Minarcik robbins 2013_ch14-wbc
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Transcript of Minarcik robbins 2013_ch14-wbc
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DISEASES of WHITE CELLS and LYMPHOID TISSUE
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Topics for Chapter 14• Leukopenia/Neutropenia• Leukocytosis• Lymphadenitis/Lymphadenopathy• (Malignant) Lymphoma• NON-Hodgkins Lymphoma• Hodgkins Lymphoma (Hodgkins Disease)• ALL/CLL (Acute/Chronic Lymphocytic Leukemia)• Multiple Myeloma• M1/M2/M3/M4/M5/M6/M7• Myeloproliferative Disorder• CML and Polycythemia Vera• Essential Thrombocytosis• Splenomegaly • Thymoma
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WBC/LYMPHOID DISORDERS
• Review of Normal WBC Structure/Function• Benign Neutrophil and Lymphoid Disorders• Leukemias• Lymph Nodes• Spleen/Thymus• REVIEW
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NEUTROPHILS• Normal TOTAL WBC count 6-11 K• Neutrophils usually 2/3 of total normal• Myeloblast Promyelocyte Myelocyte
Metamyelocyte Band (stab) Mature Neutrophil (Poly, PMN, Neutrophilic Granulocyte)
• Produced in red (hematopoetic) marrow, sequester (pool) in spleen, live in peripheral blood, migrate OUT of vascular compartment PRN, live a couple days normally
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NEUTROPHIL
Neutrophil
Polymorphonuclear Leukocyte, PMN, PML
“Leukocyte”
Granulocyte, Neutrophilic granulocyte
“Poly-”
Polymorph
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NEUTROPHIL MATURATION
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LYSOSOMAL CONSTITUENTS• PRIMARY• Also called
AZUROPHILIC, or NON-specific
• Myeloperoxidase• Lysozyme (anit-Bact.)• Acid Hydrolases
• SECONDARY• Also called SPECIFIC• Lactoferrin (anti-Bact.)• Lysozyme (anti-Bact.)• Alkaline Phosphatase• Collagenase
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FUNCTIONS• Margination• Rolling• Adhesion• Transmigration (Diapedesis)• Chemotaxis• Phagocytosis:
RecognitionEngulfmentKilling (digestion)• Equilibrium with splenic pool
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PELGER-HUET ANOMALY• Genetic: Autosomal Dominant)• Sometimes ACQUIRED (Pseudo-PELGER-HUET)
• All neutrophils look like BANDS• NOT serious, mostly a cute incidental finding
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CHEDIAK-HIGASHI SYNDROME• Also genetic: Autosomal Recessive• Abnormal LARGE irregular neutrophil granules• Impaired lysosomal digestion of bacteria• Associated with pigment and bleeding disorders• CAN be serious, especially in kids
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LEUKO-penia/NEUTRO-peniaNeutropenia/Agranulocytosis
• INADEQUATE PRODUCTION• INCREASED DESTRUCTION
• 500-1000/mm3 is the DANGER zone!
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INADEQUATE PRODUCTION• Stem cell suppression, e.g., aplastic anemias• DRUGS, esp. CHEMO, MANY antibiotics,
aminopyrene, thio-uracil, phenylbutazone• DNA suppression due to
megaloblastic/myelodysplastic states• Kostmann Syndrome: (A-R) (genetic, congenital)• Marrow usually shows granulocytic HYPO-
plasia, just as in RBC and PLAT decreased production
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INCREASED DESTRUCTION• Immune mediated–By itself (idiopathic), or as in SLE–After “sensitization” by many drugs
• Splenic sequestration, hypersplenism• Increased peripheral demand, as in
overwhelming infections, esp. fungal• Marrow usually shows granulocytic
HYPER-plasia, just as in RBC and PLAT increased destructions
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Leukocytosis/Neutrophilia• Marrow and splenic pool size• Rate of release between pool and circulation• Marginating pool• Rate of WBCs (neutrophils/monocytes) leaving the
vascular compartment• NON-vascular pools FIFTY times larger than the
vascular pools• TNF/IL-1/cytokines stimulate T-cells to produce
CSF, the WBC equivalent of EPO
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NEUTROPHIL INCREASES(e.g., “NEUTROPHILIA”)
• BACTERIA• TISSUE NECROSIS, e.g., MI• DÖHLE BODIES and TOXIC
GRANULES are often seen with NEUTROPHILIA
• Accompanied by a “LEFT” shift
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EOSINOPHIL INCREASES(i.e., “EOSINOPHILIA”)
• ALLERGIES (esp. DRUG allergies)• PARASITES
Is there such a thing as a specific eosino-penia?
