GI: WBC Disorders Flashcards by James Wren

Absolute Leukocyte count usually >25,000 to 30,000 cells/mm³
May involve neutrophils, Lymphocytes, or Eosinophils
Normal Bone marrow response to Cytokines released by cells to infection or trauma
Normal albeit exaggerated response to an infection

Leukemoid Reaction

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Presence of Immature bone marrow WBCs and Nucleated RBCs in Peripheral blood ‘Peripheralization’ of the Bone marrow, irrespective of Total Leukocyte count
Peripheral blood findings
- Myeloblasts, Progranulocytes, and other Leukocyte precursors
- Nucleated RBCs and Teardrop RBCs (if fibrosis is present)

Leukoerythroblastosis

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A low WBC count (< 5K)
A/w advanced HIV
Following therapy w/ Glucocorticoids or Cytotoxic drugs
Autoimmune disorders
Malnutrition
Acute Viral Infections –> Type I interferons –> T lymphocytes activation –> sequestration of activated T cells in Lymph nodes and increased adherence to Endothelial cells

Leukopenia

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A high WBC count (> 10K)
Increased Production in the Marrow
- Chronic Infection or Inflammation
- Paraneoplastic
- Myeloproliferative disorders
Increased Release from Marrow
- Endotoxemia, Infection, Hypoxia
Decreased Margination
- Exercise, Catecholamines
Decreased Extravasation into Tissues
- Glococorticoids

Leukocytosis

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Decreased number of circulating neutrophils <1500 cells/mm³ (Serious if <500 cells/mm³)
Aplastic anemia
Immune destruction – SLE and Paroxysmal nocturnal Hemoglobinuria
Septic shock
Ticks, Viral, Bacterial, Fungal, XRT
Drug toxicity (Chemo w/ alkylating agents) - Dmg to stem cells results in decreased production of WBCs, especially neutrophils, anti-Metabolites for Chemo Tx.
Severe Infection (gram-negative sepsis) – increased movement of neutrophils into tissues results in decreased circulating neutrophils
As a Tx: GM-CSF or G-CSF may be used to Boost Granulocyte production, thereby decreasing risk of infection in Neutrophenic

Neutropenia

(Agranulocytosis)

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Decreased number of circulating lymphocytes
Immunodeficiency (DiGeorge syndrome or HIV)
High cortisol state (exogenous corticosteroids or Cushing syndrome) –> increased Cortisol –> Apoptosis
Autoimmune destruction (SLE)
Whole body radiation – Lymphocytes are highly sensitive to XRT – Lymphopenia is the earliest change to emerge after Whole Body XRT

Lymphopenia

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Increased circulating Neutrophils >7500 cells/mm³
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 Fc receptors (CD16)
High cortisol state – impaires leukocyte adhesion, leading to release of Marginated pool of Neutrophils
Chronic Infections and Chronic Inflammation (Lung abcesses) –> expansion of Myeloid precursor pool in Bone marrow

Neutrophilic Leukocytosis

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Increased circulating monocytes >800 cells/mm³
Chronic inflammatory states (autoimmune (RA) and infectious (TB, Subacute infective endocarditis, Cirrhosis))
Malignancy (carcinomas and lymphomas)

Monocytosis

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Hypercortisolism (Cushing syndrome, Coricosteroids)
Corticosteroids sequester Eosinophils in Lymph noes and Trigger apoptosis

Eosinopenia

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Increased circulating eosinophils > 400 cells/mm³
Allergic reactions (Type I Hypersensitivity – Mast cells)
No sequestering of Eosinophils in Lymph nodes
Parasitic infctions (Protozoa, Helminths)
Polyarteritis nodosa, Churg-Strauss syndrome
Job syndrome
Addison disease (Cortisol deficiency)
Hodgkin lymphoma (Tumor –> increased IL-5 production)
Driven by increased Eosinophil chemotactic factor

Eosinohilia

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Increased ciruclating basophils >110 cells/mm³
Classically seen in Chronic Myeloid Leukemia (CML)
Chronic myeloproliferative disorders (Polycythemia vera)

Basophilia

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Increased circulating lymphocytes >5000 cells/mm³ in Adults and >8000 cells/mm³ in Children
Viral infections – T lymphocytes undergo Hyperplasia in response to virally infected cells, Mononucleosis and Cytomegalovirus (CMV)
Bordetella pertussis infection – Bacteria produce lymphocytosis – promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph node (Whooping cough) and Tuberculosis
Drugs – Phenytoin and Tetracycline
“Stuck in the blood” –> Increased [WBC]

