Non-Hodgkins Lymphoma
Background
Non-Hodgkin's Lymphomas (NHL) is a monoclonal expansion of B or T cells characterized by nodal or focal presentation compared with disseminated presentation of leukemias. NHL differs from Hodgkin's Lymphoma in that NHL typically involves more nodes at presentation, is more likely to be extranodal, is more likely to spread in a non-contiguous fashion and has a prognosis more strongly affected by histologic subtype than HL.
NHL presents with painless adenopathy in the axilla, inguinal and femoral regions. About 30% have B signs. Waxing and waning adenopath are suggestive of a more indolent form of NHL. Tumor bulk may be symptomatic due to compression or mass effect. As with HL, NHL B signs are fever > 38 (101) > 10% body weight loss oover 6 months and drenching night sweats.
There is a rising incidence of NHL in the US. The 2008 incidence was 66,120 with 19,160 deaths. The median age is 60 -65 years. Key conditions related to (possibly causitive) development of NHL include:
- Immunodeficiency: SCID, ataxia telangiectasia, HIV, transplant immune suppression
- Autoimmune disorders: Sjogren's, Hashimoto's rheumatoid arthritis, lupus
- Environmental agents: pesticides and solvents
- Viral:
- EBV: Burkitt's, NK/T cell (also Hodgkins Lymphoma)
- HTLV: adult T-cell leukemia (Japan, Carribean → bodily fluid contact)
- HHV-8: Kaposi's sarcoma
- HCV: Extranodal B-cell NHL
- Bacteria: Helicobacter → MALT
- Radiation: weak association
- Chemotherapy: alkylating agents
The NCI Working Group Formulation groups NHL by clinical aggressiveness or grade with subgroups based on cell type or presentation.
- Low-grade NHL:
- follicular lymphoma Grades 1 and 2
- Chronic lymphocytic leukemia
- MALT
- mycosis fungoides
- Intermediate Grade NHL
- Grade 3 follicular cell
- mantle cell lymphomas
- Diffuse large B-cell lymphoma (DLBCL)
- NK/T cell lymphoma
- peripheral T-cell lymphoma
- anaplastic large cell lymphoma
- High Grade NHL
- Burkitt's Lymphoma
- lymphoblastic lymphoma
The WHO classification system of NHL divides the disease into B-cell and T/NK-cell neoplasms with indolent, aggressive and highly aggressive subgroups. These groupings roughly match the NCI Working Group Formulations. Patients with indolent disease have survival measured in years. Patients with aggressive disease have survival measured in months, and those with highly aggressive disease have survival measured in weeks.
Approximately 35% of NHL is indolent by WHO definitions. Of the indolent disease:
- 95% of indolent NHLare follicular lymphoma, Grades 1 - 2 (FL-65% of indolent)
- 18% are small lymphocytic lymphoma (SLL)
- Small lymphocytic lymphoma is the same disease entity as CLL but with a predominant manifestation in the spleen, liver or nodes as opposed to peripheral blood as in CLL.
- Richter Syndrome is the transformation of SLL into CLL or CLL into DLBCL. It occurs in about 5% of all cases.
- 12% are marginal zone B-cell lymphomas or MALT lymphomas. (MZL)
Cytogenetic abnormalities associated with indolent NHL include:
- t(14:18) in 90% of FLThis results in overexpression of bcl-2 (anti-apoptosis).
- Chromosme 13 Deletion, t(14:19) and trisomy 12 are associated with SLL and CLL.
- Trisomy 3 and t(11:18) are associated with MALT
Follicular lymphoma is graded based on the mix of centrocytes (small cleaved cells) and centroblasts (large, non-cleave cells). Grade correlates to the density of centroblasts per high powered field: 0 - 5 = Grade 1; > 15 = Grade 3a.
Follicular lymphomas present as Stage IV most of the time (60%), I-II next most commonly at 21% and Stage III 19%. The three common grades are Grade 1: small cleaved FL, Grade 2: Mixed FL, Grade 3: large FL.
MALT (extrandoal marginal zone B-cell lymphoma) commonly involves the stomach, ocular adenexa, skin, thyroid, parotid, lung and breast. Most present as Stage I/II.
Mantle Cell lymphomas commonly present with disseminated disase with spleen, bone marrow, and gastrointestinal involvement. MCL are associated with poor prognosis, with median survival time of 3 years. They are also associated with t(11;14)(q13;32) with overexpression of cyclin D1. The median age at diagnosis is 60, males predominate 4:1.
Workup and Staging
As with HL, and everything else in medicine we start with the H&P. The history should elicit B-signs, adenopathy. The physical exam should include comprehensive nodal group assessments including epitrochlear and popliteal groups. Cervical adenopathy above the hyoid bone should prompt evaluation of the ENT. Waldeyer's Ring is more frequently involved in NHL than in HL. Examination of extranodal at risk sites include liver, spleen, testicles, bones abdomen and flanks as appropriate.
Laboratory studies should include CBC/diff, CMP, LDH β2-microglobulin, serum protein electrophoresis, HIV, HBV, and HCV titers. HBV titer is essential, since rituximab is a cornerstone treatment and HBV may reactivate with retuximab treatment. Bone marrow biopsy should be performed for all lymphomas. If there are CNS signs/symptoms,testicular or paranasal sinus involvement or immunodeficiency, an LP should be performed to assess the CNS.
Imaging should include CT C/A/P and PET is appropriate in most cases. MRI should be performed for CNS symptoms, testicular, paranasal sinus or immunodeficiency.
Staging
NHL staging is the Ann Arbor Staging System as is HL. Splenic involvement is suffixed with "S."
The Ann Arbor staging system is considered limited in NHL in that NHL tends to spread in a less contiguous fashion than HL, thus Stage I disease in NHL is quite rare. Many "practically stage" NHL by dividing the disease into limited or advanced stages. Limited stage consists of AA Stage I-II with ≤ 3 adjacent LN regions, no B signs and no bulky disease (> 10 cm). Advanced stage includes everything else. For follicular lymphoma, limited stage includes AA Stage I-II non-bulky, non-abdominal disease only.