96 Hodgkin Lymphoma

Question 1

Hodgkin lymphoma is derived from

Answer 1

Germinal center B cell

Question 2

Defined by the presence of malignant Hodgkin and Reed-Sternberg (HRS) cells with a characteristic immunophenotype and appropriate cellular background

Answer 2

Classic Hodgkin lymphoma (cHL)

Question 3

Characterized by malignant lymphocyte-predominant (LP) cells or “popcorn cells” embedded within B-cell rich nodules

Answer 3

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)

Question 4

LP cells express typical B-cell antigens namely _____________ and rarely express CD30 or CD15

Answer 4

(CD) 20, OCT2, and BOB

Question 5

cHL subtype that predominates in young adults

Answer 5

Nodular sclerosis subtype

Question 6

cHL subtype that is more common in children and adults older than 60 years of age and among immunosuppressed populations, including patients with HIV infection

Answer 6

Mixed cellularity subtype

Question 7

cHL has (male/female) predominance at all ages, which is more prominent beyond the ______ decade of life

Answer 7

Male

Third

Question 8

Factors for increased risk of cHL

Answer 8

• High socioeconomic status
• A personal or family history of an autoimmune disorder or systemic disease, particularly sarcoidosis
• EBV

Question 9

Factors for reduced risk of cHL

Answer 9

Living in a rental home, sharing a bedroom, and attending daycare or nursery school and early parity in women

Question 10

TRUE OR FALSE

The presence of the Epstein- Barr virus (EBV) in HRS cells is more common in less developed countries and in pediatric and older adult cases

Answer 10

TRUE

The presence of the Epstein- Barr virus (EBV) in HRS cells is more common in less developed countries and in pediatric and older adult cases

Question 11

A threefold increased risk of cHL in young adults is conferred by a prior history of serologically confirmed __________________

Answer 11

Infectious mononucleosis

Question 12

EBV-associated cases are more common in the following cases

Answer 12

• Mixed cellularity histology
• Hispanic ethnicity
• Patients older than the age of 60 years

Question 13

TRUE OR FALSE

The incidence of cHL is 10–20 times higher in patients with HIV infection than in the general population, and such cases typically have detectable EBV within HRS cells.

Answer 13

TRUE

The incidence of cHL is 10–20 times higher in patients with HIV infection than in the general population, and such cases typically have detectable EBV within HRS cells.

In contrast to non-Hodgkin lymphoma (NHL), the incidence of cHL in the HIV-infected population has increased despite less-severe immunosuppression in the era of highly active antiretroviral therapy.

Question 14

TRUE OR FALSE

The increased risk of the disease among identical AND fraternal twins provides the strongest evidence for a genetic association.

Answer 14

FALSE

The increased risk of the disease among identical, but not fraternal, twins provides the strongest evidence for a genetic association.

Question 15

TRUE OR FALSE

HRS cells are pathognomonic for cHL

Answer 15

FALSE

HRS cells are NOT pathognomonic for cHL

May be seen in reactive and other neoplastic conditions such as chronic lymphocytic leukemia.

Question 16

TRUE OR FALSE

HRS cells show a global loss of their B-cell phenotype, retaining only B-cell features associated with their interaction with T cells and their antigenpresenting function.

Answer 16

TRUE

HRS cells show a global loss of their B-cell phenotype, retaining only B-cell features associated with their interaction with T cells and their antigenpresenting function.

The lack of expression of numerous B-cell genes is the result of loss of transcription factor expression (OCT2, BOB1, PU.1) and epigenetic silencing

Question 17

Studies show that HRS cells harbor near universal genetic alterations of chromosome _________ , leading to overexpression of the programmed death-1 (PD-1) ligands, PD-L1 and PD-L2, along with Janus kinase 2 (JAK2).

Answer 17

Chromosome 9p24.1

Question 18

The most commonly mutated gene in cHL.

Answer 18

β-2 microglobulin (β2M)

Occur in approximately 70% of patients with cHL and are associated with younger age and the nodular sclerosis subtype.

Decreased or absent β2M/MHC class I expression has been identified as a poor prognostic factor independent of 9p24.1 status.

Question 19

Viral protein involved in the association of EBV with cHL

Answer 19

Latent membrane protein 1 (LMP1) and Latent membrane protein 2 (LMP2)

Question 20

Represent the largest and probably most important population of cells in the HRS microenvironment

Answer 20

T cells

Question 21

An antiphagocytic “don’t eat me” signal secreted by HRS cells, which binds to signal regulatory protein α on macrophages to suppress phagocytosis.

