Hodgkin Lymphoma Overview

HL (Hodgkin Lymphoma)

• Accounts for 15% of all lymphomas.
• Evades immune surveillance by upregulating PDL1 and PDL2.
• Exhibits a bimodal age distribution, peaking at 15-35 years (NSCHL) and 50-70 years.

Classical HL (CHL) and Nodular Lymphocyte Predominant HL (NLPHL)

• CHL is CD15 and CD30 positive, while NLPHL is CD20 positive and CD15/30 negative.
• CHL is characterized by Reed-Sternberg cells (giant B cell derivatives with an owl eye appearance).
• NLPHL exhibits a popcorn morphology, where popcorn cells are variants of Reed-Sternberg cells.
• CHL subtypes include nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted.
• Most CHL cases are EBV positive, except for the lymphocyte-rich subtype.
• Nodular sclerosis CHL (NSCHL) is more common in females (F>M).
• Lymphocyte-depleted HL is associated with HIV.

Nodular Sclerosis CHL (NSCHL)

• More common in females, similar to follicular lymphoma (FL) and MALT lymphoma for NHL.
• Typically affects individuals aged 15-35 years.
• Commonly involves cervical lymph nodes and the mediastinum (80%).
• Bulky disease (large mediastinal mass >= 10 cm) indicates an early unfavorable prognosis (54%).
• Spleen and lung involvement are uncommon.
• Bone marrow and liver involvement are least common.
• Characterized by lacunar morphology.
• 40% present with B symptoms.
• Has the best prognosis among the four HL subtypes.

Spread

• Spreads in an orderly and contiguous manner.
• Typically involves a single group of lymph nodes.
• Extranodal spread (e.g., to bone marrow) is uncommon, but more common than in NHL.
• Axial nodes are commonly involved: cervical > mediastinal, para-aortic, mediastinum is common, unlike NHL.

B Symptoms

• Include fever, night sweats, and weight loss (loss of >10% of body weight in 6 months).
• More common in HL than in other lymphomas.
• Associated with NSCHL and DLBCL.

Clinical Features

• Lymphadenopathy is present in the cervical, inguinal, axillary, and supraclavicular regions.
• Splenomegaly is slightly less common than in NHL.
• Hepatomegaly is very rare, much rarer than in NHL.

Investigation

• Includes B symptoms history
• Includes a complete blood picture, PET-CT scan, and serology for HBV, HCV, and HIV.

Lugano Staging

• Stages are limited (1,2) or advanced (3,4).
• Bulky disease (X) is defined as ≥ 10 cm, but sometimes ≥7 cm in stage 1 or 2 for HL.
• Staging is histology-dependent for NHL.
• FL is staged at ≥ 6 cm, DLBCL at ≥ 7.5 cm or 7-10 cm.
• A and B designations apply to HL only.
• A = no B symptoms
• B = presence of B symptoms

Stage Definitions

• Stage 1: Involvement of only 1 lymph node region or lymphoid structure (spleen, thymus, Waldeyer's ring), including all nodal disease within the mediastinum.
• Stage 1E: Only 1 extranodal site involved, without lymph node involvement.
• Stage 2: ≥ 2 lymph node regions or lymphoid structures on the same side of the diaphragm with bilateral hilar node involvement. Contiguous nodes are next to each other.
• Stage 2E: Direct extension to a nearby extranodal site from an involved lymph node region, on the same side of the diaphragm.
• Stage 3: Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm.
• Stage 4: Diffuse or disseminated involvement of 1 or more extranodal organs or non-contiguous extranodal involvement (stage 2E but not direct extension), may involve liver, multiple lung lesions, bone marrow, or CSF, is stage 3 + any extranodal site.

Prognosis Groups in HL

• Prognosis groups affect treatment decisions.
• Stage 2B is considered advanced.
• Early unfavorable status is indicated by at least one of the following:
  • Large mediastinal mass ≥ 10 cm
  • Extranodal spread
  • ≥ 3 lymph node regions
  • Presence of B symptoms (but 2B is advanced)
  • Increased erythrocyte sedimentation rate (>30 mm/h for B stage, >50 mm/h for A stage)

Management for Classical Hodgkin Lymphoma (CHL)

• Infraclavicular nodes separate cervical from mediastinal involvement; supraclavicular nodes belong to cervical region.
• ABVD regimen: doxorubicin, bleomycin, vinblastine, dacarbazine.
• Brentuximab vedotin (A) targets CD30.

Early Favorable Disease

• Managed with 3-6 cycles of ABVD for chemo only.
• Alternatively, 2-4 cycles of ABVD followed by involved-site radiation therapy (ISRT) after 3-4 weeks.
• Elderly patients may receive radiation therapy (RT) alone.

Early Unfavorable Disease

• Managed with 6 cycles of ABVD for chemo only.
• Alternatively, 4 cycles of ABVD followed by ISRT after 3-4 weeks.

Advanced Disease

• Brentuximab vedotin + AVD for 6 cycles is administered, Pola-R-CHP is used for noncon stage 2/3,4 DLBCL has no specified no. of cycle, then ISRT

Refractory Cases

• Managed with nivolumab/pembrolizumab, A and chemo, followed by stem cell transplant.

