YL6: 04.

12b WBC Disorders: WBC Neoplasms

10/08/2019 Basic Pathologies 2
07:30-11:30 Jan Dy-Ledesma, MD, DPSP
PATHOLOGY

TABLE OF CONTENTS C. LEUKEMIA AND LYMPHOMA

• Difference lies in the distribution or location of the malignancy
I. WBC NEOPLASMS.......................................................................... 1 → Leukemia
A. CATEGORIES ........................................................................ 1 ▪ Disease confined to the bone marrow (where it begins)
B. COMMON ETIOLOGIES ......................................................... 1 and peripheral blood (where it spills over)
C. LEUKEMIA AND LYMPHOMA ................................................ 1 ▪ Essentially a blood disease
D. IMPORTANT PRINCIPLES ..................................................... 1
▪ No discrete mass
II. LYMPHOID NEOPLASMS ............................................................... 1
A. PRECURSOR B AND T-CELL NEOPLASMS .......................... 1 → Lymphoma
B. PERIPHERAL B-CELL NEOPLASMS...................................... 3 ▪ Disease confined to lymph nodes with potential
C. NON-HODGKIN'S LYMPHOMA .............................................. 4 involvement of spleen and/or liver
D. HODGKIN’S LYMPHOMA....................................................... 6 ▪ Proliferations that arise as discrete soft tissue masses
E. PLASMA CELL NEOPLASMS ................................................. 8 • Sometimes, the disease changes or evolves
F. PERIPHERAL T-CELL NEOPLASMS ...................................... 9 → It can start as a leukemia (confined in blood), after a long time
III. MYELOID NEOPLASMS .............................................................. 11 it progresses and starts to seeds the lymph organs, producing
A. ACUTE MYELOID LEUKEMIA (AML) .................................... 11 a nodal mass
B. MYELOPROLIFERATIVE DISORDER................................... 13 → It can start as a lymphoma that spills over to the bone marrow
C. MYELODYSPLASTIC SYNDROME ...................................... 14 and peripheral blood
IV. HISTIOCYTOSIS ......................................................................... 14 They are two sides of the same coin. (Dy-Ledesma, 2019)
A. LANGERHANS CELL HISTIOCYTOSIS ................................ 14
QUICK REVIEW ............................................................................... 15
SUMMARY OF TERMS ............................................................ 15 D. IMPORTANT PRINCIPLES
REVIEW QUESTIONS .............................................................. 16 • Histological examination
REFERENCES ................................................................................. 16 → Biopsy is needed to make a diagnosis
REQUIRED .............................................................................. 16 → Clinical symptoms are not enough to demonstrate the disease
APPENDIX ....................................................................................... 17 • Monoclonal, unique DNA sequence
→ A malignant neoplastic cell is monoclonal (only one type of
cell is proliferating)
I. WBC NEOPLASMS → Genetic or karyotyping studies is not only helpful in diagnosis
• Most important clinical disorders of WBCs but also in predicting prognosis
• Cluster designation (CD)
A. CATEGORIES → Used to identify B and T cell tumors
• Lymphoid ▪ T cells: CD4 and CD8
→ Originating from B, T, NK cell, plasma cell ▪ Plasma cells: CD68, CD158, etc.
→ Phenotype of the neoplastic cell resembles that of the  Chemotherapy regimen and prognosis are different
particular stage of normal lymphocyte differentiation  T cell neoplasms are generally worse than B cell neoplasms
• Myeloid • Associated with autoimmune diseases and infections
→ Arise from early hematopoietic progenitors → Due to chronic inflammation process underlying these
▪ Acute Myeloid Leukemia (AML) diseases
o Accumulation of immature progenitor cells in the
bone marrow II. LYMPHOID NEOPLASMS
▪ Myelodysplastic Syndrome (MDS) A. PRECURSOR B AND T-CELL NEOPLASMS
o Ineffective hematopoiesis and peripheral blood Acute Lymphoblastic Leukemia/Lymphoma (ALL)
cytopenias • Neoplasms of immature B or T cells (lymphoblasts)
▪ Chronic myeloproliferative disorders • Most common cancer among children
o Elevated peripheral blood counts due to increased • Terminology
production of terminally differentiated myeloid → Leukemia: Confined to bone marrow and peripheral blood
elements → Lymphoma: Confined to organs, particularly the thymus
• Histiocytosis
→ Uncommon proliferative lesions of macrophages and dendritic Demographic
cells
• B-ALL
→ E.g. Langerhans cell histiocytosis – immature dendritic cell
→ 85% of ALLs are B-ALL
→ Typically manifests as childhood acute leukemia
B. COMMON ETIOLOGIES ▪ Peak incidence at about the age of 3 because the
• Chromosomal translocations and acquired mutations number of normal bone marrow immature B cells is
→ Important to know for target therapies greatest very early in life (Kumar et al., 2015)
• Hereditary factors • T-ALL
→ A lot of leukemias are hereditary → Less common than B-ALL
• Viruses (oncogenic) → Presents in adolescent males as thymic lymphomas (i.e. with
→ E.g. EBV virus is implicated in a lot of B-cell leukemia and a mass in the mediastinum or at the neck area)
lymphomas; HTLV ▪ Peak incidence is in adolescence, the age when the
• Autoimmune diseases thymus reaches maximum size (Kumar et al., 2015)
• Chronic inflammation
→ Induces development of leukemias and lymphomas Pathophysiology
• Iatrogenic factors • Chromosomal Aberrations
→ E.g. Radiotherapy, chemotherapy (particularly DNA  Many of chromosomal aberrations seen in ALL dysregulate
topoisomerase and etoposide which usually cause therapy- the expression and function of transcription factors which are
related leukemias and lymphomas after a long time) required for normal B and T cell development
• Smoking → B-ALL
→ Increases risk for acute myeloid leukemia ▪ t(12;21): Translocation of chromosomes 12 and 21
▪ Loss-of-function mutations in PAX5, E2A, and EBF:
Genes required for B-cell development
→ T-ALL
▪ 70% of T-ALLs have gain-of-function mutations in
NOTCH1: Gene essential for early T cell development

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 Hyper/hypoploidy
 Most common is hyperploidy (>50 chromosomes)
 Hypoploidy and a variety of balanced chromosomal
translocations are also seen
Multi-Step Origin of Cancer
• Single mutations are not sufficient to produce ALL
“You need a lot of genetic changes (multiple hits) within you to
produce a malignant neoplasm.” (Dy-Ledesma, 2019)
• Fewer than 10 mutations are sufficient to produce full-blown ALL
Immunophenotype
• TdT (terminal deoxyribonucleotide transferase)
→ Marker of the immaturity of the cell (i.e. expressed in both
immature B- and T-cells)
→ Immunostaining
• PanB-cell markers in B-ALL
→ CD 10, CD19, CD20, CD23 and PAX5
→ Indicates an inclination to a B cell differentiation
• PanT-cell markers in T-ALL
→ CD1, CD2, CD3, CD5 and CD7
→ Indicates an inclination to a T cell differentiation
 Flow Cytometry: Gold standard in diagnosing leukemia
 Cells are injected with dyes and CD22 lights up which is a
marker for young white blood cell
NOTE
• CD PanB-cell markers are greater than or equal to 10: CD 10,
19, 20, 23 then PAX5
• CD PanT-cell markers are less than 10: CD 1, 2, 3, 5, 7
Clinical Manifestations
• Similar with myeloid leukemias
• Abrupt, stormy onset
→ ALL is an aggressive disease, and most patients present
within a few weeks of the onset of symptoms
• Symptoms related to depression of marrow function
→ Fatigue: Due to decrease in RBCs (less oxygen to brain)
→ Fever: Due to leukopenia and susceptibility to infections
→ Bleeding: Due to thrombocytopenia
• Mass effects caused by neoplastic infiltration
→ Bone pain
▪ Due to marrow expansion and infiltration of
subperiosteum
→ Generalized lymphadenopathy
→ Hepatosplenomegaly
▪ Due to sequestration
▪ Due to compensatory extramedullary hematopoiesis
→ Complications related to compression of large vessels
and airways in the mediastinum in T-ALL
• Central nervous system manifestations
→ Headache, vomiting, and nerve palsies
▪ Due to meningeal seeding
• Testicular enlargement
→ Common site for leukemic cells to “hide”
▪ Minimal residual disease
 Adults cannot tolerate the way the chemotherapy is
given
 Patient with minimal residual disease is
asymptomatic
• Philadelphia chromosome, t(9;22)
→ Creates a fusion gene which encodes an active BCR-ABL
tyrosine kinase
→ More strongly associated in CML but also seen in a
fraction of ALL cases
▪ Philadelphia chromosome in ALL has a smaller
molecular weight
▪ Difference lies in the size, break point, and location
→ Candidate for Imatinib targeted gene therapy
 Improved outcome for this molecular subtype in children (Dy-
Ledesma, 2019)
→ Presence in adult cases signifies poor outcome (Kumar et al.,
2015)
Histology (Kumar et al., 2015)
• Hypercellular marrow, packed with lymphoblasts
• Size
→ A little bigger than usual lymphocyte
• Cytoplasm
→ Scant basophilic, no granules which would ordinarily indicate
differentiation toward myeloid or granulocytic series
• Nuclei
→ Larger than those of small lymphocytes
• Chromatin
→ Delicate, finely stippled
• Nucleoli
→ Absent or inconspicuous, indicates immaturity
• Nuclear membrane
→ Deeply subdivided giving the cell a convoluted appearance
• Cytochemical staining
→ (-) Myeloperoxidase
→ (+) Periodic Acid Schiff Stain
→ MPO stains myeloid cells, but not lymphoid cells
▪ MPO preferentially stains the granules in granulocytic or
myeloid cells
▪ Lymphocytes are agranular cells, thus the negative
result
▪ Will only become positive during CML
→ Cytoplasmic material is PAS positive (Kumar et al., 2015)
→ Cheap compared to flow cytometry but very few use it today

