Diseases of WBCS, Lymph Nodes, Spleen & Thymus: Pathology

PATHOLOGY
Diseases of WBCs, Lymph nodes,

Spleen & Thymus
Dr. Magkasi | 2020 | 1st Semester
OUTLINE
I. WBC disorders
II. Neoplastic Proliferation of WBC
III. Plasma cell Neoplasm
IV. Thymic disorders
V. Splenic disorders
REVIEW
● Hemodynamic components:
○ Myeloid: B.M., RBC, Platelets, WBC
○ Lymphoid: L.N., Lymphocytes, Spleen, Thymus
● B.M. (bone marrow)- progenitors of cells
● 3rd week - yolk sac - RBC progen, Hemo. Stem cell (HSC)
○ Mesoderm, Embryonic aorta, mesoderm ROS)
● 3rd month: cell go to liver and p[lacenta
● 4th month: to BM (decrease in liver)
● Puberty: actives in axial skel, stop-distal bone
● Adult: active ½ of BM - axial skeleton
● HSCs have two essential properties that required for
maintenance of hematopoiesis:
1. Pluripotency: refer to ability of single HSC to generate all
mature blood cells
2. Capacity of self-renewal: when HSC divides, atleast one
daughter cell must self-renew toavoid stem cell depletion
● After lifespan-mature blood elements-replaced
MORPHOLOGY
● Marrow response to short-term physiologic needs is regulated
by hematopoietic GF through their effect on committed
progenitors ● BM: unique micrienvironment that supports the orderly
● EPO, GM-CSF, GCSF, TPO proliferation, differentiation and release of blood cells
o A growth factor; act on receptors that are expressed only ● It is filled with network of thin-walled sinusoids lined by single
on committed progenitors with more restrictive potentials layer of endothelial cells
● Stem cell factor (KIT ligand) and FLT3 ligand: ● Normal megakaryocytes lie next to sinusoids and extend
o A growth factor, act through receptors that are expressed cytoplasmic process that bud off into bloodstream to produce
very early committed progenitors platelets
● Tumors of hematopoietic origin: ● RBC precursors often surround macrophages that dispose of
o When progenitor cell mutation is blocked (mutation nuclear remnant produce when cells disgorge their nucleus
occurs) replacement by underregulated growth of clones prior to release
(tumor hematopoietic organs) ● Leukoerythroblastosis: abnormal release of immature
● Normal- orderly sequence of: Proliferation, maturation and precursors into peripheral blood
release of blood cells (by transmigration through sinusoidal ● Marrow aspirate smnears: provide best assessment of
endothelial cells, where macrophages nucleus of RBC before morphology of hematopoietic stem cells
going into the blood ● Immature precursor (blast form): identified using lineage-
specific antibodies and histologic markers
● Normal adult ratio of fat cell to hematopoietic elements
1:1
● Hypoplastic state (aplastic anemia): fat cell increased;
inability of the BM to produce blood elements
● Compensatory hyperplasia (hemolytic anemia) and
neoplastic proliferation (leukemia): fat cell decrease
● Metastatic cancers and granulomatous disease: induce
local fibrosis, hence marrow cannot be aspirated; lesions are
best seen in biopsies
Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin 1

PATHOLOGY
Diseases of WBC, Lymph nodes,
Spleen, & Thymus
BM DEPOSITS o Alkylating agents and antimetabolites (drug treatment): dose

related agranulocytosis
● BM deposits (cancer cells, granulomas) distort the marrow, with o Antipsychotic (e.g., chlorpromazine, phenothiazine): has
release of immature precursors toxic effect pm granulocyte precursors in bone marrow
● Diagnosis of blood elements- confirmed by: o Sulfonamides: antibody mediated destruction of eutrophils
○ BM smears: to see blast forms
➔ use specific Ab and histochemical markers
➔ If BM is fibrotic (ex. granuloma) do biopsy MORPHOLOGY
○ BM biopsy: determine ratio of fat/ hemo cells
➔ Ex: tumor infiltrates- fat cells replaced and disappear ● Hypocellularity
○ Due to compensatory increase in granulocytic precursor
WBC DISORDERS ○ Neutropenias caused by ineffective granulopoiesis
○ Occurs in megaloblastic anemia & MDS
● Two categories: ● Agranulocytosis
○ Proliferative disorders ○ caused by agents that suppress or destroy granulocyte
➔ which there is an expansion of leukocytes precursors is associated with marrow hypocellularity.
➔ can be reactive (infections or inflammatory ● Infections- common consequence of agranulocytosis.
processes) or neoplastic Typically deep, undermined, and covered by gray to green-
○ Leukopenia black necrotic membranes from which numerous bacteria or
➔ which are defined as a deficiency of leukocytes fungi can be isolated.
● Increased growth- reactive leukocytosis, neoplastic ○ Ulcerating necrotizing lesions of the gingiva
● Decreased: leucopenia (neutropenia, lymphopenia) ○ floor of the mouth,buccal mucosa
● Reactive proliferation of white cells and lymph nodes: ○ pharynx
o Leukocytosis ○ oral cavity (agranulocytic angina)
o Lymphadenitis ● Less frequently: ulcerative lesions occur in the skin, vagina,
o Hemophagocytic lymphocytosis anus, or gastrointestinal tract. Severe life-threatening invasive
bacterial or fungal infections may occur in the lungs, urinary
LEUKOPENIA tract and kidneys
● Leucopenia: usually neutropenia (agranulocytosis) ● Neutropenic patients are at particularly high risk for deep
○ susceptibility to infection (bacterial, fungal) fungal infections caused by Candida and Aspergillus.
○ Lymphopenia: loss of activated T-cells in lymph node ● Sites of infection often show a massive growth of organisms
➔ Increased adhesion to endothelial cells with little leukocytic response.
➔ Ex: Malaria, viral infection, typhoid, HIV, steroid ● In some instances, bacteria grow in colonies (botryomycosis)
treatment, malnutrition, drugs. resembling those seen on agar plates.
➔ Acute viral infection:
 Lymphopenia: due to lyphocute redistribution
rather than decrease in number of lymphocyte in CONSEQUENCE
the body ● Increased infection, fungal infection
 Induce production of type I IFN which activates ○ Agranulocytosis: (marked reduction in neutrophils, has the
lymphocyte and change expression of surface serious consequence of making individuals susceptible to
protein that regulate T cell migration bacterial and fungal infections)
➔ overwhelming infection, sepsis
PATHOGENESIS
● Inadequate or ineffective granulopoiesis is observed in: CLINICALFEATURES
o HSC suppression (Ex. Aplastic anemia) ● symptoms and signs of neutropenia
➔ in these conditions, granulocytopenia is accompanied ○ include malaise, chills, and fever, often followed by marked
by anemia and thrombocytopenia weakness and fatigability
○ Drugs- suppress committed granulocyte ○ With agranulocytosis
○ BM defective precursors - ineffective hemopoiesis (Ex. ➔ infections are often overwhelming and may cause
Megaloblastic anemia, myelodys. syn) which defective death within hours to days
precursors die in the marrow.
○ Congenital - gene defect (e.g., Kostmann syndrome) TREATMENT
● Increased destruction or sequestration of neutrophils in
the periphery occurs with: ● Broad spectrum antibiotics for fulminant infections
o Immunologically mediated injury to neutrophils: can be ● Myelosuppressive chemotherapy
idiopathic or caused by drugs ○ G-CSF-stimulate BM precursors
o Splenomegaly: splenic enlargement ➔ a growth factor that stimulates the production of
o Increased peripheral utilization: overwhelming bacterial, granulocytes from marrow precursors.
fungal or rickettsial infection
● DRUG TOXICITY: most common cause of agranulocytosis
Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

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PATHOLOGY
Spleen, & Thymus
LEUKOCYTOSIS Table 13.3 Causes of Leukocytosis

● Leukocytosis Type of Leukocytosis Causes
○ refers to an increase in the number of white cells in the Neutrophilic Acute bacterial infections, especially those
blood leukocytosis caused by pyogenic organisms; sterile
inflammation caused by, for example, tissue
PATHOGENESIS necrosis (myocardial infarction, burns)
● Peripheral blood leukocyte count is influenced by several Eosinophilia Allergic disorders such as asthma, hay fever,
factors, including parasitic infestations; drug reactions; certain
○ Size of the myeloid and lymphoid precursor and storage malignancies (e.g., Hodgkin and some non-
cell pools in the bone marrow, thymus, circulation, and Hodgkin lymphomas); autoimmune disorders
peripheral tissues. (e.g., pemphigus, dermatitis herpetiformis) and
○ Rate of release of cells from the storage pools into the some vasculitides; atheroembolic disease
circulation. (transient)
○ proportion of cells that are adherent to blood vessel walls Basophilia Rare, often indicative of a myeloproliferative
at any time (the marginal pool) neoplasm (e.g., chronic myeloid leukemia)
○ rate of extravasation of cells from the blood into tissues
Monocytosis Chronic infections (e.g., tuberculosis), bacterial
● Maintenance of WBC hemostasis endocarditis, rickettsiosis, and malaria;
○ for growth, maturation and extravasation of WBC- autoimmune disorders (e.g., systemic lupus
cytokines, SGF, adhesion molecules erythematosus); inflammatory bowel diseases
● Important cause: Infection (Increase BM, neutrophil, TNF, IL-1) (e.g., ulcerative colitis)
● If prolonged infection- enter T cells and macrophages Lymphocytosis Accompanies monocytosis in many disorders
● Increased GA. Maturation of neutrophil progenitor associated with chronic immunologic
● IL-5 increased eosinophils stimulation (e.g., tuberculosis, brucellosis); viral
● In sepsis- leukocytosis with morphologic changes like infections (e.g., hepatitis A, cytomegalovirus,
➔ Toxic granule (neutro. cytoplasm) Epstein-Barr virus); Bordetella pertussis
➔ Dohle bodies (dilated ER) infection
➔ Cytoplasmic granules
LYMPHADENITIS
● Precursors in central/primary lymphoid organs
● Lymphocyte circulate through blood under influence of
chemokines and cytokines then home to peripheral/secondary
lymphoid tissue (lymph node, spleen, tonsil, adenoid, peyers
patches)
● Lymph node are discreaste encapsulated structure that contain
separate B cell & T cell zone
● Lymph node antigen stimulation
o B-zone
→ Primary follicle enlarge; develop pale staining
germinal centers
→ B cell acquire capacity to make high affinity
antibodies against antigens
o T-zone
→ Paracortical region undergo hyperplasia
ACUTE NONSPECIFIC LYMPHADENITIS

Reactive changes in cases of sepsis  Acute lymphadenitis in:
Reactive o Cervical region: infection of teeth or tonsil
changes in cases o Axillary or inguinal region: infection in extremities
of sepsis 1 o Mesenteric LN: acute appendicitis, inflammatory
o’clock position & conditions involving gut
center: plenty of o Acute generalized lymphadenopathy: systemic viral
cytoplasmic infection and bacteremia
granules 6  Nodes involved:
o’clock position o Swollen and painful
normal 7 o’clock o Become fluctuant when abscess is extensive
o Healing of lesion is associated with scarring
position: dilated
dohle body

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PATHOLOGY
Spleen, & Thymus
Morphology  An immature dendritic cell that gives rise to a

 Nodes are swollen, gray-red and engorged spectrum of neoplastic disorders referred to as the
 Microscopic: Langerhans cell histiocytoses
 When caused by pyogenic bacteria: neutrophils are
prominent; centers of follicle may undergo necrosis
CHRONIC NONSPECIFIC LYMPHADENITIS

Morphology
Follicular Hyperplasia
 Caused by activated humoral response
 Presence of large oblong germinal centers (secondary
follicles) surrounded by small resting naïve B cells (mantle
zone)
 Germinal center as 2 distinct regions:
1. Centroblast: dark zone with proliferating blast like B
cells
2. Centrocyte: light zone composed of B cell with
irregular nucleus
 Causes: RA, toxoplasmosis, early HIV infection
Paracortical Hyperplasia
 Caused by stimuli that trigger T cell mediated immune
response
 T cell region contain immunoblast activated T cells 3-4x the
size of resting lymphocyte
 Expanded T cell zone may efface B cell follicles
 Hypertrophy of sinusoidal and vascular endothelial cells
accompanied by infiltrating macrophages and eosinophils
Sinus Histiocytosis/Reticular Hyperplasia
 Increased number and size of endothelial cells that line
lymphatic sinusoids
 Increased numbers of intrasinusoidal macrophages
 Prominent in LN draining cancers
PART II: NEOPLASTIC PROLIFERATION OF WBC

OVERVIEW MUTATION:
 Malignancies are clinically the most important disorders of white  Loss of function (interference)
cells. These diseases fall into three broad categories:  Gain of function (abnormal increase reactivity)
o Lymphoid neoplasms – include diverese group of tumors 1. Oncoproteins
from origin of: o Block normal functions
→ B-cell o Protect cells from apoptosis
→ T-cell
→ NK-cell 2. Enable self-renewal (like stem cells they continue to grow)
o Myeloid neoplasms – arise from early hematopietic o Activates TK-Act. RAS-NBK/AKT and MAP
progenitors. Three categories: 3. Inhibit apoptosis
→ Acute myeloid leukemias (AMLs) o Abnormal cells will not die, because apoptosis is
 immature progenitor accumulate in the bone marrow inhibited
→ Myelodysplastic syndromes (MDSs)
 associated with with ineffective hematopoiesis
 resultant peripheral blood cytopenias ETIOLOGIC FACTORS:
→ Myeloproliferative neoplasms 1. Chromosomal translocations:
 in which increased production of one or more o When chromosomal translocations happen maturation
terminally differentiated myeloid elements (e.g., is block and cell renewal is enhanced
granulocytes)  elevated peripheral blood counts
2. Inherited genetic factor
o Histocytoses
→ “tissue cell”, uncommon proliferative lesions of o When genetic factor is inherited there will be genomic
macrophages and dendritic cells instability (commonly seen in leukemias)
→ Langerhans cell 3. Viruses
o Infection by viruses (intracellular)
o lymphotropic viruses: EVB, HTLVI-I, HHV8 (Kaposi

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PATHOLOGY
Spleen, & Thymus
sarcoma) peripheral blood

o can suppress immune function or activate oncogenes
(HTLV-I,II,V) and HIV-1 Table 13.4 WHO: Classification of Lymphoid Neoplasms
4. Chronic inflammation
o H. pylori gastritis, B cell lymphoma, T cell lymphoma-glutten
sensitive enteropathy,
o HIV (increased risk of B cell lymphoma)
5. Iatrogenic
o Radiation (mutagenic) increase the risk of myeloid and
lymphoid neoplasm
o Chemo drugs which can act on hematolymphoid progenitor
cells
6. Smoking
o Incidence of AML is increased to 1.3 to 2 times risk,
presumably due to benzene exposure, in tobacco
Pathogenesis of white cell malignancies. Various tumors harbor

mutations that principally effect maturation or enhance selfrenewal drive
growth, or prevent apoptosis.
LYMPHOID NEOPLASMS
 Leukemia: WBC increase in peripheral blood & widespread
lymphoid cells
o Lymphocytic: tumor cells replacing the bone marrow (BM)
 If bone marrow is replaced the BM hematopoietic cells
is diminished
o Plasma cells: bone destruction (fracture-pain)
 Lymphoma: Tissue Mass produced by Lymhpocytes and WBC
can be reversed
 Can be reversed: that mass can produce a leukemia or a
leukemia can produce a mass.
 Clinical presentation: depends on anatomic distribution
 Other symptoms: due to proteins from tumor cells
ADDITIONAL TERMINOLOGIES
 Leukemia – abnormal cells present in both the BM & blood
 Aleukemic leukemia – abnormal cells confined to the bone
marrow and do not circulate
 Lymphoma – neoplastic growth of cells confined to lymphatic
tissue (lymph nodes)
 Leukemic lymphoma – lymphoma spread to the bone marrow and