Management for Nodular Lymphocyte Predominant HL (NLPHL)

• ABVD for 2-3 cycles
• Limited field RT (ISRT)
• Rituximab (anti-CD20) given with chemo/RT
• Active surveillance is used for asymptomatic patients

Involved Site Radiation Therapy (ISRT)

• Applicable to all stages of HL and ECOG 0-3.
• Post-chemotherapy PET is required for advanced stage IIB-IV HL and for all suitable DLBCL cases before ISRT (30 Gy for PET-, 30-36 Gy for PET+ DLBCL).
• Administered 3-4 weeks post-chemo.
• Simulation: Patient is supine, with 3D/4DCT imaging.
• Breath-hold technique is used for thorax and abdomen.
• Head and neck LN: Arms by side/on chest, chin extended, neck support and immobilisation mask
• Thorax LN: Arms above head or by sides. Vacuum device and wingboard are used.
• Pelvis LN: Arms on chest, knee supports and ankle stocks.
• Beam delivery techniques: 3DCRT/IMRT/ VMAT/ B-VMAT (only for HL)
• Energy: 6-18 MV
• Daily CBCT/kV planar imaging is used.
  • Doses as follows:
    • 1-2A: 2 Gy/fraction x 10
    • 2B-4 PET-: 2 Gy x 15
    • 2B-4 PET+: 1.5/2 Gy x 20 (SIB)
    • Refractory: 1.8 Gy x 20-25
  • GTV (Gross Tumor Volume) is residual soft tissues (post-chemo imaging).
  • CTV (Clinical Target Volume) includes the sup/inf extent of the pre-chemo GTV and the lateral post-chemo imaging and pre-chemo GTV
  • ITV (Internal Target Volume) is delineated by 4DCT and consider uncertainties of image fusion and pre chemo extent of disease and surrounding radiosensitive structures
  • PTV (Planning Target Volume) = CTV/ITV + 0.3-1 cm

B-VMAT (bulky-VMAT)

• Uses 8 partial arcs.
• Used for mediastinal CHL.
• Use Separate deep inspirational breath hold
• PTV = CTV + 0.5cm
• Reduces dose to heart, lungs, and right breast.
• Offers faster delivery than IMRT.

Non-Hodgkin Lymphoma (NHL)

• Very common in Hong Kong, quite common worldwide.
• More common at age 55+ (HL has bimodal distribution).
• Heterogeneous group of malignancies.
• Arises in lymph nodes in ¾ of cases.
• Multiple lymph nodes are typically involved (HL usually involves a single LN group).
• Spreads non-contiguously.
• Higher tendency for extranodal and peripheral LN involvement (HL is axial, mostly cervical and mediastinal).
• Common to mesenteric nodes and Waldeyer ring, less common to mediastinal
• Waldeyer ring and GI tract most common extranodal sites
• Bone marrow and GI tract much more common than HL
• GI tract most common: DLBCL, MALT(stomach)
• More common than HL to bone marrow, GI tract, waldeyer ring and peripheral LN such as mesenteric nodes and inguinal nodes
• NK cell lymphomas are rare but very deadly.
• FL and DLBCL are usually radioresponsive, so they have RT
• Can be indolent or aggressive. Including
  • DLBCL (aggressive, but better than primary CNS)
  • Follicular lymphoma (25-35% upgrade to DLBCL)
  • Marginal zone lymphoma (80% MALT)
  • Mycosis fungoides / cutaneous T-cell lymphoma (only 15% of NHL)

Clinical Features

• Peripheral lymphadenopathy is most commonly found in the cervical, inguinal, and retroperitoneal regions. (HL is more common in the cervical, inguinal, axillary, and supraclavicular regions.)
• Splenomegaly is similar to HL.
• Hepatomegaly is more common than in HL.

FL

• It is most common in females (F>M)

Follicular Lymphoma (FL)

• Cervical and inguinal lymph nodes are the most common sites.

• Common extranodal sites include bone marrow, liver, spleen, and peripheral blood.

• 25-35% of cases upgrade to Diffuse Large B-Cell Lymphoma (DLBCL)

• t(14;18)(q32;q21) with IGH/BCL2 translocation is common.

• Overexpression of BCL2 protein prevents apoptosis

• Grade 3B FL (>15 centroblasts lacking centrocytes) may not be treated with radiation therapy (RT).

• High stage disease may not need ISRT

• Bone marrow is one of the most common extranodal sites, but only 20% of marginal zone lymphoma (MZL) has bone marrow involvement.

