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DISEASES of WHITE CELLS and LYMPHOID TISSUE

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1 DISEASES of WHITE CELLS and LYMPHOID TISSUE
Classical features of peripheral white cells, recognition algorhythms

2 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 Linear topics

3 WBC/LYMPHOID DISORDERS
Review of Normal WBC Structure/Function Benign Neutrophil and Lymphoid Disorders Leukemias Lymph Nodes Spleen/Thymus REVIEW Grouped topics

4 Classical features of peripheral white cells, recognition points.

5 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

6 NEUTROPHIL Neutrophil Polymorphonuclear Leukocyte, PMN, PML
Granulocyte, Neutrophilic granulocyte “Poly-” Polymorph Many names, same cell

7 NEUTROPHIL MATURATION
ALL blasts look the same on routine stains, whether they are myeloblasts, lymphoblasts, monoblasts, etc. A blast is a blast is a blast is a blast is a blast is a blast is a blast is a blast is a blast is a blast is a blast is a blast is a blast! Please remember you have all been conditioned to think a NUCLEOLUS is darker than the rest of the NUCLEUS, as it is on H&E, but in the usual stains we stain bone marrow smears or peripheral smears with, i.e., Wright or Giemsa respectively, the nucleoli are LIGHTER!!!

8 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 MYELOPEROXIDASE stains are often use to identify cells believed to be of MYELOID origin, such as blastic looking cells, because you cannot really tell for sure on Wright’s or Giemsa stains. Are these substances part on innate or learned immunity? ANS: INNATE

9 FUNCTIONS Margination Rolling Adhesion Transmigration (Diapedesis)
Chemotaxis Phagocytosis: RecognitionEngulfmentKilling (digestion) Equilibrium with splenic pool

10 PELGER-HUET ANOMALY All neutrophils look like BANDS
Genetic: Autosomal Dominant) Sometimes ACQUIRED (Pseudo-PELGER-HUET) All neutrophils look like BANDS NOT serious, mostly a cute incidental finding

11 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

12 LEUKO-penia/NEUTRO-penia Neutropenia/Agranulocytosis
INADEQUATE PRODUCTION INCREASED DESTRUCTION /mm3 is the DANGER zone! Notice the parallel with anemia and thrombocytopenia.

13 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

14 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

15 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

16 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 TOXIC GRANULES are EXAGGERATIONS of the marrow’s normal granularity, DOHLE bodies are fragments of remaining dilated rough ER. Neutrophilia can be viewed as a NONSPECIFIC index of acute infection, especially bacterial, but also tissue necrosis. The causes of NEUTROPHILIA can be said to be as the same causes of ACUTE INFLAMMATION!

17 EOSINOPHIL INCREASES (i.e., “EOSINOPHILIA”)
ALLERGIES (esp. DRUG allergies) PARASITES Following activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxic granule cationic proteins that are capable of inducing tissue damage and dysfunction. These include: 1) major basic protein (MBP) 2) eosinophil cationic protein (ECP) 3) eosinophil peroxidase (EPO) 4) eosinophil-derived neurotoxin (EDN) Is there such a thing as eosino-penia? ANS: NO

18 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 Not only are basophils RARE to find normally, but pure “basophilia” is also VERY rare. When activated, basophils degranulate to release histamine, proteoglycans (e.g. heparin and chondroitin), and proteolytic enzymes (e.g. elastase and lysophospholipase). They also secrete lipid mediators like leukotrienes, and several cytokines Is there such a thing as baso-penia? ANS: NO

19 MONOCYTE INCREASES (i.e., “MONOCYTOSIS”)
TB SBE RICKETTSIAL DISEASES MALARIA SLE IBD, i.e., ULCERATIVE COLITIS Why would monocytosis be linked to granulomatous diseases? Answer: Monocytes are macrophages in circulation, and granulomatous diseaseas are macrophage diseases. Is it surprising that many classical granulomatous diseases are also characterized by monocytosis, because macrophages are the CHIEF cells of granulomas? Answer: NO, not surprizing, it would be logical even!

