White Blood Cell Disorders Flashcards
(106 cards)
1
Q
What is the surface marker for hematopoietic stem cells?
A
CD34+
2
Q
What is a normal WBC count?
Low?
High?
A
A normal white blood cell (WBC) count is approximately 5-10 K/uL.
- A low WBC count(< 5 K) is called leukopenia.
- A high WBC count (> 10 K) is called leukocytosis.
- A low or high WBC count is usually due to a decrease or increase in one particular cell lineage.
3
Q
What is Leukopenia?
A
Low neutrophils and/or lymphocytes
4
Q
Neutropenia
What causes it?
How can it be treated?
A
refers to a decreased number of circulating neutrophils.
Causes include
-
Drug toxicity (e.g., chemotherapy with alkylating agents)-Damage to stem cells
results in decreased production ofWBCs, especially neutrophils. -
Severe infection (e.g., gram-negative sepsis)- Increased movement of neutrophils
into tissues results in decreased circulating neutrophils.
GM-CSF or G-CSF may be used pharmacologically to boost granulocyte production, thereby decreasing risk of infection.
5
Q
What is Lymphopenia?
Causes?
A
Lymphopenia refers to a decreased number of circulating lymphocytes.
Causes include
- Immunodeficiency (e.g., DiGeorge syndrome or HIV)
-
High cortisol state (e.g., exogenous corticosteroids or Cushing syndrome)induces
apoptosis of lymphocytes - Autoimmune destruction (e.g., systemic lupus erythematosus)
-
Whole body radiation-Lymphocytes are highly sensitive to radiation;
lymphopenia is the earliest change to emerge after whole body radiation.
6
Q
What is Neutrophilic Leukocytosis?
$ Name 2 causes
A
Neutrophilic leukocytosis refers to increased circulating neutrophils.
Causes include
- Bacterial infection or tissue necrosis- induces release of marginated pool and bone marrow neutrophils, including $ immature forms (left shift); immature cells are characterized by decreased Fe receptors (CD16).
- High cortisol state-impairs leukocyte adhesion, leading to release of marginated pool of neutrophils
7
Q
What is monocytosis
Causes
A
Monocytosis refers to increased circulating monocytes.
chronic inflammatory states (e.g., autoimmune and infectious) and malignancy
8
Q
What is Eosinophilia?
$ Which malignancy is this state seen in?
A
Eosinophilia refers to increased circulating eosinophils. Causes include allergic reactions (type I hypersensitivity), parasitic infections, and
$ Hodgkin lymphoma - Eosinophilia is driven by increased eosinophil chemotactic factor. Increased production of IL-5
9
Q
$ Which malignant state is basophilia classically seen?
A
Basophilia refers to increased circulating basophils;
$classically seen in chronic myeloid leukemia
10
Q
What is Lymphocytic leukocytosis?
$ What is a particularly high yield exception to the rule that neutrophilic leukocytosis is the typical response to bacterial invasion?
A
Lymphocytic leukocytosis refers to increased circulating lymphocytes. Causes include
-
Viral infections- I lymphocytes undergo hyperplasia in response to virally
infected cells.
2.$ Bordetella pertussis infection-Bacteria produce lymphocytosis-promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph node.
11
Q
Organs EBV primarily affects
A
- Oropharynx, resulting in pharyngitis
- Liver, resulting in hepatitis with hepatomegaly and elevated liver enzymes
- B cells
12
Q
$Which area of the lymph node will be enlarged in EBV infection?
A
l. Generalized lymphadenopathy (LA D) due to T-cell hyperplasia in the lymph node paracortex
2. **Splenomegaly **due to T-cell hyperplasia in the periarterial lymphatic sheath
13
Q
An EBV infection may lead to a high WBC and the presence of this type of cell?
A
High WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood - large nucleus with abundant cytoplasm, looks like monocyte but actually T-cell.
14
Q
What test is used to screen for Mono?
What does a negative result suggest?
A
The monospot test is used for screening.
1. Detects IgM antibodies that cross-react with horse or sheep red blood cells
(heterophile antibodies)
2. Usually turns positive within 1 week after infection
3. A negative monospot test suggests CMV as a possible cause of IM.
4. Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen.
15
Q
Complicationsof EBV infection?
A
E. Complications
l. Increased risk for splenic rupture (Fig. 6.3); patients are generally advised to
avoid contact sports for one year.
2. Rash if exposed to ampicillin
3. Dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g., HIV) develops.
16
Q
Define Acute Leukemia
What is presentation of patient?
