Hematology — ASCP Exam Prep Mature Lymphoid Neoplasms Part 1

Master CLL, hairy cell leukemia, and mature B-cell neoplasm classification and lab patterns for ASCP hematology.

ASCPprep.com | Hematology

Chapter 22 — MATURE LYMPHOID NEOPLASMS

ASCP Board Exam · Lab-Focused Study Guide

Normal Lymph Node & B-Cell Differentiation · Lymph Node Processing · Reactive Lymphadenopathies · WHO 2008 Classification · CLL/SLL · PLL · Hairy Cell Leukemia · Mantle Cell · Follicular · MALT · Plasma Cell Neoplasms (Myeloma, MGUS) · DLBCL · Burkitt · Mycosis Fungoides/Sézary · PTCL · ALCL · Hodgkin Lymphoma · Practice Questions

1 · Priority Table & Quick Foundation

Topic	Priority	Why It’s Tested
CLL/SLL: smudge cells, soccer-ball chromatin, CD5⁺ CD23⁺ B cells, ≥5000/µL, light chain restriction	HIGH	Most common exam lymphoproliferative disorder
CLL vs mantle cell lymphoma (CD23/LEF1 vs cyclin D1/SOX11/t(11;14))	HIGH	Rodak Q4; key differential
Hairy cell leukemia: CD11c, CD25, CD103, TRAP, annexin A1, CD123; splenomegaly, pancytopenia	HIGH	Classic morphology + markers
Follicular lymphoma t(14;18) BCL2; Burkitt t(8;14) MYC, starry sky	HIGH	Rodak Q7; translocation matching
Plasma cell myeloma: CRAB, CD138/CD38, CD19/20 −; MGUS vs myeloma vs plasma cell leukemia	HIGH	Table 36-3; Rodak Q10
Mycosis fungoides / Sézary: CD4⁺, CD7 loss, cerebriform nuclei, Pautrier microabscesses	HIGH	Rodak Q5
Hodgkin: Reed-Sternberg cells CD30⁺ CD15⁺ CD45⁻; subtypes; NLPHL popcorn cells	HIGH	Rodak Q2, Q6; Table 36-4/36-5
DLBCL: large cells, most common aggressive NHL (30–40%)	HIGH	Case study
Normal lymph node compartments and germinal center function	MEDIUM	Rodak Q3, Q8
Reactive patterns: follicular, paracortical, sinusoidal, mixed (Toxoplasma)	MEDIUM	Rodak Q9
MALT lymphoma: H. pylori, lymphoepithelial lesions, t(11;18)	MEDIUM	Antigen-driven lymphoma
ALCL: CD30, ALK-1, t(2;5), hallmark cells; PTCL NOS	MEDIUM	T-cell lymphomas
Lymph node processing and fixation	LOW	Pre-analytical

🎯 KEY POINT — Where to spend your time

Focus: the immunophenotype/translocation table (Table 36-2), CLL vs mantle cell, hairy cell markers, plasma cell neoplasm definitions (CRAB, MGUS), mycosis fungoides/Sézary, Reed-Sternberg immunophenotype and Hodgkin subtypes. Skim: rare WHO entities in Table 36-1, processing fixatives, NGS prognostic genes.

Quick Foundation — from zero

Lymphomas are cancers of lymphocytes. Each one freezes a normal stage of B- or T-cell development, so knowing normal development tells you the tumor markers.
Mature lymphoid neoplasms come from lymphocytes that have left the marrow (unlike ALL, which comes from precursors).
Most present as enlarged lymph nodes; some are mainly in blood and marrow (CLL, hairy cell leukemia, myeloma), and some in extranodal tissue (MALT, skin).
Diagnosis combines morphology, immunophenotype (flow cytometry, immunohistochemistry), genetics and clinical data.
Key clue to malignancy in B cells: clonality — all cells carry the same light chain (κ or λ = light chain restriction).
Indolent lymphomas grow slowly but are largely incurable; aggressive lymphomas grow fast but are more often cured.

💡 Analogy

A B cell life is a school career: naive student (CD5⁺ primary follicle) → intensive tutoring in the germinal center (CD10, BCL6; somatic mutation) → graduate (memory B cell, BCL2 back on) → professional (plasma cell, CD138). Each lymphoma is a student stuck at one grade: mantle cell = stuck in the mantle, follicular and Burkitt = stuck in germinal center class (CD10), myeloma = professional who won’t stop working. The translocation is the forged report card that keeps them there (t(14;18) BCL2 = never dies; t(8;14) MYC = never stops dividing).

🏥 Why this matters clinically

Burkitt is a medical emergency (extremely short doubling time) but curable with intensive therapy. Hairy cell leukemia responds to purine analogues, not standard lymphoma therapy. Gastric MALT lymphoma may disappear after H. pylori antibiotics. A lymphocytosis flagged on a routine CBC may be the first sign of CLL — flow cytometry confirms it.

Concept	Plain-English Explanation
Light chain restriction	All B cells express only κ or only λ — marks a clone
Germinal center	Follicle center where B cells mutate antibodies for best affinity
Starry sky	Pale macrophages with apoptotic debris scattered among dark tumor cells
Smudge cell	Fragile CLL lymphocyte crushed during smear preparation
Reed-Sternberg cell	Large bilobed cell with ‘owl-eye’ nucleoli — Hodgkin lymphoma
Cerebriform nucleus	Folded, brain-like nucleus of Sézary/mycosis fungoides cells
Epidermotropism	Lymphoma cells homing into the skin epidermis
Indolent vs aggressive	Slow and incurable vs fast and often curable

