Other 13 Flashcards

Question

Lymphopenia causes

Answer 1

Decreased number of circulating lymphocytes Immunodeficiency (Di George syndrome [chromosome 22q11 deletion]) High cortisol state (Cushing syndrome) Autoimmune destruction (SLE) Whole body radiation

Answer 2

Increased circulating neutrophils Bacterial infection or tissue necrosis (left shift) with Decreased CD16 and Fc receptors High cortisol state

Answer 3

``` Increased circulating eosinophils Allergic reactions (type I hypersensitivity) Parasitic infections Hodgkin lymphoma Drug reactions Some vasculitides *increased IL5 --> eosinophils ```

Answer 4

Increased circulating basophils CML (chronic myeloid leukemia) Rare, except in CML ^^

Answer 5

``` Increased circulating monocytes Chronic inflammatory states (autoimmune or infectious) TB, bacterial endocarditis, malaria Malignancy Collagen vascular disorders (SLE) Inflammatory bowel diseases ```

Answer 6

``` Increased circulating lymphocytes Viral infections (HAV, CMV, EBV) Bordetella pertussis infection Chronic immunologic stimulation (TB, brucellosis) Often accompanies monocytosis ```

Answer 7

Develop in lymph nodes within several days of antigenic stimulation due to enlargement of primary follicles; pale staining Highly dynamic structures where B cells acquire the capacity to make high-affinity antibodies against specific Antigens Dark zone of proliferating centroblasts (blast like B cells) Light zone of centrocytes (B cells with irregular or cleaved nuclear contours

Answer 8

Localized: Direct microbiologic drainage (i.e. cervical region due to dental or tonsillar infection; axillary or inguinal regions due to infections in the extremities

Answer 9

Systemic: Associated with bacteremia and viral infections (particularly in children

Answer 10

Mesenteric: An infection that causes mesenteric lymph nodes to enlarge and become tender Can look like appendicitis

Answer 11

Large germinal centers with numerous mitotic figures Nodes are swollen, gray-red and engorged Presence of macrophages with particulate debris In severe infections the entire lymph node can become necrotic or a bag of pus Less severe infections have scattered infiltrates of neutrophils that accumulate in the lymphoid sinuses Endothelial cell hyperplasia (lining the sinus

Answer 12

Clinical Affected nodes are enlarged and tender; may become fluctuant (moveable) when abscess formations is extensive; overlying skin is red suppurative infections that penetrate the lymph node capsule & track to the skin --> draining sinuses --> scar

Answer 13

Nontender lymph nodes without acute inflammation or tissue damage Tender LAD == acute process (infection) nontender LAD == chronic process (cancer) Common in inguinal and axillary lymph nodes as they drain large areas of the body and are stimulated by trivial injury/infections of extremities

Answer 14

chronic immune reactions can promote the appearance of organized collections of immune cells in nonlymphoid tissues chronic gastritis caused by Helicobacter pylori infection --> peyer’s patch hyperplasia can lead to MALToma (marginal cell lymphoma) rheumatoid arthritis --> B-cell follicles appear in the inflamed synovium can lead to MALToma (marginal cell lymphoma) lymphotoxin is probably involved

Answer 15

due to stimuli activating the humoral immune response Presence of large oblong germinal centers (2° follicles) surrounded by a collar of small resting naive B cells (mantle zone) Germinal centers contain centroblasts (dark) and centrocytes (light) Dendritic cells and tingible-body macrophages are interspersed tingible-body macrophages == macrophages that have phagocytosed the apoptotic B-cells May be due to rheumatoid arthritis, toxoplasmosis, or early HIV -- B cell responses

Answer 16

Tingible-body macrophages Contain the nuclear debris of B cells B cells undergo apoptosis if they fail to produce an antibody with a high affinity for antigen Seen in ALL and Burkitt Lymphoma tingible body == apoptotic B cells in a macrophage

Answer 17

Preservation of lymph node architecture -- neoplastic means things are going awry Marked variation in follicular shape and size Frequent mitotic figures, phagocytic macrophages and recognizable light (-cyte) and dark (-blast) zones

Answer 18

due to stimuli triggering the T-cell mediated immune response (e.g. acute viral infection) infectious mononucleosis (EBV) In exuberant reactions, the T-cell zones (containing immunoblasts) may encroach on the B-cell follicles Hypertrophy of sinusoidal and vascular endothelial cells May be accompanied by infiltrating macrophages and eosinophils

Answer 19

Activated T cells 3-4 times the size of resting lymphocytes Round nuclei, open chromatin, several prominent nucleoli, moderate amounts of pale cytoplasm If numerous, exclude lymphoid neoplasm from differential diagnoses

Answer 20

inus Histiocytes (aka reticular hyperplasia) Increase in the number and size of cells that line lymphatic sinusoids Nonspecific, but can be prominent in lymph nodes draining cancers such as carcinoma of the breast lymphatic endothelial cells are markedly hypertrophied and significant increases in macrophages occurs Expansion and distension of the sinuses sinus histiocytosis does not mean metastatic cancer; these lymph nodes are reactive; sinus histiocytosis is a reactive phenomenon in a lymph node draining cancer histiocytosis X is dendritic cell proliferation -- what does the X stand for??

Answer 21

Definition: macrophage activating syndrome Reactive condition with cytopenias and signs and symptoms of systemic inflammation due to macrophage activation Familial (early onset) and sporadic (any age

Answer 22

Systemic activation of macrophage and CD8+ cytotoxic T-cells macrophages phagocytose blood cell progenitors in the marrow and formed elements in peripheral tissues Mediators released from macrophage and lymphocytes suppress hematopoiesis and produce signs and symptoms of systemic inflammation "Cytokine storm" or SIRS can occur due to the cytopenias SIRS criteria Hyper/Hypo-thermia Tachycardia Tachypnea Leukocytosis/leukopenia Appear shock-like unbridled HLH is associated with extremely high levels of inflammatory mediators such as IFNγ, TNFα, IL-6, and IL-12, as well as soluble IL-2 receptor infection is the most common trigger for HLH, especially Epstein-Barr virus (EBV

Answer 23

patients present with acute febrile illness and hepatosplenomegaly Hemophagocytosis may be seen on bone marrow exam -- neither sufficient nor required to make diagnosis Anemia, thrombocytopenia, increased plasma ferritin and soluble IL-2 receptor (indicators of severe inflammation) Elevated LFT's and TGs (related to hepatitis) coagulation studies may show evidence of DIC Untreated = rapid progression to multiorgan failure, shock, death

Answer 24

Immunosuppressive drugs and "mild" chemotherapy Germline mutations or persistent/resistant disease? HSC transplantation Treated: 50% survive May have significant sequelae (renal damage in adults, growth and mental retardation in children) Untreated: grim prognosis, < 2 months survival if familial

Answer 25

Mutations impact the ability of cytotoxic T cells and NK to properly form or deploy cytotoxic granules Uncontrolled disease Greatly increased IFNγ, TNFα, IL6, IL12 and soluble IL2 receptor familial form is more severe

Answer 26

Elevated in reactive WBC disorders LAP will be high in reactive states, e.g. infection Low in myeloproliferative and neoplastic WBC disorders

Answer 27

WBC Neoplasms Lymphoid Myeloid Histiocytoses

Answer 28

Neoplasm of B-cell, T-cell and NK-cell origin | Phenotype may resemble a particular stage of normal maturation -- useful for diagnosis and classification

Answer 29

Neoplasm of early hematopoietic progenitors | Tend to evolve over time to more aggressive forms of disease -- clinically important

Answer 30

Immature progenitor cells (blasts) accumulate in the bone marrow suppressing normal hematopoiesis Both myelodysplastic syndromes and myeloproliferative disorders can "transform" to this disease

Answer 31

Ineffective hematopoiesis due to defective maturation of myeloid progenitors Resultant peripheral blood cytopenias more severe than myeloproliferative disorders

Answer 32

hronic Myeloproliferative Disease Increased production of one or more terminally differentiated myeloid elements leads to elevated peripheral blood counts Polycythemia Vera, Essential Thrombocytopenia, Primary Myelofibrosis, and CML

Answer 33

Uncommon proliferative lesions of macrophage and dendritic cells Langerhans cell (special type of immature dendritic cell) gives rise to a spectrum of neoplastic disorders referred to as the Langerhans cell histiocytoses look for cutaneous involvement; all are CD4 +ve

Answer 34

Chromosomal translocations and other acquired mutations Inherited genetic factors acute leukemias: dominant negative oncogenic mutations involving transcription factors are often present that interfere with early stages of lymphoid or myeloid cell differentiation Viruses Chronic inflammation (i.e. Helicobacter Pylori) Iatrogenic factors (radiation and some chemotherapy) Smoking oncogenic mutations occur most frequently in germinal center B cells during attempted antibody diversification class switching == intragenic recombination event in which the IgM heavy-chain constant gene segment is replaced with a different constant gene somatic hypermutation == point mutations within Ig genes that may increase antibody affinity for antigen

Answer 35

Translocations in WBC neoplasms | Most common nonrandom chromosomal abnormality seen in WBC neoplasms

Answer 36

Play crucial roles in the development, growth or survival of the normal counterpart to the malignant cell (gain or loss of function) Oncoproteins can block normal maturation, activate pro-growth signals or inhibit apoptosis Protooncogenes may be activated during gene rearrangement and diversification

Answer 37

This enzyme is upregulated after Antigen stimulation in germinal center B cells Allows Ig class switching and somatic hypermutation to increased antibody affinity May induce MYC/Ig translocations -- AID creates lesions in DNA that lead to chromosomal breaks Can activate protooncogenes (i.e. BCL6

Answer 38

This enzyme cuts DNA at specific sites within the Ig and T-cell receptor loci May go awry, leading to the joining of portions of other genes to Ag receptor gene regulatory elements Unique to B and T cells

Answer 39

``` Leukemia & Lymphoma can be influenced by: Inherited genetic factors: Down syndrome (trisomy 21) associated with an increased risk of Acute Lymphoblastic Leukemia (ALL) in children < 5 years Bloom syndrome Fanconi anemia ataxia telangiectasia Type I neurofibromatosis ```

Answer 40

HTLV1: adult T-cell leukemia/lymphoma (ATLL

Answer 41

EBV: Burkitt lymphoma, Hodgkin lymphoma, other B-cell Lymphoma EBV infects B cells in the cortex; response to EBV infection is a paracortical hyperplasia of T-cells

Answer 42

KSHV/HHV8: B-cell Lymphoma that presents as a malignant effusion in the pleural cavity

Answer 43

HIV: B-cell Lymphoma

Answer 44

Helicobacter pylori: Gastric B-cell Lymphomas Gluten sensitive enteropathy: intestinal T-cell Lymphomas Breast implants: T-cell Lymphoma

Answer 45

Iatrogenic factors leading to blood neoplasia | Radiation and chemo can affect the myeloid and lymphoid precursors to cause neoplasia

Answer 46

Acute Myeloid Leukemia increased, especially due to benzene

Answer 47

(Lymphocytic) Leukemia: neoplasms that have wide spread involvement of the bone marrow and often (not always) the peripheral blood signs and symptoms related to the suppression of normal hematopoiesis by tumor cells in the bone marrow "acute" leukemia == most common leukemia of childhood (ALL) infections --> thrombocytosis; leukemia --> thrombocytopenia generally: acute means kids and are -blasts; chronic means adults and are -cytes

Answer 48

Lymphoma: proliferations of lymphoid cells that arise as discrete tissue masses -- involvement of the tissue makes it an "-oma" ("-oma" means mass) 2/3 of non-Hodgkin's lymphomas and virtually all Hodgkin's lymphomas present as enlarged, nontender lymph nodes; 1/3 of remaining non-Hodgkin's lymphomas present with symptoms related to tissue/organ involvement

Answer 49

Leukemia vs. Lymphoma Lymphomas more commonly exhibit tissue involvement ("-oma" means mass) leukemia and lymphoma reflect the usual tissue distribution of each disease at presentation

