White Blood Cell Disorders

Question 1

What are the different lineages of cells that can develop from CD34+ HSCs?

Answer 1

Myeloid (erythroblasts, myeloblasts, monoblasts, megakaryoblasts) and lymphoid (B lymphoblasts, T lymphoblasts) stem cells.

Pathoma, page 53

Question 2

Describe how drug toxicity and severe infection can lead to neutropenia? What supporting treatment can be used?

Answer 2

1) Chemotherapy with alkylating agents commonly cause of neutropenia by damaging stem cells.
2) Severe infection, especially gram-negative sepsis, can result in neutropenia/decreased circulating neutrophils due to increased transmigration of neutrophils into tisues.

Treat with GM-CSF or G-CSF to boost granulocyte production.

Pathoma, page 53

Question 3

What is a left shift and under what circumstances does this occur? Characterization of left shift?

Answer 3

Left shift is the release of immature forms of bone marrow neutrophils (resulting in neutrophilic leukocytosis) during bacterial infection or tissue necrosis.

These immature cells are characterized by decreased expression of Fc receptors (or CD16) which are used by neutrophils to recognize opsonins.

Pathoma, page 53

Question 4

How does high cortisol state lead to increased circulating neutrophils?

Answer 4

High cortisol state impairs leukocyte adhesion, leading to release of marginated pool of neutrophils in the lungs into the circulation.

Pathoma, page 53

Question 5

What are the associated conditions in which we would see the following:

1) Neutrophilic leukocytosis
2) Monocytosis
3) Eosinophilia
4) Basophilia
5) Lymphocytic leukocytosis

Answer 5

1) Neutrophilic leukocytosis: Bacterial infection, tissue necrosis, high cortisol state
2) Monocytosis: chronic inflammatory states, malignancy
3) Eosinophilia: allergic reactions (type I hypersensitivity), parasitic infections, Hodgkin lymphoma (via increased chemotactic factor IL-5)
4) Basophilia: classically in chronic myeloid leukemia (CML)
5) Lymphocytic leukocytosis: viral infections (CD8), Bordatella pertusis (bacterial infections usually lead to neutrophilic leukocytosis but pertusis forms lymphocytosis-promoting factor that blocks circulating lymphocytes from leaving blood and into lymph node)

Pathoma, page 54

Question 6

What is the most common cause of infectious mononucleosis? How is the immune system affected in IM and clinical findings? How is screening and definitive diagnosis achieved?

Answer 6

EBV infection, transmitted by saliva, is most common cause especially in teenagers (“kissing disease”). It infects the oropharynx (pharyngitis), liver (hepatitis/hepatomegaly), and B cells.

Infection leads to lymphocytic leukocytosis comprising of reactive CD8+ T cells. Findings include generalized lymphadenopathy (result of T cell hyperplasia in lymph node paracortex), splenomegaly (result of T cell hyerplasia in periarterial lymphatic sheath, can get splenic rupture), and high WBC count.

Screen with monospot test, which detect heterophile IgM antibodies that cross-react with horse/sheep RBCs–usually positive 1 week post-infection (negative suggests CMV as possible cause). Definitive diagnosis with serologic test for EBV viral capsid antigen.

Pathoma, page 54

Question 7

What is the definition of acute leukemia? What would be seen on smear?

Answer 7

Acute leukemia is the result of a cell’s ability to mature, resulting in neoplastic proliferation of immature blasts. The bone marrow would consist of > 20% blasts, whereas normal would be 1-2%, and can result in high WBC count as they “leak” into bloodstream.

Smear would reveal large immature cells, often with “punched out” nucleoli.

Pathoma, page 55

Question 8

What is the characteristic marker for lymphoblasts? What would you look for to identify myeloid blasts?

Answer 8

TdT, a DNA polymerase present ONLY in the nuclei of lymphoblasts–ABSENT from mature lymphocytes and myeloid blasts.

