BL - Lymphomas & Plasma Cell Disorders

Question 1

Basic anatomy of normal lymph node (outermost to innermost)

Answer 1

Capsule - usually thin and fibrous
Cortex - lymphoid follicles (primary and secondary)
Paracortex - interfollicular T cell zone
Medulla - medullary cords (lymphocytes, plasma cells, macrophages, and dendritic cells) and medullary sinuses

(Sinuses - subcapsular, cortical, and medullary)

Question 2

Abnormal lymph node patterns seen in lymphomas

Answer 2

Capsule can be thickened and fibrotic in reactive conditions (syphilitic lymphadenitis) or neoplastic processes (nodular sclerosis Hodgkin lymphoma)

Question 3

Lymphadenopathy

Answer 3

Swelling/disease of lymph nodes. Present in both benign and malignant circumstances.

Question 4

Basic principles for WHO classification of lymphomas

Answer 4

Based on several criteria: morphology, immunophenotype, genetic findings, location, age

Question 5

Indolent lymphomas

Answer 5

Slow-growing. Not usually considered curable because they grow too slowly to be targeted by most modern treatments

Question 6

Aggressive lymphomas

Answer 6

Faster-growing than indolent. Example: MCL.

Question 7

Highly aggressive

Answer 7

Faster-growing than aggressive and indolent lymphomas, but more curable because they are more easily targeted than indolent lymphomas. Example: BL.

Question 8

Lymphoma in children vs. adults

Answer 8

Children: BL (30% of childhood lymphomas), mixed cellularity CHL
Adults: plasma cell myeloma (~90% of patients > 50 years of age); nodular sclerosis CHL (NSHL) in young adults, especially females; follicular lymphoma (median age at diagnosis 60 years).

Question 9

Markers of germinal center B-cells

Answer 9

BCL6, CD10

Question 10

CLL/SLL demographics/presentation

Answer 10

Most common leukemia in Western world, 30% of all leukemia. 7% of NHL. Median age 65 years, male:female predominance 2:1. Most patients either asymptomatic or mildly symptomatic; some with fatigue, infection, AIHA, hepatosplenomegaly, lymphadenopathy, extranodal involvement.

Question 11

CLL/SLL cytology

Answer 11

Small and monotonous cells with round, condensed chromatin in nuclei. Inconspicuous nucleoli. Scant/agranular cytoplasm. Frequent smudge cells and basket cells.

Question 12

CLL/SLL pattern of growth

Answer 12

Lymph node involvement - effacement of nodal architecture with diffuse infiltration. Proliferation centers are pale areas containing transformed larger cells.

Question 13

CLL/SLL immunophenotype

Answer 13

Immunophenotype: Strongly positive CD5, CD19, CD23. Weakly positive CD20, surface immunoglobulin. Negative CD10, FMC7 (markers of germinal center).

Question 14

FL demographics/presentation

Answer 14

40% of adult lymphomas in US, 20% worldwide. Median age 60 years. Male:female predominance equal. >80% of cases are stage III/IV at diagnosis, 40% with bone marrow involvement. Patients often asymptomatic except for lymphadenopathy.

Question 15

FL cytology

Answer 15

No dark zone, light zone, or typical tingible-body macrophages in neoplastic follicles. Neoplastic follicles relatively uniform in size, evenly distributed in lymph node cortex/medulla

Question 16

FL pattern of growth

Answer 16

Germinal center B cell origin. Mostly in lymph nodes but also spleen, bone marrow, Waldeyer’s ring, GI tract, skin and soft tissue

Question 17

FL immunophenotype

Answer 17

Positive for B-cell markers CD19, CD20. Positive for germinal center markers CD10, BCL6. Positive for BCL2. Negative for CD5, CD23.

Question 18

FL genetic alteration

Answer 18

t(14;18) causing FL cells to be positive for BCL2 which makes cells unable to suppress apoptosis (cells don’t die during selection)

Question 19

MCL demographics/presentation

Answer 19

3-10% of NHL. Median age 60 years. Male:female predominance 2:1. Most patients with stage III/IV disease at diagnosis. Lymphadenopathy, hepatosplenomegaly, >50% of cases with massive splenomegaly and marrow involvement.

Question 20

MCL cytology

Answer 20

Small to medium in size, slightly irregular nuclei, small/inconspicuous nucleoli.

Question 21

MCL pattern of growth

Answer 21

Moderately aggressive. Mostly in lymph nodes but also spleen, bone marrow, GI tract, Waldeyer’s ring. Effacement of lymph node structure, diffuse infiltration of lymphoma cells.

Question 22

MCL immunophenotype

Answer 22

Positive for B cell markers CD19, CD20. Positive for CD5. Positive for cyclin D1 (BCL1, differentiates MCL from most other B cell lymphomas). Negative for CD23 (differentiates MCL from CLL/SLL). Negative for CD10, BCL6.

Question 23

MCL genetic alteration

Answer 23

t(11;14)(q13;q32) induces persistent overexpression of BCL1 protein, accelerating passage through G1 phase and increases risk of lymphoma development.

Question 24

BL demographics/presentation

Answer 24

1) Endemic typically in malaria belt of equatorial Africa. Peak age 4-7 years. Located in jaw or abdomen; 95% associated with EBV.
2) Sporadic mostly in children, young adults. Located in ileocecal area, ~30% associated with EBV.
3) Immunodeficiency-associated primarily in HIV patients, 25-40% associated with EBV.

