Chronic lymphoproliferative disorders
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CHRONIC LYMPHOPROLIFERATIVE DISORDERS
PRESENTER- DR. ANKITA BAGHEL
MODERATOR- DR. MANJULA K.
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CONTENTS
NORMAL HISTOLOGY WHAT IS CLPD CELL DIFFERENTIATION CLASSIFICATION INDIVIDUAL DISORDERS APPROACH TO DIAGNOSIS CYTOCHEMISTRY IMMUNOPHENOTYPING CYTOGENETICS REFERENCES
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NORMAL HISTOLOGY OF LYMPH NODE
CORTEX- Outer most portion- B-cell lymphoid follicles- Primary follicles(small lymphocytes)- Secondary follicle-Germinal center(centroblasts,centrocytes)
PARACORTEX- Below and between the follicle- T-cells, histiocytes, interdigitating Dendritic Cells And Langerhans Cells
MEDULLA
- Deep portion- Plasma cell-rich medullary cords
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B CELL DIFFERENTIATION
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T CELL DIFFERENTIATION
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CHRONIC LYMPHOPROLIFERATIVE DISORDERS(CLPDS) are a heterogeneous group of malignancies characterised by the proliferation of mature B and rarely T lymphoid cells in the peripheral blood, bone marrow and/or lymph nodes/spleen and other lymphoid tissues.
Classification-
1. FAB- MORPHOLOGY+CYTOCHEMISTRY+IMMUNOHISTOCHEMISTRY
2. WHO-• Morphology• Cytochemistry• Immunophenotypic analysis• Cytogenetic and molecular alterations.
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WHO CLASSIFICATION
PRECURSOR LYMPHOID NEOPLASM
MATURE LYMPHOID NEOPLASM
HODGKIN’S LYMPHOMA
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PRECURSOR LYMPHOID NEOPLASMS
Precursor-B lymphoblastic leukemia/lymphoma
Precursor-T lymphoblastic leukemia/lymphoma
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MATURE B-CELL NEOPLASMS1. CHRONIC LYMPHOCYTIC LEUKEMIA/ SMALL LYMPHOCYTIC
LYMPHOMA
2. B- CELL PROLYMPHOCYTIC LEUKEMIA
3. LYMPHOPLASMACYTIC LYMPHOMA
4. SPLENIC MARGINAL ZONE LYMPHOMAS
5. EXTRANODAL MARGINAL ZONE LYMPHOMA
6. MANTLE CELL LYMPHOMA
7. FOLLICULAR LYMPHOMA
8. NODAL MARGINAL ZONE LYMPHOMA
9. HAIRY CELL LEUKEMIA
10.PLASMACYTOMA/PLASMA CELL MYELOMA
11.DIFFUSE LARGE B-CELL LYMPHOMA
12.BURKITT’S LYMPHOMA
13.PLASMABLASTIC LYMPHOMA
14.WALDENSTROM MACROGLOBULINEMIA
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MATURE T-CELL & NK-CELL NEOPLASMS1. T-CELL PROLYMPHOCYTIC LEUKEMIA
2. LARGE GRANULAR LYMPHOCYTIC LEUKEMIA
3. PERIPHERAL T-CELL LYMPHOMA
4. UNSPECIFIED ANAPLASTIC LARGE CELL LYMPHOMA
5. ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
6. ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA
7. PANNICULITIS-LIKE-T-CELL LYMPHOMA
8. HEPATOSPLENIC T-CELL LYMPHOMA
9. ADULT T-CELL LEUKEMIA/LYMPHOMA
10.AGGRESSIVE NK/T-CELL LYMPHOMA
11.NK-CELL LEUKEMIA
12.SEZARY SYNDROME
13.MYCOSIS FUNGOIDES
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HODGKIN’S LYMPHOMA
1. CLASSICAL SUBTYPES-
a. NODULAR SCLEOSIS
b. MIXED CELLULARITY
c. LYMPHOCYTE-RICH
d. LYMPHOCYTE DEPLETION
2. NODULAR LYMPHOCYTE PREDOMINANT
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CHRONIC LYMPHOID LEUKEMIA-SUBTYPESB- CELL TYPE
1. B-CELL CLL
• CLL(PROLYMPHOCYTES <10%)
• CLL/PLL(PROLYMPHOCYTES 11-55%)
• RICHTER SYNDROME
2. PROLYMPHOCYTIC LEUKEMIA(PROLYMPHOCYTES >55%)
3. HAIRY CELL LEUKEMIA
4. PLASMA CELL LEUKEMIA, WALDENSTROM MACROGLOBULINEMIA
5. LYMPHOMA SPILL OVER-
• SPLENIC LYMPHOMA WITH VILLOUS LYMPHOCYTES(SLVL)
• MANTLE CELL LYMPHOMA
