WBC, Lymph Nodes, Spleen, and Thymus
Far Eastern University – Nicanor Reyes Medical Foundation
Pathology A – Diseases of WBC, Lymph Nodes, Spleen and Thymus
Cherry Tan M.D.
INTRODUCTION
 Myeloid tissues are the bone marrow and cells derived from it
 Lymphoid tissues are thymus, lymph nodes and spleen
DEVELOPMENT AND MAINTENANCE OF HEMATOPOIETIC TISSUES
 Blood cell progenitors first appear during third week of
development
 Hematopoietic stem cells arise several week later in the
mesoderm of the intraembryonic aorta / gonad / mesonephros
region
 Liver becomes the chief site of hematopoiesis from the third
month and shortly before birth
 HSC also resides in the placenta and at the fourth month occurs at
the bone marrow
 At birth, the marrow serves as the chief site of hematopoiesis
until puberty, where it only occur at the axial skeleton
 Formed elements of blood have a common origin from HSCs, the
pluripotent cells that sit at the apex of a hierarchy of bone
marrow progenitors
 Colony forming units produce colonies composed of specific kinds
of mature cells when grown in culture
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 Pluripotency and capacity for self-renewal are essential
properties of HSCs for maintenance of hematopoiesis
 Marrow response to short-term physiologic needs is regulated by
hematopoietic growth factors through the effects on committed
progenitors
 Multipotent progenitors are more proliferative than HSCs but
have a lesser capacity for self-renewal
 Stem cell factor (KIT ligand), FLT3-ligand act through receptors
expressed in very early committed progenitors
 Erythropoietin, GM-CSF, G-CSF and thrombopoietin act through
receptors of restricted committed progenitors
 Primary tumors of hematopoietic cells are the most important
disease the interfere marrow function
 Tumors of hematopoietic origin are often associated with
mutations that block progenitor cell maturation or abrogate
growth factor dependence
DISORDERS OF WHITE CELLS
 Proliferative disorders – expansion of leukocytes
 Reactive proliferations – in the setting of infections or
inflammation
 Neoplastic proliferations – less frequent, more important
clinically
 Leukopenias – deficiency of leukocytes
Leukopenia
 An abnormally low WBC count that results from reduced numbers
of neutrophils (neutropenia, granulocytopenia)
 Lymphopenia is less common, but can be congenital or acquired,
commonly observed in HIV infection, drug therapy, autoimmune
disorders, malnutrition and acute viral infections
 Granulocytopenia is more common and often associated with
diminished granulocyte function
Neutropenia, Agranulocytosis
 Neutropenia is the reduction in the number of neutrophils in the
blood
 Agranulocytosis is the clinically significant reduction in neutrophils
which makes the individual susceptible for bacterial and fungal
infections
Pathogenesis
 Caused by:
1. Inadequate or ineffective granulopoiesis
 Suppression of HSCs – occurring in aplastic anemia and
infiltrative marrow disorders. Accompanied by anemia and
thrombocytopenia
 Suppression of committed granulocytic precursors –
exposure to drugs
 Ineffective hematopoiesis – defective precursors die in the
marrow as seen in megaloblastic anemia and
myelodysplastic syndromes
 Rare congenital conditions – defects in genes as seen in
Kostmann syndrome
 2. Accelerated destruction or sequestration of neutrophils REACTIVE PROLIFERATIONS OF WHITE CELLS AND LYMPH NODES
 Immunologically mediated injury – can be idiopathic, seen
in SLE or drug exposure Leukocytosis
 Splenomegaly – leads to modest neutropenia, associated  Increase in the number of WBC in the blood
with anemia and thrombocytopenia  Common reaction to a variety of inflammatory stress
 Increased peripheral utilization – bacterial, fungal or
rickettsial infections Pathogenesis
 Drug toxicity is the most common cause of agranulocytosis:
 Generalized suppression of hematopoiesis is due to
alkylating agents and anti-metabolites used in cancer
treatment
 Idiosyncratic reaction is caused by aminopyrine,
chloramphenicol, sulfonamides, thiouracil, chlorpromazine
and phenylbutazone
 Chlorpromazine and phenylbutazone produces a toxic
effect on granulocytic precursors on the marrow
 Sulfonamides, aminopyrine, thiouracil and antibodies
induce immune destruction of mature PMNs
 Monoclonal proliferations of large granular lymphocytes (LGL
leukemia) can also produce severe neutropenia

Morphology
 Alterations on the bone marrow vary with the etiology
 Hypercellular due to:  Factors that influence blood leukocyte count:
 Compensatory increase in granulocytic precursors due to  Size of myeloid and lymphoid precursor and storage cell pools
destruction of mature granulocyte in the marrow, thymus, circulation and peripheral tissues
 Ineffective granulopoiesis as seen in megaloblastic anemia  Rate of release of cells to the circulation
and myelodysplastic syndromes
 Proportion of cells adherent to vessel walls at any time
 Hypocellular as seen in agranulocytosis induced by suppression or (marginal pool)
destruction of granulocytic precursors  Rate of extravasation of cells into the tissue
 Infections are common consequences of agranulocytosis  Factors that cause leukocytosis:
 Severe and life threatening infections occur in the lungs,
urinary tract and kidneys
Neutrophilic Acute bacterial infections, especially those
 Increased risk for fungal infections caused by Candida and leukocytosis caused by pyogenic organisms; sterile
Aspergillus inflammation caused by, for example, tissue
 Site of infection has little WBC response and cause an necrosis (myocardial infarction, burns)
inflamed or enlarged regional lymph node Eosinophilic Allergic disorders such as asthma, hay fever,
 Ulcerating necrotizing lesions of the oral cavity (agranulocytic leukocytosis parasitic infestations; drug reactions; certain
angina) (eosinophilia) malignancies (e.g., Hodgkin and some non-
Hodgkin lymphomas); automimmune disorders
 Deep, undermined and gray to green-black necrotizing
(e.g., pemphigus, dermatitis herpetiformis) and
necrotic membranes inhabited by bacteria and fungi
some vasculitides; atheroembolic disease
 Can also occur in the skin, vagina, anus or GIT (transient)
Basophilic Rare, often indicative of a myeloproliferative
Clinical Features leukocytosis disease (e.g., chronic myelogenous leukemia)
 Infection, malaise, chills and fever followed by marked weakness (basophilia)
and fatigability Monocytosis Chronic infections (e.g., tuberculosis), bacterial
 Agranulocytosic infections may cause death within hours to days endocarditis, rickettsiosis, and malaria;
3 autoimmune disorders (e.g., systemic lupus
 Most serious infections present <500 per mm PMNs while <1,000
3 erythematosus); inflammatory bowel diseases
per mm is quite worrisome
(e.g., ulcerative colitis)
 Broad spectrum antibiotics are given whenever signs or symptoms Lymphocytosis Chronic infections (e.g., tuberculosis), bacterial
appear endocarditis, rickettsiosis, and malaria;
 G-CSF stimulates the production of granulocytes from marrow autoimmune disorders (e.g., systemic lupus
precursor and is given for myelosuppresive chemotherapy erythematosus); inflammatory bowel diseases
(e.g., ulcerative colitis)

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 In sepsis or severe inflammatory disorders, leukocytosis is
accompanied by:
 Toxic granules – coarser and darker than the normal
neutrophilic granules and represents abnormal azurophilic
(primary) granules
 Dohle bodies – patches of dilated ERs that appear as sky blue
cytoplasmic puddles
 Cytoplasmic vacuoles
 Acute viral infections in children cause appearance of large
numbers of activated lymphocytes that resemble neoplastic
lymphoid cells
 Leukemoid reaction is the increase in granulocytes in blood due
to severe infections
Lymphadenitis
 Activation of resident immune cells leads to morphological
changes in lymph nodes
 Primary follicles enlarge and develop pale staining germinal
centers that are highly dynamic structures in which B cells make
antibodies
 Paracortical T-cell zones may also undergo hyperplasia
 Degree and pattern of morphologic changes are dependent on the
inciting stimulus and intensity of the response
a. Acute Nonspecific Lymphadenitis
 Often occurs in the cervical region due to drainage of microbes or
microbial products from infections of the teeth or tonsils
 In the axillary or inguinal region, often caused by infections of the
extremities
 Mesenteric nodes are affected due to acute appendicitis
 Acute generalized lymphadenopathy is due to systemic viral
infections, particularly in children, and bacteremia
Morphology
 Nodes involved are large, swollen, gray-red and painful, when
abscess forms, nodes become fluctuant and the overlying skin is
red
 Suppurative infections penetrate through the capsule of the node
and tract to the skin producing draining sinuses
 Healing is associated with scarring
 Prominence of large reactive germinal centers containing
numerous mitotic figures
 Macrophages often contain debris from bacteria and necrotic cells
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 Neutrophils are prominent and centers of follicles undergo
necrosis due to pyogenic organisms
 Endothelial cells undergo hyperplasia
b. Chronic nonspecific lymphadenitis
 Lymph nodes are nontender and inflammation is absent
 Common in the inguinal and axillary nodes
 Promote the appearance of organized collections of immune cells
in nonlymphoid tissues (tertiary lymphoid organs)
Morphology
1. Follicular hyperplasia – seen in humoral immune response
 Presence of large oblong germinal centers surrounded by naive
B cells
 Due to rheumatoid arthritis, toxoplasmosis and early stage HIV
 Morphologically similar to follicular lymphoma except for:
intact architecture, marked variation in size and shape of
follicles and frequency of mitotic figures, macrophages and light
and dark zones
 Marginal zone b cell hyperplasia extends to the mantle zone
2. Paracortical hyperplasia – caused by T-cell mediated immune
response
 Contains immunoblasts that are three to four times the site of
resting lymphocytes with round nuclei, open chromatin,
prominent nucleoli and moderate amount of pale cytoplasm
 T cell zones expand and efface B cell follicles
 Hypertrophy of sinusoidal and vascular endothelial cells
accompanied by macrophages and eosinophils
3. Reticular hyperplasia – sinus histiocytosis, refers to an increase in
the size and number of cells lining the sinusoids
 Prominent in nodes draining cancers
 Lining lymphatic endothelial cells are hypertrophied and
macrophages are in great numbers
 Expansion and distension of the sinuses
c. Hemophagocytic Lymphohistiocytes (HLH)
 Reactive condition marked by cytopenias and systemic
inflammation related to macrophage activation
 Referred to as macrophage activation syndrome
Pathogenesis
 Common feature of all forms of HLH is systemic activation of
macrophages and CD8+ cytotoxic T cells
 Leads to cytopenias and a shock-like picture referred to as
“cytokine storm” or SIRS
 Familial forms are associated with several different mutations,
impacting the ability of cytotoxic T cells and NK to form or deploy
cytotoxic granules
 Most common trigger for HLH is infection, particularly EBV
Clinical Features:
 Acute febrile illness associated with splenohepatomegaly
 Hemophagocytosis is seen on bone marrow examination
 Anemia, thrombocytopenia and very high levels of plasma ferritin
and soluble IL-2e receptor
 Elevated liver function tests and triglyceride levels
 DIC may be seen in coagulation studies
 Can progress rapidly to multiple organ failure, shock and death
Neoplastic Proliferations of WBC:
 Malignancies are clinically the most important disorders of WBC.
 Lymphoid Neoplasms