MPO is the characteristic cytoplasmic stain for myeloid blasts. Additionally, MPO can crystallize to form Auer rods that are visible on blood smear.

Pathoma, page 55

Question 9

What would the surface markers of a person with B-ALL vs. T-ALL look like?

Answer 9

B-ALL would have TdT+ lymphoblasts expressing CD10, CD19, and CD20.

T-ALL patients would have TdT+ lymphoblasts expressing CD2-CD8 markers.

Pathoma, page 55

Question 10

How does B-ALL fair in response to chemotherapy (CTX)? Why is prophylactic CTX performed on the scrotum and CSF? How is the prognosis for B-ALL determined?

Answer 10

B-ALL responds well to CTX. Prophylactic CTX is injected directly to the scrotum and CSF because these are immune-privileged sites CTX cannot normally reach (does not cross BBB).

The prognosis is based on cytogenetic abnormalities:

1) t(12;22) good prognosis, common in children.
2) t(9;22)/Philadelphia chromosome, poor prognosis, common in adults. Ph+ chromosome classically seen in CML but there are subset of patients with Ph+ with B-ALL.

B-ALL most commonly arises in children, and is associated with Down syndrome arising usually AFTER THE AGE OF 5.

Pathoma, page 55

Question 11

What is the usual clinical finding for T-ALL? What is it also known as?

Answer 11

T-ALL usually presents in TEENAGERS as a THYMIC (mediastinal) mass, and because of this it is called acute lymphoblastic LYMPHOMA.

Pathoma, page 56

Question 12

How is AML subclassified?

Answer 12

Subclassified by cytogenetic abnormalities, as well as cell lineages if no cytogenetic abnormalities.

Question 13

What is the cause of acute promyelocytic leukemia? Treatment + MoA?

Answer 13

t(15;17) translocation that leads RAR (retinoic acid receptor) disruption, resulting in block in promyelocyte’s ability to mature (thereby, getting accumulation of blasts). Auer rods have the potential to activate the coagulation cascade, putting patient at risk for DIC (MEDICAL EMERGENCY).

Treatment for APL is ATRA (all-trans-retinoic acid), which is a vitamin A derivative that binds altered receptor to stimulate blast maturation.

Pathoma, page 56

Question 14

What are some characteristics of the following subsets of acute myeloid leukemia:

1) Acute monocytic leukemia
2) Acute megakaryoblastic leukemia

Answer 14

1) Acute monocytic leukemia is a proliferative of monoblasts that LACK MPO. Blasts characteristically infiltrate gums.
2) Acute megakaryoblastic leukemia is a proliferation of megakaryoblasts that LACK MPO. It is associated with Down Syndrome BEFORE age 5.

Pathoma, page 56

Question 15

Down syndrome’s association with acute leukemia?

Answer 15

Down syndrome is associated with acute megakaryoblastic leukemia (subset of AML) BEFORE age 5, and associated with B-ALL AFTER age 5.

Pathoma, page 55-56

Question 16

AML arising from pre-existing dysplasia?

Answer 16

AML can arise from pre-existing dysplasia (myelodysplastic syndromes), especially with prior exposure to alkylating agents or radiotherapy.

Myelodysplastic patients usually present with cytopenias with hypercellular bone marrow consisting of abnormal maturation of cells/increased blast (<20%). Most die from infection or bleeding, but some progress to acute leukemia if circulating blast cont > 20%.

Pathoma, page 56

Question 17

What is the pathophysiology for chronic leukemias and who do they usually affect? How does this compare to acute leukemias?

Answer 17

Chronic leukemias involve a neoplastic proliferation of MATURE circulating lymphocytes, resulting in high WBC count. They are usually insidious in onset and seen in older adults. This is in contrast to acute leukemias, which involve proliferation of immature blasts and commonly affect children.

Pathoma, page 56

Question 18

What are the characteristic marker findings for chronic lymphocytic leukemia (CLL)? What would you see on smear? Clinical findings and complications?

