WBC Disorders: Step 1 Review
Learning objectives
- LO 1Tell white blood cell disorders apart by their clinical and pathophysiologic features.
- LO 2Use ancillary test results (flow, cytogenetics, molecular) to reach a diagnosis.
- LO 3Build a differential diagnosis from the clinical findings and lab data.
- LO 4Use histologic features to support a specific diagnosis.
- LO 5Pick the right answer in board-style cases and explain why each distractor is wrong.
- LO 6Review T-lymphoblastic lymphoma/ALL, CLL, hairy cell leukemia and polycythemia vera.
MAPSort any WBC vignette before you read the choices
LO 1Distinguishing WBC disorders
Q1. How do I tell a blast from a mature cell, and lymphoid from myeloid?
Blast
- Huge nucleus, fine/open chromatin, nucleoli, scant cytoplasm, mitoses
- TdT+ (lymphoblasts), CD34+
- → acute leukemia / lymphoblastic lymphoma; days–weeks
- Blasts in blood → acute leukemia (≥20% in marrow)
Mature cell
- Small, condensed nucleus, clumped chromatin
- TdT−
- → chronic leukemia, indolent lymphoma, MPN; months
Lymphoid
- Nodes, lymphocytosis, B or T markers (CD19/20 · CD2/3/7)
- Replace normal cells → cytopenias
Myeloid (MPN)
- High counts (granulocytes, RBCs, platelets), big spleen
- Tyrosine kinase mutations (JAK2, BCR-ABL); CD13/33
- Overproduce → burn out (fibrosis) or blast out (AML)
In-house exam
Mature lymphocyte = condensed small nucleus; blast = huge nucleus, multiple nucleoli, open chromatin. Pancytopenia argues against an MPN.
Memory tool
Lymphoid neoplasms replace (cytopenias, nodes); MPNs overproduce (high counts, big spleen), then burn out (fibrosis) or blast out (AML).
Q2. How do age and tempo narrow the list?
Age
- 2–5 y: B-ALL (most common childhood cancer)
- Teens/young adults: T-lymphoblastic, Hodgkin, Burkitt, DLBCL; not indolent NHL or plasma cell disorders
- 40s–50s: broad; hairy cell (men), CML, PV
- 60s+: widest list: CLL, mantle, follicular, MDS, MPN, myeloma, metastases
Tempo
- Days: lymphoblastic or aggressive lymphoma
- Weeks: building symptoms, e.g., hyperviscosity (PV)
- Months: indolent: CLL, hairy cell, indolent lymphoma
ApplyLO 1 application question
A1A 4-year-old has bone pain and petechiae; marrow blasts are TdT+, CD10+, CD19+ with t(12;21). Diagnosis and prognosis?
LO 2Using ancillary tests
Q1. What question does each test answer?
| Test | Answers | Example |
|---|---|---|
| CBC + differential | Which lines are up or down? | Pancytopenia (HCL) · lymphocytosis (CLL) · all lines up (PV) |
| Smear | Mature or blasts? Abnormal forms? | Smudge cells, hairy projections, large platelets, nRBCs |
| Flow cytometry | B, T or myeloid? Immature or mature? | CD19+ CD5+ CD23+ = CLL |
| Cytogenetics / FISH | Which translocation or copy change? | t(11;14) mantle · t(9;22) CML |
| Molecular | Which point mutation? Clonal? | JAK2, BRAF, NOTCH1; Ig or TCR rearrangement |
| Biopsy | Architecture + morphology | Proliferation centers (CLL); effaced thymus (T-LBL) |
Q2. What does each marker mean?
| Marker | Means | Seen in |
|---|---|---|
| TdT | Immature lymphoid cell (B or T precursor) | ALL / lymphoblastic lymphoma; negative in Burkitt, CLL |
| CD34 | Stem/progenitor | ALL, AML |
| CD1a, CD2, CD3, CD5, CD7 | T cell (CD1a = cortical thymocyte) | T-LBL / T-ALL |
| CD19, CD20, CD22 | B cell | B-ALL, CLL, HCL, most NHL |
| CD10 | Germinal center / precursor B | B-ALL, Burkitt, follicular |
| CD5 on a B cell | Aberrant | CLL/SLL and mantle cell |
| CD23 | Splits the CD5+ pair | CLL +, mantle − |
| CD11c, CD25, CD103, CD123 | Hairy cell profile | Hairy cell |
| CD15, CD30 · CD138 | Reed-Sternberg · plasma cell | Hodgkin · myeloma |
| CD13, CD33 | Myeloid | AML |
Memory tool
TdT = "Tiny Developing" cells (blasts). CD5+ B cell = CLL or mantle → CLL has the 23. Hairy cell: "11c, 25, 103 make the hairs grow."
In-house exam
CLL = CD19, CD20, CD5, CD23. Hairy cell = CD11c, CD25, CD103 (+ CD20, CD22).