Answer 21

CD47

Question 22

TRUE OR FALSE: T CELL CHANGES

A hallmark of these changes is the shift from an antitumor, cytotoxic T-helper 1 response to a protumor, humoral T-helper 2 response

Answer 22

TRUE

A hallmark of these changes is the shift from an antitumor, cytotoxic T-helper 1 response to a protumor, humoral T-helper 2 response

Question 23

TRUE OR FALSE: Macrophages in the microenvironment

Macrophages are also abundant in the tumor microenvironment, and an increased number of tumor-associated macrophages is strongly associated with inferior outcomes in cHL.

Answer 23

TRUE

Macrophages are also abundant in the tumor microenvironment, and an increased number of tumor-associated macrophages is strongly associated with inferior outcomes in cHL.

Question 24

anti CTLA4

Answer 24

Ipilimumab

Question 25

anti CD47

Answer 25

Magrolimab

Question 26

anti CD30

Answer 26

Brentuximab vedotin

Question 27

anti PD1

Answer 27

Nivolumab Pembrolizumab

Question 28

anti CD25

Answer 28

Camidanlumab tesirine

Question 29

A cyclic pattern of high fevers in HL for 1–2 weeks alternating with afebrile periods of similar duration

Answer 29

Pel-Ebstein fever

Question 30

# TRUE OR FALSE Fevers in HL are usually of high grade and regular

Answer 30

FALSE Fevers in HL are usually of **low grade and irregular** ## Footnote Fever in excess of 38  C, drenching night sweats, and unexplained weight loss exceeding 10% of baseline body weight during the 6 months preceding diagnosis are designated as **“B” symptoms.**

Question 31

Symptom that occurs in **fewer than 10%** of patients but is **nearly specific to cHL**

Answer 31

Pain in involved lymph nodes immediately after the ingestion of alcohol

Question 32

The most common presentation of cHL

Answer 32

**Unusual mass or swelling in the superficial, supradiaphragmatic lymph nodes** **(60–70%) cervical and supraclavicular** (15–20%) axillary ## Footnote **15% to 20%** of patients have **infradiaphragmatic** disease Lymphadenopathy is usually **nontender** and has a **“rubbery”** consistency.

Question 33

**Intrathoracic disease** is present at diagnosis in _________ of patients.

Answer 33

Two-thirds ## Footnote Mediastinal adenopathy is common in cHL, particularly in **young women** with the **nodular sclerosis subtype**.

Question 34

Mediastinal adenopathy is common in cHL, particularly in young____________ with the ________________subtype.

Answer 34

Women Nodular sclerosis

Question 35

# TRUE OR FALSE PET is sensitive for the presence of marrow involvement at diagnosis, and the absence of marrow uptake obviates the need for marrow biopsy.

Answer 35

TRUE PET is sensitive for the presence of marrow involvement at diagnosis, and the absence of marrow uptake obviates the need for marrow biopsy. ## Footnote Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become standard in the staging of cHL

Question 36

Causes of false-positve results of PET CT Scan

Answer 36

Thymic hyperplasia, brown fat, granulomatous disease, or infectious disorders

Question 37

# TRUE OR FALSE Achieving a complete remission (CR) by PET after two cycles of ABVD is predictive of favorable outcomes in cHL.

Answer 37

TRUE Achieving a **complete remission (CR) by PET after two cycles** of ABVD is predictive of **favorable** outcomes in cHL.

Question 38

Morphologic charateristics of cHL

Answer 38

Scattered **large mononuclear or multinucleated HRS cells** within an inflammatory infiltrate of small lymphocytes, histiocytes, neutrophils, eosinophils, plasma cells, fibroblasts, and collagen fibers

Question 39

Characteristic immunophenotype of HRS cHL

Answer 39

CD30 and dim staining for PAX5 CD15 is commonly expressed (75–85% of cases) Negative CD20 Bcell markers OCT2 and BOB.1 T-cell markers CD3 and ALK ## Footnote Because HRS cells typically constitute only 1% to 5% of cells in the tissue infiltrate, **flow cytometry is typically negative in cHL and is not a useful diagnostic test.**

Question 40

Constitutes **60% to 70%** of cHL and has a distinct histologic appearance with a **thickened capsule and fibrous bands** that divide the lymphoid tissue into cellular nodules.