Prognosis and Treatment

 80-90% of patients can undergo remission
• Favorable outcome
→ 95% remission
▪ Remission – symptoms are removed and tumor cells are
detectable but very low
→ 85% cure rate (high for a leukemia)
▪ Cure rate – absence of tumor cells and symptoms for a
minimum of 5 years
→ Conditions that allow for a favorable outcome
▪ 2-10 years
▪ A low white cell count
▪ Hyperploidy
▪ Trisomy of chromosomes 4, 7, and 10
▪ Presence of t(12;21) Figure 1. Acute lymphoblastic leukemia PAS stain (ALL). (A)
• Poor outcome, cure rate around 50% Lymphoblasts (B, C) Flow cytometry results. The tumor cells are positive
→ Conditions that predict a poor outcome for the B cell markers CD19 and CD22; CD10 (a marker expressed on
▪ <2 years a subset of ALLs), and TdT (a specialized DNA polymerase that is
▪ Translocations involving the MLL gene expressed in pre-B and pre-T cells). These results show that the cells
▪ Presentation in adolescence or adulthood are relatively immature and show a slight maturation inclined toward the
▪ High tumor load: blast count >100,000 B lineage (Kumar et al., 2015)

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 B. PERIPHERAL B-CELL NEOPLASMS ▪ Can undergo changes similar to that of Diffuse Large B-
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Cell Lymphoma (DLBCL)
Lymphoma (SLL)  Development of a rapidly enlarging mass within a
 Need to know the origin of the tumor for aggressiveness (Trans lymph node or spleen
2021) ▪ Acquires more mutations → more aggressive
 Mantle zone – more aggressive • BTK (Bruton tyrosine kinase) inhibitors can be used for
 Germinal center – less aggressive management
 CLL cells reply on signal transduced by cascade of kinases
Demographic that include BTK
• Most common leukemia in adults in the Western world  BTK is defective in patients with congenital X-linked
→ Elderly: Around 60 years old agammaglobulinemia
→ Male: Around 2:1
Histology
Pathophysiology • Smudge cells or basket cells
• Deletions of 13q14.3, 11q, and 17p → Highly friable: Very delicate cytoplasm
• Trisomy 12q → “Smudged” during chromatography/peripheral blood smear
• Some have somatically hypermutated Ig genes • Lymph nodes – diffusely effaced by small lymphocyte infiltrates
• Cell growth is largely confined to proliferation centers → Architectural features are distorted
→ Stromal cells in proliferation centers express factors that ▪ No germinal centers
stimulate activity of NF-kB ▪ Slightly irregular nuclei
▪ NF-kB – transcription factors which promotes cell growth ▪ Condensed chromatin
and survival ▪ Scant cytoplasm
→ Pale proliferation centers
Immunophenotype ▪ Look similar to germinal centers, but only one type of cell
is present under HPO
• Mature B cells
▪ “Soccer ball cells:” Small cells with chromatin clumping
→ Pan B-cell cell markers CD19, CD20, CD23, CD5 ▪ Must be demonstrated to diagnose CLL
▪ Origin of the tumor B cell (either post-germinal or naïve  Proliferation of neoplastic lymphocytes in the spleen and liver
B cell)
→ Typical low-level expression of surface Ig (IgM only, IgM and
IgD)

Clinical Manifestations
• Nonspecific symptoms: Fever, fatiguability, weight loss, and
anorexia
→ Similar to TB
• Generalized lymphadenopathy and hepatosplenomegaly
→ Due to sequestration
• Highly variable leukocyte count
→ Not as elevated as compared to ALL Figure 2. CLL/SLL lymph node (Left) and soccer ball like cells in HPO
→ Can also be normal if the WBC’s are sequestered in the of the lymph node (Right) (Dy-Ledesma, 2019)
tissues (i.e., lymphoma)
→ If leukemic disease (i.e. a chronic lymphocytic leukemia), then
the WBC count is high
→ If lymphocytic disease (i.e. small lymphocytic lymphoma),
then the WBC count may be normal because the disease is
found in the tissue
• Absolute lymphocyte count: >5000/mm3
→ Points of comparison with ALL
▪ Presence of a mass
▪ Significantly lower compared to ALL which can be as
high as hundreds of thousands
→ Leukemias have higher lymphocyte count compared to
lymphomas where the disease is confined to a tissue or lymph
node
• Hypogammaglobulinemia
→ Increased risk for infection
• Thrombocytopenia, hemolytic anemia Figure 3. Smudge cells in CLL peripheral blood smear (Kumar et al.,
→ Autoantibodies made by non-neoplastic B cells 2015)
• Infection

Prognosis and Treatment

• 4-6 years with or without chemotherapy
→ Very dependent on the stage or tumor burden (i.e. how
widespread)
→ The higher the WBC count, the tumor will advance faster
• Poor outcome factors
→ Deletions of 11q and 17p
→ Translocations are rare
▪ Big difference from other types of leukemia
 Lack of somatic hypermutation
 Tumor has not yet differentiated
 Have immature type of B cell
 Very anaplastic = more malignant behavior
 Expression of ZAP-70
 Protein that augments signals produced by Ig receptors
 NOTCH1 mutations Figure 4. Periportal lymphocytic infiltrate in CLL/SLL involving the liver
→ Richter Syndrome: Tendency to transform to more (Kumar et al., 2015)
aggressive tumors
▪ Can become more pleomorphic

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 Hairy Cell Leukemia
NICE TO KNOW
Demographics
Bertha A. Bouroncle Pereny, M.D. (1919-2003)
• Very rare leukemia in our country
• Usually seen in White (Caucasian), elderly (~55 years old), male

Pathophysiology
• BRAF point mutation
→ Encodes for serine/threonine kinase

Immunophenotype
• Pan B-cell markers (CD19 and CD20)
• CD11c, CD25, CD 103, annexin A1
→ CD11c – unique in hairy cell leukemia

Clinical Manifestations
• Hepatosplenomegaly
• Pancytopenia
→ Marrow involvement and splenic sequestration
• Atypical mycobacterial infections
→ Possibly related to unexplained monocytopenia • Peruvian-American Hematologist
• First female full professor and chief resident in Ohio State
Prognosis and Treatment University
• Excellent and follows an indolent course • First investigator to identify hairy cell leukemia
• Curable and very responsive to “gentle” chemotherapy • Discovered the tumor and developed a drug to treat hairy cell
→ Gentle chemotherapy leukemia
▪ IFN-γ is given instead of alkylating agents to minimize
toxic damage to the body
→ Tumor is usually induced into remission after one cycle C. NON-HODGKIN'S LYMPHOMA
▪ Long-lasting remission Characteristics of Non-Hodgkin Lymphoma
→ Doesn’t develop any resistance Frequent involvement of multiple peripheral nodes
• BRAF inhibitors appear to produce excellent responses on tumor Non-contiguous spread
Mesenteric nodes and Waldeyer ring often involved
Histology Common extra-nodal presentation
• Cells with fine hair-like projections from the cytoplasm in phase
contrast microscopy Follicular Lymphoma
Demographics
• Peripheral blood smear
→ Hairy cells with round, oblong, or reniform (kidney-shaped) • Middle-aged men
nuclei due to multiple infoldings
→ Moderate amount of pale blue cytoplasm with threadlike or Pathophysiology
bleb-like extensions • t(14;18)
• Cytoplasm and hairy cells are seen positive in TRAP stain → Over-expression of BCL2
→ Nothings stops the division of the B-cells
• Germinal center B-cells
→ In follicular lymphoma, it is where BCL2 can be found which
causes proliferation of B cells
→ Normally, BCL2 is only found in the mantle zone
 MLL2 mutation

Figure 5. Hairy cell leukemia on peripheral blood smear. (Left) Phase Immunophenotype
contrast microscopy shows tumor cells with fine hair-like cytoplasmic • CD19, CD20, CD10
projections (Right) In stained smears, cells have round or folded nuclei • IgG, BCL2, BCL6
and modest amounts of pale blue, agranular cytoplasm (Kumar et al,
2015)
Clinical Manifestations
NEED TO KNOW • Painless, generalized lymphadenopathy
TRAP Stain • Can undergo histologic transformation to diffuse large B-cell
lymphoma

Prognosis and Treatment

• Incurable but indolent (7-9 years)
• Low-dose chemotherapy + anti-CD20 therapy (Rituximab)
 May

Histology
• Spleen
→ White pulp lesions
• Bone marrow
→ Lymphocytes are para-trabecular (beside the trabecula)
Figure 6. Characteristic hairy-cell WBC’s on TRAP stain in HCL • Lymph nodes
peripheral blood smear. (Indian J Pathol Microbiology, 2019) → Presence of centrocytes and centroblasts
→ Many macrophages are present because the B-cells won’t die
• Tartrate Resistant Acid Phosphatase ▪ Macrophages are plain (nothing inside) because they
• Histochemical marker used before to identify hairy cell leukemia cannot phagocytose the B-cells → unable to become
• Not used in other countries because of the switch to tingible-body macrophages
immunohistochemical stains but is still used in the Philippines

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 Prognosis and Treatment
NEED TO KNOW
Follicular Hyperplasia • Aggressive, fatal without treatment
• Follicular hyperplasia • Chemotherapy + anti-CD20
→ Germinal centers: secondary follicles (large and oblong) → 60-80% remission
▪ Dark zone (centroblasts): proliferating blastlike B-cells → 50% cure rate
▪ Light zone (centrocytes): B-cells with irregular or • Molecular subtypes used for newer treatments
cleaved nuclear contours
→ Mantle zone: collar of naïve B-cells Histology
→ Tingible-body macrophages • Spleen
▪ Inconspicuous network of antigen-presenting → Diffuse, no pattern
dendritic cells and macrophages → Large, pleiomorphic, prominent nuclei
▪ Contains nuclear debris of self-reactive B-cells