2 · Core Content Tables

2.1 Normal Lymph Node Compartments

Feature	Details
Cortex	Beneath the capsule; primary follicles (naive B cells: CD19, CD20, often CD5⁺) and secondary follicles with germinal centers; follicular dendritic cell meshworks (CD21)
Germinal center	Pan-B markers + CD10 and BCL6; BCL2 negative (lack anti-apoptotic protein). Dark zone: centroblasts (large, vesicular nuclei, basophilic cytoplasm) — proliferation and somatic mutation. Light zone: centrocytes (smaller, irregular nuclei). Low-affinity centrocytes die → tingible-body macrophages → ‘starry sky’
Mantle zone	Displaced naive B cells around the germinal center
Marginal zone	High-affinity centrocytes lose CD10/BCL6 → memory B cells (BCL2⁺); medium cells with clear cytoplasm, indented nuclei
Plasma cells	Terminal stage; in medullary cords and marrow; CD19⁻, CD20⁻, sIg⁻; CD138, CD38, cytoplasmic Ig
Paracortex	Between follicles; T cells (CD3, CD5, CD2, CD7; CD4 and CD8), interdigitating dendritic cells, high-endothelial venules; T immunoblasts after stimulation
Medulla	Innermost; medullary cords with plasma cells and medullary sinuses
Sinuses	Afferent lymphatics → subcapsular sinus → cortical → medullary sinuses → efferent lymphatic at hilum; filled with macrophages (sinus histiocytes)

2.2 B-Cell Differentiation Markers (Rodak Figure 36-3)

Stage	Markers	Related Neoplasm*
Naive B cell / primary follicle	CD19⁺ CD20⁺ CD5⁺(±)	Mantle cell lymphoma
Centroblast (dark zone)	CD19, CD20, CD10, BCL6 ⁺; BCL2⁻; sIg⁻	Burkitt, DLBCL (GC type)
Centrocyte (light zone)	CD19, CD20, CD10, BCL6 ⁺; BCL2⁻; sIg⁺	Follicular lymphoma (but BCL2⁺ from t(14;18))
Memory B cell	CD19, CD20, BCL2 ⁺; BCL6⁻; sIg⁺	CLL (memory/marginal zone), hairy cell, MALT
Plasma cell	CD19⁻ CD20⁻ CD38⁺ CD138⁺ cIg⁺	Myeloma

*The mapping of neoplasms to stages is drawn from the cell-of-origin column of Table 36-2.

2.3 Lymph Node Processing

Feature	Details
Transport	Sealed sterile jar on gauze moistened with sterile saline or in tissue culture media — prevent drying
Sectioning	3-mm-thick slices; send portion for culture if granulomas/suppuration
Touch imprints	Gently touch cut surface to slide; fix (formalin/alcohol) or air-dry for Wright-Giemsa
Fixation	Thin sections in 10% buffered formalin; also B5 or zinc formalin for cytologic detail
Flow cytometry	Fresh tissue in RPMI culture medium — especially useful for monoclonal light chains
Storage	Remaining fresh tissue at −70 °C

2.4 Reactive Lymphadenopathies

Pattern	Features	Associations
Follicular (most common)	Expanded reactive follicles into medulla; polarization, tingible-body macrophages, mitoses, preserved mantle zones	Children/adolescents with infections; RA, SLE, syphilis, early HIV
Paracortical	Immunoblasts, mitoses, vascular proliferation, necrosis foci	Viral (IM), drug reactions; dermatopathic lymphadenopathy (mottled — histiocytes with melanin, Langerhans cells)
Sinusoidal	Expanded sinuses with histiocytes; monocytoid B cells	Nodes draining limbs/abdomen, inflammation, malignancy; HIV, Toxoplasma; Langerhans cell histiocytosis, lymphomas, carcinomas like sinuses
Mixed	All compartments expanded	Toxoplasma gondii: florid follicular hyperplasia + paracortical expansion + epithelioid histiocyte clusters + monocytoid B cells in sinuses

2.5 Lymphoma — General

Feature	Details
Incidence	~86,000 new cases/year in the U.S.; most in previously healthy people
Strongest risk factor	Altered immune function — immunocompromised or autoimmune disease
Others	Viral/bacterial infections; chemicals and herbicides
Sites	Mostly lymph nodes; some extranodal; leukemic phase varies by subtype
Classification	Old: Rappaport, Kiel, Working Formulation → WHO: morphology + immunophenotype + genetics + clinical (Table 36-1)
Most common B lymphomas	Follicular lymphoma and DLBCL
Most common T lymphomas (U.S./Europe)	PTCL, unspecified and ALCL
B-cell clonality	Monoclonal light chain immunoglobulins and/or clonal Ig gene rearrangement

2.6 Morphologic & Immunophenotypic Features of Mature B-Cell Lymphomas (Rodak Table 36-2)

Subtype	Architecture	Cytology	Immunophenotype / Cytogenetics	Cell of Origin
CLL/SLL	Diffuse with growth (proliferation) centers	Small lymphoid cells	CD20⁺, CD19⁺, CD5⁺, CD23⁺, LEF1	Memory and marginal zone B cells
B-PLL	Diffuse	Medium cells, ‘punched-out’ nucleoli, abundant cytoplasm	CD20⁺, CD19⁺, FMC7⁺, CD5⁺/⁻	Unknown mature B cell
Mantle cell	Diffuse, nodular or mantle zone	Medium cells, irregular nuclei	CD20⁺, CD19⁺, CD5⁺, FMC7⁺, SOX11, cyclin D1⁺, t(11;14)	Mantle zone cell
Follicular	Follicular pattern	Medium cells with indented nuclei + variable large cells	CD20⁺, CD19⁺, CD10⁺, BCL6⁺, BCL2⁺, t(14;18)	Germinal center cell
MALT	Diffuse, occasional marginal zone/nodular	Medium cells, irregular nuclei, clear abundant cytoplasm	CD20⁺, CD19⁺, CD43⁺/⁻ (CD5⁻, CD10⁻)	Marginal zone cell
Plasma cell myeloma	Sheets/aggregates of plasma cells	Plasma cells, often atypical	CD20⁻, CD19⁺/⁻, CD38⁺, CD138⁺, cytoplasmic light chain⁺	Plasma cell
DLBCL	Diffuse	Large lymphoid cells	CD20⁺, CD19⁺, CD10⁺/⁻, BCL6⁺/⁻, BCL2⁺/⁻, CD5⁺/⁻	Different stages of mature B cells
Burkitt	Diffuse with starry sky	Medium cells, even chromatin, inconspicuous nucleoli	CD20⁺, CD19⁺, CD10⁺, BCL6⁺, BCL2⁻, very high proliferation, t(8;14)	Germinal center cell

