Unit II Flashcards
Hematologic malignancies share the common characteristic that they arise from ______ ____ that came from a transformed cell of marrow derivation
clonal populations
leukemia
malignancy of hematopoetic cells, where the chief manifestation is involvement of the blood and marrow
lymphoma
a malignancy of hematopoetic cells, derived from lymphocytes or their precursors, which presents primarily as a solid mass
Extramedullary myeloid tumor
(granulocytic sarcoma)-a malignancy of hemaotpoetic cells, derived from myeloid cells or their precursors (granulocytes, monocytes, etc) which presents primarily as a solid mass
Persistant findings of chromosomal translocation are important to note because:
1) their persistence allows them to be used as diagnostic markers for certain hematological malignancies
2) Their persistent presence suggests they play critical role in development of the hematological malignancy they are associated with
What might be one explanation of the frequent translocations in lymphocytes?
genomic instability during immunoglobulin/T cell receptor rearrangement in B and T cells
3 viruses known to play a role in lymphomas:
1) Epstein-Barr virus (EBV)
2) Human T cell leukemia virus-1 (HTLV-1)
3) Kaposi sarcoma herpesvirus/Human herpesvirus-8 (KSV/HHV-8)
Acute Leukemias
Usually due to rapid accumulation of (usually) immature cells in the marrow. They often replace many normal marrow cells, resulting in cytopenias. Most can be classified as Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia
Myelodysplastic syndromes
a group of conditions where a clonal population derived from a neoplastic HSC takes over marrow, and is NOT capable of making normal blood cells in one or more lineages (dysplasia). Categorized by falling peripheral blood cell counts. Often MDS can progress to AML
Myeloproliferative Neoplasms
neoplastic clonal proliferations of the marrow where the clone makes normal functioning blood cells, usually in multiple lineages, but makes too many of them in one or more lineages.
What causes the signs and symptoms of acute leukemia?
When immature leukemic cells accumulate in the bone marrow, they displace normal hematopoetic elements.
Chromosomal abnormalities may be found in __% of AML patients and ___% of ALL patients
95
90
Different types of AML:
granulocytic, monocytic, erythroid, megakaryocytic
Risk factors for acute leukemia
- previous chemo, esp. with DNA alkylating agents and topoisomerase II inhibitors
- tobaccos smoke
- ionizing radiation
- benzene exposure
- Syndromes: Down, Bloom, Fanconi anemia, ataxia-telangiectasia
Signs and symptoms of acute leukemia
fatigue, malaise, dyspnea, easy bruisability, weight loss, bone pain, anemia and pallor, thrombocytopenia, hemorrhage, ecchymoses, petechia, fundal hemorrhage, fever and infection, adenopathy, hepatosplenomegaly, mediastinal mass
Most common age for ALL
75% of cases of ALL occur in children under age 6
In order to diagnose ALL, lymphoblasts must be identified. This is done with :
immunophenotyping
Immunophenotyping markers to diagnose ALL
CD34-marks immature lymphobasts, but often expressed by myloblasts.
TdT-expressed by immature lymphocytes only
Does B-ALL or T-ALL account for more cases of ALL?
B-ALL accounts for 80-85% of all cases of ALL
B lymphoblasts express Be lineage antigens:
CD19, CD22, CD79a
usually do not express mature B cell markers such as CD20
Recurrent cytogenetic abnormalities of B-ALL
1) t(9,22) BCR-ABL1
2) t of 11q23, MLL
3) t(12;21) ETV6-RUNX1
Rank the prognoses of the most common B-ALL cytogenetic abnormalities
t(12;21) > t 11q23 MLL > t(9;22)
What age group does T-ALL occur in most commonly?
adolescents and young adults and males more than females
How does T-ALL often present?
with a component of lymphoblastic lymphoma (T-LBL), often manifesting as a large mediastinal mass
T lymphoblasts express T-lineage antigens ___, ___, and/or ____. They may express both ___ and ___ concurrently, or may express just one/neither. They often express T-lineage antigens only seen in immature T cells, such as ____and ___
CD2, CD3, CD7
CD4, CD8
CD99, CD!a
What is the prognosis for ALL in children? In adults?