20 LYMPHOCYTE INCREASES (i.e., “LYMPHOCYTOSIS”)
TB VIRAL Hep-A CMV EBV Pertussis (whooping cough) Would it be a fair statement to say that whereas, neutrophilia is characterized by bacterial infections, lymphocytosis can be an index of many viral infections? Answer: Yes, it is fair, but there are many exceptions.

21 “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 EXTRAMEDULLARY HEMATOPOESIS is most common in the spleen, liver, and lymph nodes. Now we move from increases of peripheral blood leukocytes to increases of marrow in general, increases in cellularity (one dimension of expansion), increases from axial to appendicular skeleton (second dimension of expansion), and increases into other organs which do not normally make marrow in adults, such as liver and spleen and lymph nodes (third dimension of expansion).

22 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” CML is the CLASSIC prototype of all myeloproliferative diseases.

23 CML SIGNIFICANT SPLENOMEGALY!!!!! 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) If a CML had much more than 10% blasts, you might suspect that the patient was going into a “blast crisis”. What is a LEUKEMOID REACTION? Ans: Extremely high benign elevations of WBCs looking like a leukemia!

24 This marrow is virtually 100% cellularity
This marrow is virtually 100% cellularity!!! This is the HALLMARK of CML, and all the cells are still marrow cells although blasts are INCREASED, i.e., more than 1-2 %. The “spaces” are NOT fat, they are blood vessels.

25 This marrow is virtually 100% cellularity
This marrow is virtually 100% cellularity!!! This is the HALLMARK of CML, and all the cells are still marrow cells although blasts are INCREASED, i.e., more than 1-2 %. In this CML megakaryocytes are proliferating so what OTHER myeloproliferative disease could this be confused with? Ans: essential thrombocythemia (also called essential thrombocytosis)

26 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

27 This marrow is about 90% cellular and looks a lot like CML. This is P
This marrow is about 90% cellular and looks a lot like CML. This is P. vera

28 ESSENTIAL THROMOCYTOSIS (THROMBASTHENIA)
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 A

29 Note that this is NOT a marrow biopsy but a smear, so TRUE marrow cellularity cannot be assessed, however MOST of the cells are megakaryocytes!

30 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 Leukoerythroblastosis is an anemic condition resulting from space-occupying lesions in the bone marrow and characterized by the presence of immature granular leukocytes and nucleated erythrocytes in the circulating blood. Also called myelophthisic anemia.

31 Note most of the marrow looks “fibrotic”
Note most of the marrow looks “fibrotic”. What stain could help you confirm that this is fibrous tissue? (trichrome would stain collagen green)

32 WBC/LYMPHOID DISORDERS
Review of Normal WBC Structure/Function Benign Neutrophil and Lymphoid Disorders Leukemias Lymph Nodes Spleen/Thymus REVIEW

33 LEUKEMIAS DEF:MALIGNANT PROLIFERATIONS of WHITE BLOOD CALLS
In the case of myeloid 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 CHRONIC leukemias, are essentially DIFFERENT from ACUTE leukemias, sorta.

34 Leukemias vs. Lymphomas
All leukemias of lymphocytes have lymphoma counterparts Primary lymphomas can have “leukemic” phases, and involve marrow, especially 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, and usually start in lymph nodes but can originate ANYWHERE there are lymphocytes! ALL leukemias involve bone marrow changes

35 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 ADJECTIVES again!

36 LEUKEMIAS Acute (blasts) or Chronic (few or NO blasts)
Myeloid (0-7) A/C or Lymphocytic A/C Childhood or Adult All involve marrow All ACUTE leukemias suppress normal hematopoesis, i.e., have anemia, thrombocytopenia, these are usually the presenting symptoms! Most have chromosomal aberrations Some can respond DRASTICALLY to chemo, most notably ALL in children, even be cured (ALL) !!!!