• OTHER NON-HODGKIN’S LYMPHOMAS
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T-CELL TYPE
1. T-CELL PROLYMPHOCYTIC LEUKEMIA
2. LARGE GRANULAR LYMPHOCYTIC LEUKEMIA
3. AGGRESSIVE NK-CELL LEUKEMIA
4. ADULT T-CELL LEUKEMIA/LYMPHOMA
5. MYCOSIS FUNGOIDES/SEZARY SYNDROME
6. PERIPHERAL T-CELL LYMPHOMA
7. ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA
8. ANAPLASTIC LARGE CELL LYMPHOMA ALK +ve
9. ANAPLASTIC LARGE CELL LYMPHOMA ALK -ve
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B CELL CHRONIC LYMPHOCYTIC LEUKEMIA
Median age at diagnosis- 70 years Incidence- Males= 2x Women Symptoms related to- Anemia
Thrombocytopenia
Neutropenia Neoplastic cells-
1. Small and mature appearing
2. Scant cytoplasm
3. Nuclei usually round
4. Chromatin regularly clumped(block-type chromatin)
5. Nucleoli inconspicuous
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Diagnosis- Lymphocytosis >5 x 109 /L
Prolymphocytes <10%
Smudge cells
Cytogenetic abnormalities-
1. Trisomy 12
2. Del 11q22.3-23.1
3. Del 6q21-23
4. Deletions at 17p13.1(p53 aberrations)
5. 14q abnormalities and complex chromosomal abnormalities
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PROLYMPHOCYTIC LEUKEMIA
Aggressive leukemic disorder .Often does not respond to
treatment.Incidence- 10% that of CLL.
Phenotypes-
1.Mature B cell
2.Mature T cell
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B CELL PLL
70% cases of PLL. Disease of adults Male:Female-4:1 Lymphocytes-
1. Large cell
2. Moderate amount of pale basophilic cytoplasm
3. Moderately condensed chromatin
4. Single prominent nucleolus
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T CELL PLL
Rare disorder of adults Lymphocyte-
1. Medium size
2. Convoluted nuclear outlines
3. Prominent nucleolus
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HAIRY CELL LEUKEMIA
Uncommon malignancy of middle age. Male:female-7:1
Presentation-
1. Massive Splenomegaly
2. Extensive bone marrow involvement
3. Pancytopenia
4. WBC count low- Neutropenia And Monocytopenia
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Neoplastic cell-
1. Abundant pale staining cytoplasm
2. Circumferential cytoplasmic projections(hairs)
3. Oval or reniform nuclei
4. Fine chromatin
Markers-
1. CD19
2. CD20(strong intensity)
3. CD22
4. CD25
5. CD103
6. CD11c
7. TRAP
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Bone marrow aspiration- DRY TAP Bone marrow biopsy- monotonous infiltrate of abnormal
lymphocytes with small nuclei and abundant pale-staining cytoplasm- FRIED EGG APPEARANCE
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LARGE GRANULAR LYMPHOCYTIC LEUKEMIA
LYMPHOCYTOSIS-
1. Abundant pale staining cytoplasm
2. Azurophilic cytoplasmic granules
3. Nuclei with mature clumped chromatin
Phenotypes-
1. T LYMPHOCYTE TYPE
2. NK CELL TYPE
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T-LGL LEUKEMIA
80% of LGLL Age- 55years
PRESENTATION- Anemia
Neutropenia
Thrombocytopenia
Splenomegaly
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NK CELL TYPE
Median age-39 years Acute presentation and aggressive course with
death within 2 months
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CUTANEOUS T CELL LYMPHOMA
Primary to skin MYCOSIS FUNGOIDES-most common variant of CTCL SEZARY SYNDROME- Erythroderma + Sezary cells
Sezary cell-
1. Mature memory helper T cell
2. Irregular, convoluted(cerebriform) nuclear outline
3. Finely distributed chromatin
4. CD3+, CD4+, CD7-
