Less Common Lymphoid and Myeloid Malignancies¶

Chapter 115 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies · Chapter 115

Key Clinical Points¶

Hodgkin lymphoma (HL) typically presents in two age peaks: childhood and adults aged 30–40 years.
Nodular Lymphocyte-Predominant HL (NLPHL) is a distinct entity (<5% of HL cases) with a chronic relapsing course, specific markers (CD20+, CD19+, BCL2+; no CD30/CD15), and a 75% male predominance.
ABVD is the preferred regimen for early-stage HL to minimize risks such as acute leukemia compared to MOPP or BEACOPP.
Survivorship of HL involves monitoring for second malignancies (especially carcinomas ≥10 years post-treatment), cardiac injury, and thyroid dysfunction.
Dry tap (inability to aspirate bone marrow) occurs in approximately 4% of attempts and is associated with conditions like myelofibrosis (14%) and hairy cell leukemia (10%).
Myeloid neoplasms are classified by the International Consensus Classification (ICC), including specific criteria for AML, MDS/AML, and MPN.
Chronic Neutrophilic Leukemia (CNL) requires ≥13 imes 10^9/L leukocytes and ≥80% neutrophils; Chronic Myelomonocytic Leukemia (CMML) requires ≥0.5 imes 10^9/L monocyte count.
Primary eosinophilia is categorized by the presence of TKGF, with M/LN-EO-TK requiring positive TKGF and CEL-NOS having no TKGF.

DEFINITION & CLASSIFICATION¶

• Nodular Lymphocyte-Predominant HL (NLPHL): Distinct from classical Hodgkin lymphoma ◦ Prevalence: <5% of all HL cases ◦ Morphology: Predominance of small lymphocytes and rare L&H cells ◦ Immunophenotype: CD20+, CD19+, BCL2+; No expression of CD30/CD15 ◦ Clinical Course: Chronic relapsing course resembling indolent B-cell NHLs ◦ Transformation Risk: May transform to diffuse large B-cell lymphoma (T-cell/histiocyte–rich subtype) ◦ Demographics: Male predominance (75% of cases)

• Myeloid Neoplasms (ICC Classification): Table 115-4 provides the International Consensus Classification for Myeloid Neoplasms ◦ AML: Classified by blast percentage (≥10% or ≥20%) and specific genetic markers (e.g., KMT2A, NPM1, TP53) ◦ MDS/AML: Includes categories based on myelodysplasia-related mutations or karyotypes ◦ MPN: Includes Chronic myeloid leukemia, Polycythemia vera, Essential thrombocythemia, and Primary myelofibrosis (PMF) ◦ Other Categories: Includes Myeloid sarcoma, Blastic plasmacytoid dendritic cell neoplasm, and Mastocytosis

EPIDEMIOLOGY & CLINICAL FEATURES¶

• Hodgkin Lymphoma (HL) Demographics: ◦ Age Peaks: Childhood and adults aged 30–40 years ◦ Presentation: Most patients present with stage I/II disease (75%) ◦ Symptoms: B symptoms are uncommon

• NLPHL Features: ◦ Clinical Course: Chronic relapsing course resembling indolent B-cell NHLs

DIAGNOSTIC APPROACH¶

Histopathology & Immunophenotyping: Used to differentiate NLPHL from other lymphomas • Identify nodular growth pattern and L&H cells • Confirm immunophenotype: CD20+/CD19+/BCL2+ without CD30/CD15 expression
Staging: • Most patients present with early-stage disease (stage I/II) • PET scanning used for risk stratification in early-stage HL
Bone Marrow Assessment: Evaluation of 'Dry Tap' (Inability to Aspirate) - Table 115-3 • Occurrence: ~4% of attempts • Associated Conditions: ◦ Metastatic carcinoma infiltration: 17% ◦ Chronic myeloid leukemia: 15% ◦ Myelofibrosis: 14% ◦ Hairy cell leukemia: 10% ◦ Acute leukemia: 10% ◦ Lymphomas, Hodgkin’s disease: 9% ◦ Normal marrow: Rare