Answer 40

Nodular sclerosis subtype

Question 41

Constitutes **20% to 30%** of cases and is commonly associated with **EBV and immunodeficiency**, including **HIV infection** More common in **older adults** and associated with **advanced-stage disease**

Answer 41

Mixed cellularity cHL

Question 42

Observed in **5% to 10%** of cases and **resembles NLPHL** morphologically but is readily distinguished by immunophenotype **(CD30+ CD20-)**

Answer 42

Lymphocyte rich cHL

Question 43

The **rarest** subtype, representing only **1%** of cases, and often occurs in the setting of **HIV infection** Present with **advanced-stage disease, B symptoms, and extranodal** involvement

Answer 43

Lymphocyte-depleted cHL

Question 44

Indications for bone marrow biopsy

Answer 44

Multifocal hypermetabolic bone lesions or unexplained cytopenias ## Footnote Marrow involvement occurs in **fewer than 10%** of patients and is almost never involved in patients with clinical **stage I–II** disease who are **young, asymptomatic, and without unexplained cytopenias.**

Question 45

Most common location of lymph nodes in HL

Answer 45

Cervical nodes 70% ## Footnote 12% axillary nodes 9% inguinal nodes A small minority of patients present exclusively with **infradiaphragmatic disease and have inferior outcomes** compared with those with supradiaphragmatic early-stage disease.

Question 46

A marker that **correlates with prognosis**, particularly in limited-stage disease Although nonspecific, it may be a useful **harbinger of recurrent disease** if serially monitored

Answer 46

Elevation of the erythrocyte sedimentation rate (ESR)

Question 47

Definition of **Bulky** mediastinal disease

Answer 47

10 cm Width greater than one-third of the maximum intrathoracic diameter

Question 48

Identified as **independent predictors of relapse** and are considered unfavorable risk factors

Answer 48

* Bulky mediastinal disease * B symptoms * Elevated ESR

Question 49

# Advanced Stage Disease Seven risk factors used in **International Prognostic Score (IPS-7)** ## Footnote Advanced-stage disease (stages III–IV and often including stage II with B symptoms or bulky mediastinal disease)

Answer 49

* Age 45 years of age or older * Male sex * Stage IV disease * White blood cell count ≥15 x109/L * Absolute lymphocyte count <0.6 x 109/L or <8% * Hemoglobin <105 g/L * Albumin <4 g/dL

Question 50

Components of IPS-3 ## Footnote A newer simpler prognostic score (IPS-3) incorporating only three variables: ____________ has also been proposed and outperformed the IPS-7 on risk prediction for PFS and OS for patients treated in the modern era.

Answer 50

Age, stage, and hemoglobin

Question 51

# TRUE OR FALSE Greater magnitude of 9p24.1 alterations by FISH (amplification vs copy gain or polysomy) and increased PD-L1 expression by immunohistochemistry are associated with inferior outcomes after ABVD or Stanford V chemotherapy.

Answer 51

TRUE **Greater magnitude of 9p24.1 alterations by FISH** (amplification vs copy gain or polysomy) and **increased PD-L1 expression** by immunohistochemistry are associated with **inferior** outcomes after ABVD or Stanford V chemotherapy.

Question 52

**Early-stage favorable cHL** is defined in North America as:

Answer 52

* Stage I–IIA supradiaphragmatic disease with no more than three nodal sites * No bulky disease * ESR less than 50 mm/h

Question 53

First CT-adapted study to evaluate omitting radiotherapy in a randomized phase 3 setting

Answer 53

Canadian HD.6 trial ## Footnote Treatment with ABVD therapy alone was superior because of a lower rate of death from secondary malignancies and other causes

Question 54

Study that demonstrated **comparable efficacy and reduced toxicity with IFRT compared to EFRT** following ABVD-based chemotherapy

Answer 54

GHSG HD8 trial

Question 55

Study that showed **Inferiority of the EBVP combination** without radiotherapy which resulted in the trial’s early closure

Answer 55

EORTC H9-F trial

Question 56

Study that patients with early-stage favorable disease to received two or four cycles of ABVD with 20- or 30-Gy IFRT was noninferior

Answer 56

GHSG HD10 trial

Question 57

Study that evaluated systematically eliminating various drugs from the ABVD combination. Patients were randomized to four cycles of ABVD, ABV, AVD, or AV with 30-Gy IFRT in all arms.