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SUBGROUP OF CHRONIC LEUKEMIC LYMPHOID MALIGNANCIES
KEY FEATURES MARKERS
1. B CELL CLL LymphocytosisSmudge cellsProlymphocytes <10%
CD19+,CD5+,CD20+ weak intensity, CD23+, FMC-Surface Ig weak intensity
2. B CELL PLL SplenomegalyMarked lymphocytosisProlymphocytes >55%
CD19+,CD20+,CD22+,CD5-/+,FMC-7+Surface Ig strong intensity
3.T CELL PLL SplenomegalySkin lesionsMarked lymphocytosisVaried morphologic appearance
4. HAIRY CELL LEUKEMIA
PancytopeniaCirculating hairy cellsBone marrow dry tapBone marrow fried egg appearance
TRAP+CD19+,CD5-,CD20+ strong intensity,CD22+,CD103+,CD11c+,CD25+Surface Ig strong intensity
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5. T CELL LGLL
LymphocytosisAnemiaNeutopeniaThrombocytopeniaRheumatoid factor often presentIndolent course
CD2+,CD3+,CD4-,CD5+,CD7+,CD8+,CD16+,CD56-/+,CD57+/-T Cell receptor clonally rearranged
6. SEZARY SYNDROME
Erythroderma(red skin)Cutaneous T cell lymphomaCirculating malignant cells
CD2+,CD3+,CD4+,CD5+,CD7-,CD8-
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MALIGNANT LYMPHOMA
HODGKIN NON-HODGKIN
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PARAMETER HODGKIN LYMPHOMA NON-HODGKIN LYMPHOMA
STAGE Usually localized Usually widespread
DISTRIBUTION Usually central nodes Usually involves peripheral nodes
MODE OF SPREAD Contiguous Non-contiguous
EXTRANODAL DISEASE Uncommon Common
PERIPHERAL BLOOD Never involved Can be involved
CELL TYPE Abnormal bizarre cells Resembles normal lymphoid cells
TREATMENT REGIMEN Often ABVD Often CHOP
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SMALL LYMPHOCYTIC LYMPHOMA
Tissue equivalent of CLL.
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FOLLICULAR LYMPHOMA
Neoplasm composed of cell originating from the germinal center.
Median age-50-60years Presentation-generalized painless lymphadenopathy
peripheral blood involvement
bone marrow involvement Lymph node-infiltrate of lymphoid cells forming poorly
circumscribed nodules Neoplastic follicles diifer from reactive follicle in
lacking apoptosis of lymphocytes Tingible body macrophages Small cleaved cells(CENTROCYTES) and large
cells(CENTROBLASTS)
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GRADING OF FOLLICULAR LYMPHOMA
GRADE DEFINITION
1 0-5 centroblasts per defined HPF
2 6-15 centroblasts per defined HPF
3 >15 centroblasts per defined HPF
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MANTLE CELL LYMPHOMA
Median age 60 years Male predominance Neoplastic cells-small to intermediate in size with
round to slightly irregular nuclear outlines. Markers-
1. CD19+
2. CD5+
3. CD23-
4. FMC7+
5. sIg+(strong intensity)
6. Cyclin D1
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MALT LYMPHOMA
Prsentation-localized extranodal disease A preceding chronic inflammatory
disorder(chronic gastritis,sjogrens,hashimotos) Neoplastic cells-
1. Small lymphocytes
2. Round to slightly cleaved nuclei
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BURKITT LYMPHOMA
High grade Non-hodgkin lymphoma High incidence in Africa(ENDEMIC SUBTYPE) 1/3rd of pediatric lymphomas outside
africa(SPORADIC SUBTYPE) Extranodal involvement Endemic-involves facial bones and jaw Sporadic- intestine,ovaries or kidney EBV associated
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Biopsy- STARRY SKY APPEARANCE-
• The SKY represents the blue nuclei of the neoplastic lymphocytes
• The STARS formed by scattered pale staining tingible body macrophages.
