Continuing Education

CASE STUDIES IN ADULT NON-HODGKIN'S LEUKEMIA

 

CASE A:

 

            A 50 year old, black female presented at an area hospital with abdominal pain and diarrhea. CT scan revealed an intra-abdominal mass with no disease above the diaphragm. Surgery was performed to remove the mass and lymph nodes. Staging biopsies were performed to determine the extent of disease. The results suggested kappa light chain restriction, but a definitive diagnosis of lymphoma was not rendered. The patient was treated with eight (8) cycles of chlorambucil and prednisone. The patient did well with no evidence of disease upon completion of therapy. After two (2) years, the patient presented at another area hospital with shortness of breath. Three taps on the pleural cavity were performed and were reported out as reactive lymphocytosis. The patient was released and referred to another area hospital, where the pleural cavity was tapped for a fourth time with the following results.

 

Chemistry:      Cholesterol                            108 mg/dL

                        Glucose                                  94 mg/dL

                        LD                                           326 IU/L

                        Protein                                    3.5 g/dL

 

Fluid Analysis:           Color                           Cream

                                    Clarity                         Turbid

                                    RBC                            1280

                                    Nucleated Cells         1920

                                    Polys                           2

                                    Lymphs                       95

                                    Basos                         1

                                    Macros                       2

 

Flow Cytometry:        CD1                negative         CD2                negative

                                    CD3                negative         CD4                negative

                                    CD5                negative         CD7                negative

                                    CD8                negative         CD10              dim positive

                                    CD19              positive           CD20              positive

                                    CD23              negative         CD25              negative        

                                    CD45              positive           MO2                negative

                                    HLA-DR         positive           Skappa          positive

                                    Slambda        negative

 

Cytogenetics:            46,XX,t(14;18)(q32;q21)


 

 



 


 

CASE B:

 

            A 42 year old, HIV positive, white male presented at a local cancer center with a rash and cervical lymphadenopathy. Biopsy results from the left cervical lymph node are as follows.

 

Flow Cytometry:        CD1%                        0                      CD2%                        72

                                    CD3%                        72                    CD4%                        25

                                    CD5%                        75                    CD7%                        66

                                    CD8%                        44                    CD10%          0

                                    CD19%                      24                    CD20%          24

                                    CD23%                      8                      CD25%          5

                                    CD45%                      100                 MO2%            3

                                    HLA-DR%                  58                    Skappa%       55

                                    Slambda%                 38

 

Anatomic Pathology/Immunopathology Special Stains:

 

            L26                 weakly positive

            LCA                positive

            CD30              equivocal

            UCHL-1          negative in neoplastic cells

            CD3                negative in neoplastic cells

            CD15              negative in neoplastic cells

            EMA               negative

            Kappa            negative

            Lambda          negative

 

Cytogenetics:            82~88,XXXY,-X,-Y,+1,-1,+2,+2,+2,+2,add(2)(q?),+3,

-3,del(3(q?26.3),+4,-4,t(4;11)(?q12;q23),-5,+6,+6,-6,

del(6)(q21),add(6)(q?),add(6)(q?),-7,-7,del(7)(q22),

del(7)(q22),+8,-8,-8,-8,+9,-9,add(9)(p?21),add(9)(p?21),-10,

-10,-10,+11,-11,-11,add(11)(q11),add(11)(p14),

del(11)(q23),+12,-12,-12,+13,-13,+14,-14,-14,+15,+15,

-15,t(15;22)(p11;q11.2), t(15;22)(p11;q11.2),-16,-16,-17,-17,

-17,-17,+18,-18,+19,-19,+20,-20,-21,-21,-21,-22,-22,

-22,+r(?),+r(?),+double r(?),+1~10mar[cp13]/46,XY[7]


 


ADULT NON-HODGKIN'S LYMPHOMA

 

            Lymphomas are a diverse group of malignancies. These malignancies have different behavior patterns and variably respond to treatment. Lymphomas are classified into two (2) major families: Hodgkin's Lymphomas (HL) and Non-Hodgkin's Lymphomas (NHL). Lymphomas, in general, originate in lymphoid tissues and can matastasize to other tissues. NHL is less predictable and has a greater tendency to disseminate into extranodal sites. Relevant prognostic factors for NHL and HL include histologic subtype, stage, and response to treatment.

 

            NHLs are divided into two (2) distinct prognostic groups. Indolent NHL is defined by a relatively good prognosis, and a median survival of approximately ten (10) years. The morphology of most indolent NHLs is nodular or follicular. Divergent histology of both indolent and aggressive disease can increase the rate of relapse and have an adverse affect on the patient's outcome.

 

            Aggressive NHL is the second prognostic group. The overall survival rate is five (5) years for roughly 50% to 60% of these patients. Aggressive forms of NHL require intensive treatment and are seen in increasing numbers in HIV-positive patients.

 

            Lymphomas are classified according to a number of different schemes. These schemes are often based on histology, cell surface markers, cytogenetics, and gene rearrangement analysis. These factors generally influence the diagnosis of, prognosis for, and treatment of the patient. Lymph node biopsies are recommended whenever possible because needle biopsies are sometimes insufficient to identify the histologic type. The two (2) most commonly used schemes for lymphoma classification are the REAL (Revised European American Lymphoma) Classification and the ILSG (International Lymphoma Study Group) Classification. The following tables outline these classification schemes.

