Endobronchial biopsy was performed on 10 patients of group I, 10 patients of group II and 5 patients of group III. The biopsy specimen was the same as in patients with CLL. Patients of group I were diagnosed with moderate proliferation or dystrophy of the bronchial epithelium. In patients with groups II and III, histological examination of biopsy specimens determined edema, atrophy of the bronchial mucosa, and in some cases focal squamous metaplasia of the epithelium was observed. In some patients of groups II and III, lymphocytic and plasma cell infiltration of varying severity was detected under the basement membrane. In patients of group I, there was a slight dilatation of capillaries, plethora of arterioles, capillaries and venules. Protein stasis in the vessels of the microcirculatory bed of the bronchi in patients with MM in stages IA and IIA would not be detected lo In patients with group II, dilatation and plethora of arterioles, capillaries, and venules were observed with varying degrees of severity. The number of arterio-venous anastomoses was increased. In some vessels of the microvasculature, accumulation of protein masses was noted. In patients with group III, dilatation of arterioles, capillaries, and venules was also diagnosed with varying degrees of severity. In patients with MM, complicated by CRF, in the vessels of the microvasculature, the accumulation of protein masses was more pronounced than in patients of group II. This can be explained by increased lung function in conditions of azotemic uremia .

In order to study microhemocirculation in the proximal parts of the bronchial tree, 30 patients with MM underwent endobronchal LDF (10 patients from group I, 10 from II and 10 from group III). The results were compared with the data of 20 people from the control group, who were conducted PBS and LDF. In patients with MM in the course of tumor progression, disturbances of microcirculatory blood circulation in the bronchial mucosa were recorded in terms of the nature and severity of the microcirculatory circulation.

The indicator of the microcirculation parameter (PM), which characterizes the state of tissue perfusion, was significantly reduced as MM progressed. In multiple myeloma, impaired microhemocirculation in the lungs and bronchi is primarily due to the syndrome of increased blood viscosity and anemia. In order to minimize the effect of anemia on the PM indicators, in patients with MM groups II and III, the anemic syndrome was stopped before the study. The hemoglobin level during LDF was not lower than 100 g / l, the content of erythrocytes was not lower than 3 × 10 9 / l. Thus, they tried to establish a decrease in the speed of red blood cells in the microvessels, which, in MM, is primarily due to the syndrome of increased blood viscosity. A significant inverse correlation was established between an increase in the serum paraprotein level and a decrease in PM (r = –0.8, P <0.01), between the duration of the disease MM and a decrease in PM (r = –0.64, P <0.05). ), between an increase in the level of creatinine in the blood and a decrease in the PM (r = –0.5, P <0.05).

The values ​​of the mean square deviation of PM (σ), reflecting the preservation of the mechanisms of blood flow regulation in the microcirculatory bed, in patients of groups I and II did not have significant differences compared with the control (P> 0.05), and decreased in group III ( P <0.001) . The coefficient of variation (Kv), which characterizes the dependence of tissue perfusion on blood flow modulation, increased during tumor progression and in all groups significantly exceeded control (P <0.001) .

When analyzing the rhythmic components of blood flow oscillations, a decrease in e-range fluctuations was observed in patients of groups II and III. In group I patients, the amplitude of oscillations in the E-band did not differ from the control indices (Table 30). A decrease in the amplitude of oscillations in the E-band indicates endothelial dysfunction and a decrease in the production of nitric oxide in MM patients in the later stages of the tumor progression. The decrease in endothelial oscillations correlated with the stage of the disease (r = –0.72, P <0.01), the level of paraprotein (r = –0.56, P <0.05) and blood creatinine (r = –0.56 P <0.05). Since in patients with another lymphoproliferative disease – CLL, there are no changes in endothelial oscillations, it can be assumed that, in MM, important factors for the development of endothelial dysfunction are paraproteinmia,dysproteinemia and uremic intoxication. Endothelial dysfunction of the microvasculature vessels contributes to a severe and prolonged course of inflammatory processes of the bronchopulmonary system in patients with MM and an increase in pressure in the pulmonary artery system.

