Non-Hodgkin Lymphoma (NHL) Overview

Incidence

• Non-Hodgkin Lymphoma (NHL) accounts for 4% of all cancers in the U.S.
• Some subtypes of NHL are more common in children, but NHL is more often diagnosed in adults, and the risk increases with age.
• NHL survival rates have substantially increased since the late 1990s, growing 2% annually from 2007 to 2016.
• The overall 5-year survival rate is 71%.
• For stage 1 NHL, the 5-year survival rate is almost 82%, while for stage IV NHL, it is 62%.
• Survival rates can vary based on cancer stage and subtype.

Types of NHL

• NHL can start anywhere lymphatic tissue is present in the body and can metastasize to almost any organ.
• It typically begins in the lymph nodes, liver, spleen, or bone marrow, but can also involve the stomach, intestines, skin, thyroid, brain, or any other part of the body. Types include:
  • B-cell lymphoma: 90% of diagnoses in western countries.
  • T-cell lymphoma: 10%, more frequent in Asian countries.
  • NK-cell lymphoma: less than 1%.
• NHL is described by how fast the cancer grows, either "indolent" or "aggressive."
  • Indolent and aggressive are equally common in adults, but aggressive is more common in children.

Subtypes of NHL

• There are over 60 subtypes of NHL, each behaving differently and requiring different treatments.

B-Cell Lymphoma Subtypes

• Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of lymphoma, accounting for approximately 30% of NHL cases in the U.S.
  • It is aggressive and involves organs other than lymph nodes 40% of the time.
• Follicular lymphoma is the second most common form of lymphoma, affecting about 20% of individuals with this subtype.
  • It usually begins in lymph nodes, is indolent, and grows slowly.
• Mantle cell lymphoma constitutes 5-7% of NHL and typically occurs in individuals older than 60.
  • It involves the bone marrow, spleen, lymph nodes, and gastrointestinal tract (esophagus, stomach, intestines).
• MALT lymphoma
• Burkitt lymphoma is a rare and aggressive form of NHL with 3 different forms.
  • 80% of patients achieve long-term remission with chemotherapy.

T-cell & NK-cell Lymphoma Subtypes

• CUTANEOUS T-CELL LYMPHOMAS
  • Primary Cutaneous Anaplastic large cell lymphoma only involves the skin
  • More often is indolent and is the 2nd most common cutaneous T cell lymphoma (CTCL).
  • Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma, arising from epidermotropic memory T-cells.
  • Sezary syndrome is also a CTCL and is a variant of MF, and is thought to arise from thymic T cells.
• PERIPHERAL T-CELL LYMPHOMAS
  • Anaplastic large cell lymphoma - 2% of adult lymphomas, and 10% of childhood lymphomas. Commonly involves ALK-1 protein in cancer cells, which is a better prognosis.
    • ALK-positive ALCL
    • ALK-negative ALCL
    • Both are treated the same – Brentuximab vedotin + CHP chemotherapy regimen (Cyclophosphamide, doxorubicin, prednisone).
    • ALK-positive usually treated with 2nd-line ALK-inhibitors (Alectinib)
  • PTCL not otherwise specified (NOS)
  • Enteropathy-associated T-cell lymphoma
  • Angioimmunoblastic T-cell lymphoma
  • Adult T-cell lymphoma/leukemia
  • Extranodal NK/T-cell lymphoma, nasal type
  • Hepatosplenic T-cell lymphoma

Risk Factors

• Age: Commonly above 60 years.
• Gender: Men are more affected.
• Personal or family history of another hematologic malignancy
• H. pylori infection, associated with MALT lymphoma in the stomach
• EBV is associated with Burkitt lymphoma, or lymphomas in persons after organ transplants; other viruses such as Hep B/C
• HIV/AIDs associated with aggressive B-cell lymphomas
• Autoimmune disorders, like Sjogren's syndrome and rheumatoid arthritis (RA)
• Organ transplant patients, due to immunosuppressive drugs increasing the risk of developing NHL
• History of chemotherapy or radiation treatment
• Genetic alterations: Chromosome translocations include t(3, 22) in DLBC and t(8, 14) in follicular lymphoma/Burkitt lymphoma.

Clinical Presentation

• Symptoms depend on the type of NHL, where the disease process began, and what organs are involved.
• Lymphadenopathy in the neck, groin, abdomen, axilla (painless and firm)
• Hepatomegaly, splenomegaly
• Unexplained fevers (not due to infections or illness)
• Unintentional weight loss: Unexplained loss of >10% of body weight over the past six months.
• Fatigue
• Night sweats
• Tumors in the chest may lead to symptoms such as cough, shortness of breath (SOB), and chest pain.
• Tumors in the spleen can cause back pain and early satiety.
• Tumors in the axilla or groin can lead to upper or lower extremity edema.

