Leukemias Tamara Datsko associate Professor of Pathology, sectional course and forensic medicine

Leukemia is a malignant neoplasm of hemopoietic tissues (blood-forming tissues) which are characterized by the progressive overgrowth of tumour cells-leukemia cells. First tumour cells increase in hematopoietic organs (bone marrow, lymph nodes, spleen) and then hematogenously spread in the whole organism with the infiltration of some organs; and also appear in circulating blood.

Progressive overgrowth of leukemia cells leads to anaemia, hemorrhagic syndrome, dystrophic changes in parenchymal (parenchymatous) organs, immunity oppression, ulcero-necrotic and septic complications.

Leukemia etiology can not be always identified because it is a polyethiologic disease. The cause can be genetic and inherited factors, chromosomal anomaly, and all factors which can cause cellular mutation in the hematopoietic system. These factors are: viruses (retrovirus HTLV-I, II, Epstein-Barr DNA-virus), ionizing radiation, chemical compounds (benzpyrene, pesticides, herbicides, benzene ring compounds, etc).

Classification of leukemia is based on the morphologic and cytochemical peculiarities of bone marrow tumour cells. The acute and chronic leukemia are divided according to the level of differentiation of the tumour blood cells and their development (non-malignant or malignant).

Acute leukemia is characterized by the proliferation of non-differentiated or differentiated, blastic cells with malignant development.

Chronic leukemia is characterized by the proliferation of differentiated leukemic cells with relative non-malignant development.

As to the quantity of leucocytes and leukemic cells there are the following variants of leukemia: leukemic (dozens and hundreds of thousands of cells per 1µ l (microliter) of blood), subleukemic (not more than 15-25 thousands cells), leukopenic (lowering of leucocytes quantity but with their presence), aleukemic (no leukemiс cells in circulating blood).

Leukemias typically fill up the marrow with abnormal cells, displacing normal hematopoiesis. The marrow here is essentially 100% cellular, but composed almost exclusively of leukemic cells. Normal hematopoiesis is reduced via replacement (a "myelophthisic" process) or by suppressed stem cell division. Thus, leukemic patients are prone to anemia, thrombocytopenia, and granulocytopenia and all of the complications that ensue, particularly complications of bleeding and infection.

At high power, the bone marrow of a patient with acute myelogenous leukemia is seen here. There is one lone megakaryocyte at the right center.

There are numerous granulocytic forms seen here, including immature myeloid cells and bands. This condition is one of the myeloproliferative states and is known as chronic myelogenous leukemia (CML) that is most prevalent in middle-aged adults. A useful test to help distinguish this disease is the leukocyte alkaline phosphatase (LAP) score, which should be low with CML and high with a leukemoid reaction.

9. Here is another view of a peripheral blood smear in a patient with CML. Often, the numbers of basophils and eosinophils, as well as bands and more immature myeloid cells (metamyelocytes and myelocytes) are increased. Unlike AML, there are not many blasts with CML.

Acute leukemia with respect to morphologic and cytochemical peculiarities of leucocytes is divided into lymphoblastic and myeloblastic leukemia or lymphoblastic and non-lymphoblastic. As to contemporary knowledge of erythropoiesis among the acute leukemia there are non-differentiated, myeloblastic with blasts maturation, promyelocytic, myelomonocytic, monocytic, monoblastic, erythroleukemia, megakaryoblastic variants which develop from spinal cell or cell precursories of class II-IV. Among the lymphoblastic leukemia according to immunal and cytogenetic characteristics 3 morphologic forms: are distinguishedL1, L2, L3.

Here is the normal appearance of a benign reactive lymph node Here is the normal appearance of a benign reactive lymph node. At the top is the capsule and just under that a subcapsular sinus where lymphatics enter that drain tissues peripheral to the node. Beneath the capsule is the paracortical zone with lymphoid follicles having a pale germinal center in which the immune responses are often generated. Beneath this are sinusoids extending to the center of the node.