Lymphocytic Leukocytosis

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EBV infection that results in a Lymphocytic leukocytosis –> Increased [WBC]
EBV is transmitted by Saliva “Kissing Disease” classically affects teenagers (15 – 24 y.o.), replicates in the epithelial cells in the Oropharynx
Comprised of reactive CD8+ T cells –> MHC class I response
CD8+ T cell response –> Generalized Lymphadenopathy (LAD) due to T-cell hyperplasia in Lymph node Paracortex
A/w Splenomegaly due to T-cell Hyperplasia in the Periarterial lymphatic Sheath (PALS): White Pulp –> B-cells and T-cells
High WBC count w/ Atypical Lumphocytes (Reactive CD8+ T cells) in the blood –> Dx w/ Heterophile Ab test (Monospot test)
CVM is a less common cause
EBV infects: Oropharynx –> Pharyngitis, Liver –> Hepatitis w/ Hepatomegaly and Elevated Liver enzymes, B-cells

Infectious Mononucleosis

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Detects IgM antibodies that cross-react w/ IgM Ab against Horse, Sheep, or Bovine RBCs (Heterophile Ab)
Usually turns Positive w/in 1 week after Infection
Negative Test suggests CMV as a possible cause or Test done too early
Definitive diagnosis is made by Serologic testing for the EBV viral capsis antigen

Monospot Test for Infectious Mononucleosis (IM)

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Increased risk of Splenic Rupture due to Splenomegaly –> Pts. are generally advised to avoid contact sports for One month – One year
Rash if exposed to Ampicillin (PCN)
Dormancy of Virus in B cells leads to Increased risk for both Recurrenc and B-cell Lymphoma, especially if Immunodeficiency (HIV) develops

Complications of Infectious Mononucleosis (IM)

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Absolute lymphocyte count <1500 cells/mm³ in Adults and <3000 cells/mm³ in Children
HIV,
DiGeorge syndrome (T-cell deficiency),
SCID (B- and T-cell def.),
Bruton agammaglobulinemia (B-cell def.),
Immune destruction (SLE)
Drugs
XRT

Lymphopenia

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Neoplastic proliferation of Blasts – Accumulation of
> 20% Blasts in the Bone Marrow
Increased Blasts “crowd-out” Normal Hematopoiesis
–> resuting in “Acute” presentation w/ Anemia (Fatigue), Thrombocytopenia (Bleeding due to loss of Platelets), or Neutropenia (Infection)
Blasts enter Blood stream –> increased [WBC] count
Blasts are Large, Immature cells, often w/ Punched out Nucleoli
Acute Leukemia is Subdivided: AML and ALL based on Blast Phenotype

Acute Leukemia Basics

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Age Ranges for Common Leukemias

More common in Adults than in Children
Newborn to 14 years old
- ALL is most common
- ALL is most common overall cancer in Children
40 – 60 y.o.
- AML – Acute Myeloblastic Leukemia
- CML – Chronic Myelogenous Leukemia
> 60 y.o.
- CLL – Chronic Lymphocytic Leukemia
- CML – Chronic Myelogenous Leukemia

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Neoplastic accumulation of Lymphoblasts (>20%) in Bone Marrow
3x White : Blacks
t(9;22) BCR-ABL - Tyrosine kinase –> Tx: Gleevec a Tyrosine kinase inhibitor
t(4,11) MLL gene on Chrom. 11q23
t(8;14)
CNS manifistations: Headache, Vomiting, Nerve palsies resulting from Meningeal spread - Neoplastic infiltration
Lymphoblasts are characterized by Positive Nuclear staining for TdT (DNA polymerase)
TdT is absent in Myeloid blasts and Mature Lymphocytes
A/w Children, w/ Down Syndrome (> 5 y.o.)
Subclassified into B-ALL and T-ALL based on Surface Markers

Acute Lymphoblastic Leukemia (ALL)

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Lymphoblasts (TdT+) that express CD10, CD19, and CD20
Loss of Function Mutations: PAX5, E2A, and EBF
Excellent response to Chemo
Mass in the Skin or a Bone
Requires prophylaxis to Scrotom and CSF
t(12;21) –> 25% have ETV6 and RUNX1 - Marrow replacement and Pancytopenia, Good prognosis – more commonly seen in Children “Childhood Acute Leukemia”
t(9;22) –> Poor prognosis – more commonly seen in Adults (Phil+ALL)

