All things WBC Flashcards
(194 cards)
1
Q
normal platelet count?
A
150-450 x 10^3 is normal range
2
Q
which cells look like?
A
eos: 1-3 lobes, granulations
basophils: just see granules
neutrophils: 3-5 lobes, granulations
monocytes: kidney shaped nucleus
3
Q
stages of RBCs
A
- Proerythroblast: large, round cell with mild basophilia
- Basophilic erythroblast: smaller cell, deeply basophilic cytoplasm
- Polychromatophilic erythroblast: basophilic ribosomes, eosinophilic cytoplasm
- Normoblasts: eosinophilic cytoplasm that resembles erythrocyte
- Nucleated red cells: not normal to see in the blood
4
Q
stages of granulocytes?
A
- Myeloblast: no cytoplasm granules, basophilic cytoplasm
- Promyelocyte: cytoplasm contains black/purple granules, nuclei may be present
- Myelocyte: eccentric round oval nucleus, primary azurphilic granules, fine secondary granules
- Metamyelocyte “Juvenile” Granulocyte: see indented nucleus as major factor
5
Q
neutrophil stages?
A
- Myeloblast: no cytoplasm granules, basophilic cytoplasm
- Promyelocyte: cytoplasm contains black/purple granules, nuclei may be present
- Myelocyte: eccentric round oval nucleus, primary azurphilic granules, fine secondary granules
- Metamyelocyte “Juvenile” Granulocyte: see indented nucleus as major factor
Metamyelocyte → Band Neutrophil (Horseshoe nucleus) → segmented polymorphonuclear leukocyte (PMN or Neutrophil or Polys)
• in PMN see lobation of granulocyte into thin thread-like chromatin filaments joining 2-5 lobes
6
Q
WBC range?
A
WBC (x103/μL) 4.8 – 10.8 (upper limit is 10,000!)
7
Q
granulocyte range?
A
Granulocytes (%) 40-70
note: absolute counts
8
Q
Leukoerythroblastosis
A
= abnormal release of immature precursors into the peripheral blood – often due to distorted marrow architecture from deposition of metastatic cancer or granulomatous disorders
9
Q
Myeloid Tissues:
A
: bone marrow and cells derived from it – RBCs, platelets, granulocytes, monocytes
10
Q
Leukocytosis
A
Proliferative disorders- increase in WBCs
see an expansion of leukocytes - increase in lymphocytes, granulocytes, and monocytes
11
Q
Leukopenia
A
= low number of circulating white cells
• most often due to reduced number of neutrophils (Leukopenia or Neutropenia)
• Lymphopenia (decreased B and T cells) is less common – and most often observed in HIV infection, glucocorticoid therapy, cytotoxic drugs, AI disorders, malnutrition, certain acute viral infections
12
Q
Neutropenia
A
reduction in number of neutrophils in the blood
o Inadequate or ineffective granulopoiesis
• suppression of HSC’s seen in aplastic anemia
• suppression of committed granulocytic precursors due to drugs
• disease states associated with ineffective hematopoiesis – megaloblastic anemia
• congenital conditions
o accelerated destruction or sequestration of neutrophils in periphery:
• immunologically mediated injury to neutrophils – such as SLE
• splenomegaly – leads to sequestration of neutrophils and modest neutropenia
• increased peripheral utilization due to overwhelming bacterial, fungal or rickettsial infection
o Symptoms of Neutropenia: infection, malaise, chills, fever, weakness and fatigability – also see ulcerating necrotizing lesions on gingiva, floor of mouth or oral cavity
13
Q
Agranulocytosis
A
= clinically significant reduction in neutrophils
o most common cause is drug toxicity~ aminopyrine, chloramphenicol, sulfonamides, chlorpromazine, thiouracil, phenylbutazone
o Symptoms: infections are overwhelming and may cause death w/in hours to days
14
Q
Leukocytosis
A
: increase in the number of white cells in the blood
• Causes:
o Increased production in marrow: due to chronic infection, paraneoplastic syndrome, chronic myeloid leukemia
• in acute infection there is a rapid increase in egress of mature granulocytes from bone marrow pool, mediated by TNF and IL-1
o increased release from marrow stores: endotoxemia, infection, hypoxia
o decreased margination: due to exercise or catecholamines
o decreased extravasation into tissues: due to glucocorticoids
15
Q
neutrophilic leukocytosis
A
- Neutrophilic Leukocytosis = acute bacterial infections, esp. with pyogenic organisms
Bacterial infections = neutrophils = Neutrophilic Leukocytosis
• Ex. Staph, Strep, Neisseria
• Exceptions? TB – see granulomatous forming of macrophages, Syphils
16
Q
eos leukocytosis
A
- Eosinophilic Leukocytosis = allergic disorders such as asthma, hay fever, parasitic infections, drug reactions
17
Q
basophilic leukocytosis
A
- Basophilic Leukocytosis = often indicative of myeloproliferative disease (chronic myelogenous leukemia)
18
Q
monocytosis
A
- Monocytosis = chronic infections (TB), bacterial endocarditis, AI disorders, inflamm. bowel disease
19
Q
lymphocytosis
A
= often accompanies monocytosis in TB and viral infections (Hep A, CMV, EBV)
20
Q
location of B and T cells?
A
o Follicular hyperplasia: B cells – RA, toxoplasmosis, HIV
o Paracortical hyperplasia: T cells – often due to acute viral infection
21
Q
Hemophagocytic Lymphohistiocytosis (HLH):
A
a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages characterised by proliferation of morphologically benign lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes.
o “macrophage activation syndrome”
o see systemic activation of macrophages and CD8+ cytotoxic T cells
o Familial forms of HLH impact the ability fo cytotoxic T cels and NK to properly form/deploy cytotoxic granules – associated with high levels of IFNgamma, TNFalpha, IL6, IL12, IL2
Clinical Features:
• acute febrile illness with associated splenomegaly and hepatomegaly
• prognosis is grim – usually survive less than 2 months
22
Q
lymphoid neoplasms
A
B-cell, T-cell, NK- cell origin
23
Q
lymphomas
A
= proliferations arise in tissue of lymph nodes (T cells and B cells)
Hodgkin Lymphoma
o All present as nontender enlarged lymph nodes
o See fever and pruritis related to release of cytokines from inflammatory cells responding to tumor cells
o HL spreads in an ORDERLY fashion, thus it can be staged
Non-Hodgkin Lymphoma
o 2/3 of NHLs present as enlarged nontender lymph nodes, remaining 1/3 present with sx related to involvement of extranodal sites (skin, stomach, brain)
o Peripheral T cell lymphomas – often see release of inflammatory cytokines and pruritis
o Spreads wide early, in a less predictable fashion than HL
Plasma Cell Neoplasms – i.e. multiple myeloma – causes bony destruction of skeleton and presents with pain due to pathologic fractures
24
Q
Leukemias
A
= are circulating neoplasms of WBC’s (granulocytes, RBCs, platelets) – term used for widespread involvement of the bone marrow and peripheral blood
• Lymphocytic leukemias normally present with sx related to suppression of normal hematopoiesis by tumor cells in bone marrow
25
Neoplasms of Immature B and T cells
ALL (both BALL and TALL)
• Bone marrow is hypercellular and packed with lymphoblasts
Clinical Presentation:
• abrupt stormy onset of sx within weeks
• Sx are due to depression of marrow function: fatigue, anemia, fever (reflecting infections secondary to neutropenia); bleeding (due to thrombocytopenia)
• bone pain: due to marrow expansion and neoplastic infiltration
• generalized lymphadenopathy; splenomegaly, hepatomegaly, testicular enlargement
• CNS manifestations: headache, vomiting, nerve palsies due to meningeal spread
26
Peripheral B cell neoplasms?