Answer 50

Precursor B cell (-blasts) neoplasms

Answer 51

Peripheral B cells (-cystes) neoplasma

Answer 52

Precursor T cell neoplasma

Answer 53

Peripheral T cell neoplasms

Answer 54

Peripheral T cell and NK cell neoplasma

Answer 55

Hodgkin lymphoma

Answer 56

Histological examination is required for diagnosis Antigen receptor gene rearrangement precedes transformation of cells -- all daughter cells derived from the malignant progenitor share the same antigen receptor gene configuration and sequence Monoclonal: all daughter cells express the same configuration and sequence, synthesizing identical proteins (immunoglobulins or TCRs) -- monoclonal means cancer, malignant Polyclonal: means that they are immature and are reactive Most resemble a recognizable stage of B or T cell differentiation (most are B cell neoplasms) even though 80% of circulating lymphocytes are T-cells Often associated with immune problems Behavior resembles normal B and T-cells most lymphoid tumors are widely disseminated at the time of diagnosis Hodgkin lymphoma: sometimes restricted to one group of lymph nodes marginal zone B-cell lymphomas: often restricted to sites of chronic inflammation MALTomas that arise in the setting of chronic inflammation t(11;18), t(14;18) or t(1;14)

Answer 57

Hodgkin's: spreads in an orderly fashion and staging is useful distinctive pathologic features and is treated in a unique fashion

Answer 58

Non-Hodgkin's: spreads widely, and less predictably

Answer 59

Neoplasm of immature lymphoblasts (most are B-ALL) There is a lot of clinical overlap between B and T-ALL Kids with a very low platelet count have ALL until proven otherwise -- most common leukemia of childhood

Answer 60

Increased risk in Hispanics>>whites > African Americans Slight male predominance Most common cancer of children (usually patients <15) *Most common cancer of children

Answer 61

Dysregulation of expression and function of transcription factors for normal B and T cell development Disturb differentiation and promote arrest of maturation, inducing self-renewal Mutations that drive cell growth (i.e. TK) are common 70% of T-ALLs have gain-of-function mutations in NOTCH1 majority of B-ALLs have loss-of-function mutations in PAX5, E2A, and RBF or a balanced t(12;21) involving the genes ETV6 and RUNX1 Numerical or structural chromosomal change: 90% (Translocations, altered ploidy) Caused by relatively few mutations as compared to solid tumors

Answer 62

Leukemic presentation: marrow is hypercellular and packed with lymphoblasts that replace the normal marrow elements Scant basophilic cytoplasm with nuclei larger than small lymphocytes Delicate, finely stippled nucleoli with a rim of condensed chromatin Subdivided nuclear membrane (convoluted) High mitotic rate "Starry sky" due to macrophage ingestion of tumor cells A bone marrow biopsy is performed and on microscopic examination shows nearly 100% cellularity with replacement by primitive cells that have large nuclei with delicate chromatin and indistinct nucleoli with scanty cytoplasm. These cells mark for CD10 (CALLA) antigen

Answer 63

must differentiate ALL from AML because they differ in their response to chemotherapy

Answer 64

More condensed chromatin Less conspicuous nuclei Smaller amounts of cytoplasm whihc lacks granules MPO(-), PAS (+), TdT (+) Abrupt; stormy onset”, within days to few weeks of first symptoms Related to depression of marrow function; fatigue due to anemia; fever due to infection from neutropenia; bleeding due to thrombocytopenia; More common in all; bone pain More common in ALL ; HA, vomiting, nerve palsies from meningeal spread

Answer 65

MPO (+) No nerve palsies

Answer 66

Clinical most common translocation == t(4;11) -- ??? (Hubbard) Normal hematopoiesis is suppressed due to physical crowding, growth factor competition, etc. Abrupt, "stormy" onset in days to weeks of first signs and symptoms Signs and symptoms related to depression of marrow function Fatigue (anemia), fever (neutropenia → infection), bleeding (thrombocytopenia) Mass effects due to neoplastic infiltration Bone pain from marrow expansion and infiltration, LAD, HSM, testicular enlargement neurological manifestations due to meningeal spread: headache, vomiting, nerve palsies; diplopia

Answer 67

still leading cause of cancer deaths in children (most common cancer) only 35-40% of adults are cured due to different molecular pathogenesis and inability to tolerate the necessary chemo regimen effective in children

Answer 68

Age < 2 (strong association of infantile ALL with translocation of MLL gene) t(9:22) Philadelphia chromosome Presentation in adolescence or adulthood Peripheral blood blast count > 100,000 (high tumor burden likely) Detection of residual disease after therapy

Answer 69

``` Age between 2 and 10 years old Low white cell count Hyper-diploidy trisomy of chromosome 4, 7, 10 Presence of t(12:21) -- involves ETV6 and RUNX1 genes ```

Answer 70

Acute childhood leukemia Peak incidence at age 3 Extensive marrow and peripheral blood involvement B-cell tumors present with cyclic tumors

Answer 71

Marrow is hypercellular and packed with lymphoblasts | Pancytopenia

Answer 72

loss-of-function mutations in PAX5, E2A, EBF or *t(12:21) ETV6/RUNX1 Hyperdiploidy and hypodiploidy may be present and are exclusive in B-ALL

Answer 73

``` TdT (+) (pre-B-cell marker) CD10, 19, 20 (+) Very immature neoplasm: CD10 (-) Mature neoplasm: IgM heavy chain (+) (μ chain) PAX5 (+) t(9:22) BCR/ABL protein ```

Answer 74

Effectively treatment in children with chemotherapy | Prophylax scrotum and CSF

Answer 75

Presents in adolescent male (teenagers) as thymic mass (mediastinal) "lymphomas"; and T-cells (thymocytes) -- mnemonic == 3 T's May evolve to a leukemia lymphadenopathy and splenomegaly Signs and symptoms may include complications related to compression of vessels or airways in the mediastinum

Answer 76

NOTCH1 gain-of-function mutations -- T-cells are NOTCH1 GOF

Answer 77

TdT (+) -- precursor lymphocyte (i.e. lymphoblast) markers CD1 and CD8 positive Immature: CD3, CD4, and CD8 negative

Answer 78

only difference between CLL and SLL is the degree of peripheral blood lymphocytosis

Answer 79

lar lymphoma == efface the normal architecture of the lymph nodes follicular hyperplasia does not t(14;18

Answer 80

t(11;18), t(14;18), or t(1;14

Answer 81

TRAP, BRAF

Answer 82

Most common leukemia of adults in the Western world *Morphologically, phenotypically and genotypically indistinguishable from SLL, differ only in the degree of peripheral blood lymphocytosis (absolute WBC count > 5000/mm3

Answer 83

Male 2:1 Age: 60yrs More common in the West than Asian countries

Answer 84

Chromosomal translocations are rare Deletions: 13q14.3(microRNAs 15a & 16-1), 11q, 17p Trisomy 12q -- "tr-elve," and the mnemonic becomes "11, 12/trelve, 13, 14, 15, 16, and 17

Answer 85

Somatic hypermutation of immunoglobulin genes can occur indicating cell of origin may be post-germinal center memory B cell or naive B cell Unmutated Ig segments = increased aggressive course NOTCH1 receptor gain of function mutations -- this is a poor prognostic factor RNA splicing mutations

Answer 86

Confined to proliferation centers NFκB is stimulated by stromal cells = promotion of growth and survival BCRs produce signals required for growth and survival via BTK (Bruton TK) *BTK inhibitors have produced sustained response in many patients

Answer 87

Proliferation centers (pathognomonic): Larger lymphocytes gathered in loose aggregates that contain mitotically active cells Smudge cells: Small round lymphocytes in the peripheral blood with scant cytoplasm, disrupted when making the smear smudge cells are not characteristic of anything (non-specific) lymph node architecture is effaced by small lymphocytes (6-12um) with round or slightly irregular nuclei, condensed chromatin and scant cytoplasm Infiltrates seen in bone marrow, splenic pulp (white + red) and hepatic portal tracts

Answer 88

CD 5, 19, 20, 23 (+) **B cell proliferation that is positive for CD5, think CLL** Low levels of surface Ig (IgM +/ IgD) are also seen When lymph node involvement occurs this becomes known as Small Lymphocytic Lymphoma only difference between CLL and SLL is the degree of peripheral blood lymphocytosis Prolymphocytes are seen in lymph nodes

Answer 89

patients are often asymptomatic at diagnosis Signs and symptoms appear as nonspecific: easy fatigability, weight loss, anorexia, generalized lymphadenopathy, hepatosplenomegaly Variable leukocyte count Leukopenia in SLL with marrow involvement Leukocytosis in CLL with heavy tumor burden Monoclonal Ig "spike" may be present in the blood -- more indicative of multiple myeloma? patients with monoclonal B cells < # than required for diagnosis can have similar genetic defects but only 1% progress to symptomatic disease Median survival 4-6 years, 10 years in patients with decreased tumor burden at diagnosis

Answer 90

Hypogammaglobulinemia = bacterial infection | Neoplastic B cell auto-antibodies = hemolytic anemia or thrombocytopenia

Answer 91

11q, 17p deletions Lack of somatic hypermutation ZAP70 (+): augments immunoglobulin receptor signaling NOTCH1 mutations Richter syndrome: tendency of CLL/SLL to transform to a more aggressive tumor in the form of diffuse large B-cell lymphoma; transformation of CLL/SLL to an aggressive B-cell lymphoma Rapidly enlarging mass within a lymph node or the spleen, likely due to additional acquired mutations large cell transformation is BAD; survival < 1 yea

Answer 92

Gentle chemotherapy Immunotherapy with antibodies to surface proteins (CD20) hematopoietic stem cell transplant is offered to young patients BTK inhibitors

Answer 93

Tumor of lymph nodes that causes obliteration of the lymph node and loss of architecture lymphoma (neoplastic) will efface lymph node architecture; hyperplasia (reactive) won't Most common form of indolent non-Hodgkin's lymphoma in the US

Answer 94

Less common in Europe | Rare in Asian population

Answer 95

Arises from germinal center cells strongly associated with chromosomal translocations involving BCL2 t(14:18) BCL2/Ig heavy chain -- seen in >90% of follicular lymphomas (characteristic translocation of follicular lymphoma) IGH locus on chromosome 14 BCL2 locus on chromosome 18 BCL2 antagonizes apoptosis (promotes cell survival) Overexpression of BCL2 inhibits apoptosis of B cells that fail somatic hypermutation Devoid of apoptotic cells because BCL2 is anti-apoptotic MLL2: histone methyltransferase (epigenetics!); mutated in >90% of follicular lymphomas Neoplastic cells grown in lymph nodes in a network of reactive follicular dendritic cells, macrophages and T cells and their microenvironment determines treatment response

Answer 96

Follicular (nodular) and diffuse proliferation of centrocytes (predominant) and centroblasts Lymphocytosis in 10%, makes it more aggressive Para-trabecular lymphoid aggregates in bone marrow (also seen in splenic white pulp and hepatic portal triads

Answer 97

Small cells with irregular or cleaved nuclear contours | Scant cytoplasm

Answer 98

Large cells with open nuclear chromatin Several nucleoli Modest amounts of cytoplasm