ANS: NO
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BASOPHIL INCREASES(i.e., “BASOPHILIA”)
• RARE. VERY RARE. Period.• But if you want to remember
something at least, remember myeloproliferative diseases in which ALL cell lines are increased
Is there such a thing as a specific baso-penia? ANS: NO
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MONOCYTE INCREASES(i.e., “MONOCYTOSIS”)
•TB• SBE• RICKETTSIAL DISEASES• MALARIA• SLE• IBD, i.e., ULCERATIVE COLITIS
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LYMPHOCYTE INCREASES(i.e., “LYMPHOCYTOSIS”)
• TB• VIRAL–Hep-A–CMV–EBV
• Pertussis (whooping cough)
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“MYELOPROLIFERATIVE”disorders
• Also called “chronic” myeloproliferative disorders because they last for years
• Differentiate: Myeloproliferative vs. Myelodysplastic• ALL marrow cell lines are affected, splenomegaly• Proliferating cells do NOT suppress residual marrow
production, and go OUTSIDE marrow, and EXPAND marrow to fatty appendicular marrow
• Associated with EXTRA-medullary hematopoesis– Chronic Myelogenous “Leukemia” (CML)– P. Vera– Essential Thrombasthenia (aka, Essential Thrombocytosis)– Myelofibrosis
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CML• NOT AT ALL like an “acute” leukemia, but can
develop into an acute leukemia, as a condition called a “blast crisis”
• Age: adult, NOT kids• 90% have the “Philadelphia” chromosome, which
are aberrations on chromosome #9 (BCR) and #22 (ABL), the BCR-ABL “fusion”
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CML• Marrow 100% cellular, NOT 50%• ALL cell lines increased, M:E ratio massively
increased, 50K-100K neutrophils with SIGNIFICANT “left shift”, but not more than 10% blasts
• SIGNIFICANT SPLENOMEGALY!!!!!• Significant breakthrough with BCR-ABL kinase
inhibitors!!! (90% remissions)
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Polycythemia Vera• All cell lines increased, NOT just RBC• HIGH marrow cell turnover stimulates
increased purines which often cause gout (10%)
• BOTH thrombosis AND bleeding risks are present because the increased platelets are AB-normal
• Do not get “blast” crises, BUT can progress to myelofibrosis
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ESSENTIAL THROMOCYTOSIS
• Platelet count often near 1 million/mm3• Often a diagnosis of exclusion. • The RAREST of all myeloproliferative
disorders• Giant platelets usually. Why? Ans: Quicker
release from marrow (RPW/RDW) (MPV/MCV)
• Massively increased megakaryocytes in the marrow
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PRIMARY MYELOFIBROSIS
• Rapid progressive marrow fibrosis• Oldest age group of all the MPD’s, >60• Can follow other MPD’s. Why?• Usually the most extensive extramedullary
hematopoesis because the marrow is NOT the primary site of hematopoesis
• LEUKOERYTHROBLASTOSIS• Like CML, 10-20% can progress to AML
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WBC/LYMPHOID DISORDERS
• Review of Normal WBC Structure/Function• Benign Neutrophil and Lymphoid Disorders
•Leukemias• Lymph Nodes• Spleen/Thymus• REVIEW
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LEUKEMIAS• MALIGNANT PROLIFERATIONS of WHITE
BLOOD CALLS• In the case of neutrophilic precursors, the
primary process is marrow and peripheral blood, but can involve any organ or tissue which receives blood
