HEMATOLOGY 2

Calamba Doctors’ College

Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester

PORTFOLIO

MYELOPROLIFERATIVE NEOPLASMS

CHAPTER 33 CUE/NOTE
Myeloproliferati ➢ Clonal hematopoietic disorders caused by genetic
ve Neoplasms mutations in HSC = expansion.
➢ Predominantly chronic with accelerated, subacute,
acute phases.
Chronic ➢ An MPN arising from single gentic translocation in a
Myelogenous pluripotential hematopoietic stem cell = clonal
Leukemia overproduction of myeloid cell line = preponderance
of immature cells in neutrophilic line.
Incidence:
❖ 20% of all cases of leukemia
❖ S/s: fatigue, decreased tolerance of exertion,
anorexia, abdominal discomfort, weight loss,
splenic enlargement
Cytogenetics of Philadelphia Chromosome:
❖ acquired somatic mutation specifically reflects the
translocation of an ABL protooncogene from band
q34 of chromosome 9 to the breakpoint cluster
region (BCR) of band q11 of chromosome 22,
resulting in a unique chimeric gene, BCR/ABL1.
Molecular Genetics:
❖ Four BCR genes in human genome: BCR1,
Philadelphia translocation; BCR2; BCR3; BCR4
❖ Major BCR - on chromosome 22 as a 5-exon region
involving exons 12 to 16 that was the area of
breakage in the traditional t(9;22) translocation.
❖ Minor BCR - n chromosome 22, one near the 59 |
head
❖ Micro BCR - one in the 39 end | tail
Pathogenic Mechanism:
❖ SH1 – binding site of ATP
❖ SH2 – docking point of phosphate receiver protein
❖ SH3 – domain that control phosphorylation
activity
Other Laboratory Findings:
❖ SH1 – binding site of ATP
❖ SH2 – docking point of phosphate receiver protein
❖ SH3 – domain that control phosphorylation
activity
Progression:
❖ Blast crisis - severe anemia, leukopenia of all WBCs
except blasts, and thrombocytopenia.
❖ Chromosome abnormalities: Philadelphia
chromosome(s); isochromosome 17; trisomy 8; loss
of Y chromosome; and trisomy 19 accumulate with
disease progression.
Related Diseases:
❖ Chronic neutrophilic leukemia
❖ Chronic monocytic leukemia
❖ Juvenile myelomonocytic leukemia
❖ Chronic myelomonocytic leukemia
Treatment:
❖ alkylating agents such as nitrogen mustard
❖ busulfan in combination with 6-thioguanine
❖ hydroxyurea and 6-mercaptopurine
❖ interferon-a - stimulates a cell-mediated
antitumor host response that reduces myeloid cell
numbers, induces cytogenetic remissions, and
increases survival
Polycythemia ➢ Neoplastic clonal myeloproliferative disorder
Vera ➢ Arises in hematopoietic stem cell
Diagnosis:
❖ Macrocytic RBC
❖ Splenomegaly
❖ Pancytopenia
❖ Triad of BM fibrosis, splenomegaly, anemia with
teardrop-shaped and poikilocytoses

REYES | 3rd YEAR COLLEGE

 HEMATOLOGY 2
Calamba Doctors’ College
Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester

PORTFOLIO

❖ Fourth, patients must demonstrate either the JAK2

V617F or other clonal mutation
❖ BM biopsy – distinguish MDS to ET
Peripheral Blood & Bone Marrow:

c. Treatment & Prognosis:

❖ Low dose aspirin
❖ Alkylating agent hydroxyurea
❖ Busulfan Treatment & Prognosis:
❖ Myelosuppressive therapy such as phosphorus ❖ Alkylating agent like hydroxyurea
P32 ❖ Hydroxyurea therapy
❖ INCB018424 (ruxolitinib) at dose of 10mg b.i.d ❖ interferon-a
Essential ➢ Clonal MPN with increased megakaryopoiesis & ❖ low dose of aspirin
Thrombocytemia thrombocytosis, usually w count >600 x 10^9/L ❖ INCB018424 (ruxolitinib) dose of 25mg b.i.d
Incidence: ❖ CEP701 (Lestaurtinib)
Pathogenic Mechanism: Primary ➢ Chronic idiopathic myelofibrosis, agnogenic. &
❖ JAK2 V617F Myelofibrosis myeloid metaplasia
❖ MPL exon 10 mutations (MPL W515L/K) Myelofibrosis:
❖ TET2 (4.4% to 5%), ASXL1 (5.6%), LNK (3% to ❖ Increases in type III collagen are detected by silver
6%), and IDH1/2 (0.8%) impregnation techniques
Clinical Presentation: ❖ increases in type I by staining with trichrome
❖ elevated platelet count ❖ increases in type IV by the presence of
❖ vascular occlusion or hemorrhage osteosclerosis, which may be diagnosed from
❖ splenic or hepatic veins, as in Budd-Chiari increased radiographic bone density
syndrome ❖ increases in marrow fibrosis may reflect a
❖ Splenomegaly reparative response to injury from benzene or
Diagnosis: ionizing radiation
❖ First, the WHO group lowered the platelet count ❖ Type IV collagen and lamina – appears as stromal
threshold to 450 3 109/L or greater sheets with neovascularization and endothelial
❖ Second, the bone marrow must show significant cell proliferation
megakaryopoiesis ❖ Type VII - linkage between type I fibers, type III
❖ Third, the condition cannot meet the criteria of fibers, and type I plus type III fibers
any other MPN, myelodysplasia, or other myeloid Hematopoiesis & Extramedullary Hematopoiesis:
neoplasm ❖ Hepatomegaly or splenomegaly