In patients with MM, no significant changes in the oscillations in the H-, M-, D- bands were detected. The amplitudes of oscillations in the C-band in patients with MM decreased in the course of tumor progression; in group I, they did not have significant differences compared to control; in groups II and III, the indices of cardiac waves decreased significantly (P <0.05 and P <0.001, respectively). A decrease in cardiac wave values ​​indicates a decrease in arterial blood flow into the microvasculature due to the development of a syndrome of increased blood viscosity. According to the data of endobronchial biopsy, in patients of the third group, protein stasis is more pronounced than in patients of the second group; therefore, in the presence of renal insufficiency, the smallest indicators of vibration amplitudes in the C-band were recorded.Significant inverse correlations were found between the level of serum paraprotein of the blood and a decrease in fluctuations in the C-range (r = –0.7, P <0.01), between the duration of MM disease and a decrease in the fluctuations in the C-range r = – 0.58, P <0.05), between the level of blood creatinine and the decrease in fluctuations in the C-band (r = –0.5, P <0.05).

It is obvious that similar violations of microhemocirculation occur in the lungs. Thus, in a significant number of patients with MM II and III groups, during radiological methods of examination, there is an increase and deformation of the pulmonary pattern, which is caused by stagnation of blood in small vessels with the development of pneumosclerosis, since due to the increased viscosity of the plasma, blood flow slows down pulmonary capillary system.

Disruption of microhemocirculation contributes to the violation of tissue trophism, the development of tissue hypoxia, metabolic disorders in the cells of the bronchial mucosa. The consequence of this are atrophic changes in the bronchial mucosa. In 40% of MM patients, bilateral diffuse atrophic endoscopy develops. At the same time, in patients with MM, in contrast to patients with CLL, outside the attachment of AML, in no case was a latent inflammatory process occurring in the bronchial mucosa, despite the fact that CLL also shows markedly abnormal microhemomas in the process of tumor progression. – circulation. This can be explained by a more pronounced decrease in cellular and humoral immunity in patients with CLL compared with patients with MM . In patients with CLL, due to the deep mismatch of all parts of the cellular and humoral immunity, against the background of a violation of the trophism of the bronchial tissues, the inflammatory process quickly develops and then acquires a chronic course.

Disruption of microhemocirculation in the vessels of the lungs and bronchi, along with pronounced secondary immunodeficiency, lymphoid and plasma cell infiltration of the lung tissue, paraproteoinosis of the lungs, contribute to the occurrence of severe and prolonged pneumonia in patients with MM. So in patients with MM I group, where no microcirculation disorders were detected, pneumonia was not registered. In group II, pneumonia was diagnosed in 10 patients (18% of the total number of patients in this group), in group III in 23 patients (42%).

The effect of cytostatic therapy on microhemocirculation indices in patients with MM was studied. In cases where, after carrying out cytostatic treatment, it was possible to reach the phase of a stable “plateau”, a decrease in blood paraprotein was noted, endobronchial LDF was repeated for MM patients. In all, an increase in the PM indices was noted, but in no case did the PM indices completely normalize. An improvement in the amplitudes of oscillations in the endothelial and cardiac ranges was noted. (Table 31).

The persistence of endobronchial microhemocirculation disorders in patients with MM, after reaching the “stable plateau” phase, is explained by the multifactorial nature of the microcirculatory disorders. In addition to the syndrome of increased blood viscosity and anemia, impaired platelet and plasma hemostasis, vascular endothelium, regulation of tissue vascular tone, pH and pO 2 , hormonal background and many other factors affect the microcirculation . In the majority of patients with MM, the plateau phase maintains a minimum PIg production.

As in CLL patients with MM, a high degree of effectiveness of the endobronchial LDF method was noted for identifying vascular and intravascular disorders of the microvasculature of the mucous bronchi in the early stages of the pathological process. The role of LDF in the diagnosis of endothelial dysfunction of microvasculature vessels is very important . The use of this method allows to assess the dynamics of microcirculatory disorders in the mucous membrane of the proximal bronchi during the treatment of myeloma.

According to the data of zonal rheography of the lung in patients of the I group, there were no violations of the general and regional ventilation of the lungs, the vertical gradient of ventilation characteristic of healthy people remained unchanged . The ratio of MOVR of the upper zones / MOVR of the lower zones did not have significant differences compared with the control . No significant impairment of the pulsatory blood flow in this group was also detected. The regional VPO indicators and the total VPO indicator of both lungs did not differ from the control indicators.

