Chapter 12: White cell disorders Flashcards
What is leukopenia?
A decrease in white blood cells
What are the two general causes of leukopenia?
Decreased production or increased destruction of white blood cells
What are causes of decreased production of white blood cells?
- Bone marrrow hypoplasia due to chemotherapy or aplastic anamia
- Drugs
- Neoplastic proliferations (lymphoma, metastasis)
- Myelodysplastic syndrome (neoplasic disease of the bone marrow)
What are causes of increased destruction of white blood cells?
Severe infections that trigger immune mediation.
What are symptoms of leukopenia?
Large ulcera (the ‘mess’ cannot be removed), infection and sepsis.
When is leukopenia referred to as neutropenia and when as agranulocytosis?
Neutropenia: reduction in the number of granulocytes. Agranulocytosis is severe neutropenia.
When is bone marrow hypercellularity seen?
When there is excessive neutrophil destruction or ineffective granulopoiesis.
What is leukocytosis?
An increase in the number of white cells in the blood.
Just know that there are different types of leukocytosis: neutrophillic, eosinophillic and basophillic leukocytosis, monocytosis and lymphocytosis. For illustration see Tabel 12.6 (Robbins Basic Pathology)
All these immune cells have been discussed in the previous exam. So (for example) if you have remembered that eosinophils are present during allergies you can remember that eosinophillic leukocytosis occurs during allergic disorders.
By what is infectious mononucleosis caused?
Disease caused by Epstein Barr Virus (EBV).
What are characteristics of infectious mononucleosis?
- Fever, sore throat and generalized lymphadenitis
- lymphocytosis of CD8+ T cells.
What are three general steps of EBV infection?
- Virus infiltrates epithelial cells and after this lymphoid tissue where mature B cells reside get infected.
- Infected B cells become activated and proliferate
- Regulation of proliferation of B cells by (mostly) CD8+ T cells. Some EBV-positive B cells escape this immune respons and persist for the life of the patient
Describe what happens to the peripheral blood, lymph nodes and spleen during EBV-infection.
- There is leukocytosis in the peripheral blood, mostly consisting of atypical lymphocytes.
- Lymph nodes are inflamed (lymphadenopathy)
- Spleen is enlarged (splenomegaly).
What cells can be seen in this picture?
Atypical lymphocytes (in infectious mononucleosis), with an oval, indented, or folded nucleus and abundant cytoplasm with a few azurophilic granules
What is acute nonspecific lymphadenitis?
Group of enlarged lymph nodes due to a local infection or generalized, systemic infection and inflammation.
What are characteristics of acute nonspecific lymphadenitis (i don’t think this is very important)?
Inflamed nodes are swollen, gray-red and engorged. Histologically, there are large germinal centers containing numerous mitotic figures.
Chronic nonspecific lymphadenitis can assume one of three patterns: follicular hyperplasia, paracortical hyperplasia or sinus histiocytosis.
Okay
When does follicular hyperplasia occur during chronic nonspecific lymphadenitis?
It occurs with infections or inflammatory processes that activate B cells, which migrate into B cell follicles and create a follicular reaction.
What can be causes of follicular hyperplasia?
Rheumatoid arthritis, toxoplasmosis and early HIV infection
When does paracortical hyperplasia occur during chronic nonspecific lymphadenitis?
It is caused by immune reactions involving T cells regions. When activated, parafollicular T cells transform into large proliferating immunoblasts that can efface the B cell follicles.
What can be causes of paracortical hyperplasia?
Viral infections, certain vaccinations and immune reactions induces by drugs.
When does sinus histiocytosis occur during chronic nonspecific lymphadenitis?
It usually is encountered in lymph nodes draining cancers and may represent an immune respons to the tumor.
What is characteristic for sinus histiocytosis?
Hypertrophy of lining endothelial cells and infiltrate of macrophages (histiocytes).
What is Cat-Scratch Disease (don’t learn this by heart)?
A self-limited lymphadenitis caused by the bacterium Bartonella henselae. It manifests with regional lymphadenopathy, most frequently in the axilla and the neck. The nodal enlargement appears approximately 2 weeks after a feline scratch or, less commonly, after a splinter or thorn injury.