2.7 CLL / SLL

Feature	Details
Definition	Accumulation of small lymphoid cells in blood, marrow and lymphoid organs; one WHO entity — CLL mostly blood/marrow, SLL mostly nodes
Blood/marrow	Small cells with coarse ‘soccer-ball’ chromatin, inconspicuous nucleoli, scant cytoplasm; smudge cells (helpful, uncommon in other lymphomas); up to 55% prolymphocytes allowed (2008 IWCLL)
FAB subtypes	Typical (>90% small mature lymphocytes, <10% prolymphocytes) vs atypical — WHO does not divide
Marrow biopsy	Nodular, diffuse or interstitial infiltrates
SLL node	Effaced architecture, diffuse small round cells + pseudofollicles (proliferation/growth centers) — pathognomonic
Diagnosis	Sustained monoclonal B cells with CLL phenotype ≥5000/µL
Immunophenotype	CD19, CD20 (weak), CD23, aberrant CD5; weak CD20 and CD79b; κ or λ restriction
vs mantle cell	CD23 and LEF1 positive; FMC7, cyclin D1, SOX11 negative
MBL	Monoclonal B-cell lymphocytosis: <5000/µL CLL-phenotype B cells in healthy people
Clinical	Older adults (24% <55); most asymptomatic; often an incidental lymphocytosis on CBC
Prognosis — IGVH	Mutated IGVH (~55%): indolent, median survival 24 years · unmutated: aggressive, ~8 years
Prognosis — FISH	del(13q14.3) good · del(11q22-23) poor · trisomy 12 intermediate · del(17p13) very poor; NGS: EZH2, NOTCH1, SF3B1, BIRC3
Richter syndrome	~5% transform to high-grade DLBCL; survival <1 year

2.8 Prolymphocytic Leukemia (PLL)

Feature	Details
Definition	Rare mature B or T leukemia; blood, marrow, spleen; nodes more in T-PLL; >55% of circulating lymphoid cells must be prolymphocytes
B-PLL cell	Medium (2× lymphocyte), round nucleus, moderate cytoplasm, distinct ‘punched-out’ central nucleolus
B-PLL counts	WBC often >100 × 10⁹/L; interstitial/nodular marrow; splenic red and white pulp
B-PLL phenotype	CD20, CD19, CD22, FMC7; brighter CD20 and sIg than CLL; some CD5⁺ → exclude mantle cell t(11;14)
T-PLL	Small–medium cells, round/irregular (Sézary-like) nuclei, cytoplasmic blebs; CD3, CD2, CD5, CD7⁺ (unlike many T lymphomas); usually CD4⁺
Prognosis	Elderly (mean 70); B-PLL median 3 years (TP53); T-PLL median 1 year — improved with alemtuzumab (anti-CD52)

2.9 Hairy Cell Leukemia (HCL)

Feature	Details
Definition	Small B cells with abundant cytoplasm and fine ‘hairy’ projections; post–germinal center (memory) B cell
Sites	Marrow and splenic red pulp; few in blood; nodes rare
Marrow	Interstitial, widely spaced cells (‘fried-egg’); may be subtle; ↑ reticulin fibers* (fibrogenic cytokines)
Cytology	Oval or indented nucleus, abundant cytoplasm, hairlike projections (polymerized actin)
Immunophenotype	Bright CD19, CD20, CD22 + CD11c, CD25, CD103, TRAP, DBA-44, CD123, annexin A1 (most specific; separate from splenic marginal zone lymphoma; replaced TRAP stain)
Clinical	Middle-aged (median 55); splenomegaly and pancytopenia
Treatment	Purine analogues → durable remission; conventional lymphoma therapy ineffective

*’Fried-egg’ appearance and monocytopenia are classic descriptions from general references.

2.10 Mantle Cell Lymphoma

Feature	Details
Definition	Medium lymphoid cells with irregular nuclei from the follicular mantle zone
Sites	Nodes; marrow, blood, spleen, GI tract
Histology	Diffuse monotonous medium cells; sometimes nodular or mantle zone pattern
Blood	Can mimic PLL; some cells with indented (cleaved) nuclei
Immunophenotype	CD19, CD20 (strong), high-density clonal light chain, CD5⁺, CD23⁻, cyclin D1⁺, SOX11⁺
Genetics	t(11;14): cyclin D1 (BCL1, G1→S regulator) juxtaposed to IgH → constitutive expression; cyclin D1-negative cases SOX11⁺
Prognosis	Aggressive, median survival 3–5 years; disseminated at presentation (marrow); incurable with chemotherapy; stem cell transplant helps some

2.11 Follicular Lymphoma

Feature	Details
Origin	Germinal center B cells; recapitulates follicles
Histology	Closely spaced neoplastic follicles replacing the node, extending into perinodal fat; no mantle zone or polarization (vs reactive)
Cells	Medium centrocyte-like (angular/indented nuclei) + variable large centroblasts
Grading	By large cells per high-power field: grade 1–2 rare large cells (indolent) · grade 3 numerous centroblasts (aggressive, treated like DLBCL with doxorubicin)
Immunophenotype	CD19, CD20, CD10, BCL6, clonal sIg + BCL2⁺ (reactive follicles are BCL2⁻)
Genetics	t(14;18)(q32;q21): BCL2 under IgH promoter → ↓ apoptosis; present in 95%
Clinical	Median age 59; mostly disseminated; marrow in ~50%

