Mushroom mycosis

Mushroom-like mycosis refers to low-grade T-cell lymphomas.

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

[1], [2]

Pathomorphology of fungal mycosis

In the early stage of fungal mycosis (erythematous), the histological pattern in many cases resembles that of subacute or chronic dermatitis and eczema. Acanthosis, hyperkeratosis with exfoliation, small-focal parakeratosis, spiny focal spongiosis in the spinous layer, sometimes with the formation of subthreshold vesicles, exocytosis of lymphocytes, small-focal hydroponic dystrophy cells of the basal layer. In the dermis - small, mainly perivascular infiltrates from lymphocytes with an admixture of histiocytes, a small number of plasma cells and zosinophils. With a more thorough study in the infiltrate, one can find, albeit in small numbers, lymphocytes with cerebriform nuclei (Cesari or Lutzner cells).

In the plaque stage, the epidermis usually has a pronounced acanthosis and is characterized by the micro-effects of Sodium, which are located in its various layers. Exocytosis of mononuclear cells is observed both in the epidermis and in the epithelium of the hair follicles with accumulation in the last municidal substance. The proliferation is mostly striped, sometimes diffusely. Severe epidermotropism is accompanied by hydrophilic dystrophy of the basal layer cells and loss of clarity of the basal membrane zone. Subepidermal dermis edematous, with signs of proliferation of postcapillary venules. Often the proliferation spreads to deeper parts of the dermis. It is polymorphic in nature, consisting mainly of small and medium lymphocytes, partly with cerebriform nuclei, immunoblasts and histiocytes, among which are lymphoplasmocytic and plasma cells with an admixture of eosinophilic granulocytes. Single single-binuclear large cells of the Hodgkin type can also be observed. Lymphocytes with characteristic cerebriform nuclei are located singly or in groups. Immunoblasts are larger cells with massive basophilic cytoplasm, rounded nuclei and centrally located nucleolus. Enzymochemically, mononuclear phagocytes with monocytic and histiocytic properties were detected in the infiltrate, and a significant number of cells with T-lymphocyte markers-CD2 +, CD3 +, CD4 +, CD5 +, CD8-, CD45RO +, CD30-, T-cell receptor of alfa-beta +, that allows to consider mushroom-like mycosis as T-helper lymphoma of the skin. However, in practice, T-suppressor (CD4-, CD8 +) or (CD4-, CD8-) variants are occasionally found.

In the tumor stage of the disease, a diffuse infiltrate is observed throughout the entire thickness of the dermis, involving the subcutaneous adipose tissue in the process. Proliferation can penetrate the epidermis, causing its atrophy, destruction and ulceration. The composition of proliferates directly correlates with the degree of tumor progression and as a consequence with the severity of the course of the fungal mycosis. Thus, with a longer and relatively benign flow 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 to lymphogranulomatosis. With a rapid and severe course, a monomorphic infiltrate develops, consisting mainly of cells like immunoblasts, lymphoblasts and large anaplastic forms.

The erythrodermal form of Allopo-Bénier has the appearance of generalized esfoliated dermatitis. The histological pattern resembles that in the erythematous stage of the classical form of fungal mycosis. But more sharply expressed. Significant acanthosis, extensive and dense proliferates, containing a large number of lymphocytes with cerebral nuclei are noted. There is pronounced proliferation of postcapillary venules.

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

Histogenesis

Cells that form proliferates in mushroom mycosis are T-lymphocytes with different degrees of differentiation, starting from the stem cell to the mature lymphocyte, having the T helper phenotype. In the late stages of fungal mycosis, some of these cells may lose the character of T-helpers and acquire a more immature phenotype.