Table 1. Follicular hyperplasia vs. follicular lymphoma

Follicular Hyperplasia
Heterogenous appearance
(centrocytes + centroblasts +
reactive T-cells + follicular
dendritic cells)
Tingible-body macrophages
Follicle interface with mantle
zone is sharply defined
Marked variation in shape and
size of follicles
Recognizable light and dark
zones
Follicular Lymphoma
Homogenous appearance
(predominantly centrocytes)
No TBM’s
Follicular edge is fuzzy and not
sharply demarcated
All follicles look the same
Zones cannot be differentiated
Figure 8. DLBCL with characteristic diffuse cells with large,
pleiomorphic nuclei. (CancerNetwork, 2019)

Burkitt Lymphoma
• 3 types: Histologically identical but have different clinical
presentations due to breakpoints in mutation of c-MYC genes
→ Endemic
▪ Present as a mass in the mandible or head and neck
▪ Present in children and young adolescents
→ Sporadic
▪ Present in the GIT, specifically in the ileocecal area
▪ Present in children and young adults
→ HIV associated (HIV+)
▪ Aggressive lymphomas occurring in those infected with
HIV

Demographics
• Endemic type presents in children and young adults
→ Usually in Africa
• Sporadic type also presents in children and young adults
→ Usually in Western countries
Figure 7. Follicular hyperplasia (Left) and follicular lymphoma (Right). • HIV-associated
(WebPathology, 2019) → Aggressive lymphomas occurring exclusively in individuals
infected with HIV
Diffuse Large B-Cell Lymphoma (DLBCL)
Demographics Pathophysiology
• Most common Non-Hodgkin Lymphoma • Due to translocations of the c-MYC gene
• >60 years old, but can also occur in the younger population  This gene is located on chromosome 8
• Slight male predominance
Immunophenotype
Pathophysiology • IgM, CD10, CD19, CD20, BCL6
• Molecularly heterogenous • (-) BCL2
• Mutation in MYC, t(14;18)
 Dyregulation of BCL6 Clinical Manifestations
• Usually manifest at extranodal sites
Immunophenotype → Mandibular
• CD 10, CD19, CD 20 → Maxillary
• BCL 6 → Ileocecal area
→ GIT
Clinical Manifestations • Endemic type presents as mandibular mass (especially in African
• Fast growing, nodal/extranodal mass children)
• Spleen → Endemic type strongly associated with EBV infection
→ Large, fungating mass • Sporadic type presents as mass that arises in ileocecal area
→ “Huge and scary-looking”
• DLBCL subtypes Prognosis and Treatment
→ Primary effusion lymphoma • Aggressive but can be cured with chemotherapy in children
→ Immunodeficiency-associated large B-cell lymphoma and young adults
▪ Associated mainly with AIDS • Children generally tolerate chemotherapy well
→ DLBCL with MYC translocation → High success rate for acute lymphoblastic leukemia
▪ Similar to Burkitt’s lymphoma • However, adults have systemic manifestations from the
chemotherapy

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 Histology
• Starry sky likeness
• Tumor cells are small-intermediate sized lymphocytes with
prominent nuclei and coarse chromatin
• Stained with H&E = blue
• Lots of macrophages because tumor grows very fast
→ Fast tumor growth means it uses up its blood supply and
nutrients quickly
→ These cells die so lots of macrophages are needed and are
present to remove dead tumor cells Figure 10. Mantle cell lymphoma. Neoplastic lymphoid cells surround
→ Presence of macrophages acts as a proliferation index, a small, atrophic, germinal center which produces a mantle zone pattern
something to remove dead necrotic tumor cells of growth (Left). Homogenous population of small lymphoid cells with
irregular nuclei outlines, condensed chromatin and scant cytoplasm
• Macrophages as stars, tumor cells as sky (think Van Gogh)
(Right) (Kumar et. al., 2015)

Marginal Zone Lymphoma

• Common
• Also known as MALTomas (mucosal associated lymphoid tumors)
when found extranodal
• Seen in areas where you have lymphoid proliferation like in the GIT
• Can arise from the lymph nodes or extranodal sites such as:
→ Stomach
→ Intestines
→ Spleen
Figure 9. Burkitt lymphoma. Numerous pale tingible body
• Arise within tissues involved by chronic inflammatory states of
macrophages are evident producing “starry sky” appearance (Left).
autoimmune or infectious etiology
Tumor cells have multiple small nuclei and high mitotic index.
Monotonous appearance due to of lack of variation in shape and size → E.g. salivary gland in Sjögren’s syndrome (autoimmune, dry
(Right) (Kumar et. al., 2015) eyes and dry mouth), stomach in H. pylori gastritis (infectious)

Mantle Cell Lymphoma Pathophysiology

• Arises from the mantle cells that you see in the periphery of the • t(11;18), (14;18), (1;14)
germinal center • BCL 10 (overexpression of BCL family limits apoptosis)

Demographics Immunophenotype
• Very uncommon • IgM, CD20
• Seen in elderly, 50-60s, male
Clinical Manifestations
Pathophysiology • Swelling of salivary gland, thyroid or orbit
• t(11;14)
• Specific protein found in the tumor is Cyclin D1 Prognosis and Treatment
→ Over-expression of cyclin D1 • Can remain localized for a prolonged time
→ Not seen in other types of lymphoma → Tumor might regress if the infection is eradicated
• Positive for Cyclin D1 and CD5

Immunophenotype D. HODGKIN’S LYMPHOMA

• Cyclin D1, IgM, IgD, CD19, CD20 Characteristics of Hodgkin Lymphoma
• (+) CD5, (-) CD23 Localized to a single group of nodes
Orderly spread by contiguity
Clinical Manifestations Mesenteric nodes and Waldeyer ring rarely involved
Rare extra-nodal presentation
• Painless lymphadenopathy
• Can sometimes spread to bone marrow, spleen, liver, gut Demographics
 Rarely spreads to the blood • Most common cancer in young adults and adolescents
• Can present as numerous small polyps in:
→ GIT Pathophysiology
→ small and large intestine • Tumor is localized only to a single group of nodes
→ Presents as lymphomatoid polyposis → Spread is predictable and orderly, can plan management of
the disease
Prognosis and Treatment
• Curable unlike in Non-Hodgkin's lymphoma
• 3-4 years, no cure
• Lymphoid tissues in tonsillar area are usually spared
• Especially if Blastoid variant, tumor cells resemble blast cells (very
• Very rarely arise in extranodal sites unlike in Non-Hodgkin's
immature)
lymphoma
→ Gives poor prognosis
→ Always arise and stay in the lymph nodes
• Treatment
→ HSC transplant Clinical Manifestations
→ Proteasome inhibitor • Painless lymphadenopathy
▪ To control growth of the tumor cells • May have cutaneous immune anergy
• Tuberculin test = no reaction
Histology
→ T cells somehow affect development of delayed
• Very tiny germinal center hypersensitivity reaction
→ Due to proliferation of mantle zone (very thick)
• Looks very monotonous due to proliferation of clonal cells Prognosis and Treatment
→ Proliferation of only one type of cells being the tumor cells • Curable in most cases
→ Example of Cyclin D1 immune histochemical state → Problem lies within treatment itself
▪ Can highlight the proliferation of mantle cells in the → Alkylating agents are used
mantle zone area → Predisposes patient to formation of secondary tumor, may
lead to therapy-related leukemia

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 Reed-Sternberg (RS) Cells
• Diagnostic neoplastic giant cells
• Need to demonstrate this cell to diagnose Hodgkin’s lymphoma
• Originates similar to Non-Hodgkin's as a germinal centered B cell
• Markers for RS cells are CD15 and CD30 depending on the type of
Hodgkin’s lymphoma
• Surrounded by reactive cells such as lymphocytes, neutrophils,
and eosinophils
→ This is because RS cells secrete cytokines
→ Cytokines act as chemoattractant for reactive cells

Histology
• Characterized by the presence of a tumor giant cells known as the
Reed-Sternberg (RS) cells
→ Enlarged cell that is bi-nucleated, two prominent nuclei always
described as “owl's eye”
→ Like someone is staring back at you
• Diagnostic/Classical variant Figure 12. Nodular sclerosis type with lacunar RS cells (Dy-Ledesma,
→ Bi-nucleated 2019)
→ “owl’s eyes”
→ Very large cell size • Mixed Cellularity Type
• Mononuclear variant → Have a lot of other cells surrounding RS cells, e.g.
→ One nucleus heterogenous cellular infiltrates (neutrophils, eosinophils)
→ Very big with clearing → Strongly associated with EBV
• Lacunar variant → RSC: Classic (owl’s eye), mononuclear variant
→ Clearing around large nucleus → Prognosis: very good
→ Looks like bone cells in lacuna
• Lymphohistiocytic variant
→ “popcorn cell”
→ Multiple convoluted nucleus infoldings - nucleus folded into
many angles
→ Resembles nucleus of histiocyte

Figure 13. Mixed cellularity type with classic and mononuclear RS

cells (Dy-Ledesma, 2019)

Figure 11. RS Cell Variants. (Top left) Classical variant, (Top right)
Mononuclear variant, (Bottom left) Lacunar variant and (Bottom right)
Lymphohistiocytic variant (Dy-Ledesma, 2019)
Ann Arbor Staging System
• Used for both Hodgkin’s and Non-Hodgkin’s lymphoma
• Growth is in a predictable manner
→ Makes disease easier to treat
→ Good prognosis if caught early on, just remove the entire
affect lymph node and the patient is healed
▪ No need for aggressive treatment
o I.e. chemotherapy and radiotherapy
 Aggressive therapy only when it has spread to liver or
spleen (Dy-Ledesma, 2019)
• Lymphocyte rich
→ Uncommon, in older males
→ Majority of infiltrates are lymphocytes
→ RSC: frequent diagnostic and mononuclear variants
→ Prognosis: very good to excellent
• Lymphocyte-depletion
→ Least common form of HL, seen in older males, third-world
countries, and HIV (+) individuals
→ Scarce lymphocytes
→ RSC: frequent diagnostic and reticular variant
→ Prognosis: less favorable

