to assess treatment efficacy (when pathological changes are detected) (ultrasound of peripheral lymph nodes, CT scan of the chest, abdomen, and pelvis OR PET/CT of the abdomen, chest CT). | Yes\No |
4 | Patients with early-stage mycosis fungoides received therapy with corticosteroids for dermatological use and/or ultraviolet skin irradiation. | Yes\No |
5 | Systemic therapy was performed in patients with newly diagnosed advanced MF stages or upon relapse. | Yes\No |
Quality of care evaluation criteria for Mycosis fungoides (inpatient stage)
№ | Quality criteria | Performance evaluation |
|---|---|---|
1 | A complete blood count was performed in a patient with suspected mycosis fungoides (MF) or confirmed MF at the initial or follow-up visit in case of systemic therapy, as well as upon relapse or progression (if not performed on an outpatient basis). | Yes\No |
2 | Pathomorphological examination of skin biopsy material was performed in a patient at the diagnosis of mycosis fungoides (MF), upon relapse, or progression (if not performed on an outpatient basis). | Yes\No |
3 | Instrumental diagnostic methods were performed in a patient with suspected or confirmed mycosis fungoides (MF) (advanced stages), as well as upon relapse or progression, at diagnosis or to assess treatment efficacy (when pathological changes are detected) (ultrasound of peripheral lymph nodes, chest, abdominal, and pelvic CT OR PET/CT), if not performed on an outpatient basis. | Yes\No |
4 | Patients with early-stage mycosis fungoides received therapy with corticosteroids for dermatological use and/or ultraviolet skin irradiation. | Yes\No |
5 | Systemic therapy was performed in patients with newly diagnosed advanced MF stages or upon relapse. | Yes\No |
References
Show references
Korgavkar K., Xiong M., Weinstock M. Changing incidence trends of cutaneous T-cell lymphoma. JAMA Dermatology. 2013; 149 (11): 1295–1299. DOI:10.1001/jamadermatol.2013.5526
Zwierzina H., Suciu S., Loeffler-Ragg J. et al. Low-dose cytosine arabinoside (LD-AraC) vs LD-AraC plus granulocyte/macrophage colony stimulating factor vs LD-AraC plus Interleukin-3 for myelodysplastic syndrome patients with a high risk of developing acute leukemia: final results of a randomized phase III study (06903) of the EORTC Leukemia Cooperative Group. Leukemia. 2005;19 (11):1929–1933. DOI:10.1038/sj.leu.2403934.
Keehn C.A., Belongie I.P., Shistik G. et al. The diagnosis, staging, and treatment options for mycosis fungoides. Cancer Control. 2007; 14 (2): 102–111. DOI:10.1177/107327480701400203.
Cerroni L. Mycosis fungoides-clinical and histopathologic features, differential diagnosis, and treatment. Semin Cutan Med Surg. 2018; 37 (1): 2–10. DOI:10.12788/j.sder.2018.002.
Willemze R. Mycosis fungoides variants-clinicopathologic features, differential diagnosis, and treatment. Semin Cutan Med Surg. 2018; 37 (1):11–17. DOI:10.12788/j.sder.2018.004.
Olsen E., Vonderheid E., Pimpinelli N. et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007 15; 110 (6): 1713–1722. DOI:10.1182/blood-2007-03-055749.