37 BLAST The most life saving thing you can learn today is how to recognize a blast! HUGE NUCLEUS NUCLEOLI (stain LIGHTER not DARKER than the rest of the nucleus on Wright stain), How many nucleoli does that one blast cell have? Answer: 3 NO cytoplasmic differentiation NOBODY IS GETTING OUT OF THIS ROOM ALIVE UNTIL THEY CAN IDENTIFY A BLAST CELL! A blast is a blast is a blast is a blast is a blast is a blast is a blast……yadda, yadda!

38 WHITE CELL NEOPLASMS Leuk/Lymph, I (Hematologic Malignancies)
Many have chromosomal translocations, predictable and characteristic, but not 100% of the time 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) Human Herpesvirus-8 (B-Cell Lymphomas) (also KS) Ataxia-Telangiectasia is characterised by: Early-onset progressive cerebellar ataxia (difficulty with control of movement) Ocular apraxia (difficulty following objects across visual field) Telangiectasias of the eyes and skin Immunodeficiency, low immunoglobulin concentrations Chromosomal instability Hyper-sensitivity to ionizing radiation Increased incidence of malignancies (primarily hematologic). Raised alpha-fetoprotein levels.[4] Absent thymic shadow on X-ray. Ovarian dysgenesis

39 WHITE CELL NEOPLASMS Leuk/Lymph, II
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 Most lymphomas are B cell lymphomas! ~ 85%

40 A.L.L./LYMPHOMAS* ANEMIA, BLEEDING, FEVER SUDDEN ONSET
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)

41 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!!!

42 A.L.L. Are the lymphoid nuclei large? Are nucleoli present?

43 C.L.L. Translocations RARE, but trisomies and deletions common
Unexplained sustained (months) lymph count of > 4000/mm3 is CLL, usually picked up on CBC M>F 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 You can usually diagnose CLL simply from a CBC printout, but should verify the cells visually. CLL does NOT go into a blast crisis, like CML does!

44 C.L.L. Many cells from CLL have a “smudge” or “basket” appearance. If you know what a NORMAL lymphocyte looks like, you can diagnose CLL purely by numbers! No marrow exam needed!

45 C.L.L. HYPO-gammaglobulinemia
15% have antibodies against RBC’s or PLATS CANNOT be classified as separate from lymphomas Why would a CLL have hypogammaglobulinemia? ANS: LYMPHS are the precursors of plasma cells!

46 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)

47 PLASMA CELL classic features
OVAL cytoplasm, ROUND nucleus off to side Cartwheel/Clockface chromatin Prominent Golgi or “Hoff” Please memorize those THREE diagnostic features of plasma cells, the malignant plasma cells of MM look like normal plasma cells usually. Ironically, most myelomas are recognized because they look like NORMAL plasma cells! Stand again?

48 MONOCLONAL “SPIKE” on SPE
Normal on left, myeloma on right. Batman sign? NORMAL MULTIPLE MYELOMA

49 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 *The presence of large proliferations of monoclonal immune proteins are believed to interfere with normal coagulation.

50 Multiple Myeloma: Skull X-ray
Note the “lytic” lesions. Often the term “punched out” is used also.

51 “Solitary” Plasmacytoma
Progression to MM is “inevitable”, with time, perhaps years even What if you have a plasmacytoma but NO monoclonal gammopathy?

52 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 What if you have a monoclonal gammopathy but NO demonstrable proliferation of plasma cells?

53 Other “GAMMOPATHIES” Waldenstrom’s MACRO-globulinemia IgM (associated with lymphomas) Heavy Chain Disease (associated with lymphomas) AMYLOID, follows MM and/or chronic granulomatous diseases What is the difference between a monoclonal and a polyclonal gammopathy? (monoclonals usually show a SPIKE on serum protein electrophoresis, SPE). Monoclonals are the result of malignant proliferations, polyclonals are generally the result of chronic inflammation.