Myeloid Differentiation Criteria¶

• CNL, aCML, and CMML (Table 115-5): Criteria for distinguishing myeloid conditions ◦ CNL: PB leukocyte count ≥13 imes 10^9/L; ≥80% neutrophils; <10% neutrophil precursors ◦ aCML: ≥13 imes 10^9/L leukocytes; ≥10% neutrophil precursors; Granulocytic dysplasia ◦ CMML: ≥0.5 imes 10^9/L monocyte count; ≥10% monocyte percentage; Persistent and lasting for at least 3 months

Eosinophilia Classification¶

• Primary Eosinophilia (Table 115-6): Classification based on eosinophil count and markers ◦ M/LN-EO-TK: ≥1500 imes 10^9/L; ≥10% eosinophils; TKGF positive ◦ CEL-NOS: ≥1500 imes 10^9/L; ≥10% eosinophils; TKGF negative ◦ Lymphocytic Variant Hypereosinophilia: ≥1500 imes 10^9/L; ≥10% eosinophils; Abnormal T lymphocyte phenotype ◦ Hypereosinophilic Syndrome: ≥1500 imes 10^9/L; ≥10% eosinophils

MANAGEMENT & TREATMENT¶

Early-Stage HL Treatment: • Primary Goal: Definitive radiotherapy (82% 15-year nonrelapse survival) • Chemotherapy Selection: ABVD preferred over MOPP/BEACOPP to reduce leukemia risk
Advanced-Stage HL Treatment: • Options: ABVD or brentuximab-AVD regimens
NLPHL Management: • Asymptomatic cases → Close observation • Symptomatic cases → Consider R-CHOP or cHL regimens (Note: R-CHOP may achieve 100% response rates in advanced-stage NLPHL with short-term follow-up)
Risk Reduction Strategies: • Thoracic Radiotherapy: Avoid in young women → Schedule screening mammograms/MRI 5–10 years post-treatment • Coronary Risk: Smoking cessation, cholesterol management • Thyroid Monitoring: Intermittent thyrotropin measurements for thoracic radiotherapy recipients

COMPLICATIONS & PROGNOSIS¶

• Second Malignancies: ◦ Carcinomas (especially breast, thyroid) ≥10 years post-treatment

• Cardiac Injury: ◦ Risk from radiotherapy and alkylating agents ◦ Result: Radiation-associated coronary artery disease

• Acute Leukemia: ◦ Risk associated with MOPP/BEACOPP regimens ◦ Higher risk in patients >60 years

• Thyroid Dysfunction: ◦ Hypothyroidism in thoracic radiotherapy recipients ◦ Lhermitte’s syndrome: Electric shock sensation on neck flexion (15% of thoracic radiotherapy recipients)

• Infertility: ◦ Alkylating agents → permanent infertility in men ◦ Women: Age-related recovery potential

KEY PEARLS & HIGH-YIELD POINTS¶

• NLPHL vs. cHL: NLPHL is characterized by the absence of CD30/CD15 and a more indolent, relapsing course. • Treatment Choice: ABVD is the standard for reducing leukemia risk in HL; R-CHOP is highly effective for advanced NLPHL. • Myeloid Differentiation: Table 115-4 provides the comprehensive ICC framework for Myeloid Neoplasms. • Eosinophilia: Distinction between M/LN-EO-TK and CEL-NOS depends on TKGF status.