1. SLL/CLL - most common leukemia of adults (mature B cells - affects bone marrow and lymph nodes)
2. FL: most common indolent lymphoma of adults - (affects follicular center B cells - lymphadenopathy)
3. DLBCL: most common NHL of adults - (diffuse pattern of growth in lymph node)
4. Burkitt Lymphoma: most aggressive - tumor of mature B cells arising at extranodal sites
27
Plasma Cell neoplasms?
* These will all secrete M proteins- monoclonal Ig!!
1. MM: neoplastic plasma cells secreting IgG or IgA
2. LL (lymphoblastic lymphoma): "hyperviscosity syndrome" see IgM
28
Uncommon Lymphoid neoplasms?
1. Mantle Cell lymphoma: indolent! naive B cells - see germinal center
2. Marginal Zone Lymphoma: indolent! primed B cells - from chronic inflammation (H. pylori)
3. Hairy Cell Leukemia: indolent! mature B cells
29
indolent tumors?
MCL, MZL, SLL/CLL, HCL
30
which two do you see massive MASSIVE splenomegally?
HCL, and CML (largest!)
31
Peripheral NK/T cell lymphomas/leukemias?
1. PTCL (Peripheral T cell Lymphoma): effaced lymph nodes with T cells- pruritis!
2. ALCL (anaplastic large cell lymphoma) - ALK positive: infiltrative T cell clusters
3. Adults T cell Leukemia: aggresive CD4+ tumor assoc. with HTLV-1, Japan
4. Mycosis Fungoides/Sezary Syndrome: CD4+ T cells that home to the skin (skin lesions)
5. Large granular lymphocytic leukemia: cytotoxic T cells/NK cells
6. Extranodal NK/T cell lymphoma: highly destructive nasopharyngeal mass
32
tumors seen in children/YA's. ...
1. BALL - most common cancer of children!
2. TALL - seen in adolescent males, thymic mass
3. African (endemic) Burkitt's lymphoma (royal blue cytoplasm, mandibular mass)
4. Anaplastic Large Cell Lymphoma: ALK positive T cell
5. Nodular Sclerosing HL- mediastinal mass
6. multifocal multisystemic langerhans cell histiocytosis: cutaneous lesions and bone lesions
33
types of hodgkins lymphomas?
1. Nodular Sclerosing HL: seen in younger adults - most common!
2. Mixed Cellularity: second most common! biphasic age
3. Lymphocyte Rich:
4. Lymphocyte depletion: HIV/developing countries
5. Lymphocyte predominance: popcorn cells, only CD20+ - younger males
34
types of myeloid neoplasms?
AML:
M1 = AML w/out maturation: very immature, >3% of blasts are myeloperoxidase positive
M2 = AML with myelocytic maturation: auer rods present (t;8;21)
M3: Acute promyelocytic leukemia (APL): many auer rods, high incidence of DIC, t(15;17)
M4: Acute Myelomonocytic leukemia (AMML): myeloperodixase positive, monoblasts positive for nonspecific esterases inv(16)
M5: Acute monocytic leukemia: myeloperoxidase negative, nonspecific esterase positive
M7: acute megakaryocytic leukemia: see blasts with platelet specific Abs such as GPIIb/IIIa or vWF
35
auer rods and t(8;21)
AML with myelocytic maturation
36
auer rods and t(15;17)
acute promyelocytic leukemia (APL)
37
inv(16)
AML with myelmonocytic maturation (AMML)
38
myeloperodixase positive, monoblasts positive for nonspecific esterases
AMML
see inv(16)
39
myeloperoxidase negative, nonspecific esterase positive
acute monocytic leukemia
40
types of myeloproliferative disorders?
1. CML (chronic myelogenous leukemia) - general leukocytosis - BCRABL and MASSIVE splenomegally, LAP is low
2. PCV (Polycythemia Vera): mostly RBCs - JAK2, low EPO, thrombosis/bleeding
3. Essential thrombocytosis: just increased platelets - JAK2, thrombosis/hemorrhage
4. Primary Myelofibrosis: collagen depsosition in the marrow; anemia and splenomegally
41
ALL
* Most common type of cancer in children! (more common in boys, white)
* May be derived from either precursor B or T cells = lymphoblasts!
* Highly aggressive tumors manifest signs of bone marrow failure, or rapidly growing masses
* tumor cells contain genetic lesions that block differentiation, leading to accumulation of immature, nonfunctional blasts
* approximately 90% present with structural chromosomal changes: most often is hyperdiploidy
* Terminal deoxynucleotidyl transferase (TdT) = seen only in pre-B and pre-T cell lymphocytes
Histology:
• Bone marrow is hypercellular and packed with lymphoblasts
• Tumor cells have scant basophilic cytoplasm and larger nuclei
• “starry sky” appearance
Clinical:
• abrupt stormy onset of sx within weeks
• Sx are due to depression of marrow function: fatigue, anemia, fever (reflecting infections secondary to neutropenia); bleeding (due to thrombocytopenia)
• bone pain: due to marrow expansion and neoplastic infiltration
• generalized lymphadenopathy; splenomegaly, hepatomegaly, testicular enlargement
• CNS manifestations: headache, vomiting, nerve palsies due to meningeal spread
** with aggressive chemo about 95% of children with ALL obtain a complete remission and 75% are cured
42
TdT
ALL: seen only in pre-B and pre-T cell lymphocytes
43
hyperdiploidy?
often seen in ALL
44
good prognosis with ALL?
age 2-10, low WBC count, hyperdiploidy, trisomes of 4/7/10, t(12;21)
45
bad prognosis with ALL?
under age 2 or adolescent/adult, peripheral blasts >100,000, t(9;22) Philadelphia chromosome resulting in BCR-ABL fusion mutation
46
BALL
B-cell acute lymphoblastic leukemia/lymphoma (BALL)
• Bone marrow precursor B cell
• Loss of function mutation in PAX5, t(12;21) with RUNX1 and ETV6 in 25%
• Markers: CD10, intracellular TdT, CD19, PAX5
Clinical Present:
• Predominantly children! peaks around age 3
• symptoms relating to loss of bone marrow → increased infection due to bacteria
• often have low platelet counts which sets up for DIC
47
T cell markers?
CD1,3,4,5,8
48
B cell markers?
CD10, CD19, CD20, 21, 23
49
monocyte markers?
CD11c, CD13, 14, 15, CD33, CD64
50
NK markers?
CD16, CD56
51
pluripotent HsC markers?
CD34
52
CD10, intracellular TdT, CD19, PAX5
BALL
53
CD1, CD2, CD5, CD7
TALL
54
t(12;21) with RUNX1 and ETV6
BALL
55
TALL
• Precursor T cell (often of thymic origin)
• Gain of function mutation in NOTCH1 gene
• Markers: CD1, CD2, CD5, CD7
Clinical Presentation:
• Present in adolescent males as thymic masses with variable bone marrow involvement
• compression of large vessels and airways in mediastinum may result from thymic enlargement
56
NOTCH1
gain of fn mutation in TALL
57
SLL/CLL
• Most common leukemia of adults in US!
o 2:1 male predominance, median age 60 y/o
• Tumor of mature B cells that usually manifests with bone marrow and lymph node involvement
• Markers: CD19, CD20, CD23 and CD5 (pan B-cell markers) – along with low level expression of IgM or IgD
• chromosomal translocations are rare – usually deletions of 13q, 11q, 17p and trisomy 12q
morphology: lymph node architecture is gone and they are effaced with infiltrates of small lymphocytes
- "smudge cells"
Clinical presentation:
• Indolent course, commonly assoc. w/ disruption of immune function, including increased susceptibility to infection and AI disorders: hypogammaglobulinemia is common and contributes to infections
• “nonspecific sx” easy fatigability, w/l, anorexia
• generalized painless lymphadenopathy and hepatosplenomegaly – present in 50% of cases
• small monoclonal Ig “spike” present in blood of some patients
58
CLL vs SLL
CLL and SLL differ only in degree of peripheral blood lymphocytosis
• CLL >5000 absolute lymphocyte count
59
Smudge cells and effaced lymph nodes
CLL/SLL
60
Richter's syndrome
= aggressive phase of CLL/SLL –> prolymphocyte evolution/ transformation to diffuse large cell lymphoma
• seen in approx. 5-10% of patients – see rapidly enlarging mass within a lymph node or spleen (less than 1 year survival rate)
61
BCL2
this is overexpressed due to t(14;18) in FL, resulting in lack of promotion of apoptosis and growth of B cells in follicles
62
Follicular lymphoma
• most common indolent lymphoma (low grade) of adults!