54 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 Well, after CML, CLL, and ALL, all that is left is the BIG ONE! Lets make this REAL easy…..ALL blasts look alike!!!! Why? Because there is NO cellular differentiation beyond the primitive stem cell appearance!

55 A.M.L. M1 AUER rods rare (COMMON) M2 AUER rods common (COMMON)
M Minimally differentiated M1 AUER rods rare (COMMON) M2 AUER rods common (COMMON) M3 Acute PRO-myelocytic leukemia (Azurophilic, primary nonspecific granules) 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 AML’s are classified according to where the arrest occurs, i.e., the cells which proliferate in marrow and peripheral smear, and organs.

56 M0M2 Blasts, blasts with AUER rods. Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts. They are composed of fused lysosomes and contain peroxidase, lysosomal enzymes, and large crystalline inclusions.

57 M3 Acute promyelocytic leukemia, remember promyelocytes have BOTH nucleoli AND nonspecific granules, true BLASTS do NOT have granules. Do you remember that M3 has a high degree of association with DIC?

58 Normal “classic” monocyte
M4-M5 In AMML, M4, many of the peripheral leukemic cells look like monocytes, while in M5, Acute Monocytic Leukemia, MOST of them look like monocytes. M5 has also been called “Schilling”-type leukemia. (NOT the same Schilling of the B12 Schilling test) Normal “classic” monocyte AMML

59 MEGAKARYOCYTIC LEUKEMIA
M6-M7 In M6, many of the cells may resemble erythroid cells, in M7, many of the cells may resemble megakaryocytes. But in reality you would probably never think the blasts of M7 are related to megakaryocytes. ERYTHROLEUKEMIA MEGAKARYOCYTIC LEUKEMIA

60 A.M.L. Anemia Thrombocytopenia (bleeding) Fever Fatigue
Petechiae Ecchymoses Fever Fatigue Lymphadenopathy 60% respond, BUT only 20 % are free of remission after 5 years, WORSE than A.L.L. Note AMAZING similarity to ALL, clinically. Surprised? Ans: NO

61 MYELO-DYSPLASTIC SYNDROMES
Increased risk of acute leukemias But, UNLIKE the myeloPROLIFERATIVE syndromes, NOT a hypercellular marrow Spontaneous or drug (chemo) 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 Know the difference between a myelo-”proliferative” and a myelo-”dysplastic” disease.

62 Ring Sideroblasts and “BUDS”

63 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

64

65 Blood flow? Lymph flow? CORTEX ---SUB-capsular Sinus
Why does the phrase “effaced architecture” appear on my pathology reports of malignant lymphomas? CORTEX ---SUB-capsular Sinus ---Follicles (Pri? Or second.?) ---PARA-follicular zone MEDULLA Blood flow? Lymph flow?

66 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

67 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)

68 BENIGN FOLLICULAR HYPERPLASIA
BENIGN FOLLICULAR HYPERPLASIA. Larger and more numerous than normal follicles. MEDULLA may be compromised.

69 BENIGN SINUS HISTIOCYTOSIS. The cortical area may be compromised
BENIGN SINUS HISTIOCYTOSIS. The cortical area may be compromised. SINUS HISTIOCYTOSIS may be seen in reaction to cancer, even if there are NO tumor cells in the lymph node.

70 (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) Mention Steve Swerdlow and link to his father!

71 DIFFUSE LYMPHOMA

72 FOLLICULAR LYMPHOMA

73 LARGE CELL LYMPHOMA

74 SMALL CELL LYMPHOMA

75 “CLEAVED” CELL LYMPHOMA
Why does the pathologist often use the word “buttocks” cell, to describe a “cleaved” cell lymphoma?

76 “Hairy” Lymphocyte “HAIRY” cell leukemia/lymphoma consists of lymphocytes which look hairy, but remember, on SEM ant TEM they all look hairy!