Question 25

BL cytology

Answer 25

Medium sized cells with round nuclei and finely dispersed chromatin. One or several small, paracentric nucleoli present. Deeply basophilic cytoplasm with lipid vacuoles and “squared off” borders.

Question 26

BL pattern of growth

Answer 26

Diffuse infiltration of monomorphic, medium-sized cells with starry sky pattern. Highly aggressive but potentially curable with aggressive therapy in 60% of cases.

Question 27

BL immunophenotype

Answer 27

Positive for CD19, CD20. Positive for CD10, BCL6. Positive for MYC. Negative for CD5, CD23.

Question 28

BL genetic alteration

Answer 28

t(8;14)(q24;q32) fuses MYC gene at 8q24 next to IGH locus at 14q32, resulting in overexpression of MYC (transcription factor).

Question 29

Importance of rearrangements of BCL2/BCL1/MYC genes in pathogenesis of lymphoma

Answer 29

Oncogenic. Some are transcription factors, some regulate apoptosis, but are dysregulated in lymphomas causing cells to survive when they shouldn't or proliferate longer than they should

Question 30

Nodular sclerosis classical Hodgkin's (NSCHL)

Answer 30

Most frequent subtype, accounts for 50-80% of all CHLs. Predominates in young adults, especially in females. EBV infection in 10-25% of cases. Immunophenotype: positive for CD15 and CD30. Morphology: thickened lymph node capsule with broad bands of collagen, nodular areas surrounded by broad bands of collagen. Lacunar cells: polypoid nuclei and small nucleoli; perinuclear clearing due to formalin fixation artifact causing cytoplasm to retract. Background of small round lymphocytes (T-cells), eosinophils, plasma cells, some neutrophils.

Question 31

Lymphocyte-rich classical Hodgkin's (LRCHL)

Answer 31

5% of all CHLs. Frequently in stages III/IV, more often below or on both sides of diaphragm. Lack of broad bands of collagen seen in NSCHL. Classic RS cells very rare.

Question 32

Mixed cellularity classical Hodgkin's (MCCHL)

Answer 32

Second most frequent subtype, 20-30% of CHLs. High percentage in children and older patients. Frequently in stages III/IV, more often below or on both sides of diaphragm. Lack of broad bands of collagen seen in NSCHL. EBV infection in 75% of cases. Morphology: occasional classic RS cells noted in background of mixed lymphocytes, histiocytes, eosinophils.

Question 33

Lymphocyte-depleted classical Hodgkin's (LDCHL)

Answer 33

Least frequent subtype, 1% of CHL. Relative paucity of lymphocytes (as name suggests). Numerous RS cells, some of which appear anaplastic and bizarre/sarcomatous. Usually EBV+.

Question 34

Reed-Sternberg cell in CHL

Answer 34

Large cell, up to 100um. Multiple or lobated nuclei. Single large, eosinophilic, viral inclusion-like nucleolus. Ample and amphophilic cytoplasm.

Question 35

Classification system for plasma cell neoplasms (5 types)

Answer 35

1) Monoclonal gammopathy of undetermined significance (MGUS)a. Precursor lesion2) Plasma cell myelomaa. Asymptomatic (smoldering) myelomab. Nonsecretory myelomac. Plasma cell leukemia3) Plasmacytomaa. Solitary plasmacytoma of boneb. Extraosseous (extramedullary) plasmacytoma4) Immunoglobulin deposition diseasesa. Primary amyloidosisb. Systemic light and heavy chain deposition diseases5) Osteosclerotic myeloma (POEMS syndrome)

Question 36

Plasma cell myeloma vs. plasmacytoma

Answer 36

Plasma cell myeloma: originates from marrow, other organs secondarily involved. Scattered circulating plasma cells noted in peripheral blood smear. Marked Rouleaux formation due to decreased Ig. Numerous neoplastic plasma cells in bone marrow smear.Plasmacytoma: In soft tissue or axial skeleton. Generally progresses to multiple myeloma. Can be solitary in bone, or extramedullary.

Question 37

Radiographic/clinical lab findings in patient with PCM

Answer 37

Clinical laboratory findings: M protein in serum or urine: in most cases >30g/L of IgG, >25g/L of IgA, or >1g/24 hours of urine light chain. Bone marrow clonal plasma cells or plasmacytoma, usually >10% of nucleated cells in marrow.Related organs/tissue impairment: CRAB = hypercalcemia (1/5 of patients), renal insufficiency, anemia (2/3 of patients), bone lesionsRadiographic findings: lytic bone lesions, osteoporosis, fractures (vertebra, pelvis, skull, rib, femur, proximal humerus)Serum protein electrophoresis: normally has only one peak (albumin). PCM has a discrete band in gamma region.

Question 38

MGUS

Answer 38

Monoclonal gammopathy of undetermined significance. Refers to presence of monoclonal Ig in serum or urine of patient with no evidence of PCM, amyloidosis, Waldenstrom's macroglobulinemia, or other lymphoproliferative disorder or disease. Most common monoclonal gammopathy, found in 3% of people >50 years old and >5% of those >70. Precursor lesion of PCM, probability for malignant transformation 1.5% a year.

Question 39

Smoldering myeloma

Answer 39

Asymptomatic myeloma

Question 40

Indolent myeloma

Answer 40

Slow-growing myeloma