Chronic lymphocytic leukemia

Chronic lymphocytic leukemia is a benign tumor, substrate which comprise mainly morphologically mature lymphocytes. The diagnosis of chronic lymphocytic leukemia is based on the finding blood and lymphatic leukocytosis diffuse lymphocytic proliferation in the bone marrow. Hyperadenosis, spleen, liver refers to the diagnostic criteria for chronic lymphocytic leukemia.

As the neoplastic process in chronic lymphocytic leukemia, apparently, involved in different cases, different clones of lymphocytes, nosological form of chronic lymphocytic leukemia should include a variety of diseases, possess a number of common features. Already morphological analysis of chronic lymphocytic leukemia reveals a variety of cell variants: the prevalence or uzkoplazmennyh, opposite, shirokoplazmennyh cell forms with younger or grubopiknotichnymi cores and intensely basophilic condensed or almost colorless cytoplasm.

To date, with the help of karyology able to confirm clonality and T-, and B-forms of chronic lymphocytic leukemia.

Lymphocyte clones with aberrant chromosome were obtained when T-forms via action on lymphocytes as a mitogen PHA. When B-lymphocytic leukemia lymphocyte division caused by exposure to polyvalent mitogens: Epstein-Barr virus, LPS from E. coli и др. Karyological data prove not only clonality, but also the nature of the mutation of chronic lymphocytic leukemia and the emergence of subclones of the development process, as can be seen on the evolution of chromosomal changes, observed in some cases.

Established, that the majority of leukemic B-lymphocytes in chronic lymphocytic leukemia monoclonal contain cytoplasmic immunoglobulin, rather, heavy chain μ- или d- or both the immunoglobulin heavy chain. Monoclonal cytoplasmic immunoglobulin proved more clearly, Monoclonal than surface, B-cell chronic lymphocytic leukemia presented immunologically immature, undifferentiated lymphocytes, located approximately at the level of pre-B-lymphocyte, although morphologically they are quite mature elements.

Manifestations of chronic lymphocytic leukemia

For many years, patients may experience a lymphocytosis - 40-50 %, although the total number of leukocytes varies near the upper limit of normal. Lymph nodes are almost normal size, but may increase with various infections. So, angina cervical lymph nodes sometimes dramatically increased, tight, slightly painful, and for the elimination of the inflammatory process is reduced to its original size.

Primarily usually gradually swollen lymph nodes in the neck, in the axillary regions, then the process extends to the mediastinum, abdominal cavity, pahovuyu region. There are common to all the phenomena of leukemia nespetsificheskne:

• Increased fatigue;
• Weakness;
• Sweating.

In most cases anemia and thrombocytopenia during the early stages of the disease not to develop.

Lymphocytosis gradually increases, with almost total replacement of bone marrow lymphocytes in the blood of their number may reach 80-90 %. Distribution of lymphatic tissue in the bone marrow can cause depression for years without the production of normal cells. Even when the high numbers of leukocytes in the blood in the --100 F 1 l am more - anemia is often missing, the platelet count is normal or slightly reduced.

In bone marrow revealed an increase of lymphocytes - usually more 30 %. This feature more or less peculiar to chronic l and m s foul goat Provided, punctate that is not significantly diluted peripheral blood. In trepanate and characteristic diffuse proliferation of lymphoid cells.

Cytological picture of chronic lymphocytic leukemia

Morphology of lymphocytes in chronic lymphocytic leukemia is not stable and characteristic features. It may change during disease influenced viral infections. Unlike other leukemias predominance of blood cells with the same name, in this case - the lymphocytes, It does not mean prevalence leukemic cells, as in circulation are often simultaneously as the B-lymphocyte leukemic clone, and increased number of polyclonal T-lymphocytes. The blood cells make up the majority of mature lymphocytes, no different from normal.

Along with such lymphocyte cells may be detected elements with more homogeneous kernel, It does not have even a rough chromatin glybchatosti mature lymphocytes, but with a broad rim of cytoplasm, which sometimes, as well as in infectious mononucleosis, a perinuclear enlightenment.

The nuclei of cells can be correctly rounded, or different kind of torsion chromatin loops, sometimes they are bean-shaped; cytoplasm with obryvchatymi contours or with the "hairy", but without the histochemical features of hairy cell leukemia.