Reference Tables¶

TABLE 115-1 Unusual Lymphoid and Myeloid Malignancies a Lymphoid Mature B-cell neoplasms¶

Harrison's 22e, p.872

Lymphoid
Mature B-cell neoplasms
B-cell prolymphocytic leukemia
Splenic marginal zone lymphoma
Hairy cell leukemia
Nodal marginal zone B-cell lymphoma
Mediastinal large B-cell lymphoma
Intravascular large B-cell lymphoma
Primary effusion lymphoma
Lymphomatoid granulomatosis
Mature T-cell and natural killer (NK) cell neoplasms
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK cell leukemia
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Blastic NK cell lymphoma
Primary cutaneous CD30+ T-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Myeloid
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia/hypereosinophilic syndrome
Histiocytic and Dendritic Cell Neoplasms
Histiocytic sarcoma
Langerhans cell histiocytosis
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma
Follicular dendritic cell sarcoma
Mast cells
Mastocytosis
Cutaneous mastocytosis
Systemic mastocytosis
Mast cell sarcoma
Extracutaneous mastocytoma

TABLE 115-2 Immunophenotype of Tumors of Small Lymphocytes Follicular lymphoma Chronic lymphoid pos leukemia B-cell…¶

Harrison's 22e, p.872

	CD5	CD20	CD43	CD10	CD103	sIG	CYCLIN D1
Follicular lymphoma	neg	pos	pos	pos	neg	pos	neg
	pos	pos	pos	neg	neg	pos
B-cell prolymphocytic leukemia	pos	pos	pos	neg	neg	pos	pos
	pos	pos	pos	neg	neg	pos
Splenic marginal zone lymphoma	neg	pos	neg	neg	neg	pos	neg
	neg	pos	?	neg	pos	pos

TABLE 115-3 Differential Diagnosis of “Dry Tap”—Inability to Aspirate Bone Marrow Dry taps occur in about 4% of…¶

Harrison's 22e, p.873

Dry taps occur in about 4% of attempts and are associated with:
Metastatic carcinoma infiltration	17%
Chronic myeloid leukemia	15%
Myelofibrosis	14%
Hairy cell leukemia	10%
Acute leukemia	10%
Lymphomas, Hodgkin’s disease	9%
Normal marrow	Rare

TABLE 115-4 International Consensus Classification of Myeloid Neoplasms 6. Acute myeloid leukemia (AML)¶

Harrison's 22e, p.876

1. Acute myeloid leukemia (AML)
  a. AML diagnosis requiring ≥10% bone marrow (BM) or peripheral blood (PB)
  blasts
  i. Acute promyelocytic leukemia
  ii. Core binding factor AML
  iii. AML with KMT2A rearrangement
  iv. AML with DEK::NUP214
  v. AML with MECOM rearrangements
  vi. AML with NPM1 mutation
  vii. AML with in-frame bZIP CEBPA mutations
  viii. AML with other rare recurring translocations
  ix. Myelodysplastic syndrome (MDS)/AML with TP53 mutations
  x. MDS/AML with myelodysplasia-related mutations
  xi. MDS/AML with myelodysplasia-related karyotype
  xii. MDS/AML not otherwise specified (NOS)
  b. AML diagnosis requiring ≥20% BM or PB blasts
  i. AML with t(9;22)-BCR::ABL1
  ii. AML with TP53 mutations, other than pure erythroid leukemia
  iii. AML with myelodysplasia-related gene mutations
  iv. AML with myelodysplasia-related karyotype
  v. AML NOS
  7. AML-related disorders
  a. Pure erythroid leukemia (PEL; TP53 mutated)
  b. Myeloid sarcoma
  c. Blastic plasmacytoid dendritic cell neoplasm
  d. Acute leukemia of ambiguous lineage
  e. Acute undifferentiated leukemia
  f. Mixed phenotype acute leukemia
  8. Myelodysplastic syndromes (MDS)
  a. MDS with mutated TP53
  b. MDS with excess blasts (5–9% BM or 2–9% PB)
  c. MDS without excess blasts (<5% BM and <2% PB)
  i. MDS with del(5q) [isolated or accompanied by only one other
  cytogenetic abnormality other than 7/del(7q); no multi-hit TP53]
  ii. MDS with SF3B1 [variant allele frequency ≥10%/no RUNX1 or multi-hit
  TP53; no del(5q), –7/del(7q), complex karyotype, or abnormal 3q26.2]
  iii. MDS, NOS–single-lineage dysplasia
  iv. MDS, NOS–multilineage dysplasia
  v. MDS, NOS without dysplasia
  9. MDS/AML
  a. MDS/AML (BM/PB blasts 10–19%)
  b. MDS/AML with mutated TP53
  10. Myeloproliferative neoplasms (MPN)
  a. Chronic myeloid leukemia
  b. Polycythemia vera
  c. Essential thrombocythemia
  d. Primary myelofibrosis (PMF)
  i. Early/prefibrotic PMF
  ii. Overt PMF
  e. MPN, unclassifiable (MPN-U)
  f. Chronic neutrophilic leukemia
  g. Chronic eosinophilic leukemia, NOS
  11. MDS/MPN
  a. Chronic myelomonocytic leukemia (CMML) (≥0.5 × 109/L absolute and ≥10%
  PB monocytes)
  i. CMML-1 (<10% BM and <5% PB blasts)
  ii. CMML-2 (10–19% BM or 5–19% PB blasts)
  b. Atypical chronic myeloid leukemia
  c. MDS/MPN with mutated SF3B1 and thrombocytosis
  d. MDS/MPN with ring sideroblasts and thrombocytosis, NOS
  e. MDS/MPN, NOS
  i. MDS/MPN with isolated isochromosome (17q)
  12. Eosinophilic disorders
  13. Mastocytosis
  14. Hematologic neoplasms with germline predisposition
  15. Pediatric myeloid malignancies
  16. Premalignant clonal hematopoiesis