Answer 99

``` CD 10, 19, 20 (+) CD5 (-) BCL6 (+) -- anti-apoptotic BCL2 (+) normal follicular cells are normally devoid of this marker Surface Ig (+) ```

Answer 100

Presents in middle age as painless, generalized lymphadenopathy Extra-nodal site involvement is uncommon Incurable with waxing-waning course; survival is 7-9 years not improved by aggressive therapy palliate the patient with low dose chemotherapy or immunotherapy (anti-CD20 antibody) Transformation in 30-50% to diffuse large B-cell Lymphoma (usually) or Burkitt Lymphoma

Answer 101

Most common form of non-Hodgkin's lymphoma | Median age: 60 years old (may also occur in young adults and children

Answer 102

3q27 mutation (translocation or acquired) involving BCL6 BCL6 is required for formation of normal germinal centers -- dysregulation of BCL6 == DLBCL Overexpression of BCL6 inhibits germinal center B-cell differentiation, growth arrest and apoptosis Other potential mutations t(14;18) involving BCL2 (anti-apoptotic) tumors with BCL2 rearrangements usually lack BCL6 rearrangements this translocation is characteristic/pathognomonic for follicular lymphoma MYC mutation myc dysregulation == Burkitt Lymphoma Histone acetyltransferase mutations (p300, CREBP) large, destructive masses; extranodal involvement this is a mature B cell neoplasm

Answer 103

Large cells (4-5X > normal lymphocytes) Diffuse pattern of growth Substantial morphologic variation Commonly has a round-oval nucleus (vesicular in appearance) Multiple (2-3) nucleoli (or single and centrally placed) Cytoplasm: moderately abundant and pale or basophilic More anaplastic tumors may contain multinucleated cells with inclusion-like nucleoli

Answer 104

CD 19, 20 (+) Variable expression of CD10 and BCL6 Most have surface immunoglobulin

Answer 105

Rapidly enlarging mass at nodal or extranodal site May arise anywhere in the body commonly Waldeyer ring (oropharyngeal lymphoid tissue including the tonsils and adenoids) DLBCL == Waldeyer ring Liver and spleen involvement leads to destructive masses Extranodal is common: GI, skin, bone, brain Bone marrow involvement is rare (late course

Answer 106

aggressive tumors that are rapidly fatal without treatment Treated: 60-80% complete remission, 40-50% cured Adjuvant treatment with anti-CD20 antibody --> improved initial response and improved outcomes Limited disease has better outcome than widespread disease or those with bulky tumor masses Inhibition of NFκB and B cell receptor pathways is beneficial MYC translocations have worse outcome and may be best treated similar to Burkitt lymphoma myc dyregulation == Burkitt Lymphoma

Answer 107

Occurs with severe T-cell immunodeficiency (HIV or allogenic bone marrow transplant) EBV infection of neoplastic B cells May regress with restoration of T cell immunity

Answer 108

Malignant pleural or ascitic effusion Most common in patients with advanced HIV or who are elderly Tumor cells infected with KSHV/HHV8 which appears to have a causal role -- always associated with Kaposi's Anaplastic tumor cells that do not express B or T cell markers Possess clonal immunoglobulin heavy chain gene rearrangements

Answer 109

Burkitt Lymphoma == "Burkitt is Burk-EIGHT" [t(8;14)] Definition Most commonly affect kids and young adults Highly associated with MYC translocations on chromosome 8 that leads to high MYC protein levels MYC increases genes for aerobic glycolysis (Warburg effect) allowing cells to biosynthesize building blocks for growth and cell division, if glucose and glutamine are available -- this is important Burkitt Lymphoma == dysregulation of c-MYC Three variants: African (endemic), sporadic (nonendemic), HIV associated histologically identical, but different in some clinical, genotypic, and virologic characteristics not ALL Burkitt lymphomas are EBV positive; All African (endemic) Burkitt lymphomas are though aka Diffuse Small Non-Cleaved Lymphoma (Hubbard)

Answer 110

t(8:14) MYC/Ig heavy chain May also be t(2:8) or t(8:22) for the light chains chromosome 2 == kappa chromosome 22 == lambda chromosome 8 == MYC chromosome 14 == IgH Induced by AID in germinal center B cells MYC overexpression, increased activity Fastest growing human tumor -- doubles in size every 36 hours Infection with EBV precedes transformation

Answer 111

Diffuse infiltrate of intermediate sized lymphoid cells Round/oval nuclei, coarse chromatin, several nucleoli, moderate amount of cytoplasm High mitotic index Numerous apoptotic B cells -- tingible body macrophage "Starry sky" pattern due to phagocytosis of nuclear remnants by macrophages If bone marrow is involved, tumor cells exhibit clumped nuclear chromatin, 2-5 nucleoli and royal blue cytoplasm with clear cytoplasmic vacuoles

Answer 112

``` CD 10, 19, 20 (+) BCL6 (+) Surface IgM (+) BCL2 (-) MYC (+) -- Burkitt Lymphoma is dysregulation of c-MYC ```

Answer 113

30% of childhood non-Hodgkin's lymphoma in the USA Aggressive lymphoma Responds well to chemotherapy Children and young adults are usually cured Older adults have more guarded outcome

Answer 114

Burkitt Lymphoma: Sporadic (nonendemic) t(8:14) Breakpoint on IgH locus is in the class switch region 15-20% of patients are latently infected with EBV Mass of ileocecum and peritoneum -- just GI

Answer 115

Burkitt Lymphoma: African (endemic) t(8:14) Breakpoint on IgH locus is in the 5' V(D)J sequence All patients are latently infected with EBV Mass of mandible/face and/or abdominal viscera (kidneys, ovaries, adrenals) Bone marrow or peripheral blood involvement is rare

Answer 116

t(8;14) 25% of patients are latently infected with EBV

Answer 117

Most common plasma cell dyscrasia == Monoclonal Gammopathy of Uncertain Significance (MGUS) most common plasma cell malignancy == multiple myeloma Cells secrete monoclonal Ig (serve as tumor markers) Will commonly see plasma cell clusters, they don’t normally present in clusters M component: a monoclonal Ig in the blood Restricted to plasma due to high molecular weight not seen in urine unless glomerular damage has occurred neoplastic plasma cells often synthesize excess light chains along with complete immunoglobulins light chains are small in size and excreted in the urine (Bence-Jones proteins) One light chain is increased others are low 15% of deaths due to lymphoid neoplasms

Answer 118

Monocolonal gammopathy Heavy chain disease == rare monoclonal gammopathy that is seen in association with a diverse group of disorders including lymphoplasmacytic lymphoma and an unusual small bowel marginal zone lymphoma that occurs in malnourished populations (so-called Mediterranean lymphoma) common feature == synthesis and secretion of free heavy chain fragments

Answer 119

Multiple Myeloma (plasma cell myeloma) == the most common plasma cell neoplasm Definition causes bony destruction of the skeleton and often presents with pain due to pathologic fractures Plasma cell neoplasm that commonly causes tumorous masses throughout the skeletal system “moth eaten” lytic bone lesions, hypercalcemia, renal failure, and acquired immune problems

Answer 120

Male African descent Peak incidence: 65-70 years old -- disease of older adults

Answer 121

Solitary myeloma: single mass in bone or soft tissue Smoldering myeloma: lack of signs and symptoms with high plasma M component does not exhibit lytic bone lesions