Include diverse group of tumors of B-cells, T-cells, NK-cell
origins. The phenotype closely resembles that of a particular
stage of normal lymphocyte maturation.
 Myeloid Neoplasms
 Arise from early hematopoietic progenitors.
 Three categories are recognized:

Acute Myeloid Leukemia – Immature progenitor cells
accumulate in the bone marrow.

Myeloid Dysplastic Syndromes – Associated with
ineffective hematopoiesis and resultant peripheral blood
cytopenias.

Chronic Myeloproliferative Disorders – Increased
production of one or more terminally differentiated
myeloid element, usually leading to elevated counts.
 Histiocytoses
 Uncommon proliferative lesions of macrophages and
dendritic cells.
 A special type of immature dendritic cell, Langhan cells, give
rise to neoplastic disorders termed as Langhan cell
histiocytoses.
ETIOLOGY AND PATHOGENESIS OF WHITE CELL NEOPLASIA
1.) Chromosomal Translocations and Acquired Mutations
 Non-random chromosomal abnormalities, most commonly
translocations, are present in majority of WC neoplasia.
 Mutated genes often play crucial roles in the development,
growth, or survival of the normal cells.
 Can be loss of function due to mutation of a dominant
negative protein that interferes with normal function.
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 Can be gain of function of inappropriate increase in some
normal activity.
 Oncoproteins created by genomic aberrations often block
normal maturation, turn on pro-growth signals, or protect cells
from apoptosis.
 Dominant negative oncogenic mutations in acute leukemia,
involve transcription factors often present that interfere with
early stage of lymphoid or myeloid differentiation.
 Transcriptional regulator mutations directly enhance the self-
renewal of tumor cells, giving such stem-cell-like properties.

Often involve tyrosine kinases that activate RAS and its
two downstream pathways PIK3/AKT and MAPK, driving
cell to growth and Warburg metabolism.
 Proto-oncogenes are often activated by errors that occur during
antigen receptor gene rearrangement and diversification.
 Potentially oncogenic mutations occur most frequently in the
germinal center B cells during attempted Ab diversification.
 After stimulation, B cells enter the centers and upregulate
expression of Activation-Induced Cytosine Deaminase (AID),
a DNA-modifying enzyme that is essential for Ig modification

Class Switching – Intragenic recombination event which the
IgM heavy chain constant gene segment is replaced.

Somatic Hypermutation – Created point mutations with Ig
Genes that may increase Ab affinity for antigens.
 MYC oncogenes are also activated in germinal B-cell
lymphomas by translocations.
2.) Inherited Genetic Factors
 Genetic diseases that promote genomic instability, such as
Bloom Syndrome, Fanconi anemia, and Ataxia telangiectasia are
at increased risk of acute leukemia.
 Down syndrome and Type 1 neurofibromatosis are associated
with increased incidence of childhood leukemia.
3.) Viruses
 Three lymphotrophic viruses have been implicated as causative
agents in particular lymphomas:
 HTLV1 (Human T-cell Leukemia Virus-1)

Associated with adult T-cell leukemia/lymphoma.
 EBV (Epstein-Barr Virus)

Found in a subset of Burkitt Lymphoma

Found in 30-40% of Hodgkin’s Lymphoma

Many B-cell lymphomas arising in the setting of T-cell
immunodeficiencies

Rare NK-cell lymphomas
 KSHV/HHV-8 (Kaposi sarcoma herpesvirus/Human herpesvirus 8)

Presents as malignant effusion, often in the pleural cavity.
4.) Chronic Inflammation
 Helicobacter pylori infections are associated with gastric B-cell
lymphomas, gluten-sensitive enteropathy, and intestinal T-cell
lymphomas.
 HIV infection is associated with an increased risk of B-cell
lymphomas that may arise virtually within any organ.
  T-cell dysregulation by HIV causes a systemic hyperplasia of
germinal center B cells associated with increased incidence of
germinal center B-cell lymphomas.
 In AIDS, severe T-cell immunodeficiency further elevates the risk
of B-cell lymphoma, particularly those associated with EBV and
KSV/HHV-8.
5.) Iatrogenic Factors
 Radiation therapy and certain form of chemotherapy used to
treat cancer, increases the risk of subsequent myeloid and
lymphoid neoplasms.
 This stems from the mutagenic effects of ionizing radiation and
chemotherapeutic drugs on hemato-lymphoid progenitor cells.
6.) Smoking
 Incidence of acute myeloid leukemia is increased 1.3-2-fold in
smokers due to exposure to carcinogens (e.g. benzene).
Lymphoid Neoplasms
DEFINITIONS AND CLASSIFICATION
 Leukemia is a term used for neoplasms that present with
widespread involvement of the bone marrow and usually but
not always the peripheral blood.
 Lymphoma is used for proliferations that arise as discrete tissue
masses.
 With large group of lymphomas, Hodgkin Lymphoma (HL) is
segregated from all other forms, which constitute the Non-
Hodgkin Lymphoma (NHL).
 Plasma cell neoplasm often arises in the bone marrow and only
infrequently involves lymph nodes or the peripheral blood.
 Clinical presentations :
 2/3 of NHL and all HL present as enlarged non-tender lymph
nodes often >2cm in size.
 Remaining 1/3 of NHL present with extranodal involvement.
 Lymphocytic leukemia has signs and symptoms related to the
suppression of normal hematopoiesis by tumor cells in the
bone marrow.
 Most common plasma cell neoplasm, multiple myeloma,
present with bony destruction associated with pain due to
pathologic fractures.
 Other symptoms related to lymphoid tumors can be
associated with proteins secreted by the tumors:
 Whole Ig fragments in plasma cell tumors.
 Cytokines from inflammatory cells in HL
 Currently, the WHO classification scheme uses morphologic,
immunophenotypic, genotypic, and clinical features to sort the
lymphoid neoplasm into broad categories:
1. Precursor B-cell neoplasms (immature B-cells)
2. Peripheral B-cell neoplasms (mature B-cells)
3. Precursor T-cell neoplasms (immature T-cells)
4. Peripheral T-cell and NK-cell neoplasms (mature T-cells and
NK-cells)
5. Hodgkin Lymphoma (Reed-Sternberg cells and variants)
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 Lymphoid neoplasia can be suspected from features but
histologic examination of the lymph nodes or other tissus is
required for diagnosis.
 Antigen receptor gene rearrangement generally precedes
transformation of lymphoid cells
 All daughter cells derived from malignant progenitor share
the same antigen receptor gene configuration and
sequence, and synthesize identical antigen receptor proteins
(Igs or T-cell receptors).
 Most lymphoid neoplasms resemble some recognizable stage of
B-cell or T-cell differentiation.
 85-90% are of B cell origin, the remainder from T-cell.
 Rarely are tumors of NK cell origin encountered.
 Markers recognized by Ab’s are helpful in characterization of
lymphomas and leukemia.
 Lymphoid Neoplasms are often associated with immune
abnormalities.
 Loss of protective immunity (susceptibility to infection) and
breakdown of tolerance (autoimmunity) can be seen.
 Ironically, those with acquired immunodeficiency are at high
risk of developing lymphoid neoplasms, particularly those
caused by viruses.
 Neoplastic B and T cells tend to recapitulate the behavior of
their normal counterpart.
 In follicular lymphomas, home to germinal centers.
 In cutaneous T-cell lymphomas, home to the skin.
 Adhesion molecules and chemokine receptors govern the
homing of the neoplastic cells.
 They also recirculate through the lymphatics and peripheral
blood to the distant sites; as a result they are widely
disseminated at the time of diagnosis.
 Exceptions are:

