Chronic Myelogenous Leukemia

- Middle aged (35-60 years)

- BCR-ABL present

- t(9:22)(q34;q11) BCR-ABL1

- Treat with Gleevec a tyrosine kinase inhibitor.

Polycythemia vera

- Middle-aged, M > F

- Major Criteria: Hb >18.5 g/dL in M or >16.5 g/dL in F; JAK2 V617F

- Minor Criteria: Hypercellular marrow with panmyelosis; low EPO; endogenous erythroid colony formation in vitro;

- Need 2 major plus 1 minor, or 1st major (high Hb) plus 2 minor

- Cytogenetics: JAK2 V617F, negative t(9;22)

- Prognosis: 10-20 years.

Primary Myelofibrosis

- > 50 years

- Major Criteria: megakaryocyte proliferation/atypia with marrow fibrosis; CML, PV, MDS ruled out; JAK2 V617F 50%

- Cytogenetics - +8, +9, del(20q), del(13q), del(1p), negative t(9;22)

- Prognosis: Dependent on the phase.  ~10 years in early prefibrotic phase, ~5 years in fibrotic phase. 

Essential Thrombocythemia

- 5th decade M=F; 2nd peak in 30s F > M

- Needs All 4 Criteria:

1. Platelet count >450 K.

2. BM with proliferation of mature megakaryocytes.

3. PV, PMF, CML, MDS ruled out.

4. JAK2 V617F or if absent, no evidence of reactive thrombocytosis

- Cytogenetics: JAK2 V617F in 50%; del(13q22), +8, +9 seen in 5-10% of cases; negative t(9;22) 

- Prognosis: Most are stable for many years.

Chronic Myelomonocytic Leukemia

- Median 65-75 years, M > F

- Monocytosis >1000, cytopenias, myeloid dysplasias, <20% blasts

- Cytogenetics - +8, -7, 12p abnormal in 20-40% of cases, negative for t(9;22)

- Prognosis - 20-40 months with progression to AML in 15-30%

Juvenile Myelomonocytic Leukemia

- younger than 3 years, M > F

- Monocytosis >1000, blasts <20%, plus 2 of the following:

- increased Hb F

- immature granulocytes

- WBC >10K

- clonal abnormality

- G-CSF hypersensitivity

- Cytogenetics - Monosomy 7, negative for t(9;22)

- Prognosis- Poor; possible benefit from BMT

Myeloid/lymphoid neoplasms with increased eosinophils and PDGFR/FGFR1

- Males 25-55 years

- Peripheral blood with increased eosinophils, bone marrow eosinophils with mast cells

- Cytogenetics - FIP1L1-PDGFRA, PDGFRB, FGFR

- Prognosis - Variable response to tyrosine kinase inhibitor

Mastocytosis

- All ages

- Mononuclear with central nuclei, variable basophilic granules (often not seen in fixed tissue); dense aggregates of spindle cells

- Cytogenetics - KIT D816V

- Prognosis:

- Cutaenous - indolent

- Systemic - variable

- Leukemia - aggressive

CEL NOS, idiopathic HES

- Usually adult male; can be any age or sex

- Peripheral blood >1.5 K eosinophils/microliter, <20% blasts

- Cytogenetics - +8, i(17q), 8p11 translocations with various partners

- Prognosis - Indolent, 80% 5 years survival

Refractory cytopenia with unilineage dysplasia, anemia, thrombocytopenia, or neutropenia

- Median age 65-70 years

- Peripheral blood with unicytopenia or bicytopenia, blasts <1%

- Bone marrow with >10% unilineage dysplasia and <5% blasts

- Cytogenetics - Del (20q), +8, abnormalities of 5 and 7

- Prognosis - low risk of progression to acute leukemia

Refractory anemia with ringed sideroblasts

- Median age 60-73 years

- Similar to refractory anemia with >15% ringed sideroblasts in BM

- Cytogenetics - Rare abnormalities of single chromosome

- Prognosis - low risk of progression to acute leukemia

Refractory cytopenia with multilineage dysplasia

- Median age 70 years

- Peripheral blood with cytopenias of >2 cell lines, <1% blasts, <1 x10⁹/L monocytes

- Bone marrow with dysplasia of >10% of precursors of >2 cell lines, <5% blasts

- Cytogenetics - +8, -5, -7, del(7q), del(20q), complex in up to 50%

- Prognosis - Intermediate risk of progression to acute leukemia

Refractory anemia with excess blasts

- Over age 50

- RAEB 1: peripheral blood with <5% blasts, <1 x 10⁹/L monocytes; bone marrow with hypercellularity, dyspoiesis, 5-9% blasts without Auer rods

