Transcript Path Chapter 13.1

Chapter 13
Diseases of White
Blood Cells, Lymph
Nodes, Spleen, and
Thymus
Components of the
Hematopoietic System
Myeloid Tissues
Bone marrow and cells derived from it
Lymphoid Tissues
Thymus, Lymph nodes, Spleen
Development and
Maintenance of the
Hemapoietic Tissues
Hemapoietic Stem Cells
Mesoderm
Migrate to the liver – Chief site of blood
cell formation until shortly before birth
At birth bone marrow throughout the skeleton
is active and then liver shuts down
At puberty activity restricted to the axial
skeleton
Figure 13-1 Differentiation
of Blood Cells
The formed elements of blood have a common origin from HSCs
HSCs – Essential properties
Pluripotency
Capacity for self-renewal
Can appear in peripheral blood during times of stress ( e.g. severe
anemia)
Niches in other tissues “unveiled” – extramedullary hematopoiesis
The marrow response to short-term physiologic needs regulated by
hematopoietic growth factors through effects on committed progenitors
Many diseases alter the production of blood cells
Tumors of hematopoietic origin are often associated with mutations that block
progenitor cell maturation or abrogate their growth factor dependence
Leukoerythroblastosis – abnormal release of immature precursors into the
peripheral blood
Table 13-1 Adult reference ranges for blood cells
Nurse cells = macrophages that supply iron to RBCs in BM
Normal fat to hempatopoeitic elements ratio = 1:1
Leukopenia
Neutropenia (granulocytopenia)
more common
agranulocytosis – clinically significant reduction, severe infecitons when neutrophil count <500/mm3
Inadequate or ineffective granulopoiesis
Suppression of HSCs
Suppression of committed granulocytic precursors by drugs – most common cause
Disease states with ineffective hematopoiesis
Rare congenital conditions – impairment of granulocytic
differentiation (Kostmann Syndrome)
Accelerated removal or destruction of neutrophils
Immunologically mediated injury
Splenomegaly
Increased peripheral utilization
Clinical features – infection, malaise, chills, fever, weakness, fatigue
Lymphopenia
immunodeficiency diseases
Treatment with steroids, cytotoxic drugs
autoimmune disorders
Acute viral infections
Leukocytosis
Mechanisms of leukocytosis -Table 13-2
Increased production
Increased release from marrow stores
Decreased margination
Decreased extravasation into tissues
Types of leukocytosis – Table 13-3
Neutrophils – acute bacterial infections, tissue necrosis
Eosinophils – allergic, parasitic, drugs, certain malignancies, collagen vascular
Basophils – myeloproliferative
Monocytosis – chronic infections, IBD
Lymphocytosis – chronic infections, viral infections, pertussis
Reactive changes – in sepsis or severe inflammatory disorders
Dohle bodies
Toxic granules
cytoplamic vacuoles
Leukomoid reaction
Lymphadenitis
The activation of resident immune cells leads to
morphologic changes in lymph nodes
Acute Nonspecific lymphadenitis – painful, red,
absecesses
Chronic Nonspecific lymphadenitis-nontender
Follicular hyperplasia (tingible-body
macrophages; B-cells, centroblasts/cytes)
Paracortical hyperplasia (T-cells)
Reticular hyperplasia ( sinus histiocytosis;
macrophage and dendritic cells)
Organized collections in non-immune tissues
Neoplastic Proliferation of
WBCs
Lymphoid neoplasms- B-cells, T-cells, NK
cells origin
Myeloid neoplasms – Acute myeloid
leukemias, myelodysplastic,
myeloproliferative
Histiocytosis – macrophages, dendritic
cells, Langerhans cells
Overview of Etiologic and
Pathogenetic Factors
Chromosome translocations and other acquired mutations
Nonrandom chromosomal abnormalities, most commonly translocations, occur in the majority
of white cell neoplasms
Mutated or altered genes often play critical roles in the development, growth, or survival of the
normal counterparts of the malignant cells ( e.g. MALTomas = B-cell lymphoma of
MALT1/BCL10 constitutively activating NF-kB)
Oncoproteins created by genomic aberrations often block normal maturation (BCL6 need for
germinal centers but turn off for maturation)
Proto-oncogenes are often activated in lymphoid cells by errors that occur during antigen
receptor gene rearrangement and diverification ( e.g. in germinal center B cells during
