Patología de leucocitos

White Blood Cell Neoplasia

Myeloid Lymphoid

Leukocytosis

Steroids & infection= bad

Mechanisms of bone marrow neoplasia• Blast cells (malignant) overpopulate the bone marrow and replace

the normal cells causing bony destruction and/or blood or lymphoid cell deficiencies. Extramedullary hematopoiesis often occurs (liver, spleen, thymus)

• Malignant cells or their descendents may appear in the peripheral blood (leukemia), in extramedullary sites such as the spleen and liver (hepatosplenomegaly) and in lymph nodes (lymphadenopathy).

• Bone marrow malignancy may be accompanied by myelofibrosis (the extensive deposition of collagen by non-neoplastic fibroblasts).

• Types of bone marrow neoplasia: Malignant transformation of hematopoietic and lymphoid cell precursors may occur at any point in their maturation. Malignant cells are classified as myeloid, lymphoid, or plasmacytic. The characteristic behavior of particular malignant stem cells determines the presentation of the disease. There are four major groups:

Types of bone marrow neoplasia

1. Myeloproliferative disorders: Characterized by the malignant transformation of developmentally pluripotent myeloid stem cells and their linage-restricted descendants.

2. Myelodysplastic syndromes: Characterized by ineffective hematopoiesis and pancytopenia.

3. Leukemia: Characterized by the appearance of neoplastic, immature dysfunctional WBCs in the peripheral circulation.

4. Plasma cell disorders: Characterized by the monoclonal proliferation of neoplastic plasma cells and plasmacytoid lymphocytes usually in the bone marrow. Non-functional clones of antibodies or antibody fragments may be produced in immense quantities.

Myeloproliferative Disorders These disorders include polycythemia rubra vera (proliferation of RBC

precursors), essential thrombocytemia (proliferation of platelet precursors) chronic myelocytic leukemia (proliferation of neutrophil precursors) and myelofibrosis (proliferation of marrow fibroblasts). These entities are interrelated and may transform one into another or into acute myeloblastic leukemia (AML).

Features common to all myeloproliferative disorders:1. Peak incidence in 40-70 years of age2. Marrow hypercellularity, except myelofibrosis which is dominated

by fibrosis3. Hepatosplenomegaly due to extramedullary hematopoiesis4. Peripheral blood abnormalities and hyperviscosity due to the high

number of cells, except for myelofibrosis

Myelodyspalstic Syndromes• Myelodysplastic syndromes (MDS, formerly known as

"preleukemia") are a diverse collection of hematological conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia (AML). Anemia requiring chronic blood transfusion is frequently present.

Myelodysplastic syndromes• Myelodysplastic syndromes (MDS) are bone marrow stem cell

disorders resulting in disorderly and ineffective hematopoiesis manifested by irreversible quantitative and qualitative defects in hematopoietic cells. In a majority of cases, the course of disease is chronic with gradually worsening cytopenias due to progressive bone marrow failure.

• Approximately one-third of patients with MDS progress to AML within months to a few years*.

• The median age at diagnosis of a MDS is between 60 and 75 years; a few patients are less than 50; MDS are rare in children. Males are slightly more commonly affected than females. Signs and symptoms are nonspecific and generally related to the blood cytopenias (anemia, neutropenia, thrombocytopenia).

• A significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. Anemia is most common and responds to transfusion, patients often suffer from iron overload. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells).

Myeloproliferative: abn cells get out of the marrow Myelodysplastic: abn cells don’t get out *

Leukemias

These are composed of two major groups: myeloid (granulocytic) and lymphoid.

Causes: The cause is unknown but some predisposing factors have been recognized:

1. Myelodysplastic syndromes precede the onset of leukemia2. Genetic factors may play a role, chromosomal syndromes

(Downs, etc.) are associated with increased risk of leukemias.3. Ionizing radiation; there is increased incidence in those exposed

to radiation for treatment or otherwise.4. Alkylating agents used in chemotherapy are associated with

increased risk5. Viruses: Human T-cell lymphocytic virus-1 (HTLV-1) is an RNA

oncogenic virus that causes T-cell leukemias6. Endogenous oncogenes play a role and are associated with

chromosomal breaks, translocations or deletions. The Philadelphia chromosome (translocation of fragments of chromosomes 9 & 22) is associated with the formation of an oncogene (a proto-oncogene on #22 separates from its expression control) and are associated with the development of CML (also ALL & AML to a lesser extent).