• In the case of lymphocytes, there is an intimate concurrence with malignant lymphomas
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Lymphocytic Leukemias vs. Lymphomas• All leukemias of lymphocytes have lymphoma
counterparts• Primary lymphomas can have “leukemic” phases,
including multiple myelomas• Any myeloid leukemia can infiltrate a lymph node, or any
other site, but if/when it does it is NOT called a lymphoma, but simply a myeloid infiltrate INTO a lymph node
• ALL lymphomas are malignant proliferations of lymphocytes
• ALL leukemias involve bone marrow changes
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LYMPHOMAS• NODAL or EXTRANODAL• T or B• SMALL or LARGE CELLS• FOLLICULAR or DIFFUSE• Hodgkins or NON-Hodgkins• “F.A.B. classification” is currently popular
this week (FrenchAmericaBritish), for the NON-Hodgkins lymphomas, also evolved into the “International” classification
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LEUKEMIAS• Acute or Chronic• Myeloid or Lymphocytic• Childhood or Adult• All involve marrow• All ACUTE leukemias suppress normal
hematopoesis, i.e., have anemia, thrombocytopenia
• Most have predictable chromosomal aberrations• Some can respond DRASTICALLY to chemo, most
notably ALL in children, even be cured!!!!
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BLAST
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WHITE CELL NEOPLASMS Leuk/Lymph• Many have predictable chromosomal
translocations• Can arise in inherited and/or genetic diseases:– Downs Syndrome (Trisomy 21)– Fanconi’s anemia (hereditary aplastic anemia)– Ataxia telangiectasia
• May have a STRONG viral relationship:– HTLV-1 (lymphoid tumors)– EBV (Burkitt Lymphoma)– (in HIV): Human Herpesvirus-8 (KS) and B-Cell
Lymphomas
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WHITE CELL NEOPLASMS Leuk/Lymph
• Can be caused by H. Pylori (gastric B-Cell lymphomas)
• Can follow celiac disease (gluten sensitive enteropathy T-Cell lymphomas)
• Are common in HIV, B-Cell lymphomas, CNS lymphomas
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A.L.L./LYMPHOMAS*• SUDDEN ONSET
• ANEMIA, BLEEDING, FEVER• Bone pain, adenopathy, hepatosplenomegaly• CNS: headaches, vomiting, nerve palsies
• (* NB: These are pretty much the clinical symptoms of A.M.L. too and vice versa)
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A.L.L./LYMPHOMAS• “Lymphoblasts” which can give rise either to T or B cells
are the cells of malignant proliferation• All lymphocytic leukemias CANNOT be classified
independently of lymphomas because they all have lymphoma counterparts
• A.L.L. mostly in children• Most have chromosomal changes, hyperploidy,
Philadelphia chromosome, translocations• SIGNIFICANT response to chemo: 90% remission, 75%
CURE!!!
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A.L.L.
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C.L.L.• Unexplained sustained (months) lymph count of >
4000/mm3 is CLL, usually picked up on CBC• M>F, age >60
• Lymphs look normal and are NOT blasts• No need for marrow exam for dx, but progressive
involvement of marrow, nodes, and other organs is the usual biologic behavior
• Liver can be involved portally or sinusoidally
• Translocations RARE, but trisomies and deletions common
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C.L.L.