Infiltrating lymphoid cells are intermediate in size with nuclei approximately the same size as the nuclei of the tingible body macrophages.
Multiple small nucleoli,mitotic figures and apoptotic bodies.
Markers-
1. CD19+
2. sIg+
3. CD10+
4. CD5-
5. t(8;14), t(2;8), t8;22)
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HODGKINS LYMPHOMA- CLASSIFICATION
SUBTYPE SCLEROSIS LYMPHOCYTES
TUMOUR CELLSVARIANTS
VARIANTS CELL TYPE
LYMPHOCYTIC PREDOMINANCE
- ++++ + L AND H B-CELL
NODULAR SCLEROSIS
PRESENT ++ ++ LACUNAR UNCERTAIN CELL OF ORIGIN
MIXED CELLULARITY
- ++ ++ - UNCERTAIN CELL OF ORIGIN
LYMPHOCYTIC RICH
- ++++ + - UNCERTAIN CELL OF ORIGIN
LYMPHOCYTIC DEPLETION
-/+ + ++++ - UNCERTAIN CELL OF ORIGIN
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ANN ARBOR STAGING OF HODGKIN’SSTAGE FEATURE
STAGE I Involvement of single lymph node region(I) or a single extra lymphatic organ/site(IE)
STAGE II Involvement of two more lymph node regions on the same side of diaphragm(II) orLocalized involvement of an extra lymphatic organ and one more more lymph node regions on the same side of the diaphragm(IIE)
STAGE III
Involvement of lymph node regions on both sides of diaphragm(III), which may also be accompanied by localized involvement of an extra lymphatic organ(IIIE) or involvement of the spleen(IIIS) or both(IIIES)
STAGE IV
Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with or without associated lymph node enlargement.
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SUBCLASSIFICATION
A- without symptoms B- Systemic symptoms:
1. Unexplained fever 38 degree Celsius.
2. Unexplained weight loss 10% body weight in preceding 6 months.
3. Night sweats.
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MALIGNANT LYMPHOMA KEY FEATURE
1. FOLLICULAR LYMPHOMA Nodular growth patternLack of tangible body macrophagesCD19+,CD20+,CD5-,CD10+Surface Ig strong intensityt(14;18)BCL-2 protein overexpressionBCL-2 gene rearrangement
2. MANTLE CELL LYMPHOMA Lack of large cellsCD19+,CD20+,CD5+,CD23-,FMC-7+Surface Ig+ strong intensityCyclin-D1 overexpressiont(11;14)BCL-1 rearrangement
3. MALT LYMPHOMA Accompanied by infectious or autoimmune diseaseOften localizedExtranodalLymphoepithelial lesionsBenign folliclesHeterogeneous neoplastic infiltratePhenotype and genotype not specific
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4. WALDENSTROM MACROGLOBULINEMIA Lymphoid malignancy with plasmacytic differentiationIgMHypervicosity syndrome
5. BURKITT LYMPHOMA Can be associated with EBVStarry sky growth patternCD19+,CD20+,CD5-,CD10+Strong surface Igt(8;14)C-MYC gene rearrangement
6. ANAPLASTIC LARGE CELL LYMPHOMA Bizarre,anaplastic cells can resemble HDT cell or Null phenotypeLCA+/-,CD30+,CD15-,EMA+/-,EBV-,ALK-1+/-t(2;5)
7. CLASSIC HODGKIN LYMPHOMA Reed-Sternberg cellsLCA-,CD15+,CD30+,ALK-1-Often EBV +
8. LYMPHOCYTIC PREDOMINANT HL Growth pattern frequently nodularL and H cellsLCA+,CD20+,CD15-,CD30-,EBV-
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PLASMA CELL DISORDERS
1. PLASMA CELL MYELOMA (MULTIPLE MYELOMA)
2. PLASMACYTOMA
3. PRIMARY AMYLOIDOSIS
4. HEAVY CHAIN DISEASE
5. MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