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PATHOLOGY
Spleen, & Thymus
Immune Cell Antigens Detected by Monoclonal Antibodies Pathogenesis

→ Notch signal pathway mutation:
o mutation in TK and RAS sequence
o 90% of AKL (normal chromosomal changes)
o T/B maturation – immature and maturation is defective;
defective stimulus
Robbins & Cotran 10th 3ed
T-ALL
 Mutation in NOTCH1: gene essential for T cell
development
B-ALL
 Mutation in gene (PAX5, TCF, EVT6, RUNX1) required
for proper differentiation of early hematopoietic
precursiors
Morphology
→ There is bone marrow replacement by lymphoblasts
→ Lymphoblast cells:
o Condensed nuclear chromatin
o Small nucleoli
o Agranular cytoplasm
Acute lymphoblastic leukemia

A. Lymphoblasts with
condensed nuclear
chromatin, small
nucleoli, and scant
agranular cytoplasm.
(B and C Phenotype of
ALL shown in (A)
analyzed by flow
cytometry.
B. The lymphoblasts
represented by the red
dots express terminal
deoxynucleotidyl
transferase (TdT) and
the B-cell marker CD22.
C. The same cells are
positive for two other
markers, CD10 and
CD19, commonly expressed on pre-B lymphoblasts. Thus this is a B-
ALL.
I. Precursor B/T cell Neoplasms

 ALL (Acute Lymphoblastic Leukemia/Lymphoma)
o Blast meaning “Pre or immature” – Pre-T, Pre-B lymphoblast
 85% are B cell ALL
o Acute leukemia in childhood <15 years old (common)
o T-ALL: adolescents, male (less common)

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PATHOLOGY
Spleen, & Thymus
Table 13.6: Neoplasms of Immature B and T Cells → Generalized lymphadenopathy

Diagnosis B-cell T-cell → Testicular enlargement
Acute lymphoblastic Acute → In T-ALL complications are related to compression of
leukemia/lymphoma lymphoblastic large vessels and airways in the mediastinum.
leukemia/lymphoma o CNS manifestations:
Cell of Bone marrow precursor B Precursor T cell → Headache, vomitting, nerve palsies (meningeal
Origin cell (often of thymic spread common in ALL)
origin)  Most common abberation in ALL alter the function of
Genotype Diverse chromosomal Diverse transcription factors, the t(9;22) instead creastes a fusion
translocations; t(12;21) chromosomal hene that encodes constitutively active BCR-ABL tyrosine
involving RUNX1 and translocations; kinase which is found in Chronic Myelogenous Leukemia
ETV6 present in 25% NOTCH1 mutations (CML)
(50%–70%)
Salient Predominantly children; Predominantly Treatment
Clinical symptoms relating to adolescent males;  Chemotherapy: 95% child survival; 30-30% adults
Features marrow replacement and thymic masses and  Better prognosis:
pancytopenia; aggressive variable bone o 2-10 years
marrow involvement; o low white cell count
aggressive o hyperploidy
o trisomy of chromosome 4, 7 and 10
Microscopic (ALL) o Presence of a t(12-21)
 “Starr Sky” pattern- diffuse infiltrates with lymphocytes (increase  Worse prognosis:
mitosis, convoluted nuclear membrane) o <2 years old: because of the strong association of infantile
 Macrophages containing debris “Stars” ALL with translocations involving the MLL gene
 Leukemic presentation: marrow is hypercellular and packed o Presensation in adolescence or adulthood
with lymhpblasts o Peripheral blast counts >100,000 (reflecting high tumor
 Starry sky appearance: interspersed macrophages ingesting burden)
apoptotic tumors  Cells with t(9-22)
 Histochemical stains:  BCR-ABL tyrosine kinase = NH3 +CT
o Lymphoblast: MPO negative; PAS positive  Intensive chemotherapy
o not usually given to older patients
Immunophenotype o curative in children
 95% Pre-T/Pre-B lymphoblasts with TdT
SUMMARY FOR ALL
 Tdt (terminal deoxynucleotidyl transferase)
→ a specialized DNA polymerase that is expressed only in  Pre-T, Pre-B (most common malignancy in children)
pre-B and pre-T lymphoblasts, is positive in more than 95%  BM decreased function due to replacement by neoplasms
of cases  Both T/B cells occur as immature blasts
 B-ALL: (+) CD19, CD20 (immature-negative)  Those with TK (BCR/ABL) abnormality reaction with NH3 +
o Immature B-ALL: CD10 negative chemotherapy  highly effective in child; less effective in adult
o More mature “late pre-B”: (+) CD10, CD19, CD20, u chain  Note A subset of tumors contains activating mutations in tyrosine
 T-ALL: (+) CD1, CD2, CD1, CD7 kinases (e.g., BCR-ABL) that are important targets of therapy
o Immature T-ALL (-) CD3, CD4, CD8
o More mature “late pre-T”: (+)CD3, CD4, CD8 II. Peripheral B-cell neoplasms
Clinical features: A. Chronic lymphocytic leukemia/Small cell lymphoma
 Accumulation of neoplastic “blasts” in the bone marrow  Chronic lymphocytic leukemia (CLL) and small lymphocytic
suppresses normal hematopoiesis by: lymphoma (SLL) differ only in the degree of peripheral blood
→ physical crowding lymphocytosis.
→ competition for growth factors, and other poorly understood  Most affected patients have sufficient lymphocytosis to fulfill the
mechanisms. diagnostic requirement for CLL (absolute lymphocyte count
 Common features and characteristic of ALL: >5000/mm3).
o Abrupt stormy onset: within days to weeks of 1st symptoms  CLL is the most common leukemia of adults in the Western
o Depression of marrow function world.
→ Fatigue - due to anemia
 The median age at diagnosis is 60 years, and there is a 2:1
→ Fever – reflecting infections secondary to neutropenia
male predominance. In contrast, SLL constitutes only 4% of
→ Bleeding – due to thrombocytopenia
NHLs.
o Mass effects caused by neoplastic infiltration (common in
ALL)
→ Bone pain – due to marrow expansion and infiltration
of the subperiosteum

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PATHOLOGY
Spleen, & Thymus
Pathogenesis Fig: CLL presenting with smudge cells (yellow arrow)

 most common genetic anomalies are deletions of 13q14.3, 11q, A characteristic finding is
and 17p and trisomy 12q. the presence of disrupted
 Molecular characterization of the region deleted on tumor cells (smudge
chromosome 13 has implicated two microRNAs, miR-15a and cells), two of which are
miR-16-1, tumor suppressor genes. present in this smear. A
o Loss of these mIRs is believed to result in overexpression coexistent autoimmune
of the anti-apoptotic protein BCL2, which is uniformly hemolytic anemia
observed in CLL/SLL explains the presence of
 Origin: memory cells in post germinal center spherocytes (red arrow)
o Arise from new B cells or naïve cells
(hyperchromatic, round
o Growth confined to proliferative centers
erythrocytes)
o 10-15% affect notch signaling pathway
o Proliferative centers expressed factors that stimulate the Orthochromic erythroblast (Nucleated RBC orange arrow)
activity of transcription factors nuclear factor kappa B (NF-
kB) which promote cell survival and MYC which promote Immunophenotype
cell growth  Positive B markers
o CD19, CD20, CD29
Morphology o High BCL2
 Lymph nodes are diffusely effaced by predominantly small o Low expression of surface Ig (IgG, IgM, IgD)
lymphocytes 6 to 12 μm in diameter with round to slightly
irregular nuclei, condensed chromatin, and scant cytoplasm. Clinical features:
 Proliferation centers  often asymptomatic at diagnosis
o are variable numbers of larger activated lymphocytes  When symptoms appear, they are nonspecific and include:
that often gather in loose aggregates o easy fatigability
o Ccontain mitotically active cells o weight loss, and anorexia
o pathognomonic for CLL/SLL. o Generalized lymphadenopathy & hepatosplenomegaly
 PBS: the blood contains variable numbers of small round are present in 50% to 60% of symptomatic patients.
lymphocytes with scant cytoplasm.  The leukocyte count is highly variable;
 Smudge cells are present in smears o leukopenia can be seen in individuals with SLL and
 The bone marrow, spleen, and liver also are involved, albeit marrow involvement
to widely varying degrees. o > 200,000/mm3 are sometimes seen in CLL patients
with heavy tumor burdens
Small lymphocytic lymphoma/chronic lymphocytic leukemia o small monoclonal Ig “spike” is present in the blood of
(lymph node) some patients.
o Monoclonal lymphocytosis
(A) Low-power view → Asymptomatic patients with monoclonal B cells in
shows diffuse effacement peripheral blood
of nodal architecture.
→ Considered precursor lesion and progresses to CLL
at a rate of 1% per year
o Hypogammaglobulinemia
o increase susceptibility to infection particularly
caused by bacteria
o Hemolytic anemia & thrombocytopenia
o Due to autoantibodies made by nonneoplastic B
cells
(B) At high power the
majority of the tumor Prognosis
cells are small round  Extremely variable and depend primarily on the clinical stage
lymphocytes.  Median survival is 4 to 6 years but is more than 10 years in
A prolymphocyte, a individuals with minimal tumor burden at diagnosis
larger cell with a centrally  Worse outcome include:
placed o the presence of deletions of 11q and 17p (the latter
nucleolus, is also present involving TP53)
in this field (arrow) o a lack of somatic hypermutation
o expression of ZAP-70, a protein that augments signals
produced by the Ig receptor
o presence of NOTCH1 mutations

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Treatment o characteristically takes the form of paratrabecular

 Symptomatic patients are generally treated with “gentle” lymphoid aggregates.
chemotherapy and immunotherapy with antibodies against  The splenic white pulp and hepatic portal triads are also
proteins found on the surface of CLL/SLL cells, particularly frequently involved.
CD20. Figure 13.10 Follicular lymphoma (lymph node).
 Newly available, highly active targeted therapies include
o BTK inhibitors and BCL2 inhibitors
 Tendency of CLL/SLL to transform to a more aggressive tumor
o Factor that impacts patient survival is the. Most
commonly this takes the form of a transformation to
diffuse large B-cell lymphoma (DLBCL), so-called
Richter syndrome (approximately 5% to 10% of
patients). A B
 Richter syndrome
o development of a rapidly enlarging mass within a lymph (A) Nodular aggregates of lymphoma cells are present throughout
node or the spleen. lymph node.
o associated with acquisition of new abnormalities (B) At high magnification, small lymphoid cells with condensed
involving TP53 or MYC chromatin and irregular or cleaved nuclear outlines (centrocytes) are
o most patients surviving less than 1 year. mixed with a population of larger cells with nucleoli (centroblasts).
Immunophenotype
B. Follicular Lymphoma
 neoplastic cells closely resemble normal germinal center B
 In US: most common indolent NHL (less common in Europe. rare
cells, expressing CD19, CD20, CD10, surface Ig, and BCL6.
in Asia)
 CD5 is not expressed (CD5 negative)
 Usually presents in middle age
 BCL2 is expressed in more than 90% of cases, in distinction to
o Males and females are equally affected
normal follicular center B cells, which are BCL2-negative
Pathogenesis
Clinical Features (Incurable)
 90% mutation of KMT2D gene (code epigen)
 Follicular lymphoma tends to present with:
 KMT2D gene
o painless, generalized lymphadenopathy
o encodes a histone methyltransferase, suggesting that
epigenetic abnormalities such as changes in the patterns  Involvement of extranodal sites, such as:
of histone marks have an important role in this neoplasm. o Gastrointestinal tract
o central nervous system
 Strongly associated with chromosomal translocations
o or testis, is relatively uncommon.
involving BCL2.
o Its hallmark is a (14;18) translocation that juxtaposes the  Incurable
IGH locus on chromosome 14 and the BCL2 locus on  Usually follows an indolent waxing and waning course
chromosome 18  Survival (median, 7 to 9 years) is not improved by aggressive
o The t(14;18) is seen in up to 90% of follicular lymphomas therapy
and leads to overexpression of BCL2
 BCL2 Treatment (Palliative)
o antagonizes apoptosis and promotes the survival of  Not improved by aggressive therapy; hence:
follicular lymphoma cells o palliate patients with low-dose chemotherapy or
immunotherapy (e.g., anti-CD20 antibody) when they
Morphology become symptomatic.
 Diffuse or nodular growth pattern is observed in involved lymph  Responsive to inhibitors of B-cell receptor signaling (e.g., BTK
nodes. inhibitors) and inhibitors of BCL2.
 Two principal cell types are present in varying proportions:  Transformation to LCBCL (30-50%) survival less than a year
o centrocytes (majority)  Histologic transformation occur mostly occur to DLCBL –
→ “small cleaved cells” frequently associated with abberation that increase expression
→ small cells with irregular or cleaved nuclear contours of MYC which drives Warburg metabolism and rapid cell growth
and scant cytoplasm
o centroblasts C. Diffuse Large B cell Lymphoma
→ larger cells with open nuclear chromatin, several
 Most common form of NHL.
nucleoli, and modest amounts of cytoplasm
 Slight male predominance.
 Peripheral blood involvement (seen in about 10% of cases)
o 10% centroblasts  The median patient age is about 60 years, but DLBCL also
o sufficient to produce lymphocytosis (usually <20,000 occurs in young adults and children.
cells/mm3)
 Bone marrow involvement (occurs in 85% of cases)
o 85% paratrabecular lymhpoid aggregates

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Pathogenesis: Heterogenous Diffuse large B-cell lymphoma

 Molecularly heterogeneous
 Dysregulation of BCL6 Diffuse large B-cell lymphoma.
o Lesions are hypothetically due to overexpression of BCL6 Tumor cells have large nuclei,
o BCL6 open chromatin, and prominent
→ A DNA-binding zinc-finger transcriptional repressor nucleoli.
that is required for the formation of normal germinal Very big and have a very
centers. prominent nucleoli.
→ represses the expression of factors that normally
serve to promote germinal center B-cell
differentiation, growth arrest, and apoptosis, and each
of these effects is believed to contribute to the Immunophenotype
development of DLBCL  mature B-cell tumors express CD19 and CD20
o 30% of DLBCLs contain various translocations that have in  show variable expression of germinal center B-cell markers
common a breakpoint in BCL6 at chromosome 3q27. such as CD10 and BCL6.
o Acquired mutations in BCL6 promoter sequences that  Most have surface Ig.
abrogate BCL6 autoregulation (an important negative-  High-level expression of both MYC and BCL2 proteins is seen
regulatory mechanism) are seen even more frequently. in some cases and may predict more aggressive behavior.
 Overexpression of BCL2 (increase anti-apoptotic BCL2) Special Subtypes

o 10% to 20% of tumors are associated with the t(14;18)
 Immunodeficiency associated large B-cell lymphoma
(discussed earlier under Follicular Lymphoma), which leads
o Occurs in the setting of T-cell immunodeficiency:
to the overexpression of the antiapoptotic protein BCL2.
→ Advanced HIV infection
o Tumors with BCL2 rearrangements usually lack BCL6
→ Recipient of organ or HSC transplants
rearrangements, suggesting that these rearrangements o Neoplastic B cells are usually infected with EBV
define two distinct molecular classes of DLBCL. Some
o Restoration of T-cell immunity  regression of proliferation
tumors with BCL2 rearrangements may arise from
 Primary effusion lymphoma
unrecognized underlying follicular lymphomas, which
o Presents as malignant pleural or ascetic effusion
frequently transform to DLBCL.
→ Mostly in patients with advanced HIV infection
o Tumor cells are anaplastic
 Translocations involving MYC
o No expression of surface B- or T-cell markers
o Roughly 5% of DLBCLs o (+) clonal IGH gene rearrangements
o These tumors may have a distinctive biology.
o All tumor cells are infected with HHV-8
 Finally, sequencing of DLBCL genomes has identified frequent Clinical features:
mutations in genes encoding histone acetyltransferases such as
p300 and CREBP, proteins that regulate gene expression by  Aggressive tumors (rapidly fatal without treatment)
modifying histones and altering chromatin structure.  DLCBL with MYC translocation have worse prognosis
 Rapidly enlarging mass at a nodal or extranodal site
Morphology o Waldeyer ring (oropharyngeal lymphoid tissue is commonly
involved)
 relatively large cell size (usually four to five times the diameter
→ Tonsils
of a small lymphocyte)
→ Adenoids
 Diffuse pattern of growth
 Destructive masses: Primary or secondary involvement of the
 Nuclei: liver and spleen
o Round or oval appearing vesicular due to chromatin
Treatment:
margination to the nuclear membrane
o Multilobated or irregular nuclei are prominent  intensive combination chemotherapy, 60% to 80% of patients
o Nucleoli may be 2 to 3 or single and centrally placed achieve a complete remission
 Cytoplasm:  40% to 50% are cured
o Moderately abundant  Adjuvant therapy with anti-CD20 antibody improves both the
o Pale or basophilic initial response and the overall outcome.
 Mutation in gene encoding histone
 More anaplastic tumors contain multinucleated cells with large Prognosis
inclusion-like nucleoli that resemble Reed-Sternberg cells  Fatal-aggressive (without treatment)
(malignant cell of Hairy cell Leukemia)  Adjuvant therapy with anti-CD20 antibody improves the outcome
 DLBCLs with MYC translocations have a worse prognosis than
those without
o may be better treated with chemotherapy regimens that are
now standard for Burkitt lymphoma.
 CAR T cells directed against the B-cell antigen CD19
o for the treatment of patients with relapsed refractory DLBCL.