Clinicopathologic characteristic Clinicopathologic characteristic. The first manifestation of the acute leukemia is the presence of blastic cells in the bone marrow of breast bone as a result of which it changes its colour and consistence (red, succulent, sometimes with grey shade under non-differentiated form; pyoid in myeloblastic form; raspberry-red in lymphoblastic leukemia). In the circulating blood the leukemic (leucemicus) hiatus develops.

It is a great number of blastic cells, too little of mature, and the total absence transferring cell forms. There is a substitution of bone marrow with the new blastic leukemic cells. Gradually leukemic infiltration appears in the spleen, liver, lymph nodes, kidneys, meninges (brain tunic) (neuroleukemia in lymphoblastic leukemia), mucous tunics of gastrointestinal tract, lungs (leukemic pneumonitis in myeloblastic leukemia) and other organs.

There develops anaemia, thrombocytopenia, and hemorrhagic syndrome on skin, mucous tunics, serous tunic, internal organs, cerebrum, necrotic tonsillitis (angina), septic complications, and dystrophic changes in parenchymatous organs.

Children have acute leukemia more often; it can be an inherited form of the disease. There are nodular infiltrations in different organs. The most common is T-dependent lymphoblastic leukemia, the less common is myeloblastic leukemia.

Causes of death: septic complications (especially at un-differentiated forms), ulcero-necrotic complications, hemorrhages (especially dangerous to the cerebrum which are in promyelocytic leukemia, progressive disease).

Medical pathomorphism: under the influence of therapy in leukemia the hemorrhagic diathesises, necrotic changes in mucous membrane of the mouth (oral) cavity; more often the ulcero-necrotic changes are met in tunics of gastroiintestinal tract; leukemic pneumonics, leukemic meningitis.

Chronic leukemia is divided into leukemia of myelocytic origin, leukemia of lymphocytic origin, and leukemia of monocytic origin (myelomonocytic leukemia and histiocytosis).

At high magnification is seen a lymph node follicle with a germinal center containing larger lymphocytes undergoing activation. At the lower right is the subcapsular sinus.

This is a more pronounced reactive change in a lymph node, with a larger follicle and germinal center containing macrophages. In general, lymph nodes in a benign reactive process are more likely to enlarge quickly and be tender.

At high magnification, the germinal center in this reactive lymph node follicle has prominent macrophages with irregular cellular debris (so-called "tingible body macrophages"). Blood vessels are also more prominent.

Here is a lymph node involved by lymphoma, a malignant process characterized by the proliferation of neoplastic lymphoid cells. The capsule of the node has been invaded and the lymphomatous cells extend into the surrounding adipose tissue. Note that the follicles are numerous and irregularly sized. This is a malignant lymphoma, small cleaved cell type, follicular (also known as: malignant lymphoma, poorly differentiated lymphocytic type, nodular).

This pattern of malignant lymphoma is diffuse and no lymphoid follicles are identified. Under low power, note that the normal architecture of the lymph node is obliterated. The lymph node is replaced by an infiltrate of small (mature-appearing) neoplastic lymphocytes, and the infiltrate extends through the capsule of the lymph node and into the surrounding fat. The diagnosis is: malignant lymphoma, small lymphocytic type, diffuse (also known as: "well-differentiated" lymphocytic lymphoma).

Chronic leukemia of myelocytic origin or myeloproliferative syndrome are represented generally by chronic myelosis or chronic myeloid leukemia, chronic erythromyelosis, polycythemia, erythromia, myelofibrosis.

Chronic myeloid leukemia has two stages: monoclonal non-malignant and polyclonal malignant. The first stage lasts for several years and is characterized by the progressive increase of neutrophils with change to myelocytes. At the later stage in 3-6 months there develops polyclonism, blastic cell form appear (myeloblasts, erythroblasts, monoblasts and other), blast crisis appears, the quantity of erythrocytes in blood increases to several millions per 1µ l, all manifestations of acute leukemia develop.