Answer 57

GHSG HD13

Question 58

# Relapsed or Refractory Disease A significant predictor of subsequent response and PFS.

Answer 58

Duration of initial remission ## Footnote **High-dose chemotherapy and ASCT** improved the outlook for such patients and is routinely used in first relapse for most patients younger than age 65 years, based on institutional and phase 3 trial experience.

Question 59

Conditioning regimens for ASCT

Answer 59

BEAM, CBV (cyclophosphamide, carmustine, etoposide), and gemcitabine-based regimens

Question 60

Trial that set the approval of **BV as posttransplant consolidation** for high-risk cHL patients

Answer 60

AETHERA trial

Question 61

**PD1 inhibitors** approved by the FDA after **failure of both ASCT and BV**

Answer 61

Nivolumab (CheckMate 205 trial) Pembrolizumab (Keynote-087 trial)

Question 62

The use of PD-1 inhibitors pretransplant may precipitate severe acute GVHD, and a **washout period** of at least ________ weeks

Answer 62

6 weeks

Question 63

# TRUE OR FALSE : Treatment of Older Adults Older adults patients more commonly present with mixed cellularity histology, advanced-stage disease, B symptoms, elevated ESR, and poorer performance status compared with younger patients.

Answer 63

TRUE Older adults patients more commonly present with **mixed cellularity histology, advanced-stage disease, B symptoms, elevated ESR, and poorer performance status** compared with younger patients.

Question 64

# HIV-Associated Classic Hodgkin Lymphoma The risk is closely related to the CD4 count with the highest incidence observed below a CD4 count of__________

Answer 64

350 cells/μL

Question 65

ART that is a potent **CYP34A inhibitor**, which may **potentiate the effects of vinblastine** resulting in **severe neutropenia and neuropathy**

Answer 65

Ritonavir ## Footnote Alternative cART regimens without ritonavir are thus recommended during ABVD chemotherapy

Question 66

# TRUE OR FALSE : HL in Pregnancy Pregnancy does not appear to alter disease biology and is associated with similar clinical presentation with regard to histologic subtype, stage at diagnosis, and long-term outcomes.

Answer 66

TRUE Pregnancy does not appear to alter disease biology and is associated with similar clinical presentation with regard to histologic subtype, stage at diagnosis, and long-term outcomes.

Question 67

Imaging recommended for pregnant patients

Answer 67

Ultrasound and magnetic resonance imaging (without gadolinium contrast) ## Footnote Routine staging modalities such as CT and PET/CT imaging cannot be performed because of risks related to fetal radiation exposure

Question 68

Therapy in pregnant patients is deferred until the__________trimester if patients are asymptomatic and can be closely monitored.

Answer 68

Second ## Footnote For pregnant patients with life-threatening disease or for those who are severely symptomatic, termination of pregnancy must be considered.

Question 69

# Treatment During Pregnancy Patients with low tumor burden or symptomology

Answer 69

Observed carefully until delivery ## Footnote For patients requiring therapy during pregnancy, the optimal chemotherapy regimen is undefined.

Question 70

This agent dooes not cross the placenta

Answer 70

Vinblastine

Question 71

Chemotherapy for pregnant patients

Answer 71

ABVD ## Footnote Current data suggest that ABVD can be administered safely without dose reduction or delays, and without the use of growth factors, despite neutropenia

Question 72

Defined by the presence of malignant LP cells or **“popcorn cells”** given their microscopic appearance with multiple nucleoli

Answer 72

NLPHL ## Footnote NLPHL is a rare subtype of HL, constituting approximately **5%** of cases. There are **bimodal** incidence peaks in childhood and in **young adults**, with a median age of **30–40 years** in the latter group. There is a 3:1 **male** predominance. Compared with cHL, there is a **stronger familial component** in NLPHL with a standardized incidence ratio of 19 in first-degree relatives in one study.

Question 73

# TRUE OR FALSE EBV is virtually always positive in LP cells and play a role in the pathogenesis of NLPHL

Answer 73

FALSE **EBV** is **virtually always negative** in LP cells and does not play a role in the pathogenesis of NLPHL

Question 74

# TRUE OR FALSE Bulky disease, mediastinal involvement, and B symptoms are common in NLPHL.

Answer 74

FALSE Bulky disease, mediastinal involvement, and B symptoms are **RARE** in NLPHL. ## Footnote In comparison with cHL, NLPHL more commonly presents with **early-stage disease (75% of cases)** and **peripheral adenopathy localized to the neck, axilla, or inguinal region.**