Classification of HL Subtypes
Classical forms
• (+) PAX5, CD15 and CD30;
• (-) other B/T-cell markers and CD45
• Nodular Sclerosis Type
→ A lot of nodules surrounded by fibrosis
→ Most common type of HL, seen in young adults
→ Usual locations of lymph node enlargement
▪ Lower cervical
▪ Supraclavicular
▪ Mediastinal
→ RSC: Lacunar variant, occasional diagnostic
→ (+) PAX5 seen in germinal center
→ Prognosis: excellent
Figure 14. Lymphocyte-rich (Left) and Lymphocyte-depletion type
(Right) (Dy-Ledesma, 2019)

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 Non-classical form
• (+) CD20 and BCL6; (-) CD15 and CD30
→ Has the immunophenotype of NHL
• Lymphocyte Predominance Type
→ Only non-classical form of HL
→ Seen in young males (usually <35 y/o)
→ Not associated with EBV
→ Cervical and axillary lymph nodes
→ Very similar to lymphocyte rich, but with absence of CD15 and
CD30
→ RSC: frequent lymphohistocytic “popcorn” variant
→ Prognosis: excellent
Figure 15. Lymphocyte predominance type (Dy-Ledesma, 2019)
E. PLASMA CELL NEOPLASMS
Multiple Myeloma (Plasma Cell Myeloma)
• Plasma cells secreting M component (an abnormal Ig fragment)
• Commonly seen in elderly African-American men
• Role of IL-6: promotes plasma cell proliferation
→ Implicated in the development of the disease
→ To highlight presence of plasma cells, use CD56 or CD138
because the cells could become immature looking that they
don’t resemble the normal ones
• No specific molecular signature or ID, just a lot of chromosomal
abnormalities
Immunophenotype
• CD138 and CD56
→ CD138: also known as syndecan-1, for cell binding
→ CD56: Adhesion molecule
Clinical Manifestations
• Pathologic fracture, bone pain as plasma goes to bone marrow and
proliferate
• Neurologic manifestations because of hypercalcemia
→ Hypercalcemia brought about by the body’s effort to correct
pathologic fracture
• Recurrent bacterial infections are common because plasma cells
become neoplastic and do not release antibodies
→ Decrease in production of Abs = Hypoagammaglobulinemia
• Renal insufficiency
→ Ig light chains produced by plasma cells are very necrotoxic
and could damage the renal tubules
→ Due to Bence-Jones protein that are produced by
neoplasmic cells that are deposited in the kidney
→ One way to detect multiple myeloma in a patient
Diagnosis
• X-ray
→ Bone and axial skeleton vertebral column, ribs, skull, pelvis
show classic “punched-out” lytic lesions which begins at
medullary area
→ Vertebra biopsy shows red, soft, gelatinous mass within
the bone marrow
• Lab tests
→ Electrophoresis
▪ Aims to demonstrate presence of monoclonal Ig
▪ Normal: All Ig are present and are represented by a
broad, diffuse band
▪ Abnormal: Only one Ig present, can be any of the three
but IgG is the most common -> production of a
YL6: 04.12b Basic Pathologies 2: WBC Disorders: WBC Neoplasms
monoclonal IgG, decreased IgA and IgM, produce
excess light chains of Kappa type
→ Serum: > 3 g/dL Ig
→ Urinalysis: check for Bence-Jones protein, > 6 g/dL
→ Biopsy of the lesion or a bone marrow aspirate
▪ Normal bone marrow aspirate: < 5% of plasma cells
(Kumar, et.al, 2015)
▪ Abnormal: proliferation of plasma cells constitutes more
than >30% of the cellularity
▪ Presence of rouleaux formation - red blood cells stick
together because of Ig
Figure 16. M protein detection in multiple myeloma. Serum protein
electrophoresis (SP) is used to screen for a monoclonal
immunoglobulin (M protein). Polyclonal IgG in normal serum (arrow)
appears as a broad band; in contrast, serum from a patient with
multiple myeloma contains a single sharp protein band (arrowhead)
in this region of the electropherogram. The suspected monoclonal
Ig is confirmed and characterized by immunofixation. The sharp
band in the patient serum is cross-linked by antisera specific for
IgG heavy chain (G) and kappa light chain (κ), indicating the
presence of an IgGκ M protein. Levels of polyclonal IgG, IgA (A),
and lambda light chain (λ) are also decreased in the patient serum
relative to normal, a finding typical of multiple myeloma (Kumar et
al., 2015).
Prognosis and Treatment
• Treatment is variable but slowly improving (4-7 years)
→ New drugs being developed
• Patients can be given:
→ Proteasome inhibitor
→ Stem cell transplants
• Most patients with multiple myeloma die from renal
complications and infections
→ Rarely die from the tumor itself
Subtypes of Multiple Myeloma
• Solitary Myeloma/Plasmacytoma
→ One solitary mass in the bone or skin (Extraosseous)
▪ Often located in the lungs, oropharynx, or nasal sinuses
→ Curable by surgery
→ Will progress to multiple myeloma but may take 10-20 years
• Smoldering Myeloma
→ Not completely benign, not completely malignant
▪ Somewhere in the middle
→ Patients are asymptomatic
→ Overtime, the condition does transform into multiple myeloma
▪ Timeframe is unknown
▪ Make sure for frequent follow-ups to check for
complications
• Monoclonal Gammopathy of Uncertain Significance (MGUS)
→ Called plasma cell dyscrasia, because not yet considered a
tumor
→ Does not fulfill criteria of a tumor
→ Patient may have this condition for 10-20 years and have
no development of multiple myeloma
→ Most benign presentation of the disease
8 of 20
 Histology

Figure 17. Multiple myeloma bone marrow aspirate Left: (UL) Normal
marrow cells are replaced by plasma cells. (UR) Presence of flame cell,
(LL) Mott cells with Russell (inclusions in the cytoplasm) and (LR) Mott
Cell with Dutcher bodies (inclusions in the nucleus). Right: Normal
Figure 18. Lymphoplasmacytic Lymphoma, shows a characteristic
marrow cells are largely replaced by plasma cells, including forms with
mixture of small lymphoid cells exhibiting various degrees of plasma cell
multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing
differentiation. In addition, a mast cell with purplish red cytoplasmic
Ig (Dy-Ledesma, 2017; Kumar et al., 2015)
granules is present at the left-hand side of the field (Kumar et al., 2015)
• Presence of cytologic variants of plasma cell from dysregulated
synthesis and secretion of immunoglobulins: F. PERIPHERAL T-CELL NEOPLASMS
▪ Flame cells – a plasma cell which is fiery red cytoplasm, • Very rare and very aggressive
more eosinophilic • Common in Asians, particularly NK Cell Lymphoma
▪ Mott cells – a plasma cell which multiple grapelike → Comprises a small portion of Non-Hodgkin's Lymphoma
cytoplasmic droplets or inclusions which are divided by • T-Cell neoplasms have a worse prognosis than B-Cell neoplasms
location into:
o Russel bodies Peripheral T-Cell Lymphoma Unspecified
→ If the globular inclusions in cytoplasm Demographic
o Dutcher bodies • More common in Asians
→ if the globular inclusions in nucleus
Pathophysiology
Lymphoplasmacytic Lymphoma • No specific genetic cause/pattern
• Very rare, more aggressive than multiple myeloma
• Presence of Waldenstrom macroglobulinemia Immunophenotype
→ Caused by hypersecretion of IgM • T-Cell Markers:
→ Hyper-viscosity syndrome which makes the blood very thick → CD2, CD3, CD4, CD5, CD8
• May have visual impairments because blood vessels in the eye are → TCR
very tiny and are greatly affected
• Predisposes the patient for stroke Clinical Manifestations
• Lymphadenopathy
Demographic
• Dermatologic symptoms
• Neoplasm of elderly, 60-70 years old
Diagnosis
Pathophysiology
• Demonstration of your T-Cell markers
• MYD88 gene - implicated specifically for development of
Lymphoplasmacytic Lymphoma Prognosis and Treatment
 Deletion of long arm chromosome 6q
• Worse than B-Cell Lymphoma
Immunophenotype
Histology
• Cells would be positive for CD20 and surface Ig
• Prominent infiltrate of reactive cells
Clinical Manifestations • Cannot really diagnose through histological method since there is
no specific pattern, diagnostic and hallmark cells
• No bony lesions
→ Doc said “she won’t bother describing the picture because
• No renal involvement there is no pathognomonic lesion”
• Lymphadenopathy and hepatosplenomegaly
• Autoimmune hemolysis
• Hyper-viscosity syndrome which you don’t see in multiple myeloma
→ Visual impairment
→ Neurologic problems
→ Bleeding
→ Cryglobulinemia

Prognosis and Treatment

• Incurable
• Best treatment is to try and remove the macroglobulins
→ Plasmaphoresis
→ Anti-CD20 medication
→ Low dose chemotherapy Figure 19. Peripheral T-cell Lymphoma, unspecified (lymph node). A
spectrum of small, intermediate, and large lymphoid cells, many with
Histology irregular nuclear contours, is visible (Kumar et al., 2015)
• Plasma cells with “clock face” or “checkerboard” nucleus
Anaplastic Large Cell Lymphoma
appearance
 PAS + inclusion shows Russell and Dutcher Bodies Demographic
• Very rare; children or young adults
• Involves soft tissue (lymph nodes)

Pathophysiology
• Rearrangement of ALK gene (chromosome 2p23)
→ Same chromosome abnormality also seen in Non-Small Cell
Lung Cancer

