Lymphoma Staging and Treatment

Diagnostic Biopsy Techniques

• Initial diagnosis of lymphoma requires specific types of tissue samples, as different methods provide varying levels of information regarding cellularity and architecture.

• Fine Needle Biopsy

  • This technique yields only individual cells and is performed by passing a fine needle, typically of $19$ or $21$ gauge, through the abnormal tissue.

  • The cells obtained are sufficient for cytology and flow cytometry.

  • It never provides tissue architecture, making it inadequate for an initial diagnosis.

  • Common uses include functioning as an initial screen for a patient presenting with an EC node to exclude other cancers like head and neck carcinoma, or to confirm a relapse in a patient with a known history of lymphoma.

• Core Biopsy

  • This method uses a larger needle to obtain a core of tissue.

  • It can be used for diagnosis if the material obtained is sufficient.

  • It is generally reserved for cases where surgical excision is difficult, such as abnormal node sites in the thorax or abdomen, or for patients with multiple comorbidities who cannot tolerate general anesthesia.

• Surgical Biopsy

  • Considered the gold standard for diagnosis.

  • Involves the partial or complete excision of abnormal tissue, such as a lymph node.

  • Provides full detail on cell morphology and tissue architecture.

  • Supplies enough material for flow cytometry, immunohistochemistry, and genetic testing, all of which are essential for accurate classification and diagnosis.

Lymphoma Staging Investigations

• Staging is the process of determining the extent of the disease and typically involves three main modalities: blood testing, imaging, and bone marrow biopsy.

• Blood testing protocols include:

  • Full blood count (FBC).

  • Biochemistry panels comprising creatinine, liver function tests (LFTs), lactate dehydrogenase (LDH), uric acid, and serum calcium.

• Imaging protocols include:

  • Computed Tomography (CT) scans of the chest, abdomen, and pelvis to identify anatomical abnormalities.

  • Positron Emission Tomography (PET) CT scans to identify functional abnormalities and areas of high glucose utilization in abnormal tissues.

  • Magnetic Resonance Imaging (MRI) is not routine for staging but is frequently utilized when there is a suspicion of Central Nervous System (CNS) lymphoma.

  • Ultrasound is not typical for staging but may be used to assess liver enlargement.

• Bone marrow evaluation includes both an aspirate and a trephine biopsy to detect evidence of lymphoma infiltration within the marrow.

The Ann Arbor Staging System

• The Ann Arbor system, named after the city in Michigan west of Detroit where it was devised, is the primary method used to distinguish local from extensive disease.

• The system evaluates disease sites, the location relative to the diaphragm, extranodal involvement, and systemic symptoms.

• B Symptoms

  • The designation "b" is added to the stage if specific systemic symptoms are present.

  • Symptoms include drenching night sweats, fevers exceeding $38^\circ\text{C}$ with no other obvious cause, and an unintentional loss of more than $10\%$ of body weight in the preceding $6$ months.

• Staging Thresholds

  • Stage I: Involvement of a single lymph node group or a group of adjacent nodes.

  • Stage II: Involvement of two or more nodal groups on the same side of the diaphragm.

  • Stage III: Advanced disease involving nodes on both sides of the diaphragm. Examples include involvement of the mediastinum along with the inguinal region or splenic involvement.

  • Stage IV: Noncontiguous extra-lymphatic involvement, meaning involvement of non-lymphoid tissue that did not arise from direct spread from an adjacent node (e.g., non-contiguous involvement of the liver).

Prognostic Indices

• Prognostic indices are tools used to divide patients into risk groups for clinical trials and to predict overall survival.

• International Prognostic Index (IPI) for Diffuse Large B-cell Lymphoma (DLBCL)

  • Points are assigned based on five risk factors ($1$ point each):

    • Age over $60$.

    • Ann Arbor Stage III or IV.

    • Two or more extranodal sites.

    • ECOG performance status of $2$ or greater.

    • LDH level greater than normal.

  • The total score categorizes patients into Low, Low-intermediate, High-intermediate, or High prognostic groups.

  • The $5$-year survival rates range from $73\%$ for the low-risk group to $26\%$ for the high-risk group.

• Other Indices

  • Age-adjusted IPI.

  • National Comprehensive Cancer Network (NCCN) IPI.

  • Follicular Lymphoma Prognostic Index (FLIPI) for low-grade lymphomas.

Chemo-immunotherapy Protocols

• Standard for Diffuse Large B-cell Lymphoma (DLBCL)

  • The standard regimen is R-CHOP, which consists of:

    • R: Rituximab (a CD20 antibody).

    • C: Cyclophosphamide.

    • H: Hydroxydoxorubicin (also known as Doxorubicin).

    • O: Oncovan (the trade name for Vincristine).

    • P: Prednisone.

• Salvage Regimens

  • Used for relapsed or refractory cases. Acronyms represent various combinations of chemo agents, including RICE, RDHAP, and RGDP.

• Follicular Lymphoma Management

  • A "watch and wait" approach is often taken for indolent cases with no evidence of progression, as early intervention may show no real benefit.

  • When treatment is necessary, it involves CD20 antibodies such as Rituximab or the newer Obinutuzumab.

  • Common regimens include:

    • Rituximab with Bendamustine (a combination of an alkylating agent and a purine analog).

    • RCVP: Identical to CHOP but omitting Hydroxydoxorubicin.

    • R-CHOP.

    • R-squared ($R^2$): A non-chemotherapy combination of Rituximab and Revlimid (Lenalidomide).

• Radiation therapy is utilized for localized disease or isolated areas of recurrence following the completion of systemic treatment.

CD20 Antibody Mechanisms and Engineering

• CD20 antibodies target the CD20 antigen expressed on the surface of both malignant and normal B cells.

• They improve response rates and overall survival in B-cell lymphomas when combined with chemotherapy.

• Methods of action include:

  1. Complement Fixation: The antibody binds and triggers the complement system.

  2. Antibody-Dependent Cellular Cytotoxicity (ADCC): The Fc portion of the antibody binds to Fc receptors on monocytes and macrophages, prompting them to kill the target cell.

  3. Active Signaling: The antigen-binding portion transduces a signal into the cell nucleus, causing apoptosis (programmed cell death).

• Engineered Antibodies

  • Obinutuzumab is a CD20 antibody genetically engineered to specifically increase ADCC.

Advanced and Targeted Therapies

• Bispecific Antibodies

  • These agents link the antigen-binding fragments of a CD3 antibody (targeting T cells) and either a CD19 or CD20 antibody (targeting lymphoma cells).

  • By physically approximating a T cell to a lymphoma cell, they enhance the immunological killing of the malignancy.

• Chimeric Antigen Receptor (CAR) T-cells

  • T cells are genetically modified with DNA encoding heavy and light chains of an antigen-binding area, a spacer, a transmembrane region, and an intracellular activation region.

  • When the receptor binds to the target antigen (most often CD19), the T cell is activated to kill the lymphoma cell.

  • A trial using the CAR T-cell therapy Axi-cel (axicabtagene ciloleucel) demonstrated a cure rate of approximately $40\%$ to $50\%$ in high-risk patients, despite significant side effects.

• Targeting B-cell Signaling Pathways

  • Researchers are exploring the inhibition of pathways like the BCR signaling pathway, the MYD88 pathway, and autocrine signaling.

  • Specific drugs being tested in combination with standard therapies like iatrop include:

    • Ibrutinib: A BTK (Bruton's tyrosine kinase) inhibitor.

    • Lenalidomide: An immunomodulator.

    • Bortezomib: A proteasome inhibitor.

    • PI3 kinase inhibitors.