• most cases associated with (14;18) translocation that results in overexpression of BCL2**
• Markers: CD19, CD20, CD10, surface Ig, BCL6, BCL2
o unlike CLL/SLL CD5 is not expressed!
o unlike normal germinal centers, BCL2 is expressed – indicative of follicular lymphoma
Histology:
• Tumor cells recapitulate the growth pattern of normal germinal center B cells
• predominantly nodular/diffuse growth pattern observed in lymph nodes
• “centrocytes” see small cells with irregular nuclear contours and scant cytoplasm
• “centroblasts” larger cells with open nuclear chromatin and modest amounts of cytoplasm
Clinical Presentation:
• painless, generalized lymphadenopathy
• involvement of extranodal sites such as GI tract, CNS and testis is relatively uncommon
• Survival mean 7-9 years
• Histological transformation occurs in 30-50% of cases to large G cell lymphoma
• lymphocytosis seen in 10% of cases
• Low dose chemotherapy is given
63
how to tell SLL/CLL from FL? from DLBCL? from Burkitts?
SLL/CLL:
- effacement of nodes
- CD5 is a marker
FL:
- germinal center follicle growth
- CD5 is not expressed, rather have BCL6, BCL2 primraily
DLBCL:
- see large cell size, and diffuse nodular effacement
- CD5 not expressed, has BCL6 primarily and BCL2
- others turn into this! its bad.
Burkitts:
- very aggressive, extranodal!
- no BCL2 like the others, has BCL6
- c-MYC transformation
64
DLBCL
• most common NHL lymphoma of adults!
o male predominance
o median age 60 y/o
• heterogenous group of mature B cell tumors that share a large morphology and aggressive behavior
• rearrangements or mutations of BCL6 gene**; 1/3 carry (14;18) translocation involving BCL2
o BCL6 represses the expression of factors that normally serve to promote germinal center B cell differentiation, growth arrest, and apoptosis
• may arise from follicular lymphoma
• Markers: CD19, CD20, CD10, BL6
Morphology:
• see relatively large cell size and diffuse pattern of growth in the lymph node
• usually moderately abundant cytoplasm
Clinical Presentation:
• presents as a rapidly enlarging mass at a nodal or extranodal site
• can arise anywhere on body, though Waldeyer ring (oropharyngeal lymphoid tissue, tonsils, adenoids are most often involved) – involvement of liver and spleen may take form of large destructive masses
• extranodal sites: GI tract, skin, bone, brain
• bone marrow involvement is uncommon and usually occurs late in the course
• aggressive tumor that is rapidly fatal without treatment!
o individuals with limited disease fare better than those with widespread disease/bulky tumor masses
Note: if has BCL2 positivity, think that it started as follicular lymphoma
65
Immunodeficiency-associated large B-cell lymphoma:
type of DLBCL that occurs insetting of severe T cell ID such as HIV – neoplastic B cells are often infected with EBV
66
Primary Effusion lymphoma:
type of DLBCL that presents as a malignant pleural or ascetic effusion – mostly in older individuals with advanced HIV
a. tumor cells are often anaplastic in appearance and fail to express surface B or T cell markers
b. all cases are infected with KSHV/HHV-8
67
c-Myc
Burkitt's lymphoma
• All forms strongly associated with proto-oncogene c-MYC, on chromosome 8 → leading to increased MYC levels
o MYC is master txn regulator that increases the expression of genes that are reqd for aerobic glycolysis, aka “Warburg Effect”
68
Burkitt's lymphoma
• Very aggressive! tumor of mature B cells that usually arise at extranodal sites
• All forms strongly associated with proto-oncogene c-MYC, on chromosome 8 → leading to increased MYC levels
o MYC is master txn regulator that increases the expression of genes that are reqd for aerobic glycolysis, aka “Warburg Effect”
• unlike other B-cell origin tumors, BL almost always fails to express BCL2
• Markers: CD19, CD20, CD10, BCL6, IgM
• Tumor cells often latently infected with EBV
o infection precedes transformation
Categories:
1. African (endemic) BL
2. Sporadic (non-endemic, American) BL
3. HIV infected BL
Morphology:
• “starry sky” morphology
• tumor exhibits high mitotic index containing numerous apoptotic cells
• see royal blue cytoplasm containing clear cytoplasmic vacuoles
Clinical Features:
• Fastest growing tumor!!
• Very aggressive, but responds well to chemotherapy – most children and young adults are cured
• Both endemic and sporadic BL are found mainly in children / young adults
• most tumors manifest at extranodal sites
• Endemic BL presents as a mass involving the mandible and shows a predilection to involvement of abdominal viscera: kidneys, ovaries, adrenal glands
• Sporadic BL most often appears as mass involving the ileocecum
69
HTLV1
Adult T-cell leukemia/lymphoma
70
starry sky night morphology? with royal blue cytoplasm and clear cytoplasmic vacuoles?
Burkitt's lymphoma
71
EBV
seen in burkitt lymphoma, Hodgkin lymphomas, many B cell-lymphomas ariseing in the setting of T –cell immunodeficiency (i.e. HIV)
72
HHV-8
“KSHV/HHV-8” – associated with unusual B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity
73
M component
a monoclonal Ig identified in the blood – in reference to myeloma. Complete M components have high MW and are restricted to the plasma and ECF
- Neoplastic plasma cells often synth. xs light chains along with complete Igs – level of free light chains is usually elevated and markedly skewed toward one light chain: light chains are small in size and are excreted in the urine
Most myelomas are associated with more than 3gm/dL of serum Ig OR more than 6mg/dL or Bence Jones proteins in urine
o most common M protein is IgG, followed by IgA
o about 1% of myelomas are nonsecretory thus the absence of detectable M proteins does not completely exclude the ddx.
74
Bence Jones Proteins:
MM- light chains that are small enough to be excreted in the urine
75
Multiple Myeloma path/genetics?
* Most common and deadly of plasma cell dyscrasias - plasma cell tumor that manifests with multiple lytic bone lesions associated with pathologic fractures and hypercalcemia
* neoplastic plasma cells suppress normal humoral immunity and secrete partial immunoglobulins that are nephrotoxic
“monoclonal spikes”: see increased levels of Igs in the blood
o Most myelomas are associated with more than 3gm/dL of serum Ig OR more than 6mg/dL or Bence Jones proteins in urine
o most common M protein is IgG, followed by IgA
o about 1% of myelomas are nonsecretory thus the absence of detectable M proteins does not completely exclude the ddx.