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 Immunophenotype Pathogenesis and Immunophenotype
• Expresses CD30 • Cutaneous Leukocyte Antigen (CLA) and CCR4 and CCR10
 Contributes to the homing of normal CD4+ T cells to the
Prognosis and Treatment skin
• Good prognosis
• Treatment for Non-Small Cell Lung Cancer can be used to treat Clinical Manifestations
Anaplastic Large Cell Lymphoma • General skin lesions but overtime can progress to T-Cell
• In the US, insurance only covers treatment of target therapy for Lymphoma, either the adult T-Cell Lymphoma or T-Cell
NSCLC not for Anaplastic Large Cell Lymphoma Unspecified Lymphoma. The difference of the two is the
→ So even if it is the same treatment, patients can’t get the presentation
treatment for free • Tumor cells are found in the skin (epidermis and upper dermis)
• Anaplastic Large Cell Lymphoma variant that is negative for ALK • Three Phases:
has poor prognosis → Initial Phase: Inflammatory Premycotic/Inflammatory
→ Treatment is limited Premycotic/Rash Phase
▪ Manifests as a rash in the skin
Histology → Second Phase: Plaque Phase
 Hallmark cells: large anaplastic cells ▪ Rash thickens to become a plaque
 Some containing horseshoe-shaped nuclei and voluminous → Third Phase: Tumoral Phase
cytoplasm ▪ Appears as a discrete mass overtime
• Lesions are milder as compared to Sezary Lesions

Figure 20. Anaplastic Large Cell Lymphoma: enlarged tumor “hallmark

cells” with horseshoe-like/kidney shaped nucleus, most of these cells
would stain positive for CD30 or ALK (Dy-Ledesma, 2019)

Adult T-Cell Leukemia/Lymphoma

Demographic
• Commonly seen in Asian countries
→ Japan/Caribbean

Pathophysiology
• CD4 cells are affected
• Observed in adults infected by HTLV-1

Clinical Manifestations
• Skin lesions, dermal presentations Figure 22. Plaque Phase (Left) and Tumor Phase (Right) (Dy-
→ Usually don’t see in B-Cell lymphoma/leukemia Ledesma, 2019)
 Generalized lymphadenopathy, hepatosplenomegaly, peripheral
blood lymphocytosis, hypercalcemia, progressive demyelinating Prognosis
disease  Indolent – survival 8 to 9 years
 Late disease progression characterized by extracutaneous spread
Prognosis and Treatment to lymph nodes and bone marrow
• Very fatal
→ Even patients undergoing aggressive chemotherapy will die Histology
within 1 month to 1 year  Epidermis and upper dermis infiltrated by neoplastic T cells
 Cerebriform appearance due to marked infolding of nuclear
Histology membrane
• Flower cells
→ Multilobated nuclei

Figure 21. Cloverleaf or flower cells in Adult T-Cell

leukemia/lymphoma (Dy-Ledesma, 2019)

Mycosis Fungoides Figure 23. Biopsy of the skin with neoplastic lymphocytes in the
• Skin lesions dermis (Dy, Ledesma, 2019)
• Overtime, can progress to T-Cell lymphoma: • Epidermis and upper dermis are found to have Neoplastic
→ Adult T-Cell lymphoma lymphocytes
→ T-Cell lymphoma unspecified • Nucleus shows a cerebral appearance a lot of convolutions or
→ No leukemia associated lobulated epidermal nucleus
• Tumor cells are confined to the epidermis

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 Sezary Syndrome Extranodal NK/T-Cell Lymphoma
• Associated with leukemia Demographic
• Very common in Asia, including the Philippines
Pathogenesis and Immunophenotype
• Same with Mycosis fungoides Pathophysiology
• Associated with EBV
Clinical Manifestations • Leads to ischemic necrosis
• Skin lesions presented is associated with leukemia •
• Tumor cells are found in the peripheral blood Immunophenotype
• Generalized exfoliative erythroderma, skin is roughing off  Lack T-cell receptor rearrangements
→ No mass  Express NK-cell markers
Prognosis
 Indolent – survival 8-9 years Clinical Manifestations
 Can progress to T-cell lymphoma as a terminal event • Presents as nasopharyngeal mass, nose or oral cavity
• Very aggressive but if caught early on, responds to chemotherapy
Histology • Mass is seen on the midline of the face
• Sezary cells with cerebriform nuclei → Fungating and Friable mass, when touched it bleeds easily
→ Tumor cells like to surround and destroy blood vessels
(angiocentric)
Histology
• Large azurophilic granules in the cytoplasm

Figure 24. Sezary cells with cerebriform nuclei (Dy-Ledesma, 2019)

Large Granular Lymphocytic Leukemia

Demographic
• Rare and unusual
• Seen in Asians with a specific NK Cell Variant

Pathogenesis and Immunophenotype

 Mutation in STAT3
 T-cell variants are CD3+ whereas NK cell large granular
lymphocytic leukemia (CD3-, CD56+) Figure 26. Extranodal NK/T-cell Lymphoma showing angiocentric
invasion (Dy-Ledesma, 2019)
Clinical Manifestations
• Mild to moderate lymphocytosis III. MYELOID NEOPLASMS
• Low counts of WBC • 3 Types of Myeloid Neoplasms
• Neutropenia → Acute Myeloid Leukemia
• Splenomegaly
→ Myeloproliferative syndrome
• Associated with rheumatologic disorders and autoimmune → Myelodysplastic syndrome
diseases
→ Felty syndrome: triad of rheumatoid arthritis, neutropenia,
A. ACUTE MYELOID LEUKEMIA (AML)
splenomegaly
• In AML, the blasts in the peripheral blood smear or in the bone
marrow should be more than 20%
Prognosis
→ In normal patients, blasts are supposedly in the body as
 NK cells: more aggressive
precursor cells, should only be less than 1 or 2%
 T cells: indolent
• Seen in any age but common in older males
Histology • The problem is because the cells are neoplastic, most of the tumor
cells presented in AML are immature
• Large proliferating NK cells
→ Immature cells show little differentiation either towards
• Large lymphocytes with abundant blue cytoplasm and few coarse myeloid or monocytic, some show erythroid maturation and
azurophilic granules platelet or megakaryocytic
• Marrow contains sparxe interstitial lymphocytic infiltrates • Commonly seen in trisomy 21, having down syndrome increases
risk of having AML
• Diagnosis of AML is through molecular testing and karyotypes

AML Subtypes
• Myeloid Leukemia is categorized based on
→ AML with Genetic Aberrations
▪ some types of AML have a unique chromosomal
signature
→ AML, therapy related
▪ Individuals who had cancer when they were younger
(30s-40s), because of the drugs they take, they develop
AML
▪ Hodgkin's lymphoma patients treated with radiotherapy
▪ Patients with therapy related AML
Figure 25. Large Granular Lymphocytic Leukemia (The Oncologist, → AML with Myelodysplastic syndromes (MDS)-like
2008) features

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 ▪ Poor prognosis Histology
→ AML Not otherwise specified (NOS)
▪ No chromosomal abnormalities
▪ Based on unique morphologic features under the
microscope

Figure 28. (A) Acute myeloid Leukemia without maturation, classified as

FAB M1. (B) Flow Cytometry analysis shows that the myeloblast express
CD34 and CD33 but not C64 and only some for CD15, which are
markers of more mature myeloid cells. This exhibits limited maturation.
(Kumar et al, 2015)

• Shows some form of maturation

• Blast is similar to lymphoblasts except for the presence of the
cytoplasm (which is a feature of the Myeloid series), more
voluminous cytoplasm in myeloblast compared to the lymphoblast
• Presence of granules
• No nucleoli since it is an immature cell
• Flow cytometry
→ Markers for the Myeloid series
▪ CD34 and CD44
Figure 27. Major Subtypes of AML in the WHO Classification (Kumar
▪ Negative for CD64
et al., 2015)
▪ Some for CD15
▪ Shows only some but limited maturation in the
• Doc highlighted only on the following subtypes:
granulocytic series due to the inexpression of CD64 and
→ AML with Genetic Aberrations CD15
▪ First two in the table are common
▪ Chromosome translocation between chromosome 8 and
21 in the long arm region 22 t (8;21) q (22,22) creates
fusion gene RUNX1/ETO
▪ Inversion of chromosome 16 (inv16), between the short
and long arm of 13 and 22 (p13; q22) produces fusion
gene RARA/PML
▪ Off all those with AML with Genetic Aberrations they are
the ones with favorable prognosis and have a chance
of a cure
▪ Translocation 15 and 17 t (15;17) produces the
RARA/PML fusion gene
o Patients with this gene would have a high risk of
DIC and may die from bleeding
▪ AML with Genetic Aberrations is curable by ATRA (All- Figure 29. Acute Promyelocytic leukemia (FAB M3 Subtype) (Kumar
Trans retinoic acid) which induces maturation that will et al., 2015)
push immature myeloid cells to mature and die
o since in the RARA/PML fusion genes, myeloid cells • Found in AML with Genetic Aberrations, t (15;17) RARA Fusion
are stuck in the immature phase and don’t die • Promyelocyte contain a lot of Auer Rods (crystalline deposits
→ AML therapy related within the cytoplasm from abnormal fusion of primary granules)
▪ Secondary type neoplasms have poor prognosis → Stick shaped bodies the cytoplasm
→ A lot of granules signify it comes from myeloid series
FAB, French-American-British Classification
• Old Classification system for AML
• Subtypes from M0-M7 (based on the differentiation neoplastic
cells)
→ AML minimally differentiated is called M0
→ Recall: Natural maturation of the myelocytes: Myeloblast →
promyelocyte → myelocyte → metamyelocyte → band form
or juvenile → neutrophils

Symptoms and Prognosis

• AML is similar to ALL (Acute Lymphatic Leukemia) symptoms wise
but AML is more severe
→ ALL: Hematoma; AML: actual bleeding Figure 30. Acute myeloid leukemia with monocytic differentiation (FAB
• Bleeding more pronounced MSb subtype) (Kumar et al., 2015)
• Infection more frequent, leukemia cutis
→ Absence of mature neutrophils (only immature blasts) • Assumes appearance of the monocytes
presents weak protection from infection → vacuoles in the cytoplasm
• Minimal CNS involvement → nucleus is ameboid or irregular in shape
→ More common in the spread to the meninges than ALL • Curable
• Can present as soft tissue mass • Cytochemical stains
→ Granulocytic sarcoma, mass composed of immature → Positive for Myeloperoxidase (MPO)
neutrophils ▪ Stains granules
→ Crossover to lymphoma → Positive for Non-Specific Esterase (NSE)
• Prognosis: 60% Remission, 15-30% 5-year survival rate ▪ Specific for monocytes
→ Chromosomal translocation has a better prognosis as
opposed to therapy related AML
• T (15;17), t (8;21), inv (16)