Q3. What do the cytogenetic and molecular findings mean?
| Finding | Effect | Disease |
|---|---|---|
| NOTCH1 point mutation | Activates a receptor needed for T-cell development → proliferation, survival | T-LBL / T-ALL |
| Clonal Ig gene rearrangement | All cells share one rearranged Ig gene = monoclonal B cells | Any B-cell neoplasm |
| Clonal TCR rearrangement | Monoclonal T cells | T-cell neoplasms |
| del(13q), +12, del(11q), del(17p) | del(13q) most common, good; del(17p) = TP53, worst | CLL |
| t(11;14) | Cyclin D1 next to IgH | Mantle cell |
| t(14;18) | BCL2 next to IgH → no apoptosis | Follicular |
| t(8;14) | MYC next to IgH | Burkitt |
| t(9;22) | BCR-ABL tyrosine kinase | CML (some adult B-ALL) |
| BRAF V600E | MAPK activation | Hairy cell |
| JAK2 V617F | Growth-factor-independent signaling | PV (~95%), ~½ ET and PMF |
| MYD88 L265P | NF-κB activation | Waldenström |
Trap — "clonal Ig rearrangement" sounds too generic
When the stem is a mature B-cell neoplasm and no listed translocation fits, it's the right answer: proof of a monoclonal B-cell population. TCR rearrangement would mean a T-cell clone.
Step 1
The 14 in a B-cell translocation is the IgH locus (always-on promoter): 8;14 Burkitt MYC · 11;14 Mantle cyclin D1 · 14;18 Follicular BCL2. 9;22 is the myeloid one.
LO 3Building the differential
Q1. What does each symptom point to?
| Clue | Think |
|---|---|
| Chest discomfort (teen) | Thymus/mediastinal nodes: lymphoblastic, Hodgkin, Burkitt/DLBCL |
| Fatigue (older adult) | Infection · anemia (always find the cause: iron, chronic disease, MDS, MPN, marrow infiltration) · malignancy |
| Recurrent pneumonias | Immunocompromised: neutropenia/monocytopenia (hairy cell), hypogammaglobulinemia (CLL), marrow failure |
| Abdominal "dragging" | Enlarged organ: spleen (or polycystic kidneys) |
| Headache + dizziness | Hyperviscosity → cerebral hypoperfusion (PV, Waldenström, leukostasis) |
| Gastric ulcers + high counts | Microvascular ischemia + basophil histamine → acid (PV) |
| Plethoric to cyanotic face | ↑ red cell mass, sluggish deoxygenated flow |
High yield — reading the stem
Read in layers: clinical → exam → labs → pathology → ancillary. Read the last sentence first (it may ask natural history, a lab or a gene). Note pertinent negatives: no hepatosplenomegaly, clear lungs, afebrile.
Q2. What is the differential for a mediastinal mass and for lymphadenopathy?
Mediastinal mass (adolescent)
- Anterior: lymphoblastic lymphoma, Hodgkin, germ cell tumors, thymic lesions (less likely)
- Middle: lymphoma (nodes)
- Posterior: neurogenic (neuroblastoma, schwannoma)
Nodes
- Localized: Hodgkin (contiguous spread)
- Generalized: lymphoblastic, aggressive NHL, CLL/indolent NHL
- Tender = infection · soft = lymphoma · hard = metastatic carcinoma
Step 1 — 4 T's of anterior mediastinal mass
Thymoma, Teratoma, Thyroid, "Terrible" lymphoma. Teen boy, fast mass → T-LBL; young woman, fibrous bands → nodular sclerosis Hodgkin.
Q3. What causes splenomegaly, and how do CBC clues sort it?
Splenomegaly
- Congestive: cirrhosis, portal hypertension
- Infection: EBV, malaria
- Hemolysis: spherocytosis, thalassemia, AIHA
- Malignancy: MPN (CML, myelofibrosis, PV), Hodgkin, NHL (indolent, hairy cell, CLL)
CBC / smear clues
- Mature lymphocytosis: viral (varied) vs CLL/mantle (monotonous)
- Pancytopenia: MDS, hairy cell, metastases, aplastic anemia, B12/folate
- All lines ↑: MPN, especially PV
- Large platelets: Bernard-Soulier, ITP, MPN
- Nucleated RBCs: hypoxia, marrow stress, infiltration/fibrosis, hemolysis
Step 1
Massive spleen + low counts → hairy cell or myelofibrosis (both dry tap). Massive spleen + high counts → CML/MPN.
Q4. Is polycythemia primary or secondary?
| Cause | EPO | O₂ sat |
|---|---|---|
| PV (JAK2) | ↓ | Normal |
| Hypoxic (COPD, altitude, smoking) | ↑ | ↓ |
| EPO-secreting tumor (RCC, HCC) | ↑ | Normal |
| Relative (dehydration) | Normal | Normal |
Step 1
PV usually also raises WBC, platelets and spleen size; secondary polycythemia raises only RBCs.