Hodgkin Lymphoma – restricted to a group of lymph node

Marginal Zone B-cell Lymphoma – restricted to sites of chronic
inflammation.
 HL spreads in an orderly fashion, while most forms of NHL
spread widely in their early course in a less predictable fashion.
Precursor B- and T-cell Neoplasms
1.) Acute Lymphoblastic Leukemia / Lymphoma
 ALLs are neoplasms composed of immature B, or T cells which
are referred to as lymphoblasts.
 About 80% are B-ALLs, which manifest as childhood acute
leukemia.
 Less common T-ALLs tend to present in adolescent males as
thymic lymphomas.
 B-ALL uncommonly presents as a mass in the skin or a bone,
many T-ALLs present with or evolve to a leukemic picture.
 ALL is the most common cancer in children.
Pathogenesis
 Chromosomal aberrations seen in ALL dysregulate the
expression and function of normal transcription factors required
for normal B- and T-cell development.
 70% have gain of function mutation in NOTCH1, a gene essential
for T-cell development.
 B-ALLs have loss of function mutations in genes that are required
for B-cell development, such as PAX5, E2A, and EBF, or a
balanced t(12;21) involving ETV6 and RUNX1.
 These mutations disturb the differentiation and promote
maturation arrest; they induce increased self-renewal, stem
cell-like phenotypes.
 Single mutations are not sufficient to produce ALLs.
Approximately 90% of ALLs have numerical or structural
chromosomal changes.
 Most common is hyperploidy (>50 chromosomes), but
hypoploidy and balanced translocations are also seen.
 B-ALL and T-ALL are associated with completely different sets of
translocations, indicating that they are pathogenetically distinct.
Morphology
 In leukemic presentations, the marrow is hypercellular and
packed with lymphoblasts, which replace the normal marrow
elements.
 Mediastinal thymic masses occur in 50-70% of T-ALLs, associated
with lymphadenopathy and splenomegaly.
 Both T-ALL and B-ALL have tumor cells which have scant
basophilic cytoplasm and nuclei larger than those small
lymphocytes.
 Nuclei chromatin is delicate and finely stippled; nucleoli are
usually small and often demarcated by a rim of condensed
chromatin.
 Nuclear membrane is deeply subdivided.
 Mitotic rate is high, hence with the aggressive clinical behavior.
 ALL vs. AML
 Compared to myeloblasts, lymphoblasts have more
condensed chromatin, less conspicuous nucleoli, and smaller
amounts of cytoplasm that usually lacks granules.
Immunophenotype
 Immunostaining for Deoxynucleotidyl Transferase (TdT), a
specialized DNA polymerase, expressed only in pre-B and pre-T
lymphoblasts, positive in 95% of cases.
 B-ALLs are arrested at different stages. Usually express the B-cell
marker CD19 and transcription factor PAX5 as well as CD10.
 CD10 is negative in very immature B-ALLs.
 T-ALLs are also arrested at different stages. Usually expresses
CD1, 2, 5, and 7.
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 Very immature T-ALLs are negative for CD3, 4, and, 8.
Clinical Features
 ALL and AML are genetically and immunophenotypically distinct,
but they are clinically very similar.
 Accumulation of neoplastic blasts in the bone marrow
suppresses the normal hematopoiesis by physical crowding,
competition with growth factors, and other unknown
mechanisms.
 ALLs have these more common characteristics:
 Abrupt stormy onset within days to a few weeks.
 Symptoms related to depression of marrow function, such
as anemia, fever, infection due neutropenia, bleeding due to
thrombocytopenia.
 Mass effects caused by neoplastic infiltration, more
common in ALL, includes bone pain, generalized
lymphadenopathy, splenomegaly, hepatomegaly, testicular
enlargement, and in T-ALL compression of vessels and
airways in the mediastinum.
 CNS manifestations such as headache, vomiting, nerve
palsies due to meningeal spread, common in ALL.
Prognosis
 Aggressive chemotherapy cures 75-80% of cases, 95% obtain a
complete remission in children, 35-40% of adults are cured.
 Factors associated with worse prognosis:
 Age younger than 2 y/o, associated with infantile ALL with
translocations involving the MLL gene.
 Presentation in adolescence or adulthood.
 Peripheral blood blast counts greater than 100,000,
reflecting high tumor burden.
 Factors with favorable prognosis:
 Age between 2-10 y/o
 Low WBC count
 Hyperdiploidy
 Trisomy of chromosomes 4,7, and 10
 Presence of a t(12;21)
Peripheral B-cell Neoplasms
1.) Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic
Lymphoma (SLL)
 CLL and SLL only differ in the degree of peripheral blood
lymphocytosis.
 Most affected patients have sufficient lymphocytosis to fulfill
3
the diagnostic requirement for CLL >5000 per mm .
 CLL is the most common leukemia of adults in the Western.
Pathogenesis
 Chromosomal translocations are rare in CLL./SLL.
 Most common genetic anomalies are deletions of 13q14.3, 11q,
17p, and trisomy 12q.
 Two microRNAs, miR-15a and miR-16-1 are possible tumor
suppressor genes involved in CLL/SLL.
 Ig genes of some CLL/SLL are somatically hypermutated, some
are not, suggesting that the cell of origin may be either a
postgerminal center memory B cell or a naïve B cell.
 Tumors from naïve B cells pursue a more aggressive course.
 There is also gain of function in NOTCH1 in 10-18% of tumors.
 The growth of CLL/SLL is largely confined to proliferation centers,
where tumor cells receive critical cue from microenvironment.
 Stromal cells seem to express variety of factors that stimulate
the activity of the transcription factor NF-κB which promotes cell
growth and survival.
Morphology
 Lymph nodes are diffusely effaced by an infiltrate of
predominantly small lymphocytes 6-12 µm in diameter with
round to slightly irregular nuclei, condensed chromatin, and
scant cytoplasm.
 Admixed with activated lymphocytes that often gathers in loose
aggregates referred to as proliferation centers, which contain
mitotically active cells.
 Proliferation centers are pathognomonic for CLL/SLL.
 Some of the cells in the blood usually disrupted in the process of
making smears produce a so-called smudge cells.
 Bone marrow is almost always involved by interstitial infiltrates
or aggregates of tumor cells, which are also always seen in the
splenic white/red pulp and hepatic portal tracts.
Immunophenotypes
 CLL/SLL express the pan B-cell markers CD19 and CD20, as well
as CD23, CD5.
 Low levels expression of surface Ig (usually IgM or IgM and IgD)
is also typical.
Clinical Features
 Patients are often asymptomatic at diagnosis.
 Symptoms are nonspecific, including easy fatigability, weight
loss, and anorexia.
 Generalized lymphadenopathy and splenomegaly.
 Leukocyte count is highly variable, leukopenia can be seen in
individuals with SLL, and marrow involvement.
3 
 Counts in excess of 200,000/mm are sometimes seen in CLL
patients with heavy tumor burdens.
 A small monoclonal Ig spike is present in the blood.
 CLL/SLL disrupts the normal immune function through
uncertain mechanisms.
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 Hypogammaglobulinemia is common and contributes to an
increased susceptibility to infections.
 10-15% develop hemolytic anemia or thrombocytopenia due
to autoantibodies made by non-neoplastic B cells.
Prognosis
 Extremely variable and depend primarily on the clinical stage.
 Overall survival is 4-6 years, but more than 10 years in
individuals with minimal tumor burdens.
 Factors with worse prognosis:
 Presence of deletions of 11q, 17p.
 A lack of somatic hypermutation.
 Expression of ZAP-70, a protein that augments signals
produced by the Ig receptors.
 Presence of NOTCH1 mutations.
 Another factor that impacts patient survival is the tendency of
CLL/SLL to transform to a more aggressive tumor.
 Most commonly takes the form is to diffuse large B-cell
lymphoma, so called Richter Syndrome.
2.) Follicular Lymphoma
 The most common form of NHL in the US.
 Presents in the middle age and afflicts males and females
equally.
Pathogensis
 Arises from germinal center B cells, strongly associated with
chromosomal translocations involving BCL2.
 Hallmark is a (14;18) translocation that juxtaposes the IGH locus
on chromosome 14 and the BCL2 locus on chromosome 18.
 BCL2 becomes overexpressed and antagonizes apoptosis and
promotes survival of follicular lymphoma.
 Follicular lymphoma is devoid of apoptotic cells.
 MLL2 gene mutations are present in 90%, it encodes for histone
methyltransferases that regulate gene expression, suggesting
epigenetic abnormalities.
 Follicular lymphoma cells grow in lymph nodes within a network
of reactive follicular dendritic cells admixed with macrophages
and T-cells.
Morphology
 Predominantly nodular or nodular and diffuse growth pattern
observed in lymph nodes.
 Two principal cell types are present in varying proportions:
 Small cells with irregular or cleaved nuclear contous and
scant cytoplasm referred to as centrocytes.
 Large cells with open nuclear chromatin, several nucleoli, and
modest amounts of cytoplasm called centroblasts.
 Small cleaved cells are in the majority.
Peripheral blood involvement sufficient to produce
3
lymphocytosis usually <20,000/mm is seen in 10% of cases.
 Bone marrow involvement in 85% of cases characteristically
takes the form of paratrabecular lymphoid aggregates.
 Splenic white pulp and hepatic portal triads are also involved.
Immunophenotype
 Neoplastic cells closely resemble normal germinal center B-cells.
 Expresses CD19, CD20, CD10, surface Ig, and BCL6.
 Unlike CLL/SLL, CD5 is not expressed.
Clinical Features
 Tends to present with painless, generalized lymphadenopathy.
 Involvement of extranodal sites, such as GIT, CNS, or testis is
relatively uncommon.
 Although incurable, it follows an indolent waxing and waning
course.
 Survival is not improved by aggressive therapy; hence, the usual
approach is to palliate the patient with low-dose chemo- or
immunotherapy when they become symptomatic.
 Histologic transformation occurs in 30-50%, most commonly to
diffuse large B-cell lymphoma. Less commonly, tumors
resembling Burkitt lymphoma emerge associated with
translocations involving MYC.
 Median survival is less than 1 year after transformation.
3.) Diffuse Large B-Cell Lymphoma
 DLBCL is the most common form of NHL.
 Median patient age is about 60 years old.
 Male is more affected then females.
Pathogenesis
 DLCBL is a molecularly heterogeneous disease.
 Frequent pathogenic event is dysregulation of BCL6, a DNA-
binding zinc-finger transcriptional repressor required for the
formation of normal germinal center.
 Another 10-20% have t(14;18) mutations, leading to
overexpression of BCL2, an antiapoptotic protein.
Morphology
 Common features are relatively large cell size, usually 4-5 times
the diameter of small lymphocyte, and a diffuse pattern of
growth.
 Tumor cells have round or oval nucleus that appears vesicular
due to migration of chromatin to nuclear membrane, but large
multilobated or cleaved nuclei are prominent.
 Nucleoli may be 2-3 times in number and located adjacent to the
nuclear membrane.
 Cytoplasm is usually abundant and may be pale or basophilic.
 More anaplastic tumors may even contain multinucleated cells
with large inclusion-like nucleoli resembling Reed-Sternberg cells
Immunophenotype
 Mature B-cell tumors expressing CD19 and CD20 and show
variable expression of germinal center B-cell markers, such as
CD10 and BCL6.
 Most have surface Igs.
Page 8 of 21
Subtypes
1.) Immunodeficiency-associated large B-cell lymphoma
 Occurs in the setting of severe T-cell deficiency (e.g. HIV)
 Neoplastic B cells are usually infected with EBV, which plays a
critical pathogenic role.
 Restoration of T-cell immunity may lead to regression.
2.) Primary effusion lymphoma
 Presents as malignant pleural or ascetic effusion.
 Mostly in patients with advanced HIV infection or older adults.
 Tumor cells are often anaplastic, typically fail to express surface
markers, but have clonal IgH gene rearrangements.
 Tumor cells are infected with KSHV/HHV-8.
Clinical Features
 Typically presents as a rapidly enlarging mass at a nodal or
extranodal site (GIT, skin, bone, brain).
 Waldeyer’s ring (Oropharyngeal Lymphoid Tissue) is commonly
involved.
 Primary or secondary liver or spleen involvement takes the form
of destructive masses.
 Bone marrow involvement is uncommon and usually occurs late.
 Rarely, a leukemic picture emerges.
 Rapidly fatal without treatment.
 Intensive combination chemotherapy, 60-80% have
remission and 40-50% are cured.
4.) Burkitt Lymphoma
 Categories:
 African Burkitt Lymphoma (Endemic)
 Sporadic Burkitt Lymphoma (Non-endemic)
 Aggressive lymphomas in HIV-infected individuals
Pathogenesis
 All forms are highly associated with translocations of the MYC
gene on chromosome 8 leading to increased MYC protein levels.
 MYC is a transcriptional regulator that increases expression of
genes required for aerobic glycolysis, so-called Warburg effect.
 It is believed to be the fastes growing human tumor.
 The translocation partner for MYC is usually the IgH locus, t(8;14)
 Essentially, all endemic Burkitt lymphoma, are latently infected
with EBV, which is also present in 25% of HIV-associated tumors
and 20% of sporadic cases.
Morphology
 Tissues are effaced by diffuse infiltrate of intermediate-sized
lymphoid cells 10-25 µm in diameter with round or oval nuclei,
coarse chromatin, several nucleoli, and a moderate amount of
cytoplasm.
 Tumor exhibits a high mitotic index and contains numerous
apoptotic cells.
 The nuclear remnants are phagocytosed by interspersed benign
macrophages. These have abundant clear cytoplasm, creating a
starry sky appearance.