10
PATHOLOGY
Spleen, & Thymus
D. Burkitt Lymphoma o An important regulator of gene expression in germinal B

cells
 Categories (these 3 are histologically identical; distinct clinical, o Drives the expression of cyclin D that collaborates with
genotypic and virologic characteristics) MYC to enable very rapid growth that characterize Burkitt
o African (endemic) Burkitt lymphoma lymphoma
o Sporadic (nonendemic) Burkitt lymphoma
o Subset of aggressive lymphomas occurring in individuals IMMUNOPHENOTYPE
with HIV
 Tumors of mature B cells that express surface IgM, CD19,
Pathogenesis CD20, CD10, and BCL6
o A phenotype consistent with a germinal center B-cell origin.
 All forms of Burkitt lymphoma are associated with
 Almost always fails to express the antiapoptotic protein BCL2
translocations of the MYC gene on chromosome 8 
increased MYC protein levels.
 MYC CLNICAL FEATURES
o Master transcriptional regulator that increases expression of
genes for aerobic glycolysis  Endemic and sporadic Burkitt lymphomas: mainly in children or
o Pro-growth, increase in growth activity  rapid growth young adults;
o Warburg effect  Most tumors manifest at extranodal sites.
 Endemic Burkitt lymphoma
→ Allows cells to biosynthesize building blocks needed o often presents as a mass involving the mandible
for growth and cell division o shows an unusual predilection for involvement of abdominal
 All endemic category: there is EBV infection (1/4 HIV) viscera particularly:
Morphology → the kidneys, ovaries, and adrenal glands

 Sporadic Burkitt lymphoma
 effaced by a diffuse infiltrate of intermediatesized lymphoid
o most often appears as a mass involving the ileocecum and
cells
peritoneum
 Tumor exhibits a high mitotic index & contains numerous o Involvement of the bone marrow and peripheral blood is
apoptotic cells uncommon, especially in endemic cases.
 Phagocytes have abundant clear cytoplasm, creating a  Burkitt lymphoma is very aggressive but responds well to
characteristic “starry sky” pattern intensive chemotherapy.
 Bone marrow o Most children and young adults can be cured
o aspirates reveal tumor cells with slightly clumped nuclear o The outcome is more guarded in older adults.
chromatin, two to five distinct nucleoli, and royal blue
cytoplasm containing clear cytoplasmic vacuoles.
E. Mantle Cell Lymphoma
Burkitt lymphoma  Uncommon lymphoid neoplasm
 Presents in the 5th to 6th decades (male predominance)
 Resemble the normal mantle zone B cells that surround germinal
centers
Mantle Cell Lymphoma
A B
(A) At low power, numerous pale
tingible body macrophages are evident, producing a “starry sky” B
appearance.
(B) At high power, tumor cells have multiple small nucleoli and high
A B
mitotic index. The lack of significant variation in nuclear shape and (A) At low power, neoplastic lymphoid cells surround a small,
size lends a monotonous appearance. atrophic germinal center, producing a mantle zone pattern of
 MYC translocation partner is usually the IGH locuse [t(8;24], Ig K growth.
[t(2;8)], lambda [t(8;22) (B) High-power view shows a homogeneous population of small
 Breakpoints in IGH locus lymphoid cells with somewhat irregular nuclear outlines, condensed
o Spoadic Burkitt: calss switching region chromatin, and scant cytoplasm. Large cells resembling
o Endemic BurkittL lie within more 5’ V(D)J sequence prolymphocytes (seen in chronic lymphocytic leukemia) and
 Both type of translocation can be induced in germinal center B centroblasts (seen in follicular lymphoma) are absent.
cells by AID, a specialized DNA modifying enzyme required for
both Ig class swithcing and somatic hypermutation
 Most umor have mutation that increase actiity of transcription
factor TCF3 and E2A

11
PATHOLOGY
Spleen, & Thymus
Pathogenesis  More mutation – clonal evolvement (B-cell survival)

 Virtually all mantle cell lymphomas have an (11;14) translocation
involving the IGH locus on chromosome 14 and the cyclin D1 G. Hairy Cell Leukemia
locus on chromosome 11  overexpression of cyclin D1.  rare but distinctive B-cell neoplasm constitutes about 2% of all
 The resulting up-regulation of cyclin D1 promotes G1- to S- leukemias.
phase progression during the cell cycle  It is predominantly a disease of middleaged white males, with a
median age of 55 and a male-to female ratio of 5:1.
MORPHOLOGY Pathogenesis
 generalized lymphadenopathy  more than 90% of cases with activating point mutations in the
 20% to 40% have peripheral blood involvement. serine/threonine kinase BRAF
o Irregular, cleaved nuclei, no centroblasts o which lies immediately downstream of RAS in the
 Extranodal involvement include: MAPK signaling cascade
o bone marrow, spleen, liver, and gut.  specific mutation
 Occasionally, mucosal involvement o a valine to glutamate substitution at residue 600 is also
o small bowel or colon produces polyp-like lesions found at high frequencies in many other neoplasms,
(lymphomatoid polyposis) including:
o of all forms of NHL, mantle cell lymphoma is most likely
to spread in this fashion. → melanoma and Langerhans cell histiocytosis
MMUNOPHENOTYPE Morphology
 expresses  Best recognized with phase contrast microscope: fine hair-like
o high levels of cyclin D1, CD19, and CD20 projections
o moderately high levels of surface Ig (usually IgM and  PBS: Hairy cells (round, oblong, or reniform nuclei, condencsed
IgD with κ or λ light chain). chromatin and pale cytoplasm)
 This tumor is usually CD5+ and CD23−  You have to do a BM biopsy
o distinguish it from CLL/SLL.  BM biopsy: Dry tap
 The IGH genes lack somatic hypermutation, supporting an origin o Cells emeshed in ECM composed of reticulin fibrils are
from a naive B cell. usually inaspirable
 NOTE: Cyclin is “pro-growth”  Splenic red pulp – usually heavily infiltrated  obliteration of
white pulp and a beefy gross appearance
CLINCIAL FEATURES  Hepatic portal triads are involved frequently
 Large painless lymphadenopathy Hairy cell leukemia (peripheral blood smear).
 50%: spleen, and gut involvement
PROGNOSIS
 Median survival is 8 to 10 years
 Blastoid variant “proliferative: expression and TP53 mutations –
shorter survivals
TREATMENT
 Moderately aggressive and incurable (A) Phase-contrast microscopy shows tumor cells with fine hairlike
 Palliative treatment cytoplasmic projections.
(B) In stained smears, these cells have round or folded nuclei and
F. Marginal Zone Lymphoma modest amounts of pale blue, agranular cytoplasm. Membrane is
 Encompasses a heterogeneous group of B-cell tumors that arise protruding threadlike
within lymph nodes, spleen, or extranodal tissues.
 Nodal and Extranodal Immunophenotype
 Mucosa-associated lymphoid tumors (or MALTomas)  typically express the pan-B-cell markers:
o Extranodal tumors were initially recognized at mucosal o CD19 and CD20; surface Ig (usually IgG);
sites  certain relatively distinctive markers:
 Origin: Memory B cell o CD11c
 Tissues with infection or autoimmune reaction: o CD25
o Sjogren’s syndrome (salivary gland) o CD103
o Hashimoto’s thyroiditis o annexin A1.
o H. pylori (gastritis)
 Localized growth – spreads late may regress (if inciting agent is
eradicated) or spread and transforms to DCBCL

12
PATHOLOGY
Spleen, & Thymus
Clinical Features  In infected tissues or autoimmune disease

 Manifestations result from infiltration of the BM, liver and spleen  Transform to DLBCL
 BM involved 7. Hairy Cell Leukemia
 Splenomegaly (most common)  Very indolent tumor of mature B cells
 Hepatomegaly (less common)  Involves spleen, liver and marrow
 Pancytopenia (50% of cases):  Mutations in the BRAF serine/threonine kinase
o due to marrow involvement and sequestration of cells  Mature B-cells: BM biopsy “Dry Tap”
in the enlarged spleen  50% pancytopenia; Cells with Hairy extensions
 Increased incidence of atypical mycobacterial infections
o Related to monocytopenia PERIPHERAL T AND NK CELL NEOPLASM
Treatment  Peripheral T-cell tumors make up about 5% to 10% of NHLs in
 sensitive to “gentle” chemotherapeutic regimens, which the United States and Europe, while NK-cell tumors are rare.
produce long-lasting remissions.  By contrast, for unknown reasons both T- and NK-cell tumors
 Tumors often relapse after 5 or more years, yet generally occur more frequently in the Far East.
respond well when retreated with the same agents, a feature
that is highly unusual among human cancers. 1. Peripheral T-cell Lymphoma
 BRAF inhibitors appear to produce excellent responses in
tumors that have failed conventional chemotherapy.  Non specified
 Overall prognosis is EXCELLENT  T cell markers express:
o CD2, CD3, CD5, and either αβ or γδ T-cell
Summary: Peripheral B cell Neoplasm receptors.
1. CLL/SCL: most common leukemia in adults o Some also express CD4 or CD8; such tumors are taken
 B cell tumor (+CD19, CD20), effaced Lymph nodes to be of helper or cytotoxic T-cell origin, respectively
 Susceptible to infections, autoimmune  Generalized lymphadenopathy, fever, pruritus
 Indolent course  Worse prognosis: when transformed to DLBCL
2. Follicular Lymphoma: most common indolent tumor in adults  DNA analysis: used to confirm presence of clonal T cell
 Tumor cells racapitulate hte growth pattern of normal germinal receptor gene arrangement
center B cels
 Most cases associated with t(14;18)  overexpression of BCL2 2. Anaplastic, Large cell lymphoma (ALK+)
 Increased B cell markers
 Cells similar to normal growth, 30-50% transform to LCBCL  Uncommon, with ALK gene re-arrangement (chromosome
 Incurable, poor prognosis, palliative treatment 2p23)
3. DLBCL: most common lymphoma of adults; aggressive behavior o These rearrangements break the ALK locus  ALK fusion
 Heterogerogenous group of mature B-cell tumors proteins, constitutively active TK that triggers RAS &
 Rearrangements or mutations of BCL6 gene JAK/STAT sginaling pathways
 1/3 t(14;18) involving BCL2 and may arise from follicular
 Composed of large anaplastic cells, some containing
lymmphomas
 5% translocations involving MYC horseshoe-shaped nuclei and voluminous cytoplasm ( hallmark
 Produce effusions cells)
 Extranodal: Waldeyer ring  Tumor cells cluster about venules and infiltrate lymphoid
 60-80% Rx chemo sinuses, mimicking metastatic carcinoma
4. Burkitt lymphoma  T-cell lymphomas with ALK rearrangements (ALK+)
 Very aggressive tumor of mature B cells
 Usually arises at extranodal sites
o children and young adults
 Mainly in children and you adults o frequently involve soft tissues
 Translocations MYC proto-oncogene o good prognosis
 Produce Warburg effect o cure rate 75% to 80%
 “Starry Sky pattern” o Inhibitors of ALK have produced excellent resposes in some
 With EBV infection, respond to chemo Rx tumors that have failed to respond to conventional
5. Mantle cell lymphoma: not common
chemotherapy
 Tumor of naive B cells that pursues a moderately
aggressive course  T-cell lymphomas ALK-
 Translocation cyclin DI gene o Tend to occur in older adults
 5th, 6th decade; t(11-14) o Worse prognosis
 Incurable  Both ALK+ and ALK- express CD30 (TNF receptor family)
 (-) CD5, CD23 (diff from CLL/SCL)  CD30
6. Marginal Zone Lymphoma (MALToma) o Have significant antitumor activity against CD30+ T-
 Indolent tumors of antigen-primed B cells that arise at sites cell lymphomas & hodgkin lymphoma
of chronic stimulation
 Often remain localized for long period of time (late spread)

13
PATHOLOGY
Spleen, & Thymus
3. Adult T cell leukemia/Lymphoma  Cutaneous leukocyte antigen and the chemokine receptors
CCR4 and CCR10, all of which contribute to the homing of
 neoplasm of CD4+ T cells is observed only in adults infected normal CD4+ T cells to the skin
by HTLV-1
 Course: rapidly progressive (moths – 1 year) 5. Large Granular Lymphocytic Leukemia
o Skin only - indolent
 T- and NK-cell variants of this rare neoplasm are recognized,
 Findings: both of which occur mainly in adults.
o Skin lesions  T-cell disease
o Generalized lymphadenopathy o usually present with mild to moderate lymphocytosis
o hepatosplenomegaly and splenomegaly
 PBS: o Lymphadenopathy and hepatomegaly are usually
o Lymphocytosis (30% to 40% STAT mutation) absent.
 NK-cell disease
o Hypercalcemia
o often presents in an even more subtle fashion
 With HTLV-1 infection o with little or no lymphocytosis or splenomegaly.
o May give rise to progressive demyelinating disease  30% to 40% of large granular lymphocytic leukemias have
of the CNS and spinal cord acquired mutations in the transcription factor STAT3
 Tumor cells o which functions downstream of cytokine receptors.
o Multilobated nuclei “cloverlear” or “flower” cells o These mutations occur in both T- and NK-cell forms of
the disease and result in cytokine-independent
o Always contain clonal HTLV-1 proviruses
activation of STAT3, which appears to have a major
(pathogenic role) role in the pathogenesis of these proliferations.
 PBS: anemia, neutropenia, large lymphocytes with blue granules
Anaplastic large-cell lymphoma.  Indolent course
 Felty syndrome, a triad of:
o rheumatoid arthritis
o splenomegaly
o neutropenia
6. Extranodal T/NK lymphoma

