Mycosis fungoides

Mycosis fungoides is a low-grade T-cell lymphoma.

Characteristic of this disease is the primary skin lesion, which proceeds for a long time without affecting the lymph nodes and internal organs. The latter are affected mainly in the final stage of the disease.

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Pathomorphology of mycosis fungoides

At the early stage of mycosis fungoides (erythematous), the histological picture in many cases resembles that of subacute or chronic dermatitis and eczema. Acanthosis, hyperkeratosis with peeling, small focal parakeratosis, focal spongiosis in the spinous layer, sometimes with the formation of subcorneal vesicles, lymphocyte exocytosis, small focal hydropnic dystrophy of the cells of the basal layer are noted. In the dermis, there are small, mainly perivascular infiltrates of lymphocytes with an admixture of histiocytes, a small number of plasma cells and eosinophils. Upon closer examination, lymphocytes with cerebriform nuclei (Sezary or Lutzner cells) can be found in the infiltrate, although in small quantities.

In the plaque stage, the epidermis usually has pronounced acanthosis and Potrier's microabescesses characteristic of this disease, located in its various layers. Exocytosis of mononuclear cells is noted both in the epidermis and in the epithelium of hair follicles with accumulation of muninous substance in the latter. The proliferate is located mostly in stripes, sometimes diffusely. Pronounced epidermotropism is accompanied by hydropic dystrophy of the cells of the basal layer and loss of clarity of the basement membrane zone. The subepidermal dermis is edematous, with signs of proliferation of postcapillary venules. Often the proliferation extends to deeper parts of the dermis. It is polymorphic in nature, consists mainly of small and medium lymphocytes, partly with cerebriform nuclei, immunoblasts and histiocytes, among which are lymphoplasmacytoid and plasma cells with an admixture of eosinophilic granulocytes. Single binuclear large cells of the Hodgkin type may also be observed. Lymphocytes with characteristic cerebriform nuclei are located singly or in groups. Immunoblasts are larger cells with massive basophilic cytoplasm, round nuclei and a centrally located nucleolus. Enzyme chemical analysis revealed mononuclear phagocytes with monocytic and histiocytic properties in the infiltrate, and immunocytochemical analysis revealed a significant number of cells with T-lymphocyte markers - CD2+, CD3+, CD4+, CD5+, CD8-, CD45RO+, CD30-, T-cell receptor alpha-beta+, which allows us to consider mycosis fungoides as a T-helper lymphoma of the skin. However, in practice, T-suppressor (CD4-, CD8+) or (CD4-, CD8-) variants are occasionally encountered.

At the tumor stage of the disease, a diffuse infiltrate is observed throughout the entire thickness of the dermis with the involvement of subcutaneous adipose tissue in the process. The proliferate can penetrate the epidermis, causing its atrophy, destruction and ulceration. The composition of the proliferate directly correlates with the degree of tumor progression and, as a consequence, with the severity of the course of mycosis fungoides. Thus, with a longer and relatively benign course, it contains a large number of fibroblasts, although there are many atypical lymphocytes, among which there are giant cells resembling Berezovsky-Sternberg cells, causing similarity with lymphogranulomatosis. With a rapid and severe course, a monomorphic infiltrate develops, consisting mainly of cells such as immunoblasts, lymphoblasts and large anaplastic forms.

The erythrodermic form of Hallopeau-Besnier has the appearance of generalized esfoliative dermatitis. The histological picture resembles that of the erythematous stage of the classical form of mycosis fungoides, but is more pronounced. Significant acanthosis, extensive and dense proliferation containing a large number of lymphocytes with cerebriform nuclei are noted. Pronounced proliferation of postcapillary venules is noted.

The form of Vidal-Broca demble is quite rare, clinically characterized by the appearance of tumor nodes on unchanged skin without preceding erythematous and plaque stages. In this case, the diagnosis is made only after histological examination. The changes are similar to those in the malignant form of the tumor stage of mycosis fungoides.

Histogenesis

The cells that form the proliferate in mycosis fungoides are T-lymphocytes with varying degrees of differentiation, ranging from a stem cell to a mature lymphocyte, having a T-helper phenotype. In the late stages of mycosis fungoides, some of these cells may lose their T-helper character and acquire a more immature phenotype.