 When bone marrow is involved, aspirates reveal tumor cells with
slightly clumped nuclear chromatin, 2-5 distinct nucleoli, and a
royal blue cytoplasm containing clear vacuoles.
Immunophenotype
 These are mature B cell tumors expressing surface IgM, CD19,
CD20, CD10, and BCL6.
 Burkitt lymphoma almost always fails to express the anti-
apoptotic protein BCL2, unlike other germinal center tumors.
Clinical Features
 Endemic and sporadic are found mainly in children or young
adults, overall it accounts for 30% of childhood NHL.
 Most manifest extranodal sites.
 Endemic often presents as a mass involving the mandible, and
shows an unusual predilection for involvement of abdominal
viscera particularly the kidneys, ovaries, and adrenals.
 Sporadic most often appears as mass involving the ileocecum
and peritoneum.
 Involvement of the bone marrow and peripheral blood is
uncommon.
 This is very aggressive but responds well to intensive
chemotherapy.
Plasma Cell Neoplasms and Related Disorders
 These B-cell proliferations contain neoplastic plasma cells that
virtually always secrete a monoclonal Ig or Ig fragment which
serves as a tumor marker and often have pathologic
consequences.
 Plasma cell neoplasms (often called dyscrasia) account for 15%
of deaths caused by lymphoid neoplasm.
 Monoclonal Ig in the blood is called the M component, in
reference to myeloma.
 They have 160,000 molecular weight making them restricted
to the plasma and ECF, and not in the urine in the absence of
glomerular damage.
 Neoplastic cells often synthesize excess light chains along with
complete Igs.
 Highly sensitive for free light chains in the blood is available.
 The level of free light chains is usually elevated and is
markedly skewed toward one light chain at the expense of
the seconds.
Since free light chains are small, they can be concentrated in
the urine, referred to as Bence-Jones proteins.
 Abnormal proteins are associated with the ff. entities:
 Multiple Myeloma

Also called Plasma Cel Myeloma.

Most important plasma cell neoplasm, usually presents as
tumorous masses scattered throughout the skeletal
system.

Solitary myeloma (Plasmacytoma) is an infrequent variant
that presents as a single massin bone or soft tissue.
Page 9 of 21

Smoldering myeloma refers to another uncommon variant
defined by lack of symptoms and high plasma M
component.
 Waldenstrom macroglobulinemia

A syndrome in which high levels of IgM lead to symptoms
related to hyperviscosity of the blood.

It occurs in older adults,most commonly in association with
lymphoplasmacytic lymphoma.
 Heavy-chain disease

A rare monoclonal gammopathy.

Seen with lymphoplasmacytic lymphoma and unusual
small bowel marginal zone lymphoma occurring in
malnourished populations (Mediterranean Lymphoma).

Common feature is the synthesis and secretion of free heavy-
chain fragment.
 Primary or Immunocyte-Associated amyloidosis

Results from a monoclonal proliferation of plasma cell
secreting light chain (usually λ isotype) that are deposited
as amyloid.

Some have overt multiple myeloma but others have only a
minor clonal population of plasma cells in the marrow.
 Monoclonal Gammopathy of Undetermined Significance
(MGUS)

Applied to patients without signs or symptoms who have
small to moderately large M components in the blood.