antobody diversificaiton AID inducing translocations and lesions in DNA)
Inherited genetic factors
Bloom, Fanconi, Down, ataxia teleangectasia and type I NF
Viruses
HTLV-1, EBV, HHV-8
Chronic Immune stimulation (H. pylori, celiacs, HIV)
Iatrogenic factors (radiation therapy)
Smoking (AML)
Lymphoid Neoplasms
Lymphocytic leukemia vs lymphoma
Widespread involvement of the bone marrow
and peripheral blood vs
Discrete tissue masses
Clinical presentations
Enlarged lymph nodes
Involvement of extranodal sites
Suppression of normal hematopoiesis
Secretion of circulating factors
Pain due to bone destruction
Lymphoid Neoplasms
Precursor B cell (immature B cells)
Peripheral B cell (mature B cells)
Precursor T cell (immature T cells)
Peripheral T cell amd NK cell ( mature
cells)
Hodgkin lymphoma ( Reed-Sternberg cells)
Lymphoid Neoplasms
Histologic examination is required for diagnosis
Most of the time, antigen receptor gene
rearrangement preceded transformation: hence
all of daughter cells share the same antigen
receptor gene configuration
Vast majority are of B cell origin ( 85-90%)
Often associated with immune abnormalities
Neoplastic B and T cells tend to behave like their
normal counterparts (T-cells to skin and B-cells
to germinal centers)
Hodgkin lymphoma spreads in an orderly fashion
ALL
85% 0f B-ALLs childhood acute leukemias
T-Alls less common, present as thymic
lymphomas in adolescent males
(lymphadenopathy and splenomegaly)
ALL is the most common cancer of
childhood
Must be distinguished from AML because
of differing responses to chemotherapy
(ALL myeloperoxidase negative)
TdT +, starry sky, hypercellular
ALL – Molecular
Pathogenesis
90% have numerical or structural chromosomal
changes (hyperploidy)
Many of the chromosomal aberrations seen in
ALL dysregulate the expression and function of
transcription factors that are required for
normal b and t cells development.
- T-cell GOF in NOTCH1, B-cell LOF in PAX5,
EBF, E2A
Single mutations are not sufficient to produce
ALL
ALL – Clinical Features
Abrupt stormy onset
Symptoms related to bone marrow
suppression
Mass effect caused by neoplastic
infiltration (testicular enlargement)
CNS manifestations
ALL – Prognostic Factors
Worse prognosis
Age under 2 (MLL gene translocations)
Presentation in adolescence or adulthood
Peripheral blast counts >100,000
Presence of particular cytogenic aberrations (Ph chromosome)
“2 Adolescents in Philadelphia stole > $100,000”
Favorable prognosis
2-10 years of age
low WBC count
hyperploidy
Trisomy of 4,7,10
Presence of t (12:21)
CLL/SLL
Most common leukemia of adults in the
Western world
Proliferation centers are pathognomic
Smudge cells
Distinctive immunophenotype (CD19/20
and low IgM/D; translocations rare,
deletions common)
CLL/SLL – Clinical features
Often asymptomatic at diagnosis
Nonspecific –fatigue, weight loss, anorexia
Generalized lymphadenopathy
Hepatosplenomegaly
Disrupts normal immune function through
uncertain mechanisms
(hypogammaglobinemia, autoantibodes ->
anemia, thrombocytopenia)
Variable course and prognosis
Tendency to transform to more aggressive
tumors – Prolymphocytic and large-cell
transformations (latter = Richter syndrome) –
poor prognosis
Follicular lymphoma
Most common form of indolent NHL
Arises from germinal center B cells
Strongly associated with chromosomal
translocations involving BCL2
Centrocytes (small cleaved cells) and
Centroblasts
t(14;18) overexpression of BCL2 (no apoptosis)
Clinical presentation
Painless, generalized lymphadenopathy
Histologic transformation to diffuse large B-cell
lymphoma
Diffuse large B-cell
lymphoma
Most common form of NHL
Large cell size and diffuse pattern of growth
Dysregulation of BCL6
t(14:18)
Immunodeficiency-associated large b-cell lymphoma in
setting of T-cell immundeficiency – EBV
Primary effusion lymphoma – KSHV/HHV-8
Clinical features
Typically presents as a rapidly enlarging mass at a
nodal or extranodal site (waldeyer ring commonly
affected)
Aggressive
Burkitt Lymphoma
African (endemic)
Sporadic (nonendemic)
Aggressive subset in HIV
Starry sky pattern – high mitotic index and numerous
apoptotic cells
Translocations of the c-MYC gene on Chromosome 8
