NHL B-Cell High-grade


  1. Peak incidence in 50-60 years.
  2. 54,370 new cases a year with 19,450 deaths.
  3. Rapidly increasing incidence even when adjusting for AIDS, better diagnostics etc.
  4. 80% are B-cell and 20% are T-cell.
  5. Less than 10% are localized.
  6. Less than 20% present in the mediastinum.
  7. More likely to involve peripheral or mesenteric nodes.
  8. Bone marrow and liver involvement are common, particularly the nodular lymphomas.
  9. B symptoms are less common than with HD.
  10. Indolent lymphomas have slow progressive nodes but over 90% have stage III or IV disease.
  11. Aggressive NHL have more rapid course but 30-45% have stage I or II disease.
  12. There is an increased risk in HIV and organ transplant patients, especially extranodal or peripheral T cell lymphoma.
  13. Etiology:
Risk Factors Type of NHL
# Epstein-Barr Virus (EBV) # Burkitt’s lymphoma
# paranasal lymphomas
# Human T-cell Lymphotropic Virus (HTLV-1) # T-cell Lymphomas
# Human Herpes Virus (HHV-8) # closely related to AID-related
# Kaposi sarcoma
# large cell type body cavity lymphoma
# Helicobacter pylori # low grade MALT of stomach
# Hepatitis C Virus (HCV) # B-cell in Italy
  1. Others risk factors for NHL include: alkylating agents, radiotherapy, immunosuppressive agents, herbicides, fungicides, organophosphayes, benzene, paint thinners, wood dust, cotton dust, hair dyes, meat.

Diagnostic Workup

  1. H/P, attn to sxs, duration, pace, pain, B sxs,
  2. Labs: CBC, Chem, Calcium, albumin, LFT, SED, LDH, alkaline phosphatase, Beta 2 microglobulin.
  3. Standard radiographs: CXR, CT of chest, abdomen, and pelvis, PET.
  4. Optional radiographs: Gallium scan (mostly replaced by PET). MRI used to determine soft tissue/bone/CNS disease.
  5. Standard specials: biopsy of node either excised or image guided, BM biopsy and aspirate.
  6. Optional specials: Extranodal site biopsy if suspicious, cytology of effusion, CSF examination for paranasal sinus, testicular, epidural lymphomas or possibly HIV.


  • Waxing and waning adenopathy.
  • B symptoms.
  • Leukemia transformation in <10-15% (Ricther\’s syndrome).
  • <20% mediastinal.


  1. The most commonly used is the US Working Formula but there is the International Lymphoma Study Group (REAL) classification.
  2. Working Formula:

** Low Grade: Median survival of 5-7 years
small lymphocytic
follicular small cleaved
follicular mixed small cleaved & large cell
mantle cell
**Intermediate Grade: **Median survival is 8mo-3yrs
follicular large cell
diffuse small cleaved
diffuse mixed small cleaved & large cell
diffuse large cell
**High Grade:
Median survival is 8mo-3yrs immunoblastic large cell
small noncleaved

  1. Most common types include: follicular small cleaved cell (prototype for low grade treatment) and diffuse large cell (prototype for intermediate grade treatment)
  2. B-cell Lymphomas
  3. MALT **lymphoma (mucosa associated lymphoid tissue)/ marginal zone:** low-grade B cell tumors associated with trisomy 3, t(11:18), Helicobacter pylori. They are typically malignant appearing cells in the stomach, thyroid, salivary glands, breast, lung, orbit, skin, and bladder. They can transform to intermediate grade.
  4. Monocytoid B cell **lymphoma occurs in older patients involving nodes and is similar to MALT lymphomas.
  5. Mantle cell lymphoma:**
  6. indolent lymphoma.
  7. Generalized disease to spleen, BM and GI tract.
  8. Cells appear similar to those in the mantle region surrounding the germinal centers of nodes.
  9. > 90% have t(11;14) tranlocation.
  10. Nuclear cyclin D1 protein is present in all cases and is the gold standard of diagnosis.
  11. Lymphoblastic **Lymphoma:** ususally T cell and young male presents with mediastinal mass. Often eith DM.
  12. Diffuse undifferentiated **lymphomas include Burkitt\’s and non-Burkitt\’s. Burkitt\’s is a B cell lymphoma, usually in children, in the jaw of African children and in the abdomen of American children. very aggressive with doubling time of 2 days.
  13. Follicular lymphoma
  14. Includes cleaved follicular and large non-cleaved follicular center cells.
  15. 2nd most common type of NHL (30%) and 70% of low-grade NHL.
  16. Most have **t(14;18) and/or BCL-2 **gene arrangements.
  17. T-Cell Lymphomas
  18. Anaplastic Large Cell Lymphoma
  19. CD30+ (but no Reed-sternberg-like cells)
  20. "hallmark" cell has prominent, eosinophilic Golgi region.
  21. Extranodal Natrual Killer/ T-cell lymphoma, Nasal Type**
  22. formerly Angiocentric lymphoma
  23. NK-cell phenotype and EBV+
  24. Frequent necrosis and angioinvasion
  25. Most commonly presenting in the midfacial region but also in other extranodal sites.