Very common in older adults and has a low but constant rate
of transformation to multiple myeloma.
1.) Multiple Myeloma
 A plasma cell neoplasm commonly associated with lytic bone
lesions, hypercalcemia, renal failure, and acquired immune
abnormalities.
Pathogenesis
 Associated with frequent rearrangements involving the IgH locus
and various proto-oncogenes.
 Included are frequent translocations with Ig heavy-chain on
14q2, cyclin D1 on chromosome 11q13, and cuclin D3 on
chromosome 6p21.
 A deletion of chromosome 17p that involves the TP53 tumor
suppressor locus also occurs.
 The proliferation and survival of myeloma cells are dependent
on several cytokines, most notably IL-6, which is an important
growth factor for plasma cells.
 High serum levels of IL-6 are seen in patients with active
disease, and associated with poor prognosis.
 Factors produced by neoplastic plasma cells mediate bone
destruction, the major pathologic feature of multiple myeloma:
 Myeloma derived MIP1α upregulates the expression of
RANKL by bone marrow stromal cells that in turn activates
osteoclasts.
 Modulators of Wnt pathway are potent inhibitors of
osteoblast functions.
 Net effect is marked increase in bone resorption, which leads
to hypercalcemia.
Morphology
 Usually presents as destructive plasma cell tumors
(Plasmacytomas) involving the axial skelton.
 Bones commonly affected (in descending order) are vertebral
column, ribs, skull, pelvis, femur, clavicle, and scapula.
 It begins in the medullary cavity, erode cancellous bone, and
progressively destroy the bony cortex.
 Bone lesions appear radiographically as punched-out defects
usually 1-4 cm in diameter, and consist of soft, gelatinous, red
tumor masses.
 The marrow contains an increased number of plasma cells,
which usually constitute 30% of the cellularity.
 Plasma cells may infiltrate the interstitium.
 Malignant plasma cells have perinuclear clearing due to
prominent Golgi bodies and have an eccentrically placed
nucleus.
 Plasmablasts may appear normal with vesicular nuclear
chromatin and a prominent single nucleolus or appear as
bizzare, multinucleated cell, such variants include:
 Flame Cells – with fiery red cytoplasm
 Mott cells – with multiple grape-like cytoplasmic droplets,
containing fibris, crystalline rods, and globules. These
inclusions are known as Russell Bodies (cytoplasmic) or
Dutcher Bodies (nuclear).
 High levels of M proteins cause red cells to form rouleaux.
 Rarely, tumor cells flood the peripheral blood giving rise to
plasma cell leukemia.
 Bence jones proteins are excreted in the urine contribute to a
form of renal disease called myeloma kidney.
Immunophenotype
 Positive for CD138, an adhesion molecule known as syndecan-1.
 They also often express CD56.
Clinical Features
 The presentation of myeloma arise from:
 Effects of plasma cell growth in tissues particularly the bone.
Production of excessive Igs, which often have abnormal
physicochemical properties.
 Suppression of normal humoral immunity.
 Bone resorption leads to pathologic fractures and chronic pain.
 The attendant hypercalcemia can give rise to neurologic
manifestations (e.g. confusion, weakness, lethargy, constipation,
and polyuria).
 Decreased normal Ig leads to recurrent bacterial infection.
Page 10 of 21
 Renal insufficiency trails only infections.
 Pathogenesis of renal involvement is multifactorial.
 Most important is the Bence-Jones proteinuria, as the
excreted light Ig chains are toxic to renal tubular epithelial
cells.
 Certain light chains are prone to cause amyloidosis of the AL
type, which can exacerbate renal dysfunction.
 In 99% of patients, lab analyses reveal increased levels of Igs in
the blood, or light chain Igs in the urine.
 The monoclonal Igs are usually first detected as abnormal
proteins pikes in the serum.
 Most myelomas are associated with more than 3gm/dL of
serum Ig, or more than 6 mg/dL of Bence jones urine protein.
 Most common is IgG, followed by IgA.
 IgM, IgD, or IgE are rare.
 Marrow involvement often gives rise to a normocytic
normochromic anemia, sometimes accompanied by leukopenia
and thrombocytopenia.
 Prognosis is variable.
2.) Solitary Myeloma (Plasmacytoma)
 3-5% of plasma cell neoplasms present as a solitary lesion of
bone or soft tissue.
 Tend to occur in same locations in multiple myeloma.
 Extraoseus lesions often involve the lungs, oronasopharynx, or
nasal sinuses.
 Modest elevations of M proteins in the blood or urine.
 Solitary osseous plasmacytoma inevitably progress to multiple
myeloma, but it can take 10-20 years or longer.
 Extraosseous plasmacytomas are cured by local resection.
3.) Smoldering Myeloma
 Defines a middle ground between multiple myeloma and
monoclonal gammopathy of uncertain significance.
 Plasma cells make up 10-30% of marrow cellularity.
 Serum M protein is > 3 gm/dL, but patients are asymptomatic.
 75% progress to multiple myeloma over 15 year period.
4.) Monoclonal Gammopathy of Uncertain Significance (MGUS)
 The most common plasma cell dyscrasia.
 Approximately 1$ develop a symptomatic plasma cell neoplasm,
usually multiple myeloma.
5.) Lymphoplasmacytic Lymphoma
th th
 A B-cell neoplasm usually presents in the 6 or 7 decade of life.
 Superficially resembles CLL/SLL but differs because a substantial
fraction of tumor cells undergo terminal differentiation to
plasma cells.
 Most commonly, the plasma cell secretes monoclonal IgM, often
in amounts to cause hyperviscosity syndrome known as
Waldenstrom macroglobulinemia.
 Unlike multiple myeloma, complications from light chain Igs are
rare and bone destruction does not occur.
Pathogenesis
 Associated with acquired mutations in MYD88, which encodes
an adaptor protein that participates in signaling events that
activate NF-kB, and also augment signals downstream of the B-
cell receptor which may promote the growth and survival of
tumor cells.
Morphology
 Marrow contains an infiltrate of lymphocytes, plasma cells, and
plasmacytoid lymphocytes in varying proportions.
 Often accompanied by mast cell hyperplasia.
 Some contain a population of larger lymphoid cells with more
vesicular nuclear chromatin and prominent nuclei.
 Period acid-schiff positive inclusions contain Ig frequently seen in
the cytoplasm (Russell bodies) or the nucleus (Dutcher bodies).
 At diagnosis, dissemination to lymph node, spleen and liver has
occurred.
 Infiltration of nerve roots, meninges, or rarely the brain.
Immunophenotype
 Expresses B-cell markers CD20 and surface Ig, whereas the
plasma cell secretes the same Ig that is expressed on the surface
of lymphoid cells.
 Usually IgM but can also be IgG or IgA.
Clinical Features
 Dominant presenting complains are non-specific.
 Half of patients have lymphadenopathy, hepatomegaly, and
splenomegaly.
 Anemia caused by marrow infiltration is common.
 10% have autoimmune hemolysis caused by cold agglutinins,
IgM antibodies that bind to red cells.
 IgM have additional signs and symptoms, because of its large
size, at high concentrations IgM increases viscosity of the blood
giving rise to hyperviscosity syndrome leading to:
 Visual Impairment associated with venous congestion.
 Neurologic Problems due to sluggish blood flow.
 Bleeding due to formation of complexes.
 Cryoglobulinemia resulting from precipitation of Ig.
 Lymphoplasmacytic lymphoma is incurable progressive dse.
 Elevated IgM can be alleviated by plasmapheresis.
 Tumor growth can be controlled.
 Median survival is about 4 years.
Mantle Cell Lymphoma
 Uncommon lymphoid neoplasm.
 Closely resemble the normal mantle zone B cells that surround
germinal centers.
Pathogenesis
 All have an (11;14) translocation involving the IgH locus on
chromosome 14 and cyclin D1 on chromosome 11, leading to
overexpression of cyclin D1.
Page 11 of 21
 Results to upregulation of D1 to promote G1-S phase
progression.
Morphology
 Generalized lymphadenopathy, 20-40% have peripheral blood
involvement.
 Frequent sites of extranodal involvement include bone, marrow,
spleen, liver, and gut.
 Mucosal involvement of small bowel produces polyp-like lesion
(lymphomatoid polyposis), of all NHL, mantle cell lymphoma is
most likely to spread in this fashion.
 Nodal tumor cells may surround reactive germinal centers to
produce nodular appearance.
 Typically, proliferations consist of a homogeneous population of
small lymphocytes with irregular to occasionally deeply clefted
unclear contours.
 Centroblasts/proliferative centers are absent unlike that of
CLL/SLL, respectively.
 In most cases, nuclear chromatin is condensed, nucleoli are
inconspicuous, and cytoplasm is scant.
Immunophenotype
 Express high levels of cyclin D1.
 Most express CD19, CD20, and moderately high levels of surface
Ig (usually IgM and IgD).
 Usually CD5+ and CD23-.
 IgH lacks somatic hypermutation, supporting an origin from a
naïve B cell.
Clinical Features
 Most common is painless lymphadenopathy.
 Related to involvement of the spleen and gut.
 Prognosis is poor, median survival is only 3-4 years.
 Non-curable with conventional chemo, most patient succumb to
organ dysfunction.
Marginal Zone Lymphomas
 Encompasses a heterogeneous group of B-cell tumors that arise
within lymph nodes, spleen, or extranodal tissues.
 Initially recognized at mucosal sites referred to as mucosa-
associated lymphoid tumors (MALTomas).
 Most tumor cells show evidence of somatic hypermutation and
considered to be of memory B-cell origin.
 Three exceptional characteristics:
 Often arise within tissues involved by chronic inflammatory
disorders of autoimmune or infectious etiology.

Example is salivary gland in Sjogren Syndrome.