Proliferative activity of lymphocytes is directly related to the involvement of the epidermis in this process. Epithelial skin tissue is an actively functioning system that performs a number of independent immunological functions and at the same time is in close and necessary interaction with other immunocompetent structures of the skin, including lymphocytes, for the immune response. Keratinocytes are able to perceive the antennal signals, initiate an immune response, influence the activation, proliferation and differentiation of T lymphocytes, interact functionally with other skin cells. Lymphoepithelial interaction is realized as a result of direct contact of keratinocytes and lymphocytes with the help of complementary immune structures on the surface of cytoplasm and cytokines, some of which are produced by epidermal cells. An important role in these processes belongs to the expression of immunoassociative HLA-DR antigens, intercellular adhesion molecules - integrins of b-E 7, which depend on the production of gamma-interferon. A direct relationship between the level of gamma-interferon and the severity of clinical manifestations in ZLK was revealed. The second important factor in the regulation of lymphoepithelial interaction is the system of cytokines and growth factors. The factor triggering the secretion of the cytokine cascade 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, which is identical in its properties to the epidermal thymocyte-activating factor, responsible for the process of non-immune differentiation of T-lymphocytes in the skin and chemotaxis in relation to lymphocytes, facilitating their migration to the lesions in the skin, which is reflected in the morphological phenomena of exocytosis and microabscesses. IL-6 has a similar orientation.

IL-1 stimulates the production of IL-2, a factor of T-cell proliferation. Intensive expression of IL-2 on proliferating lymphocyte membranes (CD25) can serve as a definite indicator of the transformation of a less malignant process into a more malignant one. In addition to IL-2, IL-4 possesses a stimulating effect, in addition to Th2-lymphocytes, there are malignant clonal lymphocytes and whose production is associated with gammopathies and an increase in the content of eosinophilic granulocytes in the lesions. As the process develops, a dynamic balance of the mutual influence of clonal lymphocytes and the system of antitumor surveillance develops in the skin, which ultimately determines the course of the pathological process. The system of immunological surveillance includes cytotoxic lymphocytes, natural killers, macrophages of the skin. Among the latter, an important role belongs to the cells of Langerhans performing antigen-specific activation of T lymphocytes, their differentiation and proliferation, as well as stimulation of cytotoxic lymphocytes. Macrophage-like dendritic cells with the phenotype CDla and CD36 also participate in antitumor surveillance, activating reactive T-lymphocytes. In the early stages of the cytokine profile, reactive Thl-lymphocytes synthesizing the tumor necrosis factor, IL-2, gamma-interferon are determined. As the clone of tumor Th2 lymphocytes increases, the production of IL-4, IL-10 increases, which exert a retarding effect on Thl-lymphocytes and natural killers and thereby promote tumor progression. The same can contribute to 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 fungal mycosis is characterized by pronounced expression of clonal cells of IL-10 and low expression of γ-interferon.

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

Symptoms of mushroom mycosis

Mushroom mycosis is less common than Hodgkin's lymphoma and other types of non-Hodgkin's lymphomas. Mushroom mycosis has a latent origin, often manifesting as a chronic itchy rash, difficult to diagnose. Starting locally, it can spread, affecting most of the skin. Places of damage are similar to plaques, but can manifest as nodules or sores. Subsequently, systemic damage to the lymph nodes, liver, spleen, lungs develops, systemic clinical manifestations are added that include fever, night sweats, unexplained weight loss.

Syndrome of granulomatous "sluggish" skin

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

Pathomorphology is characterized by dense diffuse proliferates from small and large lymphocytes with cerebral nuclei and the presence of giant multinucleate cells with a macrophage phenotype (CD68 and CD14) among them. The coloring on the elastic reveals the almost complete absence of elastic fibers. The prognosis for this form of lymphoma is unknown, however, observations of its transformation into lymphogranulomatosis are described.

Forms of mushroom mycosis

There are three forms of fungal mycosis: the classical form of Aliber-Bazin, erythrodermic Allopo-Bienier, the Vidal-Broca d'emble form and the leukemia variant, referred to as Cesari syndrome.

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

In the erythematous stage there is a polymorphism of the rashes, which resembles various dermatoses (eczema, psoriasis, parapsoriasis, seborrheic dermatitis, neurodermatitis and erythrodermia of various origin). There are scattered or fused erythematous, as well as erythematous-squamous, reddish-cyanotic color, strongly itching foci.