 

TABLE I: REAL CLASSIFICATION SCHEME (Cannellos, et al., 1998)

 

B-Cell Neoplasms

 

Precursor B-Cell Neoplasm

            Precursor B-Lymphoblastic Leukemia/Lymphoma

Peripheral B-Cell Neoplasms

1.                  B-Cell Chronic Lymphocytic Lymphoma (CLL)/Prolymphocytic

Lymphoma (PLL)/Small Cell Lymphocytic Lymphoma (SLL)

2.                  Lymphoplasmacytoid Lymphoma/Immunocytoma

3.                  Mantle Cell Lymphoma

4.                  Follicle Center Lymphoma, Follicular

Provisional cytologic grades: I(small), II(mixed), III (large)

Provisional subtype: diffuse, predominantly small cell

5.                  Marginal Zone B-Cell Lymphoma

Extranodal (MALT + monocytoid B Cells)

6.                  Provisional Entity: Splenic Marginal Zone Lymphoma

7.                  Hairy Cell Leukemia

8.                  Plasmacytoma/Myeloma

9.                  Diffuse Large B-Cell Lymphoma

10.             Burkitt's Lymphoma

11.             Provisional Entity: High-Grade B-Cell Lymphoma, Burkitt's-like

 

T-Cell and Putative NK (Natural Killer)-Cell Neoplasms

 

Precursor T-Cell Neoplasm

            Precursor T-Lymphoblastic Leukemia/Lymphoma

Precursor T-Cell and NK-Cell Neoplasms

1.                  T-Cell CLL/PLL

2.                  Large Granular Lymphocytic Leukemia

3.                  Mycosis Fungoides/Sézary's Syndrome

4.                  Peripheral T-Cell Lymphoma, Unspecified

Provisional categories: medium, mixed, large, lymphoepitheliod

Provisional subtypes: hepatosplenic gdT-Cell Lymphoma

             Subcutaneous panniculitic T-Cell Lymphoma

5.                  Adult T-Cell Lymphoma/Leukemia

6.                  Angioimmunoblastic T-Cell Lymphoma

7.                  Angiocentric Lymphoma/Nasal T/NK-Cell Lymphoma

8.                  Intestinal T-Cell Lymphoma (+ enteropathy)

9.                  Anaplastic Large Cell Lymphoma (T/Null)

10.             Provisional: Anaplastic Large Cell Lymphoma (ALCL) Hodgkin's-Like

 

Hodgkin's Disease

 

1.                  Lymphocyte Predominance (nodular + diffuse)

2.                  Nodular Sclerosis

3.                  Mixed Cellularity

4.                  Lymphocyte Depletion

5.                  Lymphocyte-rich Classic HD (provisional subtype)

 

TABLE II: ILSG CLASSIFICATION SCHEME (Cannellos, et al., 1998)

 

I.                    Indolent Lymphomas and Lymphoid Leukemias

 

B-Cell

            B-CLL/SLL

            Lymphoplasmacytoid lymphoma

            Follicle center lymphoma, follicular (small and mixed)

            Marginal zone B-Cell lymphoma

            Hairy cell leukemia

            Plasmacytoma/myeloma

T-Cell

            Large granular lymphocyte leukemia

            ATL/L (smoldering)

            Mycosis fungoides/Sézary's Syndrome

 

II.                  Moderately Aggressive Lymphomas and Lymphoid Leukemias

 

B-Cell

            B-PLL

            Mantle cell lymphoma

            Follicle center lymphoma (follicular large cell)

T-Cell

            T-CLL/PLL

            ATL/L (chronic)

            Angiocentric lymphoma

            Angioimmunoblastic lymphoma

 

III.                Aggressive Lymphoma

 

B-Cell

            Large B-Cell lymphoma

T-Cell

            Peripheral T-Cell lymphomas

            Intestinal T-Cell lymphomas

            Anaplastic large cell lymphoma

 

IV.               Highly Aggressive Lymphomas and Lymphoid Leukemias

 

B-Cell

            Precursor B-lymphoblastic leukemia (B-LBL)/lymphoma

            Burkitt's lymphoma

            High-grade B-Cell lymphoma, Burkitt's-like

T-Cell

            Precursor T-lymphoblastic leukemia (T-LBL)/lymphoma

            Adult T-Cell leukemia/lymphoma (ATL/L) (acute and lymphomatous)

 

            The Ann Arbor staging system is commonly used for patients with NHL. In this system, stages I, II, III, and IV adult NHL can be subclassified into A and B categories: B for those with well-defined generalized symptoms and A for those without. The B designation is given to patients with any of the following symptoms:

 

            -unexplained loss of more than 10% of body weight in the 6 months

before diagnosis

-unexplained fever with temperatures above 38°C

-drenching night sweats

 

Stage I NHL means involvement of a single lymph node region or localized involvement of a single extra-lymphatic organ or site. Stage II means involvement of two (2) or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extra-lymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm. The number of lymph node regions may be indicated by a subscript (e.g., II3). Stage III NHL means involvement of lymph node regions on both sides of the diaphragm that may also be accompanied by localized involvement of an extra-lymphatic organ or site, by involvement of the spleen, or both. Stage IV NHL means disseminated (multi-focal) involvement of one or more extra-lymphatic sites with or without associated lymph node involvement or isolated extra-lymphatic organ involvement with distant (non-regional) nodal involvement. Current clinical practice assigns a clinical stage based on the findings made as a result of invasive procedures beyond the initial biopsy (i.e., bone marrow aspiration/biopsy, liver biopsy). (Cancernet, 1999)

 

            Pathologic and clinical staging relies on a number of laboratory analyses. Many of these analyses overlap with chronic and acute lymphocytic leukemias. The following tables outline possible results for the four most commonly used diagnositc tests, and associates these results with the clinical symptoms and disease pheontype.