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C.L.L.• HYPO-gammaglobulinemia• 15% have antibodies against RBC’s
or PLATS• CANNOT be classified as separate
from lymphomas
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MULTIPLE MYELOMA• DEFINED AS A MALIGNANT PROLIFERATION OF
PLASMA CELLS (i.e., former B-lymphocytes)• Can have a “leukemic” phase, but the BONE
MARROW is the usual primary site of origin• Usually have MONOCLONAL GAMMOPATHIES• Secrete Heavy and Light chains, and Light chains
in the urine is known as Bence-Jones protein• Usually have elevated IL-6 (bad prognosis)
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PLASMA CELL classic features• OVAL cytoplasm, ROUND
nucleus off to side• Cartwheel/Clockface
chromatin• Prominent Golgi or “Hoff”
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MONOCLONAL “SPIKE” on SPE
NORMAL MULTIPLE MYELOMA
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MULTIPLE MYELOMA• BONE DESTRUCTION• Various deletions and translocations• Plasma cells usually 1-3% of marrow, but >20% or plasma
cells in SHEETS is diagnostic• Plasma cells usually look normal• IgG >> IgA, other immunoglobulins are rare• Staph, Strep, E. coli infections• Bleeding*• Amyloidosis• RENAL FAILURE
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Multiple Myeloma: Skull X-ray
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“Solitary” Plasmacytoma• Progression to MM is “inevitable”,
with time, perhaps 10-20 years even
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M.G.U.S.•Monoclonal Gammopathy of Unknown
Significance, i.e., no plasma cell proliferation is found
• Age related• 1% of 50-year olds, 3% of 70-year olds, etc.• Same chromosomal aberrations as MM, but
generally follow a BENIGN course
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Other “GAMMOPATHIES”• Waldenstrom’s MACRO-globulinemia
IgM (associated with lymphomas)
• Heavy Chain Disease (associated with lymphomas)
•AMYLOID, follows MM and/or chronic granulomatous diseases
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A.M.L.• GENETIC ABERRATIONS INHIBIT DIFFERENTIATION• Many have various TRANSLOCATIONS• F.A.B. classifies them as M0 M7• MORE than 20% of BLASTS are needed in the
marrow for a diagnosis of acute leukemia!!! (i.e., ANY kind of BLAST
• NORMALLY, a marrow should have only about 1-2 % blasts
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A.M.L.• M0 Minimally differentiated
• M1 AUER rods rare (COMMON)• M2 AUER rods common (COMMON)• M3 Acute PRO-myelocytic leukemia
• M4 AMML (myelo-Mono cytic) (COMMON)• M5 Monocytic• M6 ErythroLeukemia• M7 Acute Megakaryocytic leukemia
NOTE: Diagnosis is CONFIRMED by special markers, not just visual identification
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M0M2
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M3
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M4-M5
AMML
Normal “classic” monocyte
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M6-M7
ERYTHROLEUKEMIA MEGAKARYOCYTIC LEUKEMIA
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A.M.L.• Anemia• Thrombocytopenia (bleeding)– Petechiae– Ecchymoses
• Fever• Fatigue• Lymphadenopathy• 60% respond, BUT only 20 % are free of remission
after 5 years, WORSE than A.L.L.
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MYELO-DYSPLASTIC SYNDROMES• Increased risk of acute leukemias• But, UNLIKE the myeloPROLIFERATIVE syndromes, NOT
a hypercellular marrow• Spontaneous or drug related (even > 5 yrs!)• Has marrow ABERRATIONS– REFRACTORY ANEMIAS
– RINGED SIDEROBLASTS (Fe in mitochondria)
– Nuclear “BUDDING”– EXCESS BLASTS, but LESS than 20%
– About, say, 25% develop into acute leukemias
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Ring Sideroblasts and “BUDS”
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LYMPH NODES• Normal Structure, Function• Benign enlargement/Benign disease– Acute– Chronic (follicular vs. “sinus histiocytosis”)
• Lymphomas/Malignant Lymphomas– Adjectives of various classifications– Features– STAGING
• Metastatic disease TO lymph nodes
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CORTEX---SUB-capsular Sinus---Follicles (Pri? Or second.?)---PARA-follicular zoneMEDULLA
Blood flow?Lymph flow?