What is typical for cat-scratch disease (don’t learn this by heart)?
Formation of sarcoidlike granulomas, these undergo central necrosis associated with an infiltrate of neutrophils.
What is Hemophagocytic Lymphohistiocytosis (HLH)? (don’t learn this by heart)
A disorder in which a viral infection triggers activation of macrophages throughout the body. This leads to phagocytosis of blood cells and their precursors, cytopenias, symptoms related to systemic inflammation and organ dysfunction.
Just read (about Hemophagocytic Lymphohistiocytosis (HLH))
Inherited defects in several genes that regulate the function of immune cells are associated with a greatly elevated risk of HLH. The involved genes and proteins are diverse, but they share a common feature in that they are required for the cytolytic function of CD8+ T cells and NK cells. Owing to this defect in “killer lymphocytes,” cytotoxic lymphocytes are unable to kill their targets (e.g. virus infected cells) and remain engaged with targeted cells for longer than normal periods of time, leading to excessive release of cytokines, such as interferon gamma, that activate macrophages. The unbridled macrophage activation results in the release of toxic levels of additional proinflammatory cytokines, such as TNF and IL-6, producing signs and symptoms that closely resemble those associated with sepsis and other conditions that lead to the systemic inflammatory response syndrome
What are clinical manifestations of Hemophagocytic Lymphohistiocytosis (HLH)? (don’t learn this by heart)
Fever, splenomegaly and pancytopenia.
Is there proliferation and/or differentiation for acute leukemias (AML, ALL), chronic myeloproliferative neoplasia (ET, PV, PMF, CML) and myelodysplastic diseases (pancytopenia)?
- Acute leukemias = proliferation, but NO differentiation
- Chronic myeloproliferative neoplasia = proliferation and differentiation
- Myelodysplastic diseases = proliferation and differentiation (into bad quality blood cells).
What kind of neoplasms are there?
Lymphoid, myeloid and histiocytic neoplasms.
What is characteristic for myeloid neoplasms?
Tumors originate from hematopoietic stem cells or precursors and typically the bone marrow is involved. Certain leukemias, myelodysplastic syndromes and myeloproliferative neoplasms belong here.
What is characteristic for histiocytic neoplasms?
Proliferative lesions of macrophages and dendritic cells are present. A special type of this neoplasm is Langerhans cell histiocytoses.
Lymphoid neoplasms can occur as leukemia or as lymphoma. When do we define a lymphoid neoplasm as leukemia or lymphoma?
Leukemia, the bone marrow and peripheral blood is involved. Lymphoma, tumors produce masses in lymph nodes or other tissues.
Name two groups of lymphomas.
Hodgkin and non-Hodgkin lymphomas.
What is specific for B and T cell tumors?
That they are composed of cells that are arrested at a specific stage of normal lymphocyte differentiation.
Why do germinal center B cells have a potential high risk for mutations?
Because of class switching and somatic hypermutation that happens here.
What is meant by the fact that lymphoid neoplasms are clonal?
Tumorcells are derived from a single transformed cell and thus share the same antigen receptor proteins.
What two complications can occur due to a lymphoid neoplasm?
Immunodeficiency and autoimmunity
Describe acute lymphoblastic leukemia/lymphomas (ALLs).
These are neoplasms composed of immature B or T cells. Most ALLs manifest as B-ALLs in childhood. T-ALLs are less common and manifest mostly in adolescent males
What are immature B (pre-B) or T (pre-T) cells called?
Lymphoblasts
In Acute Lymphoblastic Leukemia (ALL) chromosomal aberrations can be seen. What is the consequence of these aberrations?
They disregulate the expression and function of transcription factors that are required for the normal differentiation of B and T cell progenitors.
In keeping with the multistep origins of cancer, mutations in transcription factor genes are not sufficient to produce ALL, what else is common in ALL?
Aberrations that drive cell growth (such as mutations that increase tyrosine kinase activity and RAS signaling)
What are morphological characteristics of leukemias?
The marrow is hypercellular and packed with lymphoblasts, which replace normal marrow elements.