 

 


ACUTE LYMPHOCYTIC LEUKEMIAS

 

PHENOTYPE

CLINICAL SYMPTOMS

MORPHOLOGY

CELL SURFACE MARKERS

CYTOGENETICS

GENES INVOLVED

OTHER NOTES

Null Cell

Fatigue, malaise, listlessness, fever, hemorrhage, bone pain, moderate lymphadenopathy, splenomegaly, hepatomegaly, petechiae, ecchymosis, ~5% CNS involvement, ~1% testicular involvement

 

-SIg

-CIg

+/-B4 (CD19)

-T antigen (CD34)

-CALLA (CD10)

 

 

33% Adults

5% Children

Common (non-B, non-T)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Same as for Null Cell

L1-predominantly small blasts; homogeneous nuclear chromatin; regular, round, occasionally clefted nuclei; inconspicuous nucleoli; scant cytoplasm; no cytoplasmic vacuolization

OR

L2-large heterogeneous cells; heterogeneous nuclear chromatin; irregular, clefted nuclei; one or more large nucleoli; variable, moderately abundant cytoplasm; variable cytoplasmic vacuolization

-SIg

-CIg

+B4 (CD19)

-T antigen (CD34)

+CALLA (CD10)

+TdT

+Ia

Normal

t(4;11)(q21;q23)

del (6q)

i(6p)

+8

del(9p)

t(9;22)(q34;q11)

t(11;19)(q23;p13)

t/del(12p)

 

AF4;MLL

 

 

 

 

ABL;BCR

MLL;ENL

-45% Adults

-68% Children

-11q23 rearrangements are most common

-del(6q) most common secondary change

-t(11;19) denotes a worse prognosis

-t(9;22) can also denote a worse prognosis

T-Cell

Same as for Null Cell

Same as for Common (non-B, non-T Cell)

-SIg

-CIg

-B4 (CD19)

+T antigen (CD34)

+/-CALLA (CD10)

+TdT

Normal

t(1;7)(p32;q34)

t(1;7)(p34;q34)

t(1;11)(p32;q23)

t(1;14)(p32-34;q11)

t(4;11)(q21;q23)

del(6q)

i(6p)

t(7;9)(q34-36;q34)

t(7;9)(q34;q32)

t(7;10)(q34-36;q24)

t(7;11)(q34-36;p13)

t(7;14)(p15;q32)

t(7;19)(q34;p13)

+8

t(8;14)(q24;q11)

del(9p)

t(9;22)(q34;q11)

t(10;11)(p13-14;q14-21)

t(10;14)(q24;q11)

t(11;14)(p15;q11)

t(11;14)(p13;q11)

t(11;19)(q23;p13)

t/del(12p)

 

TAL1;TCRB

LCK;TCRB

AF1P;MLL

TAL1;TCRD

AF4;MLL

 

 

TCRB;TAN1

TCRB;TAL2

TCRB;HOX11

TCRB;RHOM2

 

TCRB;LYL1

 

MYC;TCRA/TCRD

 

ABL;BCR

 

HOX11;TCRD

RBTN1;TCRD

RBTN2;TCRD

MLL;ENL

 

-20% Adults

-10% Children

-t(4;11)(q21;q23), other 11q23 rearrangements, and t(8;14)(q24;q11) are most commonly seen

-t(11;14)(p13-15;q11) accounts for 5% to 10% of abnormalities

-t(11;19)(q23;p13) and t(9;22)(q34;q11) denotes a worse prognosis

-del(6q) is the most common secondary change

Pre-B Cell

 

 

 

 

 

 

 

Pre-B Cell

Same as for Null Cell

Same as for Common (non-B, non-T cell)

-SIg

+CIg

+B4 (CD19)

-T antigen (CD34)

+CALLA (CD10)

+TdT

+Ia

t(1;19)(q23;p13)

dup(1)(q12-21;q31-32)

dic(7;9)(p11-13;p11)

i(7q)

+/dic(9;12)(p11-12;p11-13)

i(9q)

t(17;19)(q22;p13)

PBX1;E2A

 

 

 

 

 

HLF;E2A

-?% Adults

-15% Children

-t(1;19) most common for this type of ALL

B-Cell

Same as for Null Cell

L3-large homogeneous cells; stippled, homogeneous nuclear chromatin; regular, round to ovoid nuclear shape; one or more prominent nucleoli; moderately abundant cytoplasm; prominent cytoplasmic vacuolation

+SIg

+CIg

+B4 (CD19)

-T antigen (CD34)

+CALLA (CD10)

-TdT

+Ia

dup(1)(q12-21;q31-32)

t(2;8)(p12;q24)

t(4;11)(q21;q23)

del(6q)

i(6p)

+8

t(8;14)(q24;q32)

t(8;22)(q24;q11)

del(9p)

t/dic(9;12)(p11-12;p11-13)

t(9;22)(q34;q11)

t(11;19)(q23;p13)

t(12;17)(p13;q21)

t/del(12p)

t(14;18)(q32;q21)

t(14;22)(q32;q11)

i(17q)

-21

+21

 

IGK;MYC

AF4;MLL

 

 

 

MYC;IGH

MYC;IGL

 

 

ABL;BCR

MLL;ENL

 

 

IGH;BCL2

?;BCR

-2% Adults

-2% Children

-t(4;11), t(8;14), & t(14;18) are most common rearrangements

-must be differentiated from

B-cell lymphomas such as Burkitt's and Follicular

 

SPECIAL FOOTNOTES:            Most common between the ages of 2 to 10 years (27 cases/ 1 million children)

                                                Secondary rise after age 40 (AML is more common than ALL)

                                                Normal chromosomes may denote the best prognosis

                                                WBC<10,000 = poor prognosis/ WBC 10-15,000 = good prognosis/ WBC>50,000 = intermediate prognosis

                                                Down's Syndrome have greater risk for ALL

                                                t(9;22)(q34;q11) is most common translocation seen in all ALL's (p.201, Heim & Mitelman)

                                                Numerical aberrations are present in half of all ALL's

                                                 -10% hypodiploid (80% with 45 chromosomes)

                                                 -?% moderate hyperdiploid (47-50 chromosomes)

-15% massive hyperdiploidy (>50 chromosomes); often associated with Pre-B-Cell ALL and better prognosis

More details concerning prognosis can be found in Table 2, p. 217, Heim & Mitelman