Question 75

Feature of NLPHL that occurs in **10%** of patients with NLPHL and is strongly associated with **transformation to THRLBCL.**

Answer 75

Splenic involvement

Question 76

Immunotype of NLPHL

Answer 76

POSITIVE CD20, strong PAX5, OCT2, and BOB.1 NEGATIVE CD30, CD15, and EBV

Question 77

Histologic variant patterns of NLPHL associated with poor prognosis

Answer 77

Patterns C–F ## Footnote LP cells are located outside of the nodules **(pattern C)** LP cells within T-cell-rich nodules **(pattern D)** LP cells within a diffuse T-cell-rich or Bcell- rich background **(patterns E and F, respectively)**

Question 78

# TRUE OR FALSE NLPHL has a more indolent course and more favorable prognosis than cHL

Answer 78

TRUE NLPHL has a more indolent course and more favorable prognosis than cHL

Question 79

Prognostic scoring system for NLPHL incorporating three adverse prognostic factors:

Answer 79

* Male sex (2 points) * Serum albumin less than 4 g/dL (1 point), * Histologic variant patterns C–F (1 point) ## Footnote low (0–1 points), intermediate (2 points), and high risk (3–4 points)

Question 80

# Based on NCCN Management of contiguous, nonbulky early-stage disease NLPHL

Answer 80

Local radiotherapy alone (30- to 36-Gy ISRT) ## Footnote ESMO guidelines recommend radiotherapy alone only for stage IA diease.

Question 81

# NCCN & ESMO Management of noncontiguous or bulky early-stage disease NLPHL

Answer 81

CMT, such as with two to four cycles of ABVD + 30- to 36-Gy ISRT ## Footnote Observation is not recommended for patients with **unfavorable features such as bulky disease, B symptoms, extranodal involvement, or histologic variant patterns C–F.**

Question 82

# TRUE OR FALSE Single-agent rituximab is recommended as frontline therapy for NLPHL

Answer 82

FALSE Single-agent rituximab is NOT recommended as frontline therapy for NLPHL ## Footnote Given near universal CD20 expression by LP cells, rituximab has also been studied in two phase 2 trials in NLPHL with **high response rates but poor durability** compared with radiotherapy-based regimens

Question 83

# TRUE OR FALSE: NLPHL Advanced Stage Disease Treatment Although there has been no randomized study comparing ABVD with CHOPbased chemotherapy for advanced-stage NLPHL, several retrospective series suggest an advantage with alkylator-based regimens.

Answer 83

TRUE Although there has been no randomized study comparing ABVD with CHOPbased chemotherapy for advanced-stage NLPHL, several retrospective series suggest an **advantage with alkylator-based regimens.**

Question 84

The NCCN guidelines recommend **surveillance CT** imaging of the neck, chest, abdomen, and pelvis

Answer 84

6, 12, and 24 months after treatment ## Footnote After which time there is no role for further surveillance imaging **ESMO** guidelines **do not recommend further routine surveillance imaging** after initial remission is confirmed.

Question 85

Leading causes of death for cHL survivors

Answer 85

Second cancers and cardiac disease

Question 86

The risk after **MOPP** was proportional to the cumulative dose of alkylating agents and associated with recurring abnormalities of___________

Answer 86

Chromosomes 5 and 7 ## Footnote The risk of acute leukemia is significantly less after ABVD chemotherapy, with long-term follow-up showing cumulative incidence rates of approximately 1%

Question 87

There is an increased relative risk of NHLs after treatment for cHL The most common histology:

Answer 87

DLBCL ## Footnote Secondary NHLs may arise from treatment-related **immunodeficiency (particularly for EBV-positive lymphomas)** or that the second NHL may **share a common cell of origin** with the antecedent cHL.

Question 88

MC side effect of BV

Answer 88

Peripheral sensory neuropathy or less commonly motor neuropathy ## Footnote **Dose reductions from 1.8 to 1.2 mg/kg** and/or **increasing the dosing interval from every 3 weeks to every 4 weeks** is commonly used for patients who develop these adverse effects on BV.

Question 89

MC side effects of nivolumab or pembrolizumab

Answer 89

**Immune-related adverse events** may affect virtually any organ system but most commonly affect the skin, thyroid, lungs, liver, and GI tract ## Footnote Grade 2 or higher immune-related adverse events are managed with prompt **corticosteroid administration (prednisone 1 mg/kg)** and dose interruptions pending improvement to grade 1 or resolution.