A characteristic feature of chronic lymphocytic leukemia - The presence of dilapidated nuclear lymphocytes, clumps of chromatin with the remnants of nucleoli, referred to Botkin-calf basket cells (basket cells). Their number is not an indication of the severity of the process. These cells are an artifact leykoliza: liquid blood in them there, They are formed during the preparation of a smear. The emergence of a small number of cells, basket cells Botkin in severe infections, Acute leukemia is not a rarity, but typical glybchatye, only slightly damaged kernels lymphocytes with nucleoli residues are found almost exclusively in chronic lymphocytic leukemia (sometimes - in infectious lymphocytosis). Detection of cell-Botkin basket cells in the early stages of the disease has a diagnostic value.

In the initial stages of chronic lymphocytic leukemia prolymphocytes, lymphoblasts are usually absent in leukogram. However, there are cases, that from the beginning occur a sharp predominance of blood prolymphocytes - cells with a homogeneous nuclear chromatin, but with distinct nucleoli. On this basis allocate prolymphocytic form of chronic lymphocytic leukemia. Sometimes the leukemia can occur with the secretion of monoclonal immunoglobulin (which in some cases it is observed in normal zrelokletochnom chronic lymphocytic leukemia) .

As the disease in the blood begin to meet single prolymphocytes and lymphoblasts. A large number of them appears only in the terminal stage, it is very rare.

For chronic lymphocytic leukemia as well as many other lymphoproliferative processes, characterized hypogammaglobulinemia. And can reduce the content of all three usually studied immunoglobulins (A,G и М) or some of the.

When secreting lymphoproliferative processes along with the increase of the monoclonal immunoglobulin generally decreases the level of normal immunoglobulins (as in paraproteinemic hemoblastoses). In doubtful situations, the low diagnostic lymphocytosis fact reduce the level of normal immunoglobulin can serve as an argument in favor of the assumption of a lymphoproliferative process. However, a typical pattern can lymphocytic leukemia with normal gamma globulins and serum immunoglobulins.

Hypogammaglobulinemia is not associated with disease duration and the degree of lymphocytosis. The mechanism of its complicated. It may be due to, eg, Disruption of interaction T- and B-lymphocytes, high content of T-suppressor, failure of leukemic B-lymphocytes respond to lymphokines, produced by normal T-lymphocyte- Tami, and t. d.

In chronic lymphocytic leukemia are often observed infiltration of the VIII pair of cranial nerves: there is hearing loss, a feeling of stuffiness and tinnitus. As in other leukemias, may develop neuroleukemia, wherein, usually, we are talking about a terminal exacerbation, when the meninges infiltrate young lymphoid cells. The clinical picture neuroleukemia not differ from that in acute leukemia. Along with the infiltration of the meninges may occur infiltration of brain substance. The appearance of radicular syndrome, caused by lymphatic infiltration of spinal nerve roots, usually it occurs in the terminal stages of the disease.

One of the manifestations of severe chronic lymphocytic leukemia - pleural effusion. Nature it may vary:

• couple- or metapnevmonichesky pleurisy when banal infection;
• tuberculous pleurisy;
• lïmfatïçeskaya infiltration pleura;
• compression or rupture of thoracic duct.

When pleurisy infectious origin in the exudate, along with lymphocytes and found a large number of neutrophils. As with infiltration of the pleura, and in compression of rupture or thoracic duct lymph exudate, but in the second case it contains a large amount of fat (chylous fluid). The mechanism of development of specific lymphoproliferative pleurisy finally clarified.

Stages of chronic lymphocytic leukemia

IN initial process step shows a modest increase more lymph nodes one or two groups, leukocytosis does not exceed 30-50 g in 1 l, and, most importantly, For many months, it shows no tendency to a significant increase in his compensation in the somatic patient. At this stage, patients remain under observation hematologist, and cytostatic therapy is not carried out.

Developed stage It is characterized by progressive leukocytosis, or progressive generalized lymphadenopathy, the appearance of recurrent infections, autoimmune cytopenias. This stage requires a cytostatic therapy.

K terminal stage include cases of malignant transformation of chronic lymphocytic leukemia.

Patients die mainly due to severe infectious complications, progressive depletion, hemorrhagic syndrome, anemïey, sarcomatous growth.

Usually, chronic lymphocytic leukemia is characterized by the prolonged absence of signs of a qualitative change in the behavior of tumor cells. Signs of progress with the release of abnormal cells from the control of cytotoxic drugs may not be available throughout the disease.