Note: P 1 – the significance of differences compared with the control; P 2 – the significance of the difference between the indices of LDF, before and after achieving remission.

In patients with MM of group II, during reopulmonography, there is a decrease in general and regional ventilation of the lungs . A significant decrease in ventilation in the middle and lower zones of both lungs, a decrease in the total MOBP from all zones of the lungs by 29.4% (P <0.05) and redistribution of ventilation from the lower and middle to the upper zones of both lungs were diagnosed . A decrease in the rheographic index of systolic blood filling (SCR) and the index of minute pulsatory blood flow (MPCr) in the right lung was diagnosed. The mccr of the right lung is reduced, compared with the control, with a reliability of <0.05. In the left lung, a significant decrease in blood flow occurred only in the middle zone. The cumulative index of MCR had no significant difference with the control (P> 0.05) . A significant increase in vascular resistance was noted in the lower and middle (to a lesser extent) zones of both lungs, which can be judged by the decrease in HSC and in the length of the Q-interval . But there was no significant redistribution of pulmonary blood flow in patients of group II. Estimating the state of the venous outflow in the small circle of blood circulation due to DSC change, an increase in this index was found in the middle and lower zones, with the greatest values ​​of the coefficient in the basal regions of the lungs. Significantly reduced VPO upper and lower zones and the left lung as a whole (P <0.001). Despite the fact that in the right lung the integral indicator of HPE did not have significant differences with the control, the total index of HPE of both lungs was reduced .

The lethal outcome was ascertained in 65 patients with MM. In the overwhelming majority of cases, death occurred due to the progression of the underlying disease — the presence of myeloma nephropathy, complicated by chronic renal failure (52 patients — 80%); hemorrhagic syndrome due to deep thrombocytopenia; anemic syndrome. Pneumonia and its complications were diagnosed in 28 patients (43% of all died), in all cases it was the direct cause of death. In 28 of 52 patients with MM (53.8%) who died with symptoms of myelomous nephropathy and chronic renal failure, inflammatory infiltrates were found in the lungs (in this situation, pneumonia was also the direct cause of death ).

A morphological study of the lungs, bronchi, and pleura of 65 patients who died from MM was performed . The following changes were diagnosed . In 26 people (40%), lymphoid and plasma cell infiltration took place in the form of cords or nodes in the inter-alveolar septa, along the vascular adventitia, in the bronchial mucosa and in the peri- bronchial spaces . The interalveolar septa were thickened due to their infiltration with plasma cells and / or lymphocytes.

Paraproteinosis of the lungs was diagnosed in 38 patients (58%). The protein masses filling the pulmonary alveoli created a pattern of protein pulmonary edema, impregnated thickened, hyalized interalveolar septa and filled small vessels (Fig. 36 – 37). Plasma cells and lymphocytes were often able to be detected along the periphery of protein masses . Manifestations of amyloidosis in this study were detected only in 9 patients (13.8% of all deaths). The masses of amyloid were stained red when using congo-mouth staining. In these patients, there was a deposition of protein masses in the alveolar spaces, perivascular, peribronchial, and also in the walls of blood vessels .

Plasma and lymphoid infiltration of the pleura occurred in 8 (12.3%) patients with MM and was accompanied by the development of exudative pleurisy, which is an extremely unfavorable preventive factor .

In 51 patients (78%), histological examination diagnosed pneumosclerosis. In 16 people (24.6%), foci of calcification were found in bronchial cartilage and interstitium. The occurrence of calcium deposits causes an inflammatory reaction with the next development of fibrosis . Many patients had one hundred uneven blood supply of pulmonary vessels, small perivascular hemorrhages. Foci of atelectasis alternated with areas of emphysematous expansion of the alveoli. In this case, we can speak of the compensatory nature of the localized emphysema. Since, due to the deposition of paraprotein and the development of atelectasis, some alveoli are excluded from ventilation, the ventilation capabilities of other alveoli are reduced as a result of edema, fibrosis, lymphoid and plasma infiltration of the interalveolar septa, the compensatory expansion of the preserved alveoli occurs.