t(8,14)
Essentially all endemic tumors are infected with EBV
Clinical features
most present as tumor at extranodal site
- Endemic = mandible, ab viscera
- Sporadic = ileocecum, peritoneum
Plasma cell neoplasms
and related disorders
Secrete a monoclonal Ig or Ig fragment
Most common and deadly is multiple
myeloma
Often synthesize excess light or heavy
chains along with complete Igs (M
component)
Bence-Jones proteins
Monoclonal
gammaopathies
Multiple myeloma
Waldenstrom macroglobulinemia (high
Igm, hyperviscosity)
Heavy-chain disease
Primary or immunocyte-associated
amyloidosis
Monoclonal gamopathy of undetermined
significance (most common pasma cell
dyscrasia; asymptomatic, M protein < 3)
Multiple myeloma
Multifocal involvement of the skeleton
The Ig genes in myeloma cells show evidence of hypermutation
The proliferation and survival of myeloma cells are dependent are several cytokines,
particularly IL-6
Factors produced by the neoplasti plasma cells mediate boney destruction
Rearrangements involving the Ig heavy chain gene of Chromosome 14q32
Axial skeleton
Punched-out defects 1-4 cm in diameter
Plasmablasts, Flame cells, Mott cells, Russell bodies (cytoplasmic), Dutcher bodies
(nuclear)
Rouleaux formation, Myeloma kidney
Clinical features
Bone resorption leading to pathologic fractures and hroni pain
Hypercalcemia
Recurrent bacterial infections
Renal insufficiency
SPE M protein
Anemia
(CRAB)
Solitary Myeloma (Plasmacytoma); Smoldering Myeloma (asymptomatic, M protein >
3)
Lympoplasmacytic
Lymphoma
Plasma cell component secretes monoclonal IgM leading to
hyperviscosity syndrome _ Waldenstrom macroglobulinemia
Clinical features
weakness, fatigue, weight loss
lymphadenopathy, hepatosplenomegaly
Anemia, auto-immune hemolysis caused by cold agglutinins
hyperviscosity syndrome
Visual impairment
neurologic problems
Bleeding
Cryoglobulinemia
Incurable, plasmapheresis
Mantle Cell Lymphoma
Tumor cells closely resemble the normal
mantle zone B cells that surround
germinal centers
Express high levels of cyclin D1
t(11:14)
Small lmphocytes with cleaved contours
Painless adenopathy
Marginal Zone Lymphomas
Maltomas
Often arise in areas of chronic
inflammation (h. pylori)
Remain localized for prolonged periods
May regress if inciting agent is eradicated
Continuum between reactive lymphoid
hyperplasia and full-blown lymphoma
Up regulations of BCL10/MALT1
Hairy Cell Leukemia
Dry tap
Spenomegaly, pancytopenia, infections
Indolent course, excellent prognosis
Pale blue cytoplasm
Peripheral T-cells and NKCell Neoplasms
Peripheral T-cell lymphoma, unspecified (malignant T cells; infiltrate
of reactive cells)
Anaplastic Large-cell lymphoma – ALK gene, hallmark cell (horseshoe shaped nuclei; involve soft tissues, good prognosis)
Adult T-cell leukemia/lymphoma- CD4+cells, HTLV-1 (cloverlef, flow
cells)
Mycosis fungoides/Sezary Syndrome
CD4+helper Tell tumor, homes to the skin (CLA and CCR4/10)
Sezary syndrome = generalized exfolaitive erythroderma
Large granular lymphocytic leukemia
neutropenia and anemia, Increased rheumatologic disorders; large
lymphocytes with abundant blue cytoplasm
Felty syndrome = rheumatoid arthritis, neutropenia, splenomegaly
Extranodal NK/Tcell Lymphoma
Destructive nasopharyngeal mass, surrounds and invades blood
vessels leading to ischemic necrois
associated with EBV
Hodgkin Lymphoma
HL arises in a single node or chain of nodes and spreads
first to anatomically contiguous lymphoid tissues
Staging is very important in guiding therapy
Reed-Sternberg cells
WHO classification
Nodular sclerosisMixed cellularity-Classical forms RS CD30/15+
Lymphocyte-richLymphocyte depletionLymphocyte predominance
Hodgkin Lymphoma
Nodular Sclerosis
Lacunar variant RS cells
Collagen bands that divide lymph nodes into circumscribed
nodules
Mixed-cellularity
T cells, eosinophils, plasma cells, macrophages, RS cells, EBV
Lymphocyte-rich
Reactive lymphocytes most of cellular infiltrate, EBV
Lymphocyte depletion
Paucity of lymphocytes, EBV
Lymphocyte predominance
Non-classical RS cells- L&H variants (popcorn cell)
Hodgkin Lymphoma
Clinical features
Painless lymphadenopathy
Constitutional symptoms – fever, night
sweats, weight loss