Immune Cell Antigens

  • T-Cell Associated: CD1-CD8
  • Monocyte/ Macrophage: CD13-CD15 , CD33
  • B-Cell Associated: CD19-CD23, CD10 (also known as CALLA, common acute lymphoblastic leukemia antigen)
  • All Leukocytes: CD 45 (known as leukocyte common antigen)
  • Rituxamab works on CD20+ cancer

Prognostic Factors

Stage Adjusted IPI

  • Age > 60
  • PS 2-4
  • LDH > 1 x normal
  • Stage I vs II


  • Age > 60
  • PS 2-4
  • LDH > 1 x normal
  • Stage III-IV
  • Extra nodal involvement > 1 site.


  1. General: Curative RT can be used solely for early indolent NHL with low doses of 25-35Gy and LC of greater than 90%. For intermediate grade RT is combined with chemotherapy, usually CHOP (cytoxan, doxorubicin, vincristine, and prednisone). Chemotherapy is used solely for the high-grade NHL.
  2. Radiation: The usual fields are involved field, extended field, or CLI, which includes waldeyer\’s ring, mantle, whole abdomen, pelvic, and femoral nodes. Involved field means treating the extranodal site and then the immediate nodal drainage sites. Extended RT means treating the next echelon of nodes. Doses for RT alone are 25-30Gy and WA to be given at 80 BID or 100cgy/fraction.

Diffuse B-cell Lymphoma

Stage I (favorable)

  • (non-bulky) w/ stage adjusted IPI of 0
  • CHOP-R x 3 + IFRT (30-36 Gy) (based on SWOG)

Stage I/II (not favorable)

  • (non-bulky) w/ stage adjusted IPI of 1+*
  • CHOP-R x 4-6 + IFRT (30-36 Gy) (based on SWOG subgroup analysis)

Stage I/II (bulky)

  • CHOP-R x 8 + IFRT 30 Gy (CR) (ECOG)
  • CHOP-R x 8 + IFRT 40 Gy (PR) (ECOG)

Stage III/IV

  • CHOP-R x 6-8
  • if No response or progressive disease consider RT especially if they are not candidate for more aggressive chemotherapy


  • should be used for all patients based on data from stage III/IV disease.

SWOG 8736

  • CHOP x 3 + RT (40 - 55Gy) vs. CHOP x 8
  • RFS-5 of 77% and 64%
  • OS-5 of 82% and 72% p = 0.02.
  • At 10 years benefit is less apparent, with late out of field recurrences in the RT arm.

For the CHOP x 3 + IFRT Subgroup Analysis

Stage Adjusted IPI Score OS-5
0 94%
1-2 71%
3+ 50%


  • CHOP-R x 3 + IFRT Still the standard
  • However, pts with 1+ Stage adjusted RF should be considered for 4-6 cycles of CHOP-R

ECOG trial

  • 345 pts. stage I&II bulky disease
  • CHOP x 8 vs CHOP x 8 + RT
  • 30Gy (CR) or 40Gy (partial response)
  • DFS was 50% in chemotherapy alone versus 73% in CMT (p=0.03).
  • Os was 70 and 84%.

Radiation Dose

Sutcliffe et al.

  • RT alone (35 Gy) for stage I/IIA achieved 77% RFS at 10-yrs.^^ ^^

British Columbia (18 yr experience).