In certain cases, Yet when the process proceeds to the terminal stage, it is characterized by the same symptoms, that other leukemias: inhibition of normal hematopoiesis germs, total replacement of bone marrow blast cells and T. d.

Transition of chronic lymphocytic leukemia in the terminal stage often characterized sarcomatous growth in the lymph node, What vlastnym crisis. These lymph nodes are rapidly increasing, becoming rocky density, infiltrate neighboring tissue and squeeze, causing swelling and pain, not peculiar to the growth of lymph nodes developed stage chronic lymphocytic leukemia.

Often sarcomatous growth in the lymph nodes accompanied by fever. Sometimes these sites are located in the subcutaneous tissue on the face, trunk, limbs, under the mucous membrane in the oral cavity, nose, and grew into their vessels give them a kind of hemorrhage; only the density of the "bleeding", his bulging above the surface indicate its nature.

In the terminal stages of the disease, the beginning of which is sometimes impossible to establish, considerable difficulty is determining the cause of a sudden appeared hyperthermia. It may be due to sarcomatous transformation process in the development of a long-existing chronic lymphocytic leukemia infections, especially tuberculosis. In these situations, determining the true cause of hypothermia requires consistent application of bacteriostatic drugs, a biopsy of the lymph nodes appeared tight.

Sometimes sarkomnaya transformation process, Metastatic bone marrow, manifested pancytopenia, associated with infection, whereby there sepsis.

One of the manifestations of end-stage disease can be severe renal insufficiency, which occurs due to infiltration of the parenchyma organ tumor cells. The sudden anuria should always be the basis for this assumption.

The forms of chronic lymphocytic leukemia

Although to date the standard classification of chronic lymphocytic leukemia does not exist, Based on the morphological and clinical signs, including and response to therapy, are the following forms of the disease:

1. Benign;
2. progressive (classical);
3. tumor;
4. splenomegalic;
5. medullary;
6. chronic lymphocytic leukemia, complicated cytolysis;
7. prolimfocitarnuû;
8. chronic lymphocytic leukemia, flowing with paraproteinemia;
9. Hairy Cell;
10. T-форму.

Benign form of chronic lymphocytic leukemia

Benign form of chronic lymphocytic leukemia is characterized by very slow, noticeable only over the years, not months, increase of lymphocytosis in the blood in parallel with the increase in the number of white blood cells. At the beginning of the disease or lymph nodes were not enlarged, or celebrated a very small increase in cervical nodes. Upon accession of infection may be a high (20-30 F in 1 l) lymfatycheskyy leukocytosis, which disappears when its liquidation. The period of very slow growth of lymphocytosis until the obvious increase in the lymph nodes can continue years, and decades. During this time, patients are under medical observation, Study full blood count and reticulocyte count is held every I-3 months.

The progressive form of chronic lymphocytic leukemia

Progressive (classical) form of chronic lymphocytic leukemia begins as, like the previous one, but the number of white blood cells increases from month to month, as markedly enlarged and lymph nodes. Consistency they can be testovatoy, soft or slightly elastic. Lymph nodes wood density is usually not observed, when they appear biopsy shows. Cytostatic therapy in these patients is usually appointed at the build-up of authentic manifestations of the disease, leukocytes and lymph node size - primarily.

Tumor form of chronic lymphocytic leukemia

A special feature of this form of chronic lymphocytic leukemia, which determined its name, a significant increase in the lymph nodes of the peripheral groups, often visceral lymph nodes, and a significant increase in the tonsils, sometimes almost interlocking with each other. Enlargement of the spleen often moderate, sometimes significantly (She speaks a few centimeters from the edge of the rib). Consistency dense lymph nodes. Leukocytosis, usually, short, in leukogram saved enough - 20% and more - the number of neutrophils. The bone marrow is usually not more than 20 40 % lymphocytes, though perhaps his total defeat. Histological examination of lymph node observed pattern of diffuse lymphatic infiltration zrelokletochnoy.

Despite considerable lymphatic tissue hyperplasia, intoxication for a long period of weakly expressed unlike generalized lymphosarcoma, which is sometimes identified with this form of chronic lymphocytic leukemia.