B cell Acute Lymphoblastic Leukemia (B-ALL)

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Lymphoblasts (TdT+) that express markers from CD2 to CD8, but NO CD10
70% have NOTCH1 - T cell development
Typically evolve to Leukemic picture
Usually presents in Teenagers as a Mediastinal (Thymic) mass (“Adolescent Males w/ Thympic Lymphomas”)
Called Acute Lymphoblastic Lymphoma because the Malignant cells form a Mass

T cell Acute Lymphoblastic Leukemia (T-ALL)

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Neoplastic accumulation of Immature Myeloid cells (>20%) in the Bone marrow
Positive Cytoplasmic staining for Myeloperoxidase (MPO)
Crystal aggregates of MPO may be seen as Auer Rods
Older adults (Average age is 50 – 60 y.o.)
Subclassified based on Cytogenic abnormalities, Lineage of Immature myeloid cells, and Surface markes
Treatment-related AML a/w which prior therapies
- Aklylating agents
- Topoisomerase II inhibitors
- XRT

Acute Myeloid Leukemia (AML)

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t(15;17) – translocation of the Chimeric protein w/ Retinoic acid receptor (RARα) fused to Promyelocytic leukemia protein (PML) –> Chrom 17 to Chrom 15; RAR disruption blocks maturation/differentiation on myeloid cells at the Promyelocytes (blasts) stage
-> Promyelocytes and Myeloblasts accumulate
Abnormal promyelocytes contain numerous Primary granules that increase risk for DIC
Tx: all-trans-retinoic acid (ATRA) (Vit. A der.)
-> binds the altered receptor and causes the blasts to mature and differentiate –> and die

Acute Promyelocytic Leukemia (APL)(Subclass of AML)

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Proliferation of monoblasts; usually lack MPO
Blasts characteristically Infiltrate the Skin and Gums (Gingival infiltrations)

Acute Monocytic Leukemia (Subclass of AML)

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* Proliferation of megakaryoblasts; usually lack MPO * A/w Down Syndrome (\< 5 y.o.)

Acute Megakaryoblastic Leukemia

* Exposure to Alkylating agents or XRT * Myelodysplastic syndromes --\> present w/ Cytopenias, Hypercellular Bone marrow, Abnormal maturation of cells, and Increased blasts (\<20%) * Pts. die from Infection or Bleeding, some progress to Acute leukemia * If Blasts are \> 20% --\> “AML has arisen in a background of dysplasia”

AML arising from pre-existing dysplasia (Myelodysplastic syndromes)

* Neoplastic proliferation of naïve B cells that co-express **CD5**, **CD 19**, **CD20**, and **CD23** - **13q14.3, 11q, and 17p, and Trisomy 12q** * Most common leukemia overall, esp. Western World * Increased Lymphocytes and Smudge cells are seen on Blood smear - 10% ***NOTCH1*** **and NF-kB and ZAP-70** * Involvement of Lymph nodes --\> Generalized lymphadenopathy and is called Small lymphocytic lymphoma (SLL)(mass ‘-oma’) * _Hypogammaglobulinemia_ – Infection most common cause of Death in CLL * _Autoimmune hemolytic anemia_ – antibodies against RBCs * _Transformation_ to Diffuse large B-cell lymphoma (Richter transformation) – marked clinically by an enlarging Lymph node or Spleen --\> Aggressive enlarging Tumor

Chronic Lymphocytic Leukemia (CLL)

* Neoplastic proliferation of Mature B cells w/ Hairy cytoplasmic processes --\> cells are positive for **TRAP** (**tartate-resistant acid phosphatase**) * **CD 11c, CD 25, CD103** * **Memory B cell** w/ **Activating *BRAF* mutations** * **Older Males** w/ **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 * Excellent response to 2-CDA (cladribine), an Adenosine deaminase inhibitor: Adenosine accumulates to toxic levels in Neoplastic B cells (Purine degradation pathway --\> death of neoplastic B cells)

Hariy Cell Leukemia

* Neoplastic proliferation of **mature CD4+ T cells** * **Helper T cells - Adults w/ cutaneous Lesions** * A/w **HTLV-1**; most commonly seen in **Japan** and **Caribbean** (Human T-cell Leukemia Virus 1) * Rash (skin infiltration) * Generalized lymphadenopathy w/ Hepatomegaly (Mature lymphocytes like to go to Lymph node and Spleen) * Lytic (punched-out) bone lesions w/ Hypercalcemia * Leads to Multiple myeloma and Adult T-cell Leukemia