• Genetics: associated with diverse translocations involving the IgH locus; frequent dysregulation and overexpression of D cyclins; 13q deletions
o high serum IL6 levels → needed for growth of plasma cells
Markers: + CD138 (ada adhesion molecule molecule syndecan-1), CD56
76
IgG, IgA
multiple myeloma
77
CD138+
MM
78
syndecan-1
MM - CD138+
79
CD56+
MM
80
MM clinical features?
Morphology:
• Bone lesions: Destructive plasma cell tumors (plasmacytomas) involving the axial skeleton – lesions begin in the medullary cavity, erode cancellous bone and progressively destroy the boney cortex. Appear as punched out lesions radiographically
• Plasmablasts: marrow contains increased number of normal plasma cells, bizarre plasma cells, flame cells, and Mott cells
• Russel bodies and Dutcher bodies = globular inclusions
• Bence Jones Proteins: light chains in the urine
• “Myeloma Kidney” = bence jones proteins can cause renal disease
• Rouleax formation: RBCs in peripheral blood smear are all clumped together – due to high level of M proteins causing peripheral blood smears to stick to one another
• rarely tumor cells flood the peripheral blood → plasma cell leukemia
Clinical Presentation:
• incidence is higher in 65-70 years, males, African descent
• Lytic bone lesions: myeloma derived proteins up-regulate the expression of RANKL → activating osteoclasts
o Axial skeleton: vertebral column**, ribs, skull, pelvis, femur, clavicle, scapula
o Bone Pain
o Pathologic Fractures
• Hypercalcemia: can give rise to neurologic manifestations, confusion, weakness, lethargy, constipation, polyuria
• Renal failure: Bence Jones proteins are toxic to renal tubular eppitheleal cells
• Hyperviscosity: due to excessive production and aggregation of M proteins
• Recurrent bacterial infections: decreased production of normal Igs (dysf. in humoral immunity)
• AL amyloidosis can also develop
• Median survival: 4-7 years
81
Russel bodies
MM
82
rearrangements involving IgH, 13q deletions?
MM
83
rouleax formation?
MM
84
bence jones proteins
MM
85
smoldering myeloma
MM precursor:
o disseminated diseases that pursues an unusually indolent course
- don't see lytic bone lesions
o middle ground b/w MM and MGUS
o patients are asymptomatic
o have high plasma M component – higher than 3 gm/dL
o plasma cells make up 10-30% of marrow cellularity
o 75% of patients progress to MM in 15 years
86
three types of MM precursors?
1. smoldering myeloma
2. solitary myeloma
3. MGUS
87
which monoclonal protein is most common in MM?
kappa chain - IgG, IgA
88
solitary myeloma
(plasmacytoma):
o solitary lesion of bone or soft tissue identical to disseminated myeloma
• extraosseous lesions often located in lungs, oronasopharynx or nasal sinuses
o modest elevations of M proteins in blood
o most progress to myeloma within 10-20 years
89
MGUS
* most common plasma cell dyscrasia in the elderly
(monoclonal gammopathy of unknown significance)
o most common plasma cell dyscrasia – occurs in adults over 50 years
o patients are without sign or sx and serum M protein levels are less than 3 gm/dL
o progresses to myeloma at rate of 1% per year – clonal plasma cells in MGUS contain many of same chromosomal deletions/translocations as full blown MM
90
lymphoplasmacytic lymphoma
• B cell lymphoma that exhibits plasmacytic differentiation – age 70
o superficial resemblence to CLL/SLL
• clinical sx dominated by hyperviscosity related to high levels of tumor-derived monoclonal IgM
o Waldenstrom macroglobulinemia = hyperviscosity syndrome of LL
o “hyperviscosity syndrome” = visual impairment from venous congestion, neurologic problems such as h/a, dizziness, stupor, bleding due to complexes interfering with platelet functions, cryoglobulinemia from precipitation of macroglobulins at low temps (Raynaud phenomene)
• highly associated with mutation sin the MYD88 gene
• unlike MM complications stemming from secretion of light chains, i.e. renal failure, is relatively rare and bone destruction does not occur
• Marker: CD20
Clinical features:
• weakness, fatigue, w/l, lymphadenopathy, hetpatomegaly, splenomegaly, anemia, AI hemoilysis, cold agglutinins
• generaly progressive, incurable, doesn’t respond as well as MM
91
MYD88
lymphoplasmacytic lymphoma
92
monclonal IgM spike?
lymphoplasmacytic lymphoma --> hyperviscosity syndrome
93
Waldenstrom macroglobulinemia
= hyperviscosity syndrome of LL
see lots of IgM
94
cold agglutinins?
lymphoplasmacytic lymphoma
95
Mantle Cell lymphoma
- indolent onset
• uncommon tumor of naïve B cells that puruses a moderately aggressive course
• presents in 5/6th decade, male predominance
• all have (11;14) translocation- involving the IgH locus on chromosome 14 and cyclin D1 locus on Ch 11 → leads to overexpression of Cyclin D1 → promotes G1 to S phase progression during cell cycle
• Markers: cyclin D1, +CD19, +CD20, CD5+, CD23- (help distinguish from CLL/SLL), high levels of surface Ig
Morphology:
• see an expanded mantle cells, with neoplastic markers
• homogenous population of small lymphocytes with irregular nuclear contours
• the germinal center here is not neoplastic (as in CLL/SLL- and large centroblasts and proliferation centers are absent)
Clinical features:
• painless lymphadenopathy
• Sx are related to hepatosplenomegaly and gut
• poor prognosis: median survival 3-4 years – this lymphoma is not curable with chemo and most succumb to organ dysfunction due to tumor infiltration
96
cyclin D1
mantle cell lymphoma
97
(11;14)translocation
mantle cell lymphoma
98
CD5+ positivity in B cell neoplasms?
SLL/CLL
mantle cell lymphoma (distinguished from SLL/CLL from high levels of surface Ig)
99
Marginal Zone lymphoma
"memory B cells"
• Indolent tumor of antigen primed B cells that arise at sites of chronic immune stimulation: arise in lymph nodes, spleen, extranodal tissues
o disease begins as polyclonal immune reaction – with acquisition of unknown initiating mutations, a B-cell clone emerges that depends on Ag-stimulated T cells for signals to drive growth and survival → promotion of infection enhances growth and survival of B cells → diffuse B cell lymphoma
o Salivary gland due to Sjogren disease, thryoid due to Hashimoto thyroiditis, stomach due to Helicobacter gastritis
o lie on a continuum b/w reactive lymphoid hyperplasia and full-blown lymphoma
• often remain localized for long periods of time
• may regress if inciting agents are eradicated
• Genetics: translocations that create MALT1 and BCL fusion genes
can transform into DLBCL
100
MALT1
Marginal Zone Lymphoma
101
+ urea breath test
think H. pylori, think marginal zone lymphoma
102
BCL fusion genes
MZL
103
BRAF
HCL
104
HCL surface markers?
• Surface Markers: + CD19, +CD20, +surface Ig, +CD11c, +CD25, +CD103, +annexin A1
105
CD11c
HCL
106
CD103
HCL
107
annexin A1
HCL
108
dry tap
HCL
109
Hairy Cell Leukemia
• indolent tumor of mature B cells
• highly associated with mutations in the BRAF serine/threonine kinase
• Genetics: point mutations in the serine/threonine kinase BRAF
• Surface Markers: + CD19, +CD20, +surface Ig, +CD11c, +CD25, +CD103, +annexin A1
Morphology:
• leukemic cells have fine hairlike projections seen on peripheral blood smears
Clinical Presentation:
• middle aged white males, 55 y/o
• “dry tap” on bone marrow aspiration due to proliferation and fibrosis of bone marrow
• Massive splenomegaly due to infiltration
• hepatomegaly is less common, lymphatdenopathy is rare
• Pancytopenia: results from marrow involvement and splenic sequestration – overall reduction in number of RBCs, WBCs and platelets
• Infections
• increased incidence of atypical mycobacterial infections
• overal prognosis is excellent – sensitive to gentl chemo
110
mycobacterial infections?