 Most frequently presents as a destructive nasopharyngeal mass;
 Less common sites of presentation include:the testis and the
skin.
(A) Several hallmark cells with horseshoe-like or embryoid nuclei and  The tumor cell infiltrate typically surrounds and invades small
abundant cytoplasm lie near the center of the field. vessels  extensive ischemic necrosis.
(B) Immunohistochemical stain demonstrating the presence of ALK  Touch preparations:
fusion protein. o large azurophilic granules are seen in the cytoplasm of
the tumor cells that resemble those found in normal NK
cells.
4. Mycosis fungoides/Sezary syndrome  Extranodal NK/T-cell lymphoma
 CD4+ helper T cells that home to the skin (producing o highly associated with Epstein-Barr virus (EBV).
plaque). o All of the tumor cells contain identical EBV episomes,
 Median survival: 10 years, transform - TCL indicating that the tumor originates from a single EBV-
 cutaneous lesions of mycosis fungoides typically progress infected cell.
through three somewhat distinct stages: o How EBV gains entry is uncertain, since the tumor
o an inflammatory premycotic phase cells do not express CD21(B-cell EBV receptor)
o plaque phase o Most tumors are CD3− and lack T-cell receptor
o tumor phase rearrangements
 Histologically, the epidermis and upper dermis o Express NK-cell markers, supporting an NK-cell origin.
o infiltrated by neoplastic T cells, which often have a  NK origin – very aggressive, with EBV infection
cerebriform appearance due to marked infolding of the  Treatment: Radiation (not chemotherapy)
nuclear membrane.  Poor prognosis
 Late disease progression is characterized by extracutaneous
spread, most commonly to lymph nodes and bone marrow. Summary: Peripheral T/NK Neoplasm
 Sézary syndrome
1. Anaplastic large cell lymphoma
o a variant in which skin involvement is manifested as a
 Aggressive T cell tumor
generalized exfoliative erythroderma.
o the skin lesions rarely proceed to tumefaction, and  Translocations  constitutive activation of the ALK TK:
there is an associated leukemia of “Sézary” cells with JAK/STAT signaling pathway
characteristic cerebriform nuclei.  70-80% cure with chemo rx- children and young adults

14
PATHOLOGY
Spleen, & Thymus
 Cells: large, horse-shoe shaped nuclei, around veins, o M1P1a (aka CCL3): chemokine, augment osteoclast
sinusoids formation
2. Adult T-cell lekemia/Lymphoma (CD4+ T cells) o WNT pathway: potent inhibitor of osteoblast function
 Aggressive tumor of CD4+ T cells o Net effect: increase bone resorption  hypercalcemia and
 Adults only, associated with HTLV-1 Infection pathologic features
 Skin lesions (also LN, spleen, liver, CNS & spinal cord) ● Lead to plasma cell leukemia
 Cells: “Flower cells” multilobed nuclei, with HTCLV-1 ○ Mutation of NF-KB gene (for B cell survival)
 Indolent: skin only, both rapidly progressive and fatal in ○ Modulation of WNT pathway (inhibit osteoblast)
months despite chemo Rx
3. Mycosis Fungiodes/Sezary Syndrome Immunophenotype
 Skin: CD4+ cells in epidermis & dermis; BM, bone  (+) CD138: adhesion molecule known as syndecan-1
 3 stages: 10 years survival, transforms to T cell  (+) CD56: helpful in identifying small opulation of neoplastic cells
lymphoma
 Sezary syndrome: General exfoliative erythroderma, Clinical Feature
leukemia  Due to
4. Large granular lymphocytic leukemia 1. Effect of plasma cell growth in tissue (bone)
 Indolent tumor of cytotoxic T cells or NK cells 2. Prodution of excessive Igs
 Mutations in the transcription factor STAT3 3. Suppression of normal humoral immunity
 Autoimmune phenomena and cytopenias  Bone resorption  pathologic fractures & chronic pain
 Rare, mainly adilts, splenomegaly (indolent)  Hypercalcemia  confusion, weakness, lethargy, constipation,
 PBS: anemia, neutropenia, large granular (blue) polyuria, renal dysfunction
lymphocytes  Decrease normal Ig  recurrent bacterial infection
 Felty’s syndrome: splenomegaly, neutropenia, RA  Lab analysis:
5. Extranodal NK/T cell lymphoma o Increase lvl of Ig in blood or light chain (BJP) in urine
 Agressive tumor, usually derived from NK cells o Abnormal protein “spike” in serum or urine electrophoresis
 Associated with EBV o >3mg/dL (serum Ig)’ >6mg/dL (urime BJP)
 Destructive nasopharyngeal lesions o Most common Ig: IgG (55%), followed by IgA(25%)
 Radiation therapy
MORPHOLOGY
PLASMA CELL NEOPLASM
● B cell proliferation with plasma cells ● destruction of axial skeleton (ribs, vertebra, pelvis, clavicle,
● Produce “M” monoclonal Ig- (light, heavy chains, Ig) skull, femur) - erode callus bone to cortex- fracture
● Bence Jones protein - in urine (light chain) ● X ray skull: punched out defects (1-2 cm) → it means it is not
● Entities of plasma cell neoplasm
○ Multiple Myeloma calcified
○ Waldenstrom macroglobulinemia syndrome ● BM - 30% plasma cells (blast) - spleen, liver, kidney
○ Heavy chain disease
○ Amyloidosis: Primary immune-associated
○ MGUS - monoclonal gammopathy of undetermined
significance
MULTIPLE MYELOMA
● Associated with lytic cone lesion, hypercalcemia, renal failure,
and acquired immune abnormalities
● 68-70 yrs. average, more in males, 10% cancer death
Pathogenesis
 Genetically heterogenous
○ Deletion of chromosome 17p (TP53)
○ IgM locus rearrangement (chrom. 22q32)
○ Cell cycle cyclin D rearrangement on chromosome
Figure. Whitish areas are the calcified areas and when
11q13→ for cell growth you have defect there is no calcium there and this are the
○ Late stage: rearrabgenebt of MYC (aggressive form infiltrated areas
● Proliferation and survival of myeloma cells are highly
dependent on IL-6: important GF for plasma cells ● Cells:
● Major pathologic feature of MM: factors produce by neoplastic ○ flame cells (red cytoplasm)
plasma cells mediate bone destruction: ○ Mott cells - gray cyto, crystal rods, droplets

15
PATHOLOGY
Spleen, & Thymus
○ Dutcher bodies - nuclear inclusions (whitish) MGUS (MONOCLONAL GAMMOPATHY OF UNDEF.

○ Rusell bodies - globular inclusions (not seen in SIGNIFICANCE)
the picture) ● Most common plasma cell disorder
● Low “M” protein, 50% in 70 yrs or more, ave - 50 yrs
● Early stage of MM development
LYMPHOPLASMACYTIC LYMPHOMA (B-CELL NEOPLASM)

● In 6-7 decades, tend to differentiate to plasma cells
● Waldenstrom’s macroglobulinemia (inc. IgM)
● Rare complications - amyloidosis, Renal failure
● No bone destruction, indolent course
● With B cell markers - CD 20, Surface Ig, Activate NF-KB
MORPHOLOGY
● BM - Plasma cells, lymphocytes, plasmacytoid lymphocytes

● PBS: Rouleaux form (↑ IgM-RBC are sticky) and mast cells hyperplasia
● Urine: Bence Jones Proteins - Renal myeloma (toxic to ● PAS positive containing Russel and Dutcher bodies,
tubules) infiltrates to LN, skin, liver nerve roots, brain (anemia) -
○ 50% patients - renal insufficiency mutation of MYD88 gene)
● Electrophoresis - protein spike (60-70% Myeloma and
Light Chains)
○ you can check here the IgM increase HYPERVISCOSITY SYNDROME
● ↑ amt of IgM
DIAGNOSIS OF M.M. “CRAB” CRITERIA ● Visual impairment: congestion, tortious retinal veins,
● Calcium-increased → you are destroying the bone hemorrhages, exudate
● Neurologic: dizziness, stupor (decrease blood flow)
● Renal dysfunction → you see the Bence Jones Proteins ● Bleeding: (platelet F-6 and macroglobulin + C.F.)
● Anemia ● Cryoglobulin - precipitation at lower temperature - Reynaud’s
● Bone lesions phenomenon and cold urticarial
○ Usually the axial skeleton but the Bone marrow is replaced ● Reynaud’s phenomenon - vasoconstriction and the fingers
by clonal plasma cells (function defect) become cyanotic
● Treatment:
➔ Prognosis: variable (4-7 yrs med. survival) ○ Plasmapheresis (alleviated)
○ 6-12 months → with bone lesions, untreated ○ Low dense chemotherapy
○ BTK inhibitor (B cell signal pathway)
○ Good-transplant, Cyclin D ○ immunotherapy - CD20 Ab
● 8 yrs. med. survival (more BTK inhibitor)
➔ Treatment: incurable
○ Palliative: biphosphonate (inhibit bone resorption and
fractures) SUMMARY: PLASMA CELL NEOPLASMS
○ It is only Palliative because you can see that the bone
marrow is infiltrated by plasma cells ● Multiple myeloma:
○ Plasma cell tumor - lytic bone lesions of axial skeleton -
SMOULDERING MYELOMA fractures (hypercalcemia)
○ Secrete B.J. protein - nephrotoxic Ig, suppress humoral
● 10-30% plasma cells in BM, with serum “M” protein (↑ 3 g/dL) immunity
● Asymptomatic - progress to MM in 15 yrs. ○ Frequent - dysregulation of Cyclin D
○ Diagnosis: :Crab” BM with inc. plasma cells
SOLITARY OSSEOUS PLASMACYTOMA ○ Incurable
● Extraosseous - nasal sinuses, nasopharynx, larynx
● 10-20 yrs - progress to MM, M protein- mod. increase ● Smouldering myeloma:
● Resistant to cure in URT ○ progress to MM - 15 yrs - indolent course, M protein
● Extraosseous plasmacytoma  involving URT: cured with local increase, disseminate
resection ● MGUS:
○ most common plasma cell disorder
○ 50 yrs (1% per year - develop to M.M. (low M. protein))

16
PATHOLOGY
Spleen, & Thymus
● Solitary Osseous Plasmacytoma:

○ osseous, extraosseous (N. Sinuses, nasopharynx,
lungs)
○ 10-20 yrs - progress MM
● Lymphoplasmacytic lymphoma:
○ B cell - plasma cell
○ Hyperviscosity (inc. IgM) - Waldenstrom’s macroglob
○ Cryoglobulin - Raynaud’s pheno (Cold Agglutination)
○ Indolent (mutation of MYD 88 gene)
HODGKIN LYMPHOMA
● One of the most common adult cancers
● Curable with radiation and chemotherapy
● Start from a single L. node - spread to a chain of nodes
● WHO subtype classification:
○ Nodular sclerosis
○ Mixed cellularity
○ Lymphocyte rich
○ Lymphocyte deficient
○ Nodular, lymphocytic, predominance
Diagnosis
● Must see R.S. cells with background of non-neoplastic

inflammatory cells
● Confirm the histologic diagnosis with immunochemistry
profile
Subtypes
● Nodular sclerosis: most common HL (65-70%)

● Lacunar RS nodule, due to division of LN by collagen
deposits in bands in the BM
● Background - eosino, plasma cells, T cells, macroph
Pathogenesis ● RS cell and EBV - not common but good prognosis
● NF KB gene activation - mutation of TNF ● Positive (markers): PAXS (T.F.) CD15, CD30 (others-
○ Rescues B cells from apoptosis (In normal cells mamatay neg)
yung B cells) ● Adolescent, young adults, lin Lymph Nodes, Liver, bld.
○ EBV - express LMP-1 (up reg. NF KB) → will not go to vessels
apoptosis
NODULAR SCLEROSIS
MORPHOLOGY
● Presence of Reed Sternberg cells (characteristic: if you

will fold the cell and 1 part of the cell is like the other, they
are similar on both sides)
● Large, multiple nuclei (or single nuclei multi bed with
inclusions and nucleolus like small lympho, abundant
cytoplasm
● Variants: Figure Big nodules in HPO. This is where you see nodular
○ Mononuclears: single nuclei, increase nucleoli
○ Lacunar cells (nodular Sclerosis) - dilated nuclei sclerosis meaning to say those are the bands of collagen that are
➔ Multilobed or molded, pale cytoplasm deposited in between those cells and are separated to form
➔ Mummification - nucleus in an empty space
○ Lymphos. Histiocytosis - polyploid nuclei nodules → forms nodules. (Nodular sclerosis = (+) collagen fibrin)
➔ Amorphous nucleoli, abundant cytoplasm

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MIXED CELLULARITY NODULAR, LYMPHOCYTIC PREDOMINANCE

● Biphasic (2 phases): ● not common (<5%)
○ 1st: young adult ● RS cells - hard to find
○ 2nd: 50 yrs ● Nodules in LN: with small lymphocytes and macrophages
*what happens is you cannot see the follicles anymore you only see (popcorn cells - multilobed nuclei)
RS cells ● Variants - with B cell markers, CD20, BCL6
● 20-25% cases - LN affected (Eosino, Plasma cells, T cells, ● Nodular because it has Expanded B follicles, follicular dendritic
Macroph, RS cell) cells
● Diagnosis: ● Males, < 35 yrs (cervical, axillary LN)
○ RS cells: mononuclear variant ○ rare in BM
➔ F70% rsc - with EBV infection
● Very good prognosis (wt. loss: Advanced case) Table 13.8 Subtypes of Hodgkin Lymphoma
Subtype Morphology & Typical clinical
immunophenotype features
Nodular Frequent lacunar cells and Most common
sclerosis occasional diagnostic RS subtype; usually
cells; background infiltrate stage I or II
composed of T lymphocytes, disease; frequent
eosinophils, macrophages, mediastinal
and plasma cells; fibrous involvement; equal
bands dividing cellular areas occurrence in males
into nodules. RS cells & females, most
CD15+, CD30+; usually patients young
EBV- adults
LYMPHOCYTE RICH Mixed Frequent mononuclear and More than 50%
● not common cellularity diagnostic RS cells; present as stage III
● L. node effaced with residual follicles background infiltrate rich in or IV disease;
● Frequent - + RS cells and mononuclear variant T lymphocytes, eosinophils, occurrence greater
● 40% with EBV infection macrophages, plasma cells; in males than
● Good prognosis RS cells CD15+, CD30+; females; biphasic
70% EBV+ incidence, peaking
in young adults and
again in adults
older than 55
Lymphocyte- Frequent mononuclear and Uncommon;
rich diagnostic RS cells; occurrence greater
background infiltrate rich in in males than
T lymphocytes; RS cells females; tends to
CD15+, CD30+; 40% EBV+ be seen in older
adults
Lymphocyte Reticular variant: Frequent Uncommon; more
depletion diagnostic RS cells and common in older
variants and a paucity of men, HIVinfected
*you cannot see the follicles anymore background reactive cells; individuals, and
RS cells CD15+, CD30+; people in low
LYMPHOCYTE DEPLETION most EBV+ income countries;
● Least common (<5%) often presents with
● Many RS cell or Variants, lymphos scarce advanced disease
● Similar to Large Cell Non Hodgkin Lymphoma so immunotyping Nodular Frequent L&H (popcorn cell) Uncommon; young
is needed lymphocyte variants in a background of males with cervical
● Older adults (immunocompromised, with HIV) predominant follicular dendritic cells and or axillary
● 90% - EBV infection reactive B cells; RS cells lymphadenopathy;
● Systemic symptoms in advanced stage CD20+, CD15−,CD30−; EB− mediastinal
● Prognosis - less favorable