Answer 122

``` athogenesis Frequent IgH (heavy chain) rearrangements Translocated with cyclin D1 and D3: good prognosis Poorer prognosis Deletion of chromosome 13q Deletion of chromosome 17p (TP53) t(4;14) MYC acquisition NFκB promoting B-cell survival high levels of IL-6 ```

Answer 123

Growth and survival IL-6 is important for growth of plasma cells, produced by neoplastic plasma cells and resident marrow stromal cells (higher levels = poor prognosis) Bone destruction is mediated by factors produced by neoplastic cells MIP1α upregulates NFκB ligand (RANKL) activating osteoclasts Osteoblasts are inhibited via Wnt pathway increased bone resorption → hypercalcemia and pathologic fractures

Answer 124

Destructive plasma cell tumors (plasmacytomas) involving the axial skeleton Vertebral column, ribs, skull, pelvis, femur, clavicle, scapula Appear as 1-4cm punched-out defects radiographically Soft, gelatinous, red tumor masses Can also present as widespread myelomatous bone disease that causes diffuse demineralization (osteopenia) instead of focal defects (i.e. pathologic fractures

Answer 125

Increased number of plasma cells in the marrow with perinuclear clearing due to large Golgi apparatus and odd placed nucleus Rouleaux formation: high level of M proteins causes RBCs in blood smears to stick together linearly characteristic/indicative but not specific -- seen whenever immunoglobulin levels are elevated Flame cells: intracellular accumulation of degraded protein with fiery red cytoplasm Mott cells: multiple grapelike cytoplasmic droplets Cells containing inclusions of fibrils, crystalline rods and globules Globular inclusions: Russell bodies (cytoplasmic) or Dutcher bodies (nuclear) Dutch == nuclear families

Answer 126

CD138 (+) (aka syndecan-1) | May be CD56 (+)

Answer 127

Effects of plasma cell growth in tissues (bones) Production of excess immunoglobulin Suppression of normal humoral immunity

Answer 128

Pathologic fracture and chronic pain due to resorption Hypercalcemia --> Neurologic signs and symptoms (confusion, weakness, lethargy) stones, bones, groans, and psychiatric moans + shortened QT Renal failure (second biggest cause of death after infections) myeloma kidney Acquired immune abnormalities Recurrent bacterial infection (most common cause of death) Cellular immunity is unaffected

Answer 129

Excreted light chains are toxic to renal tubular epithelial cells --> myeloma kidney --> renal failure/insufficiency (second most common cause of death in multiple myeloma, after infection) Some (λ3, λ6) may be prone to amyloidosis of the AL type primary or immunocyte-associated amyloidosis results from a monoclonal proliferation of plasma cells secreting light chains (usually of the λ isotype) that are deposited as amyloid Increased immunoglobulins (especially IgG) and/or light chains in the plasma & urine most multiple myelomas are IgG with kappa light chains - ??? Monoclonal immunoglobulins M proteins: IgG (55%), IgA (25%) Excessive production and aggregation of M proteins, especially IgA or IgG3 --> hyperviscosity Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma

Answer 130

Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma

Answer 131

Diagnosis requires bone marrow examination | Marrow involvement often gives rise to a normocytic, normochromic anemia +/- moderate leukopenia and thrombocytopenia

Answer 132

survival is 4-7 years; no cure Proteasome inhibitors: Degrade unwanted proteins (cells are prone to accumulation of misfolded, unpaired immunoglobulin chains). Induce cell death and retard bone resorption (through stromal cells) also thalidomide Bisphosphonates inhibit bone resorption; reduce the amount of pathologic fractures but can exacerbate renal complications of disease; ensure patient is adequately hydrated; follow creatinine HSC transplant prolongs life but is not curative

Answer 133

Solitary lesion of bone or soft tissue Bone lesion in same locations as multiple myeloma → multiple myeloma in 10-20 years even if it is resected solitary osseous plasmacytoma almost inevitably progresses to multiple myeloma extraosseous lesions in lungs, oronasopharynx or nasal sinuses → cured by local resection Modest increase in M proteins in blood or urine

Answer 134

Middle ground between multiple myeloma and Monoclonal Gammopathy of Uncertain Significance (MGUS) Plasma cells are 10-30% of marrow cellularity Elevated serum M protein > 3gm/dl (same level as in multiple myeloma, but no signs and symptoms) patients are asymptomatic 75% progress (unpredictably) to multiple myeloma in 15 years

Answer 135

Most common plasma cell disorder/dyscrasia most common plasma cell neoplasm/malignancy == multiple myeloma 3% of people > 50 5% of people > 70 Asymptomatic patients with small to moderately large M components in their blood (< 3g/dl) low but constant rate of transformation to symptomatic monoclonal gammopathies most often multiple myeloma 1% of patients progress to symptomatic plasma cell neoplasm every year May be a precursor to multiple myeloma as many of the same chromosomal aberrations are present (unpredictable) monitor Bence-Jones Proteinuria and serum levels of M component to trend and predict transformation

Answer 136

Elevated m component Symptoms

Answer 137

Elevated m component | No sym[toms

Answer 138

No m component No symptoms

Answer 139

Definition B-cell neoplasm of older adults (6-7th decade) Substantial fraction of the tumor cells undergo terminal differentiation to plasma cells how it differs from CLL/SLL Can cause hyperviscosity (Waldenström macroglobulinemia) Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma Rarely does damage from secretion of light chains or bone destruction occur

Answer 140

Acquired MYD88 mutation Normally codes a protein that activates NFκB and augments signals downstream of the B-cell receptor (Ig) complex (aka it promotes the growth and survival of tumor cells

Answer 141

Marrow infiltrate of lymphocytes, plasma cells and plasmacytoid lymphocytes Mast cell hyperplasia Russell bodies: PAS (+) inclusions with Ig in the cytoplasm Dutcher bodies: PAS (+) inclusions with Ig in the nucleus Dutch == nuclear families Dutcher and Russell bodies only seen in plasma cell dyscrasias At diagnosis: tumor spread to lymph nodes, spleen and liver Nerve Roots, meninges and brain may be affected with progression

Answer 142

CD20 (+) Surface Ig (+) Plasma cells will secrete the same Ig that is expressed on the surface of the lymphoid cells Usually IgM (may be IgG or IgA)

Answer 143

Nonspecific signs and symptoms: weakness, fatigue, weight loss lymphadenopathy and hepatosplenomegaly in 50% 10% have autoimmune hemolysis due to cold agglutinins (IgM binding RBCs at T < 37°C) No bone lesions

Answer 144

Waldenström macroglobulinemia == a syndrome in which high levels of IgM lead to symptoms related to hyperviscosity of the blood; occurs in older adults; associated with lymphoplasmacytic lymphoma IgM secreting tumors cause a hyperviscosity syndrome retinopathy neuro symptoms: HA to seizures and coma spontaneous bleeding Plasmapheresis alleviates signs and symptoms of increased IgM Visual impairment due to venous congestion Retinal vein tortuosity and distention +/- retinal hemorrhage and exudates Neurological problems due to sluggish blood flow: headache, dizziness, deafness, and stupor Bleeding due to macroglobulin-clotting factor complex formation and effects on platelet function Cryoglobulinemia due to precipitation of macroglobulins at low Temperature == Raynaud phenomena and cold urticaria cold agglutinin antibodies (IgM

Answer 145

Incurable, progressive disease that rarely progresses to large cell lymphoma Low dose chemotherapy and immunotherapy (antiCD20) may control tumor growth for a period of time Median survival of 4 years

Answer 146

Uncommon non-Hodgkin's lymphoma | tumor cells closely resemble the normal mantle zone B cells that surround germinal centers

Answer 147

Presents in 5-6th decade | male predominance

Answer 148

t(11:14) cyclin D1/IgH --> overexpression of cyclin D1 promotes G1 to S phase progression IgH genes lack somatic hypermutation (== naïve B cell origin

Answer 149

Generalized painless lymphadenopathy, +/- peripheral blood involvement Extranodal sites: bone marrow, spleen, liver, gut Lymphomatoid polyposis: if mucosal involvement of the small bowel or colon → polyps (can be misdiagnosed as ulcerative colitis) mantle cell lymphoma frequently presents in the GIT

Answer 150

Nodular appearance or diffusely efface the lymph node Homogenous population of small lymphocytes with irregular/clefted (cleaved) nuclei Condensed nuclear chromatin, inconspicuous nucleoli and scant cytoplasm No centroblasts or proliferation centers (distinguished from CLL/SLL) Requires immunophenotyping to distinguish blastoid variants from ALL Can look like follicular lymphoma Follicular lymphoma don’t have a germinal center Mantel cell lymphoma will have a germinal center

Answer 151

Immunophenotype Increased cyclin D1 CD 5, 19, 20 (+) CD 23 (-) == distinguished from CLL/SLL Elevated levels of surface Ig (usually IgM and IgD with κ or λ light chain) IgH lacks somatic hypermutation (origin = naive B cell)

Answer 152

Painless lymphadenopathy Spleen and gut involvement are common -- mantle cell lymphoma frequently presents in the GIT Poor prognosis Median survival: 3-4 years COD: organ dysfunction due to lack of effective chemo and tumor infiltration Blastoid variant and "proliferative" expression --> decreased survival

Answer 153

Chemo is not helpful | HSC and proteasome inhibitors are now being used with potential

Answer 154

Heterogenous group of B-cell tumors in lymph nodes, spleen, or extranodal tissue Tumor cells show evidence of somatic hypermutation (== memory B-cell origin) marginal zone lymphoma and hairy cell leukemia are memory B-cell origin Often referred to as MALTomas

Answer 155

Arise in tissues affected by chronic inflammation (autoimmune or infectious) i.e. Sjogren's (salivary glands), Hashimotos (thyroid) and stomach (H. Pylori) Remain localized for long periods of time, but may spread late in their course May regress if the inciting agent (i.e. Helicobacter) is eliminated -- cure cancer with antibiotics! Lies on a spectrum of reactive lymphoid hyperplasia and full-blown lymphoma

Answer 156

Initially: polyclonal immune reaction that acquires mutations → B-cell clone that depends on Ag stimulated Th cells (eventually becomes monoclonal) Withdrawal at this stage = involution of tumor Additional mutations acquired over time renders growth and survival to be Ag independent t(11:18), t(14:18) or t(1:14) which leads to activation of NFκB and promotes cell growth/survival t(11:18), t(14:18) or t(1:14) are specific for extranodal marginal zone lymphomas (MALTomas) upregulate the expression and function of BCL10 or MALT1 --> NFκB --> growth and survival Further evolution = metastasis and transformation to large B-cell lymphoma

Answer 157

Rare B-cell neoplasm that has hair-like projections coming out of the leukemic cells -- hence, "hairy cell" marginal zone lymphoma and hairy cell leukemia are memory B-cell origin Patients at risk Middle age (55), white males (males 5:1) Pathogenesis BRAF (serine/threonine kinase) activating mutation (valine → glutamate) BRAF is positioned immediately downstream of RAS in the MAPK signaling cascade

Answer 158

Leukemic cells have fine, hair-like projections Round, oblong or reniform (kidney shaped) nuclei Moderate amounts of pale blue cytoplasm with bleb-like extensions "Dry tap" because tumor cells are trapped in the ECM Only seen on marrow biopsy Heavily infiltrated splenic red pulp = obliteration of white pulp with a beefy red gross appearance Hepatic portal triads may be involved

Answer 159

CD 11c, 19, 20, 25, 103 (+) annexin A1 (+) Surface Ig (IgG) +ve tartrate-resistant acid phosphatase (TRAP) +ve

Answer 160

Massive splenomegaly (hepatomegaly and lymphadenopathy are rare) many patients will present with splenomegaly (dragging sensation in the LUQ) Pancytopenia (from marrow involvement and splenic sequestration (hypersplenism) 1/3 have infection (often atypical mycobacterial) increased susceptibility to mycobacterium kansasii Exceptionally sensitive to gentle chemotherapy = long lasting remission Relapse in 5 years but respond well to re-treatment with the same agents BRAF inhibitors = excellent tumor response in patients who fail chemotherapy Excellent prognosis

Answer 161

Hairy cell leukemia is trap positive

Answer 162

Derived from mature T cells so it has T-cell markers | diagnosis of exclusion

Answer 163

CD2+, CD3+, and CD5+ some may be CD4+ or CD8+ either αβ or γδ TCRs requires immunophenotyping

Answer 164

Tumors efface lymph nodes diffusely Pleomorphic mix of variably sized malignant T-cells Prominent infiltrate of reactive cells (eosinophils, macrophages) attracted by tumor cytokines Neoangiogenesis may be seen

Answer 165

Present with general lymphadenopathy +/- pruritus, eosinophilia, fever, weight loss Cure is rare, worse prognosis than comparably aggressive B cell neoplasms

Answer 166

T-cell lymphoma with good prognosis

Answer 167

ALK rearrangement on chromosome 2p23 --> break the ALK locus and lead to formation of chimeric genes encoding ALK fusion proteins, constitutive active tyrosine kinases that trigger RAS and JAK/STAT pathways ALK is not expressed in normal lymphocytes therefore the detection of ALK in tumor cells is a reliable indicator of an ALK gene rearrangement -- presence of ALK is pathognomonic

Answer 168

CD30 positive | CD8 cell is anaplastic

Answer 169

Large anaplastic cells with horseshoe nuclei and voluminous cytoplasm ("hallmark cells") Tumor cells surround venules, infiltrating lymphoid sinuses (mimic metastatic carcinoma

Answer 170

More common in children and young adults Involve soft tissue == very good prognosis Chemotherapeutic cure = 75-80% ALK (-) tumors in older adults have a worse prognosis Recombinant anti CD30 antibodies have produced promising responses in patients

Answer 171

Neoplasm of CD4+ T-cells patients are infected with HTLV-1 Common in Japan, West Africa and the Caribbean

Answer 172

Virus produces Tax protein that activates NFκB

Answer 173

Morphology | Cells have multi-lobulated nuclei ("cloverleaf" or "flower" cells) and contain clonal HTLV1 proteins

Answer 174

Skin lesions, general lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia HTLV-1 can also cause a progressive demyelinating disease of the CNS and spinal cord

Answer 175

Rapidly progressive disease, fatal in months to 1 year despite aggressive chemotherapy If only skin is involved (rare), disease has a more indolent course

Answer 176

Tumor of CD4+ helper T-cells that homes to the skin Cutaneous lesions progress through three phases: premycotic, plaque, and tumor Epidermis and upper dermis are infiltrated by neoplastic T cells with a cerebriform appearance due to nuclear membrane infolding Late disease progresses extracutaneously, commonly to lymph nodes and bone marrow Mycosis fungoides (with no relationship to fungi) is one form of cutaneous T-cell lymphoma. The abnormal CD4 cell proliferation is infiltrating the skin and producing erythroderma. If these neoplastic cells circulate, it is known as Sezary syndrome

Answer 177

Tumor of CD4+ helper T-cells that homes to the skin Rarely progresses to tumefaction Generalized exfoliative erythroderma Associated leukemia of cells with characteristic cerebriform nuclei

Answer 178

CLA (+) *cutaneous leukocyte antigen CCR4 and CCR10 (+) -- chemokine receptors Homes to skin Tumor cells circulate through the blood, bone marrow, and lymph nodes Indolent tumors Median survival of 8-9 years Occasionally transforms to aggressive T-cell lymphoma (terminal event)

Answer 179

T-cells variant (indolent): CD3 (+) | NK cells variant (subtler, common, aggressive): CD56 (

Answer 180

STAT3 mutation Large lymphocytes with abundant blue cytoplasm and azurophilic granules Sparse lymphocytic infiltrates in the marrow, spleen and liver

Answer 181

Clinical Neutropenia and anemia dominate the clinical picture (despite low marrow involvement) neutropenia --> striking decrease in late myeloid forms in the marrow Mild-moderate lymphocytosis and splenomegaly of adults No lymphadenopathy or hepatomegaly Increased incidence of rheumatoid disorders -- autoimmunity provoked by the tumor seems likely Variable course based on cytopenias and their response to low dose chemo or steroids

Answer 182

Felty Syndrome == rheumatoid arthritis + Splenomegaly + Neutropenia *associated with large granular lymphocytic leukemia as an underlying cause

Answer 183

Extranodal NK/T-cell Lymphoma (nee lethal midline granuloma disorder) Definition Destructive nasopharyngeal mass extra-nodal == extra-nosal May also be seen in the testis and skin Surrounds and invades small vessels = ischemic necrosis More common in Asia Tumor originates from a single *EBV-infected cell

Answer 184

Large azurophilic granules in tumor cell cytoplasm | small to large pyknotic cells cuffing and invading small vessels with ischemic necrosis

Answer 185

``` No CD21 (B-cell EBV receptor) implication is that EBV has other receptors associated with it that are not CD21 No CD3 No TCR rearrangements Express NK cell markers ```

Answer 186

Highly aggressive; respond well to radiation; resistant to chemotherapy Poor prognosis in patients with advanced disease

Answer 187

Often localized to a single, axial group of lymph nodes (cervical, mediastinal, para-aortic, axillary, groin) Hodgkin Lymphoma arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissues Mesenteric lymph nodes and Waldeyer ring rarely involved Extranodal presentation is rare Presence of Reed-Sternberg cells: transformed B cells **fever!**

Answer 188

non-Hodgkin Lymphoma vs Hodgkin Lymphoma non-Hodgkin Lymphoma has: Frequent involvement of multiple peripheral lymph nodes Noncontiguous spread (not predictable) Waldeyer ring and mesenteric lymph nodes commonly involved Extranodal presentation common