HCL
111
pruritis
think T cells
112
Peripheral T-Cell lymphoma, unspecified
• tumor that effaces lymph nodes diffusely and typically composed of pleomorphic mixture of variably sized malignant T cells
• Markers: CD2, CD3, CD5, some also have CD4, CD8
Clinical Presentation:
• generalized lymphadenopathy
• eosinophilia, pruritis, fever, w/l (not seen in B cell lymphomas!)
• ddx reqs. immunophenotyping
• much worse prognosis than diffuse B cell lymphoma
113
ALK positive
Anaplastic lymphoma kinase (ALK) - seen in Anaplastic Large cell lymphoma
114
Anaplastic Large cell lymphoma:
ALK positive)
• aggressive T cell tumor
• associated with mutations in ALK tyrosine kinase on Chr 2p23 – ALK is not expressed in other lymphomas
• CD30+ neoplasm
Morphology:
• tumor cells cluster about venules, and infiltrate sinuses, mimicking the appearnce of metastatic carcinoma
• tumor composed of large anaplastic cells, often with horseshoe-shaped nuclei and lots of cytoplasm
Clinical Presentation:
• ALK rearrangements tend to occur in children or y/a’s
• frequently present as soft tissue “masses”
• have very good prognosis unlike other T cell neoplasms
115
CD30+
ALCL
116
Adult T cell Leukemia/Lymphoma:
• aggressive tumor of CD4+ T cells that’s uniformly associated with HTLV-1 infection (human T-cell luekemia retrovirus type 1)
o endemic in Japan, West Africa, Caribbean basin
Morphology:
• multilobated nuclei “cloverleaf” or “flower cells”
Clincal Presentation:
• skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia
• rapidly progressive disease – fatal w/in a year despite chemo
• may cause a progressive demyelinating disease of CNS/spinal cord
117
Mycosis Fungoides
• different manifestations of a tumor of CD4+ helper T cells that home to the skin
• Markers: adhesion molecule utaneous leukocyte antigen (CLA), CCR4, CCR10 – which help with homing of CD4+T cells to the skin
Morphology:
• epidermis, upper dermis are infiltrated by neoplastic T cells
Clinical Presentation:
• cutaneous lesions progress through different stages
• “Sezary Zyndrome” = a variant in which skin involvment is manifested as generalized exfoliative erythroderma, with associated leukemia
118
Sezary syndrome
= a variant of mycosis fungoides in which skin involvment is manifested as generalized exfoliative erythroderma, with associated leukemia
119
CCR4
Mycosis Fungoides/Sezary Syndrome
120
CCR10
Mycosis Fungoides/Sezary Syndrome
121
STAT3
Large granular lymphocytic leukemia:
122
Large granular lymphocytic leukemia:
• indolent tumor of cytotoxic T cells or NK cells – occurs mainly in adults
• associated with txn factor STAT3
• associated with autoimmune phenomena and cytopenias: neurtropenia and anemia
Morphology:
• tumor cells are large with abundant blue cytoplasm and scant coarse azurophilic granules
123
Extranodal NK/T cell lymphoma:
• aggressive tumor
• usually derived from NK cells
• strongly associated with EBV infection
Morphology: surrounds and invades small vessels leading to extensive ischemic necrosis
Clinical Presentation: presents as highly destructive nasopharyngeal mass, rare in US
124
Reed-Sternberg Cell
seen in HL
neoplastic giant cell
surrounded by reactive lymphocytes, macrophages, granulocytes
**See suppression of TH1 by RS cells, and upregulation of TH2 response! along with other “cross-talk"
125
NF-kB
HL
126
Hodgkin Lymphoma
• arises in a single node or chain of nodes and spreads first to anatomically continguous lymphoid tissues – thus staging is important
• activation of txn factor NF-kappaB is common:
o most often expressed due to EBV infection
• Reed-Sternberg Cells: cells that release factors that induce the accumulation of reactive lymphocytes, macrophages and granulocytes. They are derived from postgerminal center B cells
o Ig genes of RS cells have unergone both VDJ recombination and somatic hypermutation and despite being B cells fail to express most B cell specific genes
o EBV proteins play a part in metamorphosis of B cells to RS cells
o accumulation of reactive cells due to RS release of IL5, IL10, M-CSF, eotaxin, galectin-1
o reactive cells produce factors that support growth and survival of the tumor cells through “cross-talk”
o May be due to epigenetic changes rather than nuclear genome changes
Morphology:
• Diagnostic Reed-Sternberg Cell: multiple nuclei, 45um in diameter, multiple lobes, with large inclusion-like nucleolus
o DDx of HL depends on RS cell in background of non-neoplastic inflammatory cells
• Mononuclear RS variants, Lacunar cells, “mummification”, Lymphohistiocytic variants
Clinical Presentation:
• average age is 32 y/o – occurs most often in the young, but also in the aged
• curable in most cases
• presents as painless lymphadenopathy
• patients with Type1/2 tend to have stage I-II disease and are usually free of systemic manifestation
• factors released from RS cells suppress TH1 immune responses → increased viral infections
• spread of HL is nodal at first → splenic → hepatic → marrow/other tissues
127
nodular sclerosis HL
* most common form of HL
* lacunar variant of RS cell
* deposition of collagen bands that divide involved lymph nodes into circumbscribed nodules
* Markers: PAX5+, CD15+, CD30+, negative for all other B cell markers
* EBV-, occasional diagnositic RS cell
Clinical Presentation:
• mediastinal mass in young person!
• propensity to involve the lower cervical, supraclavicular, mediastinal LN’s of adolescents/young adults
• excellent prognosis!
128
PAX5+, CD15+, CD30+, negative for all other B cell markers
nodular sclerosis HL
129
which HL are associated with EBV?
lymphocyte depletion > mixed cellularity > lymphocyte rich
130
Mixed cellularity HL
• second most common
• involved LN’s are diffusely effaced by heterogenous cellular infiltrate which includes: T cells, eos, plasma cells, macrophages along with RS cells
• Frequent RS cells and mononuclear variants
• EBV+ 70% of time
• Markers: CD15+, CD30+
Clinical Presentation:
• more common in males, older age – biiphasic in terms of age
• see systemic sx like n/s, w/l, more advanced tumor stage
• good prognosis!
131
CD15+, CD30+
mixed cellularity HL
132
nodular sclerosis vs. mixed cellularity
both are CD15, CD30+
NS: younger person, PAX5+, deposition of collagen bands, occasional RS cells - cervical/supraclavicular nodes, no EBV
MC: older male, diffusely effaced LN, frequent RS cells, EBV+, systemic sx.
133
lymphocyte rich HL
* frequent RS cells, reactive lymphocytes make up vast majority of cellular infiltrate
* Markers: CD15+, CD30+, EBV+/EBV-
* very good prognosis!
134
Lymphocyte depletion HL
* Frequent RS cells; most are CD15+, CD30+, EBV+
* more common in oler males; HIV infected individuals, developing countries
* outcome less favorable
135
HIV infection and RS cells?
lymphocyte depletion HL
136
lymphocyte predominance HL?