A
Neoplastic proliferation of blasts; defined as the accumulation of > 20% blasts in the bone marrow.
Increased blasts “crowd-out” normal hematopoiesis, resulting in an
“acute” presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropen ia
(infection).
17
Q
How is Acute leukemia subdivided?
A
Acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) based on the phenotype of the blasts.
18
Q
ACUTE LYMPHOBLASTIC LEUKEMIA
A
Neoplastic accumulation of lymphoblasts (> 20%) in the bone marrow
- Lymphoblasts are characterized by positive nuclear staining for TdT, a DNA polymerase.
- TdT is absent in myeloid blasts and mature lymphocytes.
19
Q
Which age group commonly gets ALL?
A
Most commonly arises in children; associated with Down syndrome (usually arises after the age of 5 years)
20
Q
How is ALL classified? What is most common type?
A
Subclassified into B-ALL and T-ALL based on surface markers
B-ALL is the most common type of ALL.
21
Q
How can B-ALL be characterized?
$ What is a consideration that must be accounted for while delivering chemotherapy? Why?
What is the prognosis for B-ALL?
A
Usually characterized by lymphoblasts (TdT+) that express CDlO, CD19, and CD20.
- Excellent response to chemotherapy; $ requires prophylaxis to scrotum and CSF
- Prognosis is based on cytogenetic abnormalities.
** t(l2;21) has a good prognosi**s; more commonly seen in children
t(9;22)has a poor prognosis; more commonly seen in adults (Philadelphia+ ALL)
22
Q
How can T-ALL be characterized?
A
T-ALL is characterized by lymphoblasts (TdT+) that express markers ranging from CD2 to CDS (e.g., CD3, CD4, CD7). The blasts do not express CO10.
Usually presents in teenagers as a mediastinal (thymic) mass (called acute lymphoblastic lymphoma because the malignant cells form a mass) - in mediastinum
23
Q
A 55 year old presents with general fatigue, weakness, and infections of variable severity with gingival bleeding, epistaxis, and ecchymoses. He also complains of bone pain in his lower legs. A Peripheral blood smear was obtained. The arrow points to a strcuture containing enzymes that perfom an important chemical reaction. What is the enzyme and what reaction does it mediate?
A
ACUTE MYELOID LEUKEMIA
Neoplastic accumulation of myeloblasts (> 20%) in the bone marrow
Myelobasts are precursors to the granulocytes (Plymorphonuclear leukocytes, Neutrophils, Basophils, Eosinophils)
Myeloblasts are usually characterized by positive cytoplasmic staining for myeloperoxidase (MPO)
1. Crystal aggregates of MPO may be seen as Auer rods
MPO converts H2O2 to HOCl* (bleach)
Neutrophils depend on Oxygen-dependent killing using NADPH oxidase to convert oxygen to an oxygen free radical, then convert it to hydrogen peroxide via superoxide dismutase (SOD), and finally to bleach. Bleach will destroy the phagocytosed microbes.
Peripheral blood with promyelocyte filled with Auer rods in acute promyelocytic leukemia. The neoplastic promyelocyte has numerous splinter-shaped inclusions in the cytoplasm (arrow) representing Auer rods
24
Q
Age group AML most often arises in?
Types?
A
Most commonly arises in older adults (average age is 50-60 years)
Subclassified based on cytogenetic abnormalities, lineage of myeloblasts, and surface
markers. High-yield subtypes include:
- Acute promyelocytic leukemia (APL)
- Acute monocytic leukemia
- Acute megakaryoblastic leukemia
25
$ How is Acute promeyelocitic leukemia (APL) characterized?
Characterized by **_t(l5;17)_**, which involves translocation of the _**retinoic acid receptor (RAR) on chromosome 17 to chromosome 15**;_
**_RAR disruption blocks maturation and promyelocytes (blasts) accumulate._**
26
$ Treatment for Acute Promyelocytic leukemia? (APL)
$ Treatment is with **all-trans-retinoic acid** (ATRA, a vitamin A derivative), which **binds the altered receptor and causes the blasts to mature (and eventually die).**
27
A derivative of which cell line has likely infiltrated the gingivae?