TABLE 115-5 International Consensus Classification (ICC) Diagnostic Criteria for Chronic Neutrophilic Leukemia (CNL)…¶

Harrison's 22e, p.877

VARIABLES	CNLa	aCML	CMML
PB leukocyte count	≥13 × 109/Ld	≥13 × 109/L
	≥80%
PB neutrophil precursorsb	<10%	≥10%
	Usually absente	<20%
PB monocyte count	<10% of leukocytes	No or minimal monocytosis	≥0.5 × 109/Lg Persistent and lasting for at least 3 months
		Yes
Dysgranulopoiesis		Yes
		<10%
PB monocyte percentage		<10%	≥10%
	Hypercellular ↑ Neutrophils, number and % <5% blasts Normal neutrophilic maturation	Hypercellular ↑ Granulocyte proliferation Granulocytic dysplasia ± erythroid/megakaryocyte Dysplasia <20% blasts
BCR-ABL1	No	No	No
	No	No
CSF3R T618I or other activating CSF3R mutation or persistent neutrophilia, splenomegaly, no identifiable cause of reactive neutrophilia,c if plasma cell neoplasm is present, need demonstration of clonality of myeloid cells by cytogenetic or molecular studies	Yes
		<20%
Evidence for other MPN: CML, PV, ET, PMF	No	No	No
	No	No

TABLE 115-6 Primary Eosinophilia Classification VARIABLES Absolute eosinophil count PB eosinophil % Documentation of…¶

Harrison's 22e, p.878

VARIABLES	EOSINOPHILIA ASSOCIATED WITH TKGF (M/LN-EO-TK)	CHRONIC EOSINOPHILIC LEUKEMIA, NOT OTHERWISE SPECIFIED (CEL-NOS)	LYMPHOCYTIC VARIANT HYPEREOSINOPHILIA	HYPEREOSINOPHILIC SYNDROME
Absolute eosinophil count	≥1500 × 109/L	≥1500 × 109/L	≥1500 × 109/L	≥1500 × 109/L
	≥10%	≥10%	≥10%
Documentation of chronicity of eosinophilia	Advised	Advised	Advised	Advised
	Absent	Absent	Absent
PB blast ≥2% or BM blast ≥5%	Yes or no	Yes or no	No	No
	Yes or no	Yes or no	No
TKGF	Yes	No	No	No
	No	No	No
Abnormal T lymphocyte phenotype or clonal T-cell clones	No	No	Yes	No
	Yes or no	Yes or no	Yes or no