- RAEB 2: peripheral blood with 5-9% blasts, or 10-19% bone marrow blasts, or Auer rods

- Cytogenetics - +8, -5, del(5q), -7, del(7q), del(20q)

- Prognosis - 1 has intermediate progression risk, 2 has high progression risk

5q- syndrome

- Middle aged to older females

- Peripheral blood - thrombocytosis, <5% blasts

- Bone Marrow - increased hypolobulated megakaryocytes, <5% blasts

- Cytogenetics - 5q- is sole abnormality

- Prognosis - low risk of progression to acute leukemia

AML with t(8;21)

CD13, CD33, CD117, CD19, CD34

- >20% blasts, >10% maturing granulocytes, Auer rods, dysplasia, abnormal granules

- Cytogenetics - t(8;21)(q22;q22) AML1/ETO

- Prognosis - more favorable

AML with inv(16)

CD13, CD33, CD14, CD4, CD64

- Blasts with both monocytic and neutrophilic differentiation, increased eosinophils/immature eosinophils

- Cytogenetics - inv(16)(p13;q22) or t(16;16)(p13;q22)

- Prognosis - more favorable

APL with t(15;17)

CD13, CD33, CD2, dim CD117

- Promyelocytes with azurophilic granules, Auer rods

- Cytogenetics - t(15;17)(q22;q12) PML/RARα; Variants all involve 17q12

- Prognosis - More favorable if responsive to all trans-retinoic acid (ATRA)

AML with t(9;11)

CD33, CD65, CD4, HLA-DR

- Monoblasts and promonocytes predominate

- Cytogenetics - t(9;11)(p22;q23) MLLT3-MLL

- Prognosis - Intermediate 

Therapy related AML

CD13, CD33, CD34, dim CD56, CD57

- Multilineage dysplasia, RS, increased basophils

- Cytogenetics - 11q23 abnormality seen with topoisomerase II inhibitors-associated AML

- Prognosis - less favorable

AML with t(6;9)

CD13, CD33, CD38, HLA-DR, CD117

- Any morphology may be seen, but myelomonocytic is most common

- Cytogenetics - DEK-NUP214; t(6;9)(p23;q35)

- Prognosis - Less favorable

AML with inv(3) or t(3;3)

CD13, CD33, HLA-DR, CD34, CD38

- Any morphology may be seen except APL

- Cytogenetics - Inv(3)(q26.2) or t(3;3)(q21;q26.2)

   RPN1-EVI1

- Prognosis - Less favorable

AML with t(1;22)

CD41, CD61, dim CD13, CD33

- Megakaryoblastic morphology with small and large megakaryocytes

- Cytogenetics - t(1;22)(p13;q13) RBM15-MKL1

- Prognosis - Less favorable

AML with FLT3 mutation/duplication

- Cell surface markers - any

- Morphology - any

- Cytogenetics - t(6;9)(p23;q34), t(15;17)(q22;q12), or normal cytogenetics

- Prognosis - less favorable

AML with NPM1 mutation

CD13, CD33, neg CD34

- Myelomonocytic and monocytic features

- Cytogenetics - NPM1 mutation, cytoplasmic expression

- Prognosis - More favorable in the abscence of FLT3

AML with CEBPA mutation

CD13, CD33, CD56, CD11b, CD15

- Variable morphology, similar to less differentiated AMLs in FAB scheme (M1,2)

- Cytogenetics - CEBPA mutation

- Prognosis - More favorable

AML NOS, minimally differentiated

CD13, CD33, CD117

Myeloblasts, <3% positive for Sudan black B, MPO, or ANA

AML without maturation

CD13, CD33, CD117

Myeloblasts >90% of nonerythroids in BM, >3% positive for MPO

AML with maturation

CD13, CD33, CD117

>20% blasts, >10% maturing granulocytes, Auer rods, dysplasia, abnormal granules. 

Similar morphology to t(8;21).