• Markers: RS cells +CD20, CD15-, CD30-, EBV-
Clinical Presentation:
• males, usually younger than 35 y/o, typically present with cervical or axillary lymphadenopathy
• EBV NOT associated with this type
• transforms into a tumor resembling a diffuse large B cell lymphoma in 5% of cases
137
+CD20, CD15-, CD30-, EBV-
lymphocyte predominance HL
138
DIFFERENCES OF HODGKIN VS NHL
HODGKIN LYMPHOMA: localized to single axial group of nodes, spreads in orderly fashion, mesenteric nodes and waldeyer ring rarely involved, extranodal presentaiton is rare
NHL: more frequent involvment of peripheral nodes, noncontiguous spread, Waldeyer ring and mesenteric commonly involved, extranodal presentation is common
139
myeloid neoplasms
* all originate from myeloid hematopoietic progenitor cells- disease primarily involves the marrow and secondary the hematopoietic organs (spleen, liver, LNs)
* Acute myeloid Leukemias: accumulation of immature myeloid forms (blasts) in the bone marrow → suppresses normal hematopoeisis (ddx based on >20% blasts in bone marrow)
* Myelodysplastic Syndromes: defective maturation of myeloid progenitors gives rise to ineffective hematopoeisis, leading to cytopenias
* Myeloproliferative Disorders: there is usually an increased production of one or more types of blood cells
- note abnormal cell population may not be discernible in peripheral blood, thus bone marrow exam is reqd!
140
cytopenia
low number of blood cells
141
leukocytosis
increased WBC count
142
thrombocytosis
too many platelets
143
thrombocytopenia
too few platelets
144
CD34, CD33
AML
145
Acute Myeloid Leukemia?
* tumor of hematopoietic progenitors caused by acquired oncogenic mutations that impedede differentiation → accumulation of myeloid blasts in marrow
* replacement of marrow → marrow failure → anemia, thrombocytopenia, neutropenia
* CD34, CD33 markers
Pathogenesis:
• disruption in genes that encode txn factors that are reqd for normal myeloid differentiation
• t(8;21) and inv (16) disrupt the RUNX1 and CBF1 → binding and resultant RUNX1/CBF1 → blocks maturation of myeloid cells
• mutations in growth factor signaling pathways collaborage with txn factor abberations to produce AML
Morphology:
• AML ddx based on >20% blasts seen in bone marrow
• Myeloblasts: delicate nuclear chromatin
• Aeur Rdods: needle like azurophilic granules
• Monoblasts
• occasionally blasts are entirely absent from blood (aleukemic leukemia): thus its imp. for bone marrow exam to exclude AML in panctyopenic patients
Clinical Presentation:
• peaks after 60 years
• fatigue (anemia), fever (neutropenia), spontaneous mucosal and cutaneous bleeding (thrombocytopenia) - (findings are similar to those of ALL)
• Thrombocytopenia: results in bleeding problems, cutaneous petechia, ecchymoses, serosal hemorrhage, mucosal hemorrhage
• frequent infections: due to neutropenia- particularly of oral cavity, skin, lungs, kidneys, urinary bladder and Pseudomonas and fungal infection
• CNS manifestations are less than in ALL
• difficult to treat; AMLs with t(15;17) have best prognosis
146
t(8;21)
AML
147
inv (16) --> disruption of RUNX1/CBF1
AML (esp. AMML)
148
t(15;17)
APL
149
t(8;21)(q22;q22)
AML - favorable
150
t(11q23;v)
AML- poor prognosis
151
ring sideroblasts
MDS
152
myelodysplastic syndrome
• group of clonal stem cell disorders characterized by ineffective hematopoiesis and high risk of transmformation to AML – bone marrow is parly or wholly replaced by clonal progeny of neoplastic MSC that retains capacity to differentiate – these abnormal cells stay w/in bone marrow → patients have peripheral blood cytopenias
• May be primary (idiopathic) or secondary (to previous genotoxic drug or radiation therapy (t-MDS – worse prognosis))
Pathogenesis:
• Epigenetic factors, RNS splicing factors, transcription factors, loss of fn. in tumor supressor genes
Morphology:
• marrow is hypercellular, normocellular or rarely hypocellular
• can effect erythroid, granulocytic, monocytic and megakaryocytic lineages variably
• ring sideroblasts – erythroblasts with iron-laden mitochondria visible with Prussian blue stain
• Myeloid blasts may be increased but <20% in marrow
Clinical Features:
• peripheral cytopenias : weakness, infections, hemorrhages due to pancytopenia
• age 70 y/o – survival from 9-29 mos.
• some progress to AML
• patients often succumb to complications of thrombocytopenia (bleeding) and neutropenia (infections)
153
peripheral blood cytopenias
think MDS
154
myeloproliferative disorders
• presence of mutated, constitutively activated tyrosine kinases/signaling pathways → leading to growth factor independence. The mutated growth factors result in independent proliferation and survival of marrow progenitors.
• The disorders to not impair differentiation, thus will see an increase in production of one or more mature blood elements
• Common features:
o increased proliferation drive of bone marrow
o extramedullary hematopoeisis due to the cells displacing bone marrow
o spent phase → marrow fibrosis and peripheral blood cytopenias
o variable transformation to acute leukemia
155
BCR-ABL
CML
o BCR-ABL kinase preferentially drives the proliferation of granulocytic and megakaryocytic progenitors
156
chronic myelogenous leukemia
• distinguished from other disorders by presence of chimeric BCR-ABL gene → directs synthesis of a constituitively active BCR-ABL tyrosine kinase “Philadelphia chromosome” t (9;22)(q34;q11)
o BCR-ABL kinase preferentially drives the proliferation of granulocytic and megakaryocytic progenitors
Morphology:
• marrow is markedly hypercellular with increased granulocytic precursors – elevated eos and basophils, and megakaryocytes
• blood reveals leukocytosis, often exceeding 100,000 cells/mm: consisting primraily of neutrophils, myelocytes, eosinophils, basophils and F
• onset is insidious – may have fatigue, weakness, anorexia
• abdominal fullness/pain (splenomegally)
• LUQ pain due to splenic infarct
• EMH may also cause mild hepatomegaly and lymphadenopathy
• median survival is 3 years w/out tx, slowly progressive
• 50% of patients enter “accelerated” phase which after 6-12 mos results in “blast crisis” resembling acute leukemia – AML/ALL like phase from an early plruipotent stem cell
Diagnosis:
• CML is best differentiated from other disorders through detection of BCR-ABL gene!
• - Leucocytosis (may be >100,000/mm3, with immature forms, <10% blasts)
• LAP (Leukocyte Alkaline Phosphatase) is low in CML and is high in other reactive states
157
“Philadelphia chromosome” t (9;22)(q34;q11)
CML
158
low LAP, but lots of leukocytes in blood?
CML
159
JAK2 kinase
think PCV, or Essential thrombocytosis
160
polycythemia vera
• Strongly associated with point mutatations in JAK2 kinase
• increased marrow production of red cells, granulocytes, platelets (panmyelosis) but increased red cells (polycythemia) is responsible for most of the clinical sx
Pathogenesis:
• JAK2 participates in JAK/STAT pathway which lies downstream of multiple hematopoietic growth factor receptors, including the erythropoietin receptor
• transformed progenitor cells have markedly decreased reqs for EPO due to constitutive JAK2 signaling
• serum EPO levels are very low!
