Radiation Oncology/NHL/Overview

< Radiation Oncology < NHL

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

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

WHO classification

B-cell neoplasms
- Precursor B-cell neoplasms
  - Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)
- Mature (peripheral) B-cell neoplasms
  - B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma
  - B-cell prolymphocytic leukemia
  - Lymphoplasmacytic lymphoma
  - Splenic marginal zone B-cell lymphoma
  - Hairy cell leukemia
  - Plasma cell myeloma/plasmacytoma
  - Extranodal marginal zone B-cell lymphoma of MALT type
  - Nodal marginal zone B-cell lymphoma
  - Follicular lymphoma
  - Mantle cell lymphoma
  - Diffuse large B-cell lymphoma
  - Burkitt lymphoma / Burkitt cell leukemia
T-cell and NK-cell neoplasms
- Precursor T-cell neoplasm
  - Precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia)
- Mature (peripheral) T/NK-cell neoplasms
  - T-cell prolymphocytic leukemia
  - T-cell granular lymphocytic leukemia
  - Aggressive NK-cell leukemia
  - Adult T-cell lymphoma/leukemia (HTLV1+)
  - Extranodal NK/T-cell lymphoma, nasal type
  - Enteropathy-type T-cell lymphoma
  - Hepatosplenic gamma-delta T-cell lymphoma
  - Subcutaneous panniculitis-like T-cell lymphoma
  - Mycosis fungoides / Sezary syndrome
  - Anaplastic large cell lymphoma, T/null cell, primary cutaneous type
  - Anaplastic large cell lymphoma, T/null cell, primary systemic type
  - Peripheral T-cell lymphoma, not otherwise characterized
  - Angioimmunoblastic T-cell lymphoma

WHO by aggressiveness

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

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

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

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

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

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

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

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

External links

Heme-Path at UMDNJ - fairly basic overview of different types of lymphomas. Great histology slides.

Molecular diagnosis

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

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

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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