REYES | 3rd YEAR COLLEGE

HEMATOLOGY 2
Calamba Doctors’ College
Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester

PORTFOLIO

❖ Increase circulating hematopoietic cells

❖ n increase in circulating unilineage and
multilineage hematopoietic progenitor cells,127
and the number of CD341 cells may be 300 times MYELODYSPLASTIC SYNDROMES
normal
Pathogenic Mechanism:
❖ JAK2 V617F mutation - 65% CHAPTER 34 CUE/NOTE
❖ CBL (6%),130 TET2 (7.7% to 17%), ASXL1 (13% Myelodysplastic ➢ Clonal hematopoietic disorders caused by genetic
to 23%), LNK (3% to 6%), EZH2 (13%), and Syndromes mutations in HSC = expansion.
IDH1/2 (4.2%) ➢ Predominantly chronic with accelerated, subacute,
Incidence & Clinical Presentation: acute phases.
❖ Fatigue
Chronic ➢ An MPN arising from single gentic translocation in a
❖ Weakness
Myelogenous pluripotential hematopoietic stem cell = clonal
❖ shortness of breath
Leukemia overproduction of myeloid cell line = preponderance
❖ palpitations
of immature cells in neutrophilic line.
❖ weight loss
❖ discomfort or pain in the left upper quadrant
associated with splenomegaly
Immune Response:
❖ Humoral immune responses
❖ increased proportions of marrow-reactive
lymphocytes, and the development of amyloidosis
Treatment & Prognosis:
❖ androgen therapy, prednisone, danazol,134
thalidomide,135,136 or lenalidomide,137 and
hemolytic anemia with glucocorticosteroids
❖ Thalidomide and lenalidomide
❖ Hydroxyurea

Morphologic Ab a. Dyserythropiesis:
in PB & BM ❖ the presence of oval macrocytes
❖ Dyserythropoiesis in the bone marrow is
evidenced by RBC precursors with more than one
nucleus or abnormal nuclear shape (lobes or buds)
❖ Nuclear fragments
❖ Internuclear bridging
❖ basophilic stippling or heterogeneous staining
❖ Ring sideroblasts
❖ erythrocytic hyperplasia or hypoplasia (in bone
marrow)
❖ Megaloblastoid cellular development in the
presence of normal vitamin B12 and folate values
b. Dysmyelopoiesis:
❖ Persistent basophilic cytoplasm
❖ Abnormal granulation
❖ Abnormal nuclear shapes
❖ Uneven cytoplasmic staining
c. Dysmegakaryopoiesis:

REYES | 3rd YEAR COLLEGE

 HEMATOLOGY 2
Calamba Doctors’ College
Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester

PORTFOLIO

❖ Giant platelets Platelets with abnormal ❖ the most common mutations include those in the
granulation TP53 gene,74RUNX1,76,77 and TET2
❖ Circulating micromegakaryocytes
❖ Large mononuclear megakaryocytes c. Epigenetics:
❖ Micromegakaryocytes or micromegakaryoblasts ❖ changes in gene expression that occur without
or both altering the DNA sequence
❖ Abnormal nuclear shapes in the ❖ incorporation of demethylating agents into the
megakaryocytes/blasts DNA appears to slow the progression of MDS
Differential Diag ✓ Dysplasia Treatment ✓ lenalidomide, azacitidine, and decitabine (FDA
✓ Copper deficiency may cause reversible approved)
myelodysplasia
✓ Fanconi anemia and congenital dyserythropoietic
anemia
✓ Parvovirus B19 ACUTE LEUKEMIAS
✓ Paroxysmal nocturnal hemoglobinuria
Abnormal • granulocytes may have decreased adhesion
Cellular Function • deficient phagocytosis
• decreased chemotaxis CHAPTER 35 CUE/NOTE
• impaired microbicidal capacity Acute ➢ FAB (French American British) classification
• Decreased levels of myeloperoxidase and alkaline Leukemias 1970, morphologic examination along with
phosphatase cytochemical stains to
• erythroid precursors may have a decreased ➢ distinguish lymphoblasts from myeloblasts
response to erythropoietin ➢ Diagnose hematopoietic malignancies – flow
• increased bleeding cytometry, genetic studies least 20% blasts in BM
is required for diagnosis of the majority of acute
Classification of a. French -American-British Classification:
leukemia
Myelodysplastic ➢ Refractory anemia
Syndromes ➢ Refractory anemia with ring sideroblasts (RARS) Leukemia Morphology:
➢ Refractory anemia with excess blasts (RAEB) Prognosis:
➢ Chronic myelomonocytic leukemia (CMML) Immunophenotyping:
➢ Refractory anemia with excess blasts in Genetic & Molecular Findings:
transformation (RAEB-t) Acute Myeloid 1. Acute Myeloid Leukemia with Minimal Differentiation
b. WHO Classification: Leukemia 2. Acute Myeloid Leukemia without Maturation
➢ Refractory cytopenia with unilineage dysplasia 3. Acute Myeloid Leukemia with Maturation
➢ Refractory anemia with ring sideroblasts 4. Acute Myelomonocytic Leukemia
➢ Refractory cytopenia with multilineage dysplasia 5. Acute Monoblastic and Monocytic Leukemias
➢ Refractory anemia with excess blasts 6. Acute Erythroid Leukemia
➢ Myelodysplastic syndrome with isolated del(5q) 7. Acute Megakaryoblastic Leukemia
➢ Myelodysplastic syndrome, unclassifiable ACL of
➢ Childhood myelodysplastic syndrome Ambiguous
(provisional) Lineage
c. Chronic Myelomonocytic Leukemia
d. Atypical Chronic Myeloid Leukemia, BCR/ABL1-
e. Juvenile Myelomonoctic Leukemia
f. Myelodysplastic/Myeloproliferative Neoplasm,
Unclassifiable
Cytogenetics, a. Cytogenetics:
Molecular Gen, & ❖ The most common abnormalities involve
Epigenetics chromosomes 5, 7, 8, 11, 13, and 20
❖ The most common single abnormalities are
trisomy 8 and monosomy 7
❖ Less common abnormalities: 12p–, iso 17, –22, and Future Directions ✓ mutated genes include KIT, FLT3, ASXL1, TP53,
loss of the Y chromosome in AL CEBPA, and NPM1. AML with mutated NPM1 and
❖ del(5q), no cytogenetic abnormality is specific to Classification AML with mutated CEBPA are provisional entities in
subtype the 2008 WHO classification
b. Molecular Alt:

REYES | 3rd YEAR COLLEGE

 HEMATOLOGY 2
Calamba Doctors’ College
Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester

PORTFOLIO

Cytochemical a. Myeloperoxidase 3 The most superficial portion of the lymph node

Stains & ❖ Enzyme in primary granules of granulocytic consisting of primary and secondary follicles.
Interpretations ❖ cells
AMLs
❖ Differentiating blast of AML and ALL
❖ Leukemic myeloblasts (MPO +)
❖ Promyelocytes test (+)
ALL
❖ Lymphoid cells (-)
❖ maturing granulocytes (MPO +)