LO 4Histologic clues
Q1. Which histology points to which diagnosis?
| Look | Diagnosis |
|---|---|
| Effaced thymus; fine chromatin, convoluted nuclei, many mitoses | T-lymphoblastic lymphoma |
| Smudge cells; node with proliferation centers | CLL/SLL |
| Hairy projections; fried-egg marrow; dry tap | Hairy cell |
| Large platelets, nRBCs; hypercellular marrow → fibrosis | PV |
| Starry sky | Burkitt |
| Back-to-back follicles | Follicular |
| Owl eyes, fibrous bands | Hodgkin (nodular sclerosis) |
| Auer rods | AML (APL) |
| Toxic granulation, Döhle bodies | Reactive (infection) |
| Plasmacytoid cells + IgM | Waldenström |
Normal thymus
- Lobules + Hassall corpuscles
T-lymphoblastic lymphoma
- Sheets of blasts efface the thymus
CLL
- Monotonous small mature lymphocytes
Hairy cell
- Hair-like projections; TRAP+
Massive spleen
- Red pulp infiltration (hairy cell)
PV smear
- Large platelets, nRBCs
Spent phase
- Teardrops → marrow fibrosis
Trap
Normal thymus has lobules, epithelial cells and Hassall corpuscles. Diffuse effacement by blasts = T-LBL, not thymoma.
LO 5The four worked cases
Strategy: each wrong choice is the right answer to a different vignette. Name that vignette and you've explained why it's wrong here.
Case 1. A 14-year-old boy has 5 days of worsening chest discomfort and generalized nodes. CT: 10-cm anterior mediastinal mass. Biopsy: lymphoid cells with lobulated nuclei, fine chromatin, scant cytoplasm, many mitoses; CD2+, CD7+; NOTCH1 point mutation; curable with chemo. Diagnosis?
Answer: lymphoblastic lymphoma (T cell).
| Distractor | Its home vignette |
|---|---|
| Burkitt | B cell, starry sky, MYC, extranodal |
| Follicular | Indolent B, older, BCL2 |
| Nodular sclerosis HL | RS cells CD15/30, fibrous bands |
| Mantle cell | Older men, CD5, cyclin D1 |
| SLL | Mature B, older, nodes + marrow |
In-house exam
T-LBL/T-ALL: NOTCH1, thymus (anterior mediastinal mass), adolescent males.
Case 2. A 70-year-old man has 6 months of fatigue and non-tender cervical and axillary nodes, no hepatosplenomegaly. Hb 9.5, MCV 90, platelets 120k, WBC 42k of monotonous small mature lymphocytes; CD19+, CD5+, TdT−. Cytogenetic/molecular finding?
Answer: clonal rearrangement of immunoglobulin genes (CLL).
| Distractor | Its home vignette |
|---|---|
| Clonal TCR rearrangement | T-cell neoplasm |
| t(8;14) MYC | Burkitt |
| t(9;22) BCR-ABL | CML |
| t(14;18) BCL2 | Follicular (CD10+, CD5−) |
Case 3. A 41-year-old man has had several pneumonias in a year, now vague abdominal pain and a dragging sensation; marked splenomegaly. Hb 8.2, platelets 63k, WBC 2,400; small cells with hair-like projections; sputum grows M. kansasii. Most characteristic lab?
Answer: CD20+ and CD11c+ lymphocytes (hairy cell leukemia).
| Distractor | Its home vignette |
|---|---|
| Auer rods | AML |
| Monoclonal IgM | Waldenström |
| t(9;22) | CML (big spleen but high WBC) |
| Toxic granulation | Reactive infection |
In-house exam
Hairy cell: pancytopenia + big spleen, men; monocytopenia → atypical mycobacteria.
Case 4. A 60-year-old woman has 5 weeks of headache and dizziness, gastric ulcers on a PPI, a plethoric-to-cyanotic face and mild splenomegaly. Hb 21.7, Hct 65%, platelets 400k, WBC 30k; large platelets and nRBCs. Natural history?