The proliferative activity of lymphocytes is directly related to the participation of the epidermis in this process. The epithelial tissue of the skin is an actively functioning system that performs a number of independent immunological functions and at the same time is in close and necessary interaction for the immune response with other immunocompetent structures of the skin, including lymphocytes. Keratinocytes are able to perceive antenna signals, initiate an immune response, influence the processes of activation, proliferation and differentiation of T-lymphocytes, and functionally interact with other skin cells. Lymphoepithelial interaction is carried out as a result of direct contact of keratinocytes and lymphocytes using complementary immune structures on the surface of the cytoplasm and cytokines, some of which are produced by epidermal cells. An important role in these processes belongs to the expression of immune-associative HLA-DR antigens, intercellular adhesion molecules - integrins b-E 7, dependent on the production of gamma interferon. A direct relationship was found between the level of gamma interferon and the severity of clinical manifestations in MLC. The second important factor regulating lymphoepithelial interaction is the system of cytokines and growth factors. The factor that triggers the secretion of a cascade of cytokines involved in the processes of inflammation and proliferation in the skin is the tumor necrosis factor. The latter, in particular, stimulates the production of IL-1, identical in its properties to the epidermal thymocyte-activating factor, responsible for the process of extrathymic differentiation of T-lymphocytes in the skin and possessing chemotaxis in relation to lymphocytes, facilitating their migration to the lesions in the skin, which is reflected in the morphological phenomena of exocytosis and Potrier microabscesses. IL-6 has a similar focus.

IL-1 stimulates the production of IL-2, a T-cell proliferation factor. Intensive expression of IL-2 on the membranes of proliferating lymphocytes (CD25) can serve as a certain indicator of the transformation of a less malignant process into a more malignant one. In addition to IL-2, IL-4 has a stimulating effect; its producers, along with Th2 lymphocytes, are malignant clonal lymphocytes, and its production is associated with gammopathies and an increase in the content of eosinophilic granulocytes in the lesions. As the process develops in the skin, a dynamic balance is formed between the mutual influence of clonal lymphocytes and the antitumor surveillance system, which ultimately determines the course of the pathological process. Cytotoxic lymphocytes, natural killers, and skin macrophages are included in the immunological surveillance system. Among the latter, an important role belongs to Langerhans cells, which carry out antigen-specific activation of T-lymphocytes, their differentiation and proliferation, as well as stimulation of cytotoxic lymphocytes. Macrophage-like dendritic cells with the CDla and CD36 phenotype also participate in antitumor surveillance, activating reactive T-lymphocytes. At early stages, the cytokine profile is determined by reactive Thl-lymphocytes synthesizing tumor necrosis factor, IL-2, and gamma-interferon. As the clone of tumor Th2-lymphocytes increases, the production of IL-4, IL-10 increases, which have an inhibitory effect on Thl-lymphocytes and natural killers and thereby contribute to tumor progression. This can also be facilitated by a decrease in the sensitivity of tumor cells to the transforming growth factor - b, which has an inhibitory effect on their proliferation. The tumor stage of mycosis fungoides is characterized by pronounced expression of IL-10 by clonal cells and low expression of γ-interferon.

Thus, malignant proliferation is based on a violation of extrathymic differentiation of T-lymphocytes under the influence of proto-oncogenic factors, in particular modified retroviruses HTLV-I with certain violations of immune cellular interactions mediated by the expression of specific receptors, adhesion molecules, and cytokines.

Symptoms of mycosis fungoides

Mycosis fungoides is less common than Hodgkin's lymphoma and other types of non-Hodgkin's lymphoma. Mycosis fungoides has an insidious onset, often manifesting as a chronic itchy rash that is difficult to diagnose. Starting locally, it can spread, affecting most of the skin. The lesions are similar to plaques, but can manifest as nodules or ulcers. Subsequently, systemic damage to the lymph nodes, liver, spleen, lungs develops, and systemic clinical manifestations are added, which include fever, night sweats, unexplained weight loss.

Granulomatous "flabby" skin syndrome

In the EORTC classification, it is placed in the section of mycosis fungoides variants. It is a very rare form of T-cell lymphoma, in which the proliferation of clonal lymphocytes is combined with pronounced degeneration of collagen fibers. Clinically, massive infiltrated formations of excess skin lacking elasticity are formed in large folds.

Pathomorphology is characterized by dense diffuse proliferations of small and large lymphocytes with cerebriform nuclei and the presence of giant multinucleated cells with a macrophage phenotype (CD68 and CD14). Staining for elastica reveals a virtually complete absence of elastic fibers. The prognosis for this form of lymphoma is unknown, but observations of its transformation into lymphogranulomatosis have been described.

Forms of mycosis fungoides

There are three forms of mycosis fungoides: the classical form of Alibert-Bazin, the erythrodermic form of Hallopeau-Besnier, the d'emble form of Vidal-Broca and the leukemic variant, referred to as Sezary syndrome.