Answer 189

efinition average age: 32 treated with radiation and chemotherapy, curable in most cases Need to see Reed-Sternberg cells on a background of non-neoplastic inflammatory cells

Answer 190

``` Nodular sclerosis (classic) Mixed cellularity (classic) Lymphocyte rich (classic) Lymphocyte depleted (classic) Lymphocyte predominance: Reed-Sternberg cells have distinctive B-cell immunophenotype ```

Answer 191

Classical: frequently associated with acquired mutations that activate NFκB and with EBV infection Lymphocyte Predominant: express B-cell markers and is not associated with EBV infection

Answer 192

Di agnosis: | depends on the identification of Reed-Sternberg cells in a background of non-neoplastic inflammatory cells

Answer 193

Pathogenesis Ig genes have undergone V(D)J recombination and somatic hypermutation, but fail to be expressed NFκB activation

Answer 194

``` EBV infection (or other mechanism promoting lymphocyte survival and proliferation) EBV+ cells have LMP1 = upregulation of NFκB Acquired loss-of-function mutations in IκB or A20 (both negative regulators of NFκB) Rescue of "crippled" germinal centers by EBV creates an environment of acquisition of other mutations --> Reed-Sternberg cells ```

Answer 195

Reed-Sternberg Cells == "Owl-Eyed Nuclei" Definition Derived from germinal center or post-germinal center B-cells Reed-Sternberg cells are transformed B cells despite having the genetic signature of a B-cell, the Reed-Sternberg cells of classical Hodgkin Lymphoma fail to express most B-cell specific genes, including the immunoglobulin genes Release factors (cytokines, chemokines, etc.) inducing accumulation of reactive lymphocytes, macrophages, and granulocytes (> 90% of tumor cells)

Answer 196

Large, aneuploid B cells with multiple nuclei or a single nucleus with multiple lobes and inclusion-like nucleolus == Owl-Eyed Nuclei Clearing around the nucleoli; abundant cytoplasm is seen background lymphocytes will be reactive Immunophenotype REL protooncogene (chromosome 2p) often gained that increase NFκB CD15, CD30, and CD40 positivity (activated via eosinophils and T-cells) Immunoglobulin (-)

Answer 197

Contain a single round or oblong nucleus with large inclusion like-nucleolus

Answer 198

Seen in nodular sclerosis subtype Delicate, folded or multilobate nuclei Abundant pale cytoplasm that retracts during tissue processing = nucleus in an empty hole (a lacuna) Seen in the nodular sclerosis type of Hodgkin Lymphoma

Answer 199

Mummification: the process by which the Reed-Sternberg cells die The cells shrink and become pyknotic

Answer 200

``` Lymphohistiocytic Variants (L&H cells) Polypoid (multilobed) nuclei Inconspicuous nucleoli Moderate cytoplasm "Popcorn cells" Seen in the lymphocyte predominant subtype of Hodgkin Lymphoma Express CD20, BCL6 No CD15 or CD30 ```

Answer 201

Classic Immunophenotype PAX5 positive CD15 and CD30 positive except lymphocyte predominant No other B-cell, T-cell markers, or CD45 (leukocyte common antigen) Hodgkin Lymphoma does not present in extranodal locations

Answer 202

Most common form of Hodgkin Lymphoma (65-70%) Adolescents and young adults Excellent prognosis

Answer 203

Lacunar variant Reed-Sternberg cells that are uncommonly found == lacunar cells Deposition of collagen bands that divide lymph nodes into circumscribed nodules Often involves cervical, supraclavicular and mediastinal lymph nodes No EBV Classic immunophenotype PAX5 positive CD15 and CD30 positive No other B-cell, T-cell markers, or CD45 (leukocyte common antigen

Answer 204

``` Second most common subtype Male predominance Biphasic age distribution Signs and symptoms include night sweats and weight loss Commonly present in advanced tumor stage Prognosis is very good ```

Answer 205

Diagnostic Reed-Sternberg cells and mononuclear variants are plentiful lymph nodes are diffusely effaced 70% of Reed-Sternberg cells are EBV+ Classic immunophenotype PAX5 positive CD15 and CD30 positive No other B-cell, T-cell markers, or CD45 (leukocyte common antigen

Answer 206

Reactive lymphocytes make up the vast majority of the cellular infiltrate Uncommon lymph nodes are diffusely effaced with vague nodularity due to occasional residual B-cell follicles Very good to excellent prognosis

Answer 207

``` Frequent mononuclear variants Diagnostic Reed-Sternberg cells 40% of cases are EBV+ Classic immunophenotype PAX5 positive CD15 and CD30 positive No other B-cell, T-cell markers, or CD45 (leukocyte common antigen ```

Answer 208

Least common form of Hodgkin Lymphoma Elderly, HIV+ individuals, non-industrialized countries Advanced stage and systemic signs and symptoms are frequent Prognosis is less favorable than other subtypes

Answer 209

Scarce lymphocytes Abundant Reed-Sternberg cells or pleomorphic variants EBV+ in 90% of cases Classic immunophenotype PAX5 positive CD15 and CD30 positive No other B-cell, T-cell markers, or CD45 (leukocyte common antigen) Essential to do immunophenotype, as most tumors with lymphocyte depletion are actually large cell non-Hodgkin Lymphoma

Answer 210

Nonclassical Hodgkin Lymphoma subtype Male < 35 years have cervical or axillary lymphadenopathy Excellent prognosis, even though it is more likely to recur as compared to the other subtypes lymph nodes are effaced with a nodular infiltrate of small lymphocytes and macrophages

Answer 211

munophenotype: L&H variants express B-cell markers in contrast to Reed-Sternberg cells from classical forms of Hodgkin Lymphoma Express CD20, BCL6 (unique) CD15 and CD30 negative

Answer 212

Not associated with EBV IgH genes have ongoing somatic hypermutation -- a feature found only in germinal centers 35% transform to diffuse large B-cell lymphoma due to expanded B-cell follicles Classic Reed-Sternberg cells are difficult to find L&H variant cells "popcorn cells" are seen Eosinophils and plasma cells are scant or absent

Answer 213

Typically stage I-II = free of systemic manifestations | 90% cure rate

Answer 214

Stage III-IV → constitutional signs and symptoms 5 year survival 60-70% Anergy (cutaneous immune unresponsive) TH1 suppression due to factors released by Reed-Sternberg cells

Answer 215

Generally presents as painless lymphadenopathy | spread is stereotyped: nodal disease → splenic disease → hepatic disease → marrow and other tissues

Answer 216

Tumor stage (not histology) is most important prognostic factor Low stage 1st cured with involved field radiotherapy: increased risk of radiotherapy induced malignancies (lung cancer, melanoma, breast cancer) 2° tumors reduced by using minimal radiation and less genotoxic chemo without loss of therapeutic efficacy AntiCD30 antibodies produce excellent response in patients failing conventional methods wouldn't work in Lymphocyte Predominant subtype as this is CD30 negative

Answer 217

Hodgkin Lymphoma: Stage I Involvement of a single lymph node region (I) Involvement of a single extra-lymphatic organ or site (IE)

Answer 218

Hodgkin Lymphoma: Stage II Involvement of 2+ lymph node regions on the same side of the diaphragm alone (II) Localized involvement of an extra-lymphatic organ or site (IIE)

Answer 219

Hodgkin Lymphoma: Stage III Involvement of lymph nodes on both sides of the diaphragm without (III) or with (IIIE) localized involvement of an extra-lymphatic organ or site

Answer 220

Hodgkin Lymphoma: Stage IV | Diffuse involvement of one or more extra-lymphatic organs or sites +/- lymphatic involvement

Answer 221

a: accumulation of immature myeloid forms (blasts) in the bone marrow suppresses normal hematopoiesis

Answer 222

D efective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, leading to cytopenias; group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML generally have a poor prognosis

Answer 223

Myeloproliferative disorders: there is usually increased production of one or more types of blood cells

Answer 224

Definition Accumulation of at least 20% or > immature myeloid blasts in the bone marrow due to acquired oncogenic mutations impeding differentiation Causes marrow failure Complications: anemia thrombocytopenia, neutropenia Increased incidence throughout life, peak after 60 years old Diagnosis is confirmed with myeloid specific antigen stains (i.e. MPO) diagnosis of AML is based on the presence of at least 20% myeloid blasts in the bone marrow Two most common chromosomal rearrangements == t(8:21) and inv(16) t(8;21) == RUNX1 disrupted inv(16) == CBFB disrupted RUNX1 and CBFB normally bind one another to form a RUNX1/CBF1β transcription factor that is required for normal hematopoiesis

Answer 225

Genetic aberrations with favorable prognosis t(8:21) == RUNX1 disrupted inv(16) == CBFB disrupted Normal cytogenetics, mutated NPM Genetic aberrations with intermediate prognosis: t(15:17) -- acute promyelocytic leukemia (subtype) Genetic aberrations with poor prognosis: t(11:q23:v)

Answer 226

``` AML with MDS-like features (myelodysplastic syndrome) Prior MDS Multi-lineage dysplasia MDS-like cytogenic aberrations All have poor prognosis ```

Answer 227

AML that is therapy related Post alkylating agent or radiation therapy = 2-8 year latency, MDS-like cytogenic aberrations Post topoisomerase II inhibitor = 1-3 year latency, MLL translocations Very poor prognosis

Answer 228

ass IV All AML's that lack features of the other classes (NOS) Classified based on degree of differentiation and lineage of leukemic blasts Intermediate prognosis

Answer 229

Minimally differentiated AML 2-3% of cases Blasts lack cytologic and cytochemical markers of myeloblasts Express myeloid lineage antigens and ultra-structurally resemble myeloblasts

Answer 230

``` AML without maturation 20% of cases Very immature cells ≥ 3% are MPO (+) Few granules or Auer rods Little maturation past myeloblast stage ```

Answer 231

``` AML with myelocytic maturation M2 == AML M3 == APL (P and 3) M4 = AMML (has four letters) 30-40% of cases Full range of myeloid maturation throughout granulocytes Auer rods present in most cases t(8:21 ```

Answer 232

``` Acute promyelocytic leukemia (APL) M2 == AML M3 == APL (P and 3) M4 = AMML (has four letters) 5-10% of cases Most cells are hypergranular promyelocytes Many Auer rods /cell Patients are younger (35-40 years old) increased incidence of DIC t(15:17) with Flt3 ```

Answer 233

AML: FAB Class M4 AML with MyeloMonocytic maturation (Acute MyeloMonocytic Leukemia (AMML) M2 == AML M3 == APL (P and 3) M4 = AMML (has four letters) 15-20% of cases Myelocytic and monocytic differentiation is evident Myeloid elements with range of maturation MPO positive Monoblasts are positive for non-specific esterase non-specific esterase is non-specific; positivity only tells you that there are monocytes present diagnostic in the setting of AML; non-specific anywhere else Inv(16

Answer 234

AML with monocytic maturation (acute monocytic leukemia) 10% of cases Monoblasts: MPO (-), non-specific esterase positive Promonocytes Older patients High incidence of organomegaly, lymphadenopathy and tissue infiltration

Answer 235

AML with erythroid maturation (acute erythroleukemia) Dysplastic erythroid precursors (megaloblastoid or multiple nuclei) dominate Nonerythroid cells = >30% myeloblasts Elderly patients *20% of therapy related AML

Answer 236

AML with megakaryoblastic maturation (acute megakaryocytic leukemia) Blasts of megakaryocytic lineage predominate Blasts react with platelet specific antibodies (GPiib/iiia or vWF) Myelofibrosis or increased reticulin

Answer 237

Genetic aberrations disrupt genes encoding transcription factors required for normal myeloid differentiation t(8:21) RUNX1, inv(16) CBFB which lead to blocking of myeloid cell maturation Mutations activating GF signaling pathways t(15:17) → PML-RARα fusion protein interferes with terminal differentiation of granulocytes treatment: all-trans retinoic acid or arsenic trioxide (chapter 7) t(15;17) == acute promyelocytic leukemia subtype of AML may exhibit early, significant, life-threatening bleeding DIC, once established, is often fatal also have frequent activating mutations of FLT3 mutation (receptor tyrosine kinase) Epigenetic alterations: DNA methylation and posttranslational modification of histones is altered

Answer 238

Diagnosis is made by > 20% myeloid blasts in the bone marrow Myeloblasts Monoblasts Megakaryoblast Erythroblast *blasts may be entirely absent from the blood (aleukemic leukemia), hence a bone marrow examination is essential (especially in pancytopenic patients

Answer 239

Delicate nuclear chromatin 2-4 nucleoli Voluminous cytoplasm (more than lymphoblasts) Peroxidase (+) azurophilic granules Auer rods: distinctive needle like azurophilic granules particularly numerous in AML with the t(15:17) (acute promyelocytic leukemia) Auer rods are formed of the cytoplasmic granules of the myeloid blasts of acute myelogenous leukemia (AML) and are a typical finding with AML. Myelodysplastic syndromes can precede development of AML, as can some cases of myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, and chemotherapeutic regimens

Answer 240

