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Radiation Oncology/NHL/Overview

< Radiation Oncology | NHL
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Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

Non-Hodgkin lymphoma: Main Page | Randomized
Overview: Overview | Follicular | Diffuse large B-cell | MALT | Nodal marginal zone | Mantle cell | CLL/SLL | Lymphoblastic | Burkitt | NK/T cell | Anaplastic large cell | Primary CNS Lymphoma
Treatment: Aggressive | Specific sites | Radioimmunotherapy


Classification

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  • Historically several systems, both in USA and Europe
  • WHO classification is used today


WHO classification

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WHO by aggressiveness

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Grade Histologies
Indolent B-cell: Follicular (Grade I/II), SLL/CLL, lymphoplasmatic lymphoma, plasma cell/myeloma, hairy cell leukemia, marginal zone B-cell, mantle cell, T-cell: T-cell large granular lymphocyte leukemia, mycosis fungoides, T-cell prolymphocytic leukemia, NK cell
Aggressive B-cell: Follicular (Grade III), DLBCL, mantle cell, T-cell: peripheral T-cell lymphoma, anaplastic large cell lymphoma
Highly aggressive B-cell: Burkitt's lymphoma, precursor B lymphoblastic leukemia/lymphoma, T-cell: adult T-cell lymphoma/leukemia, precursor T lymphoblastic leukemia/lymphoma

Translocations

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  • Lymphoma cells generally do not exhibit significant microsatellite instability (unlike many solid tumors)
  • Chromosomal translocations are a hallmark of lymphomatous disorders
    • t(8;14) - Burkitt's lymphoma (c-myc)
    • t(11;14) - mantle cell lymphoma (bcl-1)
    • t(11;18) - MALT lymphoma
    • t(14;18) - follicular lymphoma (bcl-2)

mnemonic: The common ones (on exams anyway) have 14 in common. The 11 sits on top of 14 (they're in sequence) like something sitting on a mantle. The 8 in Burkitt's resembles the bilaterally swollen neck lymph nodes like you typically see in a picture of a child with Burkitt's. The 8 (18) of follicular resembles two little follicles stuck together to form the 8. The oddball one is MALT which doesn't have the 14.

Epidemiology

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  • USA - 59,000 cases/yr (in 2006)


  • ILSG, 1997 PMID 9166827 -- "A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project." ([No authors listed], Blood. 1997 Jun 1;89(11):3909-18.)
    • Multinational. 1403 cases at 9 sites around the world classified by 5 pathologists
Adult Type Proportion
Diffuse large B-cell 31%
Follicular 22%
Marginal zone B-cell (MALT) 8%
Peripheral T-cell 7%
CLL 7%
Mantle cell 6%
Mediastinal large B-cell 2%
Anaplastic large T-cell 2%
Burkitt-like B-cell 2%
Marginal zone B-cell (nodal) 2%
Precursor T-lymphoblastic 2%
Lymphoplasmacytoid 1%
Marginal zone B-cell (splenic) <1%
Mycosis fungoides <1%
Burkitt's <1%
All others <1%


  • Pediatric (based on Cancer, DeVita, 7th edition, 2005)
Pediatric Type Proportion
Burkitt's lymphoma 40-50%
Precursor T-lymphoblastic 25%
Diffuse large B-cell 15%
Anaplastic large cell 10%
Precursor B-lymphoblastic 5%

Staging

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  • Uses the Ann Arbor classification, which was developed for Hodgkin's lymphoma.
  • Since disease spread in non-Hodgkin's lymphoma differs from that in Hodgkin's lymphoma, in which spread occurs to adjacent nodal groups in a stepwise fashion, the Ann Arbor classification which relies on nodal staging is not as predictive for NHL.

International Prognostic Index

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Risk factors:

  • LDH greater than normal
  • Age > 60
  • Performance status ECOG 2 or worse
  • Extranodal sites of disease (more than 1)
  • Stage III or IV
    Mnemonic: LAKES (LDH,age,Karnofsky,Extranodal,Stage)

Risk groups:

  • Low - 0 or 1 risk factors
  • Low intermediate - 2
  • High intermediate - 3
  • High - 4 or 5

Prognosis:

  • Low risk: 87% CR and 73% OS at 5 years
  • High risk: 44% CR and 26% OS

Based on pts with aggressive lymphomas treated with doxorubicin-based combination chemotherapy. It is also useful in indolent lymphomas and T-cell lymphomas. These factors independently predict complete response to therapy, relapse-free survival, and overall survival.

From PMID 8141877 Full text — "A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project." N Engl J Med. 1993 Sep 30;329(14):987-94.

Modifications

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Age-Adjusted International Prognostic Index: Developed for pts younger than 60. Uses tumor stage, performance status, and LDH (but not extranodal sites or age). Assigned score of 0 to 3 based on number of risk factors and assigned same labels (low, low int, high int, or high).


Reference: PMID 8141877 Full text - "A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project." N Engl J Med. 1993 Sep 30;329(14):987-94.