Horwitz S.M., Olsen E.A., Duvic M. et al. Review of the treatment of mycosis fungoides and sézary syndrome: a stage-based approach. J Natl Compr Canc Netw. 2008; 6 (4): 436–442. doi: 10.6004/jnccn.2008.0033
Delfau-Larue M.H., Laroche L., Wechsler J. et al. Diagnostic value of dominant T-cell clones in peripheral blood in 363 patients presenting consecutively with a clinical suspicion of cutaneous lymphoma. Blood. 2000; 96 (9): 2987–2992. DOI:10.1182/blood.v96.9.2987
Ponti R., Quaglino P., Novelli M. et al. T-cell receptor γ gene rearrangement by multiplex polymerase chain reaction/heteroduplex analysis in patients with cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome) and benign inflammatory disease: Correlation with clinical, histological and immunophenotypical findings. Br J Dermatol. 2005; 153 (3): 565–573. DOI:10.1111/j.1365-2133.2005.06649.x
Kirsch I.R., Watanabe R., O’Malley J.T. et al. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med. 2015 Oct 7;7 (308): 308ra158. DOI:10.1126/scitranslmed.aaa9122
Matos T.R., de Rie M.A., Teunissen M.B. Research techniques made simple: High-throughput sequencing of the T-cell receptor. J Invest Dermatol. 2017; 137 (6): e131–e138. DOI:10.1016/j.jid.2017.04.001
Scherer F., Kurtz D.M., Diehn M., Alizadeh A.A. High-throughput sequencing for noninvasive disease detection in hematologic malignancies. Blood. 2017; 130 (4): 440–452. DOI:10.1182/blood-2017-03-735639
Jawed S.I., Myskowski P.L., Horwitz S. et al. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): part I. Diagnosis: clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol. 2014; 70 (2): 205.e1–16 DOI:10.1016/j.jaad.2013.07.049
Rea B., Haun P., Emerson R. et al. Role of high-throughput sequencing in the diagnosis of cutaneous T-cell lymphoma. J Clin Pathol. 2018; 71 (9): 814–820. DOI:10.1136/jclinpath-2018-205004
Ferner R.E. Adverse drug reactions in dermatology. Clin Exp Dermatol. 2015; 40 (2): 105–109. DOI:10.1111/ced.12572
Federico M., Bellei M., Marcheselli L. et al. Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network. Br J Haematol. 2018; 181 (6): 760–769. DOI:10.1111/bjh.15258
Huang D.Y., Hu Y.F., Wei N., et al. Innovative analysis of predictors for overall survival from systemic non-Hodgkin T cell lymphoma using quantile regression analysis. Chin Med J (Engl). 2019; 132 (3): 294–301. DOI:10.1097/CM9.0000000000000088
Olsen E.A. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther. 2003; 16 (4): 311–321. DOI:10.1111/j.1396-0296.2003.01643.x
Campbell J.M., Bateman E., Stephenson M.D. et al. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol. 2016; 78 (1): 27–39. DOI:10.1007/s00280-016-3043-5
Mann B.S., Johnson J.R., Cohen M.H. et al. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T‐cell lymphoma. Oncologist. 2007; 12 (10): 1247–1252. DOI:10.1634/theoncologist.12-10-1247
Prince H.M., Kim Y.H., Horwitz S. et al. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017; 390 (10094): 555–566. DOI:10.1016/S0140-6736(17)31266-7
Gerami P., Guitart J. The spectrum of histopathologic and immunohistochemical findings in folliculotropic mycosis fungoides. Am J Surg Pathol. 2007; 31 (9): 1430–1438. DOI:10.1097/PAS.0b013e3180439bdc
Alpdogan O., Kartan S., Johnson W. et al. Systemic therapy of cutaneous T-cell lymphoma (CTCL). Chin Clin Oncol. 2019; 8 (1): 10. DOI:10.21037/cco.2019.01.02
Swerdlow S.H., Campo E., Pileri S.A. et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127 (20): 2375–2390. DOI:10.1182/blood-2016-01-643569
Guitart J., Kennedy J., Ronan S. et al. Histologic criteria for the diagnosis of mycosis fungoides: Proposal for a grading system to standardize pathology reporting. J Cutan Pathol. 2001; 28 (4): 174–183. DOI:10.1034/j.1600-0560.2001.028004174.x
Raghavan S.S., Kim J. Histopathologic approach to epidermotropic lymphocytic infiltrates. Semin Cutan Med Surg. 2018; 37 (1): 56–60. DOI:10.12788/j.sder.2018.003