 

 


CHRONIC LYMPHOCYTIC LEUKEMIAS

 

PHENOTYPE

CLINICAL SYMPTOMS

MORPHOLOGY

CELL SURFACE MARKERS

CYTOGENETICS

MOLECULAR GENETICS

OTHER NOTES

T-cell CLL, helper

(2%-5% of all CLL cases)

<40 years of age; 15 mo. survival; very aggressive lymphadeno-pathy; skin, diffuse bone marrow, & CNS involvement; hepato-splenomegaly

Leukemic cells are small w/agranular cytoplasm & irregular nuclei without nucleoli

 

inv(14)(q11q32)

t(14;14)(q11;q32)

del/t(14)(q11)

TCRA, TCRD, TCL1, MTCP1, TCRG, TCRB

 

T-cell CLL, suppressor

severe neutropenia, moderate lymphocytosis, mild anemia, splenomegaly, little to no lymphadeno-pathy, rheumatoid arthritis or other autoimmune disease, more commonly found in adults, is associated w/HTLV-1

large granular lymphocytes w/round to irregular nuclei, chromatin is condensed, & cytoplasm has prominent variably-sized red granules

 

14q+/other rearrangements

t(14;14)(q11;q32)

inv(14)(q11q32)

del(14)(q11q13)

6q-

rearrangements of 1p, 1q, 3q, 5p, 5q, 9q, 10p, 10q, 11q, 12q, 18q, & 4

trisomies 3, 7, & 21

loss of sex chromosomes

TCRD, TCRA, TCL1

rearrangements of 14q are found in >20%

Prolymphocytic Leukemia

(75%-80% B-cell)

(20%-25% T-cell)

 

 

 

 

 

 

 

 

Prolymphocytic Leukemia

(75%-80% B-cell)

(20%-25% T-cell)

marked splenomegaly, minimal lymphadeno-pathy, marked leukocytosis, thrombocyto-penia, T-cell - skin involvement

predominantly prolymphs w/large amounts of cytoplasm; coarse nuclear chromatin w/single prominent nucleolus; T-prolymphs stain positive w/acid phosphatase & nonspecific esterase in a focal pattern

T-cell

TdT-

B-PLL

14q+(14q32)

t(11;14)(q13;q32)

t(14;17)(q32;q11)

t(6;12)(q15;p13)

+12

del(1)(q32)

del(6)(q21)

 

T-PLL

inv(14)(q11q32)

14q+/other rearrangements

del/t(7)(q34-q36)

i(8q)

B-PLL

BCL1(PRAD1);

IGH

 

T-PLL

TCRA, TCRB

B-PLL

14q+(14q32) - 50%

del(1)(q32) - 20% secondary

del(6)(q21) -

10 % secondary

worse prognosis, usually B-cell in origin

 

T-PLL

median survival <1 year

Hairy Cell Leukemia

splenomegaly, minimal lymphadeno-pathy, cytopenia, often dry tap as aspirate, bone marrow core biopsy more useful, mainly found in middle-aged men (20% female)

atypical lymphocytes (B-cell origin); ground-glass, spongy nuclear chromatin; light blue-gray cytoplasm (abundant) w/characteristic "hairy" projections; nuclei may be ovoid, clefted, or sometimes convoluted; TRAP positive; non-specific esterase moderately positive in crescent-like fashion; S100 positive cytoplasm

 

 

 

Strong Ig (IgM & D-)

pan B+

CD5-

CD10-

CD11c+-(strong)

CD25+-(strong)

CD103+

TRAP+

Normal

14q+ rearrangements

+5

rearrangements of 2, 5, & 1q42

6q-

del(14)(q22q32)

 

Normal karyotype is most common; 14q+ rearrangements present in 1/5 of cases;

6q- is most common secondary aberration;

difficult to stimulate into mitotic activity - B-cell mitogen stimulation suggested;

most frequently misdiagnosed as CLL or some other process; interferon & deoxyformycin showing treatment promise

Lymphosarcoma Cell Leukemia

 

involvement of peripheral blood by lymphoma cells; WBC not greater than 25x103/mL; generally falls under category of NHL

depends on the type of lymphoma

depends on the type of lymphoma

depends on the type of lymphoma

depends on the type of lymphoma

depends on the type of lymphoma

SÁzary's Syndrome

 

 

Sézary's Syndrome

skin involvement; blood variant of mycosis fungoides; HIV-related lymphoma; lymphadenopathy denotes poorer prognosis; LN3 & LN4 grades have a significantly worse prognosis

medium-sized lymphs w/moderate to scant cytoplasm & cerebriform nuclei; >15% in peripheral blood representative of malignant cells; acid phosphatase & non-specific esterase positive in dot-like fashion; inconspicuous nucleoli

 

del/t(2p)

del(6q)

14q+

hsr(17q)

 

 

Mycosis fungoides

same as SÁzary's Syndrome; skin involvement only

same as SÁzary's Syndrome

S100+

CD1a+

CD7-

CD15+

Leu-8-

del(6q)

14q+

 

 

Cutaneous T-Cell Lymphoma

same as SÁzary's Syndrome

same as SÁzary's Syndrome

 

t(2p)

del(6q)

 

 

Adult T-Cell Leukemia/Lym-phoma

 

Adult T-Cell Leukemia/Lym-phoma

malignant T-lymphs in lymph nodes, skin, spleen & peripheral blood; HTLV-1 transmitted; hypercalcemia

scant cytoplasm; lobated nucleus w/clumped chromatin

TdT-

T6-

del(6q)

chromosome 7 rearrangements

14q+

14q11 rearrangements

 

responds poorly to therapy

B-Cell CLL

 

 

 

 

 

 

 

 

 

 

B-Cell CLL

 

follicular, mantle cell, B-lineage

Faint sIgM(D)+

CD19+

CD20+

CD5+

CD23+

+12

14q+(14q32)

del/t(13q)

del(6q)