* *Acute monocytic leukemia (AML)**
i. Proliferation of **monoblasts;** usually lack MPO
ii. **_Blasts characteristically infiltrate gums_**
28
$ Key association with Acute megakaryoblastic leukemia? (AML)
Acute megakaryoblastic leukemia
i. Proliferation of megakaryoblasts; lack MPO
ii. Associated with **_Down syndrome (usually arises before the age of 5)_**
29
CHRONIC LEUKEMIA
* Neoplastic proliferation of mature circulaling lymphocytes; characterized by a high WBCcount
* Usually insidious in onset and seen in older adults
30
What is the most common leukemia overall?
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Neoplastic proliferation of naive B cells that co-express **_CD5(normally on T cellls, now on B)_ and CD20**
31
What is seen on blood smear with CLL?
Increased lymphocytes and **smudge cells (damaged lymphocytes)** are seen on blood smear
Involvement of lymph nodes leads to generalized lymphadenopathy and is called **small lymphocytic lymphoma.**
32
Complications of CLL?
What is the most common cause of death in CLL?
* *Hypogammaglobulinemia** - **_lnfection_ is the most common cause of death in CLL.**
2. **Autoimmune hemolytic anemia**
3. Transformation to diffuse large B-celllymphoma (Richter transformation)marked clinically by an enlarging lymph node or spleen
33
HAIRY CELL LEUKEMIA
$ What do cells stain positive for?
Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes
Cells are positive for **tartrate-resistant acid phosphatase (TRAP).**
34
$ Clinical features of this disease?
**Hairy Cell Leukemia**
Clinical features include **_$splenomegaly_** (**due to accumulation of hairy cells in red pulp**) and "dry tap" on bone marrow aspiration (due to marrow fibrosis).
Lymphadenopathy is usually **absent** - trapped in spleen!
Peripheral smear from a patient with hairy cell leukemia. Panel A: normal view of five hairy cells. The cells have abundant, irregularly distributed cytoplasm. The nuclei vary from round to oval to slightly lobulated. Panel B: same view but with the contrast adjusted to show the irregular cytoplasmic outlines, giving the cells their "hairy" appearance (arrows). Wright-Giemsa stain.
35
$ Treatment for Hairy cell Leukemia?
Excellent response to **2-CDA (cladribine)**, an **adenosine deaminase inhibitor**; adenosine accumulates to toxic levels in neoplastic B cells.
36
What is ATLL? What is it associated with?
Features?
A. Neoplastic **proliferation of mature CD4+ T cells**
R. Associated with **HTLV-1**; most commonly seen in Japan and the Caribbean
C. Clinical features include **rash (skin infiltration), generalized lymphadenopathy with hepatosplenomegaly,** and$ **lytic (punched-out) bone lesions with hypercalcemia.**
37
MYCOSIS FUNGOIDES
**Neoplastic proliferation of mature CD4+ T cells** that infiltrate the skin, producing localized skin rash, plaques, and nodules.
**Aggregates of neoplastic cells in the epidermis are called $ _Pautrier microabscesses_.**
38
$ What is a complication of MYCOSIS FUNGOIDES?
Cells can spread to involve the blood, producing **_Sezary syndrome_**
Characteristic lymphocytes with **$ cerebriform nuclei (Sezary cells) are seen on blood smear**
39
Basic principles of Myeloproliferative disorders?
Age?
Blood panel?
How are they classified?
Complications?
A. Neoplastic proliferation of **mature cells of myeloid lineage; disease of late adulthood (average age is 50-60 years)**
B. Results in **high WBC count with hypercellular bone marrow**
1. Cells of all myeloid lineages are increased; classified based on the dominant myeloid cell produced
Complications include
1. Increased risk for hyperuricemia and gout due to high turnover of cells
2. Progression to marrow fibrosis or transformation to acute leukemia
40
What is CML?
Neoplastic proliferation of **mature myeloid cells**, especially **granulocytes** and their **precursors**; **basophils** are characteristically increased
Driven by t(9;22) (Philadelphia chromosome) which generates a BCR-ABL fusion protein with increased tyrosine kinase activity.
1. First line treatment is imatinib, which blocks tyrosine kinase activity.
41
Presentation of CML?
What is a complication of CML?
Splenomegaly is common. Enlarging spleen suggests accelerated phase of disease; transformation to acute leukemia usually follows shortly thereafter.
Can transform to **_$ AML (2/3 of cases) or ALL (1/3 of cases)_** since mutation is in a pluripotent stem cell.
42
How would you distinguish CML from a leukemoid reaction?