Charli-Joseph Y., Toussaint-Caire S., Lome-Maldonado C. et al. Approach to dermal-based lymphoid infiltrates and proliferations. Semin Cutan Med Surg. 2018; 37 (1): 61–74. DOI:10.12788/j.sder.2018.015
Kempf W., Mitteldorf C. Pathologic diagnosis of cutaneous lymphomas. Dermatol Clin. 2015; 33 (4): 655–681. DOI: 10.1016/j.det.2015.05.002
Vandergriff T., Nezafati K.A., Susa J. et al. Defining early mycosis fungoides: Validation of a diagnostic algorithm proposed by the International Society for Cutaneous Lymphomas. J Cutan Pathol. 2015; 42 (5): 318–328. DOI:10.1111/cup.12470
Pimpinelli N., Olsen E.A., Santucci M. et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005; 53 (6): 1053–1063. DOI:10.1016/j.jaad.2005.08.057
Kash N., Massone C., Fink-Puches R. et al. Phenotypic variation in different lesions of mycosis fungoides biopsied within a short period of time from the same patient. Am J Dermatopathol. 2016; 38 (7): 541–545. DOI:10.1097/DAD.0000000000000493
De Masson A., Battistella M., Vignon-Pennamen M.D. et al. Syringotropic mycosis fungoides: Clinical and histologic features, response to treatment, and outcome in 19 patients. J Am Acad Dermatol. 2014; 71 (5): 926–934. DOI:10.1016/j.jaad.2014.06.033
Zhang Y., Wang Y., Yu R. et al. Molecular markers of early-stage mycosis fungoides. J Invest Dermatol. 2012; 132 (6): 1698–1706. DOI:10.1038/jid.2012.13
Haghighi B., Smoller B.R., LeBoit P.E. et al. Pagetoid reticulosis (Woringer-Kolopp disease): An immunophenotypic, molecular, and clinicopathologic study. Mod Pathol. 2000; 13 (5): 502–510. DOI:10.1038/modpathol.3880088
Haththotuwa R., Zilinskiene L., Oliff J. et al. Biopsy correlation of surface area vs. single‐axis measurements on computed tomography scan of lymph nodes in patients with erythrodermic mycosis fungoides and Sézary syndrome. Br J Dermatol. 2017; 177 (3): 877–878. DOI:10.1111/bjd.15266
Salhany K.E., Greer J.P., Cousar J.B. et al. Marrow involvement in cutaneous T-cell lymphoma. A clinicopathologic study of 60 cases. Am J Clin Pathol. 1989; 92 (6): 747–754. DOI:10.1093/ajcp/92.6.747
Horna P., Wang S.A., Wolniak K.L. et al. Flow cytometric evaluation of peripheral blood for suspected Sézary syndrome or mycosis fungoides: International guidelines for assay characteristics. Cytometry B Clin Cytom. 2021; 100 (2): 142–155. DOI:10.1002/cyto.b.21878
Kim E.J., Hess S., Richardson S.K. et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest. 2005; 115 (4): 798–812. DOI:10.1172/jci24826
Zackheim H.S. Treatment of patch-stage mycosis fungoides with topical corticosteroids. Dermatol Ther. 2003; 16 (4): 283–287. DOI:10.1111/j.1396-0296.2003.01639.x
Diederen P.V., Van Weelden H., Sanders C.J. et al. Narrowband UVB and psoralen-UVA in the treatment of early-stage mycosis fungoides: A retrospective study. J Am Acad Dermatol. 2003; 48 (2): 215–219. DOI:10.1067/mjd.2003.80
Gathers R.C., Scherschun L., Malick F. et al. Narrowband UVB phototherapy for early-stage mycosis fungoides. J Am Acad Dermatol. 2002; 47 (2): 191–197. DOI:10.1067/mjd.2002.120911
Ponte P., Serrão V., Apetato M. Efficacy of narrowband UVB vs. PUVA in patients with early-stage mycosis fungoides. J Eur Acad Dermatology Venereol. 2010; 24 (6): 716–721. DOI:10.1111/j.1468-3083.2009.03500.x
Kubanov AA, Karamova AE, Znamenskaya LF, et al. Phototherapy of mycosis fungoides. Oncohematology. 2019; 14 (4): 39–47.
Querfeld C., Rosen S.T., Kuzel T.M. et al. Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy. Arch Dermatol. 2005; 141 (3): 305–311. DOI:10.1001/archderm.141.3.305
Hoppe R.T. Mycosis fungoides: radiation therapy. Dermatol Ther. 2003; 16 (4): 347–354. DOI:10.1111/j.1396-0296.2003.01647.x
Hymes K.B. Choices in the treatment of cutaneous T-cell lymphoma. Oncology (Williston Park). 2007; 21 (2 Suppl. 1): 18–23.