Morphology: The bone marrow is reddish grey, succulent and pyoid; the blood is greyish red; internal organs are anaemic; the spleen weight is abruptly increased to 6-8 kg (13,22-17,64 lbs), of grey with brown colour, atrophied follicles, sclerosis and hemosiderosis of the pulp, leukemic infiltrates, leukemic thrombi in vessels; the liver weight is increased to 5-6 kg (11,02-13,22 lbs), of grey with brown colour, leukemic infiltration along the sinusoid, fatty dystrophy of hepatocytes, hemosiderosis; lymph nodes are diffusely very increased, soft, of greyish red colour.

Myelofibrosis is characterized by the presence of myeloid leukemia manifestations and the change of bone marrow to connective or bone (osseous) tissue. Thus the disease has a prolonged non-malignant course.

Erythromia is encountered in elderly people and is characterized by an increase in the mass of erythrocytes, thrombocytes, granulocytes in circulating blood, increased blood (arterial) pressure, inclination to thrombosis, splenomegaly.

Chronic leukemia of lymphocytic origin are represented by chronic lympholeukemia, skin lymphomatosis (Caesary’s disease), and paraproteinemic leukemia. Chronic lympholeukemia develops in elderly people, appears from B-lymphocytes, but with abrupt lowering of immunoglobulin formation, the development of autoimmune reactions, the increased quantity of leucocytes in circulating blood to 100 thousands per 1 µ l, leukemic infiltrates are present in all organs. Caesary’s disease

Morphology: the bone marrow is red; the spleen is increased to 1 kg (2,2 lbs), of red colour, follicles are increased due to leukemic infiltrations; the liver is increased, of grayish brown colour, leukemic infiltration along the portal tract, fatty dystrophy of hepatocytes; lymph nodes are abruptly increased, thick, in the form of bags, can squeeze the neighbouring organs, of grey with pink colour; kidneys are greatly increased, leukemic infiltration abruptly disturbs parenchymal structure. Infectious complication and hemolytic states are typical.

Tumours of plasmatic cells or paraproteinemic leukemia develop from B-lymphocytic system, the precursors of plasmatic cells. These cells synthesize the pathologic proteins, paraproteins. This type of leukemia includes: myeloma (myelomatosis, plasmocytoma, Kahler's disease), Waldenström’s macroglobulinemia, Franklin’s disease of heavy chains.

Myeloma is characterized by the spread of tumour cells of lymphoplasmocytic line – myelomic cells in bone marrow with bones destruction. The abnormal proteins (paraproteins) accumulate in circulating blood, which segregates into urine through the kidneys (Bence-Jones protein).Depending on the character of myelomic infiltrates in the bone marrow, diffusive, diffusive-nodal and multiple forms of disease are distinguished.

The most affected are the flat bones (skull and ribs), vertebras, more seldom tubular with the development of bone tissue destruction. In the bones osteolysis and osteoporosis develop. Myelomic infiltration is also observed in the internal organs: spleen, liver, kidneys, lungs, lymph nodes. Complications: paraproteinemic nephrosis, *myelomicly wrinkled kidneys*, renal amyloidosis (amyloid nephrosis), inflammatory changes as pneumonia, pyelonephritis. The other forms of paraproteinemic leukemia are seldom accompanied with bones destructions. Acute monoblastic leukemia .Case of acute monoblastic leukemia A, Cases typically present with high counts due to circulating monoblasts. B, Bone marrow aspirate is packed with monoblasts and shows few granulocytic elements. D, Absence of a granulocytic component can be illustrated with the combined esterase reaction. Most cells show the α-naphthyl butyrate reaction product (orange–brown). Only rare granulocytes show the blue reaction product from the chloroacetate esterase reaction. E, The biopsy sample usually is packed with sheets of monoblasts with fine nuclear chromatin and abundant pink cytoplasm.