Acute myelomonocytic leukemia

Variable CD13, CD33, CD14, CD4, CD11b, CD11c, CD64, CD36, CD68

Monocytic and granulocytic cells, each 20-80%

Acute monoblastic/monocytic leukemia

CD13, CD33, CD117, CD14, CD4, CD11b, CD11c, CD64, CD68, CD36

>80% of nonerythroid monoblasts (M5a) or differentiating monos (M5b)

Erythroleukemia

Glycophorin A in erythroids

CD13, CD33, CD117 in myeloblasts

Acute megakaryoblastic leukemia

Positive - CD41, CD61, CD36, often CD13, CD33

Blasts with cytoplasmic blebs, often clusters; Peripheral blood may show megakaryocytic fragments; MPO negative.

t(1;22)

T cell prolymphocytic leukemia (PLL)

CD7, CD4 (60%), CD4/8 (25%), CD8 (15%)

- Prolymphocyte morphology

- mostly males; median age, 65 years; lymphocytosis >100K/μL, anemia, thrombocytopenia, HSM, skin lesions

- Gene rearrangements - TCR-γδ, TCR-αβ,

inv(14)(q11;q32)

LGL leukemia

CD3, CD8, CD57, TCR-γδ; some variants are CD4+ or CD4/8+ or CD4/8-; CD4 -

- LGL morphology

- Median age 63 years; neutropenia with infections, anemia, mild lymphocytosis (>2K/μL)

- Gene rearrangements - TCR rearrangements

Aggressive NK cell leukemia

Positive - cCD3ε, CD2, CD56

Negative - sCD3, CD57

- Variable morphology may resemble LGL or appear blastic

- Asian teens to young adults; constitutional symptoms, HSM, variable WBC count

- Gene rearrangement - TCR-γδ, TCR-αβ, Clonal EBV, del(6)(q21;q25)

Adult T cell leukemia/lymphoma

Positive - CD2, CD3, CD4, CD5, CD25, often CD30

Negative - CD7, CD8

- Moderately large blastic cells with convoluted nuclei (floret cells), agranular, basophilic cytoplasm

- Associated with HTLV-1, frequent in Japan, Caribbean, Central Africa; acute variant with skin, lymph node involvement, hypercalcemia

- Genetics - TCR rearrangements

Extranodal NK/T cell lymphoma, nasal type

Positive - CD2, CD56, cytotoxic granules, cCD3ε

Negative - sCD3

- Angiocentric and destructive, involving upper aerodigestive tract

- Most prevalent in Asia, Native Americans of Mexico, and Cental/South America

- Genetics - Germline receptor genes

Enteropathy-associated T cell lymphoma

Positive - CD3, CD7, CD103; CD3, CD8, CD56 (type II)

Negative - CD4, CD5

- Large cells with inflammatory background, occasionally monomorphic (type II) medium sized cells

- All ages and regions; increased in celiac disease (may present concurrently), jejunum and ileum

- Genetics -TCR rearrangements

Hepatosplenic T cell lymphoma

Positive - CD3, dim CD8, dim CD56

Negative - CD4, CD5, often CD4/CD8 double negative

- Medium-sized cells involving splenic red pulp and sinuses of liver and marrow

- Rare, increased in adolescents and young adults with chronic immunosuppressive therapy; involves liver/spleen/marrow

- Gene rearrangement - TCR-γδ

Subcutaneous panniculitis-like T cell lymphoma

Positive - CD3, βF1, CD8, cytoxic granules

Negative - CD4, CD56

- Involves fat lobules, spares septa, variable-sized monomorphic cells, rimming of fat cells, histiocytes

- Rare, F > M; subcutaneous panniculitis with neoplastic cells

- Genetic rearrangement - TCR-γδ, TCR-αβ

Peripheral T cell lymphoma (PTCL)

Positive - CD4, Pan T cell markers (3,2,5,7) are usually positive but are often abberantly dropped.

Negative - often drops 5, 7, 3, or 2 (pan T cell markers)

- Varies in cell size and from polymorphic to monomorphic

- Peripheral nodes, disseminated disease, sometimes cutaneous

- Gene rearrangements -  TCR rearrangements

Angioimmunoblastic T cell lymphoma

Positive - CD3, CD2, CD5, CD4, (reactive CD8), CD10, CXCL13

Negative - CD8

- Partial nodal effacement involving paracortex, increased venules, clear cell clusters, EBV+ B cells

- Middle-aged and elderly; generalized disease, systemic symptoms, hypergammaglobulinemia

-  Genetics - TCR-γδ, TCR-αβ, +3, +5, +X

Mycosis fungoides (MF)/Sezary Syndrome (SS)

Positive - CD2, CD3, CD4

Negative - CD7, CD8

- Dermal band-like inflitrates of lymphocytes with cerebriform nuclei, microabscesses