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KEY FEATURES OF PLASMA CELL DISORDERSNEOPLASM FEATURES
1. MULTIPLE (PLASMA CELL) MYELOMA • LYTIC BONE LESIONS• “M” SPIKE ON SERUM/URINE ELECTROPHORESIS• ROULEAUX ON BLOOD SMEAR• >30% PLASMA CELLS IN BONE MARROW
2. PLAMACYTOMA • LOCALIZED MASS• MONOCLONAL PLASMA CELLS
3. MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
• MONOCLONAL SERUM PROTEIN• MONOCLONAL PROTEIN <3gm/dl• LYTIC BONE LESIONS ABSENT• BONE MARROW PLASMA CELLS <10%
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CRITERIA FOR DIAGNOSIS OF MULTIPLE MYELOMA(SALMON AND DURIE)MAJOR CRITERIA-1. Plasmacytoma on biopsy2. Bone marrow plasmacytosis >30% plasma cells3. M band in serum• IgG >3.5 g/dl OR IgA >2 g/dl• Light chain excretion in urine >/= 1 g/24 HOURS
MINOR CRITERIA-1. Bone marrow plasmacytosis 10-30% plasma cells2. Monoclonal globulin spike IgG <3.5 g/DL, or IgA <2g/DL3. Lytic bone lesions4. Normal IgM <50 mg/dl, IgA <0.1 g/dl OR IgG <0.6 g/dl
CRITERIA FOR MMDiagnossi of myeloma is confirmed when at least-• One major + one minor criteria OR• 3 minor criteria, that must include 1 and 2 of minor criteria.
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APPROACH TO DIAGNOSIS OF LYMPHOMA??
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CELL SIZE DETERMINATION
Neoplastic cells are compared with the Reactive Histiocytes interspersed among the lymphoma cells.
SMALL- Nuclei smaller than that of reactive histiocytes.
MEDIUM- Nuclei approx. same as that of histiocytes.
LARGE- Nuclei larger than those of histiocytes.
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MEDIUM SIZED FOLLICLES-APPROACH TO DIAGNOSIS
MAJOR DIFFERENTIAL DIAGNOSIS
1. Reactive follicular hyperplasia
2. Follicular lymphoma
3. Nodular mantle cell lymphoma
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How to distinguish between reactive follicular hyperplasia and follicular lymphoma?FEATURE REACTIVE
FOLLICULAR HYPERPLASIA
FOLLICULAR LYMPHOMA
FOLLICLES Discrete and separeated by interfollicular lymphoid tissue
A pattern of back to back follicles with little interfollicular tissue
TINGIBLE BODY MACROPHAGES
Present Lack
CELLULAR POLARIZATION Into light and dark zones present
Absent
POPULATION Heterogeneous population of follicular cells
Predominance of centrocytes in the follicles
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LARGE LYMPHOID NODULES: APPROACH TO DIAGNOSIS
MAJOR DIFFERENTIAL DIAGNOSIS
1. NLPHL
2. N-LRCHL
3. NSHL
4. PTGC
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DIFFUSE SMALL B-CELL LYMPHOMAS- APPROACH TO CLASSIFICATION
MAJOR DIFFERENTIAL DIAGNOSIS
1. CLL/SLL
2. Lymphoplasmacytic lymphoma
3. Mantle cell lymphoma
4. Extranodal marginal cell lymphoma
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LARGE CELL SCATTERED IN A BACKGROUND OF SMALL LYMPHOCYTES
MAJOR DIFFERENTIAL DIAGNOSIS
1. Reactive lymphoid hyperplasia
2. T-cell/histiocytic rich large B-cell lymphoma
3. Hodgkin lymphoma
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Possible diagnosis All large cells show morphologic features acceptable for immunoblasts or centroblasts( nuclear size <x2.5 small lymphocyte nucleus: nuclear contour round to oval)
