Radiation Oncology/NHL/Overview

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

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


 * Pediatric (based on Cancer, DeVita, 7th edition, 2005)

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 &mdash; "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.)


 * 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

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

Involved field
 * CALGB guidelines (done for Hodgkin's disease) - PMID 12078908 Full text (2002) &mdash; "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.)