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Definition of TERMS• Lymphadenopathy• Lymphadenitis• Dermatopathic• Normal size?• Palpation• What to do if a lymph node is enlarged?• Diffuse/Follicular• T/B/NK, Small/Large, Cleaved/Non-cleaved• Precursor/Peripheral• HD/Non-HD
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BENIGN ENLARGEMENT• Also called LYMPHADENITIS, and HYPERPLASIA• Can be ACUTE (tender), or CHRONIC (non-tender)• Usually SUBSIDE in, say, less than 6 weeks• FOLLICULAR HYPERPLASIA is enlargement of the cortical
secondary follicles and increase in number of the cortical secondary follicles
• SINUS HISTIOCYTOSIS is prominence in medullary sinuses (also called “reticular” hyperplasia)
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(MALIGNANT) LYMPHOMAS
• Terms in historic classifications:– Diffuse/Follicular, Small/Large, Cleaved/Non-cleaved– Hodgkins (REED-STERNBERG CELL) /NON-Hodgkins– Lukes, Rappaport, etc.– Working Formulation, WHO, NIH, FAB, Intl., etc.
–B–T–PRECURSOR (less mature looking)–PERIPHERAL (more mature looking)
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DIFFUSE LYMPHOMA
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FOLLICULAR LYMPHOMA
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LARGE CELL LYMPHOMA
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SMALL CELL LYMPHOMA
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“CLEAVED” CELL LYMPHOMA
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“Hairy” Lymphocyte
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FEATURES of LYMPHOMAS• The antigen receptor genes re-arrangement PRECEDES
malignant transformation, so the cells are MONOCLONAL, NOT the usual POLYCLONAL
• 85% B-cell, 15% T-Cell• The tumor cells congregate wherever T and B cell
congregate normally however
• DISRUPTED or “EFFACED” normal architecture, obliterated subcapsular sinus
• HD/Non-HD staging CRUCIALLY IMPORTANT, esp. HD. Why? HD grows (spreads) more “linearly”, i.e., more “predictably”.
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LATEST CLASSIFICATION• NON-HODGKIN–PRECURSOR B–PERIPHERAL B–PRECURSOR T–PERIPHERAL T
• HODGKIN’S DISEASE (i.e., HODGKINS
LYMPHOMA) NS, LP, MC, LD
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PRECURSOR B• Precursor B LYMPHOBLASTIC
LEUKEMIA/LYMPHOMA
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PERIPHERAL B• CHRONIC LYMPHOCYTIC LEUKEMIA/LYMPHOMA• B-Cell PRO-lymphocytic LEUKEMIA• Lymphoplasmacytic• Splenic and Nodal Marginal Zone• EXTRA-nodal Marginal Zone• Mantle Cell• Follicular• Marginal Zone• Hairy Cell Leukemia• Plasmacytoma/Multiple Myeloma• Diffuse B Cell• BURKITT LYMPHOMA (Starry Sky)
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PRECURSOR T• Precursor T LYMPHOBLASTIC
LEUKEMIA/LYMPHOMA
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PERIPHERAL T and NK• T-Cell PRO-Lymphocytic Leukemia• Large Granular• Mycossis fungoides/Sezary Cell syndrome (skin)• Peripheral T-Cell• Anaplastic large cell• Angioimmunoblastic T-Cell• Enteropathy-associated T-Cell• Panniculitis-like• Hepatosplenic gamma-delta• Adult T-Cell• NK/T Cell nasal• NK-Cell leukemia
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LYMPHOCYTE MARKERS (CD-)i.e., LYMPHOCYTE ANTIGENS
• T-Cell: 1,3,4,5,8• B-Cell: 10 (CALLA), 19,20,21,23,79a• Mono/Mac: 11c, 13, 14, 15, 33, 34• STEM: 34• RS: 15, 30• All: 45 (Leukocyte Common Antigen)• NK: (16, 56)
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HODGKINS DISEASE• NEED R-S (Reed-Sternberg, or Sternberg-Reed)
cells for correct diagnosis
–NODULAR SCLEROSIS (Young Women), the R-S cells may be called “LACUNAR” cells
–MIXED CELLULARITY– Lymphocyte RICH– Lymphocyte POOR– Lymphocyte PREDOMINANCE
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STERNBERG-REED CELL
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STAGING, HD & NHD• I ONE NODE or NODE GROUP
• II MORE than ONE, but on ONE side of diaph.