- M > F, middle aged to older; dermatitis progressing to ulcerated lesions; peripheral blood involvement in SS

- Genetics -  TCR-γδ, TCR-αβ

Primary cutaneous CD30+ Lymphoproliferative Disorder

Positive - CD4, CD30

Negative - CD2, CD3, CD5, ALK

- polymorphic lymphoid cells, some anaplastic

- M > F, adults to elderly; limited to skin lesions

- Genetics - TCR-γδ, TCR-αβ

Anaplastic large cell lymphoma

Positive - CD30 (cytoplasmic and golgi), CD2, CD4, CD5

Negative - CD3, CD7, EBV

- Pleomorphic large cells, wreath-like nuclei, multiple nucleoli, abundant cytoplasm

- M > F, teens, young adults; peripheral, abdominal adenopathy, extranodal and BM involvement, frequent B symptoms

- Genetics - TCR rearrangements, t(2;5)(p23;q35), other variants involve 2p23

CLL/SLL

- M>F, over 60 years; insidious onset of fatigue, lymphoadenopathy; WBC >5K/μL, anemia thrombocytopenia, occasionally AIHA

- Small lymphocytes with condensed chromatin

- Positive - CD19, CD20, CD5, CD22, CD23, CD79a, dim sIg

- Negative - CD10, bcl6, FMC7

- Cytogenetics - +12, del(13q14.3), del(11q22-23),

del(17q)(TP53)

B cell prolymphocytic leukemia

- M>F, mean age 65 years; massive splenomegaly, minimal lymphadenopathy, WBC > 100K

- Prolymphocytes >55%

- Positive - CD19, CD20, FMC-7, bright sIg

- Negative - CD5 and CD23 often negative

- Cytogenetics - occasional del(17p), del(13q14)

Hairy cell leukemia

- M > F, median age 50 years; insidious onset with splenomegaly, leukopenia with monocytopenia

- Medium-sized cells with round to oval indented nuclei, reticular chromatin, frayed cytoplasmic borders

- Dry taps due to marrow fibrosis

- Positive - CD20, CD22, CD79a, CD103, CD25, CD11c

- Negative - CD5, CD10, CD23

Lymphoplasmacytic lymphoma

- M > F, mean age 63 years; BM, nodal, and splenic involvement; symptomatic IgM paraprotein

- Plasmacytoid lymphocytes and plasma cells with PAS-positive inclusions (Dutcher bodies)

-Positive - CD19, CD20, CD22, CD25, CD38, CD79a,

bright sIgM, cIgM

- Negative - CD5, CD10, CD23, CD103, bcl-6

- Cytogentics - del(6q), +3, +4, +18, non-specific

Heavy chain disease

- Younger adults in poorer Mediterranean communities with malabsorption, diarrhea

- Lymphoplasmacytic infiltrate of intestinal mucosa, variant of MALT

- Positive - NA

- Negative - NA

Marginal zone lymphomas; splenic, nodal, MALT

- F > M, median age 61 years; indolent course involving stomach, other mucosal sites, spleen, or nodes

- Lymphocytes with condensed chromatin and moderate cytoplasm; lymphoepithelial lesions in MALT type

- Positive - CD20, CD79a, sIgM, bcl-2

- Negative - CD5, CD10, CD23, bcl-6

- Cytogenetics - +3, t(11;18)(q21;q21) in MALT type, 7q abnormalities

Follicular Lymphoma

- F > M, median age 59 years; lymphadenopathy, BM, and splenic involvement frequent

- Follicule-like structures with centrocytes and varying numbers of centroblasts

- Positive - CD19, CD20, CD22, CD23, CD79a, CD10, bcl-2, bcl-6, sIgM

- Negative - CD5, CD43

- Cytogenetics - t(14;18)(q32;q21)

- bcl 6 and CD10 indicate germinal center cell origin.  bcl-2 should be negative in normal germinal center cells.  bcl-2 positivity is abnormal.  Marginal zone lymphoma can invade follicles and be bcl-2 positive, but it is CD10 and bcl-6 negative.