CML is distinguished from a leukemoid reaction (reactive neutrophilic leukocytosis) by
$ 1. **Negative leukocyte alkaline phosphatase** (LAP) stain (granulocytes in a leukemoid reaction are LAP positive)
$ 2. **Increased basophils** (absent with leukemoid reaction)
$ 3. **t(9;22) (absent in leukemoid reaction)**
43
POLYCYTHEMIA VERA (PV)
$ What drives PV?
Neoplastic proliferation of mature myeloid cells, especially RBCs
1. Granulocytes and platelets are also increased.
$ Associated with **_JAK2 kinase mutation_**
44
What cause the clinical symptoms seen in PV?
Clinical symptoms are mostly due to **hyperviscosity** of blood.
1. Blurry vision and headache
$2. Increased risk of **venous thrombosis (e.g., hepatic vein, portal vein, and dural sinus**)
3. Flushed face due to congestion (plethora}
4. **Itching, especially after bathing (due to histamine release from increased mast
cells)**
45
Treatment for PV?
$ What must PV be distinguished from?
Treatment is phlebotomy; second-line therapy is hydroxyurea.
1. Without treatment, death usually occurs within one year.
E. PV must be distinguished from reactive polycythemia.
$ 1. **In PV, erythropoietin (EPO) levels are decreased, and Sao2 is normal.**
2. In reactive polycythemia due to high altitude or lung disease, Sao2 is low, and **EPO is increased**.
$ 3. In reactive polycythemia due to ectopic **EPO production from renal cell carcinoma, EPO is high, and Sao2 is normal.**
46
ESSENTIAL THROMBOCYTHEMIA (ET)
$ What drives ET?
A. Neoplastic proliferation of mature myeloid cells, especially platelets (Fig. 6.12)
1. RBCs and granulocytes are also increased.
$ B. Associated with **JAK2 kinase mutation**
C. Symptoms are related to an increased risk of bleeding and/or thrombosis.
1. Rarely progresses to marrow fibrosis or acute leukemia
2. **No significant risk for hyperuricemia or gout**
47
MYELOFIBROSIS
$ Association?
Mechanism for marrow fibrosis?
Neoplastic proliferation of mature myeloid cells, especially megakaryocytes
$ Associated with **JAK2 kinase mutation (50% of cases)**
B. Megakaryocytes produce excess **platelet-derived growth factor (PDGF)** causing marrow fibrosis
48
A Blood smear is obtained. What cell shows the greatest neoplastic proliferation in this diseas?
What clinical findings would you see in a patient with the following blood smear? Complications?
MYELOFIBROSIS - neoplastic proliferation of mature myeloid cells, especially **megakaryocytes**
Clinical features include
1. **Splenomegaly** due to extramedullary hematopoiesis
2. **Leukoerythroblastic smear** (tear-drop RBCs, nucleated RBCs, and immature
granulocytes,
3. **Increased risk of infection, thrombosis, and bleeding**
49
Painful vs Painless LAD
1. Painful LAD is usually seen in lymph nodes that are draining a region of **acute infection (acute lymphadenitis**).
2. Painless LAD can be seen with **chronic inflammation** (chronic lymphadenitis), metastatic carcinoma, or lymphoma.
50
RA would likely cause which region of the lymph node to enlarge?
**Follicular hyperplasia** {B-cell region) is seen with rheumatoid arthritis and **early stages of HIV infection**, for example.
51
$ In a lymph node draining a tissue with cancer, which region of the lymph node is likely enlarged?
**Hyperplasia of _sinus (medulla) histiocytes_** is seen in lymph nodes that are draining a tissue with cancer.
52
LYMPHOMA
Neoplastic proliferation of lymphoid cells that forms a mass; may arise in a lymph node or in extranodal tissue
Divided into non-Hodgkin lymphoma (NHL, 60%) and Hodgkin lymphoma (HL 40%)
53
How is NHL classified?
NHL is further classified based on cell type (e.g., B versus T), cell size, pattern of cell growth, expression of surface markers, and cytogenetic translocations.
1. **Small B cells**-follicular lymphoma, mantle cell lymphoma, marginal zone
lymphoma, and small lymphocytic lymphoma (i.e., CLL cells that involve tissue)
2. **Intermediate**-sized B cells- Burkitt lymphoma
3. **Large B cells-diffuse large B-cell lymphoma (most common)**
54
What has driven the process that has occured based on the slide below?