Answer 18

Characteristic marker finding would be CO-EXPRESSION of CD5 and CD20 on NAIVE B CELLS (just produced from bone marrow)–CD5 normally expressed on T cells but wrongly expressed on B cells in CLL.

Smear would see increased lymphocytes and “smudge” cells.

Can involve lymph nodes (SMALL lymphocytic LYMPHOMA/SLL with formation of mass) leading to generalized lymphadenopathy. Complications include:

1) Hypogammaglobulinemia - infection most common cause of death
2) Autoimmune hemolytic anemia -
3) Richter transformation to diffuse LARGE B-cell lymphoma - enlarging lymph node or spleen due to increased tumor aggression

Pathoma, page 57

Question 19

Hairy cell leukemia characterized by? Clinical features? Treatment?

Answer 19

Hairy cell leukemia involves neoplastic proliferation of MATURE B cells characterized by hairy cytoplasmic processes. Cells are also positive for TRAP, or tartrate-resistant aid phosphatase.

Clinical features include:

1) Splenomegaly due to hairy cell accumulation in RED pulp, as opposed to white pulp.
2) “Dry tap” on bone marrow aspiration due to fibrosis.
3) Lymphadenopathy is usually ABSENT due to cells being “TRAPped” in red pulp (unusual for WBCs to be in red pulp vs. normal white pulp) of spleen and bone marrow (cannot reach lymph nodes).

Excellent reponse to 2-CDA (cladribine), an ADA inhibitor that results in accumulation of adenosine to toxic levels in neoplastic B cells.

Pathoma, page 57

Question 20

Adult T-Cell leukemia/lymphoma (ATLL) involve neoplastic proliferation of what cells? Clinical features? How to differentiate from multiple myeloma?

Answer 20

ATLL involves neoplastic proliferation of MATURE CD4+ T cells. It is associated with HTLV-1 (human T cell leukemia virus-1), most commonly seen in Japan in the Carribean.

Clinical features include:

1) Rash - mature CD4+ T cells like to infiltrate skin
2) Generalized lymphadenopathy + hepatosplenomegalty
3) Lytic “punched out” bone lesions with hypercalcemia, which is also a common finding in multiple myeloma. However, we do not see skin infiltration in MM.

Pathoma, page 57

Question 21

What condition is it that we find Pautrier microbascesses and what are these? What happens if cells spread to involve the blood and what do we expect to find on smear?

Answer 21

Pautrier microabscesses are found in mycosis fungoides and are comprised of aggregates of neoplastic mature CD4+ cells in the epidermis to prouce localized skin rash, plaques, and nodules. These are characteristic of mycosis fungoides.

Cells can spread to involve the blood to produce Sezary syndrome. Characteristic cells for Sezary syndrome are Sezary cells with cerebriform nuclei.

Pathoma, page 57

Question 22

Which age group do myeloproliferative disorders tend to affect? Explain the following complications associated with MPDs:

1) Hyperuricemia and gout
2) “Spent phase”
3) Transformation to acute leukemia

What is the exception for these complications?

Answer 22

MPDs are usually diseases of late adulthood (average age 50-60 years).

1) Hyperuricemia and gout due to high cell turnover
2) Marrow fibrosis
3) Mutations accumulate to where cells are arrested in the blast phase and unable to continue to maturation

It is RARE for essential thrombocythemia (ET) to progress to marrow fibrosis/acute leukemia. There is also no significant increased risk for hyperuricemia/gout because platelets are anuclear (just buds of megakaryocyte cytoplasm!).

Pathoma, page 58-9

Question 23

What would you see on blood smear for CML, especially characteristic finding(s)?

Answer 23

Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors. CHARACTERISTIC INCREASE in basophils–basophilia!

Question 24

Cause of chronic myeloid leukemia/CML? Treatment/mechanism of action? What clinical finding suggests acceleration of disease? What is the worse type of progression CML can turn to and how/why?