Mantle cell lymphoma

- M > F, median age 60 years; lymphoadenopathy, splenomegaly, BM involment; typically refractory

- Atrophic germinal centers, prominent mantle zones, small lymphos with irregular nuclei; blastoid/pleomorphic variants

- Positive - CD5, CD43, FMC-7, bcl-2, cyclin D1, sIgM

- Negative - CD10, CD23, bcl-6

- Cytogenetics - t(11;14)(q13;q32)

Diffuse large B cell lymphoma

- M > F, all ages, moderately aggressive but responds to chemo and anti-CD20

- Diffuse infiltrate of large B cells, variable morphology

- Positive - CD19, CD20, CD22, CD79a, sIg, bcl-2±,

bcl-6±, CD30±, MUM1 in post-GC types

- Negative - CD5 (usually)

- Cytogenetics - t(14;18) in 20%, 3q27 (bcl-6) abnomalities in 30%, occasional secondary myc translocations

Mediastinal large B cell lymphoma

- F > M, young to middle-aged adults; airway compression, superior vena cava syndrome

- Sclerotic lesions with clear, multilobulated or RS-like cells

- Positive - CD19, CD20, CD22, CD79a, CD30

- Negative - CD5, CD10

- Cytogenetics - Amplifications of 9p24, 2p15, others

Primary effusion lymphoma

- Rare, associated with HHV-8 in immunosuppressed younger male homosexuals; pleural effusion

- Immunoblastic or anaplastic cells

- Positive - CD45, CD30, CD38, CD138

- Negative - CD19, CD20, CD79a, sIg, bcl-6

Plasmablastic lymphoma

- Rare, associated with EBV in immunosuppressed

- Plasmacytoid

- Positive - CD38, CD138, CD79a, MUM1, cIgG

- Negative - CD45, CD20, and PAX-5 are negative or weak

EBV associated chronic inflammation of the elderly, lymphomatoid granulomatosis, post-transplant

- Immunosuppressed, elderly, others

- Variable morphology

- Positive - CD20, EBV-EBER

Burkitt lymphoma

- Demographics

1. Endemic: children in Africa, jaw mass M > F

2. Sporadic: children to young adults, worldwide, M>F

3. Immunodeficiency-associated: HIV patients

- Uniform cells with round to oval nuclei, multiple nucleoli, high mitotic rate

- Positive - CD19, CD20, CD10, bcl-6, sIg

- Negative - TdT, bcl-2

- Cytogenetics - t(8;14)(q24;q32), t(2;8)(p12;q24),

t(8;22)(q24;q11)

Intermediate Burkitt lymphoma/DLBCL

- Children with rapidly growing mass, adults

- Intermediate between Burkitt lymphoma and DLBCL

- Positive - CD19, CD20, CD10, bcl-6, sIg

- Cytogenetics - t(8;14)(q24;q32), 8q24/MYC, variable, others

Nodular Lymphocyte Predominant Hodgkin Lymphoma

- M > F, 30-50 years, with peripheral lymphadenopathy

- Mononuclear cells with convoluted nuclei (popcorn or L&H cells) loosely aggregated in nodules of small B cells

- Markers - CD45+, CD20+, bcl-6+, J-chain+, Oct-2+, BOB.1+, EBV absent in LP cells

- Prognosis - Excellent for stages I and II  

Nodular Sclerosis Hodgkin Lymphoma

- M=F, <30 years with mediastinal mass, occasional spleen or lung involvement; 40% have B symptoms; most patients present with stage II disease

- Broad bands of collagen, nodules of lymphoid tissue with aggregates of RS cells and lacunar cells, multinucleated variants

- Markers - CD15+, CD30+, CD45-, EBV+ in 1-40%

- Prognosis - Good with systemic therapy

Mixed Cellularity Hodgkin Lymphoma

- M>F; median age 38 years; peripheral adenopathy is common; also involves spleen, BM; B symptoms common; patients often Stage III or IV

- Classic RS cells in mixture of lymphocytes, plasma cells, eosinophils, histiocytes

- Markers - CD15+, CD30+, CD45-, EBV+ in 75%

- Prognosis - Good with systemic therapy

Lymphocyte Depleted Hodgkin Lymphoma

- M>F; median age, 30-37 years; B symptoms, advanced stage common; associated with HIV

- Classic RS cells common with paucity of background lymphocytes; pleomorphic RS cells mimic sarcoma

- Markers - CD15+, CD30+, CD45-, EBV+ in HIV- patients

- Prognosis - Associated with advanced stage

Lymphocyte-Rich Classical Hodgkin Lymphoma

- M>F, older age; peripheral lymphadenopathy; B symptoms rare; most patients with stage I or II disease

- Scattered classic RS cells among numerous small lymphocytes; nodular growth pattern

- Markers - CD15+, CD30+; Oct2 and BOB.1 vary;

J-chain(-); EBV+ in 40-75%

- Prognosis - Good similar to NLPHL