2.12 Extranodal Marginal Zone Lymphoma of MALT

Feature	Details
Types of MZL	Nodal, extranodal (MALT), splenic
Associations	Autoimmune (Sjögren, Hashimoto thyroiditis) or infection (Helicobacter pylori gastritis, hepatitis C) — persistent antigen stimulation
Cells	Mixture of small–medium marginal zone cells (irregular nuclei), plasma cells, scattered large cells; residual germinal centers colonized
Hallmark	Lymphoepithelial lesions — tumor cells invading glandular epithelium
Immunophenotype	CD20, CD19, monoclonal Ig; CD5⁻ and CD10⁻; CD43 coexpressed in 30%
Genetics	~30%: t(11;18)(q21;q21) API2-MLT
Clinical	GI tract most common site; lung, thyroid, ocular adnexa, breast; localized; marrow less often involved. H. pylori⁺ gastric MALT may remit with antibiotics

2.13 Plasma Cell Neoplasms (Rodak Table 36-3)

Disorder	Defining Features
Plasma cell myeloma	Monoclonal protein in serum or urine · clonal marrow plasma cells or plasmacytoma · organ/tissue impairment — CRAB: hyperCalcemia, Renal insufficiency, Anemia, Bone lesions
Plasma cell leukemia	Myeloma features + blood involvement: >2 × 10⁹/L or >20% circulating plasma cells; spleen, liver, body fluids possible
MGUS	Marrow plasmacytosis <10%; monoclonal gammopathy <30 g/L; no lytic lesions or organ impairment
Solitary plasmacytoma of bone	Localized bone mass of plasma cells
Extraosseous plasmacytoma	Localized extraosseous mass (nasopharynx, oropharynx, sinuses)

2.14 Plasma Cell Myeloma — Details

Feature	Details
Marrow	Large aggregates and sheets, often >30% of cellularity; atypia (high N:C ratio, dispersed chromatin, nucleoli) — rare in reactive/MGUS. Reactive plasmacytosis = scattered, perivascular clusters
Immunophenotype	CD19⁻, CD20⁻, sIg⁻; CD138 (syndecan-1), bright CD38, monoclonal cytoplasmic Ig; aberrant CD56 and myeloid markers
M protein	Complete Ig (most often IgG or IgA) or isolated light chains in serum/urine
Clinical	Median age 70; bone pain, pathologic fractures (lytic lesions), hypercalcemia; renal insufficiency (monoclonal protein damage); cytopenias; infections (↓ normal Ig); hyperviscosity, coagulation interference; amyloidosis (kidney, heart, liver, neuropathy)
Prognosis	Median survival 3 years; worse with >50% plasma cells, renal failure, severe anemia
Plasmacytoma	Younger; responds to local radiation; ~15% progress to myeloma
MGUS	<5% of people >70; 25% develop myeloma → monitor

2.15 Diffuse Large B-Cell Lymphoma (DLBCL)

Feature	Details
Defining feature	Large cell size (≥2× small lymphocyte); single or multiple nucleoli, ample cytoplasm
Frequency	30–40% of non-Hodgkin lymphoma
Histology	Diffuse proliferation replacing node; some cases rich in histiocytes/small lymphocytes
Immunophenotype	Pan-B antigens; variable CD5, CD10, BCL6, CD30, CD138
Clinical	Median 60s but also children/young adults; usually localized group of nodes; marrow involvement rare at presentation; extranodal (GI, CNS, bone, effusions)
Behavior	Aggressive, proliferation >40% → sensitive to multiagent chemotherapy; follicle center origin (gene expression) has better survival

2.16 Burkitt Lymphoma

Feature	Details
Variants	Endemic (Africa; children 4–7; jaw mass) · sporadic (U.S./Europe; abdominal mass, GI, gonads, breasts) · immunodeficiency-associated (HIV; nodal; worse prognosis)
Histology	Diffuse with ‘starry sky’ (tingible-body macrophages eating apoptotic debris)
Cytology	Medium cells, round nuclei, fine chromatin, small nucleoli; deeply basophilic, vacuolated cytoplasm (touch imprints)
Immunophenotype	CD19, CD20, CD10, BCL6, monoclonal sIg; BCL2 absent; ~100% proliferating
Genetics	MYC translocation to Ig heavy or light chain gene: t(8;14), t(2;8), t(8;22) — pathognomonic, required for diagnosis
Clinical	CNS, marrow, blood (Burkitt leukemia); EBV in a proportion; medical emergency; intensive regimens cure 60–90%

2.17 Mature T-Cell & NK-Cell Lymphomas

Feature	Details
Frequency	~10% of lymphomas; geographic variation; more extranodal than B-cell
Diagnosis	Morphology and phenotype less specific → integrate molecular and clinical data; clonality by TCR gene rearrangement or flow cytometry (TCR variable-region antibodies)

2.18 Mycosis Fungoides & Sézary Syndrome

Feature	Details
MF	Most common cutaneous lymphoma; small–medium cells with cerebriform nuclei, epidermotropism; may spread to nodes
MF progression	Patchy/lichenoid dermal infiltrate → Pautrier microabscesses (aggregates in epidermis) → dense tumor-like lesions → nodes and blood
Immunophenotype	CD3, CD5, CD2, CD4⁺; loss of CD7 (rare in benign infiltrates); clonal TCR rearrangement
Sézary syndrome	Disseminated: erythroderma, lymphadenopathy, circulating Sézary cells (cerebriform)
Sézary criteria	≥1000 Sézary cells/µL, CD4:CD8 >10, aberrant phenotype (loss of CD7, CD26 or T markers on CD4 cells)
Prognosis	MF: age 55–60; early stage 10-year survival 97–98%; local treatment · Sézary: aggressive, 5-year survival 10–20%

