Patho sheet.hematology#3 - Shadi Jarrar Almo7taram

Pathology sheet-Hematology #3
Done by Shadi B.Jarrar

Myeloid Neoplasms

Myeloid neoplasms arise from hematopoietic stem cells and typically give rise to monoclonal proliferations that replace normal bone marrow cells.

Acute Myelogenous Leukemia
AML primarily affects older adults, with the median age being 50 years

The clinical signs and symptoms, which closely resemble those produced by ALL, are usually related to marrow failure caused by the replacement of normal marrow elements by leukemic blasts.

Fatigue and pallor, abnormal bleeding, and infections are common in newly diagnosed patients, who typically present within a few weeks of the onset of symptoms. Splenomegaly and lymphadenopathy are in general less prominent than in ALL, but, rarely, AML presents as a discrete tissue mass (a so-called granulocytic
sarcoma). Ideally the diagnosis and classification of AML are based on the results of morphologic, histochemical, immunophenotypic, and karyotypic studies. Of these tests, karyotyping is most predictive of outcome..

Most AMLs are associated with acquired mutations in transcription factors that inhibit normal myeloid differentiation, leading to the accumulation of cells at earlier stages of development. Of particular interest is the t(15;17) translocation in acute promyelocytic leukemia. This translocation results in the fusion of the retinoic acid
receptor α (RARA ) gene on chromosome 17 with the PML gene on chromosome 15. The chimeric gene(s) produce abnormal PML/RARA fusion proteins that block myeloid differentiation at the promyelocytic stage, probably by inhibiting the function of normal RARA receptors.

pharmacologic doses of retinoic acid overcome this block and cause the neoplastic promyelocytes to terminally differentiate into neutrophils

this is an important example of an effective therapy that is targeted at a tumor-specific molecular defect.

Classification : Two classifications are used : FAB / WHO

Histochemistry: myeloperoxidase is used for detection of granulocytic differentiation and lysosomal nonspecific esterase staining is used for detection of monocytic differentiation.

Immunophenotyping: myeloid associated antigens are: CD13,CD14,CD 15,CD15,CD 64 CD 117.

CD33 is expressed on pluripotent stem cells but is retained on myeloid progenitor cells

Prognosis

(t[8;21], inv[16]) are associated with
a 50% chance of long-term disease-free survival, but the overall long-term disease-free survival is only 15% to 30% with conventional chemotherapy.

Chronic Myeloproliferative Disorders

These disorders are marked by the hyperproliferation of neoplastic myeloid progenitors that retain the capacity for terminal differentiation; as a result, there is an increase in one or more formed elements of the peripheral blood.

The neoplastic progenitors tend to seed secondary hematopoietic organs (the spleen, liver, and lymph nodes), resulting in hepatosplenomegaly (caused by neoplastic extramedullary hematopoiesis) and mild lymphadenopathy.

A common theme is the association of these disorders with mutated tyrosine kinases, which generate high-intensity constitutive signals that mimic those that regulate the growth and survival of normal myeloid cells. This insight provides a satisfying explanation for the observed overproduction of myeloid cells and is important therapeutically because of the availability of tyrosine kinase inhibitors.

Most patients with this disease subgroup fall into one of four diagnostic entities: chronic myelogenous leukemia(CML), polycythemia vera (PCV), primary myelofibrosis, and essential thrombocythemia.

CML is clearly separated from the other disorders by being associated with a characteristic abnormality, the presence of a BCR-
ABL fusion gene. In contrast, the other myeloproliferative disorders show considerable overlap clinically and genetically. Mutations of the JAK2 kinase are the single most common genetic abnormality in this group. It isseen in >90% of cases of polycythemia vera, 50% of primary myelofibrosis, and 30% of essential thrombocythemias.

most, if not all, myeloproliferative disorders are associated with an abnormal increase in the activity of one or another tyrosine kinase, which appears to stimulate the same signaling pathways that are normally activated by hematopoietic growth factors .

Chronic Myelogenous Leukemia

CML principally affects adults between 25 and 60 years of age and accounts for 15% to 20% of all cases of leukemia.

CML is uniformly associated with the presence of an acquired genetic abnormality, a BCR-ABL fusion gene .

In about 95% of cases the BCR-ABL fusion gene is the product of a (9;22) translocation

The derivative chromosome 22 is often referred to as the Philadelphia (Ph) chromosome

In individuals with CML the BCR-ABL fusion gene is present in granulocytic, erythroid, megakaryocytic, and B-cell precursors, and in some cases T-cell
precursors as well. This finding is firm evidence for the origin of CML from a pluripotent stem cell.