• III BOTH sides of diaph., but still in nodes only
• IV OUTSIDE of NODES, e.g., liver, marrow, etc.
• A No systemic symptoms• B fever and/or night sweats and/or 10% weight loss
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METASTATIC CARCINOMA
• Perhaps the single most important staging and prognostic feature of tumors
• The metastatic cells FIRST enter into the SUBCAPSULAR SINUS
• The tumor may replace the entire node and enlarge it
• The tumor may be focal• The tumor usually looks the same as it’s
primary or other metastases• The tumor usually ENLARGES the node
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METASTATIC SQUAMOUS CELL CARCINOMA
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METASTATIC ADENOCARCINOMA
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SUBCAPSULAR SINUS
*
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SPLEEN• 150 grams POST-LUQ (just like kidney, 1/10 of liver)• Bordered by diaphragm, kidney, pancreas, splenic flexure,
stomach• SMOOTH & GLISTENING capsule• ~~~50% RED pulp, 50% WHITE pulp
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ABNORMAL SPLEEN
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ABNORMAL SPLEEN
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SPLENIC FUNCTION• REMOVE OLD BLOOD CELLS• MAJOR SECONDARY ORGAN of the IMMUNE
SYSTEM• HEMATOPOIESIS• SEQUESTER (POOL) BLOOD CELLS• 15% of body’s PHAGOCYTIC activity is in the
spleen (liver has >80)
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SPLENOMEGALY• CONGESTIVE vs INFILTRATIVE• HYPERSPLENISM–Anemia–Leukopenia–Thrombocytopenia
• DECISION for SPLENECTOMY
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SPLENOMEGALY• INFECTIONS: TB, Mono, Malaria, Fungus
• PORTAL HTN: CHF, CIRRHOSIS, PV Thromb.
• LYMPHOHEMATOGENOUS: Leuk, Lymph, esp. CML
• IMMUNE: RA, SLE
• STORAGE: Gaucher, Niemann-Pick
• MISC: Amyloid, mets (melanoma, lymphoma, germ cell tumors of testis)
LONG STANDING CONGESTION breeds FIBROSIS
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INFARCT
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PRIMARY TUMORS (RARE)
•HEMANGIOMA• LYMPHANGIOMA• fibroma• osteoma• chondroma
•LYMPHOMA
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MISC• Congenital Absence (very rare)• “Accessory” spleens (very very
common, especially with splenomegaly!)
•RUPTURE
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THYMUS• Mother of all T-Cells• Massive in newborns, virtually absent in the
elderly, bilobed• Under manubrium• 1) Thymocytes• 2) Epithelial Ret. Cells• 3) Hassal’s Corpuscles
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HASSAL’s CORPUSCLES
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DISEASES•HYPOPLASIA/APLASIA
– DiGeorge Syndrome (i.e., velocardiofacial, 22q11.2 deletion)
•CYSTS (incidental)
•THYMOMAS
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THYMOMAS• ALL (most) thymomas show counterparts of
BOTH lymphoid as well as epithelial reticular cells, hence, the classic name “LYMPHOEPITHELIOMA”–Benign thymoma: (encapsulated)–Malignant Thymoma I: (locally invasive)–Malignant Thymoma II: (easily metastasizable)
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THYMOMAS