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,
-10,-10,+11,-11,-11,add(11)(q11),add(11)(p14),
-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)
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.
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
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
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)
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
B-PLL
Mantle cell lymphoma
Follicle center lymphoma (follicular
large cell)
T-Cell
T-CLL/PLL
ATL/L (chronic)
Angiocentric
lymphoma
Angioimmunoblastic
lymphoma
Large B-Cell lymphoma
T-Cell
Peripheral T-Cell lymphomas
Intestinal T-Cell lymphomas
Anaplastic
large cell lymphoma
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
-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 |
t(4;11)(q21;q23) i(6p) +8 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 - -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 |
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) 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) 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 - |
|
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) i(6p) +8 t(8;14)(q24;q32) t(8;22)(q24;q11) 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) 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 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% 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+ |
14q+ rearrangements +5 rearrangements of 2, 5, & 1q42 6q- |
|
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) 14q+ hsr(17q) |
|
|
|
Mycosis fungoides |
same as SÁzary's Syndrome; skin involvement only |
same as SÁzary's Syndrome |
S100+ CD1a+ CD7- CD15+ Leu-8- |
14q+ |
|
|
|
Cutaneous T-Cell Lymphoma |
same as SÁzary's Syndrome |
same as SÁzary's Syndrome |
|
t(2p) |
|
|
|
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- |
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) +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 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- der(1;7)(q10;p10) 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+ hypodiploid hyperdiploid t(11;14)(q13;q32) t(8;14)(q24;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
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.
|
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 ·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 ·-/ +/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) 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 +7 9q rearrangements t(10;14)(q24;q32) t(9;14)(p13;q32) t(11;14)(q13;q32) t(11;18)(q21;q21) +12 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 ·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- |
1p & 1q rearrangements +3 3q rearrangements +7 9q rearrangements t(10;14)(q24;q32) 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) +7 9q rearrangements t(9;14)(p13;q32) t(10;14)(q24;q32) t(11;14)(q13;q32) t(11;18)(q21;q21) +12 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 ·~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-CellCD10+ CD34+ CD19+ CD20- CD22- CD45- T-CellCD4+ CD8+ CD10+ HLA-DR- |
1p & 1q rearrangements +3 3q rearrangements 6p rearrangements +7 9q rearrangements 14q11 rearrangements +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 +18 -X/+X/-Y |
TCRA/TCRD |
·associated with
HTLV-1 ·common in |
|
|
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 |
|
|
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 ClassicCD15+ CD30+ CD45- B-Cell Phenotype CD20+ CD57+ |
1p & 1q rearrangements 3q rearrangements 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,
Kjeldsberg,
C., Foucar, K., McKenna, R., Perkins, S., Peterson,
L., Peterson, P., & Rodgers, G., (1995) Practical
Diagnosis of Hematologic Disorders, 2nd
Edition. ASCP Press,
Heim, S., & Mitelman,
F., (1995) Cancer Cytogenetics,
2nd Edition.
Adult Non-Hodgkin's Lymphoma, (1999),
http://www.graylab.ac.uk/cancernet/100066.html