+3

11q-

12p-

14q-

+18

+12

t(5;12)(q21-22;q23-24)

IGH;BCL1

PRAD1, BCL2, BCL3, DBM

+12 found in 1/3 all abnormal cases; 14q+/- most common secondary aberrations; +12 next most common secondary aberration; t(5;12) seen in acute transformation, also known as Richter's syndrome; t(11;14)(q13;q32) is most common 14q rearrangement; t(14;18)(q32;q21) is 2nd most common 14q rearrangement; t(2;14)(p13;q32) is a rare form found in children

Waldenstrom's Macroglobuli-nemia

 

 

 

 

 

 

IgM monoclonal spike on serum protein electrophoresis; 60 to 70 years of age; indolent w/long survival; normal WBC; lymphadeno-pathy, hepato-splenomegaly; bone lesions are infrequent; de-creased platelet aggregation

 

 

Inconclusive numerical changes

del(3)(p25)

i(6p)

t(8;14)(q24;q32)

t(14;18)(q32;q21)

may have other cytogenetically unrelated clones

 

 

Multiple Myeloma

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Multiple Myeloma

monoclonal proliferation of plasma cells; discrete tumor nodules formed in bone marrow; clinical manifestations depend on extent of lytic bone destruction; impairment of normal marrow function; inpaired renal function; increased susceptibility to infection

 

10%-15% only light chains excreted

chromosome 1 rearrangements

14q+

hypodiploid cells

pseudodiploid cells

hyperdiploid cells

17p+

del/t(22)(q11)

6q-

del(7q)

der(1;7)(q10;p10)

del(5)(q13q31)

most common numerical aberrations include 3, 7, 9, 11 & 13

have been seen but are not definitive t(11;14)(q13;q32)

t(1;20)(q12;p13)

dup(1)(q21q32)

t(1;20)(q21;q11)

inv(1)(p36q21)

t(1;10)(p36;p13)

 

majority of mitotic cells in culture are normal marrow due to low plasma cell turnover; have to analyze a large number of metaphases; AML can occur secondary to treatment for multiple myeloma

Plasma Cell Leukemia

 

very aggressive, rapidly proliferative; plasma cells infiltrating the bone marrow; transformation of multiple myeloma to PCL has been reported and re-lationship between the 2 is unresolved

 

 

Chromosome 1 rearrangements

14q+

del(6q)

hypodiploid

hyperdiploid

t(11;14)(q13;q32)

t(8;14)(q24;q32)

del(1)(q32)

monosomy 18

t(9;22)(q34;q11)

 

 

 

Rai's Staging

 

Stage 0 - Absolute lymphocytosis of >15x109/L & 40% or more lymphocytes in bone marrow

Stage 1 - Absolute lymphocytosis plus enlarged lymph nodes

Stage 2 - Absolute lymphocytosis plus enlarged liver and/or spleen; lymphadenopathy may or may not be present

Stage 3 - Absolute lymphocytosis plus anemia (Hgb<110g/L or Hct<0.33%); lymph nodes, spleen, or liver may or may not be enlarged

Stage 4 - Absolute lymphocytosis & thrombocytopenia (plt,100x109/L); anemia & organomegaly may or may not be present

 

General Notes

 

Normal karyotypes have a better prognosis than those with clonal aberration (15 years vs. 7.7 years).

A higher proportion of abnormal metaphases in mixed normal/abnormal karyotypes have a poorer prognosis.

The more complex the karyotype, the worse the prognosis.

+12 as the sole anomaly has an unfavorable prognosis.

14q+ markers have a poorer prognosis than those w/ 6q- and 13q abnormalities.

TP53, patients who have had a mutation to this gene, generally have more aggressive disease/>resistance to chemotherapy.

 

 

MALIGNANT LYMPHOMAS

 

PHENOTYPE

CLINICAL SYMPTOMS

MORPHOLOGY

CELL SURFACE MARKERS

CYTO-GENETICS

GENES INVOLVED

OTHER NOTES

Follicular Lymphoma

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Follicular Lymphoma (continued)

Enlarged, usually painless lymph nodes or abdominal mass; fever, weight loss, and anorexia; symptoms secondary to vital organ compression; gastrointestinal involvement less common; peak incidence 50 to 60 years of age; Stage III or IV disease at diagnosis; ~10% have circulating malignant cells

Heterogeneous cytologic composition is hallmark; (1) small cleaved cell most common, <25% large cells present, bone marrow and liver involvement common; (2) large cell, > 50% large cells present, poorer prognosis, prone to progression, uncommon to find bone marrow and liver involvment; (3) mixed small and large cell, 25-50% large cells

Sig+

Cig+

CD19+

CD20+ (Brighter than 19)

CD22+

CD10+

CD5-

IIc-

23+

43-

BCL2+

 

t(2;3)(p12;q27)

t(2;18)(p12;q21)

t(3;14)(q27;a32)

t(3;22)(q27;q11)

t(14;18)(q32;q21)

t(18;22)(q21;q11)

follicular small cleaved cell - ~25% have a normal karyotype

 

IGK;LAZ3

IGK;FVT1

LAZ3;IGH

LAZ3;IGL

IGH;BCL2

BCL2;IGL

· generally good prognosis

·commonly found in US and

Western Europe

·accounts ~50% of all NHLs

·rarely seen in those < 35 years of age

·equal frequency in both sexes

·most common of all NHLs seen in US

·less common in African-American and Asian populations

·t(14;18) most common cytogenetic aberration

·-/del(6q), +/dup(7),

+/dup(12), +3, +18, or +21 can denote progression

·a rare but clearly super-imposed t(8;14) on t(14;18)