2.19 Peripheral T-Cell Lymphoma, Unspecified & ALCL

Feature	Details
PTCL NOS	Heterogeneous mature T cells; diffuse node involvement, vascular proliferation, medium–large pleomorphic cells, reactive background (eosinophils, histiocytes); mostly CD4⁺, variable loss of pan-T antigens (CD7); marrow often involved; average age 60; B symptoms, pancytopenia; 3-year survival ~40%
ALCL cells	Large pleomorphic cells with eccentric kidney-shaped ‘hallmark’ nuclei; sinus involvement; fibrosis can mimic Hodgkin
ALCL phenotype	CD30 and usually ALK-1; cytotoxic TIA-1, granzyme, perforin; pan-T (CD3, CD7, CD5) often absent; CD4 and CD2 most common; CD45 only in some; myeloid CD13/CD33/CD15 in ~50%
ALCL genetics	t(2;5)(p23;q35) ALK–nucleophosmin (NPM)
ALCL clinical	10–15% of childhood lymphomas; disseminated nodal + extranodal (skin); ALK⁺ favorable, ALK⁻ like PTCL

2.20 Large-Cell Lymphoma Immunophenotypes (Rodak Table 36-4)

Antigen	NLPHL	Classical HL	DLBCL	ALCL
CD30	−	+	+/−	+
CD15	−	+	−	−
CD45	+	−	+	+/−
CD20	+	+/− (weak, some cells)	+	−
CD3	−	−	−	+/− (CD2, CD4 more often)

2.21 Hodgkin Lymphoma

Feature	Details
Two groups	Nodular lymphocyte-predominant (NLPHL) and classical HL — both in young people, biologically distinct
NLPHL	Rare neoplastic lymphocytic/histiocytic (‘popcorn’) cells — multilobed vesicular nuclei, inconspicuous nucleoli — in nodules of small B cells, T cells and CD21⁺ FDC meshworks. B phenotype: CD20, BCL6, Ig; EBV negative. Males in 30s; localized peripheral nodes; mediastinum rare; survival 80–90%
Classical HL	From germinal center; few Reed-Sternberg cells in a rich reactive background; U.S. ~7400/year; bimodal: 15–34 and >54
Reed-Sternberg cell	Large, bilobed nucleus or two nuclei with prominent eosinophilic nucleoli, abundant cytoplasm — pathognomonic in the right background
Variants	Hodgkin cells (mononuclear), mummified cells (apoptotic, pyknotic), lacunar cells (nodular sclerosis; formalin retraction artifact)
Immunophenotype	CD30⁺ (all), CD15⁺ (~80%, may be weak), CD20 weak/absent, CD45⁻; background mostly CD4⁺ T cells; EBV frequency varies by subtype
Outcome	Cure 80–90% with chemo + radiotherapy; best in nodular sclerosis; risk of secondary lung/breast cancer and acute leukemia

2.22 Subtypes of Classical Hodgkin Lymphoma (Rodak Table 36-5)

Subtype	Neoplastic Cells	Background / Features	Notes
Nodular sclerosis	RS cells, Hodgkin cells, lacunar cells	Broad collagen bands, thick capsule; small lymphocytes, eosinophils, histiocytes	Most common (70%); lowest EBV; mediastinal nodes; best prognosis
Mixed cellularity	RS and Hodgkin cells (mummified; no lacunar)	Diffuse mixed lymphocytes, histiocytes, eosinophils, neutrophils, plasma cells; no fibrotic bands	~20%; EBV in 75%
Lymphocyte rich	RS and Hodgkin cells	Vaguely nodular small lymphocytes; few eos/neutrophils	Slightly older patients
Lymphocyte depleted	Numerous RS and Hodgkin cells	Few background lymphocytes	Rare; immunodeficiency/HIV; mostly EBV⁺; most aggressive; may involve marrow

3 · Visual Memory Hooks

🧠 Node map
“Cortex = B (follicles), Paracortex = T, Medulla = plasma”.

🧠 Germinal center
“Dark zone Divides & mutates; Light zone Learns (selection)”.

🧠 BCL2
“Germinal center is BCL2-free; follicular lymphoma cheats with t(14;18)”.

🧠 CLL
“Soccer balls and smudges; CD5 + CD23”.

🧠 CLL vs mantle
“23 = CLL; Cyclin D1 = Mantle (11;14)”.

🧠 CLL prognosis
“13q good, 12 so-so, 11q bad, 17p terrible”.

🧠 PLL
“Punched-out nucleolus, WBC over 100”.

🧠 Hairy cell
“Hairy cells wear 11c, 25, 103 and a TRAP hat”; big spleen, low counts.

🧠 Follicular
“14;18 → Follicles Forever (BCL2 blocks death)”.

🧠 Burkitt
“8;14 → MYC → starry sky, 100% dividing, emergency”.

🧠 Burkitt variants
“Endemic Jaw, Sporadic Stomach (abdomen)”.

🧠 MALT
“MALT = H. pylori-fed; kill the bug, cure the lymphoma”; t(11;18).

🧠 Myeloma
“CRAB: Calcium, Renal, Anemia, Bones”; CD138/CD38, no CD19/20.

🧠 MGUS
“MGUS = Minor: <10% plasma cells, <30 g/L, no CRAB” — 25% progress.

🧠 Plasma cell leukemia
“>2 × 10⁹/L or >20% circulating”.

🧠 MF/Sézary
“Brainy (cerebriform) CD4 cells lose 7 and love skin”.

🧠 Sézary numbers
“1000 cells, CD4:CD8 >10”.

🧠 ALCL
“ALCL = ALK + CD30, 2;5, kidney-shaped hallmark cells, kids”.

🧠 Reed-Sternberg
“Owl eyes: CD30 + CD15 +, CD45 −”*.

🧠 NLPHL
“Popcorn cells are B cells: CD20 +, CD15/CD30 −”.