Driven by **t(14;18)**
***BCL2*** on chromosome 18 translocates to the Ig heavy chain locus on chromosome 14.
Results in overexpression ofBcl2, which inhibits apoptosis allowing **Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules -\>**
FOLLICULAR LYMPHOMA
Clinically presents in late adulthood with painless lymphadenopathy
55
What is the treatment for follicular lymphoma?
Is it a bad prognosis? What may make it worse?
Treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or **rituximab** (anti-CD20 antibody).
Progression to **diffuse large B-celllymphoma** is an important complication; presents as an enlarging lymph node
56
How is Follicular lymphoma is distinguished from reactive follicular hyperplasia?
Follicular lymphoma is distinguished from reactive follicular hyperplasia by
1. **Disruption of normally from node architecture** (maintained in follicular hyperplasia)
2. **Lack of tingible body macrophages in germinal centers** (tingible body macrophages are present in follicular hyperplasia
3. **Bcl2 expression in follicles** (not expressed in follicular hyperplasia)
4. **Monoclonality** (follicular hyperplasia is polyclonal)
57
$ What causes Mantle Cell Lymphoma?
$Driven by **t(11;14)**
1. **Cyclin D1 gene** on chromosome 11 translocates to Ig heavy chain locus on chromosome 14.
$2. Overexpression of **cyclin D1 promotes G1/S transition in the cell cycle, facilitating neoplastic proliferation.**
58
What is Mantle cell lymphoma? When does it present?
Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone
Clinically presents in late adulthood with painless lymphadenopathy
**t(11;14) -\> Cyclin D1**
59
What type of cell proliferates in Marginal zone lymphoma?
A. Neoplastic proliferation of **_small B cells (CD20+) that expands the marginal zone_**
B. Associated with **_chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis_**
l. The marginal zone is formed by post-germinal center B cells.
C. MALToma is marginal zone lymphoma in mucosal sites.
l. Gastric MALToma may regress with treatment of H Pylori.
60
The majority of cells seen in this slide display what surface marker?
BURKITT LYMPHOMA
Neoplastic proliferation of **intermediate-sized B cells (CD20+)**; associated with EBV
Classically presents as an extranodal mass in a child or young adult
61
What is the etiology of the following condition?
Driven by translocations of c-myc (chromosome 8)
1. **t(8;14) is most common, resulting in translocation of c-myc to the Ig heavy chain
locus on chromosome 14.**
2. **Overexpression of _c-myc_ (a transcription factor) oncogene promotes cell growth.**
62
Most common form of NHL?
DIFFUSE LARGE B-CELL LYMPHOMA
A. Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
l. Most common form ofNHL
2. Clinically aggressive (high-grade)
B. Arises sporadically or from transformation of a low-grade lymphoma (e.g., follicular lymphoma)
1. Presents in late adulthood as an enlarging lymph node or an extranodal mass
63
$ The following cell would classically stain positive for which surface proteins?
Neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B cells with multilobed nuclei and prominent nucleoli ('owl-eyed nuclei', Fig. 6.18); classically positive for **CD15** and **CD30**
HODGKIN LYMPHOMA (HL)
**RS cells secrete cytokines**
1. Occasionally results in **'B' symptoms (fever, chills, and night sweats)**
2. Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils
3. May lead to fibrosis
64
In HL, what makes up the bulk of the tumor?
What are the 4 major subtypes of HL? Which one is most common?
Reactive inflammatory cells make up a bulk of the tumor and form the basis for classification of HL. Subtypes include
* *1. Nodular sclerosis (70%)
2. Lymphocyte-rich
3. Mixed cellularity
4. Lymphocyte-depleted**
65
$ A 25 year old woman presents to your clinic with an enlarging cervical lymph node with a mediastinal mass. Most likely diagnosis?
**Nodular sclerosis HL**. Period.
(but you must observe RS to make definitive diagnosis in real life)
Nodular sclerosis is the most common subtype ofHL (70% of all cases).
1. Classic presentation is an enlarging cervical or mediastinal lymph node in a
young adult, usually female.
2. Lymph node is divided by bands of sclerosis **RS cells are present in lake-like spaces (RS variants called lacunar cells)**
66
HL with best prognosis?
Lymphocyte-rich has the best prognosis of all types.
67
$$ Which type of HL is associated with Abundant eosinophils? Why do they have abundant eosinophils?
**Mixed cellularity** is often associated with abundant eosinophils (**RS cells produce IL-5**)
68
HL with worst prognosis?
Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly men \>50 and HIV-positive individuals.