Classification of hematopoietic and lymphoid tissue tumors. WHO

Less than 7 years separates this edition from the first consensus classification of lymphomas, published in the journal Blood in 1994. The implementation of this project in one of the most difficult areas of onco-hematology can be an example of the coordinated work of pathologists from various countries and scientific schools aimed at achieving a common goal – systematization and generalization of extensive molecular biological, genetic, immunological and morphological knowledge of lymphomas in the form of a list of actually existing ones (consonance to the accustomed abbreviation REAL — from English. Revised Eur opean American Lymphoma classification) of nosological units.

To be fair, it should be noted that by far not all the publication of the REAL classification in 1994 was accepted without objection. The work was criticized by the editors of the journal Blood. Serious complaints related to the clinical significance of the classification, its reproducibility, and even the very principle of diagnosis, taking into account the T or B linearity of the tumor cells, has been questioned.

A special clinical committee of leading hematologists of the world was established, which confirmed the clinical significance of the classification.

The final classification takes into account the comments made, and it differs significantly from the first publication. Added new nosological forms, many of the previously proposed are excluded.

“Nowhere in pathology is the chaos of names obscured by clear concepts to the same extent as in the subject of lymphoid tumors.” I want to believe that these words of RA Willis are in the past, and the modern names of variants of lymphomas, giving an increasingly complete picture of the nature of tumor cells based on their degree of maturity and linear affiliation, will, on the contrary, clarify the essence of these diseases and contribute to their more effective treatment. .

Acute myeloid leukemia

Acute myeloid leukemias with multilinear dysplasia in residual normal sprouts of hemopoiesis are distinguished on the basis of certain morphological features, the presence of which sometimes makes it difficult to diagnose a specific variant of acute leukemia. In accordance with recent views in the classification indicates that the presence of multilinear dysplasia is a poor prognostic sign. A number of authors, including us, have shown that the presence of dysplasia does not in itself have a negative prognostic value, and a poor prognosis is determined by the frequent presence of unfavorable chromosomal aberrations in patients of this group. Most likely, this rubric will disappear from the classification in the future.

Rationally, in our opinion, the selection in a separate section of acute myeloid leukemia and myelodysplastic syndromes, the development of which can be associated with previous therapy, mainly with the use of alkylating drugs, topoisomerase II inhibitors and radiation therapy. These leukemias also have fairly well-defined biological features — often a period of myelodysplasia preceding the development of leukemia, often with characteristic or multiple chromosomal aberrations, often worse than de novo response to therapy and prognosis. In this group, in each case, when making a diagnosis, the notation is used in accordance with the FAB classification.

If acute myeloid leukemias do not belong to any of the listed groups, they are characterized in accordance with the FAB classification. It should be noted that in practice the classification of FAB is always used, and this must be recognized as rational, as it allows you to accurately determine which variant of acute myeloid leukemia is involved, and thus avoid erroneous conclusions in assessing the results obtained by different authors.

Myelodysplastic syndrome

Significant changes have been made in the classification of myelodysplastic syndromes compared with the FAB classification. Cases with the number of power cells of more than 20%, previously designated as RAIB-T (refractory anemia with an excess of blast at the stage of transformation into acute leukemia), are now considered as acute leukemia, which should be considered completely fair, given the further development of the disease in cases of with so many blast cells and, as a rule, the rapid emergence of all signs of acute leukemia.

It is fair to recognize the release of refractory cytopenia with dysplasia of two or more sprouts of hemopoiesis {refractory cytopenia with multilinear dysplasia). Hematologists are well aware that there are various variants of cytopenia with dysplasia or cases of multilinear dysplasia, but without anemia. Previously, they all had to be designated as refractory anemia.

The allocation of unclassifiable myelodysplastic syndrome is correct, since it is often in the group of myelodysplastic syndromes that there are often cases when, in the presence of obvious features of myelodysplasia, the disease for a very long time is difficult to attribute to a specific variant. A completely new is the allocation of myelo-dysplastic syndrome with an isolated deletion of the long arm of chromosome 5 – 5q- syndrome. In recent years, this syndrome has been considered as a special variant of myelodysplastic syndrome, characterized by significant anemia and at the same time a favorable long course. It is a more favorable prognosis than with other variants of myelodysplastic syndromes, and the absence of the need for intensive therapy serve as the basis for highlighting this option in a separate rubric.