Although the Ph chromosome is highly characteristic of CML, it should be remembered that it is also present in 25% of adults with ALL and rare cases of
adults with AML.

Normal myeloid progenitors depend on signals generated by growth factors and their receptors for growth and survival, but CML progenitors have much decreased requirements. This altered growth-factor dependence is due to the presence of the BCR-ABL tyrosine kinase, which generates constitutive signals that mimic the effects of growth-factor receptor activation. Although the BCR-ABL fusion gene is present in multiple lineages, for unclear reasons the granulocyte precursors are most affected. As is evident from the markedly elevated number of granulocytes in the bone marrow and peripheral blood, the proliferating CML progenitors retain the capacity for terminal differentiation .

Morphology

The peripheral blood findings are highly characteristic. The leukocyte count is elevated, often exceeding 100,000 cells/µL. The circulating cells are predominantly neutrophils, metamyelocytes, and myelocytes , but basophils and eosinophils are
also prominent. A small proportion of myeloblasts, usually less than 5%, can be seen
in the peripheral blood. An increased number of platelets (thrombocytosis) is also
typical. The bone marrow is hypercellular as a result of a hyperplasia of granulocytic
and megakaryocytic precursors. Myeloblasts are usually only slightly increased, and
there is frequently an increase in the number of phagocytes. The red pulp of the
enlarged spleen has an appearance that resembles bone marrow because of the extensive extramedullary hematopoiesis. This burgeoning mass of hematopoietic cells
often compromises the local blood supply, leading to splenic infarcts.

Clinical features

The onset of CML is usually slow, and the initial symptoms are often nonspecific, (e.g., easy fatigability weakness, and weight loss). Sometimes the first symptom is a dragging sensation in the abdomen, caused by the extreme splenomegaly that is characteristic of this condition. On occasion it may be necessary to distinguish CML
from a "leukemoid reaction," a dramatic elevation of the granulocyte count in response to infection, stress, chronic inflammation, and certain neoplasms. The presence of the Ph chromosome is the most definitive way of distinguishing CML
from leukemoid reactions (and the other chronic myeloproliferative diseases).

Measurement of leukocyte alkaline phosphatase can also be helpful, because the granulocytes in CML are almost completely
devoid of this enzyme, whereas it is increased in leukemoid reactions and other myeloproliferative disorders

After a period of slow progression, approximately 50% of individuals with CML enter an accelerated phase, during which there is a gradual failure in the response to treatment; increasing anemia and new thrombocytopenia; the appearance of additional cytogenetic abnormalities; and, finally, transformation into a picture resembling acute leukemia

In the remaining 50% blast crisis occurs abruptly, without an intermediate accelerated phase.

In 30% of patients, the blast crisis is of a pre-B-cell type. In the remaining 70% of patients, the blast crisis resembles AML.

Less commonly, CML progresses to a phase of extensive bone marrow fibrosis resembling that seen in other myeloproliferative disorders, most notably myeloid metaplasia with myelofibrosis

Bone marrow transplantation was (and remains) a definitive form of therapy, being curative in 70% of patients.

An inhibitor of the BCR-ABL tyrosine kinase, Gleevec (imantinib mesylate), induces complete remission in a high fraction of individuals with stable-phase CML

When CML sufferers on imantinib mesylate relapse, they often have new mutations in the active site of BCR-ABL that prevent the binding of imantinib mesylate; this proves that the drug is working by "hitting the target."

it is an excellent therapy for persons who cannot undergo bone marrow transplantation

Polycythemia Vera

The hallmark of PCV is the excessive neoplastic proliferation and maturation of erythroid, granulocytic, and megakaryocytic elements, producing a panmyelosis. Although platelet and granulocyte numbers are increased, the most obvious clinical signs and symptoms are related to the absolute increase in red cell mass.

This must be distinguished from relative polycythemia, which results from hemoconcentration. Unlike reactive forms of absolute polycythemia, PCV is associated with low levels of erythropoietin in the serum, which is a reflection of the hypersensitivity of the neoplastic clone to erythropoietin and other growth factors.

Recently it was observe that in nearly all cases, PCV cells carry a particular mutation in JAK2, a tyrosine kinase that acts in the signaling pathways downstream of the erythropoietin receptor and other growth factor receptors. This mutation, which
results in a valine-to-phenylalanine substitution at residue 617, is sufficient to render cells expressing the erythropoietic receptor hypersensitive to erythropoietin, suggesting that it is probably an important part of the pathogenesis of PCV.

Morphology

The major anatomic changes in PCV stem from the increase in blood volume and
viscosity brought about by the polycythemia.