+MYC rearrangement

could be lethal

·~10% of FCLs are predominantly large cell, have more aggressive natural history, but if caught in Stage I disease, this subtype has seen some long

term complete remissions but usually indolent and incurable by today's

therapeutic modalities

·? genetic predisposition

·transformation to a higher grade associated with mutations of p53 gene

Small Lymphocytic Lymphoma

Same as for Follicular with the exception of gastrointestinal involvement and presence of mediastinal mass; occurs in both young and old; twice as common in men; splenic marginal zone more common in men than women and more common in adults

diffuse infiltration of lymph node; small norma-appearing lymphs; histology indistinguishable from CLL; differentiated from Hodgkin's by Reed-Sternberg cells and monoclonality for B-cells

>90% monoclonal

B-cell

FaintIg (IgM+, D+)

CD19>20

CD5+

10-

BCL-3+

IIc+

23+

43+

splenic small cell is CD5-

t(9;14)(p13;q32)

del(11q)

t(11;14)(q13;q32)

 

t(11;18)(q21;q21)

+12

?;IGH

 

BCL1/PRAD1;IGH

 

 

Intermediate Lymphocytic Leukemia

Intermediate Lymphocytic Leukemia (continued)

65 years median age and is closely related to small lymphocytic leukemia

cross between small lymphocytic and small cleaved cell; featuring diffuse proliferation of small lymphs having slightly irregular or indented nuclei

usually monoclonal B-cell

1p & 1q rearrangements

+3

3q rearrangements

del(6q)

+7

9q rearrangements

t(10;14)(q24;q32)

t(9;14)(p13;q32)

del(11q)

t(11;14)(q13;q32)

 

t(11;18)(q21;q21)

+12

del(14q)

14q32 rearrangements

+18

-X/+X/-Y

 

 

 

 

 

 

 

 

 

LYT10;IGH

?;IGH

 

BCL1/PRAD1;IGH

 

 

 

 

IGH

not commonly represented in most classification schemes

Mantle Zone Lymphoma

 

 

 

 

 

 

 

 

 

 

Mantle Zone Lymphoma (continued)

Follicular variant of intermediate lymphocytic lymphoma; predilection for GI tract; high male to female ratio; lymph node, spleen, bone marrow and Waldeyer's ring involvement; intermediate grade Stage III or IV disease

slightly larger than normal lymph, finely clumped chromatin, scant cytoplasm, and inconspicuous nucleoli, irregular or cleaved nuclei; small atypical lymphoid cells that appear as wide mantles around small benign appearing germinal centers; can be misdiagnosed as benign lymph hyperplasia; must be differentiated from lymphomatous polyposis; 25% large nuclei, dispersed chromatin, and higher proliferation factor; epithelioid histiocytes

CD5+

cyclin D1+

Strong Ig

pan B+

10-

IIc

23-

43+

BCL2+

t(2;3)(p12;q27)

t(2;18)(p12;q21)

t(3;14)(q27;q32)

t(3;22)(q27;q11)

t(14;18)(q32;q21)

t(18;22)(q21;q11)

t(11;14)(q13;q32)

may also see cytogenetic aberrations listed in lymphocytic lymphoma

IGK;LAZ3

IGK;FVT1

LAZ3;IGH

LAZ3;IGL

IGH;BCL2

BCL2;IGL

·t(11;14)(q13;q32) most common

·3 to 5 year survival rate

·PRAD1 over expression

·most common in Southern Europe

·does not respond well with available treatments

Diffuse Small Cleaved Cell Lymphoma

almost never seen in children and is rare in adults

 

Ki67+

HLA-DR+

CD38+

PanB-

Ig-

CAM markers -

1p & 1q rearrangements

+3

3q rearrangements

del(6q)

+7

9q rearrangements

t(10;14)(q24;q32)

del(14q)

14q32 rearrangements

+18

-X/+X/-Y

 

 

 

 

 

 

 

 

 

 

LYT10;IGH

 

 

IGH

frequently originates in B-Cell but can be T-Cell

Diffuse, Mixed Small and Large Cell Lymphoma

primarily seen in adults and rarely seen in children

mixture of small cleaved and large lymphocytes

Possibility of seeing both markers of small and large cell origin

1p & 1q rearrangements

t(2;3)(p12;q27)

+3

3q rearrangements

t(3;14)(q27;q23)

t(3;22)(q27;q11)

del(6q)

+7

9q rearrangements

t(9;14)(p13;q32)

t(10;14)(q24;q32)

del(11q)

t(11;14)(q13;q32)

 

t(11;18)(q21;q21)

+12

del(14q)

14q32 rearrangements

t(14;18)(q32;q21)

+18

-X/+X/-Y

 

 

IGK;LAZ3

 

 

 

LAZ3;IGH

LAZ3;IGL

 

 

 

 

?;IGH

LYT10;IGH

 

BCL1;PRAD1;IGH

 

 

 

 

IGH

IGH;BCL2

 

Diffuse Large Cell Lymphomas

 

 

Diffuse Large Cell Lymphomas (continued)

localized disease more frequent in extranodal sites (i.e., nasopharynx, GI tract, skin, soft tissues, bone, lungs & mediastinum); peripheral blood involvement rare; generally produces large, irregular often destructive tumors in the liver and spleen; may bear close resemblance to metastatic carcinoma; cytochemistry , immunologic cell markers, and electron microscopy can be used to differentiate

proliferation of large mononuclear cells with large nuclei, vesicular chromatin, prominent nucleoli, basophilic cytoplasm, and a moderate to high proliferation fraction; marked variation in nuclear contours may be seen

CD19+

CD20+

CD22+

CD79a+

HLA-DR+

SIg-

CIg+

CD25+

PanB-

PanT-

CD30+

CD45-

t(2;3)(p12;q27)

t(3;14)(q27:q23)

t(3;22)(q27;q11)

+12

t(14;18)(q32;q21)

IGK;LAZ3

LAZ3;IGH

LAZ3;IGL

 