Thyroid gland in Hashimoto’s thyroiditis

Stomach in Helicobacter gastritis.
 Remain localized for prolonged periods.
 May regress if inciting agent is eradicated.
 These suggest extranodal margicnal lymphomas arising in
chronically inflamed tissues lie on a continuum between
reactive lymphoid hyperplasia and full-blown lymphoma.
 The disease begins as polyclonal immune reaction, with the
acquisition of still unknown initiating mutations, a B-cell clone
emerges that sill depends on antigen-stimulated T-helper cell
signals.
 At this stage, removal of the inciting agent may cause tumor
involution.
Hairy Cell Leukemia
 Rare, distinctive B-cell neoplasm constitutes 2% of al leukemia.
 Predominantly a disease of middle-aged white males, median
age of 55 years old.
 Male to female ratio of 5:1
Pathogenesis
 Associated with 90% of cases with activating point mutation in
the serine/threonine kinase BRAF, which is immediately
downstream of RAS in the MAPK cascade.
 Specific mutation is a Valine to Glutamate substitution at the
th
600 residue (also found in melanomas and langerhan cell
histiocytosis).
Morphology
 Appearance of leukemic cells which have fine hair-like
projections that are best recognized under phase-contrast
microscope.
 Hairy cells have round, oblong, or reniform nuclei and moderate
amounts of pale blue cytoplasm with thread-like or bleb-like
extensions.
 Marrow is involved by a diffuse interstitial infiltrate of cells with
oblong and reniform nuclei.
 Usually cannot be aspirated because these cells are enmeshed in
an ECM composed of reticulin fibrils ( a clinical difficulty called as
dry tap), only seen in marrow biopsies.
 Splenic red pulp is usually heavily infiltrated, with obliteration of
the white pulp; hepatic portal triads are also affected.
Immunophenotype
 Express the pan-B-cell markers CD19 and CD20, surface Ig, and
certain relatively distinctive markers such as CD11c, CD25,
CD103, and annexin A1.
Page 12 of 21
Clinical Features
 Results from infiltration of the bone marrow, liver, & spleen.
 Splenomegaly is often massive, most common physical finding.
 Hepatomegaly is less common.
 Lymphadenopathy is rare.
 Pancytopenia resulting from marrow involvement and splenic
sequestration is seen.
 1/3 of affected patients present with infections.
 Increased incidence of atypical mycobacterial infections.
 Related to frequent unexplained monocytopenia.
 Exceptionally sensitive to gentle chemotherapy, which produces
long lasting remissions.
 The tumor replaces after 5 years but still responds to the
same agent.
 BRAF Inhibitors produce excellent responses.
Peripheral T-Cell and NK-Cell Neoplasms
 .
1.) Peripheral T-Cell Lymphoma, Unspecified
 Under wastebasket diagnosis, since these are not easily
categorized.
 No morphologic feature is pathognomonic.
 These tumors efface the lymph nodes diffusely and are typically
composed of a pleomorphic mixture of variably sized malignant
T cells.
 Brisk neoangiogenesis can be seen.
 All peripheral T-cell lymphomas are derived from mature T-cells,
usually express CD3, CD5, and either αβ or γ∆ T-cell receptors.
 Most patients present with generalized lymphadenopathy,
sometimes accompanied with eosinophilia, pruritus, fever, and
weight loss.
2.) Anaplastic Large-Cell Lymphoma (ALK Positive)
 Uncommon entity is defined by the presence of rearrangements
in the ALK gene on chromosome 2p23.
 These break the ALK locus and lead to formation of chimeric
genes encoding for ALK fusion proteins.
 The tumor is typically composed of large anaplastic cells, some
contain horseshoe-shaped nuclei and voluminous cytoplasm (so-
called hallmark cells).
 Tumor cells often cluster about venules and infiltrate lymphoid
sinuses, mimicking the appearance of metastatic carcinoma.
 T-cell lymphomas with ALK rearrangement occur in children or
young adult involving soft tissues, and have good prognosis.
 Cure rate is 75-80%.
 Both ALK+ and ALK- tumors express CD30, a member of TNF
receptor family, recombinant antibodies bind and kill CD30-
expressing cells.
3.) Adult T-cell leukemia /lymphoma
 Neoplasm of CD4+ T cells is only observed in adults infected by
HTLV-1.
 Common findings include skin lesions, generalized
lymphadenopathy, hepatosplenomegaly, peripheral blood
lymphocytosis, and hypercalcemia.
 Appearance of tumor cells has multilobated nuclei (cloverleaf or
flower cell).
 They often contain clonal HTLV-1 provirus.
 HTLV encodes for a protein called Tax that activate NF-kb, which
enhances lymphocyte growth and survival.
 Most patients present with rapidly progressive disease that is
fatal within months to a year.
4.) Mycosis Fungoides / Sezary Syndrome
 These are different manifestations of a tumor of CD4+ T-cells
that home to the skin.
 Cutaneous lesions of Mycosis fungoides progress through three
distinct stages:
 Inflammatory premycotic phase.
 Plaque Phase
 Tumor Phase
 Histologically, the dermis and upper dermis are infiltrated by
neoplastic cells having a cerebriform appearance due to marked
infolding of the nuclear membrane.
 Late disease progression leads to extracutaneous spread to
lymph nodes or bone marrow.
 Sezary syndrome, a variant in which skin involvement manifests
as generalized exfoliative erythroderma, and there is associated
leukemia of Sezary cells with characteristic cerebriform nuclei.
 Tumor cells express adhesion molecule cutaneous leukocyte
antigen (CLA) and chemokine receptor CCR4 and CCR10.
5.) Large Granular Lymphocytic Leukemia
 T-cell and NK-cell variants of this rare neoplasm occur in adults.
 Usually present with mild to moderate lymphocytosis and
splenomegaly.
 Lymphadenopathy and hepatomegaly are usually absent.
 30-40% have STAT3 mutations, which functions as downstream
of cytokine receptors
 Tumor cells are large lymphocytes with abundant blue cytoplasm
and a few coarse azurophilic granules.
 Marrow usually contains sparse interstitial lymphocytic
infiltrates, which can be difficult to appreciate without
immunohistochemical stain.
 T-cell variants are CD3+, NK-cell variants are CD3- and CD56+
 Neutropenia and anemia dominate the clinical picture.
 Neutropenia is accompanied by striking decrease in late
myeloid forms in the marrow.
 Rarely, pure red cell aplasia is seen.
 Increased incidence of rheumatologic disorder
 Felty syndrome is seen in some patients, a triad of
rheumatoid arthritis, splenomegaly, and neutropenia.
Page 13 of 21
6.) Extranodal NK/T-Cell Lymphoma
 Rare, presents most commonly as a destructive nasopharyngeal
mass, less common site include the testis and the skin.
 Tumor cells infiltrate typically surrounds and invades small
vessels, leading to extensive ischemic necrosis.
 Large azurophilic granules are seen in the cytoplasm of the cells.
 High associated with EBV, no consistent chromosome aberration
has been described.
 Most are highly aggressive neoplasms that respond well to
radiation but are resistant to chemotherapy.
Hodgkin Lymphoma
 Encompasses a group of lymphoid neoplasms that differ from
NHL. HL arises in a single nod or chain of nodes and spread first
to anatomically contiguous lymphoid tissue.
 It is characterized by the presence of neoplastic cells called
Reed-Sternberg Cells (RS Cells).
 These cells release factors that induce accumulation of reactive
lymphocytes, macrophages, and granulocytes.
 In most HLs, the RS cells are mostly derived from germinal
center or post-germinal center B cells.
 Average age at diagnosis is 32 years old.
 First human cancer to be successfully treated with radiation and
chemotherapy, and is curable in most cases.
Classification
1. Nodular Sclerosis
2. Mixed Cellularity
3. Lymphocyte-Rich
4. Lymphocyte-Depletion
5. Lymphocyte-Predominance
 In the first four subtypes, the RS cells have similar
immunophenotype, these are often clumped together in the
classical HL.
 The remaining, lymphocyte predominance, have RS cells that
have distinctive B-cell immunophenotype.
Pathogenesis
 The Ig genes of RS cells have undergone both V(D)J
recombination and somatic hypermutation, establishing an
origin from a germinal center or post-germinal center B cell.
 RS cells fail to express most B-cell-specific genes, including the Ig.
 Presumably it results from widespread epigenetic changes.
 Activation of NF-kB is a common event in classical HL.
 This can occur via:
 Activated by EBV infection or by some other mechanisms
that promote lymphocyte survival and proliferation.
 EBV expresses Latent Membrane Protein 1 (LMP1) that
transmit signals that upregulate NF-kB.
 Activation of NF-kb may occur in EBV tumors as a result of
loss of function in IkB or A20 which are negative regulators of
NF-kB.
 It is hypothesized that activation of NF-kB by EBV rescues
crippled germinal center B cells that cannot express Igs from
apoptosis.
 The accumulation of reactive cells in classical HL occurs in
response to cytokines, chemokines, and other factors secreted
by the RS cells.
 The attracted cells produce factors that support the growth and
survival of the tumor cells and modify the reactive cell response.
 RS cells are aneuploid and possess direrse clonal chromosomal
aberrations.
 Copy number gains in the REL proto-oncogenes on chromosome
2p are common and may contribute to increased NF-kB activity.
Morphology
 RS cells are large cells (45µm in diameter) with multiple nuclei or
a single nucleus with multiple lobes, each with large inclusion-
like nucleolus about the size of the small lymphocyte.
 Mononuclear variants contain a single nucleus with large
inclusion-like nucleolus.
 Lacunar cells have more delicate, folded, or multilobate nuclei
and abundant pale cytoplasm, often disrupted during cutting
sections.
 In classic forms, RS undergo peculiar form of cell death in which
the cells shrink and become pyknotic, a process described as
mummification.
 Lymphohistiocytic variants (L&H) with polypoid nuclei,
inconspicuous nucleoli, and moderately abundant cytoplasm are
of lymphocyte predominance type.
Page 14 of 21
1.) Nodular Sclerosis
 Most common form, 65-70% of cases.
 Characterized by the presence of lacunar variant RS cells and the
deposition of collagen in bands that divide the involved lymph
node into circumscribed nodules.
 Fibrosis may be scant t abundant.
 RS cells are found in a polymorphous background of T cells,
eosinophils, plasma cells, and macrophages.
 This subtype is uncommonly associated with EBV.
 Immunophenotype:
 Positive for PAX5, CD15, and CD30
 Negative for other B-cell markers, T-cell markers, and CD45.
 Occurs with equal frequency in male and female.
 Has the propensity to involve the lower cervical, supraclavicular,
and mediastinal lymph nodes.
 Prognosis is excellent.
2.) Mixed Cellularity Type
 Constitutes about 20-25% of the cases.
 Lymph nodes are diffusely effaced by a heterogeneous cellular
infiltrate (T-cell, eosinophil, plasma cells, and macrophages).
 RS cells are mononuclear variants, usually plentiful.
 70% are infected with EBV.
 Immunophenotype is same with Nodular Sclerosis.
 More common in males, more likely associated with older age.
 Accompanied by systemic symptoms such as night sweats, and
weight loss, but overall prognosis is good.
3.) Lymphocyte-Rich Type
 An uncommon form in which reactive lymphocyte make up the
vast majority of the cellular infiltrate.
 Lymph nodes are usually effaced, but vague nodularity to
presence of residual B-cell follicles.
 There is presence of mononuclear variants of RS cells.
 Classic immunophenotype.
 40% is associated with EBV.
 Very good prognonsis.
4.) Lymphocyte Depletion Type
 Least common form, 5% of cases.
 Characterized by paucity of lymphocytes and a reactive
abundance of RS cells or their pleomorphic variants.
 RS cells are 90% infected with EBV.
 Occurs predominantly in adults, HIV+ patients, and non-
industrialized countries.
 Overall outcome is somewhat less favorable than the others.
5.) Lymphocyte Predominance Type
 Uncommon, Non-classical variant accounts for 5% of cases.
 Nodes are effaced by a nodular infiltrate of small lymphocytes
admixed with variable number of macrophages.
 Classic RS cells are usually difficult to find, but Lymphocytic and
Histiocytic variants are common having a multilobed nucleus
resembling a popcorn kernel (popcorn cell).
 Eosinophils or plasma cells are usually absent.
 L&H variants express B-cell markers typical of germinal center B
cells, such as CD20 and BCL6 and are usually negative of CD15
and CD30.
Clinical Features
 Most commonly present as painless lymphadenopathy.
 Nodular sclerosis and lymphocyte predominance type have stage
I-II disease and are usually free from systemic manifestations.
 Patients with disseminated disease (Type III, IV) or mixed-
cellularity or lymphocyte depletion type have constitutional
symptoms such as fever, weight loss, and night sweats.
 Anergy resulting from depressed cell-mediated immunity is seen.
 Cure rate with Stages I and IIA have 90%.
Myeloid Neoplasms
 Common feature of this heterogeneous group of neoplasm is an
origin from hematopoietic progenitor cells.
 Primarily involve the marrow and to a lesser degree the
secondary hematopietic organs (spleen, liver, lymph nodes).
 Three broad categories:
1.) Acute Myeloid Leukemia – accumulation of immature blast
forms in the bone marrow suppresses normal hematopoiesis.
2.) Myelodysplastic Syndromes – defective maturation, gives
rise to ineffective hematopoiesis, leading to cytopenias.
3.) Myeloproliferative disorder – increased production of one or
more cell types.
Pathogenesis
 Normal hematopoiesis is tuned by homeostatic feedback
mechanisms involving cytokines and growth factors.
 These are deranged in marrow involvement which escape from
normal homeostatic control and suppress the function of the
residual normal stem cells.
 Influenced by:
 Position of the transformed cell in the hierarchy
 Effect of transforming events on differentiation.
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Acute Myeloid Leukemia (AML)
 Caused by acquired oncogenic mutation that impedes
differentiation, leading to accumulation of immature myeloid
blasts in the marrow.
 Replacement of marrow with blasts produces marrow failure
and complications leading to anemia, thrombocytopenia, and
neutropenia.
Classification
 Divided into 4 classification
 First classification includes forms of AML with particular genetic
aberrations.
 AML arising after a myelodysplastic disorder.
 Therapy related AMLs
 Lastly, a fourth ‘wastebasket’ includes AMLs lacking any of these
features.
 They are classified based on degree of differentiation and
lineage of the leukemic blasts.
Pathogenesis
 Recurrent genetic aberration disrupts genes encoding
transcription factors that are acquired for normal myeloid
differentiation.
 Two most common:
 T(8;21) disrupts RUNX1
 Inv(16) disrupts CBFB
 Both create chimeric genes encoding fusion proteins that
interfere with the functions and block the maturation of myeloid
cells.
Morphology
 Diagnosis of AML is based on the presence of at least 20% of
myeloid blasts in the bone marrow.
 Several blasts are recognized.
 They have delicate nuclear chromatin, 2-4 nucleoli, and more
voluminous cytoplasm than lymphoblasts.
 Cytoplasm often contains fine, peroxidase positive azurophilic
granules.
 Auer Rods are distinctive needle-like azurophilic granules which
are present in most cases.
 Monoblasts have folded or lobulated nuclei, lack auer rods, and
are non-specific esterase positive.
 Some blasts show megakaryocytic differentiation, accompanied
by marrow fibrosis caused by release of fibrogenic cytokines.
 Occasionally, blasts are entirely absent from the blood,
aleukemic leukemia. Bone marrow examination is essential.
Immunophenotype
 Diagnosis of AML is confirmed by performing stains for myeloid-
specific antigens.
Clinical Features
 Present within few weeks or months at the onset of symptoms
related to anemia, neutropenia, and thrombocytopenia.
 Most notably fatigue, fever, and spontaneous mucosal and
cutaneous bleeding.
 Infections are frequent, particularly the oral cavity, skin, lungs,
kidney, bladder, and colon caused by opportunistic pathogens.
 Tumors with monocytic differentiation infiltrate the skin
(Leukemia cutis) and the gingiva.
 AML occasionally presents as a localized soft-tissue mass known
variously as myeloblastoma, granulocytic sarcoma, or chloroma.
Prognosis
 Generally a difficult disease to treat.
 60% active complete remission with chemotherapy, but only 15-
30% remain free of the disease for 5 years.
 Treatment with all-trans retinoic acid and arsenic salts in AML
with t(15;17) have best prognosis, 80% cure rate.
 AML with t(8;12) or inv(6) have good prognosis with
conventional chemotherapy.
Myelodysplastic Syndromes (MDS)
 MDS refers to a group of clonal stem cell disorders characterized
by maturation defects that are associated with ineffective
hematopoiesis and a high risk of transformation to AML.
 Bone marrow is partly or wholly replaced by the clonal progeny
of neoplastic multipotent cells that retains the capacity to
differentiate but does so in an ineffective and disordered fashion
 These abnormal cells stay within the marrow, thus patients
experience cytopenias.
 MDS can be Primary (idiopathic) or Secondary (exposure to
genotoxic drugs or radiation therapy).
Pathogenesis
 Poorly understood.
 There are number of recurrently mutated genes and can be
lumped into three major functional categories:
 Epigenetic Factors
 RNA Splicing Factors
 Transcription Factors
 10% of MDS have loss of function mutations in TP53 (tumor
suppressor genes).
Morphology
 Marrow is usually hypercellular, it is sometimes normocellular or
rarely hypocellular.
 Most characteristic finding is dysplastic differentiation affecting
erythroid, granulocytic, monocytic, and megakaryocytic lineage.
 Within erythroid series common abnormalities include ring
sideroblasts, erythroblasts with iron-laden mitochondria.
 Megaloblastoid Maturation resembling that seen in Vit. B12 and
Vit. B9 deficiency.
 Nuclear Budding Abnormalities, recognazied as nuclei with
misshapen often polyploid outlines.
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 Neutrophils contain decreased number of secondary granules,
toxic granulates, and Dohle bodies.
 Pseudo-Pelger-Huet cells are neutrophils with 2 lobes,
commonly observed.
 Pawn Ball Megakaryocyte contains single nuclear lobes with
multiple separate nuclei are seen.
 Blast cells may be increased but make up less than 20% of
overall marrow cellularity.
Clinical Features
 Primary MDS is predominantly a disease of adults, usually
discovered incidentally; If symptomatic, presents as weakness,
infections, and hemorrhage due to pancytopenia.
 Primary MDS is divided into 8 categories.
 Treatment is fairly limited.
 In younger individuals, allogeneic hematopoietic stem cell
transplant offers hope for reconstitution of normal
hematopoiesis.
 In older patients, MDS is treated with support antibiotic and
blood product transfusions.
 Thalidomide-like drugs, and DNA methylation inhibitors
improve effectiveness of hematopoiesis.
Myeloproliferative Disorders
 Common pathogenic feature is the presence of mutated,
constitutively activated tyrosine kinases or other acquired
aberrations that lead to growth factor independence.
 Most common consequence is an increase in the production of
one or more mature blood elements.
 Most of this disorder arises from multipotent myeloid
progenitors.
 Common features:
 Increased proliferative drive.
 Homing of neoplastic stem cells to secondary hematopoietic
organs (extramedullary hematopoiesis).
 Marrow fibrosis and peripheral cytopenias
 Variable transformation to acute leukemia
1.) Chronic Myelogenous Leukemia (CML)
 Distinguished from others by presence of chimeric BCR-ABL gene
derived from portions of BCR from chromosome 22, and BL on
chromosome 9.
 Philadelphia Chromosome.
 Cell of origin is a pluripotent hematopoietic stem cell.
Pathogenesis
 BCR-ABL contains dimerization domain that self-associates,
leading to activation of ABL tyrosine kinase moiety.
 ABL kinase in turn phosphorylates proteins that induce signaling
through the same pro-growth and pro-survival pathways turned
on by normal hematopoietic pathways.
 BCR-ABL preferentially drives proliferation of granulocytic and
megakaryocytic progenitors, causing abnormal release of
immature granulocytic forms to the blood.