What is seen in this picture of ALL-cells?
Tumor cells have scant basophillic (agranular) cytoplasm and condensed nuclear chromatin and small nucleoli.
What enzyme is specifically expressed in pre-B and pre-T cells and thus can distinguish ALL from AML?
Terminal deoxynucleotidyl transferase (TdT)
Which three general clinical features are there for ALL?
- Symptoms related to depression of marrow function.
- Mass effects caused by neoplastic infiltration
- Central nervous system manifestation
What symptoms related to depression of marrow function can occur in ALL?
Fatigue resulting from anemia, fever, secondary infections due to neutropenia, bleeding due to thrombocytopenia.
What mass effects caused by neoplastic infiltrations can occur in ALL?
Bone pain resulting from marrow expansion and infiltration, lymphadenopathy, splenomegaly and hepatomegaly
Which manifestations of the central nervous system can occur in ALL?
Headache, vomiting and nerve palsies resulting from meningeal spread.
Which factors are associated with a worse prognosis of ALL?
- Age younger than 2 years
- presentation in adolescene or adulthood
- peripheral blood blast counts greater than 100.000.
Which factors are associated with a favorable prognosis of ALL?
- Age between 2 and 10 years. 2. Low white cell count 3. hyperdiploidy
Just read
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially identical, differing only in the extent of peripheral blood involvement. Somewhat arbitrarily, if the peripheral blood lymphocyte count exceeds 5000 cells/µL, the patient is diagnosed with CLL.
What is interesting about Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)?
Tumors are indolent and slowly growing. Tumor cell survival seems to be more important than tumor cell proliferation.
CLL/SLL is a neoplasm of mature B cells expressing CD20 and surface immunoglobulins. What else does the tumor express and is a helpful diagnostic clue?
CD5
Greater than 85% of follicular lymphomas have a characteristic (14;18) translocation that fuses the BCL2 gene on chromosome 18 to the IgH locus on chromosome 14. What does this chromosomal rearrangement result in?
In the inappropriate overexpression of BCL2 protein (inhibitor of apoptosis) and so contributes to tumor cell survival.
What do follicular lymphomas express?
CD20 (B cell markers) CD10 (germinal center marker) and BCL6 (transcription factor required for generation of germinal center B cells).
Just read
Follicular lymphoma mainly occurs in adults older than 50 years of age and affects males and females equally. It usually manifests as painless, generalized lymphadenopathy. The bone marrow is involved at diagnosis in approximately 80% of cases.
Name the two acute leukemias discussed in the lecture
Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL)
How do neoplastic cells during acute myeloid leukemia (AML) develop?
Myeloid cell development is blocked at an early stage.
Where do immature myeloid cells reside (in AML)?
The immature myeloid cells (blasts) accumulate in the marrow and replace normal elements, and frequently circulate in the peripheral blood.
What are myeloid neoplasms?
They arise from hematopoietic progenitors and typically give rise to proliferations that involve the bone marrow and replace normal marrow elements.
What other myeloid neoplasms are there besides acute myeloid leukemia?
Myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS)
How do myeloproliferative neoplasms (MPN) arise?
Here, the neoplastic clone continues to undergo terminal differentiation but exhibits increased or dysregulated growth. ((((Commonly, these are associated with an increase in one or more of the formed elements (red cells, platelets, and/or granulocytes) in the peripheral blood.))))
What happens during myelodysplastic syndromes (MDS)?
There is terminal differentiation, but in a disorderd and ineffective fashion (ineffective hematopoiesis). This leads to the appearance of dysplastic marrow precursors and peripheral blood cytopenias.
What can myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) result in?
They often transform to AML and some neoplasms have features of both MPN as MDS.
Who is often affected by Acute Myeloid Leukemia (AML)?
Older adults; the median age is 50 years.
What are common symptoms of Acute Myeloid Leukemia (AML)?
Fatigue, pallor, abnormal bleeding and infections.
The diagnosis and classification of AML are based on…
morphologic, histochemical, immunophenotypic, and karyotypic findings.
What genes are usually mutated in AML?