🧠 HL subtypes
“Nodular Sclerosis = Neck/mediastinum, Numerous (70%), Nice prognosis”.

*’Owl eyes’ is classic RS-cell imagery not used in Rodak.

Pattern Triggers

If you see…	Think…	Because…
Elderly, lymphocytes 25 × 10⁹/L, smudge cells, CD5⁺ CD23⁺, λ-restricted	CLL
CD5⁺ B cells, CD23⁻, cyclin D1⁺, GI involvement	Mantle cell lymphoma	t(11;14)
WBC 150, medium cells with punched-out nucleoli, FMC7⁺	B-PLL
Pancytopenia, massive spleen, cells with hairy projections, CD103⁺	Hairy cell leukemia	Purine analogues
Back-to-back follicles without mantle zones, BCL2⁺	Follicular lymphoma	t(14;18)
Child with abdominal mass, starry sky, vacuolated basophilic cells, Ki-67 ~100%	Burkitt	t(8;14)
Gastric lymphoma with lymphoepithelial lesions, H. pylori	MALT lymphoma	Antibiotics
Bone pain, hypercalcemia, renal failure, M-spike, CD138⁺ sheets	Plasma cell myeloma	CRAB
M-spike 15 g/L, 6% marrow plasma cells, no symptoms	MGUS	Monitor
Rouleaux, >20% circulating plasma cells	Plasma cell leukemia
Erythroderma, cerebriform CD4⁺ CD7⁻ cells in blood	Sézary syndrome
Skin patches, Pautrier microabscesses	Mycosis fungoides
Child, large pleomorphic kidney-shaped cells, CD30⁺ ALK⁺	ALCL	t(2;5); good
Young adult, mediastinal mass, fibrous bands, lacunar cells, CD30⁺ CD15⁺	Nodular sclerosis cHL
Popcorn cells CD20⁺, CD15⁻, CD30⁻, male in 30s	NLPHL
46-year-old, single 2-cm node, large cells CD20⁺ CD10⁺ BCL6⁺, focal CD30	DLBCL (GC type)	Rodak case study
Node with immunoblasts, paracortical expansion after mononucleosis	Reactive paracortical hyperplasia
Cat exposure, follicular hyperplasia + epithelioid histiocytes + monocytoid B cells	Toxoplasma lymphadenitis	Mixed pattern

Commonly Confused Pairs

Feature	A	B
CLL vs mantle cell	CD23⁺, LEF1⁺, weak CD20, cyclin D1⁻	CD23⁻, bright CD20, cyclin D1⁺/SOX11⁺, t(11;14)
CLL vs MBL	≥5000/µL clonal B cells	<5000/µL, healthy person
CLL vs PLL	Soccer-ball chromatin, <55% prolymphocytes	>55% prolymphocytes, punched-out nucleoli
Hairy cell vs splenic MZL	CD103, CD25, annexin A1, CD123	Annexin A1 negative
Reactive follicle vs follicular lymphoma	BCL2⁻, mantle zone, polarization, tingible bodies	BCL2⁺, no mantle/polarization, back-to-back
Follicular vs Burkitt (both CD10⁺)	BCL2⁺, t(14;18), indolent	BCL2⁻, t(8;14), ~100% proliferation
Myeloma vs MGUS	≥ clonal plasmacytosis + CRAB	<10%, <30 g/L, no CRAB
Myeloma vs reactive plasmacytosis	Sheets, atypia, monoclonal cIg, CD56	Scattered perivascular, polyclonal
MF vs Sézary	Skin-limited, excellent early survival	Erythroderma + blood, 10–20% 5-yr
ALK⁺ vs ALK⁻ ALCL	Favorable, children	Like PTCL
cHL vs NLPHL	RS cells CD30/CD15⁺, CD45⁻	Popcorn cells CD20⁺, CD45⁺, CD30/15⁻
Nodular sclerosis vs mixed cellularity	Collagen bands, lacunar cells, lowest EBV	No bands, 75% EBV
Indolent vs aggressive lymphoma	Slow, incurable (FL, CLL)	Fast, higher cure (DLBCL, Burkitt)

Timeline Table

Disease	Typical Age	Median Survival / Outcome	Best Exam Use
CLL mutated IGVH	Older adults	24 years	Prognosis
CLL unmutated IGVH	Older adults	~8 years	Prognosis
Richter transformation	~5% of CLL	<1 year	Complication
B-PLL / T-PLL	Mean 70	3 years / 1 year	Prognosis
Hairy cell	Median 55	Durable remission (purine analogue)	Treatment
Mantle cell	Adults	3–5 years	Aggressive
Follicular	Median 59	Indolent (grade 1–2)	Grading
Myeloma	Median 70	3 years	Prognosis
Burkitt endemic	4–7 years	60–90% cure	Variant
MF early	55–60	10-yr 97–98%	Prognosis
Sézary	Adults	5-yr 10–20%	Prognosis
cHL	15–34 and >54	80–90% cure	Bimodal
NLPHL	Men in 30s	80–90%	Epidemiology

4 · Diagnostic Flowcharts

Flowchart 1 — Lymphocytosis in an older adult

Absolute lymphocytosis, small mature cells, smudge cells	→	Flow cytometry
Monoclonal B cells, CD5⁺ CD23⁺, weak CD20/sIg	→	CLL if ≥5000/µL · MBL if <5000/µL
CD5⁺ CD23⁻, bright CD20	→	Mantle cell → cyclin D1/SOX11, t(11;14)
FMC7⁺, >55% prolymphocytes, WBC >100	→	PLL
CD11c/CD25/CD103⁺, pancytopenia, spleen	→	Hairy cell leukemia
Polyclonal, reactive morphology	→	Reactive (viral)
⚠️ Common mistake: diagnosing CLL from morphology alone — mantle cell and MBL must be excluded by flow cytometry.