Large cells are atypical(with irregular nuclear folding or granular chromatin),but most nuclei are <x2.5 small lymphocyte nucleus
Most large cells have nuclei >x3 small lymphocyte nucleus
Reactive lymphoid hyperplasia
+ - -
TCRBCL + + +
Hodgkin’s lymphoma
- - +
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CELL IDENTIFICATION BY CYTOCHEMISTRYCYTOCHEMICAL REACTION CELL TYPES
1. NON SPECIFIC ESTERASE • MYELOID CELLS• MONOCYTES• MEGAKARYOCYTES• T LYMPHOCYTES(dot like staining)
2. CHLOROACETATE ESTERASE • MYELOID CELLS• MAST CELLS
3. PEROXIDASE • MYELOID CELLS• EOSINOPHILS• MONOCYTES
4. SUDAN BLACK B • MYELOID CELLS• MONOCYTES
5. METHYL GREEN PYRONINE • PLASMA CELLS• IMMUNOBLASTS
6.PERIODIC ACID-SCHIFF WITH DIASTASE • PLASMA CELLS
7. TARTRATE-RESISTANT ACID PHOSPHATASE • HAIRY CELL LEUKEMIA
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PROBLEM TO BE ASSESSED FIRST-LINE ANTIBODIES
B LINEAGE ? CD20( or CD79a, PAX5)
T LINEAGE ? CD3( OR CD2)
NK LINEAGE ? CD56, SURFACE CD3, CYTOPLASMIC CD3, TCR
FOLLICULAR CENTER CELL ? CD10( OR BCL6, HGAL)
FOLLICULAR LYMPHOMA OR HYPERPLASIA ? BCL2, CD10(interfollicular invasion)
CLL ? CD5, CD23
NORMAL MANTLE ZONE CELLS ? IgD
MANTLE CELL LYMPHOMA ? CYCLIN D1, CD5
BURKITT LYMPHOMA ? Ki67, CD10(+/-BCL6), BCL2, MYC
IMMATURE(PRECURSOR LYMPHOBLASTIC)CELL ? TdT
ANAPLASTIC LARGE CELL LYMPHOMA ? CD30, ALK
PLASMA CELL ? CD20- , CD138+
HISTIOCYTE ? CD163( or CD68)
INTERDIGITATIONG DENDRITIC OR LANGERHANS CELL ?
S100( also LANGERIN/ CD207 for the latter cell type)
FOLLICULAR DENDRITIC CELL ? CD21 or CD35
HODGKIN LYMPHOMA ? CD30, CD15, PAX5
MOST USEFUL ANTIBODIES FOR ASSESSMENT OF LYMPHOID PROLIFERATIONS
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CHARACTERISTIC CYTOGENETIC FINDINGS IN SPECIFIC LYMPHOMA TYPESLYMPHOMA TYPE SPECIFIC CHROMOSOMAL
TRANSLOCATIONONCOGENE OR TUMOUR SUPPRESSOR GEENE IMPLICATED
Follicular lymphoma t(14;18)(q32;q21) BCL2
Mantle cell lymphoma t(11;14)(q13;q32) CCND1
Extranodal marginal zone lymphoma of MALT type
t(11;18)(q21;q21)t(1;14)(p22;q32)t(14;18)(q32;q21)t(3;14)(p14.1;q32)
API2, MALT1BCL10MALT1FOXP1
Burkitt lymphoma t(8;14)(q24;q32)t(8;22)(q24;q11)t(2;8)(p12;q24)
MYC
T-lymphoblastic lymphoma/leukemia
t(1;14)
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RELATIVE FREQUENCIES OF B-CELL LYMPHOMA SUBTYPES IN ADULTS
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RELATIVE FREQUENCIES OF MATURE T-CELL LYMPHOMA SUBTYPES IN ADULTS
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REACTIVE LYMPADENOPATHIES AND THEIR DISTICTION FROM LYMPHOMA
INFECTIOUS MONONUCLEOSIS AND OTHER VIRAL INFECTIONS
HYPERSENSITIVITY REACTIONS(PHENYTOIN) KIKUCHI LYMPHADENITIS
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REFERENCES
MCKENZIE-2ND EDITION,VOLUME 2 WHO CLASSIFICATION OF TUMOURS OF
HAEMATOPOIETIC AND LYMPHOID MALIGNANCIES-4TH EDITION
WINTROBES-11TH EDITION ROBBINS- 18TH EDITION DIAGNOSTIC HISTOPATHOLOGY OF TUMOURS-
FLETCHER 4TH EDITION,VOLUME 2 IOACHIM’S LYMPH NODE PATHOLOGY INTERNET
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THANK YOU