• The stomach is not a common extranodal site, but bone marrow is (FL) vs stomach (MALT)

• The germinal center is associated with FL, while the marginal zone is associated with MALT

Management of FL

(DLBCL sin begin classify bulky/non bulky)

• R-CHOP only begins from noncontiguous stage 2
• Watchful waiting is used for asymptomatic patients with the same approach as in NLPHL.
• Stage 1/contiguous 2 and grade 1-3a : ISRT (2 Gy/ fr x 12-15, total 24-30 Gy)
• Noncontiguous stage 2/3/4: induction R-CHOP(cyclophosphamide,doxorubicin,vincristine,prednisone) then rituximab once every 2-3 months

RT of FL

points also applicable to DLBCL

• Indication is highlighted above
• Simulation is same as HL: supine, 3D/4DCT (colorectal and anus only 3DCT), site specific/ 3DCRT/IMRT/VMAT, 6-18 MV, daily CBCT or kV planar
• If treating large volume of abdomen, use 1.5 Gy/fr.
• GTV= involved nodes / surgical bed post biopsy
• CTV= -individualised CTVs for extranodal FL - GTV + whole nodal compartment ( axial) - GTV + a few cm along the LN chain (sup / inf) - nearby enlarged/ equivocal nodes, even if low FDG avidity - clip CTV to anatomical boundaries
• CTV boost of anus stage 1-3 chemoRT, use cisplatin,5 FU for all stages
• ITV= same as HL
• PTV= same as HL

DLBCL (Diffuse Large B-Cell Lymphoma)

• Diffuse pattern, extranodal involvement is common with large bulky
• 71% of cases involve ≥ 1 site of extranodal disease
• 40% of cases are purely extranodal
• Bulky disease is defined as ≥5cm in 76% of cases
• Shares similar B symptoms to NSCHL
• Most common in the GI tract and MALT stomach
• Bone marrow involvement at 16%
• 53% of cases show increased lactate dehydrogenase (LDH)

Management of DLBCL

( all stages have RT and chemo , however for FL only stage1/contiguous 2,grade 1-3a can do RT)

1. Stage 1/contiguous 2 (only go for RT if bulky) (FL RT alone if grade 1-3a) non bulky disease (<7cm): 4 cycles R-CHOP bulky disease (>7.5cm or > 7-10 cm): 4-6 cycles R-CHOP unlike HL+ post chemo ISRT If bulky/ inadequate response to chemo/ relapse go for RT

2. noncontiguous stage 2 /3 / 4 ( FL didn't specify the cycles for R-CHOP): Pola-R-CHP (HL delete bleomycin forA+AVD, this delete vincristine)- Polatuzumab vedotin Pola = polatuzumab vedotin R-CHOP 2nd choice Bone marrow transplant or stem cell transplant ( refractory HL) for consolidative RT Go for consolidative RT if have PET+ residual disease/ bulky, ≥ 10 cm but can’t transplant / if can safely treated by RT CNS prophylaxis ( testicular) prevent Can't reduce risk for renal, adrenal, 3+ extranodal sites after intrathecal methotrexate with a 4-6 Doses of intrathecal methotrexate 3. CNS dissemination presents at diagnosis / relapse: then autologous stem cell transplant

   • ISRT for DLBCL PET- : 2 Gy / fr x 15 ( same as HL advanced stage 2B-4 PET-) (ISRT for FL 2Gy x 12-15fr) PET+ : 2 Gy/ fr x 15-18 fr to involved site plus 5-7 fr boost to residual PET+ Target volume same as HL Quick comparison: 1. FL only stage 1/ con 2 do ISRT alone, and only have R-CHOP starting from noncon stage 2 2. but DLBCL all stages have chemo and RT, and only go for RT if bulky 3. RT dose for PET+ DLBCL (30-36 Gy, give 10-14Gy boost to PET+ residual), PET- is 30 Gy, higher than FL (24-30 Gy)
   4. NHL stage1/con2 VS stage noncon2 /3/4, but DLBCL will also classify bulky/not
   5. HL early favouable/un or advanced or refractory
   6. post-chemo imaging for advanced stage HL, all eligible DLBCL
   7. R-CHOP 4 cycles vs 4-6 cycles for non/bulky stage 1/con 2 DLBCL, only this specify the cycles for R-CHOP
   8. polatuzumab vedotin have unspecified number of cycles and a stem cell transplant (refractory HL + noncon2/3-4 + CNS dissemination DLBCL + primary CNS) Only eso, anus can give GTVp and GTVn in different margin, CTV boost GTVp+1cm sup inf and GTVn +0.5-1cm if outside volume

• Only T4b of colorectal also “adhere” to adj structure, others all invade / mongolia highest incidence in stomach, liver/ gall bladder and anus female risk more than male
• Other items include pancreas BRCA mutation, CEA for colorectal, AFP for liver, pancreas inflammation,
• Jaundice starts from stomach, ends at colorectal liver, diabetes and tongue Primary CNS is equivalent to DLBCL and brain eye, spinal cord and all others and can also be multinodular

Management

• High-dose IV methotrexate-based for consolidation and matrix regimen
• CNS prophylaxis for DLBCL use intrathecal methotrexate

MALT:

• 80% extranodal MALT, 20% splenic/ Low grade B cell lymphoma, heterogenous and will affect the stomach (FL common in BM, liver), distant = rare grade

management

• gastric, ocular adnexal, skin malt + other low grade Lymphoma

treatment options Ifrt/chop