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 B. MYELOPROLIFERATIVE DISORDER NOTE
• Increased proliferation of all cell lines in bone marrow Polycythemia Vera, Primary Myelofibrosis, and Essential
→ Genetic abnormalities Thrombocytosis were not discussed by doc since she wanted to focus
→ Polyclonal cells at first, but overtime due to proliferation and on CML. The following information are from 2022 Trans and Robbins.
acquisition of new mutations cells become clonal and
malignant
Polycythemia Vera
• Extramedullary hematopoiesis
• Increased marrow production of red cells, granulocytes, platelets
→ Bone marrow is now producing neoplastic cells so cells need
(panmyelosis)
to find other areas where normal hematopoetic cells
reproduce → Increase in RBC (polycythemia) that causes the clinical
symptoms
→ Hematopoiesis may happen in the spleen that may lead to
Pathogenesis
hepatosplenomegaly
• Marrow fibrosis and peripheral blood cytopenias • Point mutation in tyrosine kinase JAK2
→ Bone marrow cannot keep up with production of cellular • Constant activation of JAK2 pathway, RBCs become insensitive to
elements erythropoietin and growth factors
→ Stops producing hematopoietic cell • No need for EPO and GF
• Variable transformation to acute leukemia
Clinical Manifestations
Chronic Myelogenous Leukemia • Reddish complexion
• Occurs in adults • Panmyelosis
• Leukocytosis (>100,000 cells/mm3) • High hematocrit
• Blasts (myeloid/lymphoid): <10% of circulating cells → RBCs clog the blood vessels and blood flow becomes
sluggish
Pathophysiology → Large platelets – bleeding and thrombotic effects
• BCR-ABL fusion gene (Philadelphia chromosome) • Eventually it will reach the spent phase
• t(9;22) (q34;q11) → Extensive marrow fibrosis that displaces hematopoietic cells
→ Translocation of BCR gene on chromosome 22 and ABL gene → Extramedullary hematopoiesis in the spleen and liver which
on chromosome 9 may lead to organomegaly

Clinical Manifestations Treatment

• Splenomegaly • Phlebotomy – constantly remove RBCs
→ Due to sequestration - proliferating WBCs trapped in the • JAK2 inhibitors
spleen • No need for chemotherapy
• Basophilia
→ Normal: <1%, 0-2 on peripheral blood smear Histology
• Basophilia
“Normal to see 0-2 basophils on peripheral blood smears but the • Large platelets
fact that you see 5-6 basophils and high counts of WBC, think of
Chronic Myeloid Leukemia” (Dy-Ledesma, 2019) Essential Thrombocytosis
Pathogenesis
Prognosis and Treatment • Point mutation in JAK2 and MPL, calreticulin
• Very indolent but can go into “accelerated phase” or blast crisis • Tyrosine kinase is activated by thrombopoeitin, platelet production
→ Accelerated phase: 10% of blast population is exceeded in is stimulated
bone marrow or peripheral blood
Clinical Manifestations
→ Blast crisis: bone marrow is overrun with blasts
▪ More than 20% of blast population • Increased platelets
▪ Signifies that the patient is leading to AML • No increase in RBCs, no polycythemia, no fibrosis
• Treatment: Target Therapy • Thrombosis, hemorrhage, erythromelalgia (burning of hands and
→ Imatinib - Tyrosine kinase inhibitors for BCR-ABL gene feet)

Histology
Histology
• Giant platelets
• Same size as RBCs

Primary Myelofibrosis
• Hallmark: obliterative marrow fibrosis
• Chief pathologic feature: extensive deposition of collagen in the
marrow by non-neoplastic fibroblasts
→ Neoplastic megakaryocytes release PDGF and TGF- β
▪ TGF- β - promotes collagen deposition and causes
angiogenesis

Pathogenesis
• Gene mutations in JAK2, MPL
• Fibrotic obliteration of the marrow space leads to extensive
extramedullary hematopoiesis
• Marrow distortion leads to leukoerythroblastosis
Figure 31. Chronic myelogenous leukemia. Peripheral blood smear → Immature granular leukocytes and nucleated erythrocytes
shows many mature neutrophils, some metamyelocytes, and a circulating in the blood
myelocyte (Kumar et al., 2015)
Clinical Manifestations
• Many neutrophils with varying stages of maturity • Splenomegaly
• Little to no blasts (myeloid/lymphoid): <10%
• Difficult to distinguish from a Leukemoid Reaction Histology
→ Seen in both benign and neoplastic conditions • Fibrosis
→ Presents with elevated WBCs but does not reach 100,000 • RBCs are distorted and squeezed out of fibrotic marrow
cells/mm3 → Rare to see immature RBC, but if present it is usually
▪ More than 100,000 cells/mm3 would be leukemia dacryocytic (tear-drop shape)

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 C. MYELODYSPLASTIC SYNDROME • Nuclear Budding in Erythrocyte
• Maturation defects associated with ineffective hematopoiesis
→ Cells do not have the usual morphology
• Seen in elderly, symptoms are usually infection secondary to
pancytopenia
Pathogenesis
• Complex karyotype
→ Need many mutations for tumor to occur
→ Mutated tyrosine kinase induces growth and proliferation
• No single, specific genetic abnormality
→ Nucleated red cell progenitors with multilobated or multiple
nuclei
→ Presence of budding in nucleus (bilobated)
→ Maturation of cytoplasm and nucleus are not in-sync
→ Normal:
▪ Immature form of RBC: Dense single nucleus in the
center
▪ Mature form: Enucleated

Clinical Manifestations
• Bone marrow findings are variable depending on what myeloid
series
• High risk of transformation to AML (10-40%)
→ A precursor for myeloid leukemia, thus not malignant

Prognosis and Treatment

• Therapy related myelodysplastic syndrome (t-MDS)
→ For example, if you are able to do get a good history, you will
find out that the patient has been previously diagnosed with
cancer and has undergone chemotherapy
→ Dysplastic changes are induced by radiation and
chemotherapy

Histology
• Pseudo Pelger-Huet Cells Figure 34. Myelodisplastic Syndrome Cell: Nuclear Budding
→ Neutrophils with only two nuclear lobes with unclear or absent
connection • Multiple “Pawnball” Megakaryocytes
→ Resembling eyeglass/sunglasses → Megakaryocytes with separate and distinct multiple nuclei
→ Normal cells: tribolated or more → Normal: Single multilobated nucleus, multiple nuclei in
megakaryocytes that are all connected
→ “Pawnball” –Three gold circles for pawnshops used in dark
ages

Figure 32. Myelodisplastic Syndrome Cell: Pseudo Pelger-Huet Cell

• Ringed Sideroblasts
→ Erythroid progenitors with iron-laden mitochondria seen as
blue perinuclear granules
▪ Prussian blue stain
→ RBCs that have a lot of iron deposits in cytoplasm
→ Pathological
Figure 35. Myelodisplastic Syndrome Cell: Multiple “Pawnball”
Megakaryocyte

IV. HISTIOCYTOSIS
A. LANGERHANS CELL HISTIOCYTOSIS
• Rare proliferative disorder of epidermal antigen-presenting cells
(dendritic cells or macrophages)
• Langerhans cells
→ Immature dendritic cells from the skin where tumor arises
• Histiocytosis
 Umbrella term for proliferations of dendritic cells and
macrophages
• Also called Histiocytosis X

Pathophysiology
• X-linked
• BRAFV600 mutation
→ Most common mutation
→ Valine-to-glutamate substitution at residue 600 in BRAF
→ Less common mutations have also been detected in TP53,
RAS, and the tyrosine kinase MET

Immunophenotype
Figure 33. Myelodisplastic Syndrome Cell: Ringed Sideroblasts • HLA-DR, S-100, CD1a
→ Expressed by tumor cells

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 Clinical Manifestations
• Letterer-Siwe disease: Multifocal and multisystem Langerhans
cell histiocytosis
→ Occurs frequently before 2 years of age
→ Lesions numerous in lungs, skin, and bones
• Eosinophilic granuloma: Unifocal and multifocal unisystem
Langerhans cell histiocytosis
 Proliferations of Langerhans cells mixed with variable
numbers of eosinophils, lymphocytes, plasma cells, and
neutrophils
→ Eosinophils
 Usually but not always a prominent component of the
infiltrate
 Typically arises within the medullary cavities of bones,
most commonly the calvarium, ribs and femur
→ Less common
 Unisystem lesions of identical histology arise in:
 Skin, lungs, or stomach
→ Unifocal lesions
 Most commonly affect the skeletal system in older
children or adults
 Bone lesions
 Asymptomatic or may cause pain Figure 37. A. Langerhans cells with folded or grooved nuclei and
 Tenderness moderately abundant pale cytoplasm are mixed with a few eosinophils.
 Pathologic fractures B. An electron micrograph shows rod-like Birbeck granules with
 Indolent and may heal spontaneously or be cured by characteristic periodicity and dilated terminal end (Kumar et al., 2015)
local excision or irradiation
→ Multifocal unisystem disease QUICK REVIEW
 Affects young children who present with multiple erosive SUMMARY OF TERMS
bony masses that sometimes expand into adjacent Categories
tissue • Lymphoid: Originating from B, T, NK cell, plasma cell
→ Hand-Schuller-Christian • Myeloid: Arise from early hematopoietic progenitors
▪ Combined → Acute Myeloid Leukemia (AML): Accumulation of immature
 Calvarial bone defects progenitor cells in the bone marrow
 Diabetes insipidus → Myelodysplastic Syndrome (MDS): Ineffective
 Exophthalmos hematopoiesis and peripheral blood cytopenias
• Chronic myeloproliferative disorders: Elevated peripheral blood
counts due to increased production of terminally differentiated
myeloid elements
• Histiocytosis: Uncommon proliferative lesions of macrophages
and dendritic cells