Cutaneous anergy
Staging – Table 13-9
Secondary Cancers
Myeloid Neoplasms
The common feature of this group is origin from
hematopoietic progenitor cells
Primarily involve the bone marrow
Usually present with altered hematopoiesis
Acute myeloid leukemia
Myelodysplastic syndromes
Myeloproliferative disorders
Manifestations due to
The position of the transformed cell within the hierarchy
of progenitors
The effect of the transporting events on differentiation
Acute Myeloid Leukemia
Tumor of hematopoietic progenitors
Caused by acquired oncogenic mutations
that impede differentiation
Leading to accumulation of immature
myeloid blasts in the marrow
Leading to marrow failure
Neutropenia,anemia, thrombocytopenia
Incidence peaks after 60 years
AML
Diagnosis
> 20% myeloid blasts in bone marrow
Auer rods
Immunophenotype helps distinguish myeloblasts from lymphoblasts
*myeloperoxidase positive
Cytogenetics – central role in classification
Many recurrent genetic aberrations seen in AML disrupt genes encoding
transcription factors that are required for normal differentiation
Evidence that mutated tyrosine kinases collaborate with transcription
factors to produce AML
t(15;17) respond to all-trans retinoic acid)
Most patients present with anemia, neutropenia, thrombocytopenia
Fever, fatigue, mucosal and cutaneous bleeding
Myelodysplastic
Syndromes
Group of clonal stem cell disorders characterized by
maturation defects
ineffective hematopoiesis
high risk of transformation to AML
Disordered differentiation
ringed sideroblasts RBCs, megaloblastic
maturation platelets, nuclear budding
abnormalities, Pseudo-Pelger-Huet cells
neutrophils, pawn ball megakarocytes, myeloid
blasts usually less than 10%
Myeloproliferative
Disorders
Common features
mutated tyrosine kinase
increased proliferative drive in the bm
Extra medullary hematopoiesis
Variable transformation to spent phase
Variable transformation to acute
leukemia
Myeloproliferative
Disorders
CML
Polycythemia vera
Essential thrombocythemia
Primary myelofibrosis
Systemic mastocytosis
Chronic eosinophilic leukemia
Stem cell leukemia
CML
Chimeric BCR-ABL gene
Ph chromosome – t (9;22) (q34;q11)
Adults, 4500 new cases per year
Hypercellular marrow
WBC >100,000
Splenomegaly (extramedullary hematopoeisis)
Insidious onset, slow progression
Blast crisis
Mutations in Ikaros
Polycythemia Vera
Increased RBCs cause the most
symptoms
Low erthropoietin
Increased blood viscosity
Bleeding and thrombosis
Point mutations in JAK2
Essential thrombocytosis
Abnormally large platelets in peripheral
smear
Dysfunctional platelets (thrombosis and
hemorrhage)
Erthromelalgia (throbbing and burning of
hands and feet)
Mutations in JAK2 or MPL
Primary myelofibrosis
Development of obliterative marrow fibrosis
Extramedullary hematopoiesis
Leukoerthroblastosis
Teardrop-shaped red cells
Increased uric acid  gout
Nonspecific symptoms due to increased
metabolism
Jak2 and MPL mutations; must have bone
marrow biopsy
Langerhans cell
histiocytosis
Birbeck granules in the cytoplasm
Letterer-Siwe Disease (multifocal)
seborrheic like skin eruption
Eosinophilic granuloma
Unifocal – bone
Multifocal
Hand-Schuller-Christian Triad
DI, exophthalmos, calvarial boney defects
Pulmonary Langerhans cell histiocytosis
Adult smokers
Regresses when smoking is stopped
Spleen
Filter for the blood
Site of immune responses to blood –borne
pathogens
Functions
Phagocytosis of blood cells and particulate matter
Antibody production
Hematopoiesis
Sequestration of formed blood elements
No spleen
Hib, pneumococcus, meningococcus
Spenomegaly
Infections
Congestive states (cirrhosis is the main cause, also portal vein thrombosis
Lymphohematogeneous disorders
Immunological
Storage diseases
Misc
Infarcts- bland or septic (bland are subcapsular, wedge-shaped; septic infarcts have suppurative necrosiis)
Accessory spleens
Rupture (trauma, malaria, mono, typhoid fever, lymphoid neoplasms)
Thymus
Third, sometimes fourth pharyngeal pouch
Hassall corpuscles
Tcells
Thymic hypopasia (DiGeorge syndrome
22q11, cysts)
Thymic hyperplasia (myasthenia gravis ->
myoid cells)
Thymomas- MG, other autoimmune
40% present because of impingement on
other mediastinal structures