GI: WBC Disorders Flashcards
- 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
- 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
- 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
- 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
- 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)
- 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
- 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
- Increased circulating monocytes >800 cells/mm3
- Chronic inflammatory states (autoimmune (RA) and infectious (TB, Subacute infective endocarditis, Cirrhosis))
- Malignancy (carcinomas and lymphomas)
Monocytosis
- Hypercortisolism (Cushing syndrome, Coricosteroids)
- Corticosteroids sequester Eosinophils in Lymph noes and Trigger apoptosis
Eosinopenia
- 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
- Increased ciruclating basophils >110 cells/mm3
- Classically seen in Chronic Myeloid Leukemia (CML)
- Chronic myeloproliferative disorders (Polycythemia vera)
Basophilia
- 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
- 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
- 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)
- 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)
- 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
- 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
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
- 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)
- 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)
- 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)
- 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)
- 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)
- Proliferation of monoblasts; usually lack MPO
- Blasts characteristically Infiltrate the Skin and Gums (Gingival infiltrations)
Acute Monocytic Leukemia (Subclass of AML)
- 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: 1st Phlebotomy, 2nd 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-IgHand 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)