Common Etiologies
→ Chromosomal translocations and acquired mutations
→ Hereditary factors
→ Viruses
→ Autoimmune diseases
→ Chronic inflammation
→ Iatrogenic factors
→ Smoking

Figure 36. Bony lesions found in the calvarium (Dy-Ledesma, 2019)
• Pulmonary Langerhans cell histiocytosis
→ Often seen in adult smokers
 May regress spontaneously upon cessation of smoking
Leukemia and lymphoma
• Leukemia: Disease confined to the bone marrow (where it begins)
and peripheral blood (where it spills over), no discrete mass
• Lymphoma: Disease confined to lymph nodes with potential
involvement of spleen and/or liver, with discrete soft tissue mass

Diagnosis Important principles

• Immunohistochemical stains using HLA-DR, S-100, CD1a • Histological examination: Biopsy is needed to make a diagnosis
because clinical symptoms are not enough to demonstrate the
Histology disease
• Birbeck granules • Monoclonal, unique DNA sequence: Genetic or karyotyping
→ Found in the cytoplasm studies is not only helpful in diagnosis but also in predicting
prognosis
→ Pentalaminar tubules with a dilated terminal end producing a • Cluster designation (CD): Used to identify B and T cell tumors
tennis racket-like appearance • Association with infection and autoimmune diseases and
→ Contains the protein langerin infections: Due to chronic inflammation process underlying these
→ Not used anymore for diagnosing because diseases

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 REVIEW QUESTIONS 11. Therapy related AML has a more favorable prognosis than AML
1. Which of the following is false? with genetic aberrations. AML is actually curable and is treated with
a) Chemotherapy can be a source of iatrogenic malignancies in ATRA (All-Trans retinoic acid).
the blood a) Only the first statement is true.
b) The presence of a soft tissue mass rules out leukemia as a b) Only the second statement is true.
diagnosis of Diabetes insipidus c) Both statements are true.
c) Clinical symptoms must be substantiated with a biopsy d) Both statements are false.
d) Leukemias and lymphomas are associated with autoimmune 12. Which of the following is not part of the Hand-Schuller-Christian
diseases due to chronic inflammation triad?
2. Which of the following is false about Acute Lymphoblastic a) Exophthalmos
Leukemia/Lymphoma? b) Calvarial bone defects
a) There is a loss-of function mutation in NOTCH1 and gain-of c) Diabetes insipidus
function mutations in PAX5, E2A, and EBF d) Skin lesions
b) Flow cytometry is the gold standard in diagnosing leukemia 13. Which of the following is not a clinical manifestation of Langerhans
c) Leukemias demonstrate a tropism for the brain and the testis Cell Histiocytosis?
d) ALL stains (-) myeloperoxidase a) Unifocal and multifocal unisystem Langerhans cell
3. This WBC disorder is characterized by deletions in the 11q and 17p histiocytosis (eosinophilic granuloma)
genes. b) Multifocal multisystem Langerhans cell histiocytosis (Letterer-
a) ALL Siwe disease)
b) CLL/SML c) Pulmonary Langerhans cell histiocytosis
c) HCL d) NOTA
d) AML Table 2. Matching Type
e) DLBCL Answer Header
4. In follicular hyperplasia, this cellular structure is formed by B-cells Acute Lymphoblastic A. Translocation of c-MYC
with irregular or cleaved nuclear contours. Leukemia gene on chromosome 8
a) Germinal center, dark zone Acute Myeloid Leukemia B.T(14,18); Over-expression
b) Germinal center, light zone of BCL2
c) Mantle zone Anaplastic Large Cell C. Rearrangements in ALK
d) Tingible-body macrophages Lymphoma gene of chromosome 2p23
e) NOTA Burkitt Lymphoma D. RARA/PML gene
5. All of the following are true of Myeloproliferative Disorders, Chronic Lymphocytic E. Non-classical form of HL
EXCEPT: Leukemia
a) Usually due to maturation defects associated with ineffective Chronic Myelogenous F. Most common form of HL
hematopoiesis Leukemia found in young adults
b) High risk for transformation to AML Follicular Lymphoma G. Involves the MYD88 gene
c) Pseudo Pelter-Huet Cells can be seen Hairy Cell Leukemia H. Involves BTK gene
d) Prognosis can be from t-MDS Langerhans Cell I. Immunophenotype: CD138
e) A-D are all true Histiocytosis and CD56
f) A-D are all false
Large Granular J. Immunophenotype: CD1,
6. Which immunophenotypes are present in multiple myeloma?
Lymphocytic Leukemia CD2, CD5, CD7
a) CD15 and CD30
Lymphocyte K. Has an NK variant that is
b) CD20 and BCL6
Predominance Type of more aggressive
c) CD56 and CD138
HL
d) CD 19 and 20
Lymphoplasmacytic L. Has an inflammatory
e) CD 5 and CD13
lymphoma premycotic phase
7. Which of the following is false about Hogdkin’s lymphoma?
a) Tumor is localized only to a single group of nodes Multiple myeloma M. BRAFV600
b) Very rarely arise in extranodal sites Mycosis Fungoides N. BRAF point mutation, Pan
c) More curable compared to Non-Hodgkin's lymphoma B-Cell Markers
d) Spread is predictable and orderly Nodular Sclerosis Type O. BCR-ABL gene
e) Always arise and stay in the lymph nodes of HL
f) AOTA
g) NOTA Answers
8. Which among the following Non-Hodgkin's lymphomas is the most 1A, 2A, 3B, 4B, 5F, 6C, 7G, 8D, 9C, 10C, 11B, 12D, 13D
uncommon? 5F. All describe myelodysplastic syndrome, not myeloproliferative
a) Follicular Lymphoma
b) Diffuse Large B-Cell Lymphoma (DLBCL)
c) Burkitt Lymphoma
d) Mantle Cell Lymphoma
e) Marginal Zone Lymphoma
9. Which of the following presents with a good prognosis?
a) Lymphoplasmacytic Lymphoma
b) Peripheral T-Cell Lymphoma Unspecified
c) Anaplastic Large Cell Lymphoma
d) Adult T-Cell Leukemia/Lymphoma
e) Mycosis Fungoides
10. Mycosis fungoides and Sezary Syndrome show similar clinical
manifestations, however differ in which of the following
characteristics? REFERENCES
a) Mycosis fungoides show exfoliated dermatitis while the REQUIRED
Sezary syndrome does not (1) Dy-Ledesma, J. (2019). WBC, Lymph Nodes [Lecture slides]
b) Mycosis fungoides show exfoliated dermatitis while the (2) ASMPH 2022. (2018). WBC Disorders: WBC Neoplasms
Sezary syndrome shows angiocentric dermatitis (3) Kumar, V., Abbas, A.K., & Aster, J.C. (2015). Robbins and Cotran
c) Mycosis fungoides tumor cells are found in the epidermis and pathologic basis of disease (9th ed.).
dermis while it is found in the peripheral blood for Sezary
IMPORTANT LINKS
syndrome
d) Mycosis fungoides tumor cells are found in the peripheral
Trans feedback: https://tinyurl.com/AcadsTransFeedback
blood while it is found in the epidermis and dermis for Sezary
Errata submission: https://tinyurl.com/ContentErrataSubmission
syndrome
Errata tracker: https://tinyurl.com/ErrataTracker

YL6: 04.12b Basic Pathologies 2: WBC Disorders: WBC Neoplasms 16 of 20

 YL6: 04.12b WBC Disorders: WBC Neoplasms
10/08/2019 Basic Pathologies 2
07:30-11:30 Jan Dy-Ledesma, MD, DPSP
PATHOLOGY

APPENDIX

Table 3. Lymphoid Neoplasms

Morphology Pathophysiology Immunophenotype Clinical Manifestations Prognosis and Treatment Histology

PRECURSOR B- & T-CELL NEOPLASMS

Acute Lymphoblastic Leukemia/Lymphoma

Hypercellular marrow, packed

with lymphoblasts
Size: A little bigger than usual
lymphocyte
Cytoplasm: Scant basophilic,
Depression of marrow function: Fatigue, fever, Favorable outcome factors: 2-10 years, low
no granules
bleeding white cell count, hyperploidy, trisomy of
Nuclei: Larger than those of
t(12;21) Neoplastic infiltration: Bone pain, generalized chromosomes 4, 7, and 10, t(12;21),
TdT small lymphocytes
B-ALL usually in Loss-of-function lymphadenopathy, hepatosplenomegaly, Philadelphia chromosome t(9;22) for
Pan B-cell markers in B-ALL: Chromatin: Delicate, finely
children as acute mutations in PAX5, E2A, compression of large vessels and airways in the Imatinib targeted gene therapy
CD 10,19, 20, 23 (higher stippled
leukemia and EBF mediastinum (T-ALL) Poor outcome factors: <2 years, MLL
numbers) and PAX5 Nucleoli: Absent or
Hyper/hypoploidy CNS: Headache, vomiting, nerve palsies translocations, blast count > 100,000, minimal
inconspicuous, indicates
Testicular enlargement residual disease
immaturity
Nuclear membrane: Deeply
subdivided
Cytochemical staining: (-)
Myeloperoxidase, (+)
Periodic Acid Schiff Stain

T-ALL usually in TdT

Gain-of-function
adolescent males PanT-cell markers in T-ALL:
mutations in NOTCH1
as thymic CD 1, 2, 3, 5, 7 (lower
Hyper/hypoploidy
lymphomas numbers)
PERIPHERAL B-CELL NEOPLASMS
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Highly friable smudge

TB-like symptoms (easy fatigability, weight loss,
4-6 years without treatment cells/basket cells
anorexia)
Poor outcome in deletions of 11q/17p and Soccer ball-cells under HPO
Variable leukocyte count
expression of ZAP-70 Distorted architectural
Hypogammaglobulinemia
Richter syndrome: Transformation into more features (irregular nuclei,
Thrombocytopenia
aggressive neoplasias condensed chromatin, scant
Hemolytic anemia
cytoplasm)