Answer: marrow fibrosis with extramedullary hematopoiesis (PV spent phase).
| Distractor | Its home vignette |
|---|---|
| Gastric NHL | MALT (H. pylori), not an MPN outcome |
| AL amyloidosis | Plasma cell disorders |
| Spontaneous remissions | PV is progressive; needs treatment |
| B-ALL transformation | MPNs transform to AML, not B-ALL |
LO 6The four review diseases
Q1. How do the four diseases compare?
| T-LBL / T-ALL | CLL / SLL | Hairy cell | PV | |
|---|---|---|---|---|
| Cell | Immature T (thymus) | Mature B | Mature B | Myeloid stem cell |
| Patient | Adolescent boy | ~70 | Middle-aged/older man | ~60 |
| Tempo | Days | Months–years | Indolent, progressive | Chronic |
| Where | Anterior mediastinum, nodes | Blood, marrow, nodes | Spleen, marrow; no big nodes | Marrow, blood, spleen |
| Counts | Variable; blasts if leukemic | Mature lymphocytosis ± anemia | Pancytopenia, monocytopenia | ↑ Hb/Hct, often ↑ WBC, platelets |
| Markers | TdT, CD1a, CD2, CD3, CD5, CD7 | CD19, CD20 (dim), CD5, CD23 | CD11c, CD25, CD103; TRAP | Low EPO |
| Driver | NOTCH1 | del(13q), +12 | BRAF V600E | JAK2 V617F |
| Feared outcome | SVC/airway compression; CNS/testis relapse | Infections, AIHA, Richter → DLBCL | Infections | Thrombosis; spent phase; AML |
| Treatment | Multi-agent chemo (curative) | Watch; BTK inhibitors, venetoclax | Cladribine | Phlebotomy + aspirin |
Memory tool
T-LBL: "Teen, thymus, TdT." CLL: "Old man, smudge cells, 5 & 23." Hairy cell: "Spleen big, counts low, TRAPped, BRAF." PV: "Red face, itchy shower, JAK2."
In-house exam
ALL cytogenetics with good prognosis = hyperdiploidy. MDS losses = monosomy 5, 7. Myeloma: IL-6 from plasma + stromal cells drives it.
Q2. How do I separate CLL from mantle cell lymphoma?
| CLL | Mantle cell | |
|---|---|---|
| Patient / nodes | Older; diffuse | Older men; diffuse; GI polyposis |
| Blood | Mature lymphocytosis, smudge cells | Less common |
| Phenotype | CD5+, CD23+ | CD5+, CD23−, cyclin D1+ |
| Genetics | del(13q), +12; Ig rearrangement | t(11;14) |
| Node | Diffuse + proliferation centers | Vaguely nodular, no proliferation centers |
Step 1
CLL = most common adult leukemia in the West; del(13q) most common, del(17p)/TP53 worst. Hairy cell → cladribine (excellent response). PV → thrombosis is the main killer.
ApplyLO 6 application questions
A1A man with PV for 12 years now has a growing spleen, falling hemoglobin, teardrop cells and a dry tap. What happened?
A2A 75-year-old with CLL develops a sudden fast-growing neck node and fevers. Diagnosis?
IDImage ID
Image 1 — tissue
Image 2 — smear
Image 3 — smear
Image 4 — smear
Image 5 — smear
MCQExam-style questions
1A 15-year-old boy has 1 week of dyspnea and facial swelling. CT shows a large anterior mediastinal mass. Biopsy shows sheets of blasts that are TdT+, CD1a+, CD7+. Which mutation is most likely?
2A 68-year-old has lymphocytosis of small mature B cells that are CD5+. Which additional marker distinguishes CLL from mantle cell lymphoma?
3In a patient with CLL, which cytogenetic finding carries the worst prognosis?
4A 52-year-old man has massive splenomegaly, pancytopenia and recurrent atypical mycobacterial infections. Marrow aspiration is a dry tap. Best treatment?
5A 62-year-old has Hct 60%, WBC 18k, platelets 650k, splenomegaly and pruritus after hot showers. Expected serum EPO and mutation?
6A smoker with COPD has Hct 58%, O₂ saturation 86% and high EPO. Platelets, WBC and spleen are normal. Diagnosis?
7A 70-year-old man has mature lymphocytosis (CD19+, CD5+, TdT−) and generalized non-tender nodes. Which molecular finding is expected?
8A patient with a myeloproliferative neoplasm is most likely to transform to which disease?
9Which feature argues most strongly against a myeloproliferative neoplasm?
10A fast-growing abdominal lymphoma in a 12-year-old is TdT-negative, CD10+, CD20+, IgM+. Which is most likely?
11A 60-year-old with polycythemia vera has gastric ulcers. What best explains them?
12Which childhood ALL cytogenetic finding is favorable?
!Source notes
| Item | Lecture | Step 1 / standard references |
|---|---|---|
| TdT in case 1 | Stem says blasts are TdT negative; explanation says TdT is usually positive | TdT+ defines lymphoblasts; a TdT− fast lymphoma suggests Burkitt |
| TdT scope | "Precursor/immature B cells" | Marks both B and T precursors |
| CLL cytogenetics | Trisomy 12 | Most common = del(13q14) (~50%); +12 ~20% |
| Mantle cell | Grouped with indolent lymphomas | Moderately aggressive; worse prognosis than CLL or follicular |
| Hairy cell age | Case: 41-year-old | Typically middle-aged to older men (median ~55) |