IGH;BCL2

·approximately 30% of diffuse aggressive NHLs

·associated with sclerosis

·65%-70% B-Cell

·10%-15% T-Cell

·immunologic phenotyping has not been successful in predicting survival difference

·large cleaved or large non-cleaved follicular center cells may have a slightly better prognosis

·responds well to therapy with long-term disease-free survival

Small, Non-cleaved ("undifferen-tiated") Lymphomas, Burkitt's Type

 

 

 

Small, Non-cleaved ("undifferen-tiated") Lymphomas, Burkitt's Type (continued)

maxillomandibular lesion - Africans; abdominal mass in non-Africans, especially in ileocecal region, retroperitineum, ovaries, kidneys, and breasts; leukemic phase is unusual; seen more commonly in children than adults, and most commonly presents as an abdominal obstruction

cells uniform in size and shape; cell nuclei are larger than small lymphocytic lymphoma or CLL, but smaller than large cell lymphoma; nuclei of "starry sky" macrophages; moderately abundant cytoplasm with lipid laden vacuoles; PAS negative; methyl green pyronine positive

TdT+

PanB+

CD10+

monoclonal Ig

l>k, M>G

CD18-

CD54-

CIgM+

Ki67+

t(2;8)(p12;q24)

t(8;14)(q24;q32)

t(8;22)(q24;q11)

IGK;MYC

MYC;IGH

MYC;IGL

 

C-MYC

·t(8;14) and t(8;22) are most the common cytogenetic aberrations

·EBV, malaria, immunodeficiency, C-MYC aberrations are endemic vs. sporadic in North America pathogenesis appears similar to HIV

·~20% have 5 year survival rate

·B-Cell in origin

·~33% pediatric lymphomas in US

·Bone marrow involvement is a poor prognostic sign

·more commonly associated with HIV

Small, Non-cleaved ("undifferen-tiated") Lymphomas, Non-Burkitt's Type

Usually present in adults

same as for Burkitt's with exception of cell nuclei vary in size and shape and lacks the monotonous cytology of Burkitt's

shares more similarities with large cell than with Burkitt's

shares more similarities with large cell than with Burkitt's

may lack C-MYC and have BCL2

·not commonly differentiated from Burkitt's in most schemes

·5 year survival rate for 35% to 40% in large cell and small non-cleaved, high growth fraction

·can have an aggressive clinical course

Lymphoblastic Lymphoma

 

 

 

 

 

 

 

 

 

 

Lymphoblastic Lymphoma (continued)

most frequently seen in children, but can occur in adults; mediastinal tumors present in ~50% to 80%; disease spreads rapidly involving bone marrow, peripheral blood and CNS; increase male to female ratio

mitotic figures are readily observed; cells stain weakly positive/negative with methyl green pyronine; uniform population of cells similar to ALL; nuclei may be convoluted or non-convoluted; fine chromatin pattern; high mitotic rate present; "starry sky" pattern in ~33% of cases

TdT+

 

B-Cell

CD10+

CD34+

CD19+

CD20-

CD22-

CD45-

 

T-Cell

CD4+

CD8+

CD10+

HLA-DR-

1p & 1q rearrangements

+3

3q rearrangements

6p rearrangements

+7

9q rearrangements

14q11 rearrangements

del(14q)

+18

-X/+X/-Y

20% to 38% are cytogenetically normal

 

 

 

 

 

 

 

 

 

 

 

 

TCRA/TCRD

·involvement of CNS has poor prognostic sign

·treated differently from other lymphomas so it must be differentiated from small non-cleaved cell and small lymphocytic lymphoma

·high grade lymphoma with rapidly growing mass

Peripheral T-Cell Lymphoma (non-lympho-blastic, T-Cell lymphomas other than Mycosis Fungoides)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Peripheral T-Cell (continued)

Stage III or IV disease involving Waldeyer's ring, skin, liver, and lungs with generalized lymphadenopathy; majority of patients are adults; survival rates are comparable to aggressive B-Cell lymphomas

diffuse mixed small and large cells or large immunoblastic types; may be misdiagnosed as Hodgkin's because of Reed-Sternberg-like cells; admixture of atypical small and medium-sized lymphs; differentiation between this and Hodgkin's may require immunologic markers and gene rearrangement studies; nuclear multilobation; prominent epithelioid histiocyte component; differentiate from angioimmunoblastic lymphadenopathy, as well

mature T-cell phenotype

TdT-

 

Helper cell phenotype

CD5-

CD8-

CD4+

HLA-DR+

1p & 1q rearrangements

+3

3q rearrangements

6p rearrangements

+7

9q rearrrangements

14q11 rearrangements

del(14q)

+18

-X/+X/-Y

 

 

 

 

 

 

 

 

 

 

 

TCRA/TCRD

·associated with HTLV-1

·common in Southwestern Japan and the Carribean

Ki-1 Lymphoma (Anaplastic Large Cell Lymphoma)

children and adults; monoclonal antibody raised against a Hodgkin's disease-derived cell line that reacts with Reed-Sternberg cells and activated lymphoid cells that are of primarily T-Cell origin; peripheral lymphadenopathy; skin lesions; may develop disseminated disease with node involvement

pleomorphic large cell lymphoma; pleomorphic cellular infiltrate; sinus infiltration; fibrosis; partial lymph node involvement; sparing of follicles; and abundance of plasma cell are large with lobated nuclei, nucleoli are present , abundant, amphophilic cytoplasm with distinct borders and have prominent Golgi region; may resemble malignant histiocytes, Hodgkin's disease; nodular sclerosis, or metastatic carcinoma

T-helper phenotype

CD30+ (hallmark)

EMA+(cu-taneous ALCL is negative)

CD45-

Golgi region is strong CD30+ and EMA+

t(2;5)(p23;q35)

Cutaneous ALCL lacks this cytogenetic aberration

ALK;NPM

·associated with a favorable prognosis in children

·ALK;NPM forms detectable fusion product

·unknown epidemiology

·primary cutaneous ALCL associated with lymphomatoid papulosis

MALT (extra-nodal marginal zone B-cell

MALT (extra-nodal marginal zone B-cell lymphoma) (continued)

indolent clinical course; many are asymptomatic; lymphadenopathy, GI Tract, thyroid, breast, skin, lung, salivary and lacrimal glands, orbits, conjuctiva, bladder, kidney, and thymus can be affected; often have a history of an autoimmune disease

+ monocytoid B-Cell; heterogeneous cellular composition, includes centrocyte like all monocytoid B-cells, small lymphs, and plasma cells; reactive germinal centers are always present

Strong Ig+

Pan B+

CD5-

CD10-

IIc+

CD23-

CD43+

t(11;18)(q21;q21)

t(1;14)(?;?)