In the rubric of acute myeloid leukemia, the WHO classification has made significant changes compared to the FAB classification, but it should be immediately emphasized that the FAB classification has also been preserved.

According to the WHO classification, all acute myeloid leukemias are divided into 5 categories based on the biological properties of the tumor: 1) with recurring chromosomal abnormalities; 2) with multilinear dysplasia; 3) acute leukemia and myelodysplastic syndromes, the development of which is associated with previous therapy; 4) acute leukemia, which cannot be characterized on the basis of any biological features; 5) acute leukemia of unclear linear affiliation (undifferentiated, bilinear and biphenotypic).

Acute leukemias with recurring chromosomal abnormalities are acute myeloblastic leukemia with t (8; 21), acute myeloid leukemia with eosinophilia in the bone marrow and aberrations of chromosome 16, acute promyelocytic leukemia with t (15; 17) and acute myeloid leukemia with aberrara leukemia with aberara leukemia with aberara leukemia with ab (15; 17) chromosomes 11-11q23.

All leukemias of this group are distinguished by certain biological features: often the characteristic morphology of tumor cells, which allows a diagnosis to be made on the basis of a morphological study and, in most cases, a predictable reaction to modern therapy. Isolation of this group of leukemias is important because they have certain approaches to therapy.
Translocation (15; 17) is pathognomonic for acute promyelocytic leukemia, in which the use of ATRA is necessary from the first days of treatment. This drug has fundamentally changed the prognosis of the disease. With modern therapy, the prognosis for leukemias with t (8; 21) and aberrations of chromosome 16 with eosinophilia in the bone marrow is generally favorable, but for leukemia with aberrations of chromosome 16, only with consolidation of remission with high doses of cytosar. The prognosis is much worse in the presence of changes in the llq23 region, therefore the detection of this aberration necessarily implies intensive therapy.

Thus, the biological characteristics of the leukemias of this group, as well as a specific reaction to therapy, justify the isolation of the leukemias of this group into a separate heading in the classification. At the same time, when establishing a diagnosis for a specific patient, each of the leukemias of this rubric is still characterized in accordance with the FAB classification.

Myeloproliferative Diseases

Among myeloproliferative diseases, “unclassifiable” is also indicated. This category includes diseases that have all the features of myeloproliferative, but without a sufficient number of signs that can be attributed to any specific nosological unit. The merit of the authors of the classification is in strict caution against making a diagnosis of myeloproliferative unclassifiable disease in those cases when all modern diagnostic methods that make it possible to accurately identify the diagnosis were not used. It is indicated that most often after some time, in cases initially diagnosed as unclassifiable, certain features of true polycythemia, or chronic idiopathic myelofibrosis, or essential thrombocythemia, appear.

In chronic myeloproliferative / myelodysplastic diseases, there are features of delayed maturation and dysplasia in any of the hematopoietic lines and / or ineffectiveness of hematopoiesis in this line. It seems to us absolutely correct to assign chronic myelomonocytic leukemia to this group, which was previously considered as one of the variants of myelodysplastic syndromes and which certainly has features of both myeloproliferative and myelodysplastic diseases. There is no doubt that the classification of juvenile myelomonocytic leukemia to this category is correct.

This group also contains a rare disease – atypical chronic myeloid leukemia, for which the term “subacute myeloid leukemia” was used long ago. The disease is characterized by hyperleukocytosis, the presence of young forms of granulocytes in the blood (promyelocytes, myelocytes, metamyelocytes), the absence of basophilia and the presence of signs of dysplasia in the cells of the granulocytic germ and sometimes also in the cells of the erythroid and / or megakaryocytic germ hemopoiesis. Chromosomal aberrations are common, but there are no specific ones among them, in particular, Ph (BCR-ABL) is not detected. The level of alkaline phosphatase in neutrophils can be any. Most likely, pathogenetic mechanisms of the development of this disease will be established in the future and it will be identified more specifically.

In this category also has unclassifiable myelodysplastic / myeloproliferative disease, which the authors designated as a disease having both laboratory features of one embodiment myelodysplastic syndrome and myeloproliferative process, such as thrombocytosis, or simultaneously features myeloproliferative and myelodysplastic processes which can not be attributed to any specific category . Chromosomal aberrations can occur, but are not specific to a particular disease.