Good prognosis in children, complete remission rate 95%, 80% cure rate. In adults, disease is much worse. Complete remission 60-80%, cure rate of <50%
Prognostic factors for all ALLs
Age (worst for infants, >10) WBC count (more=worse) Slow response to therapy, disease left after treatment hyperdiploidy=good, hypodiploidy=bad T cell worse
Who does AML occur in most commonly?
average age id 65, rare in children and young adults
the diagnosis of AML is usually based on:
identifications of increased myeloblasts accounting for 20% or more of nucleated cells in the marrow or peripheral blood. (exception: if one can document presence of Auer rods)
Auer rods
Indicate AML and are found in myeloblast
Myeloblasts often express myeloid antigens such as
CD117 (C-kit), myeloperoxidase
Recurrent AML cytogenteic abnormalities and prognosis
1) t(8;21) RUNX!-RUNX1T1-Good
2) inv (16) or t(16;16) CBFB-MYH11-good
3) t(15;17) PML-RARA
- This is APL-best prognosis of AMLs with ATRA
4) t(1;22) RBM15-MKL1-good
5) abnormalities of 11q23 MLL-Poor
In rare cases, APL can give rise to:
disseminated intravascular differentiation (DIC)
Which AML cytogenetic abnormality is associated with infants with Down syndrome?
AML with t(1;22) RBM15-MKL1, usually showing megakaryoblastic differentiation
Two most common types of therapy related AML (t-AML):
1) secondary to alkylating agents or radiation
2) secondary to topoisomerase II inhibitors
Molecular findings that are the most important prognostic factors in AML, NOS
FLT3 ITD (- prognosis)
NPM1 (+)
CEBPA (+)
Myelodysplastic syndrome
group of conditions where the marrow is replaced by a malignant clone, derived from a transformed stem cells or progenitor cell
Characteristics of Myelodysplastic syndrome (MDS
1) ineffective hematopoesis (clone can’t make functioning blood cells-they often die before leaving marrow and look dysplastic
2) risk of transformation to AML
Median age of Primary (idiopathic) MDS
70, usually occurs after age 50
Secondary MDS (t-MDS) occurs:
as a part of the spectrum of therapy-realted AML, generally 2-8 years after therapy with DNA alkylating agents or ionizing radiation
Secondary MDS (t-MDS) karyotype
generally complex, whole or partial deletions of chromosomes 5 and/or 7
MDS is generally diagnosed after noticing:
1) persistant peripheral cytopenia in one or more lineages that cannot be otherwise explained (highly likely if advanced age and 2+ cytopenias). If there is a cytopenia in a single lineage, it is not usually MDS
MDS diagnosis can be made in setting of persistent cytopenia with wine of the following modalities:
1) Morphological evidence of dysplasia
2) Increased myeloblasts, but less than 20% of blood and marrow cells
3) presence of a clonal cytogenetic abnormality
dyshematopoiesis
When more than 10% of the cells in one lineage (erythroid cells, granulocytes, megakaryocytic) appear dysplastic.
dyshematopoiesis can be sub classified as:
Dyserythropoiesis, Dysgranulopoiesis, Dysmegakaryopoiesis
DYSERYTHROPOIESIS morphological characteristics
Megaloblastoid Chromatin Patterns in
RBC Precursors, Nuclear Irregularities
(irregular contour, irregular shape, nuclear budding, multiple nuclei) in RBC precursors, Prominent Ring Sideroblasts
MORPHOLOGIC EVIDENCE OF:
DYSGRANULOPOIESIS
POOR CYTOPLASMIC GRANULATION (Hypogranular), Abnormal Nuclear Segmentation (neutrophils with 2 lobes- pseudo-Pelger-Huet, because they resemble the bilobed nuclei seen in the neutrophils of patients with Pelger-Huet anomaly, a benign congenital condition)
MORPHOLOGIC EVIDENCE OF:
DYSMEGAKARYOPOIESIS
Small, often hypolobated or non-lobated nuclei
The presence of one of the following MDS- related abnormalities within the clone is DIAGNOSTIC of MDS:
- complex karyotype with whole or partial deletions of chromosomes 5 and/or 7
- isolated deletion 5q
- trisomy 8
In a patient with suspected MDS, but negative for elevated myeloblasts and negative for a clonal cytogenetic abnormality, and only having morphologic evidence of dysplasia, be sure to exclude potential causes of secondary myelodysplasia. These include:
- VITAMIN DEFICIENCY (B12, folate, etc.)