Genes encoding transcription factors that are required for normal myeloid cell differentiation. (There are also mutations found that direcly impact the epigenome.)
What kind of cells can be seen in this picture and how can you define these?
Myeloblasts in acute myeloid leukemia (AML). You can see this by the delicate nuclear chromatin, prominent nucleoli (3-5) and fine azurophilic cytoplasmic granules.
What other structure can be found in myeloblasts?
Auer rods, distinctive red-staining rodlike structures.
Nowadays AML is classified by genetic defects. Which of the two genetic defect has poor prognostic sign and which of the two has good prognostic sign? t(15;17), t(8;21), inv16 t(9;22), 5(6;9), inv 3
t(15;17), t(8;21), inv16 -> poor prognostic sign t(9;22), t(6;9), inv3 -> good prognostic sign
What happens to the bone marrow in myelodysplastic syndromes (MDS)?
The bone marrow is partly or wholly replaced by the clonal progeny of a transformed multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets, but in a manner that is both ineffective and disordered. As a result, the marrow usually is hypercellular or normocelluclar.
How can myelodysplastic syndromes (MDS) transform into AML?
The abnormal stem cell clones are genetically unstable and prone to the acquisition of additional mutation and the eventual transformation to AML.
Which genes are recurrently mutated in myelodysplastic syndromes (MDS)?
Epigenetic factors (e.g. factors that regulate DNA methylation), RNA splicing factors and transcription factors.
In myeloproliferative neoplasms (MPN) the neoplastic clone continues to undergo terminal differentiation but exhibits increased or dysregulated growth. What is mutated that causes a dysregulated growth?
Tyrosine kinases are mutated (or other acquired aberration in signaling pathways that lead to growth factor independence) and therefore are constitutively activated.
Commonly, myeloproliferative neoplasms are associated with an increase in one or more of the formed elements (red cells, platelets, and/or granulocytes) in the peripheral blood. Why is this?
Because of the acquired aberrations in signaling pathways that lead to growth factor independence.
How does hepatosplenomegaly occur in myeloproliferative neoplasms (MPN)?
Because of the neoplastic progenitors that tend to seed secondary hematopoietic organs (spleen, liver and lymph nodes).
How is Chronic Myeloid Leukemia (CML) distinguished from other myeloproliferative neoplasms (MPN)?
By the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosoom 22 and the ABL gene on chromosome 9.
Normal myeloid progenitors depend on signals generated by growth factors and their receptors for growth and survival. How is growth factor independence generated in Chronic Myeloid Leukemia (CML)?
The growth factor dependence of CML progenitors is greatly decreased by constitutive signals generated by BCR-ABL that mimic the effects of growth factor receptor activation.
What are morphological characterisations of Chronic Myeloid Leukemia (CML)?
Leukocyte count is elevated, circulating cells are neutrophils, metamyelocytes and myelocytes. But also basophils and eosinophil also exist. The bone marrow is hypercellular due to increased numbers of maturing granylocytic and megakaryocytic precursors.
What is a clinical characteristic of Chronic Myeloid Leukemia (CML)?
Huge splenomegaly
What is another disease that involves mutations in tyrosine kinase (JAK2)?
Polycythemia Vera (PV)
Two main groups can be distinguished in acute leukemia. Which two main groups are those?
Acute myeloide leukemia (AML) en acute lymphoid leukemia (ALL)
Two main groups can be distinguished in acute leukemia. Why is the distinction been made?
Differences in therapy, different prognosis
What’s the difference and similarity between Hodgkin lymphoma and non-Hodgkin lymphoma (NHL)?
They arise most commonly in lymphoid tissues. But Hodgkin lymphoma has neoplastic RS giant cells which are outnumbered by nonneoplastic inflammatory cells.
Do Non-Hodgekin Lymphomas (NHLs) only manifest at particular tissue sites?
No, sensitive molecular assays usually show that the tumor is widely disseminated at diagnosis. (As a result, with few exceptions, only systemic therapies are curative for those with NHL.)
Do Hodgkin lymphomas only arise at particular tissue sites?
They arise at a single site and spreads in a predicatable fashion to contiquous lymph node groups.