b. Sudan Black
❖ stains cellular lipids, more sensitive
❖ Monocytic cells (-)
❖ Lymphoid cells (no stain)
ALL
❖ 3% blast cells (+)
c. Esterases
❖ differentiate myeloblasts and neutrophilic
❖ granulocytes from cells of monocytic origin
❖ 2 substrate: a-naphthyl acetate and anaphthyl
butyrate (both nonspecific)
❖ Naphthol AS-D chloroacetate (specific)
❖ only granulocytic cells show staining
❖ Non specific stain b. Paracortex
❖ (+) in other cells 4 Occupies the area separating the follicles &
❖ a. a-Naphthyl acetate extends toward medullary cords.
❖ strong esterase activity in monocytes 5 Contains numerous B immunoblasts.
❖ inhibit by: sodium fluoride c. Medulla
❖ Granulocytes and lymphoid cells (-) 6 Represents the innermost portion of the lymph
❖ b. a-naphthyl butyrate esterase reaction node surrounding hilum.
❖ monooocytes, less sensitive, more specific 7 Composed of medullary cords w plasma &
medullary sinuses.
d. Sinusis
8 Filtration of lymphatic fluid through lymph nodes
is accomplished via afferent lymphatics
MATURE LYMPHOID NEOPLASMS communicating w a subcapsulalar sinus, which is
situated immediately beneath the capsule.
Lymph Node 9 Fresh lymph node is cut into 3-mm-thick sections
Processing for the evaluation of nodal architecture.
CHAPTER 36 CUE/NOTE Touch imprints - ensure adequacy of the specimen & to
Lymphomas 1 Neoplasms of lymphoid system. perform special studies.
2 Diagnosis is based on a combination of biologic 10 Can be fixed in formalin/alcohol soln/air dried for
features such as morphology immunotype and subsequent Wright-Giemsa staining.
molecular genetic characteristics, and clin. Info. Reactive a. Follicular Pattern
Morphologic & Lymphadenopath • Follicular hyperplasia - Most common form of
Immunophenoty ies reactive lymphadenopathies.
pic Features of • Secondary follicles – retain all the hallmarks of
Normal Lymph reactive germinal centers, including distinct
Nodes polarization, presence of tangible-body
macrophages, abundant mitotic figures, &
preserved mantle zones.
b. Paracortical Pattern
• Paracortical expansion – associated w viral
infections and drug reax and is also seen in
patients w chronic skin diseases.
• Dermatopathic Lymphadenopathy – paracortex
a. Cortex has a characteristic mottled appearance as a result
REYES | 3rd YEAR COLLEGE
HEMATOLOGY 2
Calamba Doctors’ College
Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester

PORTFOLIO

of an increased number of large cells w abundant Lymphomas a. Mature B Cell Lymphoma

