Lymphoproliferative Disorders Flashcards
malignancies arising from hematologic cells
can occur in any lineage and at any age
hematologic neoplasms
Hematologic neoplasms occur secondary to genetic mutations resulting in:
- arrest maturation
- increase proliferation rate
- prolong survival
- disordered maturation
- dysfunctional effect
Hematologic neoplasms due to genetic mutations can be either inherited or acquired
- hereditary predisposition: germline mutations
- acquired: due to chemotherapy, infections, radiation or toxins
Classification of Hematologic neoplams
- Lineage: myeloid, lymphoid, histiocytic, dendritic
- lineage plasticity: immature or mature
- genetic abnormalities: chromosomal abnormality or genetic mutations
- other: morphologic features, immunophenotyping (flow cytometry)
Leukemia
- malignant proliferation of cells in blood and bone marrow
- myeloid OR lymphoid
- acute or chronic
- mature or immature cells
Examples of Leukemias
- acute myeloid leukemia
- acute lymphoblastic leukemia
- chronic lymphocytic leukemia
- chronic myeloid leukemia
Lymphoma
- malignant proliferation of abnormal lymphoid cells in the lymphoid system (lymph nodes, spleen , etc.)
- lymphoid
- acute or chronic
- mature cells
- peripheral blood OR bone marrow (leukemic phase of lymphoma)
Examples of Lymphomas
- mantle cell lymphoma
- large B-cell lymphoma
- Burkitt lymphoma
lymphoid neoplasms/disorders mainly involve these but can also involve these
lymphoid organs (lymphomas); peripheral blood or BM (leukemia)
Clinical manifestations of B-cell neoplasms
- variable; asymptomatic or symptomatic
- “B symptoms”
- unintentional weight, fever + night sweats
- depending on lymphoma type + tissue involved = enlarged lymph nodes, splenomegaly, GI symptoms, secondary immunodef, bone pains, AIHA, ITP
cytogenetics
- detection of genetic changes (chromosome # + structure) in leukemias and lymphomas
- methods: karyotyping, fluorescent in situ hybridization
B-LPDs (lymphorproliferative disorders)
- chronic lymphocytic leukemia
- hairy cell leukemia
- plasma cell myeloma
- diffuse large B-cell lymphoma
- Burkitt’s lymphoma
- Hodgkin lymphoma
T-LPDs
- T-cell large granular lymphocytic leukemia
- adult T-cell leukemia/lymphoma
- angioimmunoblastic T-cell lymphoma
- mycosis fungoides
- Sezary syndrome
the most common B-cell LPD in western world
Chronic lymphocytic leukemia (CLL)
- incidence increases w/ age; commonly >50 y/o
tissue equivalent of CLL
SLL (small lymphocytic lymphoma)
symptomatic CLL
secondary to autoimmune mechanism anemia (AIHA), thrombocytopenia (ITP), secondary immune deficiency
- asymptomatic = accidentally discovered on routine CBCD
CLL morphologic findings
- monomorphic small mature lymphocytes (HAS TO BE >5.0x10^9/L)
- soccer ball or earth-cracked nuclei
- smudge cells (fragile CLL cells, spherpcytes and thrombocytopenia
- in BM: nodular or interstitial or diffuse
- may transform to prolymphocytic leukemia
- Richter’s transformation
Richter’s transformation
a rare complication of Chronic Lymphocytic Leukaemia (CLL) and/or Small Lymphocytic Lymphoma (SLL). It is characterized by the sudden transformation of the CLL/SLL into a significantly more aggressive form of large cell lymphoma
CLL/SLL immunophenotyping
- monoclonal (kappa or lambda), dim expression
- positive for CD19, 23, and CD20 (dim)
- positive expression of CD200
CLL/SLL cytogenetic abnormalities
- 13q14 del
- Trisomy 12
Monoclonal B-cell lymphocytosis (MBL)
- <5x10^9/L in PB
- CLL-like immunophenotype or non-CLL phenotype
- may progress to CLL (all CLLs are preceded by MB: but not all MBL progress to CLL)
- extensive workup needed to rule out SLL or other lymphoproliferative disorder
hairy cell leukemia (HCL)
- b-cell lineage; mature
- rare (2% of lymphomas)
- rare in blood; mainly BM (fibrosis) and spleen (marked splenomegaly)
- clinical presentation: weakness, fatigue, ab pain, early satiety, fever, bleeding, infections
HCL diagnosis PB
- pancytopenia with monocytopenia + hairy cells
round to oval nuclei, mature chromatin, characteristic hair-like cytoplasmic projections
hairy cells
HCL diagnosis BM
- increase fibrosis (difficult to aspirate (dry tap)
- diffuse infiltration with widely spaced cells (fried egg appearance)
HCL molecular mutation
BRAF V600F present in 100% of cases
this is uniquely sensitive to interferon alpha and purine analogues (complete and durable remission)
HCL
HCL IHC stains for diagnosis
cyclin D1 and annexin A1
HCL immunophenotype by flow
- B-cell markersL Cd20, Cd19, Cd22
- Clona bright expression (kappa or lambda)
- unique: CD11c++, CD103++, CD25++, CD200+
TRAP stain in hairy cells
- tartrate resistant acid phosphatase
- hairy cells = isoenzyme
- most cells take up acid phosphatase but when tartrate is added hairy cells remain stained while staining in other cells fade
HCL-v
exhibit variant cytological and hematological features
- increase WBC; monocytes
- no dry tap
- less/absent shaggy contours or hairy projections, prominent nucleoli
- lack CD25, CD123, and annexin A1 expression
- no BRAF V600F mutation!