Tumour diseases of lymph nodes or lymphomas Tumour diseases of lymph nodes or lymphomas. To this group belong: lymphosarcoma, mycosis fungoides, Caesary’s disease, reticulosarcoma, Hodgkin's disease (lymphogranulomatosis). There are Hodgkin’s and non-Hodgkin’s lymphomas. They can be B- and T-cellular. Lymphomas or lymphocytomas are ectomarrow tumours which consist of different lymphocytes or of lymphocytes and prolymphocytes.

They appear in lymph nodes or lymphoid tissue of the other internal organs. They are characterized by the local growth and non-malignant course. The first manifestation of lymphomas are increased peripheral lymph nodes, they become thicker, mobile, non-painful. Later there appear the manifestations of intoxication, general weakness, weight loss, night sweat, which is the manifestation of the tumour process. Transformation into lymphosarcoma is rarely met and after the long time.

Many non-Hodgkin's lymphomas seen in adults are large cell lymphomas such as the one here at medium power, but they can be associated with immunosuppressed states (such as AIDS), and are typically of B cell origin. The cells are large, with prominent nucleoli and abundant cytoplasm. This disease tends to be localized (low stage), but with more rapid enlargement, and a greater propensity to be extranodal than the low grade lymphomas.

Lymphosarcoma is a malignant lymphoma of mediastinal, extraperitoneal, inguinal lymph nodes, and lymph tissue of gastroiintestinal tract. The nodes increase with the necrotic and hemorrhagic areas. Process generalization courses lymphaticly and hematogenously. To this group belong: Burkitt's lymphoma (Burkitt's tumor) - endemic disease of African children when facial skeleton bones are damaged. The cause is the herpetiformis virus. Enlarged lymph nodes

The malignant lymphocytes here are very large with a moderately abundant cytoplasm, and the nuclei are round to ovoid with prominent nucleoli and occasional mitoses. The diagnosis is diffuse large B cell lymphoma (also known as immunoblastic lymphoma). The major differential diagnosis in this case would be a metastatic carcinoma. The presence of monoclonal immunoglobulin as demonstrated by immunoperoxidase technique would help to confirm this lesion as a malignant lymphoma. Demonstration of CD19 and 20 antigens would classify it as B cell in origin.

A bone marrow biopsy can reveal malignant lymphoma A bone marrow biopsy can reveal malignant lymphoma. Here, there is a peritrabecular infiltrate of small blue cells which is the lymphomatous infiltrate.

Hodgkin's disease (lymphogranulomatosis) is a chronic recurrent lymphoma with the affection of cervical, mediastinal, extraperitoneal, inguinal lymph nodes. There are isolated (local) and spread (generalized) forms. The spleen is often affected (necrosis nidi of white with yellow colour, sclerosis, lymphocytic infiltration), that’s why it turns to variegated and porphyric look. This is a liver that is involved with Hodgkin lymphoma. The staging of Hodgkin's disease is very important in determining therapy. Thus, it is important to determine whether the patient has only a single lymph node region involved, multiple node regions, or extranodal involvement. This picture could probably suffice for non-Hodgkin lymphomatous hepatic disease as well.

At high power, there are scattered large cells with a surrounding prominent clear space, an artefact of formalin fixation. These are the lacunar cells characteristic for the nodular sclerosis type of Hodgkin lymphoma.

Note the large cells with large, pale nuclei containing large purple nucleoli at the arrowheads. These are Reed-Sternberg cells that are indicative of Hodgkin's disease. Most of the cellular content of foci of Hodgkin lymphoma consists of reactive lymphoid cells. There are four main subtypes of classic Hodgkin lymphoma with CD15+ Reed-Sternberg cells and variants: lymphocyte rich, nodular sclerosis, mixed cellularity, and lymphocyte depletion. The lymphocyte predominance subtype with CD15- Reed-Sternberg variant cells acts more like a low-grade B-cell lymphoma.