Specht L., Dabaja B., Illidge T. et al. Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2015; 92 (1): 32–39. DOI:10.1016/j.ijrobp.2015.01.008
Zackheim H.S., Kashani-Sabet M., McMillan A. Low-dose methotrexate to treat mycosis fungoides: A retrospective study in 69 patients. J Am Acad Dermatol. 2003; 49 (5): 873–878. DOI:10.1016/S0190-9622(03)01591-3
Prince H.M., Whittaker S., Hoppe R.T. How I treat mycosis fungoides and Sézary syndrome. Blood. 2009; 114 (20): 4337–4353. DOI:10.1182/blood-2009-07-202895
Duvic M., Talpur R., Ni X. et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007; 109 (1): 31–39. DOI:10.1182/blood-2006-06-025999
Olsen E.A., Kim Y.H., Kuzel T.M. et al. Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007; 25 (21): 3109–3115. DOI:10.1200/JCO.2006.10.2434
Duvic M., Olsen E., Breneman D. et al. Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymphoma Myeloma. 2009; 9 (6): 412–416. DOI:10.3816/CLM.2009.n.082
Zinzani P.L., Baliva G., Magagnoli M. et al. Gemcitabine treatment in pretreated cutaneous T-cell lymphoma: Experience in 44 patients. J Clin Oncol. 2000; 18 (13): 2603–2606. DOI:10.1200/JCO.2000.18.13.2603
Kim Y.H., Tavallaee M., Sundram U. et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides and Sézary syndrome with variable CD30 expression level: A multi-institution collaborative project. J Clin Oncol. 2015; 33 (32): 3750–3758. DOI:10.1200/JCO.2014.60.3969
Chung C.G., Poligone B. Other chemotherapeutic agents in cutaneous T-cell lymphoma. Dermatol Clin. 2015; 33 (4): 787–805. DOI:10.1016/j.det.2015.05.012
Purnak S., Azar J., Mark L.A. Etoposide as a single agent in the treatment of mycosis fungoides: A retrospective analysis. Dermatol Ther. 2018; 31 (2): e12586. DOI:10.1111/dth.12586
Damaj G., Gressin R., Bouabdallah K. et al. Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: The BENTLY trial. J Clin Oncol. 2013; 31 (1): 104–110. DOI:10.1200/JCO.2012.43.7285
Zinzani P.L., Musuraca G., Toni M. et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007; 25 (27): 4293–4297. DOI:10.1200/JCO.2007.11.4207
Fisher R.I., Gaynor E.R., Dahlberg S. et al. Comparison of a Standard Regimen (CHOP) with Three Intensive Chemotherapy Regimens for Advanced Non-Hodgkin’s Lymphoma. N Engl J Med. 1993; 328 (14): 1002–1006. DOI:10.1056/nejm199304083281404
Trautinger F., Eder J., Assaf C. et al. European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – Update 2017. Eur J Cancer. 2017 May; 77: 57–74. DOI:10.1016/j.ejca.2017.02.027
Grozea P.N., Jones S.E., McKelvey E.M. Combination chemotherapy for mycosis fungoides: a Southwest Oncology Group study. Cancer Treat Rep. 1979; 63 (4): 647–653.
Kim S.J., Yoon D.H., Kang H.J. et al. Bortezomib in combination with CHOP as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas: A multicentre, single-arm, phase 2 trial. Eur J Cancer. 2012; 48 (17): 3223–3231. DOI:10.1016/j.ejca.2012.06.003
Wu P.A., Kim Y.H., Lavori P.W. et al. A meta-analysis of patients receiving allogeneic or autologous hematopoietic stem cell transplant in mycosis fungoides and Sézary syndrome. Biol Blood Marrow Transplant. 2009; 15 (8): 982–990. DOI:10.1016/j.bbmt.2009.04.017
Duarte R.F., Canals C., Onida F. et al. Allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: A retrospective analysis of the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2010; 28 (29): 4492–4499. DOI:10.1200/JCO.2010.29.3241
Serrano L., Martinez-Escala M.E., Zhou X.A. et al. Pruritus in cutaneous T-cell lymphoma and its management. Dermatol Clin. 2018; 36 (3): 245–258. DOI:10.1016/j.det.2018.02.011
Lezvinskaya EM, Vavilov AM. Cutaneous lymphoproliferative tumors: a guide for physicians. Moscow: Prakticheskaya Meditsina; 2010, 366 p.