HCL-v
exhibit variant cytological and hematological features
- increase WBC; monocytes
- no dry tap
- less/absent shaggy contours or hairy projections, prominent nucleoli
- lack CD25, CD123, and annexin A1 expression
- no BRAF V600F mutation!
Plasma Cell Myelomas/Neoplasms (PCM/PCN)
- B-LPD; mature
- plasma B cells
- affect elderly indivs (>70; more in males)
- expansion of clonal plasma cells = secrete a monoclonal M-protein which increase immunoglobulins and total protein
disease spectrum of plasma cell myelomas
- monoclonal gammopathy of undetermined significance (MGUS)
- smoldering asymptomatic myeloma
- multiple myeloma/plasma cell myeloma
- plasma cell leukemia
- plasmacytoma
- primary amyloidosis
Plasma cell myeloma diagnosis
- PB: Rouleaux, anemia
- BM: increased plasma cells
- M peak on protein electrophoresis (serum and maybe urine)
- increased/decreased free kappa/lambda ratio
- CRAB (hypercalcemia, renal failure, anemia, lytic bone lesions)
- bright CD38 + CD138; loss of CD19; aberrant CD56
- CD45 dim or neg
- 17 p deletion
- t(11;14)
- t(4;14)
diffuse large b-cell lymphoma (DLBCL)
- b-cell neoplas of large mtature B-cells (>2x size of normal lymphocytes in diffuse pattern
- aggressive!!!
- high mitotic activity
- heterogenous both clinically and morphologically
- may arise de novo or transformed from low grade symptoms
DLBCL presentation
- B symptoms (common)
- usually rapidly enlarging tumour
- > 50% have advanced disease
DLBCL morphologic variants
centroblastic (most common)
immunoblastic
anaplastic
DLBCL molecular variants
GC ( germinal centre) subtype
activated B-cell ABC subtype
DLBCL morphology
- large cells
- speckled/vesicular chromatin,
high N/C ratio - prominent nucleoli
- basophilic cytoplasm
- no granules but occasional vacuoles
- mitotic figures
DLBCL diagnosis
- B cells of germ centre origin (GCB OR post-germ (ABC subtype)
- CD20, 19, 22, CD79a
- MYC + BCL2 &/or BCL6 rearrangements
- rearrangement of 33q27 region involving BCL6 is the most common translocation
Burkitt Lymphoma (BL)
- highly aggressive but curable
- presents in extranodal sites or acute leukemia
- germ centre B-cells
frequent EBV infection
Two types of BL
- endemic; most common childhood malignancy in equatorial Africa
- sporadic = seen worldwide; 1-2% of lymphomas
BL diagnosis
- monomorphic med sized B cells
- basophilic
- vacuolated cytoplasm; lipid droplets
- v high mitotic activity
- starry sky pattern (macs in the background of neoplastic cell)
this is used to stain the vacuoles in BL diagnosis
oil red O staining to stain
immunophenotyping for BL
CD19+, CD20+, CD22+, CD10+!