• elevated hematocrit → thrombosis and bleeding, due to increased blood viscosity and sludging
Morphology:
• marrow is hypercellular, and increase in red cell progenitors is subtle and usually accompanied by an increase in granulocytic precursors and megakarycotyes as well
• mild organomegally is common
• in late PCV, progresses to spent phase, characterized by extensive marrow fibrosis that displaces hematopoietic cells, accompanied by increased EMH, and prominent organomegaly
Clinical features:
• insiduious onset, late middle age
• abnormal blood flow, particularly on low pressure venous side→ distension
• cyanosis
• headache, dizziness, HTN, GI sx
• pruritus, peptic ulceration
• blood hematocrit elevated >55%
• hyperuricemia due to increased purines and pyramidines being released due to RBC destruction → gout
• *** bleeding and thrombotic episodes: DVT, MI, stroke, minor hemorrhages
• w/out tx death from bleeding/thrombosis occurs in months
• tx: phlebotomy, can extend life by 10 years
• “spent phase” = secondary myelofibrosis - obliterative fibrosis in bone marrow, hematopoiesis, huge splenomegally – may progress to AML
161
Essential thrombocytosis
• Thrombocytosis without polycythemia (RBC increase) or marrow fibrosis = just increased platelets
o some cases may be PCV disguised by irone deficiency
• often associated with JAK2 kinase or MPL – a receptor tyrosine kinase that is normally activated by thrombopoietin
Morphology:
• bone marrow cellularity is usually only midly increased, megakaryocytes are often markedly increased in bone marrow, and platelets are increased in periphery
• modest degrees of organomegaly
Clinical Presentation:
• older age, insidious onset with few sx
• thrombosis and hemorrhage- platelets are icnreased in number and show abnormalities
• DVT, portal/hepatic vein thrombosis, MI
• Erythromelalgia: throbbing or burning of hands and feet caused by occlusion of small arterioles by platelet aggregates which may also be seen in PVC
• its a ddx of exclusion
• survival rate is 12-15 years
162
primary myelofibrosis
• development of obliterative marrow fibrosis – replacement of marrow by fibrous tissues reduces bone marrow hematopoiesis → cytopenias and extensive extramedullary hematopoiesis
• chief pathologic feature: extensive deposition of collagen in the marrow by non-neoplastic fibroblasts→ marrow failure
Morphology:
• marrow is often hypercellular early in course
• with progression the marrow becomesmore hypocellular and diffuse fibrotic
• fibrotic marrow may be turned to bone → osteosclerosis
• fibrotic obliteration of marrow space leads to extensive extramedullary hematopoiesis → large splenomegally
• tear drop shaped red cells
Clinical Features:
• older than 60 y/o, comes to attention because of progressive anemia and splenomegally → sensation of fullnes in LUQ
• fatigue, w/l, n/s
• hyperuricemia and secondary gout due to high rate of cell turnover
• lab studies show normochromic normocytic anemia
• survival is 3-5 years → may result in AML
• problems with infections, thrombotic episodes, bleeding
163
S-100+, CD1a+ and HLA-DR+
Langerhans cell hystiocytosis
164
CCR6/CCR7
Langerhans cell hystiocytosis
165
Langerhans cell hystiocytosis
* “histiocytosis” = broad term indicating proliferative disorder of dendritic cells or macrophages
* Langerhans histiocytosis = proliferation of special immature dendritic cell
* presence of Birbeck granules in cytoplasm is characteristic = tennis racket-like appearance, contains langerin
* Markers: S-100+, CD1a+ and HLA-DR+
* express homing ligands CCR6/CCR7
166
Multifocal multisystemic Langerhans Cell Histiocytosis
a. occurs most before 2 years of age
b. development of cutaneous lesions – caused by infiltrations on Langerhans cells over front and back of trunk and scalp
c. hepatosplenomegaly, lymphoadenopathy, pulmonary lesions, bone lesions
d. fever, infections
e. extensive infiltration of marrow → anemia, thrombocytopenia, increased infections
f. course of untreated disease is rapidly fatal, 50% survive 5 years with chemo
167
Unifocal and multifocal unisystem LCH (eosinophilic granuloma)
a. characterized by proliferations of LCs admixed with eos, lymphocytes, plasma cells and neutrophils
b. arises with medullary cavities of bones
c. less commonly see pulmonary, skin, GI lesions
d. “Unifocal lesions” most commonly affect skeletal system of older children/adults
e. “Multifocal unisystem disease” usually affects young children who present with multiple erosive bony masses that sometimes expand into soft tissue
f. “Hand-Shuller-Christiann triad” = combo of calvarial bone defects, diabetes insipidus (due to pressure on pituitary stalk of hypothalamus), exopthalmos
g. many pts have spontaneous resolution
168
Hand-Shuller-Christiann triad”
= combo of calvarial bone defects, diabetes insipidus (due to pressure on pituitary stalk of hypothalamus), exopthalmos
169
child, gets sick quickly with fatigue, anemia, fever, bleeding, bone pain, lyphadenophathy?
BALL
170
• Most common leukemia of adults in US!
o 2:1 male predominance, median age 60 y/o
* Indolent course, commonly assoc. w/ disruption of immune function, including increased susceptibility to infection and AI disorders: hypogammaglobulinemia is common and contributes to infections
* “nonspecific sx” easy fatigability, w/l, anorexia
* generalized painless lymphadenopathy and hepatosplenomegaly – present in 50% of cases
* small monoclonal Ig “spike” present in blood of some patients
2. Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia:
171
• most common indolent lymphoma (low grade) of adults!
Clinical Presentation:
• painless, generalized lymphadenopathy
• involvement of extranodal sites such as GI tract, CNS and testis is relatively uncommon
• Survival mean 7-9 years
• Histological transformation occurs in 30-50% of cases to large G cell lymphoma
• lymphocytosis seen in 10% of cases
• Low dose chemotherapy is given
Follicular lymphoma
172
• most common NHL lymphoma of adults!
o male predominance
o median age 60 y/o
Clinical Presentation:
• presents as a rapidly enlarging mass at a nodal or extranodal site
• can arise anywhere on body, though Waldeyer ring (oropharyngeal lymphoid tissue, tonsils, adenoids are most often involved) – involvement of liver and spleen may take form of large destructive masses
• extranodal sites: GI tract, skin, bone, brain
• bone marrow involvement is uncommon and usually occurs late in the course
• aggressive tumor that is rapidly fatal without treatment!
o individuals with limited disease fare better than those with widespread disease/bulky tumor masses
Note: if has BCL2 positivity, think that it started as follicular lymphoma
DLBCL
173
Clinical Features:
• Fastest growing tumor!!