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CLINICAL HODGKIN LYMPHOMA: Painless lymphadenopathy

dysregulation of BCL2 in follicular lymphoma (leading to
● No manifestations resistance to apoptosis)
○ Stage 1 and 2 (N. sclerosis, inc. lymphocyte) ● PD-1 ligand gene amplification in Hodgkin lymphoma
○ Stage 3 and 4 - disseminated (mixed cells, decrease (leading to evasion of host immunity)
● events leading to loss of cell cycle control (cyclin D1
lympho) → fever, night sweats, weight loss, anergy)
rearrangements in mantle cell lymphoma and loss of the
● Stereotypical spread - you cannot predict because it is a chain CDKN2A gene in acute lymphoblastic leukemia [ALL])
mutations in various transcription factors, particularly in
going from one event to another and you have the spread in
ALL, that block differentiation and enhance “leukemia
the → LN, spleen, liver, and BM stem cell” self-renewal and chronic immune stimulation,
● Biopsy and X ray - basis for staging (prognosis) in marginal zone lymphoma.
○ Stage 1 - 90% (very good prognosis) ● Such alterations not only highlight important pathogenic
○ Stage IV A and B: 60-70% (5 years survival) principles, but are increasingly the targets of effective
● Treatment: therapies, such as antibodies that block PD-1 (Hodgkin
○ Low stage: field radiotherapy - cure lymphoma) and drugs that antagonize BCL2 (follicular
○ Higher stage: alkyl agents (risk to transform in Acute lymphoma and other B-cell tumors). By contrast,
Myelogenous Leukemia) because lymphoid cells normally circulate throughout the
● Classic HL: immunotherapy if above treatment fails body, there is relatively little selective pressure in
○ Ex: checkpoint inhibitors (block PDI - prevent T8 lympho lymphoid malignancies for aberrations that increase
exhaustion) 90% sustained response; others-not respond angiogenesis or activate invasion and metastasis, points
of distinction from other forms of cancer.
Key points: Hodgkin Lymphoma
● RS - classic HL→ produce cytokines, chemokines, lympho. MYELOID NEOPLASMS

infiltrates (host response) → support growth tumor ● Common feature of this heterogenous group of neoplasm is
their origin from hematopoietic progenitor cells
● Other cells → active lymphos, eosino, plasma cells, ● Pathogenesis: best understood in contect of normal
hematopoiesis which involves hierarchy of HSCs, committed
macroph, stromal cells → with RS and variants
progenitors & more differentiated elements
● Types: classic HL and Nod. Lympho pred. (immunotype ● Specific manifestation of different myeloid neoplasms are
basis) influenced by:
● Lympho. Predominant - with B cell markers, no EBV 1. Position of the transformed cell within the hierarchy of
● Classic HL: respond to immune checkpoint inhibitor progenitors
(antagonize PDL1 and PDL2 in RS cell) 2. Effect of the transforming events on differentiation
 Common mutations:
Pathogenic Lessons of Lymphoid Neoplasms (Robbins 10th ed.) 1. MYC gene dysregulation
➔ proliferation
➔ Ex. Burkitt Lymphoma
➔ Warburg metabolism - rapid growth because in the
metabolism of glucose instead of having the usual 36
to 38 ATP they only use 4 ATP and the rest are
needed for the production of the components of the
tumor
2. BCL2 Dysregulation
➔ Ex. Follicular Lymphoma
➔ Cells that are supposed to die will resist apoptosis
(anti-apoptosis)
3. PD-1 lipid protein amplification

➔ Loss of Cyclin control (inc Cyclin D) → amplify the
growth of the cell
➔ Ex: Mantle cell lymphoma
includes: 4. Loss of CDK NaN

● dysregulation of MYC in Burkitt lymphoma (leading to ➔ Ex. ALL (Acute Lymphoblastic Leukemia) block stem
Warburg metabolisms and rapid cell growth);
cell differentiation → they will stay young (sanaol)

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➔ Clonal immune system Pathogenesis

➔ Ex: Marginal zone lymphoma ● transcription factor mutation (block maturation of myeloid cells)
○ Ex. t (8:21) and inv. (16) (not mat of myeloid cells)
Note: no 1-4 alteration in pathogenic principles (target of therapy, Ex: ○ Ex. T (15-17) fusion protein → interfere with maturation of
PD 1 blocked by Ab (H.L.)
granulocytes
○ Treatment: all-trans retinoid + arsenic trioxide
● Altered hemopoiesis (progenitors in B.M.) others
● Signal pathway mutation: active pro-growth survival pathway
○ Ex. AML t (15:17) with mut of FLT3 (increase cell
Review: normal hematopoiesis fig. 13.1
proliferation and survival)
● Epigenome gene reg. and mutation

Categories
○ Absent DNA methylation pathway → mutation that will be
AML (Acute blast in BM → replace hemopoietic cells → active for survival of the cells
Myeloid ○ Ex: enzyme IDH1 and IDH2 mutation gain new activity
Leukemia) suppress hemopoiesis ➔ Use IDH inhibitors for treatment (targeted therapy:
individualize assessment of the limitation of the px)
MDS defective maturation of myeloid progenitors →
(Myelodysplastic ● P53 mutation: assoc with complex karyotypes (dysplasia)
syndrome) they can’t grow old → cytopenia ○ Poor prognosis (reaction restricted to standard treatment)
MORPHOLOGY
MPN increased production of 1 or more types of
(Myeloproliferativ blood cells
e Neoplasm) ● basis for Dx: BM 20% inc. myeloblasts
○ Myeloblasts: more cytoplasm, 2-4 nucleoli
➔ Auer rods: fine, azurophilic gram. In cytoplasm,
needle-like (in t(15:17) peroxidase
ACUTE MYELOID LEUKEMIA (AML) ➔ Monoblasts - no rods, no esterase
◆ Nuclei lobulated, folded
● Tumor of hematopoietic progenitors caused by acquired
➔ Megakaryocyte differentiation: BM fibrosis
oncogenic mutation that impede differentiation  accumulation
◆ Rare: RBC differentiation
of immature myeloid blasts in the marrow
○ PBS-leukemic cells variable, 100,000 lasts
● AML occurs at all ages: peak 60 years old
➔ 50% cases - less 100,000 blasts
○ Aleukemic leukemia: PBS. No blasts (BM exam)
Influences affecting manifestations of myeloid tumors
● transformed cells position in progenitor hierarchy (youngest to ● Immunotype- use stains for M. specific Ag
oldest) ○ Cytokinetics: 50-70% with karyotype abnormal
● Effect on differentiation of transforming events ○ Correlate clinically - chrom. t(8:21), t (15:17)
○ Oncogenic mutation- inhibit, skew, derange ○ After radiation/chemo Rx - AML (no transloc)
○ Transform to AML (MDS, MPN)
○ Older adults with normal bld. count (but more mutations ● Clinical - pancytopenia (RBC, platelets, neutro)
associated with neoplastic hemopoiesis) ○ Fatigue, fever, bleeding (gums, mucosa, viscera)
● Acute Myeloid Leukemia (AML) - impaired differentiation → ○ Procoagulants and fibrinolytic factors by leukemia cells
- exacerbate bleeding)
accumulation of myeloid blasts in the bone marrow. ○ Opportunistic (fungal) infections - skin, gums
● BM replaced by blasts - failure - anemia, thrombocytopenia, ○ Soft tissue mass (myeloblastoma) occasional
neutropenia
● All ages, more in 60 yrs. old ● Prognosis: guarded - 60% remission - 5 yrs
● WHO classification (diff. and blast lineage) ○ Worst: ↑ 60 yrs
1. Assoc. with genetic aberration (important for prognosis,
➔ Disease with genotoxic treatment
and looking for Rx)
➔ Associated with p53 mutation
2. Arise from MDS (myelodysplastic syndrome)
➔ Treatment: best 90% cure targeted therapy
3. Arise from MDS-like condition and from therapy related to
(trans retinoic acid, arsenic salts)
AML
○ Good: t (8:21) IM (16) chemotherapy
○ No. 2 and 3: poor response to Rx (treatment)
○ Stem cell transplantation (yound patients)
4. Lack above features

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PATHOLOGY
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Figure: 13.31 AML subtypes  CHIP (clonal hematopoiesis of indeterminate potential)

o This is an asymptomatic state where MDS frequently arise
o Defined by the presence of one or more pathogenic
mutations assiciated with MDS in an individual with normal
blood count
MORPHOLOGY
 BM
o Usually hypercellular at dx; normocellular (sometimes)
hypocellular (uncommon)
(A) Acute promyelocytic leukemia with the t(15;17) (FAB M3 subtype).
o Most characteristic finding:
Bone marrow aspirate shows neoplastic promyelocytes with abnormally
→ Dysplastic (disordered) differentiation affecting the
coarse and numerous azurophilic granules. Other characteristic findings
erythroid, granulocytic, monocytic and
megakaryocytic lineages
include the presence of several cells with bilobed nuclei and a cell in the
 Erythroid series
center of the field that contains multiple needle-like Auer rods.
o Ringed sideroblasts
(B) Acute myeloid leukemia with monocytic differentiation (FAB M5b → Erythroblasts with iron-laden mitochondria
subtype). Peripheral smear shows one monoblast and five (perinuclear granules in Prussian blue biopsy)
promonocytes with folded nuclear membranes. o Megaloblastoid maturation
o Nuclear budding abnormalities
MYELODYSPLASTIC SYNDROME  Pseudo-pelger-Huet
→ Bilobed (normal : 3-5 lobes) neutrophil with normal
● refers to a group of clonal stem cell disorders characterized by
function
mutation defects associated with:
 Dohle bodies
○ ineffective hematopoiesis
○ High risk of transformation to AML  Pawn ball megakaryocytes
→ Megakaryocytes with single nulear lobe or multiple
 Bone marrow is replaced by the clonal progeny of neoplastic
separate nuclei
MSC  peripheral blood cytopenias
 Primary (idiopathic)
FIG13.32 Myelodysplasia
 Secondary
o Genotoxic drug
o Radiation therapy (t-MDS)
→ Appears from 2 – 8 years after exposure
 DNA sequencing: routinely used to help establish the diagnosis
PATHOGENESIS
 MDS is associated with driver mutations that partially overlap
with those seen in AML, which is unsurprising given that MDS A B
often evolves to AML.
 The affected proteins can be lumped into three major
functional categories:
o Epigenetic factors (same with AML) – are factors that
regulate:
→ DNA methylation
→ Histone modifications
→ Chromatin looping
o RNA splicing factors C D
→ Mutations involving 3’ end of the RNA splicing
machinery (A) Nucleated red cell progenitors with multilobated or multiple nuclei
o Transcription factors – mutations affect transcription (B)Ringed sideroblasts, erythroid progenitors with iron-laden
factors that are required for normal myelopoiesis and mitochondria seen as blue perinuclear granules (Prussian blue stain)
(C) Pseudo-Pelger-Hüet cells, neutrophils with only two nuclear lobes
contribute to deranged differentiation. Such as:
instead of the normal three to four, are observed at the top and
→ RUNX1 bottom of this field.
 10%: loss of function mutations in TP53  poor outcome (D) Megakaryocytes with multiple nuclei instead of the normal single
 Both primary MDS and t-MDS are associated with similar multilobated nucleus.
hromosomal abnormalities such as: (A, B, and D, Marrow aspirates; C, peripheral blood smear.)
→ Monosomies 5 & 7
→ deletions: 5q, 7q & 20q
 5q contains RPS14  ineffective erythropoiesis
→ trisomy 8 (most common form of aneuploidy)
 Ineffective erythropoiesis (one of the hallmark of MDS)

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CLINICAL FEATURES  Dx/treatment criteria: molecular tests for TK mutations (for

 Primary MDS available kinase inhibitors for Rx)
o Predominantly a disease of older adults (mean age 70) o TK mutation affects normal control  growth factor
o Asymptomatic (half of the case discovered incidentally on independence proliferation and BM progenitor survival
routine blood testing) o GF independence means that they will continue to
o Symptomatic (due to pancytopenia): proliferate even without GF signal.
→ Weakness  Systemic mastocytosis – neoplasm associated with KIT TK
→ Infections
→ hemorrhages Table 13.1 Mutations that activate TK signaling in MPN
o 6 categories based on morphologic & cytogenic features by Disorder Mutation Frequency Consequnces
the WHO: (additional input) CML BCR-ABL 100% Constitutive
→ MDS with multilineage dysplasia (MDS-MLD) fusion ABL kinase
→ MDS with single lineage dysplasia (MDS-SLD) gene activation
→ MDS with ring sideroblasts (MDS-RS) Polycythemia JAK2 95% Constitutive
→ MDS with excess blasts (MDS-EB) Vera mutations JAK2 kinase
→ MDS with isolated del(5q) activation
→ MDS unclassifiable (MDS-U) Essential JAK2 50-60% Constitutive
thrombocythemia mutations JAK2 kinase
PROGNOSIS activation
 Primary MDS: CALR 25-35% Alternative
o Median survival 6months to >5years mutations MPL ligand
o Progression to AML is more rapid (poor prognostic group) MPL 5-10% Constitutive
o Patients succumb to complications: mutations MPL kinase
→ Thrombocytopenia (bleeding) activation
→ Neutropenia (infection Primary JAK2 50-60% Constitutive
 t-MDS: myelofibrosis mutations JAK2 kinase
o Grimmer outlook, median survival of 4 to 8 months activation
o Often progresses to AML within 2 to 3 months of Dx CALR 25-35% Alternative
 mutations MPL ligand
TREATMENT (fairly limited options) MPL 5-10% Constitutive
mutations MPL kinase
 Younger patients activation
o Allogenic HSC transplataion
Systemic KIT >90% Constitutive
→ reconstitution of normal hematopoiesis & possible
mastocytosis mutations KIT kinase
cure
activation
 Older patients
Chronic FIP IL I- Common Constitutive
o Treated supportedly with antibiotics and blood transfussion
eosinophilic PDGFRA PDGFRα
 Thialidomide-like drugs and DNA methylation inhibitors leukemia fusion kinase
o Improve effectiveness of hematopoiesis and peripheral gene activation
blood counts
PDE4DIP- Rare Constitutive
o Isolated 5q deletion – hematologic response to
PDGFRB PDGFRβ
thialidomide-like drugs
fusion kinase
gene activation
MPN: MYELOPROLIFERATIVE NEOPLASMS Myeloid/lymphoid Various 100% Constitutive TK
 Presence of mutated, constitutively activated tyrosine kinases neoplasms with genes activation
or other acquired aberrations in signaling pathways  GF eosinophilia and involving
independence TK gene FGFR1,
 GF-independent proliferation will lead to: mutations PDGFRA,
o Increased production of one or more mature blood elements PDGFRB,
or JAK2
 Not impair differentiation (lymphoid, myeloid): matured blood
elements (derived from progenitors, stem cells) are seen.
 Strongly associated with mutations of specific TK CHRONIC MYELOID LEUKEMIA (CML)
 Common features:  Origin: Pluripotent HSC
o Increased proliferative drive in the BM  presence of a chimeric BCR-ABL gene derived from portions
o Extramedullary hematopoiesis of the BCR gene on chromosome 22 and the ABL gene on
→ Produced by homing of neoplastic stem cells to chromosome 9
secondary hematopoietic organs  BCR-ABL
o Cytopenia with marrow fibrosis: spent phase o In 90% of cases, created by reciprocal (9;22)(q34;q11)
→ Bcause you cannot produce hemopoiesis translocation (the so-called Philadelphia chromosome [Ph])
o Variable transformation to acute leukemia  Sometime translocation of (Cq43qN)