77 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”. MOST IMPT! “Effacement” means any pattern in which follicles in the cortex and cords/sinuses in the medulla cannot be recognized because they are “effaced” or “obliterated”

78 LATEST CLASSIFICATION
NON-HODGKIN PRECURSOR B PERIPHERAL B PRECURSOR T PERIPHERAL T HODGKIN’S DISEASE (i.e., HODGKINS LYMPHOMA) NS, LP, MC, LD Most pathologists HATE lymphoma classifications with a passion!

79 PRECURSOR B Precursor B LYMPHOBLASTIC LEUKEMIA/LYMPHOMA

80 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) I HATE this slide.

81 PRECURSOR T Precursor T LYMPHOBLASTIC LEUKEMIA/LYMPHOMA

82 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 I HATE this slide even worse.

83 LYMPHOCYTE MARKERS (CD-) i.e., LYMPHOCYTE ANTIGENS
T-Cell: 1,3,4,5,8 (single digit) 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) If you feel the need to memorize this fine, but better to remember: T markers <10 B markers 19-23 Mono/Mac teens RS 15, 30

84 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 Prognosis of HD disease is related directly of percentage of lymphocytes and inversely to number of RS cells.

85 STERNBERG-REED CELL STERNBERG REED cells are called “lacunar” cells in one of the most common forms of HD called NODULAR SCLEROSING

86 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

87 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, eventually

88 METASTATIC SQUAMOUS CELL CARCINOMA

89 METASTATIC ADENOCARCINOMA
If there was only one tiny microscopic focus of metastatic tumor cells in this lymph node, where would it most likely be?

90 SUBCAPSULAR SINUS * The subcapsular sinus of the lymph node is the FIRST place you will spot a metastatic tumor nest!

91 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

92 We can also use the 50/50 principle generally for the spleen too: 50% “red” pulp, 50% “white” pulp.
RED PULP = RBCs (grossly and microscopically) WHITE PULP = LYMPHS (grossly only, BLUE, microscopically)

93 ABNORMAL SPLEEN Notice the “confluence” of WHITE pulp? Could this be lymphoma involvement? Ans: Yes Could this be granulomas? Ans: YES

94 ABNORMAL SPLEEN Portal hypertension, prominence of RED pulp, i.e., red pulp >> 50%

95 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)

96 SPLENOMEGALY CONGESTIVE vs INFILTRATIVE HYPERSPLENISM
Anemia Leukopenia Thrombocytopenia DECISION for SPLENECTOMY

97 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) What 3 malignancies have the highest preference for splenic metastases? malignant melanoma lymphomas testicular germ cell tumors LONG STANDING CONGESTION breeds FIBROSIS, not to mention hypersplenism functionally!

98 INFARCT Why is a splenic infarct a “pale” infarct? Answer: single end-artery blood source

99 LYMPHOMA PRIMARY TUMORS (RARE) HEMANGIOMA LYMPHANGIOMA
fibroma osteoma chondroma LYMPHOMA Not surprising, because there are NO epithelial cells native to the spleen! Note all these are benign, except fot the lymphoma. The commonest MALIGNANT tumor primary to the spleen is a LYMPHOMA, by far!

100 MISC RUPTURE Congenital Absence (very rare)
“Accessory” spleens (very very common, especially with splenomegaly!) RUPTURE

101 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

102 HASSAL’s CORPUSCLES Hassal’s corpuscles are fused epithelial reticular cells

103 DISEASES HYPOPLASIA/APLASIA CYSTS (incidental) THYMOMAS
DiGeorge Syndrome (i.e., velocardiofacial, 22q11.2 deletion) CYSTS (incidental) THYMOMAS Oldage atrophy (involution) is so common, you can hardly call it a disease

104 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)

105 THYMOMAS Benign (encapsulated), Malignant I (invasive), and Malignant II (easily metastasizable) Note that the classification of thymomas has little to do with the appearance of the cells, but in the BEHAVIOR of the tumor grossly: 1) Encapsulated 2) Invasive 3) Metastatic


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