Morphology
 Marrow is markedly hypercellular.
 Elevated proportion of eosniophils and basophils.
 Megakaryocytes are also increased, usually include small,
dysplastic forms.
 Erythroid progenitors are also present in mildly decreased
numbers.
 Presence of scattered macrophages with abundant wrinkled,
green-blue cytoplasm so-called sea-blue histiocytes
3 erythropoiesis.
 Blood reveals leukocytosis often exceeding 100,000 cells/mm .
 It consists primarily of neutrophils, band forms, metamyelocytes,
myelocytes, eosinophils, and basophils.
Clinical Features
th th
 Primarily a disease of adults, peak incidence at 5 to 6 decade.
 Onset is insidious.
 Mild to moderate anemia and hypermetabolism which can lead
to fatigability, weakness, weight loss, and anorexia.
 Splenomegaly can cause acute left upper quadrant pain due to
splenic infarction.
2.) Polycythemia Vera
 Strongly associated with activating point mutations in the
tyrosine kinase JAK2.
 PCV is characterized by increased marrow production of red
cells, granulocytes, platelet, but its increased RBC production is
the one responsible for the most clinical symptoms.
Pathogenesis
 JAK2 participates in JAK/STAT pathway, which lies downstram of
multiple hematopoietic growth factor receptors, including the
erythropoietin receptor.
 PCV cells have decreased requirements for erythropoietin and
other factors due to constitutive JAK2 signaling.
 97% is associated with valine to phenylalanine substitution in
JAK2 at residue 617.
 The proliferative drive is less compared to CML.
Page 17 of 21
Morphology
 Marrow is hypercellular, but some residual fat is present.
 Increase in red cell progenitors is subtle and usually
accompanied by an increase in granulocytic precursors and
megakaryocytes as well.
 Moderate to marked increase in reticulin fibers is seen.
 Mild organomegaly is common caused by congestion.
 Peripheral blood contains increased number of basophils and
abnormally large platelets.
 Spent phase – late in the course, PCV is characterize by
extensive marrow fibrosis that displaces hematopoietic cells.
Clinical Features
 PCV is uncommon and appears insidiously.
 Most symptoms are related to increased red cell mass and
hematocrit.
 Usually there is also an increased total blood volume
 Patients are plethoric and cyanotic due to stagnation and
deoxygenation of blood in the peripheral vessels.
 Intense pruritus and peptic ulceration may occur due to release
of histamine from basophils.
 Abnormal blood flow and platelet function may lead to an
increased risk of bleeding and thrombotic episode.
 Hgb concentration ranges from 14-18, and hematocrit is usually
60% or more.
 Chronic bleeding leads to iron deficiency, which can suppress
 White cell count ranges from 12,000 – 50,000 cells, and platelet
count is often greater than 500,000 platelets and exhibit
abnormal morphology such as giant forms.
3.) Essential Thrombocytosis
 Associated with activation point mutations in JAK2 or MPL (a
tyrosine kinase normally activated by thrombopoietin).
 ET manifests with elevated platelet and is separated from PCV by
the absence of polycythemia, and primarily myelofibrosis by the
absence of marrow fibrosis.
 Constitutive JAK2 and MPL renders progenitors thrombopoietin-
independent and leads to hyperproliferation.
 Bone marrow cellularity is usually only mildly increased but
megakaryocytes are markedly increased with abnormal forms.
 Erythromelalgia, a throbbing and burning sensation of the hands
and feet caused by occlusion of small arterioles by platelet
aggregates is seen.
4.) Primary Myelofibrosis
 Development of obliterative marrow fibrosis
 Replacement of marrow tissue by fibrous tissue reduces bone
marrow hematopoiesis, leading to cytopenias and extensive
extramedullary hematopoiesis.
 The appearance is identical to the spent phase that occurs in
other myeloproliferative disorders.
 Chief pathologic feature is the extensive deposition of collagen
in the marrow by the non-neoplastic fibroblasts.
 The fibrosis displaces hematopoietic elements from the marrow. SPLEEN
 Two fibrinogenic factors have been implicated:  Filter for the blood and a site for immune responses to blood-
 PDGF borne antigens
 TGF-β  Functions of the spleen that impact disease states:
 Phagocytosis of blood cells and particulate matter – splenic
Morphology macrophages are responsible for “pitting red cells”, the
 Marrow is often hypercellular. process where Heinz bodies and Howell-Jolly bodies are
 Erythroid and Granulocytic appear normal but Megakaryocytes excised and for the removal of particles such as bacteria in the
are large, dysplastic, and abnormally clustered. blood
 Bone marrow becomes more hypocellular and diffusely fibrotic.  Antibody production – important site for production of
 Cloud-like clusters of atypical megakaryocytes are usually seen. antibodies against microbial polysaccharides and
 Osteosclerosis or the change of the marrow in to bone may be autoantiboides
seen very late in the course.  Hematopoiesis – for compensatory extramedullary
 Extensive extramedullary hematopoiesis in the spleen. hematopoiesis
 In the blood, premature relase of nucleated erythroid and early  Sequestration of formed blood elements – can induce
granulocyte progenitors (leukoeryhtrobalstosis) is seen. thrombocytopenia and leukopenia
 Dacrocytes (Teardrop-shaped cells) were probably damaged  Splenic insufficiency due to splenectomy or autoinfarction has
during the birthing process of the fibrotic marrow are also seen. increased susceptibility of sepsis induced by encapsulated
bacteria such as pneumococci, meningococci, Haemophilus
Clinical Features influenza
 Less common, usually occurs in 60 years older patients.
 It comes to attention due to progressive anemia and Splenomegaly
splenomegaly.  When sufficiently enlarged, can cause a dragging sensation in the
 Nonspecific symptoms are also present. LUQ and through pressure on the stomach, discomfort after
 Labs show a moderate to severe normochromic, normocytic eating
anemia accompanied by leukoerythroblastosis.  Hypersplenism – characterized by anemia, leukopenia,
 WBC is usually normal or reduced; platelet is usually normal or thrombocytopenia alone or in combination
elevated, blood findings are usually non-specific.
 Harder to treat than PCV or ET. Disorders associated with splenomegaly
Infections Nonspecific splenitis of various blood-
Langerhans Cell Hisitocytosis borne infections, Infectious
mononucleosis, Tuberculosis, Typhoid
 A designation for a variety of proliferative disorders of dendritic
fever, Brucellosis, Cytomegalovirus,
cells or macrophages.
Syphilis, Malaria, Histoplasmosis,
 Some are malignant (e.g. Lymphomas), and some are benign Toxoplasmosis, Kala-azar,
(e.g. Reactive Proliferations). Trypanosomiasis, Schistosomiasis,
 The origin and nature has been controversial leading to a Leishmaniasis, Echinococcosis
discussion whether it is better considered as a neoplasm or a Congestive States Cirrhosis of the liver
reactive process. Related to Portal Portal or splenic vein thrombosis
Hypertension Cardiac failure
 The Langerhans cells have abundant, often vacuolated cytoplasm
and vesicular nuclei containing linear grooves or folds. Lymphohematogenous Hodgkin lymphoma
Disorders Non-Hodgkin lymphomas and
 Presence of Birbeck granules is characteristic, these are lymphocytic leukemias
pentalaminar tubules, often with dilated terminal end, producing Multiple myeloma
a tennis-racket like appearance. Myeloproliferative disorders
 Can present as several clinicopathologic entities: Hemolytic anemias
 Multifocal Multisystem LCH (Letterer-Siwe Disease) Immunologic- Rheumatoid arthritis
 Unifocal and Multifocal Unisystem LCH (Eosinophilic Inflammatory Systemic lupus erythematosus
granuloma) Conditions
 Pulmonary LCH Storage Diseases Gaucher disease
Niemann-Pick disease
 One factor contributing to neoplastic Langerhans cells is the Mucopolysaccharidoses
aberrant expression of chemokine receptors.
Miscellaneous Disorders Amyloidosis
Primary neoplasms and cysts
Secondary neoplasms