RS cells frequent
69
A 66 year old man complains generalized weakness and fatigue as well as chest and back pain made worse by movement. He states that he coughed 2 days ago after which he developed excruciating pain in his "rib". Labs reveal a normocytic, normochromic anemia (Hb \<12g/dL), and elevated creatinine. A Wright Giemsa stain of marrow aspirate is shown below. Explain the pathogenesis of this disease
Neoplastic plasma cells activate the RANK
receptor on osteoclasts, leading to bone destruction.
Bone marrow aspirate smears from two different patients with multiple myeloma, illustrating a preponderance of mostly mature-appearing plasma cells with eccentrically placed nuclei and prominent Golgi zones (arrow)
70
Clinical features of MM
A. Malignant proliferation of plasma cells in the bone marrow
l. Most common primary malignancy of bone; metastatic cancer, however, is the
most common malignant lesion of bone overall.
2. High serum IL-6 is sometimes present; stimulates plasma cell growth and
immunoglobulin production
B. Clinical features include
l. **Bone pain** with hypercalcemia-Neoplastic plasma cells activate the RANK
receptor on osteoclasts, leading to bone destruction. Lytic, 'punched-out' skeletal
lesions are seen on x-ray (Fig. 6.20A), especially in the vertebrae and skull;
increased risk for fracture
2. **Elevated serum protein**-Neoplastic plasma cells produce immunoglobulin; M
spike is present on serum protein electrophoresis (SPEP), most commonly due to
monoclonal IgG or IgA.
3. **Increased risk of infection**-Monoclonal antibody lacks antigenic diversity;
infection is the most common cause of death in multiple myeloma.
4. **Rouleaux formation** ofRBCs on blood smear- Increased serum protein
decreases charge between RBCs (Fig. 6.208).
5. **Primary AL amyloidosis**-Free light chains circulate in serum and deposit in
tissues.
6. **Proteinuria**-Free light chain is excreted in the urine as **Bence Jones protein;**
deposition in kidney tubules leads to risk for renal failure (myeloma kidney).
71
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
lncreased serum protein with M spike on SPEP; other features of multiple myeloma are absent (e.g., no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria).
Common in elderly (seen in 5% of 70-year-old individuals);
1% of patients with MGUS develop multiple myeloma each year.
72
WALDENSTROM MACROGLOBULINEMIA
Clinical features?
How are acute complications managed?
**B-cell lymphoma** with **monoclonal IgM production**
Clinical features include:
1. **Generalized lymphadenopathy**; lytic bone lesions are absent.
2. **Increased serum protein** with M spike (comprised oflgM)
3. **Visual and neurologic deficits** (e.g., retinal hemorrhage or stroke)-IgM (large pentamer) causes serum hyperviscosity.
4. **Bleeding** - Viscous serum results in defective platelet aggregation.
Acute complications are treated with plasmapheresis, which removes lgM from the serum.
73
What are Langerhans cells?
What are histiocytes?
Langerhans cells are specialized dendritic cells fo und predominantly in the skin.
1. Derived from bone marrow monocytes
2. Present antigen to naive T cells
A histiocyte is a macrophage in connective tissue
74
A 2 year old boy presents with an eczematous rash resembling a candidal infection. An Electron Microscopy image below reveals the following finding.
$ What is seen in the image and what are the immunohistochemical characteristics of this disease?
What is the most common manifestation of this disease in addition to the skin rash?
**Langerhans cell histiocytosis** is a neoplastic proliferation of Langerhans cells.
3 Types:
* Letterer-Siwe disease
* Eosinophiic granuloma
* Hand-Schuller-Christian disease
1. Characteristic **Birbeck (tennis racket) granules** are seen on electron microscopy. Birbeck granules are intracytoplasmic rod-shaped organelles with central striation. Occasionally, there is terminal vesicular dilation giving the Birbeck granule the appearance of a “tennis racket”.
Cells are **CD1a+** and **100+** by immunohistochemistry.
**Lytic bone lesions** are common
75
Classic presentation is skin rash and cystic skeletal defects in an infant(\< 2 years old)
LETTERER-SIWE DISEASE
A. Malignant proliferation of Langerhans cells
B. Classic presentation is skin rash and cystic skeletal defects in an infant(\< 2 years old).
C. **Multiple organs may be involved; rapidly fatal**
76
Classic presentation is pathologic fracture in an adolescent; skin is not involved
**EOSINOPHILIC GRANULOMA**
A. **_Benign_** proliferation of Langerhans cells in bone
B. Classic presentation is pathologic fracture in an adolescent; skin is not involved.
C. **Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous
eosinophils.**
77
Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child.