Work-Up & Diagnosis

• Blood work
  • CBC - anemia, thrombocytopenia, leukopenia, or thrombocytosis, lymphocytosis
  • LDH - elevated with infiltration of the liver
  • Serum β2-microglobulin (B2M) - prognostic indicator in follicular lymphoma, now being tested in multiple subtypes for prognosis and treatment efficacy.
    • Low levels of B2M indicate a lower turnover of lymphoma cells after chemotherapy and may indicate achievement of remission.
  • HIV testing
• Imaging
  • Chest x-ray
  • CT of abdomen, pelvis, neck
  • PET scan
• Confirmatory Diagnosis
  • Excisional lymph node biopsy to confirm diagnosis
    • Lymph nodes should be biopsied if a patient presents with one or more of: significant enlargement, persistence for more than 4 to 6 weeks, progressive increase in size.
    • Lymph nodes > 2 cm in diameter have the best diagnostic yields.
  • Flow cytometry is performed to identify the type of NHL, for example:
    • CD10, CD21, Bcl-2, Bcl-6 - Follicular lymphoma
    • Cyclin D1, SOX11 - Mantle cell lymphoma
    • B-cell lymphomas are CD5+ / CD10+

Staging

• Stage I: One node or a group of adjacent nodes / Single Extranodal lesions without nodal involvement
• Stage II: Two or more nodal groups on the same side of the diaphragm / Stage I or II by nodal extent with limited contiguous Extranodal involvement
  • Stage II bulky: Stage II as above, with "bulky" disease
• Stage III: Nodes on both sides of the diaphragm; IIIs involves spleen, IIIE involves an extranodal site, IIIES is Extranodal and spleen involvement
• Stage IV: Widespread disease in multiple organs, with or without lymph node involvement

Conventional Treatment

• Cutaneous lymphomas (Mycosis Fungoides/Sezary Syndrome)
  • Limited/Local disease
    • Involved-site radiation therapy (ISRT)
    • Phototherapy (UVB or narrowband UVB)
    • Topical corticosteroids, or imiquimod, nitrogen mustard, retinoids, etc.
  • Generalized skin involvement
    • Phototherapy (UVB or PUVA)
    • Topical corticosteroids, or nitrogen mustard, total skin electron beam therapy (TSEBT)
  • Systemic chemotherapies
    • Brentuximab vedotin
    • Monoclonal antibody that targets CD30 and inhibits tubulin formation
      • Leads to cell cycle arrest and apoptosis
      • Common side effect: Peripheral neuropathy
        • Natural support - Vitamin B6, ALA, carnitine, Vitamin B12, glutamine, magnesium
• Peripheral T-cell lymphomas
  • Anaplastic Large Cell Lymphoma (ALCL-positive or negative) regimens include:
    • Brentuximab vedotin + CHP
    • CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)
      • Cyclophosphamide: Alkylating agent binding to DNA and inhibits protein synthesis
        • SE: Cardiotoxic
          • Natural support - CoQ10, Hawthorne, fish oil
          • CONTRAINDICATED - Curcumin
      • Doxorubicin: anthracycline antibiotic that binds to DNA, inhibits DNA repair and RNA synthesis.
        • SE: Cardiotoxic, so provide same natural therapies as above
      • Vincristine: Vinca alkaloid, mitosis inhibitor
      • Prednisone: corticosteroid used to prevent adverse reactions during chemotherapy regimens.

Natural Treatments

• Treat common side effects of chemotherapy
  • Nausea / Vomiting
    • Ginger
    • Chamomile and/or Yarrow tea
    • Acupuncture
  • Fatigue
    • Exercise
    • CoQ10
    • L-Carnitine
    • Ginseng
    • Royal Jelly
  • Peripheral Neuropathy
    • L-Carnitine
    • ALA
    • B12
    • B6
  • Anorexia / Weight loss
    • L-Carnitine
    • Fish oil
    • High-calorie smoothies
  • Diarrhea
    • Probiotics
    • Apple pectin fiber
• NHL specific integrative support
  • Curcumin
    • Curcumin downregulates STAT3, Bcl-2 and surviving and it impairs NF-κB in lymphoma therapy. Curcumin reduces levels of c-Myc, survivin, XIAP, c-IAP1, Bcl-2 and Bcl-xL via suppressing NF-κB and STAT3, causing apoptosis and decreased proliferation of lymphoma cells
  • EGCG
    • EGCG-mediated growth inhibition occurs through increased activation of caspases and Bcl-2 family proteins that induce apoptosis.
  • Quercetin
    • The antitumor effects of quercetin are related to its potential in reducing tumor growth, inducing apoptosis, promoting cell-cycle arrest, and suppressing mitotic processes, which are performed by modulating cyclin, proapoptotic, and mitogen-activated protein kinase (MAPK) molecular pathways. Inhibits c-Myc expression and the PI3K/AKT/mTOR pathway