Flowchart 2 — CD10⁺ B-cell lymphoma

CD19/CD20⁺, CD10⁺ BCL6⁺	→	Germinal center origin
BCL2⁺, follicular pattern, t(14;18)	→	Follicular lymphoma → grade by centroblasts
BCL2⁻, starry sky, ~100% Ki-67, MYC t(8;14)	→	Burkitt — emergency
Large cells, diffuse	→	DLBCL (GC type)
⚠️ Common mistake: calling Burkitt DLBCL without testing MYC — Burkitt requires the translocation.

Flowchart 3 — Monoclonal protein workup

M-spike in serum/urine	→	Marrow plasma cell % + CRAB assessment
<10% plasma cells, <30 g/L, no CRAB	→	MGUS → monitor (25% progress)
Clonal plasma cells + CRAB	→	Plasma cell myeloma
>2 × 10⁹/L or >20% blood plasma cells	→	Plasma cell leukemia
Single bone/soft-tissue mass	→	Plasmacytoma → radiation
⚠️ Common mistake: confusing reactive plasmacytosis (polyclonal, scattered) with myeloma.

Flowchart 4 — Large-cell lymphoma immunophenotyping (Table 36-4)

CD30⁺ CD15⁺ CD45⁻ CD20 weak/−, few big cells in reactive background	→	Classical Hodgkin
CD20⁺ CD45⁺ CD30⁻ CD15⁻ popcorn cells	→	NLPHL
CD20⁺ CD45⁺ sheets of large cells	→	DLBCL
CD30⁺ ALK⁺ CD15⁻, T/null, hallmark cells	→	ALCL
⚠️ Common mistake: diagnosing Hodgkin from CD30 alone — ALCL and some DLBCL are CD30⁺ too.

Flowchart 5 — Rodak case study

46-year-old, isolated 2-cm cervical node, no symptoms	→	Excision
Diffuse large cells; CD20⁺, CD10⁺, BCL6⁺, focal CD30	→	DLBCL (germinal center phenotype)
Flow cytometry confirmation	→	Pan-B antigens (CD19, CD20) + CD10 + monoclonal κ or λ light chain
Staging expectation	→	DLBCL usually localized; marrow involvement rare at presentation
⚠️ Common mistake: calling it Hodgkin because of focal CD30 — sheets of CD20⁺ large cells argue for DLBCL*.

*Case answers are my interpretation; the appendix isn’t in the upload.

Flowchart 6 — Enlarged lymph node: reactive or lymphoma?

Architecture preserved; follicles polarized with mantle zones and tingible bodies	→	Reactive follicular hyperplasia
Paracortical expansion with immunoblasts	→	Viral (IM), drug, dermatopathic
Sinus histiocytosis / monocytoid B cells	→	Reactive sinusoidal (Toxoplasma, HIV) — check for tumor in sinuses
Effaced architecture, monotonous cells, light chain restriction	→	Lymphoma
⚠️ Common mistake: overcalling florid reactive immunoblasts as lymphoma.

5 · 25 High-Yield Facts

#	Fact
1	Lymphomas recapitulate specific stages of normal lymphoid differentiation.
2	The lymph node cortex holds B-cell follicles, the paracortex T cells, and the medulla plasma cells.
3	Germinal center B cells express CD10 and BCL6 and lack BCL2.
4	The germinal center generates B cells with the highest-affinity immunoglobulins through somatic mutation.
5	Follicular hyperplasia is the most common reactive lymphadenopathy.
6	Marked paracortical expansion is typical of viral infections, drug reactions and dermatopathic lymphadenopathy.
7	The strongest risk factor for lymphoma is altered immune function.
8	Follicular lymphoma and DLBCL are the most common mature B-cell lymphomas.
9	CLL shows small lymphocytes with soccer-ball chromatin and smudge cells.
10	CLL cells are CD19⁺, CD20 weak, CD5⁺ and CD23⁺ with light chain restriction; ≥5000/µL is required.
11	Mutated IGVH CLL has a median survival of 24 years; unmutated about 8 years.
12	del(17p13) is the worst FISH abnormality in CLL; about 5% transform to DLBCL (Richter).
13	PLL requires more than 55% prolymphocytes with punched-out nucleoli.
14	Hairy cell leukemia expresses CD11c, CD25, CD103, TRAP, CD123 and annexin A1 and responds to purine analogues.
15	Mantle cell lymphoma is CD5⁺, CD23⁻, cyclin D1⁺ with t(11;14).
16	Follicular lymphoma is BCL2⁺ due to t(14;18), present in 95% of cases.
17	MALT lymphoma shows lymphoepithelial lesions and may remit after H. pylori eradication.
18	Myeloma plasma cells are CD138⁺ and CD38⁺ but CD19⁻ and CD20⁻.
19	Myeloma organ damage is summarized as CRAB: hypercalcemia, renal insufficiency, anemia, bone lesions.
20	MGUS has <10% marrow plasma cells, M protein <30 g/L and no organ damage; 25% progress to myeloma.
21	DLBCL accounts for 30–40% of non-Hodgkin lymphomas and is usually localized at presentation.
22	Burkitt lymphoma has a starry-sky pattern, ~100% proliferation, BCL2 negativity and MYC t(8;14).
23	Mycosis fungoides/Sézary cells are CD4⁺ with loss of CD7 and cerebriform nuclei.
24	ALCL is CD30⁺, usually ALK-1⁺ from t(2;5), and ALK⁺ cases have a favorable prognosis.
25	Reed-Sternberg cells are CD30⁺, CD15⁺ and CD45⁻; nodular sclerosis is the most common classical HL subtype.