Adult T-cell Leukemia / Lymphoma (ATLL)

* Neoplastic proliferation of Mature CD4+ T cells that Infiltrate the skin --\> localized Skin rash, Plaques, and Nodules * Helper T cells - Adulta w/ destructive extranodal patches, plaques, nodules, or generalized erythema * Aggregates of neoplastic cells in the Epidermis (“Pautrier microabscesses”) * Cells can spread to involve the blood --\> Sezary syndrome (lobish nuclei) * Characteristic lymphocytes w/ Cerebriform nuclei (Sezary cells) are seen on Blood smear

Mycosis Fungoides Sezary syndrome

* Neoplastic proliferation of Mature cells of Myeloid lineage * Disease of Late adulthood: 50 – 60 y.o. * High WBC count w/ Hypercellular Bone marrow (*increased* granulocyte production --\> *incrased* [WBC]) * Cells of ALL myeloid lineages are increased BUT classified based on the Dominant Myeloid cell produced * *Increased* risk for Hyperuricemia and Gout due to High turnover of cells * A/w Post-therapy myelodysplasia * Ringed sideroblasts, Megaloblasts, Abnormal megakaryocytes, and Myeloblasts in the Marrow * *Progression* to Marrow fibrosis --\> ‘Spent phase’ or ‘Burnt-out phase’) of Transformation to Acute leukemia

Myeloproliferative Disorders – Basics

* Neoplastic proliferation of Mature Myeloid cells: esp. Granulocytes and precursors; Basophils are characteristically *increased* * t(9;22) (Phili+ chromosome) which generates a BCR-ABL fusion protien w/ *increased* Tyrosine kinase activity --\> overproduction of neoplastic cells * Tx: Imatinib – blocks Tyrosine Kinase activity * Splenomegaly – suggests progression to accelerated phase of disease, (3) Phases: Chronic, Accelerated (enlarging), and Transformation * Transformation to acute leukemia usually follows shortly therafter * Can transform to AML (2/3) or ALL (1/3) since mutation is in a Pluripotent stem cell * Distingusing factors: * Negative Leukocyte alkaline phosphate (LAP) stain (Granulocytes in Leukemoid rxn are LAP positive) * *Increased* Basophils (absent in Leukemoid rxn) * t(9;22) (absent in Leukemoid rxn)

Chronic Myeloid Leukemia (CML)

* Neoplastic proliferation of Mature Myeloid cells, especially RBCs * Granulocytes and Platelets are also *increased* * A/w JAK2 kinase mutation (Granulocytosis and Thrombocytosis) * Symptoms mostly due to Hyperviscosity of Blood --\> Super-thick * Blurry vision and Headache * *Increased* risk of Venous Thrombosis (Hepatic vein, Portal vein, Dural sinus)(a/w Budd-chiari syndrome --\> Hepatic vein thrombosis) * Flushed face due to congestion (Plethora) * Itching, especially after Bathing (Histamine release from increased # mast cells --\> Pruritis) * Tx: 1^st Phlebotomy, 2^nd Hydroxyurea and w/out Tx: Death w/in 1 year * PV vs. Reacitve Polycythemia * PV, Erythropoietin (EPO) lvls *decreased* and SaO₂ are normal * Reactive Polycythemia due to High altitude or Lund disease; *increased* EPO SaO₂ is low * Ractive Polycthemia: Renal cell carcinoma --\> *increased* [EPO] w/ normal Oxygen sat.

Polycythemia Vera (PV)

* Neoplastic proliferation of Mature Myeloid cells, Especially Platelets from myeloid stem cells * RBCs and Granulocytes are also *increased* * A/w JAK2 kinase mutation * *Increased* risk of Bleeding and/or Thrombosis * Rarely progresses to Marrow fibrosis or Acute leukemia * No significant risk for Hyperuricemia or Gout

Essential Thrombocythemia (ET)

* Neoplastic proliferation of Mature Myeloid cells, Especially Megakaryoytes * A/w JAK2 kinase mutation (50% of cases) * Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing Marrow fibrosis * Splenomegaly due to Extramedullary hematopoiesis * Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and Immature Granulocytes --\> Reticuline gaits prevent immature cells to exit into the Blood; Big cells must divide to pass through * *Increased* risk of Infection, Thrombosis, and Bleeding (Bone Marrow is no longer producing WBCs, RBCs, and Platelets)