**HAND-SCHULLER-CHRISTIAN DISEASE**
Malignant proliferation of Langerhans cells
Clinical findings
a. General
(1) **Fever**
(2) **Localized rash on scalp and in ear canals**
b. Classic triad due to infiltrative disease
(1) Lytic lesion in the skull
(2) Diabetes insipidus due to invasion of posterior pituitary
(3) Exophthalmos from infiltration of the orbit
C. Intermediate prognosis
78
Leukemia seen in Newborns to 14 years old
(1) Acute lymphoblastic leukemia (ALL)
(2) Most common leukemia in children
(3) Most common cancer in children
79
Most common leukemia ages 15-60?
Acute myeloblastic leukemia (AML)
80
Most common form of leukemia in persons 40 to 60 years old
(1) AML (\>60% of cases)
(2) Chronic myelogenous leukemia (CML; ∼40% of cases)
CML: 40-60+ years old
May occur in patients \> 60 years old
81
Most common leukemia in persons \> 60 years of age
Most common overall type of leukemia: CLL
## Footnote
Chronic lymphocytic leukemia (CLL)
82
Most important test for diagnosing leukemia?
bone marrow examination
83
Clinical findings in chronic leukemia
Chronic leukemia: insidious onset
* Insidious onset
* Slightly more common than acute leukemia
* Hepatosplenomegaly
* Generalized painless lymphadenopathy
84
Give the 5 year survival rates for the following leukemias:
ALL
AML
CLL
CML
* Acute lymphoblastic leukemia: **87%** 5-year survival rate
* Acute myelogenous leukemia: **21%** 5-year survival rate
* Chronic lymphocytic leukemia: **75%** 5-year survival rate
* Chronic myelogenous leukemia: **89%** 5-year survival rate
85
What is the difference between RBC count and RBC mass?
(1) RBC count is the number of RBCs per microliter (μL) of blood.
(2) RBC mass is the total number of RBCs in the body in mL/kg.
RBC count = RBC mass/PV
86
Best initial test if PV is suspected?
serum EPO best initial test
Polycythemia vera: only polycythemia with **↑ PV and ↓ EPO**
87
Lab findings in CML?
(1) Peripheral WBC count **50,000 to 200,000 cells/mm3**
(a) Myeloid series in all stages of development
(b) **Basophilia**
(2) **Normocytic to macrocytic anemia**
Macrocytic if folate is depleted in the production of leukemic cells
(3) Platelet count
(a) **Thrombocytosis in 40% to 50% of cases** (uncommon in leukemia)
CML: only leukemia with thrombocytosis
(b) **Thrombocytopenia in the remainder of cases**
88
Most sensitive and specific test for CML?
**BCR-ABL fusion gene (100% of cases)**
Positive Philadelphia chromosome (95% of cases)
(a) It is not specific for CML and is present in other leukemias (e.g., ALL).
(b) It is not lost during therapy unless α-interferon is used.
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Gum infiltration
**M5**: Acute monocytic (AML)
Acute myeloblastic leukemia
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Increased incidence in Down syndrome in children \< 3 years old
M7: Acute megakaryocytic
Acute myeloblastic leukemia
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t(15;17) translocation
Treatment?
**M3**: Acute promyelocytic
Acute myeloblastic leukemia
DIC is invariably present
Numerous Auer rods
Abnormal retinoic acid metabolism: high doses of all-trans-retinoic acid may induce remission by maturing cells
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Most common class of acute myeloblastic leukemia?
**M2**: AML with maturation
* Most common type (30-40% of cases).
* Auer rods present
* 15-59-year-old age bracket
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occurs between 15 and 59 years of age
Acute myeloblastic leukemia
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Pathogenesis of Adult T-cell leukemia
Activation of TAX gene, which inhibits the TP53 suppressor gene
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HL survival statistics
Five-year survival rate is 85%; 10-year survival rate is 80%
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Red pulp of spleen
Red pulp: fixed macrophages
Contains the **cords of Billroth** with fixed macrophages and sinusoids
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White pulp of spleen?
Contains B and T cells
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Important functions of the speen?
Blood filtration; macrophages remove:
(1) Hematopoietic elements (e.g., old red blood cells)
(2) Intraerythrocytic parasites (e.g., malaria)
(3) Encapsulated bacteria
Examples-Streptococcus pneumoniae
Antigen trapping and processing in macrophages
Reservoir for one third of the peripheral blood platelet pool
Site for extramedullary hematopoiesis
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Lysosomal storage diseases can cause splenomegaly. What has accumulated in this cell?
