# Radiation Oncology/NHL/Overview

* 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

* 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

## External links

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

## Molecular diagnosis

    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

    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

* 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.)