• Very aggressive, but responds well to chemotherapy – most children and young adults are cured
• Both forms are found mainly in children / young adults
• most tumors manifest at extranodal sites
• one form presents as a mass involving the mandible and shows a predilection to involvement of abdominal viscera: kidneys, ovaries, adrenal glands
• one form most often appears as mass involving the ileocecum
Burkitt's lymphoma
174
Clinical Presentation:
• incidence is higher in 65-70 years, males, African descent
• Lytic bone lesions: myeloma derived proteins up-regulate the expression of RANKL → activating osteoclasts
o Axial skeleton: vertebral column**, ribs, skull, pelvis, femur, clavicle, scapula
o Bone Pain
o Pathologic Fractures
• Hypercalcemia: can give rise to neurologic manifestations, confusion, weakness, lethargy, constipation, polyuria
• Renal failure: Bence Jones proteins are toxic to renal tubular eppitheleal cells
• Hyperviscosity: due to excessive production and aggregation of M proteins
• Recurrent bacterial infections: decreased production of normal Igs (dysf. in humoral immunity)
• AL amyloidosis can also develop
• Median survival: 4-7 years
Multiple Myeloma
175
• Marker: CD20
Clinical features:
• weakness, fatigue, w/l, lymphadenopathy, hetpatomegaly, splenomegaly, anemia, AI hemoilysis, cold agglutinins
• generaly progressive, incurable, doesn’t respond as well as MM
lymphoblastic lymphoma
176
Morphology:
• see an expanded mantle cells, with neoplastic markers
• homogenous population of small lymphocytes with irregular nuclear contours
• the germinal center here is not neoplastic (as in CLL/SLL- and large centroblasts and proliferation centers are absent)
Clinical features:
• painless lymphadenopathy
• Sx are related to hepatosplenomegaly and gut
• poor prognosis: median survival 3-4 years – this lymphoma is not curable with chemo and most succumb to organ dysfunction due to tumor infiltration
Mantle Cell lymphoma
177
• Indolent tumor of antigen primed B cells that arise at sites of chronic immune stimulation: arise in lymph nodes, spleen, extranodal tissues
o disease begins as polyclonal immune reaction – with acquisition of unknown initiating mutations, a B-cell clone emerges that depends on Ag-stimulated T cells for signals to drive growth and survival → promotion of infection enhances growth and survival of B cells → diffuse B cell lymphoma
o Salivary gland due to Sjogren disease, thryoid due to Hashimoto thyroiditis, stomach due to Helicobacter gastritis
o lie on a continuum b/w reactive lymphoid hyperplasia and full-blown lymphoma
• often remain localized for long periods of time
• may regress if inciting agents are eradicated
• Genetics: translocations that create MALT1 and BCL fusion genes
marginal zone lymphoma
178
Clinical Presentation:
• middle aged white males, 55 y/o
• “dry tap” on bone marrow aspiration due to proliferation and fibrosis of bone marrow
• Massive splenomegaly due to infiltration
• hepatomegaly is less common, lymphatdenopathy is rare
• Pancytopenia: results from marrow involvement and splenic sequestration – overall reduction in number of RBCs, WBCs and platelets
• Infections
• increased incidence of atypical mycobacterial infections
• overal prognosis is excellent – sensitive to gentl chemo
hairy cell leukemia
179
Clinical Presentation:
• generalized lymphadenopathy
• eosinophilia, pruritis, fever, w/l (not seen in B cell lymphomas!)
• ddx reqs. immunophenotyping
• much worse prognosis than diffuse B cell lymphoma
Peripheral T cell lymphoma
180
Clinical Presentation:
• ALK rearrangements tend to occur in children or y/a’s
• frequently present as soft tissue “masses”
• have very good prognosis unlike other T cell neoplasms
anaplastic large cell lymphoma
181
• aggressive tumor of CD4+ T cells that’s uniformly associated with HTLV-1 infection (human T-cell luekemia retrovirus type 1)
o endemic in Japan, West Africa, Caribbean basin
Morphology:
• multilobated nuclei “cloverleaf” or “flower cells”
Clincal Presentation:
• skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, hypercalcemia
• rapidly progressive disease – fatal w/in a year despite chemo
• may cause a progressive demyelinating disease of CNS/spinal cord
Adult T cell leukemia
182
Clinical Presentation:
• cutaneous lesions progress through different stages
• “Sezary Zyndrome” = a variant in which skin involvment is manifested as generalized exfoliative erythroderma, with associated leukemia
4. Mycosis Fungoides/Sezary Syndrome
183
• indolent tumor of cytotoxic T cells or NK cells – occurs mainly in adults
• associated with txn factor STAT3
• associated with autoimmune phenomena and cytopenias: neurtropenia and anemia
Morphology:
• tumor cells are large with abundant blue cytoplasm and scant coarse azurophilic granules
large cell granular lymphocytic leukemia
184
• aggressive tumor
• usually derived from NK cells
• strongly associated with EBV infection
Morphology: surrounds and invades small vessels leading to extensive ischemic necrosis
Clinical Presentation: presents as highly destructive nasopharyngeal mass, rare in US
6. Extranodal NK/T cell lymphoma:
185
Clinical Presentation:
• average age is 32 y/o – occurs most often in the young, but also in the aged
• curable in most cases
• presents as painless lymphadenopathy
• patients with Type1/2 tend to have stage I-II disease and are usually free of systemic manifestation
• factors released from RS cells suppress TH1 immune responses → increased viral infections
• spread of HL is nodal at first → splenic → hepatic → marrow/other tissues
HL
186
Clinical Presentation:
• mediastinal mass in young person!
• propensity to involve the lower cervical, supraclavicular, mediastinal LN’s of adolescents/young adults
• excellent prognosis!
nodular sclerosis HL
187
Clinical Presentation:
• peaks after 60 years
• fatigue (anemia), fever (neutropenia), spontaneous mucosal and cutaneous bleeding (thrombocytopenia) - (findings are similar to those of ALL)
• Thrombocytopenia: results in bleeding problems, cutaneous petechia, ecchymoses, serosal hemorrhage, mucosal hemorrhage
• frequent infections: due to neutropenia- particularly of oral cavity, skin, lungs, kidneys, urinary bladder and Pseudomonas and fungal infection
• CNS manifestations are less than in ALL
• difficult to treat; AMLs with t(15;17) have best prognosis
AML
188
Clinical Features:
• peripheral cytopenias : weakness, infections, hemorrhages due to pancytopenia
• age 70 y/o – survival from 9-29 mos.
• some progress to AML
• patients often succumb to complications of thrombocytopenia (bleeding) and neutropenia (infections)
myelodysplastic syndrome
189
Clinical Presentation:
• avg age is 50 years, M>F
• onset is insidious – may have fatigue, weakness, anorexia
• abdominal fullness/pain (splenomegally)
• LUQ pain due to splenic infarct
• EMH may also cause mild hepatomegaly and lymphadenopathy
• median survival is 3 years w/out tx, slowly progressive
• 50% of patients enter “accelerated” phase which after 6-12 mos results in “blast crisis” resembling acute leukemia – AML/ALL like phase from an early plruipotent stem cell
CML
190
Clinical features:
• insiduious onset, late middle age
• abnormal blood flow, particularly on low pressure venous side→ distension
• cyanosis
• headache, dizziness, HTN, GI sx
• pruritus, peptic ulceration
• blood hematocrit elevated >55%
• hyperuricemia due to increased purines and pyramidines being released due to RBC destruction → gout
• *** bleeding and thrombotic episodes: DVT, MI, stroke, minor hemorrhages
• w/out tx death from bleeding/thrombosis occurs in months
• tx: phlebotomy, can extend life by 10 years
• “spent phase” = secondary myelofibrosis - obliterative fibrosis in bone marrow, hematopoiesis, huge splenomegally – may progress to AML
PCV
191
Clinical Presentation:
• older age, insidious onset with few sx
• thrombosis and hemorrhage- platelets are icnreased in number and show abnormalities
• DVT, portal/hepatic vein thrombosis, MI
• Erythromelalgia: throbbing or burning of hands and feet caused by occlusion of small arterioles by platelet aggregates which may also be seen in PVC
• its a ddx of exclusion
• survival rate is 12-15 years
essential thrombosis
192
Clinical Features:
• older than 60 y/o, comes to attention because of progressive anemia and splenomegally → sensation of fullnes in LUQ
• fatigue, w/l, n/s
• hyperuricemia and secondary gout due to high rate of cell turnover
• lab studies show normochromic normocytic anemia
• survival is 3-5 years → may result in AML
• problems with infections, thrombotic episodes, bleeding
primary myelofibrosis
193
b. development of cutaneous lesions – caused by infiltrations on Langerhans cells over front and back of trunk and scalp
c. hepatosplenomegaly, lymphoadenopathy, pulmonary lesions, bone lesions
d. fever, infections
1. Multifocal multisystemic Langerhans Cell Histiocytosis
194
b. arises with medullary cavities of bones
c. less commonly see pulmonary, skin, GI lesions
d. “Unifocal lesions” most commonly affect skeletal system of older children/adults
2. Unifocal and multifocal unisystem LCH (eosinophilic granuloma)