Wolff J.M., Zitelli J.A., Rabin B.S. et al. Intralesional interferon in the treatment of early mycosis fungoides. J Am Acad Dermatol. 1985; 13 (4): 604–612. doi: 10.1016/s0190-9622(85)70205-8
Tan E., Tay Y.K., Giam Y.C. Profile and outcome of childhood mycosis fungoides in Singapore. Pediatr Dermatol. 2000; 17 (5): 352–356. doi: 10.1046/j.1525-1470.2000.017005352.x
Geller S., Myskowski P.L. Topical clobetasol propionate treatment and cutaneous adverse effects in patients with early-stage mycosis fungoides: an observational study. Cutis. 2020; 105 (5): E27–E32
Patraquim C., Gomes M.M., Garcez C. et al. Childhood hypopigmented mycosis fungoides: A rare diagnosis. Case Rep Pediatr. 2016; 2016: 8564389. doi: 10.1155/2016/8564389
Itoh K., Ohtsu T., Fukuda H. et al. Randomized phase II study of biweekly CHOP and dose-escalated CHOP with prophylactic use of lenograstim (glycosylated G-CSF) in aggressive non-Hodgkin"s lymphoma: Japan Clinical Oncology Group Study 9505. Ann Oncol. 2002; 13 (9): 1347–1355. doi: 10.1093/annonc/mdf287
Foss F.M., Sjak-Shie N., Goy A. et al. A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study. Leuk Lymphoma. 2013; 54 (7): 1373–1379. doi: 10.3109/10428194.2012.742521
Aparna C, Renuka IV, Rajani M, Sailabala G, Annapurna P. Primary extranodal lymphomas - spectrum of distribution and morphology with immunophenotyping: A 3-year institutional study. Med J DY Patil Univ 2015; 8: 138–143. DOI:10.4103/0975-2870.153137
Hooper M., Zhang Y., Taylor E. et al. Practice patterns in children, adolescents, and young adults with mycosis fungoides: Single institution study. J Clin Oncol. 2021; 39 (15 Suppl.). Meeting Abstract. 2021 ASCO Annual Meeting I: e19553. DOI: 10.1200/JCO.2021.39.15_suppl.e19553
Myakova NV, Abramov DS, Pshonkin AV, Konovalov DM. A rare case of mycosis fungoides in children. Case report and literature review. Doctor.Ru. 2015; 13 (114): 73–79.
Reich A., Wróbel G., Kazanowska B. et al. Skin involvement in highly malignant non-Hodgkin lymphomas of childhood and adolescence. Acta Dermatovenerol Alp Pannonica Adriat. 2006; 15 (4): 158–168.
Gorenkova LG, Penskaya EA, Kravchenko SK, et al. Treatment of resistant forms of mycosis fungoides and Sézary syndrome. Clinical Oncohematology. Basic Research and Clinical Practice. 2017; 10 (3): 366–371. DOI: 10.21320/2500-2139-2017-10-3-366-371
Appendix A1. Working Group Composition
Kubanov Alexey Alekseevich – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, President of the Russian Society of Dermatovenereologists and Cosmetologists.
Poddubnaya Irina Vladimirovna – Academician of the Russian Academy of Sciences, Honored Worker of Education of the RF, Doctor of Medical Sciences, Professor, Chairman of the Russian Society of Oncohematologists.
Belousova Irena Eduardovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
Samtsov Alexey Viktorovich – Doctor of Medical Sciences, Professor, Honored Scientist of the RF, Honored Doctor of the RF, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
Znamenskaya Lyudmila Fedorovna – Doctor of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
Chikin Vadim Viktorovich – Doctor of Medical Sciences, member of the Russian Society of Dermatovenereologists and Cosmetologists.
Karamova Arfenya Eduardovna – Candidate of Medical Sciences, Member of the Russian Society of Dermatovenereologists and Cosmetologists.
Kuzmin Alexey Alexandrovich, Chief Physician of the Kirov Regional Center for Oncology and Medical Radiology, Kirov.
Gorenkova Liliya Gamilevna – Candidate of Medical Sciences, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation "National Hematological Society".
Kravchenko Sergey Kirillovich – Candidate of Medical Sciences, member of the Association for the Promotion of Hematology and Bone Marrow Transplantation "National Hematological Society".
Chernova Natalia Gennadievna – Candidate of Medical Sciences, Head of the Department of Hematology and Chemotherapy, City Clinical Hospital No. 40.
Stefanov Dmitry Nikolaevich – Researcher, Head of the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the Russian Society of Oncohematologists.
Vorontsova Anastasia Alexandrovna – Researcher at the Department of Dermatology, State Research Center of Dermatovenereology and Cosmetology of the Russian Ministry of Health, member of the Russian Society of Dermatovenereologists and Cosmetologists.