  • 1982-1987. 3273 pts. Allowed diffuse mixed, diffuse large-cell, or large-cell immunoblastic histologies from the Working Formulation (overlaps with intermediate and high grade but doesn't include all subtypes). Also allowed Kiel and Rappaport. Pts were treated on Phase II-III study. All received combination chemo consisting of doxorubicin. Evaluated potential prognostic factors: sex, age, tumor stage, performance status, B symptoms, sites of involvement, number of extranodal sites, size of tumor, LDH, albumin, and beta-2-microglobulin. Complete information obtained in 1872 pts.

Miller's Stage-Modified IPI:

  • (LDH, Age > 60, Performance Status, Stage II). Doesn't include extranodal.
  • Used for Stage I-II pts.
  • Low 0-1, Intermediate 2, High 3-4
  • 5-yr PFS: Low 77%, Int 60%, High 34%
  • 5-yr OS: Low 82%, Int 71%, High 48%
  • PMID 9647875 (1998)

NCCN IPI:

  • Rituximab era
  • PMID 24264230 (2014) -- "An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era." (Zhou Z,Blood. 2014 Feb 6;123(6):837-42.)

Survival

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Estimates from AJCC staging manual, 6th edition:

  • Follicular lymphoma: 2-year OS 85%, 5-year 70%. FFS (failure free survival) 2-year 65%, 5-year 45%.
  • Diffuse large B-cell lymphoma: 2-year OS 60%, 5-year 50%. FFS 2-year 50%, 5-year 45%.
  • Mantle cell lymphoma: 2-year OS 60%, 5-year 25%. FFS 2-year 30%, 5-year 10%.
  • Small lymphocytic lymphoma: 2-year OS 70%, 5-year 50%. FFS 2-year 50%, 5-year 30%.


Response Assessment

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  • Lugano Classification
    • 2014 PMID 25113753 -- "Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification." (Cheson DB, J Clin Oncol. 2014 Sep 20;32(27):3059-68.)
  • International Harmonization Project on Lymphoma
    • 2007 PMID 17242396 -- "Revised response criteria for malignant lymphoma." (Cheson BD, J Clin Oncol. 2007 Feb 10;25(5):579-86.)


Response Definition Nodal Masses Spleen/Liver Bone Marrow
CR Disappearance of all disease 1) If FDG avid prior, FDG cold but can be any size on CT post

2) If FDG variable/cold prior, FDG cold and normal size on CT post

1) Not palpable

2) No nodules on CT

Repeat BMBx negative
PR Regression of measurable disease and no new sites >= 50% in SPD in up to 6 largest masses >=50% in SPD of nodules If positive prior, irrelevant
SD Not CR/PR or PD No new sites N/A N/A
PD 1) Any new lesion

2) Increase >=50% in SPD

1) New lesion >1.5cm

2) >=50% increase in SPD

>50% increase in SPD New/recurrent involvement
SPD = sum of the product of the diameters


    • 2007 PMID 17242397 -- "Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma." (Juweid ME, J Clin Oncol. 2007 Feb 10;25(5):571-8.)
      • PET after Chemotherapy/chemoimmunotherapy: at least 3 weeks, preferably 6-8 weeks
      • PET after Radiotherapy/Chemoradiotherapy: 8-12 weeks
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  • Heme-Path at UMDNJ - fairly basic overview of different types of lymphomas. Great histology slides.


Molecular diagnosis

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See also: List of chromosomal translocations
  • Burkitt lymphoma - t(8;14) / c-myc translocation, Ki-67 > 90%, CD10+ and/or BCL-6+, CD19+ or CD20+
    Usually BCL-2 and t(14;18) negative.
  • Follicular lymphoma - t(14;18), most common translocation in lmphoma / bcl-2 translocation. Is CD10+
    Mnemonic: "F is for follicular and fourteen"
  • Mantle cell lymphoma - t(11;14), bcl-1, CD15-, cyclin D1
  • MALT lymphoma - t(11;18)
  • Diffuse large B-cell lymphoma - bcl-6 (is favorable)
  • Anaplastic lymphoma - CD30+, Ki-1


Radiation technique

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See also: Radiation_Oncology/Hodgkin#Radiation_fields

Involved field

  • CALGB guidelines (done for Hodgkin's disease) - PMID 12078908 Full text (2002) — "The involved field is back: issues in delineating the radiation field in Hodgkin's disease." Yahalom J et al. Ann Oncol. 2002;13 Suppl 1:79-83.
    Boundaries of the involved fields.


Whole-Abdomen

  • Washington University, 1994 (1978-1990) PMID 8029434 -- "Non-Hodgkin lymphoma: whole-abdomen irradiation as an adjuvant to chemotherapy." (Valicenti RK, Radiology. 1994 Aug;192(2):571-6.)
    • Retrospective. 39 patients with abdominal NHL treated with modified whole-abdomen RT. 34 adjunct to chemo, 5 primary
    • Toxicity: treatment terminated in 4 patients, interrupted in 19. Four Grade 3-4 late toxicities
    • Conclusion: Whole-abdomen RT is safe adjunct in high risk for intraabdominal failure

Reviews

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  • 1985: PMID 2579725 Full text -- "The role of radiation therapy in the management of the non-Hodgkin's lymphomas." (Hoppe RT, Cancer. 1985 May 1;55(9 Suppl):2176-83.)
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