Myelofibrosis

* Enlarged lymph nodes * Painful LAD: Lymph nodes that are draining a region of Acute infection (Acute lymphadenitis) * Painless LAD: Chronic inflammation (chronic lymphadenitis), metastatic carcinoma, or Lymphoma * Inflammation: Lymph node enlargement is due to Hyperplasia of Particular regions of the Lymph nodes * _Follicular Hyperplasia_ (B-cell region) seen w/ Rheumatoid arthritis and early stages of HIV infection (B-cell – Cortex) (CD4+ T cells + Follicular cells) * _Paracortex Hyperplasia_ (T-cell region) seen w/ Viral infections (IM) * _Hyperplasia of Sinus Histiocytes_ seen in Lymph nodes that are draining a tissue that has Cancer --\> Reactive due to *increased* draining of an area that has Cancer

Lymphadenopathy – Basics

* Neoplastic proliferation of Lymphoid cells that forms a Mass * May arise in a Lymph node or in Extranodal tissue * Hodgkin Lymphoma (HL) and non-Hodgkin Lymphoma (NHL) * NHL is futher classified based on Cell type (B vs. T), Cell size, Pattern of Cell growth, Expression of Surface markers, and Cytogenetic translocations * (4) _Small B cells_ * Follicular lymphoma * Mantle cell Lymphoma * Marginal zone lymphoma * Small Lymphocytic Lymphoma (CLL cells that involve tissue) * _Intermediate-sized B cells_ – Burkitt Lymphoma * _Large B cells_ – Diffuse Large B-cell Lymphoma

Lymphoma – Basics

* 40% * Malignant cells are Reed-Sternberg cells * Mass Composition is Predominantly Reactive cells (inflammatory cells and Fibrose) * Painless Lymphadenopathy occasionally w/ ‘B’ symptoms (younger adults) * Contiguous spread (Orderly Fasion); rarely extranodal * Staging guides therapy; XRT is mainstay of Tx * Leukemic phase DOES NOT occur

Hodgkin Lymphoma

* 60% * Malignant cells are Lymphoid cells * Mass Composition is Lymphoid cells * Painless Lymphadenopathy, usually arises in Late adulthood * Diffuse spread (Less predictable); often Extranodal * Leukemic phase occurs

Non-Hodgkin Lymphoma

* Neoplastic proliferation of Small B cells (CD20) that form Follicle like nodules * Presents in Late adulthood w/ Painless Lymphadenopathy and Marrow involvement (NHL) * **t(14;18)** --\> **BCL2-IgH fusion gene** on Chrom. 18 translocates to the Ig Heavy chain locus on Chrom 14 --\> Overexpression of BCL2 --\> Inhibits apoptosis * ***MLL2*** encodes **Histone methyltransferase** that regulates gene expression --\> epigenetic abnormalities * Tx: Reserved for pts. who are symptomatic and involves Low-dose Chemo or Rituximab (anti-CD20 Ab) * Enlarging Lymph node --\> Progression to Diffuse Large B-cell lymphoma --\> indicates additional mutations

Follicular Lymphoma (NHL)

* Neoplastic proliferation of Small B cells (CD20) that expands the Mantle zone or ‘Expands the region immediately adjacent to Follicle zone’ - **Older Males** * Late adulthood w/ Painless Lymphadenopathy (NHL) * Naive B cell w/ **t(11;14) – Cyclin D1-IgH** gene on Chrom 11 translocates to Ig Heavy chain locus on Chrom 14 * Overexpression of Cyclin D1 promotes G₁ --\> S phase transition in the Cell cycle --\> Facilitating neoplastic proliferation

Mantle Cell Lymphoma (NHL)

* Neoplastic proliferation of Small B cells (CD20) that expands the Marginal zone * **Memory B cell** * **t(11;18), t(1;14), and t(14;18)** creating ***MALT1-IAP2, BCL 10-IgH*and *MALT1-IgH* Fusion genes** * A/w Chronic inflammatory states, Hashimoto thyroiditis, Sjogren syndrome, *H pylori* gastris * The marginal zone is formed by Post-germinal center B cells --\> mucosal enlargment of parotid * MALToma is a Marginal Zone Lymphoma in mucosal sites * Gastric MALToma may regress w/ treatment of *H pylori*