``` onoblast morphology Folded or lobulated nuclei Lack Auer rods Nonspecific esterase (+) Peroxidase (-) ```

Answer 241

Younger adults: Balanced translocations t(8:21), inv(16), and t(15:17) Following MDS or chemo or radiation: Deletions or monosomy of chromosome 5 or 7 with a lack of translocations Following topoisomerase II inhibitors: MLL translocation chromosome 11q23 Older adults: Worse aberrations (deletion of 5q, 7q)

Answer 242

Signs and symptoms very similar to ALL Anemia, fatigue, neutropenia. Fever due to opportunistic infections of oral cavity, skin, lungs, kidneys, bladder, colon (fungi, Pseudomonas, commensals) Thrombocytopenia = spontaneous mucosal and cutaneous bleeding (gingiva, urinary tract); cutaneous petechiae and ecchymoses; exacerbated by procoagulants and fibrinolytics released by leukemic cells (especially in AML with the t(15;17

Answer 243

Signs and symptoms due to involvement of tissues other than bone marrow is less striking than in ALL CNS involvement is less common Often infiltrate the skin (leukemic cutis) and gingiva May present as a localized soft-tissue mass (myeloblastoma, granulocytic sarcoma/chloroma) Without systemic treatment these will progress to full-blown disease

Answer 244

60% remission with chemotherapy 5 years: 70-85% relapse Molecular subtype targeted therapy improves outcomes 80% of t(15:17) are cured with all-trans retinoic acid and arsenic salts t(8:21), inv(16) without KIT mutation = good prognosis with chemotherapy AMLs that follow MDS or genotoxic therapy, in older adults, or returned AML = dismal prognosis HSC transplant is performed with these "high-risk" disease

Answer 245

MDS generally have a poor prognosis

Answer 246

Clonal stem cell disorders with maturation defects associated with ineffective hematopoiesis Increased risk of transformation to AML Bone marrow is partly or wholly replaced by clonal progeny of a neoplastic multipotent stem cell with the capacity to differentiate (but does so ineffectively) Peripheral blood *pancytopenias occur primary MDS == idiopathic t-MDS == secondary to previous genotoxic drug or radiation therapy (iatrogenic?) More severe Typically, older adults myelodysplasias are characterized by thrombocytopenia

Answer 247

May be primary or secondary to genotoxic drug or radiation (t-MDS) and appears 2-8 years after exposure Transformation to AML occurs most rapidly and most frequently in t-MDS

Answer 248

Mutations of epigenetic factors regulating DNA methylation and histone modifications Mutations of RNA splicing factors involving the 3' end of the RNA splicing machinery Mutation of transcription factors for normal myelopoiesis 10% have TP53 loss-of-function mutations (poor outcome) Monosomies 5 and 7; deletions of 5q, 7q, 20q; trisomy 8 MYC gene is on chromosome 8

Answer 249

Hypercellular marrow is common, but can also be normal or hypocellular Disordered differentiation of erythroid, granulocytic, monocytic and megakaryocytic lineages to varying degrees is the most characteristic finding

Answer 250

Ring sideroblasts: erythroblasts with iron-laden mitochondria visible as perinuclear granules seen with Prussian blue stain of aspirates or biopsies Megaloblastoid maturation similar to B12 and folate deficiencies Nuclear budding problems = misshapen nuclei (often with polypoid outlines

Answer 251

Neutrophils with decreased numbers of secondary granules, toxic granulations or Dohle bodies Pseudo-Pelger-Hüet cells: Neutrophils with only two nuclear lobes Hüet == Duet Neutrophils lacking nuclear segmentation Myeloblasts may be increased but account for < 20% of the overall marrow cellularity recall: AML is when myeloblasts account for at least 20% of the marrow aspirate

Answer 252

Cells with single nuclear lobes or multiple separate nuclei ('pawn ball') are characteristic

Answer 253

Average age: 70 years 50% discovered incidentally on routine blood tests Survive 9-29 months (up to 5+ years) Signs and symptoms of weakness, infection, hemorrhage (due to pancytopenia) Worse outcomes: higher blast counts, more severe cytopenias, multiple clonal chromosomal abnormalities 10-40% progress to AML (high rate of transformation to AML is in the definition) cause of death: thrombocytopenia (bleeding) and neutropenia (infection

Answer 254

Appears 2-8 years after treatment with genotoxic agents Median survival of 4.8 months -- terrible prognosis Cytopenias are severe Progression to AML is rapid

Answer 255

HSC transplant in young patients Older patients receive antibiotics and transfusions Thalidomide-like drugs and DNA methylation inhibitors Improve effectiveness of hematopoiesis and peripheral blood counts in some patients

Answer 256

Mutated, constitutively active tyrosine kinases or other aberrations in signaling pathways → growth factor independence so there are lots of cells tyrosine kinase inhibitors are a big deal here (e.g. Gleevec!) Do not impair differentiation Increased production of one or more mature blood elements -- high counts of everything (pancytosis) Originate in multipotent myeloid progenitors Paradoxically, there is bleeding because the platelets are functionally abnormal, even though there are lots of them

Answer 257

Increased proliferative drive in the bone marrow -- tend to have thrombocytosis Displace normal bone and suppress hematopoiesis Homing of neoplastic stem cells to secondary hematopoietic organs → extramedullary hematopoiesis (liver) Variable transformation to a spent phase with marrow fibrosis and peripheral blood cytopenias Variable transformation to acute leukemia

Answer 258

Can either turn into AML (from the common myeloid progenitor) or go into a spent phase A few will turn into an ALL and they have a terrible prognosis, even worse than if they turn into an AML

Answer 259

Chimeric BCR-ABL gene driven by t(9:22), Philadelphia chromosome Constitutive BCR-ABL tyrosine kinase activation driving growth factor independent proliferation and survival of bone marrow progenitors Does not interfere with differentiation Originates from pluripotent hematopoietic stem cell Preferentially drives proliferation of granulocytic and megakaryocytic progenitors Most common of the myeloproliferative disorders

Answer 260

Hypercellular marrow from increased maturing granulocytic precursors **Basophilia + eosinophilia Increased megakaryocytes (small, dysplastic), increased platelets Erythroid precursors are found at normal levels Sea-blue histiocytes are a characteristic finding Increased reticulin deposition

Answer 261

Scattered macrophages with abundant wrinkled, green-blue cytoplasm Seen in chronic myelogenous leukemia (CML)

Answer 262

Primarily a disease of adults (5-6th decade) with insidious onset Putthoff: male predominance Huge spleen (extramedullary hematopoiesis) +/- infarcts, potential hepatomegaly, and lymphadenopathy patients may present with fatigue, weight loss, anemia, anorexia and hyper-metabolism (increased cell turnover) or LUQ pain due to splenomegaly (dragging sensation) or splenic infarction Much worse prognosis if they don’t have the Philadelphia chromosome Gleevec treats the Philadelphia chromosome

Answer 263

BCR-ABL gene is detected via PCR or chromosome analysis Leukocyte alkaline phosphatase (LAP) is low LAP will be high in reactive states, e.g. infection Blasts are < 10% of circulating cells (has to be less than 20% or else it's an AML

Answer 264

Without treatment patients survive 3 years "accelerated phase" == increased anemia and thrombocytopenia +/- basophilia within 6-12 months, the accelerated phase terminates in a picture resembling acute leukemia (blast crisis) 70% are myeloid in origin, 30% are lymphoid in origin indicating the disease originates from a pluripotent stem cell with both myeloid and lymphoid potential

Answer 265

90% of patients achieve remission with BCR-ABL inhibitors (Gleevec!) Resistance has emerged due to mutations and are treated with 2nd and 3rd generation kinase inhibitors hematopoietic stem cell transplant may be offered to young patients (75% cured) Prognosis is less favorable when accelerated phase or blast crisis supervenes

Answer 266

Polycythemia Vera (PCV) == markedly increased red cell mass Definition Activating point mutation in JAK2 (tyrosine kinase) Greatly increased RBCs (main source of signs and symptoms), slight increase in granulocytes and platelets

Answer 267

Valine → phenylalanine at residue 617 -- feels like a Dobson question JAK2 then acts independently of growth factor two mutated copies: higher WBC counts, more significant splenomegaly, pruritus and greater progression rate of the spent phase Constitutively active JAK2 affects the JAK/STAT signaling pathway, downstream of the hematopoietic growth factor receptors Decreased requirements for EPO (often suppressed

Answer 268

Subtle increase in RBC progenitors with an associated increase in granulocytic precursors and megakaryocytes Hypercellular marrow with residual fat Increased reticulin fibers (10%) Early phase: organomegaly due to congestion, and peripheral blood shows basophilia and large platelets

Answer 269

Late in the course Extensive marrow fibrosis that displaces hematopoietic cells, increased extramedullary hematopoiesis (hepatosplenomegaly) 1% transform to AML

Answer 270

Insidious, uncommon disease of adults Signs and symptoms related to increased RBC mass and hematocrit (hyperviscosity) → abnormal blood flow elevated hematocrit --> increased blood viscosity, + thrombocytosis and abnormal platelet function --> --> patients with PVC are prone to both thrombosis and bleeding Venous circulation becomes congested and distended (patients are "plethoric" in the face (flushed)) pruritus after taking a hot shower Deoxygenated blood remains in peripheral vessels longer → HA, dizziness, HTN, GI signs and symptoms

Answer 271

Increased risk of thrombosis: DVT, hepatic vein (Budd-Chiari), portal vein, dural sinus thrombi Pruritus due to basophil release of histamine, can also cause peptic ulcers Hyperuricemia due to high cell turnover (gout

Answer 272

Increased hemoglobin Greatly increased hematocrit (>60%) Iron deficiency due to chronic bleeding can suppress EPO, which decreases hematocrit to the normal range Increased WBC (leukocytosis) increased platelet count with morphologic abnormalities (giant with defective aggregation

Answer 273

Untreated = death within months -- not good Phlebotomy, maintaining normal RBC mass extends survival to 10+ years Evolves to a spent phase after this 2% transform to AML lacking JAK2 mutations Disease is likely due to a progenitor mutation committed to myeloid differentiation ALL transformation is rare (different from CML)

Answer 274

15-20% of patients transition around 10 years into their disease (less common than other MPD) Obliterative fibrosis of marrow (myelofibrosis) Extensive medullary hematopoiesis (*spleen) Massive splenomegaly

Answer 275

Elevated platelet counts without polycythemia or marrow fibrosis Increased megakaryocytes Mild leukocytosis Diagnosis of exclusion

Answer 276

mportant mutations Activating JAK2 mutation (50%) MPL (5-10%) [receptor tyrosine kinase normally activated by thrombopoietin] Calreticulin

Answer 277

Adults > 60 (signs and symptoms may resemble PCV) Extramedullary hematopoiesis → organomegaly Thrombosis and hemorrhage due to platelet dysfunction and increased number DVT, portal and hepatic vein thrombosis, myocardial infarct Thrombosis in patients with increased platelet counts and homozygous JAK2 mutations Erythromelalgia: occlusion of small arterioles by platelet aggregates → burning and throbbing of hands and feet (may also be seen in PVC, peripheral neuropathy, peripheral vascular deficiency) this is a non-specific finding