**Gaucher's disease**
Gaucher's disease: ↓ glucocerebrosidase,
**↑ glucocerebroside**
(a) Deficiency of glucocerebrosidase
Lysosomal accumulation of glucocerebrosides
(b) Macrophages have a fibrillary appearance
Note the fibrillary appearance of the cytoplasm in the macrophages (arrow)
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Lysosomal storage diseases can cause splenomegaly. What has accumulated within this macrophage?
Niemann-Pick disease
Niemann-Pick: ↓ sphingomyelinase, **↑ sphingomyelin**
(a) Deficiency of sphingomyelinase
Lysosomal accumulation of sphingomyelin
(b) Macrophages have soap bubble appearance
Niemann-Pick disease. Note the soap bubble appearance of the cytoplasm in the macrophages (arrow)
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$ Splenic dysfunction predisposes to infections. Which organisms and what is the mechanism for this increased risk?
Predisposition to infections by encapsulated pathogens
(1) Infections include septicemia, peritonitis, osteomyelitis.
Streptococcus pneumoniae, Haemophilus influenzae, Salmonella, Neisseria meningitidis
(2) Mechanisms
Mechanisms: **↓ IgM, ↓ tuftsin, ↓ splenic macrophages**
(a) Concentration of IgM drops leading to a decrease in complement system activation
** The spleen is a site for IgM synthesis.**
(b) Macrophages are not present to phagocytose the opsonized encapsulated pathogens.
(c) Loss of tuftsin, which is normally synthesized in the spleen
Tuftsin activates receptors on macrophages to increase their phagocytic activity.
(3) Pathogens commonly involved
(a) Streptococcus pneumoniae
(b) Other pathogens include Haemophilus influenzae and ***Salmonella paratyphi*** (osteomyelitis in sickle cell disease).
Immunization helps prevent infectious complications
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What is the primary leukocyte alteration in rheumatoid arthritis?
**Monocytosis** is the primary leukocyte alteration in **chronic inflammation** (e.g., rheumatoid arthritis).
The photograph shows a monocyte with grayish-blue cytoplasm that contains many fine azurophilic granules and nucleus that is horse-shoe shaped (this monocyte), round, or kidney shaped.
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Bruton’s agammaglobulinemia
an X-linked disorder characterized by failure of pre-B cells to develop into B cells. This produces hypogammaglobulinemia, because there are not sufficient numbers of B cells to be antigenically stimulated to become plasma cells. Deficiency of IgG produces an opsonizing defect. The antigen recognition site of IgG attaches to the bacteria, and the Fc portion of the immunoglobulin attaches to receptors in the plasma membrane of phagocytic leukocytes (neutrophils, monocytes, macrophages). This facilitates the phagocytosis of bacteria by triggering engulfment of bacteria by pseudopods and eventual formation of a phagocytic vacuole.
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A 52-year-old woman had a modified radical mastectomy 12 years ago. She now has pain in the pelvic girdle and point tenderness over the lower lumbar vertebra. A complete blood cell count shows a mild normocytic anemia, a slightly increased total WBC count, and a normal platelet count. There is no hepatosplenomegaly. The photograph shows a representative section of the peripheral blood smear. Which of the following is the most likely diagnosis?
**Metastatic disease to the bone marrow**
The patient has breast cancer metastatic to the bone marrow, with subsequent reactive fibrosis (myelofibrosis) causing displacement of normal bone marrow cells into the peripheral blood. The peripheral blood in this patient shows a **nucleated normoblast (small nucleated cell) and immature myeloid cells (large nucleated cell), which are normal in the bone marrow but abnormal in the peripheral blood.** The tear-drop shape of many of the RBCs in the peripheral blood smear is caused by membrane damage that occurs when they **exit the fibrotic bone marrow.** Breast cancer commonly metastasizes to bone, often to the vertebral column, as in this patient.
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$$$ Why is DIC often present in Acute Promyelocytic leukemia?
DIC is invariably present in APL, because the release of procoagulants from the granules of the promyelocytes activates the coagulation system cascade. DIC causes multiple coagulation factor deficiencies (prolonged prothrombin time and partial thromboplastin time), thrombocytopenia (which causes petechiae and ecchymoses), and activation of the fibrinolytic system (increased d-dimers).
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