The classic form of Aliber-Bazin is clinically and histologically divided into three stages: erythematous, plaque and tumor, although morphological elements characteristic of one or another stage may simultaneously exist.

In the erythematous stage, polymorphism of rashes is observed, which resembles various dermatoses (eczema, psoriasis, parapsoriasis, seborrheic dermatitis, neurodermatitis and erythroderma of various origins). There are scattered or merging erythematous, as well as erythematous-squamous, reddish-bluish, intensely itchy foci.

The plaque stage is characterized by the presence of multiple, sharply defined infiltrated plaques of varying sizes and densities, with a shagreen-like surface, dark red or bluish in color, often sunken in the center, with the formation of ring-shaped, and when merging - polycyclic figures. With regression, poikilodermic changes occur.

In the third stage, along with the elements listed above, nodes of a deep red color with a bluish tint appear, quickly disintegrating with the formation of deep ulcerative lesions.

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Diagnosis of mycosis fungoides

The diagnosis is based on skin biopsy, but the histology may be questionable in the early stages due to the lack of lymphoma cells. The malignant cells are mature T cells (T4, T11, T12). Microabscesses are characteristic and may appear in the epidermis. In some cases, a leukemic phase called Sezary syndrome is detected, characterized by the appearance of malignant T cells with convoluted nuclei in the peripheral blood.

Staging of mycosis fungoides is done using CT scanning and bone marrow biopsy to assess the extent of the lesion. If visceral organ involvement is suspected, PET may be performed.

Differential diagnosis of mycosis fungoides in the early stages is very difficult, there are no unambiguous criteria. A wide range of non-specific changes prevail here, which are found in contact dermatitis, noirodermatitis, parapsoriasis, psoriasis and erythroderma. Potrier's microabscesses, which can also be observed in contact dermatitis, lichen simplex chronicus, and various other forms of skin lymphomas, are not always pathognomonic. In cases of polymorphism of the proliferate at the tumor stage, it is necessary to differentiate it from lymphogranulomatosis, and in case of monomorphic proliferate - from lymphomas of another type. In these cases, it is necessary to take into account clinical data.

Changes in the lymph nodes in mycosis fungoides are quite common. Their enlargement is an early sign of mycosis fungoides. According to L. L. Kalamkaryan (1967), enlargement of the lymph nodes in stage I of the disease is observed in 78% of cases, but in stage II - in 84%, in stage III - in 97%, and in the erythrodermic form - in 100%. In stage I, a picture of non-specific reactive changes develops in them - the so-called dermatopathic lymphadenitis, which is characterized by the expansion of the paracortical zone, where macrophages containing melanin and lipids in their cytoplasm are located between the lymphocytes. In stage II of the disease, focal infiltrates are determined in the paracortical zone, an increased number of lymphocytes, including those with cerebriform nuclei. There are many reticular cells, plasma and tissue basophils, as well as eosinophilic granulocytes. Pathological mitoses are encountered. In the tumor stage, there are only small areas with preserved lymph node structure (B-zone), while the paracortical zone is completely filled with atypical lymphocytes with cerebriform nuclei and histiocytes. Sometimes multinucleated Sternberg-Reed cells are encountered.

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Treatment of mycosis fungoides

Highly effective are accelerated electron beam radiation therapy, which absorbs the energy in the outer 5-10 mm of tissue, and local nitrogen mustard treatment. Phototherapy and local glucocorticoids may be used to target plaques. Systemic therapy with alkylating agents and folate antagonists results in temporary tumor regression, but these methods are used when other therapies have failed, after relapse, or in patients with documented extranodal and/or extracutaneous lesions.

Extracorporeal phototherapy in combination with chemosensitizers demonstrates moderate efficacy. Promising in terms of efficacy are the adenosine deaminase inhibitors fludarabine and 2-chlorodeoxyadenosine.

Prognosis for mycosis fungoides

Most patients are diagnosed after the age of 50. Average life expectancy after diagnosis is about 7-10 years, even without treatment. Survival of patients depends on the stage at which the disease is detected. Patients who received therapy at stage IA of the disease have a life expectancy similar to people of the same age, gender, and race who do not have mycosis fungoides. Patients who received treatment at stage IIB of the disease have a survival rate of about 3 years. Patients with mycosis fungoides treated at stage III of the disease have an average survival rate of 4-6 years, and at stage IVA or IVB (extranodal lesions) the survival rate does not exceed 1.5 years.