96 Hodgkin Lymphoma Flashcards
Hodgkin lymphoma is derived from
Germinal center B cell
Defined by the presence of malignant Hodgkin and Reed-Sternberg (HRS) cells with a characteristic immunophenotype and appropriate cellular background
Classic Hodgkin lymphoma (cHL)
Characterized by malignant lymphocyte-predominant (LP) cells or “popcorn cells” embedded within B-cell rich nodules
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)
LP cells express typical B-cell antigens namely _____________ and rarely express CD30 or CD15
(CD) 20, OCT2, and BOB
cHL subtype that predominates in young adults
Nodular sclerosis subtype
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
Mixed cellularity subtype
cHL has (male/female) predominance at all ages, which is more prominent beyond the ______ decade of life
Male
Third
Factors for increased risk of cHL
- High socioeconomic status
- A personal or family history of an autoimmune disorder or systemic disease, particularly sarcoidosis
- EBV
Factors for reduced risk of cHL
Living in a rental home, sharing a bedroom, and attending daycare or nursery school and early parity in women
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
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
A threefold increased risk of cHL in young adults is conferred by a prior history of serologically confirmed __________________
Infectious mononucleosis
EBV-associated cases are more common in the following cases
- Mixed cellularity histology
- Hispanic ethnicity
- Patients older than the age of 60 years
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.
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.
TRUE OR FALSE
The increased risk of the disease among identical AND fraternal twins provides the strongest evidence for a genetic association.
FALSE
The increased risk of the disease among identical, but not fraternal, twins provides the strongest evidence for a genetic association.
TRUE OR FALSE
HRS cells are pathognomonic for cHL
FALSE
HRS cells are NOT pathognomonic for cHL
May be seen in reactive and other neoplastic conditions such as chronic lymphocytic leukemia.
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.
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
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).
Chromosome 9p24.1
The most commonly mutated gene in cHL.
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.
Viral protein involved in the association of EBV with cHL
Latent membrane protein 1 (LMP1) and Latent membrane protein 2 (LMP2)
Represent the largest and probably most important population of cells in the HRS microenvironment
T cells
An antiphagocytic “don’t eat me” signal secreted by HRS cells, which binds to signal regulatory protein α on macrophages to suppress phagocytosis.
CD47
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
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
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.
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.
anti CTLA4
Ipilimumab
anti CD47
Magrolimab
anti CD30
Brentuximab vedotin
anti PD1
Nivolumab
Pembrolizumab
anti CD25
Camidanlumab tesirine
A cyclic pattern of high fevers in HL for 1–2 weeks alternating with afebrile periods of similar duration
Pel-Ebstein fever
TRUE OR FALSE
Fevers in HL are usually of high grade and regular
FALSE
Fevers in HL are usually of low grade and irregular
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.
Symptom that occurs in fewer than 10% of patients but is nearly specific to cHL
Pain in involved lymph nodes immediately after the ingestion of alcohol
The most common presentation of cHL
Unusual mass or swelling in the superficial, supradiaphragmatic lymph nodes
(60–70%) cervical and supraclavicular
(15–20%) axillary
15% to 20% of patients have infradiaphragmatic disease
Lymphadenopathy is usually nontender and has a “rubbery” consistency.
Intrathoracic disease is present at diagnosis in _________ of patients.
Two-thirds
Mediastinal adenopathy is common in cHL, particularly in young women with the nodular sclerosis subtype.
Mediastinal adenopathy is common in cHL, particularly in young____________ with the ________________subtype.
Women
Nodular sclerosis
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.
TRUE
PET is sensitive for the presence of marrow involvement at diagnosis, and the absence of marrow uptake obviates the need for marrow biopsy.
Whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become standard in the staging of cHL
Causes of false-positve results of PET CT Scan
Thymic hyperplasia, brown fat, granulomatous disease, or infectious disorders
TRUE OR FALSE
Achieving a complete remission (CR) by PET after two cycles of ABVD is predictive of favorable outcomes in cHL.
TRUE
Achieving a complete remission (CR) by PET after two cycles of ABVD is predictive of favorable outcomes in cHL.
Morphologic charateristics of cHL
Scattered large mononuclear or multinucleated HRS cells within an inflammatory infiltrate of small lymphocytes, histiocytes, neutrophils, eosinophils, plasma cells, fibroblasts, and collagen fibers
Characteristic immunophenotype of HRS cHL
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
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.
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.
Nodular sclerosis subtype
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
Mixed cellularity cHL
Observed in 5% to 10% of cases and resembles NLPHL morphologically but is readily distinguished by immunophenotype (CD30+ CD20-)
Lymphocyte rich cHL
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
Lymphocyte-depleted cHL
Indications for bone marrow biopsy
Multifocal hypermetabolic bone lesions or unexplained cytopenias
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.
Most common location of lymph nodes in HL
Cervical nodes 70%
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.
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
Elevation of the erythrocyte sedimentation rate (ESR)
Definition of Bulky mediastinal disease
10 cm
Width greater than one-third of the maximum intrathoracic diameter
Identified as independent predictors of relapse and are considered unfavorable risk factors
- Bulky mediastinal disease
- B symptoms
- Elevated ESR
Advanced Stage Disease
Seven risk factors used in International Prognostic Score (IPS-7)
Advanced-stage disease (stages III–IV and often including stage II with B symptoms or bulky mediastinal disease)
- 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
Components of IPS-3
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.
Age, stage, and hemoglobin
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.
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.