Answer 278

Insidious: long asymptomatic phase with occasional thrombotic or hemorrhagic crises Survival: 12-15 years

Answer 279

Treatment: gentle chemotherapy to suppress thrombopoiesis

Answer 280

Development of obliterative marrow fibrosis due to non-neoplastic fibroblasts Decreased bone marrow hematopoiesis → cytopenias and extramedullary hematopoiesis Appears identical to the spent phase of other myeloproliferative disorders Least common of the MPDs chief pathologic feature == extensive deposition of collagen in the marrow by non-neoplastic fibroblasts

Answer 281

Activating JAK2 or MPL mutations (also calreticulin

Answer 282

Extensive deposition of collagen in the marrow by non-neoplastic fibroblasts Displaces normal cells = marrow failure Inappropriately released megakaryocyte factors: PDGF and TGFβ -- both cause fibrosis and scarring ^^ bother are fibroblast mitogens Extramedullary hematopoiesis takes over in spleen, liver and lymph node Red cell production is impaired --> anemia

Answer 283

Marrow is hypercellular with large, dysplastic megakaryocytes that are abnormally clustered Minimal fibrosis with leukocytosis and thrombocytosis

Answer 284

Marrow becomes hypocellular and diffusely fibrotic "Cloudlike" clusters of megakaryocytes (spleen?) Sinusoids are markedly dilated Osteosclerosis (fibrotic marrow → bone

Answer 285

Marked splenomegaly, appearing red-gray and firm Subcapsular infarcts occur Initially hematopoiesis occurs in the sinusoids, but extends to the cords later Liver and lymph nodes may also be involved in hematopoiesis (lymphadenopathy is uncommon)

Answer 286

Leukoerythroblastosis: Premature release of nucleated erythroid and early granulocyte precursors DaCRYocytes: Tear drop shaped cells damaged during release from the fibrotic marrow seen in pulmonary myelofibrosis, myelophthisic anemia, thalassemia, s/p splenomegaly Abnormally large platelets Basophilia *these are also seen in other infiltrative disorders of the marrow (granulomatous disease and metastatic tumors

Answer 287

patients > 60 years old Present with progressive anemia and LUQ "fullness" Night sweats, fatigue and weight loss due to increased metabolism Hyperuricemia and secondary gout due to high cell turnover Diagnosis: bone marrow biopsy

Answer 288

Normocytic, normochromic anemia with leukoerythroblastosis WBC count is variable Platelet count is variable, but thrombocytopenia will eventually show

Answer 289

Prognosis Survival: 3-5 years Infection, thrombotic episodes, bleeding, transformation to AML (5-20%)

Answer 290

JAK2 inhibitors for splenomegaly and signs and symptoms and HSC in young patients

Answer 291

Umbrella designation for a variety of proliferative disorders of dendritic cells or macrophages considered neoplasms

Answer 292

Abundant, vacuolated cytoplasm Vesicular nuclei with linear grooves or folds *Birbeck granules in the cytoplasm is characteristic: pantalaminar tubules with a dilated terminal end ("tennis racket" appearance) *contain langerin Immunophenoty

Answer 293

HLA-DR, S100, and CD1a positive

Answer 294

BRAF activating mutation (600: valine → glutamate) as seen in hairy cell leukemia Other mutations in tp53, RAS and MET (a tyrosine kinase

Answer 295

(D) CORRECT. The Langerhans cell histiocytoses include Letterer-Siwe disease (as in this case, it is typically a disseminated disease of children), and localized eosinophilic granuloma (often involving bone).

Answer 296

Malignant proliferation of Langerhans cells | Mostly seen in kids <2 years old, but can be seen in adults