Splenomegalic form of chronic lymphocytic leukemia

Splenomegalic form of chronic lymphocytic leukemia is characterized mainly by an increase in the spleen with a moderate increase in the lymph nodes. The level of leukocytosis may be different.

From the spleen limfotsitomy form differs diffuse growth lymph elements in the bone marrow (trephine), lymph nodes and of the spleen. Often increases (not very much) and liver.

Bone marrow form of chronic lymphocytic leukemia

For this form of leukemia characterized by rapidly progressive pancytopenia, and total or partial replacement of the bone marrow is diffusely growing mature lymphocytes. Lymph nodes were not enlarged, spleen, with very few exceptions also increased, liver normal size.

Morphologically marked homogeneity of the structure of nuclear chromatin, sometimes picnotic, more rarely, the presence of elements of structure, separately reminiscent blast; cytoplasm with marked basophilic, narrow, often obryvchataya.

Chronic lymphocytic leukemia, complicated cytolysis

Chronic lymphocytic leukemia, complicated cytolysis, more often than not is diagnostic difficulties, although its clinical characteristics is not unique: may significantly increase the lymph nodes or no lymphadenopathy, very high leukocytosis or lymphatic disease course of subleukemic variant.

Enhanced dissolution of red blood cells accompanied by reticulocytosis, increased levels of bilirubin and content erythrokaryocytes in the bone marrow, its shape and the immune - positive direct Coombs test. Elevated platelet lysis determined thrombocytopenia, megakariotsitozom high or normal megakaryocyte number in bone marrow, it is easier detected in trepanate, rather than punctate.

Much more difficult to detect an increased lysis of granulocytes, as the content of their precursors in the bone marrow against the background of total lymphoid proliferation can not be determined. On increasing decay of granulocytes with a certain probability we can judge by their sudden disappearance from the peripheral blood (assess the level of granulocytes in this case, in absolute numbers). However, the nature of the cytolytic process in this case is not proven, as the possible mechanism may equally be selective suppression of the bone marrow granulocytopoiesis.

The partial disappearance of- or germ in the bone marrow is the basis for the assumption of a intramedullary cytolysis.

Prolymphocytic form of chronic lymphocytic leukemia

Prolymphocytic form of chronic lymphocytic leukemia is distinguished primarily by the morphology of lymphocytes, which smears of bone marrow (sometimes the blood), prints and histological preparations of the lymph nodes and spleen have large clear nucleoli; condensation of chromatin in the nucleus, as shown by electron microscopy, It is moderate and substantially peripherally. Cytochemical characteristics of these cells are absent.

Immunological characterization reveals the B-, the T-cell nature of lymphocytic leukemia, but more often - the first. Unlike B-CLL lymphocytes typical for this form of the disease on the surface of leukemic lymphocytes revealed an abundance of immunoglobulin M or G.

Clinical features of this form of lymphocytic leukemia – the rapid development process, significant splenomegaly and a slight increase in peripheral lymph nodes.

Apparently, this form of chronic lymphocytic leukemia should be allocated on a combination of clinical and morphological characters, and not only on the characterization of lymphocytes, There are cases of the disease with characteristic prolymphocytic leukemic lymphocytes, but with a form of chronic lymphocytic leukemia tumor, are clinically proceed more favorably, than prolymphocytic form.

Chronic lymphocytic leukemia, flowing with paraproteinemia

Chronic lymphocytic leukemia, flowing with paraproteinemia, characterized by the usual clinical picture of one of the forms listed earlier process, accompanied monoklomalnoy (M или G) hypergammaglobulinaemia (gammapatieй).

In the first case we speak of Waldenstrom's disease, the second type of secretion author no name. Any particular feature in the course of the process according to the fact that secretion of secreted immunoglobulin or the type of note fails, although the high secretion paraprotein can lead to hyperviscosity syndrome.

Hairy form of chronic lymphocytic leukemia

Hairy form of chronic lymphocytic leukemia is quite common. The name of this form due to its morphological features representing lymphocyte. The nucleus of these cells homogeneously, sometimes resembling a structural core of blasts, often irregular in shape and with indistinct contours, may contain residues of nucleoli.

The cytoplasm of the cells varied: wide with scalloped edge or obryvchataya, does not surround the entire perimeter of the cage, or processes, resembling hairs or fluff. In some cases, the cytoplasm of lymphocytes in this form of chronic lymphocytic leukemia basophilic, but mostly grayish-blue. Granularity in cytoplasm of these cells no.