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 Other fusion genes are seen and tested by: PCR and FISH CML: Blood Smear and Spleen
 BCR-ABL granulocyte and megakaryocyte growth Figure 13.34 Chronic
myeloid leukemia.
PATHOGENESIS Peripheral blood smear
shows many mature
 BCR moiety of BCR-ABL contains a dimerization domain that neutrophils, some
self-associates  activation of the ABL tyrosine kinase metamyelocytes, and a
moiety. myelocyte.
 The ABL kinase  phosphorylates proteins that induce Red: Band neutrophils
signaling through the same pro-growth and prosurvival Yellow: Myelocyte
pathways that are turned on by hematopoietic growth factors, Green: Metamyelocyte
including the RAS and JAK/STAT pathways.
Chronic myeloid
 BCR-ABL preferentially drives the proliferation of granulocytic leukemia (spleen).
and megakaryocytic progenitors and  abnormal release of Enlarged spleen
immature granulocytic forms from the marrow into the blood. (2630 g; normal:
150 to 200 g) with
Pathogenesis of chronic greatly expanded
myeloid leukemia. Breakage red pulp stemming
and joining of BCR and ABL from neoplastic
creates a chimeric BCR-ABL hematopoiesis.
fusion gene that encodes a
constitutively active BCR-ABL
tyrosine kinase. BCR-ABL CLINICAL FEATURE:
activates multiple downstream
pathways, which drive growth  primarily a disease of adults but also occurs in children and
factor– independent adolescents.
proliferation and survival of  The peak incidence is in the fifth to sixth decades of life.
bone marrow progenitors.
 onset is insidious.
Because BCR-ABL does not
interfere with differentiation, the  Mild-to-moderate anemia and hypermetabolism due to
net result is an increase in increased cell turnover lead to:
mature elements in the o fatigability, weakness, weight loss, and anorexia.
peripheral blood, particularly  Sometimes the first symptom is a :
granulocytes and platelets. der, o dragging sensation in the abdomen caused by
Derivative chromosome. splenomegaly or
o the acute onset of left upper quadrant pain due to splenic
infarction.
MORPHOLOGY  Without treatment ( slow progress – 3 years survival)
 BM is markedly hypercellular due to massively increased
numbers of maturing ganulocytic precursors which usually DIAGNOSIS
include:  Detection of BCR-ABL fusion gene through either
o Elevated proportions of eosinophils and basophils chromosomal analysis or PCR-based tests
o Megakaryocytes are also increased (small dysplastic
forms) COURSE
 Characteristic finding: Sea-blue histiocytes
 PBS: leukocytosis ( >100,000 granulocytes) predominantly:  After 3 years about 50% of patients enter an “accelerated
o Neutrophils, band forms, metamyelocytes, myelocytes, phase” marked by:
eosinophils and basophils o increasing anemia and thrombocytopenia, sometimes
o Blasts: <10% accompanied by a rise in the number of basophils in the
o Platelets are usually increased blood.
 Spleen: often greatly enlarged due to extramedullary o Additional clonal cytogenetic abnormalities, such as
hematopoisis, often contains infarcts trisomy 8, isochromosome 17q, or duplication of the Ph
chromosome, often appear.
 Extramedullary hematopoiesis can produce mild
hepatomegaly & lymphadenopathy  Blast Crisis (resembles acute leukemia)
o 6 to 12 months after accelerated phase
NOTE: Remember base on FAB (French-American-British) o In the other 50% of patients, blast crises occur abruptly
classification of leukemia, diagnostic criteria for without an accelerated phase.
o In 70% of crises, the blasts are of myeloid origin (myeloid
 Chronic: <10% blasts in the peripheral blood
blast crisis),
 Acute: >30% blasts in the peripheral blood
o in most of the remainder the blasts are of pre–B cell origin
(lymphoid blast crisis 80%).

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TREATMENT CLINICAL FEATURES

 Drugs target BCR-ABL (inhibitors): imatinib, Dasatinib, etc  Increase hematocrit, blood volume and RBC
o 90% remission (not kill stem cells)  High viscosity of blood  slower flow  cyanosis
o Decrease transfer to blast crises  Headache, dizzines, Increased BP, pruritus, peptic ulcer
o 50% resistant to inhibitor  5-10% gout (increase uric acid)
→ Develop 2nd, 3rd generation  Bleeding and thrombosis (25% DVT, chronic bleed)
 Cure: 75% in young – HSC transplantation (not effective in  Budd-Chiari syndrome: hepatic vein thrombosis
blast crises)  Bowel infarct (portal vein thrombosis)
 NOTE: CML patients with philadelphia chromosome have a  PBS: increase hemoglobin, WBC, platelets (giant forms)
better prognosis than CML patients not exhibiting philadelphia
chromosome TREATMENT
 NONE (death in months but can be extended)
POLYCYTHEMIA VERA (PV)  Phlebotomy: 10 years
 Increased RBC, platelets, granulocytes  Target therapy if there is JAK2: JAK2 inhibitor (not as
 90% mutation of JAK2 TK signaling pathway effective)
 Increase serum hemopoietin, hematocrit and RBC  If extended survival gp tp “spent phase”
 25 – 30%: 2 copies (2 mutations) o 10 year (primary myelofibrosis – obliterated BM)
 increased WBC, enlarged spleen, pruritus Figure 13.36 PCV, Spent phase. Massive Splenomegaly
 Increase progression to spent phase
o Fibrosis and failure of the marrow Massive splenomegaly
(3020 g; normal: 150 to
PATHOGENESIS 200 g) largely due to
extramedullary
 In PCV, the transformed progenitor cells have markedly hematopoiesis occurring in
decreased requirements for erythropoietin and other the setting of advanced
hematopoietic growth factors due to activating mutations marrow myelofibrosis.
in the tyrosine kinase JAK2.
 JAK/STAT pathway,
o which lies downstream of multiple hematopoietic growth
factor receptors, including the erythropoietin receptor.
pathway is constitutively active and red cell numbers are ESSENTIAL THROMBOCYTOSIS (ET)
abnormally high, serum erythropoietin levels in PCV are
low. This is in contradistinction to secondary forms of  associated with diverse mutations that increase JAK-
polycythemia, in which erythropoietin levels are high. STAT signaling and mimic constitutive growth factor
 The elevated hematocrit  increased blood viscosity and receptor signaling.
sludging.  Diverse mutatation of JAK-STAT signaling pathway (decrease
 These hemodynamic factors, together with thrombocytosis GFR signal (90% mutation)
and abnormal platelet function,  prone to both thrombosis  No polycythemia, marrow fibrosis(red cells are NOT
and bleeding. increased)
 Increase platelets
MORPHOLOGY  Before you Dx ET, you have to exclude reactive
thrombocytosis
 Early: Hypercellular BM, some residual fat is present
 Over 90% of cases have either:
o Increase in red cell progenitors is subtle & accompanied
o activating mutations in JAK2 (approximately 50% to 60%
by increase in granulocytic & megakaryocytic precursors.
of cases)
o Progression: increase cells 10% reticulin fibers of marrow
o MPL (5% to 10% of cases), a receptor tyrosine kinase that
o Extramedullary hemopoiesis is minimal
is normally activated by thrombopoietin and that signals
o Peripheral blood: increased basophils & abnormally large
through JAK2;
platelets
o calreticulin (approximately 30% of cases)
 1% transform to AML
 Late course: PATHOGENESIS
o PCV progresses to spent phase
→ extensive marrow fibrosis displacing hematopoietic  Skin proliferation by JAK2 or MPC (progenitors independent of
cells TPO)
o Extramedullary hematopoiesis: spleen, liver  prominent  Constitutive JAK2 or MPL signaling renders the progenitors
organomegally thrombopoietin-independent and leads to hyperproliferation.
 The JAK2 mutation is the same as that found in almost all
cases of PCV.
 Some cases thought to be ET may in fact be PCV disguised by
iron deficiency (which is more common in individuals diagnosed
with ET), but this is probably true of only a small fraction of
patients.

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PATHOLOGY
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CLINICAL FEATURES:  Blood findings (BM fibrosis)

 60 years or more; young adults can be affected o Leukoerythrocytosis: nucleated RBC & granulocytes
 PBS: high platelet count, large  thrombosis o Extramedullary hematopoiesis: release immature cells
 Median survival: 12 – 15 years o Dacrocytosis: “Tear drop” RBC (changed in BM)
→ Same in granulomas and tumor met to BM
 Occasional hemorrhagic crises
CLINICAL FEATURES:
TREATMENT:
 Less common (LUQ heaviness)
 Supress thrombopoiesis (mild chemo rx)
 Lab: normocytic, normochromic anemia, leukoerythroblastosis
Figure 13.37 Essential thrombocytosis
DIAGNOSIS:
Peripheral blood smear  BM biopsy is needed
shows marked
thrombocytosis including TREATMENT:
giant platelets
 Difficult to treat
approximating the size of
surrounding red cells.  Median survival: 3 – 5 years
Yellow arrow: giant  Threats to life:
platelets o Intercurrent infections
o Thrombotic episodes
o Bleeding related to platelt abnormalities
o Transformation to AML (in 5 to 20% of cases)
 JAK2 inhibitors
PMF: PRIMARY MYELOFIBROSIS
o Can be used in patients with splenomegaly (decrease in
 Hallmark: obliterative marrow fibrosis. size)
 The replacement of the marrow by fibrous tissue  bone  HSC transplantation: you patients (cured)
marrow hematopoiesis  cytopenias and extensive
extramedullary hematopoiesis. Figure 13.38 Primary myelofibrosis (PBS)
 Histologically, the appearance is identical to the spent phase Two nucleated erythroid
that occurs occasionally late in the course of other precursors and several
myeloproliferative neoplasms. teardrop-shaped red cells
 The genetics of primary myelofibrosis is very similar to ET; (dacryocytes) are evident.
approximately 90% cases have activating mutations of JAK2, Immature myeloid cells
CALR, or MPL. were present in other
fields. An identical picture
PATHOGENESIS can be seen in other
diseases producing
 extensive deposition of collagen in the marrow by marrow distortion and
nonneoplastic fibroblasts. fibrosis
 Hallmark: obliterative fibrosis of BM, cytopenia amd
extramedullary hematopoiesis Yellow Arrow: Dacrocytes “tear drop cells”
o like “spent phase” – late in MPN
o Like ET (90% activity mutation of JAK2, CALR, MPD) KEY CONCEPTS: MYELOID NEOPLASM
 HSC in secondary hematopoietic organs: (LN, spleen, liver) –
severe anemia  AML (Acute Myelogenous Leukemia)
 The fibrosis inexorably displaces hematopoietic elements, o Aggressive
including stem cells, from the marrow  marrow failure. → BM blast replacement: suppress hemopoiesis
 Caused by the inappropriate release of fibrogenic factors from → Mutation: abnormal transcript factor, interfere with
neoplastic megakaryocytes. differentiation
→ Epigenome regulator mutation (GFR)
 Two factors synthesized by megakaryocytes have been
 Dx: 20% BM myeloblast (auer rods, Faggots M3)
implicated:
 Treatment: targeted therapy, HSC
o platelet-derived growth factor
transplantation
o TGF-β.
 MFD (Myelofibrosis disease)
MORPHOLOGY o High blood count, extensive increase myeloid elements
o Common: BCR-ABL kinase (with CML)
 Early: BM (hypercellular) → Mutation JAK2 in AML, PV
 PBS: leukocytosis, thrombocytosis, cluster of megakaryocytes o All condicion can become acute leukemia severe
 Late: BM hypocellular – diffuse fibrosis (to bone) o “spent phase” of BM, with anemia, splenomegaly &
 Cloud-like megakaryocytes (unusual shapes) decreased platelets
 Fibrosis – distorded cells in the sinusoids  MDS
 Extensive extramedullary hematopoiesis in: liver and spleen o Dysmaturation: dsordered ineffective hemopoiesis

25
PATHOLOGY
Spleen, & Thymus
o Follows genotoxic exposure o Arises within medullary cavities of bones (calvaria, ribs &
o Often: go to AML femur)
o Mutation: epigenetic, transcription, splicing factors o Unifocal lesions (one area)
→ most commonly affect the skeletal system in older
LANGERHAN CELL HISTIOCYTOSIS (LCH) children and adults;
→ Bones (pain, fractures, tenderness)
 Langerhan cells → Indolent
o are young, immature dendritic cells → may heal spontaneously
o part of innate immunity → may be cured by local excision or irradiation
o myeloid tumor o Multifocal unisystem disease
 Proliferative disorders of dendritic cells, macrophage → affects young children who present with errosive
 Benign (reactive proliferation) bony masses that expand into adjacent soft tissue
 Malignant: sarcoma o Hand-Schuller-Christian thriad:
 Spectrum (clones – Langerhan cells) → bone defects
→ diabetes insipidus
PATHOGENESIS → exophthalmos
 most common mutation o Patient may experience spontaneous regression
o an activating valine-to-glutamate substitution at residue o Treatment:
600 in BRAF. → chemotherapy (can be successful)
 Less common mutations → BRAF inhibitors are active against BRAF mutated
o TP53, RAS, and the receptor tyrosine kinase MET dsease (but not curative
→ One factor that contributes to the homing of  Pulmonary Langerhans cell histiocytosis
neoplastic o Often seen in adult smokers, which may regress
 Noroccurs momal epidermal Langerhans cells express CCR6 spontaneously upon cessation of smoking
 neoplastic counterparts express both CCR6 and CCR7. o Reactive proliferations of Langerhans cells
o allows the neoplastic cells to migrate into tissues that o 40% are associated with BRAF mutations
express the relevant chemokines: o Neoplastc in orgin
→ CCL20 (a ligand for CCR6) skin and bone
→ CCL19 and CCL21 (ligands for CCR7) in lymphoid TREATMENT
organs  NONE: rapidly fatal
 Intense Chemo Rx: 5 years survival
MORPHOLOGY
 proliferating Langerhans cells have abundant, often SPLENIC DISORDERS
vacuolated cytoplasm and vesicular nuclei containing linear ● SPLEEN
grooves or folds ○ ROLES
 the tumor cells also typically express HLA-DR, S-100, and ➔ Filter of Ag in blood
CD1a ➔ Immune response
 Birbeck granules ○ GROSS
o present in the cytoplasm is characteristic. ➔ 150 grams (adult), encapsulated, follicles-red pulp
o are pentalaminar tubules, often with a dilated terminal end ○ MICRO
producing a tennis racket–like appearance, which contain ➔ Red pulp: cord of Bilroth (lining gaps) with blood in
the protein langerin. sinusoids between white pulp
➔ B cell center nodules w/ periarteriolar sheath
CLINICAL FEATURES lymphocytes
 Letterer-Siwe disease (multifocal multisystem langerhan cell ○ CIRCULATION
histiocytosis) ➔ Open - RBC pass via gaps, macrophages with long
o Occurs most frequently <2 years of age dendritic process (physical and functional filter,
o Occasionally affects adults Robbins 10th)
o Cutaneous lesions (resembling seborrhec eruption) ➔ Closed - Capillaries to splenic veins
→ Caused by infiltrates of langerhans cells (front and ● FUNCTIONS
back of trunk and scalp) ○ Hematopoiesis stops before birth
o Hepatosplenomegaly, lymphadenopathy, pulmonary ○ Phagocytosis: In conditions in which red cell deformability
lesions and destructive osteolytic bone lesions
o Extensive infiltration will lead to is decreased, red cells become trapped in the cords
→ Anemia →phagocytosed by macrophages (Robbins 10th).
→ Thrombocytopenia
→ Recurrent infections (otits media & mastoiditis) ➔ RBC ‘’Pitting’’ → RBC inclusions excised
 Eosinophilic granuloma (Unifocal and multifocal unisystem ➔ Ex. Heinz and Howell jolly bodies removed
Langerhans cell histiocytosis) ○ Ab production: Ag trapped → T and B cell interaction in
the white pulp produce plasma cells → Ab (against RC,