Types of Leukemias 1. Acute Lymphoblastic leukemia (ALL) ~30% of all leukemias, the

most common among children under 5 years old a second peak occurs after age 60. The marrow contains more than 30% lymphoblasts. The prognosis is inversely proportional to age, responds remarkably well to chemotherapy & marrow transplant, 85% long term survival in 1-10 year olds, ~50% in adults.

2. Acute myelogenous leukemia (AML) ~80% of acute leukemias in adults. Marrow has >20% myeloblasts. Overall prognosis is poor with relapse after chemotherapy and most do not survive more than 5 years after diagnosis. Two forms; acute denovo AML(better prognosis ~70% 5 year (especially acute promyelocytic~90% 5 year) or as an end-stage of CML and myelofibrosis (poorer prognosis~15% 5 year).

AML

ALL

Types of Leukemias 3. Chronic lymphocytic leukemia (CLL) Peak incidence is in elderly

males >60years old. Bone marrow has >40% lymphoid cells, peripheral blood has >150,000. Neoplastic cells resemble B-lymphocytes and infiltrate marrow, spleen ,liver & nodes. CLL has an indolent course over 7-10 years, it responds poorly to chemotherapy. It is closely related to small cell lymphoma and lymphadenopathy is common.

4. Chronic myelogenous leukemias (CML) Peak incidence is 35-50 years old. Symptoms are related to loss of normal marrow functioning; anemia, bleeding & infection. Associated wit hthe presence of the Philadelphia chromosome. Peripheral WBC counts in the 20-50,000 range with large component of “more mature” myeloid precursors. Prominent splenomegaly, greater than hepatomegaly or adenopathy. Frequently terminates in a “blast” crisis with peripheral WBCs of >100,000 with immature myeloid cells. Prognosis is poor despite chemotherapy.

Plasma cell disordersMain types

– Multiple myeloma– Waldenstrom macroglobulinemia: A malignancy of

plasmacytoid lymphocytes that secrete IgM resulting in a hyperviscosity syndrome with renal, retinal and cerebral ischemia as a result of microvascular occlusion. Infiltration of plasmacytoid cells in the marrow, spleen and nodes.

– Monoclonal gammopathy of unknown significance: often diagnosed in asymptomatic elderly patients. It is present in ~1% of patients over 60 years old and 3% of patients over 70. There is a 1% risk of developing multiple myeloma. The vast majority suffer no ill effects.

Clinical features– Tend to occur in those >45 years old.– Neoplastic plasma cells produce a monoclonal immunoglobulin

component that can be identified by serum electrophoresis– Deposition of light chain immunoglobulin may form amyloid

deposits in the kidneys, vessels and other organs.

Multiple Myeloma • A neoplasm of mature plasma

cells (usually a single clonal linage) that respond poorly to chemotherapy with an average survival of ~3 years after diagnosis. Renal damage due to protein deposition is the most common cause of death. Infection, systemic amyloidosis, anemia, hyperviscosity and metabolic disorders contribute to the poor outcome.

Multiple MyelomaClinical Presentation:  - Pts present in their middle fifties or

older (60-70 yr)- Constitutional symptoms, anemia,

thrombocytopenia, and renal failure;

- Approx 80% of pts have chief complaint of bone pain w/ diffuse bone tenderness, particularly over the sternum and pelvis.

- Pathological fracture of spine or femur may be heralding event.

- Bone symptoms are due to nests of malignant plasma cells which secrete osteoclast activating factor

- Symptoms range in duration from as short as few wks to as long as 2 yrs.

• Neoplastic cells secrete a monoclonal immunoglobulin: IgG 60%, IgA 20% and IgD, IgE or the heavy or light chain 20%. Normal immunoglobulins are suppressed increasing the risk of infection.

• Multiple bone lesions are composed of nests of neoplastic cells and appear as “punch” lesions in bones. Bony lesions may cause symptomatic hypercalcemia, metastatic calcification also occurs.

• Excess immunoglobulin may be deposited in peripheral tissue forming amyloid. They may be secreted in the urine as Bence-Jones proteins, occasionally proteins obstruct renal tubules resulting in renal failure.