Early-stage favorable cHL is defined in North America as:
- Stage I–IIA supradiaphragmatic disease with no more than three nodal sites
- No bulky disease
- ESR less than 50 mm/h
First CT-adapted study to evaluate omitting radiotherapy in a randomized phase 3 setting
Canadian HD.6 trial
Treatment with ABVD therapy alone was superior because of a lower rate of death from secondary malignancies and other causes
Study that demonstrated comparable efficacy and reduced toxicity with IFRT compared to EFRT following ABVD-based chemotherapy
GHSG HD8 trial
Study that showed Inferiority of the EBVP combination without radiotherapy which resulted in the trial’s early closure
EORTC H9-F trial
Study that patients with early-stage favorable disease to received two or four cycles of ABVD with 20- or 30-Gy IFRT was noninferior
GHSG HD10 trial
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.
GHSG HD13
Relapsed or Refractory Disease
A significant predictor of subsequent response and PFS.
Duration of initial remission
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.
Conditioning regimens for ASCT
BEAM, CBV (cyclophosphamide, carmustine, etoposide), and gemcitabine-based regimens
Trial that set the approval of BV as posttransplant consolidation for high-risk cHL patients
AETHERA trial
PD1 inhibitors approved by the FDA after failure of both ASCT and BV
Nivolumab (CheckMate 205 trial)
Pembrolizumab (Keynote-087 trial)
The use of PD-1 inhibitors pretransplant may precipitate severe acute GVHD, and a washout period of at least ________ weeks
6 weeks
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.
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.
HIV-Associated Classic Hodgkin Lymphoma
The risk is closely related to the CD4 count with the highest incidence observed below a CD4 count of__________
350 cells/μL
ART that is a potent CYP34A inhibitor, which may potentiate the effects of vinblastine resulting in severe neutropenia and neuropathy
Ritonavir
Alternative cART regimens without ritonavir are thus recommended during ABVD chemotherapy
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.
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.
Imaging recommended for pregnant patients
Ultrasound and magnetic resonance imaging (without gadolinium contrast)
Routine staging modalities such as CT and PET/CT imaging cannot be performed because of risks related to fetal radiation exposure
Therapy in pregnant patients is deferred until the__________trimester if patients are asymptomatic and can be closely monitored.
Second
For pregnant patients with life-threatening disease or for those who are severely symptomatic, termination of pregnancy must be considered.
Treatment During Pregnancy
Patients with low tumor burden or symptomology
Observed carefully until delivery
For patients requiring therapy during pregnancy, the optimal chemotherapy regimen is undefined.
This agent dooes not cross the placenta
Vinblastine
Chemotherapy for pregnant patients
ABVD
Current data suggest that ABVD can be administered safely without dose reduction or delays, and without the use of growth factors, despite neutropenia
Defined by the presence of malignant LP cells or “popcorn cells” given their microscopic appearance with multiple nucleoli
NLPHL
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.
TRUE OR FALSE
EBV is virtually always positive in LP cells and play a role in the pathogenesis of NLPHL
FALSE
EBV is virtually always negative in LP cells and does not play a role in the pathogenesis of NLPHL
TRUE OR FALSE
Bulky disease, mediastinal involvement, and B symptoms are common in NLPHL.
FALSE
Bulky disease, mediastinal involvement, and B symptoms are RARE in NLPHL.
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.
Feature of NLPHL that occurs in 10% of patients with NLPHL and is strongly associated with transformation to THRLBCL.
Splenic involvement
Immunotype of NLPHL
POSITIVE
CD20, strong PAX5, OCT2, and BOB.1
NEGATIVE
CD30, CD15, and EBV
Histologic variant patterns of NLPHL associated with poor prognosis
Patterns C–F
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)
TRUE OR FALSE
NLPHL has a more indolent course and more favorable prognosis than cHL
TRUE
NLPHL has a more indolent course and more favorable prognosis than cHL
Prognostic scoring system for NLPHL incorporating three adverse prognostic factors:
- Male sex (2 points)
- Serum albumin less than 4 g/dL (1 point),
- Histologic variant patterns C–F (1 point)
low (0–1 points), intermediate (2 points), and high risk (3–4 points)
Based on NCCN
Management of contiguous, nonbulky early-stage disease NLPHL
Local radiotherapy alone (30- to 36-Gy ISRT)
ESMO guidelines recommend radiotherapy alone only for stage IA diease.
NCCN & ESMO
Management of noncontiguous or bulky early-stage disease NLPHL
CMT, such as with two to four cycles of ABVD + 30- to 36-Gy ISRT
Observation is not recommended for patients with unfavorable features such as bulky disease, B symptoms, extranodal involvement, or histologic variant patterns C–F.
TRUE OR FALSE
Single-agent rituximab is recommended as frontline therapy for NLPHL
FALSE
Single-agent rituximab is NOT recommended as frontline therapy for NLPHL
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
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.
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.
The NCCN guidelines recommend surveillance CT imaging of the neck, chest, abdomen, and pelvis
6, 12, and 24 months after treatment
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.
Leading causes of death for cHL survivors
Second cancers and cardiac disease
The risk after MOPP was proportional to the cumulative dose of alkylating agents and associated with recurring abnormalities of___________
Chromosomes 5 and 7
The risk of acute leukemia is significantly less after ABVD chemotherapy, with long-term follow-up showing cumulative incidence rates of approximately 1%
There is an increased relative risk of NHLs after treatment for cHL
The most common histology:
DLBCL
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.
MC side effect of BV
Peripheral sensory neuropathy or less commonly motor neuropathy
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.
MC side effects of nivolumab or pembrolizumab
Immune-related adverse events may affect virtually any organ system but most commonly affect the skin, thyroid, lungs, liver, and GI tract
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.