It should be recognized that almost every hematologist meets with diseases that can not be attributed to any particular category. The merit of the authors of the classification is that they have designated this provision, although the term “unclassifiable” disease, even assigned to a specific group, cannot fully satisfy. It reflects the current state of science and the obscurity of the biological mechanisms underlying some clinical and morphological syndromes.

Chronic neutrophilic leukemia

Chronic neutrophilic leukemia differs in the blood picture from chronic myeloid leukemia by its lower leukocytosis and the absence of immature forms of myelopoiesis in the blood or by the presence of very small numbers of them. These signs are not enough for the differential diagnosis of these diseases, so the diagnosis of neutrophilic leukemia is made only on the basis of cytogenetic data. Previously, Ph (BCR-ABL) -negative cases and BCR-ABL-positive chronic myeloid leukemia with p230 protein production were ranked as chronic neutrophilic leukemia. In this classification, the diagnosis of chronic neutrophilic leukemia is left only for the BCR-ABL-non-affective variant; a disease with t (9; 22) and p230 protein production is considered as a variant of chronic myeloid leukemia. This seems to us to be absolutely fair and corresponding to the role of t (9; 22) in the pathogenesis of the disease.

In determining chronic eosinophilic leukemia and the hypereosinophilic syndrome, difficulties in differential diagnosis are emphasized. Currently, the hypereosinophilic syndrome includes a heterogeneous group of diseases characterized by persistent high eosinophilia of unknown origin. Appeared work, which showed that, at least in some cases, high eosinophilia occurs as a result of interstitial deletion of the long arm of chromosome 4 and the consequent formation of a chimeric gene with tyrosine kinase function. It is possible that such cases will be referred to as eosinophilic leukemia and the name “hypereosinophilic syndrome” will disappear, but now this term is used in all publications.

It should be recognized that this introduces a certain confusion, since reactive eosinophilia is sometimes described in practice under this term. At the same time, hypereosinophilic syndrome is a clearly defined symptom complex with a severe course and almost always an extremely poor prognosis. Cytogenetic analysis in cases of hypereosinophilia of unclear genesis is very important, since with eosinophilic syndrome with interstitial deletion of chromosome 4, Gleevec is effectively used.

Classification of hematopoietic and lymphoid tissue tumors. WHO

Work began in 1995. Initially, it was carried out by 10 national committees, which included more than 50 leading pathologists in the world. The classification is based on the same principles that were used as the basis for the REAL classification of lymphomas (Revised European-American Classification of Lymphoid Neoplasms): morphological (histological and cytological) studies, immunophenotyping, cytogenetic research and analysis of clinical data are necessary to establish the diagnosis. Thus, when creating the classification, the authors were based on the biological features of the tumor determined by modern methods.

As soon as the classification was formulated by pathologists, a committee was created to verify its clinical value, which included more than 40 leading oncologists and hematologists in the world. After their work in 1997 at a special meeting of clinicians and pathologists, all the disputed clinical issues were discussed and agreed upon. Only after an agreement was reached at this meeting, was the WHO classification finalized and published.

Thus, as a result of the involvement of many specialists in most countries, the WHO classification has become the first classification of hematological tumors that is currently accepted and used throughout the world. Nevertheless, there are controversial issues in the classification. In all likelihood, it will still be refined and changed.

In the WHO classification, all hematological neoplasms are divided into groups according to the blood line to which the cells constitute the morphological substrate of this tumor: tumors from myeloid cells, lymphoid cells, histiocytic / dendritic cells (histiocytosis) and mast cells (mastocytosis).
Tumors from lymphoid cells in accordance with this classification are discussed in detail in the manual, but here is the view of one of the well-known immunologists, prof. N. N. Tupitsyn on the value of this classification. At the same time, the section on tumors of myeloid cells, in our opinion, should be considered.

Tumors from myeloid cells are divided into 4 large groups:

1) chronic myeloproliferative diseases;
2) diseases that have features of both myeloproliferative diseases and myelodysplasias;
3) myelodysplastic syndromes;
4) acute myeloid leukemia.