Marginal Zone Lymphoma (NHL)

* Neoplastic proliferation of Intermediate-sized B cells (CD20) - Germinal-center B-cells; * *IgM, CD 10, CD 19, CD 20** and A/w **EBV** * **High mitotic index** and **‘Starry-sky’** appearance on Histo * **Extranodal mass** in a **Child or Young adult** * African form --\> involves the Jaw * Sporadic form --\> involves the Abdomen * **46,XY, t(8,14)** is most common "Warburg effect" - -\> Translocation of ***c-MYC* - aerobic glycolysis (Chrom 8**) to the **Ig** Heavy chain locus on Chrom 14 * Overexpression of ***c-myc*** oncogene promotes cell growth

Burkitt Lymphoma (NHL)

* Neoplastic proliferation of **Large B cells** (**CD 19 and CD20**) that grow diffusely in Sheets, particularly of the **Waldeyer ring** * Germinal-center or Post-Germinal center B-cells * ***Dysregulation of BCL6*** **at 3q27** (30%), ***BCL2* at t(14;18)** (10%), ***MYC*** (5%) **and p300 and CREBP** * Most common form of NHL - Older Adults * "Rapidly Growing Mass" - Aggressive (High-grade), Not well differentiated * Arises sporadically or from Transformation of Low-grade Lymphoma (e.g. Follicular lymphoma) * Late adulthood as an *enlarging* Lymph noed or an Extranodal mass

Diffuse Large B-cell Lymphoma (NHL) | (DLBCL)

* Neoplastis proliferation of Reed-Sternberg (RS) cells * Large B cells w/ Multilobed nuclei and Prominent Nucleoli (‘owl-eyed nuclei’) * Positive for CD15 and CD30 – NO CD20 expression * RS cells secrete Cytokines * ‘B’ symptoms (Fever, Chills, Weight loss, Night sweats) * Attract reactive Lymphocytes, Plasma cells, Macrophages, and Eosinophils * May lead to Fibrosis * Reactive inflammatory cells make up a bulk of the Tumor and form basis of classification (4) Subtypes

Hodgkin Lymphoma – Basics

* 70% cases * *Enlarging* Cervical or Mediatinal Lymph node in a Young adult, usually Female * Lymph node is divided by Bands of Sclerosis * RS cells are present in ‘Lake-like spaces’ – Lacunar cells

Nodular Sclerosis (HL)

* Best prognosis of HL subtypes

Lymphocyte-rich (HL)

* A/w Abundant Eosinophils * RS cells produce IL-5 --\> Draws in Eosinophils * Worst subtype

Mixed Cellularity (HL)

* Most aggressive HL subtype * Usually seen in Elderly and HIV positive pts

Lymphocyte-depleted (HL)

* Malignant proliferation of Plasma cells in the Bone marrow - Diverese rearrangement w/ ***IgH*** and **13q del.** * **Post-Germinal-Center Bone marrow homing Plasma cell** * Most common Primary malignancy of the Bone * High serum IL-6 – stimulates Plasma cell growth and Ig production * "**C-R-A-B" "hyperCalcemia, Renal insufficiency (light chain nepthropathy), Anemia normocytic normochromatic, and Bone lesions"** * _Bone pain w/ **Hypercalcemia** and **Alkaline Phosphatase**_ – plasma cells activate **RANKL receptor** on Osetoclasts --\> Bone destruction --\> Lytic **‘punched-out’** skeletal lesions on x-ray, Vertebrae and Skull --\> *Increased* risk of Fracture --\> Destruction mediatiated by ***RANKL,* Dx w/ IL-6** for **Plasma cells** * _Elevated serum protein_ – plasma cells produce Ig – M-**'Spike'** is present on Serum Protein Electrophoresis (SPEP), commonly IgG or IgA * _Increased risk of Infection_ – Monoclonal Ab lacks antigenic diversity; Inf. Is most common cause of Death in Multiple Myeloma * _Rouleux formation of RBC on Blood smear_ – *increased* serum protein *decreases* Charge Between RBCs * _Primary AL amyloidosis_ – Free light chains circulate in Serum and Deposit in Tissues * _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)