The plaque stage is characterized by the presence of multiple, sharply outlined infiltrated plaques, of various sizes and densities, with a shagreen-like surface, dark red or bluish color, often sinking in the center, forming annular, and when merging - polycyclic figures. With regression, there are poikilodermic changes.

In the third stage, along with the elements listed above, there are nodes of a rich red color with a bluish tinge, rapidly disintegrating with the formation of deep ulcerative lesions.

[3], [4], [5]

Diagnosis of mushroom mycosis

The diagnosis is based on the results of a study of skin biopsy specimens, but a histological picture at an early stage may be questionable due to an insufficient number of lymphoma cells. Malignant cells are mature T cells (T4, T11, T12). Characteristic are microabscesses, which can appear in the epidermis. In some cases, a leukemia phase is identified, called the Cesary syndrome, characterized by the appearance of malignant T cells with sinuous cores in the peripheral blood.

Staging of fungal mycosis is performed using CT scan and bone marrow biopsy examination to assess the extent of the lesion. PET can be performed if suspicion of involvement of visceral organs is suspected.

Differential diagnosis of fungal mycosis at early stages is very difficult, there are no unambiguous criteria. Here a wide range of nonspecific changes prevail, which occur in contact dermatitis, atrodermite, parapsorizme, psoriasis and erythrodermia. Patients, which can also be observed with contact dermatitis, lichen simplex chronicus, various other forms of lymphomas of the skin, are not always pathognomonic. In the tumor stage in cases of polymorphism of proliferates it is necessary to differentiate it from lymphogranulomatosis, and in case of monomorphic proliferation it is differentiated from lymphoma of another type. In these cases it is necessary to take into account clinical data.

Changes in the lymph nodes with mushroom mycosis are quite frequent. Increasing them is an early indication of fungal mycosis. According to LL, Kalamkaryan (1967), lymph node enlargement in the first stage of the disease is observed in 78% of cases, but II - in 84%, in III - in 97%, and in erythrodermic form - in 100%. In the first stage, they develop a pattern of nonspecific reactive changes - the so-called dermatopathic lymphadenitis, which is characterized by an expansion of the paracortical zone, where between the lymphocytes there are macrophages containing melanin and lipids in their cytoplasm. In stage II of the disease in the paracortical zone, focal infiltrates, an increased number of lymphocytes, including cerebroform nuclei, are determined. Many reticular cells, plasma and tissue basophils, as well as eosinophilic granulocytes. There are pathological mitoses. In the tumor stage there are only small areas with a preserved lymph node structure (B-zone), the paracortical zone is completely filled with atypical lymphocytes with cerebral nuclei and histiocytes. Sometimes there are multinuclear Sternberg-Read cells.

[6], [7], [8]

Treatment of mushroom mycosis

Radiation therapy with accelerated electrons is highly effective, at which energy is absorbed in external 5-10 mm tissue, and local treatment with nitrogen mustard. To influence the plaques, phototherapy and topical glucocorticoids can be used. Systemic therapy with alkylating agents and antagonists of folic acid leads to a temporary regression of the tumor, but these methods are used in the ineffectiveness of other therapies, after relapse, or in patients with documented extranodal and / or subcutaneous lesions.

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

Prognosis with mushroom mycosis

In most patients, the diagnosis is set at the age of over 50 years. The average life expectancy after diagnosis is about 7-10 years, even without treatment. Survival of patients depends on the stage at the time of detection of the disease. Patients who received therapy at the IA stage of the disease have a life expectancy similar to those corresponding to age, sex and race to people who do not have fungal mycosis. In patients who received treatment for stage IIB disease, the survival rate is about 3 years. In patients with fungal mycosis, treated at stage III of the disease, the average survival is 4-6 years, and in IVA or IVB stage (extranodal lesions), the survival rate does not exceed 1.5 years.