- TOXIN EXPOSURE (e.g. heavy metals)
- EXPOSURE TO CERTAIN DRUGS
- VIRAL INFECTIONS
MDS is classified into two types:
Low and high grade MDS
Characteristics of low grade MDS
Myeloblasts account for <2% of blood cells
Characteristics of high grade MDS
Myeloblasts account for 5-19% of marrow cells, and/or 3-19% of blood cells
Types of low grade MDS:
Refractory Cytopenia with Unilineage Dysplasia (RCUD)
Refractory Cytopenia with Multilineage Dysplasia (RCMD)
Refractory Cytopenia with Unilineage Dysplasia (RCUD)
- Low grade MDS with dysplasia in ONE lineage
- Mostly cases of refractory anemia, rarely may be refractory neutropenia or refractory thrombocytopenia
- Relatively good prognosis: - Median survival >5 years
- Only 2% of cases transform to AML by 5 years
Refractory Cytopenia with Multilineage Dysplasia (RCMD)
- Low grade MDS with dysplasia in 2 or more lineages
- Worse prognosis than RCUD:
- Median survival: 2.5 years
- 10% of cases transform to AML by 2 years
Types of High grade MDS
Refractory Anemia with Excess Blasts-1 (RAEB-1)
Refractory Anemia with Excess Blasts-2 (RAEB-2)
Refractory Anemia with Excess Blasts-1 (RAEB-1)
- 5-9% blasts in marrow, and/or 2-4% blasts in blood
- Relatively dismal prognosis: - Median survival of 16 months
- 25% of cases will transform to AML
Refractory Anemia with Excess Blasts-2 (RAEB-2)
- 10-19% blasts in marrow, and/or 5-19% blasts in blood
- Very dismal prognosis:
- Median survival of 9 months
- 33% of cases will transform to AML
Myeloproliferative neoplasms (MPNs)
- Clonal hematopoietic neoplasm arising from a transformed hematopoietic stem cell
- neoplastic clone partially or entirely replaces the normal marrow cells in multiple lineages
- neoplastic clone gives rise to increased numbers of normal (not dysplastic) blood cells in one or more lineages
Myeloproliferative neoplasms usually occur in the following age group:
middle aged-elderly adults, rare in children
Common themes of MPNs:
1) Early disease=increase in 1+ blood cell types, increased marrow cellularity
2) splenomegaly and/or hepatomegaly
3) Usually insidious onset
4) W/o treatment, progress to excessive marrow fibrosis, resultant bone marrow failure and/or transformation to acute leukemia (much less common for MPNs than for MDS)
Without treatment, myeloproliferative neoplasms progress to….
-excessive marrow fibrosis with resultant bone marrow failure - -transformation to acute leukemia (much less common for MPNs than for MDS)
Historically, MPNs were classified based on the _____________________, and the appearance of the marrow on biopsy
type(s) of cells being overproduced
Important types of myeloproliferative neoplasms
Chronic Myelogenous Leukemia (CML) Polycythemia Vera (PV) Primary Myelofibrosis (PMF) Essential Thrombocythemia (ET)
Chronic myelogenous leukemia often manifests as
persistent neutrophilic leukocytosis from a CBC. Some are symptomatic at diagnosis. Others have non-specific signs/symptoms, including night sweats, weight loss, splenomegaly, and anemia
Typical age of CML diagnosis
Typical age at diagnosis: 40-60; rare in children and young adults
Stages of CML are ____ and _____. when are people usually diagnosed?
chronic phase, blast phase. Large majority of CML cases are diagnosed in the initial phase of disease, chronic phase
Characteristics of chronic phase CML
- Leukocytosis from neutrophilia - Increased basophils in blood
- Often increased platelets in blood
- Hypercellular bone marrow with granulocytic hyperplasia (neutrophilic granulocytes in peripheral blood increased)
Appearance of megakaryocytic in chronic phase CML bone marrow biopsy
Frequent Small Megakaryocytes with Non-Lobated Nuclei
Definition of blast phase of CML
defined by 20% or more blasts in the marrow or blood (essentially, CML-blast phase is CML that has transformed to acute leukemia)
Types of blasts present in marrow and blood CML blast phase
In 70% of cases of CML-blast phase, the blasts are myeloblasts
30% of cases, the blasts are lymphoblasts
How can CML progress from chronic–> blast phase?
Directly from chronic phase–> blast phase
or
through an intermediate phase known as accelerated phase
CML translocation, how it differs from ALL
breakpoint in the major breakpoint cluster region of BCR (M-BCR), giving rise to a 210kd fusion protein (p210).