26
PATHOLOGY
Spleen, & Thymus
platelets) found on the sinuses of the red pulp. (Robbins CONGESTIVE SPLENOMEGALY
● Chronic obstruction of venous outflow may be caused by
10th)
intrahepatic disorders that retard portal venous drainage or
➔ Ex. thrombocytopenic purpura, Immune-hemolytic extrahepatic disorders that directly impinge upon the portal or
anemia splenic veins (Robbins 10th)
● Portal/ Splenic hypertension → Pressure on the veins or portal
○ Hematopoiesis → In specially the bone marrow is not
drainage
functioning, there is fibrosis these areas that are stimulated
● Systemic congestion or central, venous congestion
→ activated (extramedullary)
➜ Ex. Myeloid leukemia (severe anemia) →encountered in cardiac decompensation
○ Sequestration of blood elements ○ Right sided heart failure
○ Left sided heart failure
➜ The normal spleen contains only about 30 to 40 mL of
○ Chronic Cor pulmonale
red cells → increases greatly with splenomegaly ○ Tricuspid/Pulmonic valve defects
➜ 80-90% platelets (also RBC and WBC)
➜ Ex. Thrombocytopenia, Anemia , Leukopenia MODERATE ENLARGEMENT
SPLENIC INSUFFICIENCY ● Rare over 500 grams
○ Liver cirrhosis
● In splenectomy, or autoinfarction (as in sickle-cell disease)
➔ main cause of massive congestive splenomegaly
○ Increased infection → sepsis (Encapsulated bacteria., ➔ The “pipe-stem” hepatic fibrosis of schistosomiasis
Pneumococcus, Meningococcus, H. influenza) causes particularly severe congestive splenomegaly,
○ Lost → Ab production , filter ( no spleen- vaccine) while the diffuse fibrous scarring of alcoholic cirrhosis
and pigment cirrhosis also evokes profound
enlargements (Robbins 10th)
SPLENOMEGALY ○ Obstruction
● Hypersplenism syndrome ➔ Extrahepatic portal/ splenic veins
○ Increase macrophages sequestration → Blood Elements ➔ Ex. Spontaneous thrombosis→ periportal veins,
○ Complaints Pyelophlebitis with tumor, Parasite
➔ LUQ heaviness, discomfort post meal → compression
of the stomach MORPHOLOGY
MAJOR DISORDERS OF SPLENOMEGALY

● Gross
○ Long standing splenic congestion, severe to moderate
ACUTE SPLENITIS, NON SPECIFIC enlarged 1000-5000 grams thick capsule
● Infection , blood borne ● Microscopic
● Immune response to cytokines and organism ○ Early congestion of red pulp→increasingly fibrotic and
cellular with time, collagen in Basement membrane of
MORPHOLOGY the sinusoids ( leads to inc. portal venous pressure →
slow flow → RBC exposed to macrophages → excessive
● Gross
○ 200-500 grams; soft destruction
● Micro
○ cellular red and white pulp (neutrophils, plasma
cells, eosinophils) SPLENIC INFARCT
○ Red pulp → congested ● Obstruct major splenic artery/ branches by emboli (septic →
○ White pulp → necrotic (particularly when the infectious endocarditis)
causative agent is a hemolytic streptococcus, ○ Blood supply compromised → enlarged ( varied size and
Robbins 10th) number, or whole spleen)

27
PATHOLOGY
Spleen, & Thymus
MORPHOLOGY THYMIC DISORDERS

● Thymus
● Gross ○ 3rd & 4th pharyngeal pouches - origin
○ bland infarcts → wedge shaped, pale, fibrin on capsule ○ weights: at birth 10-35 grams, puberty 20-50 grams,
Elderly 5-15 grams
○ In septic infarcts → suppurative necrosis, depressed ➜ The thymus also may involute in children and young
scars→ healed adults in response to severe illness and HIV
infection(Robbins 10th)
○ Cells
➔ Diverse types of cells populate the thymus, but thymic
epithelial cells and immature T lymphocytes, also
called thymocytes, predominate (Robbins 10th)
➔ cortex - T lymphocytes, polygonal (immature) with
dendritic extensions
➔ Medulla - epithelial, spindle cells, whorls of medullary
epithelial cells → Hassal’s corpuscles (keratin core)
macrophages, B cells, eosinophils, dendritic cells,
scattered myoid (muscle-like) cells
➔ The myoid cells are of particular interest because
they likely play some role in the development of
myasthenia gravis, a musculoskeletal disorder of
NEOPLASMS immune origin. (Robbins 10th)
● rare except in myeloid and lymphoid tumors, which often cause ○ Atrophic → T cells decrease, others still present
splenomegaly
○ Ex. benign fibromas, lymphangiomas
○ Common : cavernous hemangioma DEVELOPMENTAL DISORDER
CONGENITAL ANOMALIES THYMIC HYPOPLASIA

● Complete absence, rare ● Aplasia
● Hypoplasia, more common ○ Digeorge syndrome
● Accessory spleen (spleniculi) → in autopsy 20-30% (Robbins ➔ severe defects in cell-mediated immunity +
hypoparathyroidism
10th, 20-35%) ➔ part of the 22q11 deletion syndrome (Robbins 10th)
○ Small, round, like the spleen (also in abdominal cavity)
○ Missed is splenectomy is done → low effect of treatment ISOLATED THYMIC CYSTS
(Ex. Hereditary spherocytosis) ● They rarely exceed 4 cm in diameter, can be spherical or
➔ Supersub Description arborizing, and are lined by stratified to columnar epithelium.
The fluid contents can be serous or mucinous and are often
RUPTURE modified by hemorrhage (Robbins 10th)
● due to blunt trauma or blow ● Like masses → compressed or distort adjacent tissue
○ Spontaneous ruptures → fragile spleen ( with infectious
mononucleosis) THYMIC HYPERPLASIA
○ Common → Malaria, lymphoid tumor, typhoid fever ● B cells in germinal centers → thymic follicular hyperplasia
○ 65-70% Myasthenia gravis ( also SLE, Rheumatoid
arthritis, Grave’s disease)
MORPHOLOGY
➔ Significance → mistaken for Thymoma (leading to
● Gross unnecessary surgical procedures)
○ tense, thin capsule , rapid enlargement →
intraperitoneal hemorrhage THYMOMA
○ Treatment : Splenectomy (immediate) ● Benign growth of thymic epithelial cells (thymocytes) with
○ Chronically enlarged spleen → Extensive Reactive immature T cells.
○ Histologic subtypes
fibrosis → not tend to rupture ( strengthening effect) ➔ cytologically benign and noninvasive (localized)
➔ cytologically benign but invasive or metastatic
➔ cytologically malignant (thymic carcinoma)

28
PATHOLOGY
Spleen, & Thymus
○ Age : 40 years and above, located at mid mediastinum

○ 20-30% antero-superior mediastinum, but sometimes they ➔ 5 years survival rate of less than 50% →extension
occur in the neck, thyroid, pulmonary hilus, or elsewhere invasion
➔ The epithelial cells are most commonly of the
TYPES OF THYMOMA cortical variety, with abundant cytoplasm and
rounded vesicular nuclei , and are usually mixed
with numerous thymocytes. In some cases the
neoplastic cells show cytologic atypia, a feature
that correlates with a propensity for more
aggressive behavior. (Robbins 10th)
● Thymic carcinoma
○ Macroscopically, they are usually fleshy, obviously
invasive masses, sometimes accompanied by
metastases to sites such as the lungs (Robbins 10th)
○ common → squamous cell carcinoma followed by
lymphoepithelioma-like
● Benign thymoma (medullary type) ○ sheets of cells w/ vague borders
○ The neoplastic epithelial cells are arranged in a swirling
○ 50% with EBV infection → lymphoepithelioma like
pattern and have bland, oval to elongated nuclei with
inconspicuous nucleoli. Only a few small, reactive pattern
lymphoid cells are interspersed (Robbins 10th)
● Non invasive thymoma
○ most often composed of medullary-type
epithelial cells or a mixture of medullary- and
cortical-type epithelial cells. The medullary-
type epithelial cells are elongated or spindle-
shaped.There is usually a sparse infiltrate of
thymocytes, which often recapitulate the
phenotype of medullary thymocytes.
○ In mixed thymomas there is an admixture of
polygonal cortical-type epithelial cells and a
denser infiltrate of thymocytes and together
account for about 50% of all thymomas.
(Robbins 10th)
● Malignant thymoma, type 1
○ The neoplastic epithelial cells are polygonal and have
round to oval, bland nuclei with inconspicuous nucleoli.
CLINICAL FEATURES
Numerous small, reactive lymphoid cells are
interspersed. The morphologic appearance of this ● 40% symptoms → pressure on mediastinal structures
tumor is identical to that of benign thymomas of the ● 30-40% accompanied with myasthenia gravis
cortical type. In this case, however, the tumor was ● Imaging status : other diseases
locally aggressive, invading adjacent lung and ○ Ex. grave’s disease, Cushing syndrome, acute immune
pericardium (Robbins 10th) disease, pernicious anemia, polymyositis,
hypogammaglobulinemia, pure red cell aplasia
● Thymocytes that arise within thymomas give rise to long-lived
CD4+ and CD8+ T cells,
MORPHOLOGY ● and cortical thymomas rich in thymocytes are more likely to be
associated with autoimmune disease (Robbins 10th)
● GROSS
○ 5-20 cm, lobulated, firm ,gray-white
➔ Encapsulated, cystic necrosis, calcification
(center)
➔ 20-25% infiltrate capsule
● Invasive : Cytological benign

○ Penetrate the capsule
○ Common: cortical cells, vesicular nuclei w/ thymocytes
○ Survival 90% minimal invasion → Excision

29
PATHOLOGY
Spleen, & Thymus
○ Non-Hodgkin lymphoma
● Myeloma: Develops in the plasma cell tumor
● Chronic Lymphocytic Leukemia

LECTURIO ○ Normally, CD19 is found on B cells; CD5 is found on B
cells
Leukemia, Lymphoma & Myeloma (Tumors of the Immune ○ In most cases of CLL, CD5 is present on the surface of
System) B cells.
● Leukemia: Develops in the bone marrow ● Post transplant Lymphoma

○ Acute lymphoblastic leukemia ○ due to EBV infection (controlled by T cells) → upon
○ Acute myeloid leukemia transplant the immunosuppressive drug cyclosporine→
○ Chronic lymphocytic leukemia
○ Chronic myeloid leukemia made memory cells nonresponsive → polyclonal
increase in EBV infected B cells
● Lymphoma: Develops in the lymphatic system ○ Uncontrolled EBV infection → B cells proliferation
○ Hodgkin lymphoma

30
PATHOLOGY
Spleen, & Thymus
○ Polyclonal B cell proliferation will improve if d. Polyclonal immunoglobulins or immunoglobulin

fractions that are produced by a clonal population of
cyclosporine is stopped → monoclonal proliferation will B-cell lineage cells
continue after cyclosporine is stopped, and the patient e. Monoclonal immunoglobulins or immunoglobulin
fractions that are produced by a clonal population of
develops the symptoms of lymphoma. B-cell lineage cells
○ with ongoing Myc translocation will occur on B cells →
Answers: 1. A. 2. A. 3. A. 4. E.
development of lymphoma
● Multiple myeloma
○ plasma cells in the bone marrow become malignant Leukemia: Acute Leukemia
○ And therefore, a clone of rapidly replicating plasma cells
● Acute Leukemia
pumping out huge amounts of antibody of a single ○ Disease of neoplastic leukocytes
specificity develop → Paraprotein → detected by ○ Predominance of immature forms, especially blasts
(myeloblasts or lymphoblasts) disease defined by > 20
electrophoretic gel (gamma region) % blasts in the bone marrow
○ In contrast, in a healthy individual, that monoclonal ○ Symptoms due to marrow failure secondary to leukemia
band is missing because their antibodies are totally infiltration causing pancytopenia anemia, leukopenia,
polyclonal; a very huge mixture of different specificities. and thrombocytopenia
Recall: ● Etiology
1. Infection with which of the following pathogens is ○ Chromosomal abnormalities (e.g. Down syndrome)
particularly associated with posttransplant lymphoma? ○ Ionizing radiation
a. Epstein–Barr virus ○ Chemical exposure
b. Cytomegalovirus ○ topoisomerase agents (chemotherapy)
c. Varicella zoster virus ○ age
d. Hepatitis C
e. Human papillomavirus ● Subtypes
○ Disease of immature granulocytes
2. Which of the following tumors is INCORRECTLY ○ Seen in young to middle-age adults (15-60 years)
matched to the associated progenitor cells?
a. Lymphoma - myeloid progenitors ● Acute lymphocytic (lymphoblastic) leukemia
b. Leukemia - lymphoid progenitors ○ Disease of immature lymphocyte pre-B and pre-T ALLs
c. Leukemia - myeloid progenitors ○ Typically seen in children (0-15 years)
d. Myeloma - plasma cell progenitors ➔ No. 1 Leukemia in this age group
e. Lymphoma - lymphoid progenitors Recall:
1. Which of the given values represents the minimum
percentage of blast cells in acute leukemia?
3. A patient presents with large numbers of mature B cells a. Greater than 15%
in his serum. Which of the following is the most likely b. Greater than 5%
diagnosis? c. Greater than 18%
a. Chronic lymphocytic leukemia d. Greater than 20%
b. Chronic myeloid leukemia e. Less than 15%
c. Non-Hodgkin's lymphoma
d. Multiple myeloma 2. Which of the following is NOT seen in bone marrow
e. Acute lymphoblastic leukemia failure secondary to leukemia?
a. Thrombocytopenia
b. Clock-face plasma cells
4. Which of the following best describes paraproteins? c. Leukopenia
a. Polyclonal immunoglobulins or immunoglobulin d. Pancytopenia
fractions that are produced by a clonal population of e. Anemia
T-cell lineage cells
b. Monoclonal immunoglobulins or immunoglobulin 3. According to FAB classification, how many subtypes of
fractions that are produced by a clonal population of AML are there?
T-cell lineage cells a. 7
c. Polyclonal immunoglobulins or immunoglobulin b. 4
fractions that are produced by a nonclonal c. 8
population of B-cell lineage cells d. 5

31
PATHOLOGY
Spleen, & Thymus
e. 6
● Pathogenesis
Answers : 1. D 2. B 3. C ○ Genetic abnormalities lead to defects in stem cell
maturation and clonal expansion of leukemic blasts.
Leukemia: Hematopoiesis ● Myelodysplastic syndrome (MDS)

○ May precede AML- ‘preleukemic’ condition
● There are only 2 types, T-type and B-type. ○ Tends to occur in older individuals
● CFU stands for colony forming unit and with this, you have ○ Especially common in those treated with prior
your granulocyte, monocyte and CSF. chemotherapy
● So these are you stimulating factors ○ Pancytopenia
● Giving rise to your granulocytes ( basophils, neutrophils and ○ Shift to immaturity in granulocytes, but < 20 % blasts
○ Dysplasia in one or more lineages
your eosinophils granulocytes)
● And in granulocytes → monocytes. ● Morphology