- coming from germ centre = CD10
molecular hallmark of BL
translocation of MYC to IGH region t(8;14)
less common: IGK t(8;22) OR IGL t(8;2)
Hodgkin lymphoma
- b-lymphoid neoplasms
- mature cells
- bimodal age distribution with a peak in young patients and 2nd peak in older adults
types of HL
nodular lymph predominant Hodgkin lymphoma (NLPHL) classic HL (10%)
morphology of both types of HL
- sparse large neoplastic cells
- Hodgkin or multinucleated Reed-Sternberg cells (Owl’s eye in CHL)
- popcorn cells
- ring of t-cells around te=hem (resetting)
- background mix of inflammatory cells
clinical presentation of HL
- enlarged lymph nodes with frequent mediastinal involvement
- B symptoms
- EBV infection variable
T cell lymphoproliferative disorders
mature T-lymphoid neoplasms
T-lymphoblastic leukemia/lymphoma
immature T-lymphoid neoplasms
classification of T-lymphoid neoplasms
- lineage plasticity: immature or mature
- genetic abnormalities: chromosomal abnormalities and genetic mutations
- other: morph. features, immunophenotyping (CD4/CD8 ratio); molecular (monoclonal TCR pattern)
sCD3/cCD3
T cells
T-cell lymphoproliferative disorders
- T-cell large granular lymphocytic leukemia (T-LGL)
- adult T-cell leukemia/lymphoma (ATLL)
- angioimmunoblastic T-cell lymphoma (AITL)
- mycosis fungoides/Sezary syndrome (MF/SS)
T-cell large granular lymphocytic leukemia (LGL)
- mature, indolent
- large; moderate to abundant cytoplasm; azurophilic granules
- linked to sustained immune stimulation (autoimmune - rheumatoid)
- asymptomatic or symptomatic due to frequent severe neutropenia
- normal counterpart = cytotoxic T cells
T-LGL diagnosis
- perisistent PB lymphocytosis (> 6 mos)
- increase LGLs in PBS, decrease neuts and PLTs, +/- anemia
- intrasinusoidal pattern in BM
- CD8+ or CD4-/CD8- (dbl neg), clonal T cells
- monoclonal TCR pattern by PCR (BUT clonal T-cell population can be seen un elderly w/out LGL; immunosenescence)
Adult T-cell leukemia/lymphoma
- mature T-lymph cells; indolent to aggressive
- adults (~58y/o); higher in males
- caused by HTLV1 virus; long latency; higher in asians
Symptoms of ATLL
- enlarged lymph nodes, liver, and spleen
- skin rash
- increase calcium lytic bone lesions
subtypes of ATLL
- acute most common, leukemic phase, most symptomatic
- lymphomatous - similar to acute but no lymphocytosis
- chronic
- smoldering
** prognosis is 2 weeks to >1 yr depending on subtype **
ATLL diagnosis
- PBS: mature, highly pleomorphic, and multilobed cells (flower)
- positive serology for HTLV-1
- CD2,3, and 5; lack CD7, CD4+/CD8-; CD25 strongly expressed
- molecular: TCR by PCR = monoclonal pattern
AITL angioimmunoblastic T-cell lymphoma
- aggressive
- EBV in nearly all cases (B-cells only; negative in neoplastic T cells)
- elderly; more in males
- symptomatic and quite sick
- poor prognosis - survival <3 yrs even with treatment
disease presentation of AITL
- systemic disease
- enlarged lymph nodes, spleen, liver
- skin rash
- hypergammaglobinemia
- pleural effusion
- ascites
- arhtritis
- hemolytic anemia,
- cold agglutinins
AITL morphology
- medium to large cells with clear cytoplasm
- rarely seen in peripheral smear; spherocytes (hemolysis), toxic changes
- bone marrow may be involved; shows mainly reactive changes
lab findings in AITL
- increase Igs on serum protein electrophoresis
- increase LDH (bilirubin, retics, haptglobin ; hemolysis!)
- surface CD3 decrease or neg
- IHC= BCL6+, CXCL-13
- monclonal pattern (B and T cells)
- abnormal in >90% of cases; most common = trisomy 3, 5, 21
- Strong expression = PD-1 (programmed cell death?)
Mycosis Fungoides and Sezary Syndrome
- 1ry cutaneous T-cell lymphoma; most common
- skin (mainly) + lymph nodes, spleen, liver, and blood; BM rare
- Sez syndrome closely related
> cells in PB >1000 microL
> CD4/CD8 ration >10
> loss of > T-cell antigens - indolent, more in adults but can be seen at any age (sezary is aggressive!!!)
- normal counter: memory T-cells
possible environmental factor playing in mycosis fungoides and Sezary syndrome
higher in farmers, painters, woodworkers, and carpenters; petrochemical and metal industry workers
MF and SS diagnosis
- PBS = small to med sized cells with cerebriform nuclei; BM: rare
- CD4+, CD7-, CD26-
- molecular monoclonal pattern of TCR
- loss of 1p, 6q, 10q
- gain of 8q, isochrome 17q
Immunophenotyping
Classification of blood cells by their membrane antigens. Synthetic antibodies, often monoclonal antibodies produced by hybridoma technology, are used to identify the antigens, called CD antigens, by flow cytometry. Important technique in the classification, diagnosis, and monitoring
of hematologic malignancies