As a result of the increased viscosity and vascular stasis, thromboses and infarctions are common, particularly in the heart, spleen, and kidneys. Hemorrhages occur in about a third of these individuals, probably as a result of excessive distention of blood vessels and abnormal platelet function.

Platelets produced from the neoplastic clone are often dysfunctional.

As in CML, the peripheral blood often shows increased basophils.

The bone marrow is hypercellular due to the hyperplasia of erythroid, myeloid, and
megakaryocytic forms.

some degree of marrow fibrosis is present in 10% of patients at the time of diagnosis. In a subset of patients, the disease progresses to myelofibrosis, where the marrow space is largely replaced by fibroblasts and collagen.

Clinical Course

PCV appears insidiously, usually in late middle age. Patients are plethoric and often somewhat cyanotic. Histamine release from the neoplastic basophils may contribute to pruritus, which can be intense.

Other complaints are referable to the thrombotic and hemorrhagic tendencies and to hypertension. Headache, dizziness, gastrointestinal symptoms, hematemesis, and melena are common.

Red cell counts range from 6 to 10 million per microliter, and the hematocrit often approaches 60%. The other myeloid lineages are also hyperproliferative:

About 30% of patients develop thrombotic complications usually affecting the brain or heart. Hepatic vein thrombosis, giving rise to the Budd-Chiari syndrome
is an uncommon but grave complication.

life-threatening hemorrhages occur in 5% to 10% of patients. In those receiving no treatment death occurs from vascular complications within months after diagnosis; however, if the red cell mass is maintained at near normal levels by phlebotomies, the median survival is around 10 years.after 10 years 15 – 20% of patients transformation to myelofibrosis.

Essential thrombocythemia

A myeloprolifrative disorder arising from multipotent stem cells, but the increased proliferation and production is confined to megakaryocytic elements.where the cells of the megakaryocytic series have diminished requirement for growth factors.

Dysfunction of platlets derived from neoplastic clone probably contribute o the major clinical features of bleeding and thrombosis.

Morphology:
Marrow cellularity is usually mildly to moderately increased: megakaryocytes are often markedly increased in number and include abnormally large forms. Peripheral smears reveal thrombocytosis (usually >600.000/m^3) and abnormally large platetlets

Neoplastic extramedullary hematopoiesis can occur within the spleen and liver, producing mild organomegaly in about 50% of cases.

uncommonly essential thrombosis can evolve into marrow fibrosis or transform to AML.

Cliniclal features:

but is also seen in young adults. Qualitative andquantitative abnormalities in platelets underlie the major clinical manifestations of thrombosis and hemorrhage. Erythromelalgia, the throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregate. Is a characteristic symptom.

Prognosis

Essential thrombocytosis has an indolent course: long asymptomatic periods are punctuated by thrombotic or hemorrhagic crises. Median survival is 12 to 15 years.

Primary myelofibrosis :

Primary marrow fibrosis with myeloid metaplasia also arises from transformed multimyeloid sten cell but differs in that progression to myelofibrosis occurs early in course.

The pathologic features stem from extensive collagen deposition in the marrow by nonneoplastic fibroblasts displacing hematopoietic elements including stem cells.

Marrow obliteration results in extensive exramedullary hematopoeisis in spleen, liver and sometimes lymph nodes.

fibrosis may be caused by inappropriate release of two fibro- blast mitogens from neoplastic megakaryocytes. platelet- derived growth factor, and TGF-P.

Morphology

• Early, the marrow is often hypercellular and contains large dysplastic clustered megakaryocytes.
With progression, diffuse fibrosis displaces hematopoietic elements. Late in the course, the fibrotic marrow space can be largely converted to bone (osteosclerosis)

Fibrotic obliteration of marrow space leads to extensive extramedallary hematopioesis, principally in the spleen and to a lesser extent in the liver and lymph nodes.

Nucleated erythroid progenitors and early granulocytes are released from the fibrotic marrow and sites of extramedullary hematopoiesis: their appearance in the circulation is termed leukoerythrohlastosis.

Other finding in peripheral smear include tear-drop erythrocytes, increased basophils and abnormally large platelets.

Moderate to severe normochromic anemia is common Thrombocytopenia often severe appears with disease progression.
Primary myelofibrosis is uncommon in individuals younger than 60 years of age. The disorder comes to attention because of progressive anemia or marked splenic enlargement

Prognosis is variant with median survival period of 1-5 years Threats to life include intercurrent infections, thrombotic episodes or bleeding related to platelet abnormalities, and transformation to AML (5%-20% of cases).


The end