Page 18 of 21
A. Nonspecific Acute Splenitis
 Cause by microbiologic agents and cytokines released as part of
immune response
Morphology
 Enlarged up to 200-400gm and soft
 Major feature is acute congestion of the red pulp, may encroach
and efface lymphoid follicles
 Neutrophils, plasma cells and eosinophils are present in white and
red pulp
 White follicles may undergo necrosis when causative agent is
haemolytic streptococcus
 Abscess may occur
B. Congestive Splenomegaly
 Caused by chronic venous outflow obstruction due to intra or
extra hepatic disorder that impinge the portal or splenic veins
 Systemic, or central venous congestion is encountered in cardiac
decompensation involving the the right side of the heart
 Cirrhosis of the liver is the main cause of congestive splenomegaly
 Spontaneous portal vein thrombosis or pylephlebitis can also
cause congestive Splenomegaly
Morphology
 Enlargement up to 1000-5000gm, firm and capsule is thickened
and fibrous
 Red pulp is congested and becomes fibrotic and cellular
 Deposition of collagen in basement membrane
 Excessive destruction due to prolonged exposure to macrophages
C. Splenic Infarcts
 Common lesions caused by occlusion of the major splenic artery
or its branches
 One of the most frequent site for emboli lodge
 Often caused by emboli arising from the heart
Morphology
 Bland infarcts are pale, wedge-shaped and subcapsular in location
 Overlying capsule is covered with fibrin
 Development of suppurative necrosis
 Large depressed scars develop in healing
Page 19 of 21
Neoplasms
 Myeloid and lymphoid tumors often cause splenomegaly
 Benign fibromas, osteomas, chondromas, lymphangiomas and
hemangiomas may occur in the spleen
Congenital Anomalies
 Complete absence is rare and may be related to situs inversus and
cardiac malformation
 Hypoplasia is a more common finding
 Accessory spleen (spleniculi) – common, small, spherical
structures found within the abdominal cavity
Rupture
 Precipitated by blunt trauma
 Predisposing conditions include infectious mononucleosis,
malaria, typhoid fever and lymphoid neoplasm
 Cause intraperitoneal hemorrhage and treated by prompt
splenectomy
THYMUS
Developmental Disorders
 Thymic hypoplasia or aplasia – seen in DiGeorge syndrome,
marked by severe defects in cell mediated immunity and
abnormalities of parathyroid development
 Thymic cysts – uncommon lesions, spherical or arborizing, lined by
stratified to columnar epithelium and not clinically significant
Thymic Hyperplasia
 Most frequently encountered in myasthenia gravis
 Also seen in Grave’s disease, SLE, scleroderma, rheumatoid
arthritis and other autoimmune disorders
Thymomas
 Restricted to tumors of thymic epithelial cells
 Contain benign immature T cells (thymocytes)
 Three histological subtypes:
 Benign and noninvasive
 Benign and invasive
 Malignant (thymic carcinoma)
 Usually occurs in >40 years old
 Males and females are equally affected
 Most arise in the the anterior superior mediastinum, but may
arise in the neck, thyroid, pulmonary hilus or elsewhere, typically
uncommon in posterior mediastinum
Morphology
 Lobulated, firm, gray-white masses up to 15-20cm in size
 Area of cystic necrosis and calcification
 Noninvasive thymomas
 Composed of medullary-type epithelial cells or a mixtyre of
medullary and cortical cells
 Sparse infiltrates of thymocytes
 Invasive thymomas
 Much more like to metastasise
 Epithelial cells are most commonly of the cortical variety with
abundant cytoplasm and rounded vesicular nuclei mixed with
numerous thymocytes
 Penetrate through the capsule into surrounding structures
 Thymic carcinoma
 Most are squamous cell carcinoma, next variant is
lymphoepithelioma-like carcinoma
 Composed of sheets of cells with indistinct borders that bears
a close histologic resemblance to nasopharyngeal carcinoma

Clinical Features
 Present with symptoms stemming from impingement on
mediastinal structures
 Detected in the course of evaluating patients with myasthenia
gravis
 Other immune disorders include hypogammaglobinemia, pure red
cell aplasia, Graves’ disease, pernicious anemia, dermatomyositis-
polymyositis and Cushing syndrome.

“Ñuhor līr
gūrēnna.”
(I will take what’s
mine)

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