○ Characterized by abnormal myeloid blasts:
○ Large nuclei
● Give rise to myeloid → a nucleated RBC →So it’s an id erythroid ○ Prominent nucleoli
progenitor. ● APL (M3)

○ Cytoplasmic granules with occasional Auer rods
● normoblast, erythroid → With the help of erythropoietin. (bundles in promyelocytic leukemia)
○ Azurophilic granules stain with antibody against
● kidney → give rise to your RBC’s. Morphology myeloperoxidase (MPO)
● FAB Classification
● platelet/thrombocytes →in the bone marrow, e, megakaryocyte ○ M0 Undifferentiated
○ M1 AML without maturation
→TPO (thrombopoietin). ○ M2 AML with maturation
○ M3 Acute promyelocytic leukemia (APL)
○ M4 Myelomonocytic
● Interleukin-5 →give rise to eosinophil. ○ M5 Monocytic/monoblastic
○ M6 Erythroleukemia
Recall: ○ M7 Megakaryoblastic leukemia
1. Which of the following is responsible for the maturation
and release of eosinophils from the bone marrow? ● Symptoms
○ Weakness, pallor, fatigue (normocytic anemia)
a. Interleukin-1
b. Interleukin-2 ○ Infection susceptibility (leukopenia)
c. Interleukin-5 ○ Easy bleeding/bruising (thrombocytopenia)
d. Interleukin-9 ○ Bone pain (marrow infiltration)
e. Interleukin-7
● Clinical Pathology
2. Which of the given interleukin families stimulates the ○ M3 (APL) associated with DIC can be effectively treated
differentiation of multipotent hematopoietic stem cells with all-trans retinoic acid (ATRA)
into myeloid progenitor cells? Recall:
1. Which of the following cytogenetic abnormalities are
a. Interleukin-1
b. Interleukin-5 associated with acute promyelocytic leukemia?
a. t(11;14)(q13;q32)
c. Interleukin-8
d. Interleukin-3 b. t(15;17)
e. Interleukin-17 c. 11q23 abnormalities
d. t(8;21)
Answers: 1. C 2. D e. t(14;18)(q32;q21)
2. Which of the given values represents the percentage of
blast cells in pre-leukemic conditions, such as AML?
Leukemia: Acute Myeloid Leukemia
a. Greater than 20%
b. Less than 10%
● Acute Myeloid Leukemia c. Greater than 25%
Associated with recurrent cytogenetic abnormalities, such as d. Less than 5%
○ t(15;17) acute promyelocytic leukemia (M3) e. Greater than 10%
○ t(8;21) acute myeloblastic leukemia with maturation
(M2) 3. Which of the following is seen in acute promyelocytic
○ 11q23 abnormalities Leukemia-M3?

32
PATHOLOGY
Spleen, & Thymus
a. Cabot rings b. Normal cytogenetics

b. Bart hemoglobin c. Age less than 2 years
c. Auer rods d. Age >11 years
d. Bence Jones protein e. Precursor B acute lymphoblastic leukemia
e. Balbiani rings
2. To which of the following body parts is lymphoblastic
4. What does the FAB classification categorize M6 as? lymphoma more likely to metastasize?
a. Acute erythroid leukemia a. Testicles
b. Acute promyelocytic leukemia b. Skeleton
c. Acute megakaryocytic leukemia c. Liver
d. Acute myelomonocytic leukemia d. Intestines
e. AML with maturation e. Kidney
5. Which of the following subtypes corresponds to acute Answers: 1. E 2. A

promyelocytic leukemia?
a. FAB subtype M4
b. FAB subtype M6
c. FAB subtype M7 Leukemia: Chronic Myelogenous Leukemia
d. FAB subtype M3
e. FAB subtype M5 ● Chronic Leukemia
○ derived from more mature leukocytes
Answers: 1. B 2. E 3. C 4. A 5. D ○ Chronic (mature) leukemias
➔ Chronic myelogenous leukemia
➔ Chronic lymphocytic leukemia
Leukemia: Acute Lymphocytic Leukemia ➔ Hairy cell leukemia
➔ Adult T-cell leukemia/lymphoma
● Acute Lymphocytic Leukemia (ALL)
○ Defective maturation of lymphocyte precursors ● Etiology
○ Can be pre-B or pre-T ALL ○ CML is defined by the presence of the Philadelphia
○ Can be extramedullary (lymphoblastic lymphoma) chromosome [t(9;22)]
○ Metastasizes to CNS, testicles ○ This results in fusion of the BCR and ABL genes
○ The ABL gene product is a tyrosine kinase that controls
● Morphology cell growth
○ Defined by > 20 % lymphoblasts ○ The BCR/ABL fusion protein results in increased,
○ Smaller than myeloblasts, with large nuclei and scant, unregulated activity of ABL leading to uncontrolled
basophilic cytoplasm growth of maturing myeloid cells
Pre- B ALL Pre- T ALL
Frequency 80% 20%
Age of onset Childhood Adolescence
Site Blood/BM Mediastinal mass
WBC count Low-Normal High
Prognosis Good Poor ● The Philadelphia chromosome translocation, t(9;22). The

Philadelphia chromosome (Ph1 ) is the derivative of
Symptoms Pancytopenia, Pancytopenia, chromosome 22, which has exchanged part of its long arm
neurologic neurologic for a segment of material from chromosome 9q that contains
symptoms, bone symptoms, bone the ABL oncogene (nonreceptor tyrosine kinase).
pain pain ● Formation of the BCR-ABLE fusion gene on the Ph 1
chromosome is the critical genetic even in the development
of chronic myelogenous leukemia.
Recall:
1. Which of the given factors is associated with a good ● Morphology
prognosis in acute lymphoblastic leukemia?
a. WBC >12,000

33
PATHOLOGY
Spleen, & Thymus
○ Peripheral blood shows leukocytosis with increased ○ Hypogammaglobulinemia and increased infections
immature granulocytes myelocytes, metamyelocytes, ○ Autoimmune hemolytic anemia (AIHA)
bands, etc ○ Immune thrombocytopenic purpura (ITP)
○ There is an absolute basophilia ● Some CLLs transform to more aggressive forms:
○ Prolymphocytic transformation
● Clinical Pathology ○ Richter syndrome transformation to diffuse large B-cell
○ Over 40 years old lymphoma
○ Onset is slow and insidious with non-specific symptoms
○ Symptoms come from:
➔ Anemia weakness, fatigue, pallor, etc. Clinical
pathology MORPHOLOGY
➔ Splenomegaly abdominal fullness, pain
○ Disease slowly progresses over years to:

➔ Accelerated phase failure of treatment and
increasing cytopenias
➔ Blast crisis identical to AML
● Treatment
○ Chronic phase treated successfully with Gleevec (ABL
tyrosine kinase inhibitor)
○ Gleevec-resistant disease treated with bone marrow
transplant
○ Imatinib ● Small, monomorphic lymphocytes with ‘’cracked’’
Recall: chromatin
1. Which of the following translocations is associated with ● ‘’Smudge cells’’
chronic myelogenous leukemia?
a. t(11;14) ● Usually occurs in older patients, median age of 70
b. t(15;17) ● WBC count varies from normal to very high (> 100,000)
c. t(14;18) ● Insidious onset with non-specific symptoms fatigue, weight
d. t(9;22) loss, anorexia
e. t(8;21) ● Lymphadenopathy and hepatosplenomegaly are often
2. Which of the given enzymes is a product of the BCR-ABL present
fusion gene? ● Progression is slow median survival is 4-6 years, < 1 year if
a. Tyrosine kinase disease transforms
b.Thiamine oxidase Recall:
c.Glutathione reductase 1. Which of the following is least likely to be associated with
d.Thymidylate synthase chronic lymphoid leukemia?
e.Topoisomerase ii a. Polycythemia vera
3. Which of the following drugs is used in the treatment of b. Hypogammaglobulinemia
chronic myelogenous leukemia? c. Autoimmune hemolytic anemia
a. Amlodipine d. Small lymphocytic lymphoma
b. Lyrica e. Immune thrombocytopenic purpura
c. Trazodone
d. Imatinib 2. Into what kind of aggressive lymphoma is chronic
e. Adderall lymphocytic leukemia most commonly transformed in
Richter syndrome?
Answers: 1. D 2. A 3. D a.Acute lymphoblastic leukemia
b. Hairy cell leukemia
c. Diffuse large b-cell lymphoma
Leukemia: Chronic Lymphoid Leukemia d. Acute myeloid leukemia
e. Chronic myeloid leukemia
● Pathogenesis 3. Which of the following cells are most often associated
○ Neoplasm of maturing peripheral lymphocytes with chronic lymphocytic leukemia?
○ May present as concurrent or isolated lymphoma (small a. Basket cells
lymphocytic lymphoma SLL) b. Popcorn cells
○ Bone marrow is always involved c. Downey Cells
○ Spleen and liver can also be involved d. Bite cells
e. Smudge cells
● CLL disrupts normal immune function:

34
PATHOLOGY
Spleen, & Thymus
Answers: 1. A 2. C 3 E 2. Which of the following conditions features a prickly

sensation after a hot bath?
a.Hairy cell leukemia
POLYCYTHEMIA b. Acute lymphoblastic leukemia
c. Acute myeloid leukemia
● Excess of RBC mass d. Renal cell carcinoma
● Etiology e.Polycythemia vera
○ Primary neoplastic, independent of erythropoietin
○ Polycythemia vera 3. Which of the following is NOT associated with secondary
● Secondary due to increased erythropoietin: polycythemia?
○ Chronic hypoxemia (lung disease, congenital heart a. Renal cell carcinoma
disease, high altitude) b. Pheochromocytoma
○ Paraneoplastic syndrome (RCC/HCC) c. Adrenal adenoma
○ Blood doping d. Von Hippel-Lindau disease
● Polycythemia vera e. Myeloproliferative disease
○ Essential thrombocythemia
○ Chronic myelogenous leukemia 4. Which of the given conditions is NOT caused by
○ Primary myelofibrosis polycythemia vera?
a. Hyperviscosity syndrome
b. Strokes
MORPHOLOGY c. Pulmonary embolism
d. Heart attacks
● Markedly increased RBCs on peripheral smear e.Thrombocytopenia
● Increased RBC and myeloid precursors in bone marrow
5. What do you call the type polycythemia that results from
plasma volume depletion?
a. Relative polycythemia
b. Absolute polycythemia
c. Primary polycythemia
d. Physiologic polycythemia
e. Chuvash polycythemia
● Left: Normal-sized megakaryocytes and normal cellularity Answers: 1. B 2. E 3. E 4. E 5. A

in a control bone marrow smear
● Right: Polycythemia Vera Types of Leukemia incl. Hairy Cell Leukemia (HCL) and
● Polycythemia vera shows trilineage expansion Adult T-Cell Leukemia/Lymphoma
(polycythemia,granulocytosis, thrombocythemia) with low
erythropoietin.
● Rare mature B-cell leukemia
○ normal range is 11 48 mU/ml
● Occurs predominantly in older males
● Patients present with splenomegaly and pancytopenia,
● Secondary polycythemia shows expansion of RBCs only
especially monocytopenia
with high erythropoietin
● Complications include opportunistic infections and vasculitis
● Increased RBC mass is more viscous and puts patients at
● Prognosis is good with treatment with purine nucleoside
risk for thrombosis (stroke, bowel infarction, hepatic vein
analogs and/or splenectomy.
thrombosis, etc.)
● Adult T-Cell Leukemia/Lymphoma
○ ATLL is caused by a retrovirus human T-cell leukemia
Recall: virus, type 1 (HTLV-1)
1. Which of the given etiological factors causes increased ○ Primarily found in HTLV-1 endemic areas Japan, the
levels of circulating red blood cells, independent of Caribbean, and central Africa
erythropoietin production? ○ Long latency, causing leukemia/lymphoma decades
a.High altitude after infection
b. Polycythemia vera ○ Patients present with widespread lymph nodes and
c. Lung disease peripheral blood involvement. The skin may also be
d. Renal cell carcinoma involved
e. Blood doping ○ Prognosis varies, but generally poor, with death usually
from opportunistic infections.
Recall:

35
PATHOLOGY
Spleen, & Thymus
1. Which of the following types of leukemia is most

commonly seen in children?
a.Chronic myeloid leukemia
b. Hairy cell leukemia
c. Acute lymphoblastic leukemia
d. Chronic lymphocytic leukemia
e. Acute myeloid leukemia
2. Which of the following types of leukemia has an excellent

prognosis?
a. Acute myeloid leukemia
b. Chronic lymphocytic leukemia
c. Hairy cell leukemia
d. Acute lymphoblastic leukemia
e. Acute T-cell leukemia
Answers: 1. C 2. D
References:
● Robbin’s 10th edition
● Lecturer’s Annotated Lecture PPT
● Lecturio

36

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PATHOLOGY

Diseases of WBCs, Lymph nodes,

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin 1

BM DEPOSITS o Alkylating agents and antimetabolites (drug treatment): dose

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

LEUKOCYTOSIS Table 13.3 Causes of Leukocytosis

ACUTE NONSPECIFIC LYMPHADENITIS

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Morphology  An immature dendritic cell that gives rise to a

CHRONIC NONSPECIFIC LYMPHADENITIS

PART II: NEOPLASTIC PROLIFERATION OF WBC

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

sarcoma) peripheral blood

Pathogenesis of white cell malignancies. Various tumors harbor

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Immune Cell Antigens Detected by Monoclonal Antibodies Pathogenesis

Acute lymphoblastic leukemia

I. Precursor B/T cell Neoplasms

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Table 13.6: Neoplasms of Immature B and T Cells → Generalized lymphadenopathy

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Pathogenesis Fig: CLL presenting with smudge cells (yellow arrow)

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Treatment o characteristically takes the form of paratrabecular

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Pathogenesis: Heterogenous Diffuse large B-cell lymphoma

 Overexpression of BCL2 (increase anti-apoptotic BCL2) Special Subtypes

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

D. Burkitt Lymphoma o An important regulator of gene expression in germinal B

Morphology → the kidneys, ovaries, and adrenal glands

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Pathogenesis  More mutation – clonal evolvement (B-cell survival)

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Clinical Features  In infected tissues or autoimmune disease

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

6. Extranodal T/NK lymphoma

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

○ Dutcher bodies - nuclear inclusions (whitish) MGUS (MONOCLONAL GAMMOPATHY OF UNDEF.

LYMPHOPLASMACYTIC LYMPHOMA (B-CELL NEOPLASM)

● BM - Plasma cells, lymphocytes, plasmacytoid lymphocytes

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

● Solitary Osseous Plasmacytoma:

● Must see R.S. cells with background of non-neoplastic

● Nodular sclerosis: most common HL (65-70%)

● Presence of Reed Sternberg cells (characteristic: if you

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

MIXED CELLULARITY NODULAR, LYMPHOCYTIC PREDOMINANCE

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

CLINICAL HODGKIN LYMPHOMA: Painless lymphadenopathy

Key points: Hodgkin Lymphoma

● RS - classic HL→ produce cytokines, chemokines, lympho. MYELOID NEOPLASMS

3. PD-1 lipid protein amplification

includes: 4. Loss of CDK NaN

Dr. Romainetic, CarbolFuchsin, Monroe, P. Aleman, Alphatoxin

➔ Clonal immune system Pathogenesis

● Epigenome gene reg. and mutation