clear cytoplasm scattered among small lymphoid • Derived from various stages of B cell
cells. differentiation.
c. Sinusoidal Pattern • Follicular lymphoma & DLBCL – most common
• Numerous malignant lesions show predilection subtypes of B cell lymphoma.
for sinuses such as Langerhans cell histiocytosis, B 1. Chronic Lymphocytic Leukemia/ Small Lymphocytic
& T cell lymphomas, & carcinomas. Lymphoma
d. Mixed Pattern ➢ Definition:
• Toxoplasma gondii – classic example of mixed- ✓ Accumulation of small lymphoid cells in
patter hyperplasia can be seen. peripheral bloo, BM, and lymphoid organs,
• Florid follicular hyperplasia – accompanied by ➢ Morphology:
paracortical expansion, aggregates of histiocytes ✓ Soccer ball pattern
encroaching on germinal centers, and expanded ➢ Diagnosis & Immunophenotype:
sinuses. ✓ Based on sustained increase in monoclonal B
lymphocytes w CLL immunophenotype which
is equal/greater than 5000 u/L.
➢ CF & Prognosis:
✓ Generally affects older adults (55 y/o | 24%)
✓ Diag: Asymptomatic
✓ CLL is a heterogenous diseases in terms of
clinical behavior.
2. Prolymphocytic Leukemia
➢ Definition:
✓ Rare mature lymphoid leukemia that can be
derived from B/T cells.
✓ Lymph node involvement is more commonly
seen in T cell PLL.
➢ Morphology & Immunophenotype:
✓ Pathogenic cell of B cell PLL is polymphocyte
of medium size w round nucleus, moderately
abundant cytoplasm, & distinct punched out
nucleus.
➢ CF & Prognosis:
✓ Disease of the elderly (70 y/o)
3. Hairy Cell Leukemia
➢ Definition:
✓ Characterized by small B lymphocytes w
abundant cytoplasm & fine cytoplasmic
projections.
➢ Morphology & Immunophenotype:
✓ Found predominantly in BM & red pulp of
spleen
✓ Lymph node involvement is rare
✓ Show strong positivity for B cell markers
coupled w bright expression of CD11c, CD25,
CD103 and such.
➢ CF & Prognosis:
✓ Rare lymphoproliferative disorder in middle-
age individuals (mid 55 y/o)
✓ Splenomegaly & pancytopenia
4. Mantle Cell Lymphoma
➢ Definition:
✓ Lymphoproliferative disorder, medium-sized
lymphoid cells w irregular nuclear outline
derived from follicular mantle zone.
➢ Morphology & Immunophenotype:
✓ Lymph nodes show a replacement of normal
nodal architecture w a diffuse proliferation of
REYES | 3rd YEAR COLLEGE
HEMATOLOGY 2
Calamba Doctors’ College
Mr. Estabillo, Jerome Tabajonda
MLS60 | 2023-2024 | BSMT3-B | 2nd Semester
PORTFOLIO
monotonous, medium-sized lymphoid cells w
irregular nuclear outlines.
➢ CF & Prognosis:
✓ Aggressive lymphoproliferative disorder w a
median survival time of 3-5 yrs.
✓ Incurable w currently available
chemotherapy, but stem cell transplantation is
successful in a proportion of patients.
5. Follicular Lymphoma
➢ Definition:
✓ Originated from germinal center B cells.
➢ Morphology & Immunophenotype:
✓ Neoplastic proliferation may extend into
perinodal adipose tissue,
➢ CF & Prognosis:
✓ 59 yrs – median age at diag
✓ Present w disseminated disease
✓ Bone marrow involvement (50% cases)
✓ Course of Disease: grade 1-2 follicular
lymphoma, grade 3 are more aggressive;
treated w doxorubicin like DLBCL
6. Extranodal Marginal Zone Lymphoma of Mucosa
Associated Lymphoid Tissue
b. Mature T Cell & NKC Lymphomas
➢ less common than the previously discussed
mature B cell neoplasms and account for
approximately 10% of all lymphomas.
Mycosis Fungoides and Sézary Syndrome
➢ Mycosis fungoides is the most common cutaneous
lymphoma.
Morphology and Immunophenotype
➢ The extent of cutaneous infiltrate is related to the
stage of the disease.
➢ Early lesions show patchy or lichenoid infiltration
of the dermis by small to medium-sized lymphoid
cells with irregular nuclear outlines.
Clinical Features and Prognosis
➢ The incidence of mycosis fungoides increases with
age, and the average age at presentation is 55 to
60 years. T
➢ Peripheral T Cell Lymphoma, Unspecified
➢ Heterogeneous group of lymphomas with mature
T cell phenotype.
Morphology and Immunophenotype
➢ Lymph node involvement is usually diffuse with a
prominent vascular proliferation.
Clinical Features and Prognosis
➢ Aggressive disease occurring predominantly in
older adults average age of 60 years.
Anaplastic Large Cell Lymphoma
➢ Can be seen a typical case of anaplastic large cell
lymphoma, characterized by large atypical cells
with pleomorphic nuclei and abundant cytoplasm
➢ Morphology and Immunophenotype
➢ Architecture is most often diffusely effaced by
malignant lymphoid cells.
➢ Anaplastic large cell lymphoma is less frequent in
adults
Presents as disseminated nodal disease with
constitutional symptoms. Extranodal sites, including skin
c. Hodgkin Lymphoma
➢ Divided into two broad categories: nodular
lymphocyte-predominant Hodgkin lymphoma and
classical Hodgkin lymphoma
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Morphology and Immunophenotype
➢ The normal architecture of a lymph node is
replaced by a nodular proliferation of small
lymphocytes and scattered
lymphocytic/histiocytic or popcorn cells.
Clinical Features and Prognosis
➢ Most patients are males in their thirties and
present with localized peripheral
lymphadenopathy.
Classical Hodgkin Lymphoma
Morphology and Immunophenotype
Divided into four subtypes
1. Nodular sclerosis
2. Mixed cellularity
3. Lymphocyte rich
4. Lymphocyte depleted
Nodular Sclerosis Classical Hodgkin Lymphoma
➢ This is the most common subtype of classical
Hodgkin lymphoma, accounting for 70% of cases.
Mixed Cellularity Classical Hodgkin Lymphoma
➢ Reed-Sternberg cells and their variants are
scattered among the diffuse background
composed of small lymphocytes, histiocytes,
eosinophils, neutrophils, and plasma cells.
➢ Approximately 20% of classical Hodgkin
lymphomas show this morphology. An association
with EBV infection is seen in 75% of cases.
Lymphocyte-Rich Classical Hodgkin Lymphoma
➢ Nodules represent remnants of mantle zones and
germinal centers.
➢ Lymphocyte-Depleted Classical Hodgkin
Lymphoma.
➢ Uncommon variant of classical Hodgkin
lymphoma occurring predominantly in
immunodeficient patients.
➢ In most cases, neoplastic cells show evidence of
EBV infection.
Clinical Features and Prognosis
➢ Slightly older population, classical Hodgkin
lymphoma is a disease of young adults with a peak
incidence at 15 to 35 years.
➢ Therapy and radiotherapy, the cure rates are 80%
to 90%, depending on the stage of the disease,
patient age, and clinical symptoms
➢ E best prognosis is seen in the nodular sclerosis
subtype.
REYES | 3rd YEAR COLLEGE