In lymph nodes there appear prolypheration of leucocytes, histiocytes, reticular cells, eosinophils, plasmatic cells, neutrophilic leucocytes, necrosis and sclerosis nidi, atypical mononuclear small and big Hodgkin’s cells, polynuclear giant Rid-Berezovsky-Stemberg’s cells. There are four clinicopathologic forms of disease: predominance of lymph tissue (lymphohistiocytic) variant – I-II stages of disease, its localized form, nodular sclerosis is met in non-malignant course of disease, mixed-cellular variant appears in disease spread and corresponds to the II-III stages, the oppression of lymph tissue variant is typical for the generalized form and has a malignant course, sometimes called Hodgkin’s sarcoma.

Following organ transplantation, particularly for heart, but also to a lesser extent with kidney and bone marrow, immunosuppressive therapy may promote an expansion of Epstein-Barr virus (EBV) infected T-cells, seen here with immunoperoxidase staining for EBV. This is a post-transplantation lymphoproliferative disorder (PTLD), which acts like a lymphoma, but will recede when immunosuppression is diminished, if possible.

The skull demonstrates the characteristic rounded "punched out" lesions of multiple myeloma.

The rounded "punched out" lesions of multiple myeloma appear as lucent areas with this skull radiograph.

Round lesions filled with a soft reddish material are indicative of foci of myeloma in this section of vertebral bone.

At low power, the abnormal plasma cells of multiple myeloma fill the marrow.

At medium power, the plasma cells of multiple myeloma here are very similar to normal plasma cells, but they may also be poorly differentiated. Usually, the plasma cells are differentiated enough to retain the function of immunoglobulin production. Thus, myelomas can be detected by an immunoglobulin "spike" on protein electrophoresis, or the presence of Bence-Jones proteins (light chains) in the urine. Immunoelectrophroesis characterizes the type of monoclonal immunoglobulin being produced.

Multiple myeloma. An unusually advanced case of myeloma shows the anterior extension of a rib tumor into subcutaneous tissues, forming a large nodular mass.

AL type of amyloidosis. Amyloidosis occurs in approximately 5% to 10% of patients with myeloma and is related to the deposition of monoclonal immunoglobulin light-chain components that are synthesized by neoplastic plasma cells. This form of amyloidosis mainly affects the heart, kidneys, gastrointestinal tract, liver, and central nervous system. Skin involvement occurs in about 30% to 40% of patients. Amyloid of the tongue can cause it to become enlarged, woody, and indurated Direct skin infiltration with amyloid can produce the featureless tightening and thickening appearance of scleroderma (middle panel). Amyloid is identified grossly by a staining reaction with iodine similar to that of starch Autopsy kidneys stained with iodine are shown in the lower panel, with an amyloid kidney on the left and a normal kidney on the right

Amyloidosis of spleen. A freshly cut splenectomy specimen displaying the wax-like appearance of amyloid deposits

Lytic boney lesions in myeloma Lytic boney lesions in myeloma. This lateral view of the cervical spine shows lytic lesions mainly involving the vertebral bodies of the cervical spine in case of myeloma (arrow, left upper panel). Sagittal MRI of the cervical spine in same patient discloses myeloma replacing mid-cervical vertebral bodies (arrow) causing anterior spinal cord compression (right upper panel). Gross specimens of vertebral columns with multiple, punched-out, hemorrhagic, lytic lesions from myeloma (middle panels) are compared to normal (lower panels).

Splenic marginal zone lymphoma (SMZL) Splenic marginal zone lymphoma (SMZL). This figure demonstrates the gross appearance of a splenectomy specimen from a case of SMZL. Multiple small (1 to 3 mm) discrete nodules of expanded white are diffusely distributed throughout the splenic parenchyma.