Features of the structure of lymphocytes, forcing suspected hairy form of chronic lymphocytic leukemia, visible under light microscopy, but in greater detail - with phase contrast and electron.

Dough, confirming the diagnosis of hairy cell leukemia, It is cytochemical characterization of leukemic cells. Lymphocytes in this form are given a very bright diffuse reaction to acid phosphatase, Do not suppress ions tartrate (0,05 M potassium sodium tartrate). The percentage of cells reacting with the cytochemical smears blood, bone marrow, in a punctate or smears of spleen matches, usually, hairy cell number in these smears.

If the reaction to the stability of acid phosphatase tartrate ions for some reason is not entirely convincing, this form of chronic lymphocytic leukemia should be installed according to the morphological characteristics of cells and cytochemical features together, typical for them:

• vivid reaction to acid phosphatase;
• positive diffuse (small individual granules) реакции на a-нафтилэстеразу, Do not suppress sodium fluoride;
• weakly positive reaction to hloratsetatesterazu;
• PAS-positive reaction, falls in diffusely granular form;
• granular, like sickle near the nucleus, reaction to butiratesterazu.

Described cytochemical characteristic of lymphocytes hairy cell leukemia is somewhat reminiscent of cytochemical characterization of myeloid elements.

On electron microscopy, cell hairy cell leukemia immunochemical method to detect the presence in them of myeloperoxidase. It is also known, that the cells in this form of leukemia have a certain ability to phagocytosis of latex particles. These features of hairy cell leukemia cells due to prolonged existing doubts about the nature of the lymphatic.

The study showed immunological methods, In most cases it is a form of B-cell chronic lymphocytic leukemia, although the described cases of hairy cell leukemia T-lymphocyte nature. Initial normal cells - precursors of hairy cell leukemia is unknown.

The clinical picture of hairy cell leukemia It characterized by varying degrees of cytopenia - moderate to severe (there may be cases without cytopenia), increasing, sometimes significant, spleen (non-permanent signs), no increase in peripheral lymph nodes.

In trepanate bone marrow can be observed interstitial (introduced the term to describe the features of the growth of lymphocytes in the bone marrow in lymphoproliferative processes) the growth of leukemia cells, usually, not forming proliferative not completely displacing hematopoietic tissue and fat.

Histology of the spleen indicates diffuse nature of the growth of leukemic lymphocytes and red, and white pulp, which leads to disruption of the structure of the body.

Hairy cell leukemia during different. It, and other forms of chronic lymphocytic leukemia, years can not detect signs of progression. Observed granulozitopenia, which sometimes leads to fatal infectious complications, and thrombocytopenia, accompanied by hemorrhagic syndrome.

T-form of chronic lymphocytic leukemia

Chronic lymphocytic leukemia, presented by T-lymphocytes, It occurs in approximately 5% cases.

It is characterized by a large splenomegaly, often hepatomegaly, non-permanent increase in peripheral lymph nodes, more frequent lesion of visceral lymph nodes, and frequent skin lesions.

Leukemic infiltration of the skin with this form of leukemia, unlike Sezary disease observed, usually, in the deep layers of the dermis and subcutaneous tissue. The age of onset of the disease varies from 25 to 78 years.

Blood picture characterized by varying degrees of leukocytosis, neutropenia, anemia. Leukemic cells have a large round, bean-shaped, or ugly polymorphic kernel, rude, often twisted, xromatin; can be detected in the cytoplasm azurophilic granules, Larger, than conventional granules lymphocytes. The dimensions of cells are polymorphic. Cytochemical in these cells can be identified high activity of acid phosphatase (lysosomal nature), a-нафтилацетатэстеразы, located in the cytoplasm locally.

Immunologically lymphocytes, substrate components of this form of leukemia, as study of the surface markers using monoclonal antibodies, It may be in some cases, T-helper cells, other - T-suppressors, in the third - and helpers, and suppressors.

When analyzing karyological T-lymphocytes form of leukemia in Japan 90 % cases were found changes in the karyotype: especially frequent symptom was trisomy 7 pairs of chromosomes, whereas translocation of the 14th chromosome pair is rarer, than other forms of lymphatic Leukemia.

T-form progresses rapidly, so often in doubt, Does it to the chronic lymphocytic leukemia or acute lymphoblastic leukemia.