Hairy Cell Leukemia

Cells with fine hair-like
projections from the
Very rare leukemia Pan-B Cell (CD19, CD20) Atypical mycobacterial infections Excellent, follows an indolent course
Serine/threonine cytoplasm
White, Caucasian CD11c, CD25, CD103, Hepatosplenomegaly Responsive to gentle chemotherapy
BRAF point mutation Reniform nuclei with multiple
elderly males annexin A1) Pancytopenia Responsive to BRAF inhibitors
infoldings
Positive in TRAP stain
 NON-HODGKIN'S LYMPHOMA
Follicular Lymphoma
White pulp lesions in spleen
t(14;18) Incurable but indolent (7-9 years)
CD19, CD20, CD10 Para-trabecular lymphocytes
Middle-aged men Overexpression of Painless, generalized lymphadenopathy Low-dose chemo + anti-CD20
IgG, BCL2, BCL6 Absence of tingible-body
BCL2 Can transform to malignant neoplasia
macrophages
Diffuse Large B-Cell Lymphoma
Fast growing extranodal mass
Molecularly Aggressive, fatal without treatment Spleen: Undifferentiated cells with
Most common NHL CD10, CD19, CD20 Huge, scary-looking mass on spleen
heterogenous Chemotherapy + anti-CD20 large, prominent, pleiomorphic
>60 years old, male BCL6 Subtypes: primary effusion lymphoma, AIDS-
t(14;18), MYC 60-80% remission, 50% cure rate nuclei
associated, DLBCL with MYC translocation
Burkitt Lymphoma
Tumor cells: small-intermediate
Endemic type = Aggressive but can be cured with sized lymphocytes with prominent
children & young Manifest at extranodal sites chemotherapy nuclei and coarse chromatin
IgM, CD10, CD19, CD20,
adults (Africa) Translocations of c- Endemic type = mandibular mass (African Children generally tolerate chemotherapy Lots of macrophages because
BCL6
Sporadic type = MYC children) well tumor grows very fast
(-) BCL2
children & young Sporadic type = mass in ileocecal area Adults have systemic manifestations from Esembles Van Gough’s starry sky
adults (Western) chemotherapy (macrophages as stars, tumor
cells as sky)
Mantle Cell Lymphoma
3-4 years, no cure Very tiny germinal center due to
Very uncommon t(11;14) Cyclin D1, IgM, IgD, CD19,
Painless lymphadenopathy Blastoid variant = very poor prognosis proliferation of mantle zone
Elderly (50-60s), (+) Cyclin D1 and CD20
small polyps in the GIT Treatment: HSC transplant, proteosome Very monotonous due to
male CD5 (+) CD5, (-) CD23
inhibitor (control tumor cell growth) proliferation of clonal cells
Marginal Zone Lymphoma
t(11;18), (14;18),
Can remain localized for a prolonged time
(1;14) t(IgM and CD20
Common Swelling of salivary gland, thyroid or orbit Tumor might regress if the infection is
Overexpression of Bcl
eradicated
10
HODGKIN’S LYMPHOMA
Nodular Sclerosis

Most common HL Involves lower cervical, supraclavicular, and A lot of nodules surrounded by
CD15 and CD30 Excellent prognosis
type mediastinal lymph nodes fibrosis

Mixed Cellularity Type

Night sweats, weight loss, advanced tumor Heterogenous cellular infiltrates
CD15 and CD30 Very good prognosis
stage surrounding RS cells
Lymphocyte-Rich Type
Presence and abundance of
Uncommon CD15 and CD30 Very good to excellent prognosis
lymphocytes
Lymphocyte-Depletion Type

Uncommon CD15 and CD30 Less favorable prognosis Lack of lymphocytes

Lymphocyte Predominance Type

Non-classical form of
Very similar to lymphocyte-rich
HL, seen in young CD20 and BCL6 Cervical or axillary lymphadenopathy Excellent prognosis
type, but without CD15 and CD30
males
 PLASMA CELL NEOPLASMS
Multiple Myeloma
Variable but promising results
Seen in elderly Pathologic bone fracture, neurologic Presence of flame cells and mott
Plasma cells secrete
African-American CD138 and CD56 manifestations, recurrent bacterial infections, cells (Russel bodies, Dutcher
M component Treatment: proteasome inhibitors,
men renal insufficiency bodies)
lenalidomide, biphosphates, HSC transplant
Solitary Myeloma/Plasmacytoma
Condition will transform into multiple
Solitary lesion often found in bone, lungs,
myeloma but may take 10-20 years, curable
oropharynx, or nasal sinuses
by surgery
Smoldering Myeloma
Not completely benign
Condition will transform into multiple
not completely
myeloma
malignant
Monoclonal Gammopathy of Uncertain Significance
Most benign
Patient may have this condition for 15 years
presentation of
with not development of multiple myeloma
disease
Lymphoplasmacytic Lymphoma
Deletion of long arm
Incurable, poor prognosis, plasmapheresis,
Neoplasm of the chromosome 6q, Positive for CD20 and surface Hyperviscosity syndrome, lymphadenopathy, Plasma cells with clock face or
low dose chemotherapy, anti-CD20
elderly, 60-70yrs abnormality in MYD88 Ig hepatosplenomegaly, visual impairment checkerboard appearance
antibody
gene
PERIPHERAL T-CELL NEOPLASMS
Peripheral T-Cell Lymphoma (Unspecified)
T Markers: CD2,3,4,5,8, and Lymphadenopathy, dermatologic symptoms Worse prognosis than B neoplasms, more Spectrum of small, intermediate,
TCR people die with T-Cell lymphoma and large lymphoid cells
Anaplastic Large Cell Lymphoma
Very rare, seen in Good prognosis, if ALK (-) poor prognosis Hallmark cells with horseshoe-like
Rearrangement of
children and young CD30 because treatment is limited or embryoid nuclei and abundant
ALK gene
adults cytoplasm
Adult T-cell Leukemia/Lymphoma
Adults infected by Skin lesions, dermal presentation Very fatal, almost all patients die even with Cloverleaf or flower cells
Affects CD4 cells CD4
HTLV-1 aggressive chemotherapy
Mycosis Fungoides
Tumor cells are found in skin with skin lesions Neoplastic Lymphocytes show lot
Initial Phase: Rash Phase of convolutions or lobulated
Second Phase: Plaque Phase epidermal nucleus, limited to
Third Phase: Tumoral Phase epidermis and dermis
Sezary Syndrome
Tumor cells are found in the peripheral blood, Sezary cells with cerebriform
Exfoliative type of dermatitis, skin is roughing off nuclei
Large Granular Lymphocytic Leukemia
Mild to moderate lymphocytosis, neutropenia,
Rare, unusual, seen Splenomegaly, associated with rheumatologic
in Asians disorders (Felty Syndrome) and autoimmune
diseases
Extranodal NK/T Cell Lymphoma
Nasopharyngeal mass, Fungating and Friable Shows angiocentric invasion of
Common in the
Associated with EBV mass on the midline of the face, angiocentric the tumor to nearby blood
Philippines
tumor vessels
Table 4. Myeloid Neoplasms
Morphology Pathophysiology Immunophenotype Clinical Manifestations Prognosis and Treatment Histology

MYELOID NEOPLASMS
Acute Myeloid Leukemia (AML)

Most common AML with

Shows some maturation, more voluminous cytoplasm,
genetic aberrations:
Subtypes include AML more granules, no nucleoli, contains Auer Rods
Seen in any age but (8;21) q (22,22) fusion Similar to ALL but more
with genetic aberrations,
common in older gene RUNX1/ETO, severe, bleeding, infection, AML with genetic aberrations are treated with
AML therapy related, shows markers CD34, CD44, negative for CD64 and
males (p13; q22) fusion gene minimal CNS involvement, ATRA (All Trans Retinoic Acid)
AML with MDS, AML CD15
RARA/PML, t (15;17) granulocytic sarcoma
NOS
fusion gene RARA/PML
Stained with MPO and NSE

MYELOPROLIFERATIVE DISORDERS
Chronic Myelogenous Leukemia
Very Indolent but can go into accelerated
BCR-ABL fusion gene phase
Many neutrophils with varying stages of maturity
(Philadelphia Splenomegaly Blast Crisis: >20% blast populations
Adults (mostly) <10% of blasts
chromosome) Basophilia indicating change to AML
Leukocytosis >100,000 cells/mm3
t(9;22) (q34;q11)
Target Therapy: Imatinib
MYELODYSPLASTIC SYNDROME
Pseudo Pelger-Huet cells - neutrophils with 2 nuclear
lobes without connection
Maturation defects with Bone marrow findings are
Elderly, symptoms Ringed Sideroblasts - Erythroid progenitors with iron-
ineffective hematopoiesis variable
are usually infection Therapy related myelodysplastic syndrome (t- laden mitochondria seen as blue perinuclear granules
secondary to MDS) Nuclear Budding in Erythrocyte - Nucleated red cell
Complex karyotype - High Risk of transformation
pancytopenia progenitors with multilobated or multiple nuclei
many mutated genes to AML (10-40%)
Multiple “Pawnball” Megakaryocyte - multiple separate
and distinct nuclei
Table 5. Histiocytosis
Morphology Pathophysiology Immunophenotype Clinical Manifestations Prognosis and Histology
Treatment
HISTIOCYTOSIS
Langerhans Cell Histiocytosis
Multifocal multisystem (Letterer-Siwe disease):
Occurs frequently before 2 years of age

Unifocal lesions:
Birbeck granules: tennis racket-like
Most commonly affect the skeletal system in older
Letterer-Siwe disease: multifocal and appearance
children or adults
X-linked multisystem Langerhans cells with folded or grooved
Valine-to-glutamate HLA-DR, S-100, Eosinophilic granuloma: Unifocal and nuclei
Multifocal unisystem disease:
substitution at CD1a multifocal unisystem: Hand-Schuller- Eosinophils surrounding neoplastic
Affects young children who present with multiple erosive
BRAFV600 Christian triad Langerhans cells
bony masses
Pulmonary Langerhans histiocytosis
Pulmonary Langerhans cell histiocytosis:
Often seen in adult smokers