  • CHOP X 3 followed by radiation 30 Gy or equivalent
  • produced excellent results in patient with non-bulky stage I/II with 10-yr PFS of 74% and OS of 63%.^^ ^^

RT alone

  • Sutcliffe et al.
  • RT alone (35 Gy) for stage I/IIA achieved 77% RFS at 10-yrs.^^ ^^
  • This is similar to CHOP x 8 arm in SWOG 8736,
  • higher than 67% OS-6 from ECOG but lower than 80% from low-risk group in GELA.
  1. Intermediate/High grade stage III and IV: **
  2. CHOP with CR, DFS, and OS were 55%, 50%, and 30% at 10 years. Salvage after recurrence include palliation, alternative chemotherapy regimens (DHAP, ESHAP), high dose therapy and ABMT/stem cell support. **Aviles et al. (Mexico) performed a phase III trial in whihch patients with DLBCL who experienced a CR with CHOP and who had preexisting bulky diease were randomized to receive RT (40 to 50 Gy) to prior sites of bulky disease difference in OS-5 was statistically significant at 81% vs 55%. ^^ ** MDA** retrospective data showed FFS but no OS benefit. Second generation chemotherapy (m-BACOD, ProMACE-CytaBOM, MACOPB-B) was equivalent to but more toxic than CHOP. ^^

Salvage for DLBCL

  1. PARMA (phase III) randomized 109 patients who had relapsed from complete remission and responded to two cycles of DHAP (dexamethasone, cytarabine, and cisplatin) to:
  2. High-dose BEAC regimen (carmustine, etoposide, cytarabine, cyclophosphamide)
  3. Continued treatment with DHAP.
  4. Bone marrow transplantation was associated with a superior failure-free survival (51% vs. 12% at 5 years) and OS (53% vs. 32% at 5 years).
  5. Salvage ABMT results in survival of approximately 50% of all patients who actually receive transplants; however, it only adds 10% to the number of newly diagnosed patients who can be cured.
  6. **Role of RT: **In PARMA, a moderate dose of 26 Gy in 20 fractions/bid was used as a conditioning regiment for patients with bulky (> 5 cm) at the time of relapse for BMT arm and 35 Gy in 20 fractions were similarly given for patients in CT arm. Despite the fact RT group was worse (ie. bulky disease) the group had a trend toward lower relapse rate 8/22 vs 18/33 p = 0.13). This result is encouraging for a role or RT in relapse.

Total Body Irradiation (TBI)

  • Late-complications
  • Interstitial Pneumonitis (dose-limiting)
  • 50% in patients who received single large fraction of TBI with ½ dying of this complication.
  • In fractionated TBI, Lung block can reduce the rate from 27% to 8% \[Labar 1992\]
  • Median time for this complication is approximately 2 months.
  • Cataracts
  • 85% risk at 11 years for single, large dose of TBI
  • 34% when 12 Gy of fractionated TBI is used.
  • Eye shield can reduce the risk
  • Hepatic dysfunction (VOD)
  • Renal Dysfunction
  • Endocrine Dysfunction
  • Thyroid dysfunction in 43% after TBI. Subclinical hypothyroidism is the most common. Dysfunction is lower with fractionation.
  • Gonadal: Most all men and women develop primary gonadal failure, a few have recovered and pregnancies have been reported in few instituitions.
  • Growth Retardation
  • Cognitive Dysfunctions
  • Secondary Malignancies
  • 20% risk at 10 years

Mantle Cell Lymphoma


  • monomorphous small to medium-sized B-cell
  • t(11,14) translocation and Bcl-1 (also known as cyclin D1)
CD5 CD10 CD 23
+ +/- -


  • 70% stage IV
  • not curable by chemotherpay
  • median survival 3-5 years


  • IF alone or IF + CHOP [1]
IF-RT +/- CT CT alone p-value
5-PFS 68% 11% 0.002

Burkitt's Lymphoma


  • Highly agressive B-cell Neoplasm
  • c-MYC on chromosome 8, EBV


  • Majority curable with high-dose chemotherapy
  • Always need Prophylactic CNS therapy


  • localized disease cured 90%
  • extensive disease cured 50%
1. Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa R, Connors JM. Limited-stage mantle-cell lymphoma.
Ann Oncol. 2003 Oct;14(10):1555-61. PMID: 14504058
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