⭐ EXAM TIP — The single most testable pattern

Match marker + translocation → lymphoma: CD5⁺CD23⁺ = CLL · CD5⁺ cyclin D1 t(11;14) = mantle cell · CD10⁺BCL2⁺ t(14;18) = follicular · CD10⁺BCL2⁻ MYC t(8;14) = Burkitt · CD103/CD25/CD11c = hairy cell · CD138/CD38 = myeloma · CD4⁺CD7⁻ = MF/Sézary · CD30⁺ALK⁺ t(2;5) = ALCL · CD30⁺CD15⁺CD45⁻ = Hodgkin.

Quick Interpretation Table

Lab Finding	Clinical Interpretation
Isolated 2-cm node, large cells CD20⁺ CD10⁺ BCL6⁺, focal CD30	DLBCL; flow: monoclonal light chain; marrow rarely involved at presentation (Rodak case study)
Lymphocytes 3500/µL, CD5⁺ CD23⁺ monoclonal, healthy person	Monoclonal B-cell lymphocytosis
CLL with del(17p13)	Very poor prognosis
Serum M-protein 42 g/L, 35% atypical plasma cells, Ca 12.5, creatinine ↑	Plasma cell myeloma
M-protein 12 g/L, 4% plasma cells, no CRAB	MGUS
Sézary cells 2400/µL, CD4:CD8 18, CD7 lost	Sézary syndrome
Large cells CD30⁺ CD15⁺ CD45⁻ in eosinophil-rich background	Classical Hodgkin lymphoma
CD19⁺ CD20⁺ CD10⁺ BCL2⁻ Ki-67 99%	Burkitt — confirm MYC translocation

🎴 Flashcards — Active Recall Practice

How it works: tap the card to flip it. Then mark it ✓ Knew It or ✗ Review Again (buttons unlock after flipping). Use 🔀 Shuffle to randomize and 🏁 Finish anytime — your summary appears at the end, and you can drill only the cards you missed.

📝 Practice Quiz — Test Your Knowledge

How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.

🪤 Trap Questions — Beat the Examiner

Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.

8 · Rapid Revision Sheet

📖 READ THIS 2 HOURS BEFORE YOUR EXAM

Normal Node

Cortex B follicles · paracortex T · medulla plasma
GC: CD10, BCL6, BCL2⁻; dark zone mutates
Tingible-body macrophages → starry sky
Memory B: BCL2⁺ · plasma: CD138/CD38
HEVs in paracortex

Reactive Patterns

Follicular (most common): kids, RA, SLE, syphilis, HIV
Paracortical: viral, drugs, dermatopathic
Sinusoidal: HIV, Toxo, draining nodes
Mixed: Toxoplasma triad
Processing: saline gauze, formalin, RPMI

CLL/SLL

Soccer-ball chromatin, smudge cells
CD5⁺ CD23⁺ LEF1⁺, weak CD20, κ or λ
≥5000/µL · MBL <5000
IGVH mutated 24 y · unmutated 8 y
13q good · 12 int · 11q poor · 17p very poor · Richter 5%

PLL & Hairy Cell

PLL >55% prolymphocytes, punched-out nucleoli
B-PLL WBC >100, FMC7 · T-PLL CD7⁺, alemtuzumab
HCL: CD11c, CD25, CD103, TRAP, CD123, annexin A1
Spleen + pancytopenia, age 55, reticulin ↑
Purine analogues

Mantle, FL, MALT

MCL: CD5⁺ CD23⁻ cyclin D1/SOX11, t(11;14), 3–5 y
FL: CD10 BCL6 BCL2⁺, t(14;18) 95%, graded by centroblasts
FL: median 59, marrow 50%
MALT: H. pylori, lymphoepithelial lesions, t(11;18)
MALT: CD5⁻ CD10⁻, GI most common

Plasma Cells

Myeloma: M protein + clonal PCs + CRAB
CD138, CD38, CD56; CD19/CD20⁻
Median 70; survival 3 y
MGUS <10%, <30 g/L, no CRAB; 25% progress
PCL >2 × 10⁹/L or >20%

Aggressive B

DLBCL 30–40% NHL; large cells; localized
Marrow rare at presentation
Burkitt: starry sky, vacuolated basophilic cells
CD10 BCL6, BCL2⁻, ~100% Ki-67, MYC t(8;14)
Endemic jaw · sporadic abdomen · HIV

T-Cell Lymphomas

~10% of lymphomas; more extranodal
MF: cerebriform, epidermotropism, Pautrier
CD4⁺ CD7⁻; Sézary ≥1000/µL, CD4:CD8 >10
PTCL NOS: CD4, loses CD7, 3-y 40%
ALCL: CD30, ALK-1, t(2;5), hallmark cells, kids

Hodgkin

RS cell: bilobed, eosinophilic nucleoli
CD30⁺ CD15⁺ CD45⁻ CD20 weak
Bimodal 15–34 and >54
Cure 80–90%; 2nd cancers
NLPHL popcorn: CD20⁺ CD45⁺ EBV⁻

cHL Subtypes

Nodular sclerosis 70%: bands, lacunar, mediastinum, best
Mixed cellularity 20%: EBV 75%
Lymphocyte rich: older
Lymphocyte depleted: HIV, worst
Table 36-4 separates cHL, NLPHL, DLBCL, ALCL

9 · Final Memory Map

🔬 MATURE LYMPHOID NEOPLASMS
- Normal & Reactive
  - Node compartments · B-cell differentiation
  - Processing · follicular, paracortical, sinusoidal, mixed
- Small B-Cell Neoplasms
  - CLL/SLL · PLL · hairy cell
  - Mantle cell · follicular · MALT
- Plasma Cell Neoplasms
  - Myeloma (CRAB) · plasma cell leukemia
  - MGUS · plasmacytoma
- Aggressive B-Cell
  - DLBCL · Burkitt (MYC)
- T/NK-Cell
  - Mycosis fungoides / Sézary
  - PTCL NOS · ALCL (ALK)
- Hodgkin
  - NLPHL (popcorn)
  - Classical: NS, MC, LR, LD