+3

+7

+12

 

·related to Sjorgen's syndrome and Hashimoto's thyroiditis

·widespread nodal involvement is infrequent and so is bone marrow involvement

·Helicobacter may be associated

·?genetic predisposition

·Seems to be a link to the populace of Feltre, Italy

 

Hodgkin's Lymphoma

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hodgkin's Lymphoma (continued)

fever, night sweats, pruritis, and weight loss; splenomegaly; hepatomegaly; extra-nodal disease unusual; progressive, painless enlargement of one or more lymph nodes in neck; occasional mediastinal mass

neoplastic mononuclear cells; reactive small lymphs; plasma cells; eosinophils; histiocytes; B-cell = germinal center cell proliferation; T-cell = mixed cellularity; Reed- Sternberg cells (a large bi-nucleated or multi-nucleated cell; moderately abundant cytoplasm; clear halo; large, prominent eosinophilic or amphophilic nucleolus)

can be B-cell or T-cell

 

Classic

CD15+

CD30+

CD45-

 

B-Cell Phenotype

CD20+

CD57+

1p & 1q rearrangements

3q rearrangements

del(6q)

7q rearrangements

12p rearrangements

13p rearrangements

14q32 rearrangements

 

 

 

 

 

 

 

 

 

 

 

 

IGH

·incidence - 35 per 1 million for white males and 26 per 1 million for white females; non-whites have a slightly lower incidence

·seen in 15 to 45 year old age group and then again after 50 years of age

 

 


            According to Kjeldsberg and others (1995), " immunoglobulin and T-cell receptor gene rearrangement studies have proven useful in diagnosing various lymphoproliferative disorders, but thus far they have not been as useful in diagnosing acute leukemia. Even so, there are cases in which information provided by gene rearrangement studies contributed directly to the classification of morphologically undifferentiated leukemias/lymphomas. Gene rearrangement studies and polymerase chain reaction (PCR ) are proving to be highly sensitive indicators of minimal residual disease and early relapse." In disagreement with the authors, molecular diagnostic techniques will probably play a major role in the future of diagnosing and treating leukemias and lymphomas.

 

            Case A's patient was definitively diagnosed with follicular lymphoma. This diagnosis could have been made without the cytogenetics confirmation. However, for following and tracking disease progression, cytogenetics can be a very useful tool. Knowing the patient's original clone, one can follow the changes in that clone to determine if the patient's disease has progressed or worsened and adjust therapies as necessary.

 

            Case B's patient had results that were inconclusive by flow cytometry and immunohistochemical staining. The cytogenetic clone was quite complex and the morphology was not the best, a result of direct harvesting of the lymph node cells. Patient B had a common translocation, t(4;11)(q21;q23), found in B Cell Lymphocytic Leukemias. This translocation can have a variable prognosis, but due to the complex nature of the clone, the prognosis for this patient was not as good as one would hope.

 

            To date, neither patient has had further specimens submitted for evaluation, and so nothing more is known concerning their clinical outcomes.

 

REFERENCES

 

            Cannellos, G.P., Lister, T.A., & Sklar, J.L., (1998) The Lymphomas. W.B. Saunders, Philadelphia, PA.

 

            Kjeldsberg, C., Foucar, K., McKenna, R., Perkins, S., Peterson, L., Peterson, P., & Rodgers, G., (1995) Practical Diagnosis of Hematologic Disorders, 2nd Edition. ASCP Press, Chicago, IL.

 

            Heim, S., & Mitelman, F., (1995) Cancer Cytogenetics, 2nd Edition. Wiley-Liss, New York.

 

            Adult Non-Hodgkin's Lymphoma, (1999), http://www.graylab.ac.uk/cancernet/100066.html



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CE Questions:

Note: You must achieve a score of 70% or better to earn PACE credit for this continuing education.

1. What is a common translocation found in Follicular Lymphoma?

2. What are common flow cytometric findings in B Cell Lymphoblastic Lymphoma?

3. What are the morphologic findings in Ki-1 Lymphoma (Anaplastic Large Cell Lymphoma)?

4. MALT may be associated with Helicobacter. True or False?

5. "Starry sky" macrophages and a t(8;14)(q24;q32) are indicative of what type of lymphoma?

6. Peripheral T Cell Lymphoma can be misdiagnosed as Hodgkin's Disease. True or False?

7. What translocation is most commonly seen in Mantle Zone Lymphoma?

8. Which lymphoma is more commonly associated with HIV infection?

9. Which lymphoma has been associated with Sjorgen's Syndrome and Hashimoto's Thyroiditis?

10. Patients with a mutation to this gene generally have a more aggressive disease and greater resistance to chemotherapy?

11. List the symptoms that give a patient the B designation in the Ann Arbor System.

12. Describe Stage I NHL.

13. List 3 moderately aggressive B Cell lymphomas according to the ILSG Classification Scheme.

14. Lymphoma classification schemes are generally based on: ________

15. Central nervous system involvement denotes a good prognosis for the patient. True or False?


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