Answer 24

Driven by Philadelphia chromosome t(9;22), resulting in BCR-ABL fusion protein that increases tyrosine kinase activity.

First line treatment is imatinib, a TK inhibitor, but is NOT curative.

Splenomegaly is common but ENLARGING spleen suggests disease acceleration with potential to develop into either AML (2/3 cases) OR ALL (1/3 cases). Either can develop because mutation is in pluripotent stem cell before differentiation into either myeloid or lymphoid lineage.

Pathoma, page 58

Question 25

What are some ways to distinguish CML from a leukemoid reaction (reactive neutrophilic leukocytosis) due to infection?

Answer 25

1) Leukocyte alkaline phosphatase (LAP) negative on granulocytes in CML, but positive with leukemoid reaction (important enzyme to fight infection).
2) Basophilia in CML
3) Philadelphia chromosome in CML t(9;22)

Pathoma, page 58

Question 26

Which group of cells would we see proliferate predominantly in polycythemia vera (PV)? What is the driving mutation for PV? Clinical symptoms? Treatment(s)?

Answer 26

Neoplastic proliferation of mature myeloid cells, ESPECIALLY RBCs.

Driving mutation for PV is JAK2 kinase mutation.

Clinical symptoms mostly related to hyperviscocity of blood:

1) blurry vision + headache
2) increased risk of venous thrombosis (number one cause for Budd-Chiari syndrome)
3) flushed face from congestion (plethora)
4) Itching, esp. after bathing, due to increased histamine release by basophils

Treat with phlebotomy, second line with hydroxyurea.

Pathoma, page 58

Question 27

How to distinguish PV from reactive polycythemia?

Answer 27

1) In PV, EPO levels are DECREASED and SaO2 is normal.
2) In reactive polycythemia due to high altitude or lung disease, EPO is INCREASED and SaO2 is low.
3) In reactive polycythemia due to ectopic EPO production from renal carcinoma, EPO is INCREASED and SaO2 is normal.

Pathoma, page 59

Question 28

Associated mutation for ET?

Answer 28

JAK2 kinase mutation

Pathoma, page 59

Question 29

What is the cause of myelofibrosis? What are the clinical features/findings on smear?

Answer 29

Associated with JAK2 kinase mutation with predominant increase in megakaryocytes. Megakaryocytes ten produce EXCESS platelet-derived growth factor (PDGF) that leads to marrow fibrosis.

Fibrotic marrow limits production of cells, leading to compensatory extramedullary hematopoiesis and as a result splenomegaly.

Leukoerythroblastic smear with immature granulocytes, nucleated RBCs, tear-drop RBCs. Instead of the normal fatty marrow we expect to see, we see fibrotic marrow spaces with lots of pink collagen.

Because bone marrow cannot make sufficient amount of other cells, we get increased risk for infection, thrombosis, and bleeding.

Pathoma, page 59

Question 30

Situations in which we would see painFUL LAD vs. painLESS LAD?

Answer 30

PAINFUL LAD - acute infection results in LN draining infection (acute lymphadenitis)

PAINLESS LAD - chronic inflammation (chronic lymphadenitis), metastatic carcinoma, lymphoma

Pathoma, page 59

Question 31

What are the different regions of the lymph nodes and the cells that reside/proliferate there? What are some conditions/diseases in which we see hyperplasia of these regions?

Answer 31

Cortex/B cells: follicular hyperplasia with RA and early HIV. HIV usually infects CD4+ cells, which include both T cells (present in paracortex) AND dendritic cells (cortex).

Paracortex/T cells: hyperplasia with viral infections (e.g. infectious mononucleosis).

Medulla/sinus histiocytes: hyperplasia with lymph nodes draining tissue with cancer. Cancer has not spread to lymph node (non-metastatic) but just reactive to cancer.

Pathoma, page 60