Conflict of interest: the authors declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
1. Medical specialists: dermatovenereologists, hematologists, oncologists.
2. Faculty members of medical educational institutions of higher and additional professional education in the specialty "Dermatovenereology"
Table 1.Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2.Levels of Evidence (LoE) grading scale for prevention, treatment and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3.Grades of Recommendation (GoR) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Diagnostic algorithm for early-stage mycosis fungoides
Features | Evaluation criteria | Score |
|---|---|---|
Clinical | ||
Major: Presence of stable and/or progressive patches or "thin" plaques. Minor: 1. Localization of rashes in areas not exposed to sunlight. 2. Variability in the shape and size of the rashes. 3. Poikiloderma. | 2 points for major and two minor criteria 1 point for major and 1 minor criterion | |
Histopathological | ||
Major: Superficial lymphoid infiltrate. Minor: 1. Epidermotropism without spongiosis. 2. Lymphoid atypia (cells with hyperchromatic enlarged nuclei or irregular or cerebriform nuclear contours). | 2 points for major and two minor features 1 point for major and 1 minor feature | |
Molecular biological | ||
Clonal rearrangement of the T-cell receptor gene | 1 point | |
Immunopathological | ||
1. Count of CD2+, CD3+, and/or CD5+ T cells < 50%. 2. Count of CD7+ T cells < 10%. 3. Epidermal/dermal discrepancy in the expression of CD2, CD3, CD5, and CD7 (loss of expression in the epidermis). | 1 point for one or more features | |
Total | * | |
*The diagnosis of mycosis fungoides is considered valid if the total score is ≥ 4 points from any sections of the table.
Staging of mycosis fungoides according to ISLE-EORTC recommendations
Skin T1 Limited patches, papules, and/or plaques covering <10% of the skin surface. T1a – patches only T1b – plaques ± patches T2 Patches, papules, and/or plaques covering >10% of the skin surface. T2a – patches only T2b – plaques ± patches T3 One or more tumors (≥1 cm in diameter) T4 Confluent erythema covering ≥80% of the body surface Lymph nodes N0 No peripheral lymph node enlargement, biopsy not required N1 Peripheral lymph nodes enlarged; histopathology Dutch grade 1 or NCI LN0-2 N1a – clone-negative N1b – clone-positive N2 Peripheral lymph nodes enlarged; histopathology Dutch grade 2 or NCI LN3 N2a – clone-negative N2b – clone-positive N3 Peripheral lymph nodes enlarged; histopathology Dutch grade 3-4 or NCI LN4, clone-positive or negative NX Peripheral lymph nodes enlarged, no histological confirmation Internal organs M0 No visceral involvement M1 Visceral involvement (with organ specification and morphological confirmation) Blood B0 Absence of significant blood involvement: atypical (Sézary) cells account for ≤5% of peripheral blood lymphocytes B0a – clone-negative B0b – clone-positive B1 Moderate blood involvement: atypical (Sézary) cells account for >5% of peripheral blood lymphocytes B1a – clone-negative B2b – clone-positive B3 Significant blood involvement: ≥1000/µL Sézary cells with positive clone | ||||
|---|---|---|---|---|
Stages | T | N | M | B |
Early IA IB IIA Late IIB III IIIA IIIB IVA1 IVA2 IVB | 1 2 1,2 3 4 4 4 1-4 1-4 1-4 | 0 0 1,2 0-2 0-2 0-2 0-2 0-2 3 0-3 | 0 0 0 0 0 0 0 0 0 1 | 0,1 0,1 0,1 0,1 0,1 0 1 2 0-2 0-2 |
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
1. Mycosis fungoides is classified as a malignant skin disease with a relatively favorable course and slow progression. Most patients with early-stage mycosis fungoides do not progress to later stages. The cause of mycosis fungoides is not established.
2. Performing a skin biopsy followed by histological and/or immunohistochemical examination allows verifying the diagnosis with a high degree of certainty.
3. In advanced stages of the disease, involvement of lymph nodes and internal organs is possible. Therefore, it is necessary to undergo regular follow-up care, visit a dermatologist regularly for staging of mycosis fungoides, adjust treatment tactics, and timely diagnose possible transformation of mycosis fungoides into a more severe disease – large cell lymphoma.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
No