Lymphomas

Neoplasms of lymphoid cells may be divided into two major groups:• Non-Hodgkin’s lymphoma ~70%• Hodgkins lymphoma ~30%Predisposing factors1. Oncogenes, both lymphomas & leukemias may share the same

oncogenes.2. Radiation increases the risk of lymphomas particularly radiation

therapy for neoplastic disorders.3. Environmental factors, Burkitt lymphoma is related to EBV

infection (particularly in Central Africa). 4. Immunodeficiency states (congenital or acquired) are associated

with an increased incidence of lymphomas; HIV is associated with CNS lymphoma.

Non-Hodgkin lymphomas

Non-Hodgkin lymphomas are a heterogeneous group of neoplasms arising from both T and B cells and their precursor cells.

• 85% of non-Hodgkins are of B-cell origin and involve marrow, lymph nodes, spleen and extranodal lymphoid tissue. Approximately 2/3rds of cases begin in lymph nodes, the remaining begin in extranodal lymphoid tissue. Multiple nodes are usually involved.

Four general categories have been identified based on cell origin, level of differentiation, genetic abnormality and clinical presentation.

1. Precursor B-cell neoplasms: present as acute lymphoblastic leukemia/lymphoma. ALL/L of infancy and childhood and is often curable. Adult ALL/L usually responds but tends to recur and is rarely cured.

2. Precursor T-cell neoplasms ALL/L involving the mediastinum, lymph nodes and spleen. These respond less well than B-cell precursor types.

Non-Hodgkin lymphomas

3. Peripheral B-cell neoplasms occur in several forms and affects adults. B-cell types are the most malignant. The most important are1. Small cell lymphocytic lymphoma, the lymphoma equivalent of

CLL. This tends to have a protracted course surviving 7-10 years after diagnosis

2. Follicular lymphoma affects elderly patients responsible for ~45% of lymphomas. Like CLL this disorder has an indolent course lasting 7-10 years.

3. Mantle cell lymphoma responds to chemotherapy but relapses are common and most survive only 3-4 years after diagnosis.

4. Diffuse B-cell lymphomas account for ~20% of all lymphomas, but represent 70% of all aggressive lymphomas in adults and are the most common rapidly proliferating lymphomas. Despite its aggressive nature ~50% are cured by chemotherapy.

5. Hairy cell leukemia is a low grade lymphoma associated with splenomegaly. The proliferation of characteristic “hairy cells” results in their appearance in peripheral blood (hence the description as leukemia).

Even though this is a lymphoma the striking presence of “hairy cells” in the peripheral blood lead to the leukemia designation.

Non-Hodgkin lymphomas4. Burkitt lymphoma is a rapidly growing B-cell lymphoma

affecting children and adults. It is related to EB virus infection. Solid tumors are often located in extranodal tissue. Response to chemotherapy is inversely related to age. In Africa (strong association with EBV, it involves the mandible or maxilla. In the US abdominal nodes are often the main site.

Hodgkin’s disease comprise several closely related neoplastic lymph node disorders that resemble lymphoma

Areas of involvement: This usually involves a neoplastic process in contiguous lymph nodes usually in the neck and mediastinum. Extranodal involvement and disease above and below the diaphragm portend poor prognosis.

Pathologic findingsAffected nodes show an inflammatory response to tumor cells and

contain infiltrates of lymphocytes, plasma cells and eosinophils

Reed-Sternberg cells (large binucleate cells (owl eyes)) surrounded other cells that identify five types:

• Nodular sclerosis the most common type• Lymphocyte predominant• Lymphocyte depletion• Mixed cellularity• Lymphocyte-rich

Clinical features include fever, sweating, weight loss, etc., (characteristic of an inflammatory process).

Prognosis depends on the stage of disease at the time of diagnosis; histological type has little influence on outcome. 5-years survival is 75%, Relapse after initial treatment has ~50% survival rate.

Severity is proportional to the number of RS cells and inversely proportional to the number of reactive lymphocytes

Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas

Hodgkin Lymphoma Non-Hodgkin Lymphoma

More often localized to a single axial group of nodes (cervical, mediastinal, para-aortic)

More frequent involvement of multiple peripheral nodes

Orderly spread by contiguity

Noncontiguous spread

Mesenteric nodes and Waldeyer ring rarely involved

Waldeyer ring and mesenteric nodes commonly involved

Extranodal involvement uncommon

Extranodal involvement common

• Major Lymph node locations.