Answer 297

``` Seborrheic eruption (rash) over the trunk and scalp HSM, LAD, pulmonary lesions and destructive osteolytic bone lesions Anemia, thrombocytopenia, recurrent infections (otitis media, mastoiditis) due to marrow involvement Anaplastic = Langerhans cell sarcoma ```

Answer 298

Untreated = rapidly fatal Treatment: intensive chemotherapy 5 year survival: 50%

Answer 299

Benign proliferation of Langerhans cells in medullary cavity of bone typically in the calvarium, ribs, femur Adolescents

Answer 300

Pain, tenderness, pathologic fracture Heal spontaneously, excised or radiated Skin, lungs or stomach are uncommonly involved Biopsy: Langerhans cells with mixed inflammatory cells (numerous eosinophils

Answer 301

Definition Benign proliferation of Langerhans cells Affects young children

Answer 302

Multiple erosive bone masses May extend into soft tissue May involve posterior pituitary stalk = diabetes insipidus (50%) Spontaneous regression or treatment with chemotherapy Hand-Schuller-Christian Triad: Calvarial bone defects, diabetes insipidus, and exophthalmos -- "probably should know that

Answer 303

Reactive proliferation of Langerhans cells Nodules and cysts in the middle and upper lobes 40% are associated with BRAF mutations and may be neoplastic in origin -- as seen in hairy cell leukemia Adult smokers (disease may regress with smoking cessation) pulmonary disease associated with smoking, shocking

Answer 304

Aberrant expression of chemokine receptors on Langerhans cells allows homing Normally express CCR6 Neoplastic: CCR6 + CCR7 allowing cells to enter tissues in skin, bone, and lymphoid organs

Answer 305

Periarteriolar lymphatic sheath: an artery with an eccentric collar of T lymphocytes; at intervals this sheath expands to form lymphoid nodules composed mainly of B lymphocytes

Answer 306

open circulation: blood flows through capillaries into the cords and then squeezes through gaps in the discontinuous basement membrane of the endothelial linings to reach the sinusoids cells are deformed when passing from cords to sinusoids

Answer 307

closed circulation: blood passes rapidly and directly from the capillaries to the splenic veins

Answer 308

primary lesions to the spleen are rare; if they happen they are benign metastatic disease to the spleen is rare

Answer 309

phagocytosis of blood cells and particulate matter conditions in which red cell deformability is decreased, more RBCs become trapped in the cords and phagocytosed by macrophages macrophage are responsible for RBC "pitting:" process by which inclusions of Heinz bodies and Howell-jolly bodies are excised Also remove particles (encapsulated bacteria

Answer 310

Plasma cells within the sinuses of the red pulp dendritic cells in periarteriolarl lymphatic sheaths present Antigens to T-lymphocytes T & B cells interact at the edge of white pulp follicles --> plasma cells within the sinuses of the red pulp Important production site against microbial polysaccharides and auto-antibodies to self-antigens

Answer 311

Major site during fetal development, but disappears at birth In chronic anemia, thalassemia, and patients with myeloproliferative disorders (CML, primary myelofibrosis) becomes an extramedullary site for production

Answer 312

Splenomegaly significantly increases the capacity from 30ml of RBCs Normally contains 30-40% of the body’s platelets but can trap 80-90% of total platelet mass (in red pulp) Thrombocytopenia and leukopenia can result when cells remain trapped in the spleen

Answer 313

infections outside of the US | alcohol and disease in the US

Answer 314

Removal or dysfunction of this organ leads to increased susceptibility to sepsis caused by encapsulated bacteria encapsulated bacteria == blood borne Sickle Cell Patients --> increased autoinfarction of the spleen --> functionally asplenic (splenic insufficiency) Decreased phagocytic capacity Decreased antibody production patients should be vaccinated against encapsulated bacteria: pneumococci, meningococci, and haemophilus influenzae

Answer 315

Due to splenomegaly Discomfort after eating due to pressure on the stomach splenomegaly can cause hypersplenism: anemia, leukopenia, and thrombocytopenia either alone or in combination

Answer 316

Reactive enlargement of the spleen that occurs due to blood borne infections (microbial agents and cytokines released due to immune response

Answer 317

Enlarged and soft spleen Major feature: acute congestion of the red pulp that may encroach on and efface lymphoid follicles White pulp follicles may undergo necrosis especially due to hemolytic streptococcus Abscess formation rarely occurs

Answer 318

Definition Due to chronic venous outflow obstruction Obstruction due to intrahepatic disorder affecting portal venous drainage

Answer 319

Cirrhosis (ETOH, parasitic schistosomiasis, pigment) Extrahepatic disorders impinging on portal or splenic veins Spontaneous portal vein thrombosis, pyelophlebitis (inflammation of the portal vein), infiltrating tumors Causes portal or splenic vein hypertension Systemic congestion (CHF) may produce a moderately enlarged spleen

Answer 320

Cut surface is gray-red to deep red Firm Thick, fibrous capsule Red pulp: congested then fibrotic Deposition of collagen in basement membrane of sinusoids that appear dilated (rigid walls) due to increased portal venous pressure Hypersplenism (excess destruction) due to slow blood flow and increased exposure to macrophages

Answer 321

Common lesions; due to occlusion of major splenic artery or branches Lack of collateral blood supply Common in markedly enlarged spleens due to tenuous blood supply that is easily compromised Common site of emboli (from the heart

Answer 322

Bland: pale, wedge shaped, subcapsular, fibrous capsule more common; splenic infarcts are usually bland Septic: suppurative necrosis that leads to depressed scars common in the setting of individuals with infective endocarditis of the mitral or aortic valves

Answer 323

Primary neoplastic involvement is rare; when it does happen it is benign Lymphoid and myeloid tumors often cause splenomegaly Benign fibromas, osteomas, chondromas, lymphangiomas, hemangiomas may arise; often cavernous in type

Answer 324

Complete absence is rare and associated with other anomalies (e.g. situs inversus and cardiac malformations) Hypoplasia is more common Accessory spleen (spleniculi): common; small, spherical structures histologically and functionally identical to the normal structure found anywhere in the abdominal cavity very important to recognize in diseases with splenectomy as a treatment (i.e. hereditary spherocytosis and immune thrombocytopenia purpura

Answer 325

more commonly precipitated by blunt trauma Spontaneous: never involves a truly normal organ, but likely involves an underlying condition most common predisposing conditions: infectious mononucleosis, malaria, typhoid fever, lymphoid neoplasm Splenomegaly with a thin, tense capsule susceptible to rupture rupture causes intraperitoneal hemorrhage that must be treated with splenectomy Chronically: unlikely to rupture due to reactive fibrosis of the capsule

Answer 326

Derived from the 3rd and 4th pharyngeal pouches Grows until puberty then involutes Lobular structures contain Thymic epithelial cells → Hassall corpuscles with keratinized cores Immature T lymphocytes Location of maturation of T cells myoid cells (muscle-like cells) found in the thymus are thought to play some role in the development of myasthenia gravis (Myasthenia Gravis is an autoimmune disease which results in muscle fatigability and weakness throughout the day. Symptoms improve with rest. Its main symptoms, which the ophthalmologist may encounter, are ptosis, diplopia, variable extra-ocular muscle palsies or incomitant strabismus, and external ophthalmoplegia.) fatigable ptosis MOA: auto-antibodies against cholinesterase

Answer 327

Thymic Hypoplasia/Aplasia (DiGeorge Syndrome) problem with the development of 3rd and 4th pharyngeal pouches Severe defects in cell-mediated immunity Variable anomalies of parathyroid development (hypoparathyroidism) --> hypocalcemia Chromosome 22q11 deletion == CATCH-22 Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia (from hypoparathyroidism) resulting from 22q11 deletions

Answer 328

Uncommon, incidental finding < 4 cm in diameter Spherical or arborizing Lined with stratified squamous to columnar epithelium Fluid may be serous or mucinous neoplastic thymic masses compress and distort adjacent normal thymus and sometimes cause cysts to form presence of a thymic cyst in a symptomatic patient should invoke a search for adjacent neoplasm (lymphoma or thymoma

Answer 329

Thymic (Follicular) Hyperplasia == B cell proliferation in the thymus Appearance of B-cell germinal centers in the thymus (thymic follicular hyperplasia) thymic hyperplasia is a B-cell lesion! (think about it) Most common in myasthenia gravis 65-75% (or Graves disease, systemic lupus erythematous, scleroderma, rheumatoid arthritis, and other autoimmune disorders) May be naturally large for a patient's age and can be mistaken for a thymoma True enlargement of the thymus is rare

Answer 330

hymoma == epithelial malignancy of squamous type cells Definition Tumor of thymic epithelial cells -- these are squamous cells thymoma is of squamous cell origin; this is an epithelial cancer; will not have abnormal peripheral blood smears (i.e. no blast count with a thymoma) Typically contain benign immature T cells (thymocytes) Adults > 40 years old; thymomas are rare in children defined as either benign (proliferation of squamous cell component) or malignant (thymic epithelium) look for cellular atypia to differentiate between benign and malignant

Answer 331

Benign Cytologically benign and noninvasive == thymoma Malignant Cytologically benign but invasive or metastatic == invasive thymoma no cellular atypia Cytologically malignant (thymic carcinoma) == malignant thymoma cellular atypia

Answer 332

Common in the anterior superior mediastinum (also a common location of some lymphomas) May cause impingement of structures

Answer 333

Morphology Lobulated, firm, gray-white masses +/- cystic necrosis and calcification Most are encapsulated 20-25% of the tumors penetrate the capsule and infiltrate peri-thymic tissues unremarkable thymic cortical and medullary regions; no atypia; whorled

Answer 334

50% of all thymomas are mixed medullary type and cortical type epithelial cells Tumors with substantial medullary epithelial cells are usually noninvasive Medullary type epithelial cells: elongated/spindle shaped Sparse infiltrate of thymocytes Cortical type epithelial cells: polygonal

Answer 335

Invasive Thymoma (Type 1) 20-25% of all thymomas Tumor that is cytologically bland but locally invasive by definition, invasive thymomas penetrate through the capsule into surrounding structures Cells are usually cortical with abundant cytoplasm and round, vesicular nuclei The prognosis depends on how much the tumor has invaded surrounding structures minimal invasion + complete excision --> 90% 5 year survival -- good prognosis extensive invasion --> 50% 5 year survival -- not great

Answer 336

5% of thymomas Fleshy, invasive masses that metastasize (often to lungs) Most are squamous cell carcinomas second most common are lymphoepithelioma-like carcinoma Sheets of cells with indistinct borders Resemble nasopharyngeal carcinoma EBV genomes are found in 50

Answer 337

40% of patients present with signs and symptoms related to mediastinum impingement 30-45% of patients present with myasthenia gravis other associated autoimmune disorders: hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositis-polymyositis, and Cushing syndrome thymocytes that arise within thymocytes give rise to long-lived CD4+ and CD8+ T cells, and cortical thymomas rich in thymocytes are more likely to be associated with autoimmune disease (statistically

Answer 338

Periarteriolar lymphatic sheath: an artery with an eccentric collar of T lymphocytes; at intervals this sheath expands to form lymphoid nodules composed mainly of B lymphocytes open circulation: blood flows through capillaries into the cords and then squeezes through gaps in the discontinuous basement membrane of the endothelial linings to reach the sinusoids cells are deformed when passing from cords to sinusoids closed circulation: blood passes rapidly and directly from the capillaries to the splenic veins primary lesions to the spleen are rare; if they happen they are benign metastatic disease to the spleen is rare

Answer 339

phagocytosis of blood cells and particulate matter conditions in which red cell deformability is decreased, more RBCs become trapped in the cords and phagocytosed by macrophages macrophage are responsible for RBC "pitting:" process by which inclusions of Heinz bodies and Howell-jolly bodies are excised Also remove particles (encapsulated bacteria*)

Answer 340

Plasma cells within the sinuses of the red pulp dendritic cells in periarteriolarl lymphatic sheaths present Antigens to T-lymphocytes T & B cells interact at the edge of white pulp follicles --> plasma cells within the sinuses of the red pulp Important production site against microbial polysaccharides and auto-antibodies to self-antigens

Answer 341

Major site during fetal development, but disappears at birth In chronic anemia, thalassemia, and patients with myeloproliferative disorders (CML, primary myelofibrosis) becomes an extramedullary site for production

Answer 342

Splenomegaly significantly increases the capacity from 30ml of RBCs Normally contains 30-40% of the body’s platelets but can trap 80-90% of total platelet mass (in red pulp) Thrombocytopenia and leukopenia can result when cells remain trapped in the spleen

Answer 343

splenomegaly is the major manifestation of disorders of the spleen infections outside of the US alcohol and disease in the US

Answer 344

Removal or dysfunction of this organ leads to increased susceptibility to sepsis caused by encapsulated bacteria encapsulated bacteria == blood borne Sickle Cell Patients --> increased autoinfarction of the spleen --> functionally asplenic (splenic insufficiency) Decreased phagocytic capacity Decreased antibody production patients should be vaccinated against encapsulated bacteria: pneumococci, meningococci, and haemophilus influenzae

Answer 345

Due to splenomegaly Discomfort after eating due to pressure on the stomach splenomegaly can cause hypersplenism: anemia, leukopenia, and thrombocytopenia either alone or in combination

Answer 346

Reactive enlargement of the spleen that occurs due to blood borne infections (microbial agents and cytokines released due to immune response

Answer 347

Enlarged and soft spleen Major feature: acute congestion of the red pulp that may encroach on and efface lymphoid follicles White pulp follicles may undergo necrosis especially due to hemolytic streptococcus Abscess formation rarely occurs

Answer 348

Due to chronic venous outflow obstruction | Obstruction due to intrahepatic disorder affecting portal venous drainage

Answer 349

Cirrhosis (ETOH, parasitic schistosomiasis, pigment) Extrahepatic disorders impinging on portal or splenic veins Spontaneous portal vein thrombosis, pyelophlebitis (inflammation of the portal vein), infiltrating tumors Causes portal or splenic vein hypertension Systemic congestion (CHF) may produce a moderately enlarged

Answer 350

Cut surface is gray-red to deep red Firm Thick, fibrous capsule Red pulp: congested then fibrotic Deposition of collagen in basement membrane of sinusoids that appear dilated (rigid walls) due to increased portal venous pressure Hypersplenism (excess destruction) due to slow blood flow and increased exposure to macrophages

Answer 351

Common lesions; due to occlusion of major splenic artery or branches Lack of collateral blood supply Common in markedly enlarged spleens due to tenuous blood supply that is easily compromised Common site of emboli (from the heart

Answer 352

Bland: pale, wedge shaped, subcapsular, fibrous capsule more common; splenic infarcts are usually bland Septic: suppurative necrosis that leads to depressed scars common in the setting of individuals with infective endocarditis of the mitral or aortic valves

Answer 353

Primary neoplastic involvement is rare; when it does happen it is benign Lymphoid and myeloid tumors often cause splenomegaly Benign fibromas, osteomas, chondromas, lymphangiomas, hemangiomas may arise; often cavernous in type

Answer 354

n: Congenital Anomalies Complete absence is rare and associated with other anomalies (e.g. situs inversus and cardiac malformations) Hypoplasia is more common Accessory spleen (spleniculi): common; small, spherical structures histologically and functionally identical to the normal structure found anywhere in the abdominal cavity very important to recognize in diseases with splenectomy as a treatment (i.e. hereditary spherocytosis and immune thrombocytopenia purpura

Answer 355

more commonly precipitated by blunt trauma Spontaneous: never involves a truly normal organ, but likely involves an underlying condition most common predisposing conditions: infectious mononucleosis, malaria, typhoid fever, lymphoid neoplasm Splenomegaly with a thin, tense capsule susceptible to rupture rupture causes intraperitoneal hemorrhage that must be treated with splenectomy Chronically: unlikely to rupture due to reactive fibrosis of the capsule

Answer 356

Derived from the 3rd and 4th pharyngeal pouches Grows until puberty then involutes Lobular structures contain Thymic epithelial cells → Hassall corpuscles with keratinized cores Immature T lymphocytes Location of maturation of T cells myoid cells (muscle-like cells) found in the thymus are thought to play some role in the development of myasthenia gravis (Myasthenia Gravis is an autoimmune disease which results in muscle fatigability and weakness throughout the day. Symptoms improve with rest. Its main symptoms, which the ophthalmologist may encounter, are ptosis, diplopia, variable extra-ocular muscle palsies or incomitant strabismus, and external ophthalmoplegia.) fatigable ptosis MOA: auto-antibodies against cholinesterase

Answer 357

Thymic Hypoplasia/Aplasia (DiGeorge Syndrome) problem with the development of 3rd and 4th pharyngeal pouches Severe defects in cell-mediated immunity Variable anomalies of parathyroid development (hypoparathyroidism) --> hypocalcemia Chromosome 22q11 deletion == CATCH-22 Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia (from hypoparathyroidism) resulting from 22q11 deletions

Answer 358

Uncommon, incidental finding < 4 cm in diameter Spherical or arborizing Lined with stratified squamous to columnar epithelium Fluid may be serous or mucinous neoplastic thymic masses compress and distort adjacent normal thymus and sometimes cause cysts to form presence of a thymic cyst in a symptomatic patient should invoke a search for adjacent neoplasm (lymphoma or thymoma

Answer 359

Thymic (Follicular) Hyperplasia == B cell proliferation in the thymus Appearance of B-cell germinal centers in the thymus (thymic follicular hyperplasia) thymic hyperplasia is a B-cell lesion! (think about it) Most common in myasthenia gravis 65-75% (or Graves disease, systemic lupus erythematous, scleroderma, rheumatoid arthritis, and other autoimmune disorders) May be naturally large for a patient's age and can be mistaken for a thymoma True enlargement of the thymus is rare

Answer 360

Tumor of thymic epithelial cells -- these are squamous cells thymoma is of squamous cell origin; this is an epithelial cancer; will not have abnormal peripheral blood smears (i.e. no blast count with a thymoma) Typically contain benign immature T cells (thymocytes) Adults > 40 years old; thymomas are rare in children defined as either benign (proliferation of squamous cell component) or malignant (thymic epithelium) look for cellular atypia to differentiate between benign and malignant

Answer 361

Cytologically benign and noninvasive == thymoma

Answer 362

Cytologically benign but invasive or metastatic == invasive thymoma no cellular atypia Cytologically malignant (thymic carcinoma) == malignant thymoma cellular atypia

Answer 363

Common in the anterior superior mediastinum (also a common location of some lymphomas) May cause impingement of structures

Answer 364

ocation of the tumor Common in the anterior superior mediastinum (also a common location of some lymphomas) May cause impingement of structures Morphology Lobulated, firm, gray-white masses +/- cystic necrosis and calcification Most are encapsulated 20-25% of the tumors penetrate the capsule and infiltrate peri-thymic tissues unremarkable thymic cortical and medullary regions; no atypia; whorled

Answer 365

50% of all thymomas are mixed medullary type and cortical type epithelial cells Tumors with substantial medullary epithelial cells are usually noninvasive Medullary type epithelial cells: elongated/spindle shaped Sparse infiltrate of thymocytes Cortical type epithelial cells: polygonal

Answer 366

Invasive Thymoma (Type 1) 20-25% of all thymomas Tumor that is cytologically bland but locally invasive by definition, invasive thymomas penetrate through the capsule into surrounding structures Cells are usually cortical with abundant cytoplasm and round, vesicular nuclei The prognosis depends on how much the tumor has invaded surrounding structures minimal invasion + complete excision --> 90% 5 year survival -- good prognosis extensive invasion --> 50% 5 year survival -- not great

Answer 367

5% of thymomas Fleshy, invasive masses that metastasize (often to lungs) Most are squamous cell carcinomas second most common are lymphoepithelioma-like carcinoma Sheets of cells with indistinct borders Resemble nasopharyngeal carcinoma EBV genomes are found in 50%

Answer 368

40% of patients present with signs and symptoms related to mediastinum impingement 30-45% of patients present with myasthenia gravis other associated autoimmune disorders: hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositis-polymyositis, and Cushing syndrome thymocytes that arise within thymocytes give rise to long-lived CD4+ and CD8+ T cells, and cortical thymomas rich in thymocytes are more likely to be associated with autoimmune disease (statistically

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