Ph+ ALL, the BCR breakpoint is usually in the minor breakpoint cluster region (m-BCR), giving rise to a 190kd fusion protein (p190)
The p190 mRNA transcripts are detectable in most cases of CML, why?
Splicing of 210kD protein can give rise to 190kd protein if it spliced
BCR-ABL1 fusion gene can be documented by
Conventional cytogenetics (karyotype) - FISH (BCR-ABL fusion probes) - RT-PCR (BCR-ABL mRNA transcripts)
Polycythemia Vera is chiefly characterized by
- by an increase in RBC mass (erythrocytosis)
- Usually, also see increased neutrophils and platelets in the blood, and trilineage hyperplasia in the marrow
What will a bone marrow biopsy of Polycythemia Vera show?
often shows clusters of bizarre megakaryocytes
Genetic factors from Polycythemia Vera
Essentially all cases of PV contain an activating mutation of JAK2, usually a V617F point mutation.
If a patient has a persistent erythrocytosis in the absence of a demonstrable JAK2 mutation, consider the possibility of a secondary (reactive) erythrocytosis. Secondary erythrocytosis may be seen in:
- Smokers (due to carboxyhemoglobin)
- Chronic hypoxia
- Certain hemoglobin disorders
- Other conditions
Phases of Polycythemia Vera, when is it usually diagnosed
polycythemic phase (diagnosis probably), spent phase
Characteristics of spent phase PV
post-PV myelofibrosis. Spent phase is characterized by extensive marrow fibrosis with a corresponding fall in blood cell counts.
Initial presenting symptoms in PV patients include:
- headaches - dizziness
- plethora (dusky, reddish skin)
- pruritus (itching)
- paresthesias (“pins and needles” sensations) - splenomegaly (70%); hepatomegaly (40%)
Most serious complication of PV
are venous or arterial thrombosis, leading to complications such as DVT, MI, and stroke. Most common cause of death!
What thromboses are particularly indicative of PV?
Thrombosis of the mesenteric vein, portal vein, or splenic vein should always raise the possibility of PV
Prognosis and risk of transformation to acute leukemia, and main therapeutic methods for PV
relatively good prognosis (without chemotherapy, risk of transformation to acute leukemia is very low), median survival times of 10-20 years
Main therapeutic methods are: - serial phlebotomy
-aspirin therapy (to help prevent clots)
Primary Myelofibrosis
an MPN characterized by granulocytic and megakaryocytic hyperplasia, but no erythrocytosis.
Genetic findings of Primary Myelofibrosis
JAK2 mutations are present in around 50% of PMF cases
Stages of Primary myelofibrosis
prefibrotic stage and fibrotic stage
Characteristics of prefibrotic stage of primary myelofibrosis
- hyper cellular marrow- granulocytic and megakaryocytic hyperplasia - large, bizarre megakaryocytes in marrow - markedly increased platelets in blood - usually increased neutrophils in blood
Characteristics of fibrotic stage of primary myelofibrosis
- reticulin fibrosis of the marrow
- Leukoerythroblastosis of the blood
- Falling blood cell counts
- Enlargement of organs (liver, spleeen, lymph nodes, others) due to extramedullary hematopoiesis
Peripheral smear of primary myelofibrosis
- immature granulocytes and immature red cells
- Tear drop-shaped RBCs (dacrocytes) in blood
- fibrosis giving the marrow cells a “streaming” appearance
- Entrapped bizarre megakaryocytes suggest an MPN
- reticulin fibrosis
Primary myelofibrosis:
- MST if diagnosed in fibrotic stage
- Most deaths from
- Transform to AML?
- MST=5yrs
- Most deaths due to bone marrow failure
- minority of cases may transform to AML
Essential Thrombocytopenia
an MPN characterized by a persistent thrombocytosis. It lacks the marrow granulocytic hyperplasia often seen in PMF, and the atypical megakaryocytes in ET are even larger than those in PMF
Genetic components of essential thrombocythemia
JAK2 mutations are present in around 50% of ET cases
Essential thrombocythemia marrow characteristics
Clusters of Very Large Megakaryocytes in Marrow
Symptoms of Essential thrombocythemia
50% of ET patients are asymptomatic
- TIAs, digital ischemia, arterial or venous thromboses
- spelnomegaly UNCOMMON
Essential thrombocythemia
- MST
- Transform to AML?
ET is indolent disease, with median survivals of over 10 years
Only rarely does ET transform to AML, or progress to myelofibrosis