Multiple Myeloma (Plasma Cell Disorder – Dyscrasias) Solitary Plasmacytoma

* Increased Serum protein w/ M spike on SPEP * No lytic Bone lesions * No Hypercalcemia * No AL amyloid * No Bence Jones proteinuria * Commonly in Elderly (5% of 70 y.o.) * 1% Pts develop Multiple Myeloma each year

Monoclonal Gammopathy of Undetermined Significance (MGUS) (Dyscrasias)

* B-cell Lymphoma w/ **Monoclonal IgM** production (Pentamer – Big Globulin) * Generalized _Lymphadenopathy w/out Lytic Bone lesions_ * *Increased* serum Protein w/ **IgM spike** (comprised of IgM) * Visual and Neurologic deficits (Retinal hemorrhage or Stroke) – IgM (large pentamer) causes Serum Hypersensitivity --\> ***Increased* viscosity** of RBCs * Bleeding – Viscous serum results in defective Platelet aggregation --\> Cold agglutinin disease --\> **Cryoglobulinemia --\> Raynaud phenoomenon** * Acute complications are treated w/ Plasmapheresis --\> removes IgM from the serum

Waldenstrom Macroglobulinemia (Dyscrasias) (Can occur w/ Monoclonal Myeloma, but stronger a/w Lympoplasmacytic lymphoma)

* Langerhans cells are specialized Dendritic cells – in the Skin mostly, organomegaly * Derived from Bone marrow monocytes * Present antigen to Naïve T cells * _Langerhans cell Histiocytosis_ is Neoplastic proliferation of Langerhans cells – characteristic _Birbeck_ (Tennis racket) _granules_ are seen on Electron microscopey – cells are CD1a+ and S100+ by immunochemistry

Langerhans Cell Histiocytosis – Basics

* Malignant proliferation of Langerhans cells - -\> Histiocytosis * **Birbeck granules** are a distinctive feature, identified by EM are found in the Cytoplasm * Classically presentation is Skin rash and Cystic skeletal defect in an Infant (\< 2 y.o.) * Multiple organs may be involved --\> rapidly fatal

Letterer-Siwe Disease

* Benign proliferation of Langerhans cells in Bones * Classic presentation is Pathologic Fracture in an adolescent * Skin is not involved * Biopsy shows Langerhans cells w/ mixed Inflammatory cells, Including numberous Eosinophils

Eosinophilic Granuloma

* Malignant proliferation of Dendritic (Langerhans) cells from Monocyte lineage * Classic Child presentation is Scalp Rash, Lytic Skull defects "big holes in the the cranium", Diabetes Insipidus, and Exophthalmos * Also presents as **Recurrent Otitis media w/ Mass** involving the **Mastoid bone** * **Immature cells** --\> do not stimulate primary **T Lymphocytes** via antigen presentation * **CD 1a and S-100** cellular expression (mesodermal origin) * Birbck granules "tennis rackets" on EM

Hand-Schuller-Christian Disease

* CD 1- Thymocytes and Langerhans cells * CD 3 - Thymocytes, Mature T cells * CD 4 - Helper T cells, subset of Thymocytes * CD 5 - T cells and small subset of B cells * CD 8 - Cytotoxic T cells, subset Thymocytes and NK cells

Primary T cell Associations

* CD 10 - Pre B-cell and Germinal center B-cell * CD 19 - Pre B-cell and Mature B-cell * CD 20 - Pre B-cell after CD 19 and Mature B, Not Plasma * CD 21 - EBV receptor, Mature B-cell, Follicular Dendritic c. * CD 23 - Activated Mature B-cell * CD 79a - Marrow Pre-B-Cell

Primary B cell Associations

* CD 11c - Granulocyte, Monocyte, Macrophage, Hairy cell * CD 13 - Immature and Mature Monocyte and Granulocyte * CD 14 - Monocytes * CD 15 - Granulocytes; Reed-Sterberg and Varients * CD 33 - Myeloid progenitor * CD 64 - Mature Myeloid cells

Primary Monocyte and Macrophage Association

* CD 16 - NK cells and Granulocytes * CD 56 - NK cells and subset of T cells

Primary NK Association

* CD 34 - Pluripotent Hematopoietic Stem cell and Progeniotr cells of Many Lineages

Primary Stem Cell Association

* CD 30 - Activation Marker

Activation Markers; B-cell T-cell Monocytes Reed Sternberg

* CD - 45 - Leukocyte Common Antigen

Common on All Leukocytes | (Leukocyte Common Antigen)

GI: WBC Disorders Flashcards

(63 cards)