Case 6
In Burkitt's Lymphoma, what is the most common age for affected patients?
Burkitt's Lymphoma primarily occurs in children. Endemic Burkitt's is associated with the Ebstein Barr virus in Africa. Sporadic Burkitt's is associated with a translocation between chromosomes 8 and 14.
Name some of the environmental and genetic associations that contribute to the development of lymphoma in children.
● Classic Hodgkin lymphoma (mixed cellularity subvariant) and Burkitt lymphoma are both strongly associated with EBV infection. ● Non-Hodgkin lymphoma has been described in association with congenital immunodeficiency states such as Wiskott-Aldrich syndrome, Ataxia-telangiectasia, Bloom syndrome, X-linked Immunodeficiency. NHL is also can occur after organ or stem cell transplantation.
What are the major types of Hodgkin lymphoma?
- Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) - Lymphocyte-rich classic Hodgkin lymphoma (descriptive but confusing name) - Nodular sclerosis Hodgkin lymphoma (NSHL) - Mixed cellularity Hodgkin lymphoma (MCHL) - Lymphocyte depleted Hodgkin lymphoma (LDHL) (extremely rare)
What are the commonly encountered side effects of monoclonal antibodies to B cell targets?
A rare, but STEP-1 relevant S/E is PML (progressive multifocal leukoencephalopathy), tumor lysis syndrome (from the contents of dead tumor cells leaking into circulation), bowel obstructions and perforations, as well as mucocutaneous reactions.
How does the normal process of antigen receptor gene rearrangement lead to the development of lymphomas?
Aberrant recombination sites fuse a promoter region of an antigen receptor gene with a gene involved in cell proliferation or resistance to apoptosis.
What are the typical sites of involvement in hairy cell leukemia
Blood, bone marrow, and spleen.
How do you diagnose lymphoma?
Diagnosis requires a pathologic confirmation from tissue or fluid sampling. For staging purposes, a bone marrow biopsy, lumbar puncture and bone scan may also be indicated. CBC, ESR, lactate dehydrogenase, uric acid and chest radiograph screening for mediastinal mass and/or effusions should be completed for all pts with lymphoma. CMP may reveal electrolyte disturbances secondary to tumor lysis syndrome. Pathologic hallmark of Hodgkin Lymphoma is identification of Reed-Sternberg cells.
What low magnification histologic feature in a lymph node biopsy best distinguishes between reactive hyperplasia and a lymphoma?
Effacement of normal lymph node architecture in a lymphoma.
The description of the pathology in a lymph node biopsy reads as follows: "Prominent germinal centers with well-formed mantle zones." What does this tell you about the immune response?
There is a B-cell response to some antigen.
Some lymphoma types have characteristic chromosomal abnormalities. What is the classic abnormality for each of the following lymphoma types and what genes are involved? Follicular lymphoma (FL) Mantle cell lymphoma (MCL) Burkitt lymphoma (BL)
FL - t(14;18) IgH (immunoglobulin heavy chain) and bcl2 (conveys resistance to apoptosis) MCL - t(11;14) IgH (again) and CCND1 (a cyclin not normally expressed in B-cells) BL - t(8;14) IgH (yet again) and c-myc (a gene involved in cell proliferation. Alternate fusions t(2;8) or t(8;22) involve fusion with an immunoglobulin light chain gene.
What are the two major genetic subtypes of diffuse large B-cell lymphoma and what is their significance?
Germinal center cell type and activated B-cell type. The activated B-cell type is clinically more aggressive and the two types respond differently to some types of treatment.
Name some of the clinical findings and complaints associated with the presentation of lymphoma.
Lymphoma traditionally presents as a malignancy that involves the lymph nodes. However, lymphoma can include any organ. Painless, firm lymphadenopathy often confined to one or two lymph node areas is the most common clinical presentation of Hodgkin lymphoma. It is usually painless unless the mass compresses on other anatomical structures and may clinically manifests as: ● Superior vena cava syndrome-Distention of neck veins (unilateral or bilateral), plethora, edema of head and neck, cyanosis, proptosis, Horner's syndrome ( a condition marked by a small pupil (miosis), ptosis(drooping of eyelid), local inability to sweat on same side of face caused by damage to sympathetic nerves on that side of neck) from superior mediastinal mass ● Tachypnea and Orthopnea-mediastinal mass compressing trachea; pleural effusions ● Abdominal discomfort- due to mass effect: hepatomegaly, splenomegaly or large intra-abdominal tumor can cause intestinal obstruction or intussusception or may mimic appendicitis. ● Jaw or neck mass-In Burkitt lymphoma doubling time is ~5 days vs approximately 30 days for Hodgkin lymphoma. Constitutional signs may include fatigue, anorexia and what is referred to as "B symptoms." The presence of one of three B symptoms has prognostic value: ● Fever- at least 100.4 (38C) for 3 consecutive days ● Drenching night sweats ● Weight loss (unintentional) of 10% or more within 6 months of diagnosis
Explain the mechanism of action of selected immune suppressors: Monoclonal Antibodies to B cell targets: Tyrosine Kinase inhibitors:
Monoclonal Antibodies to B cell targets: CD20 is a unique molecule on B cells and can be blocked with a monoclonal antibody. When these proteins are blocked, they have dramatically reduced cell activity. In fact, many are life/death signals and when they are not functional, the cell is often marked for death. The complete physiologic effect of CD20 is unknown, but it is an important marker for B cell activation and effector function. When the antibody is bound to the CD20 molecule, two processes can occur: cell death of the offending B cell by ADCC (antibody-dependent cell mediated cytotoxicity) and complement-dependent cytotoxicity (CDC). Also, a conjugated toxin can be internalized and cause apoptosis if the toxin is bound to the antibody. The conjugated toxins can be immunoconjugates or radioimmunoconjugates. Third, monoclonal antibodies can act by inhibition of underlying mechanisms of cell growth and proliferation by simply interfering with homeostatic protein-ligand interactions. Tyrosine Kinase inhibitors reduce the signal transduction of tyrosine kinases. These are on/off enzymes that maintain cell homeostasis. Common tyrosine kinases include: Epidermal Growth Factor (EGFR), Insulin, Platelet-derived growth factor, vascular endothelial growth factor, etc. These enzymes all transfer a phosphate molecule from an ATP to a protein. They all have the suffix - nib. They are most often orally administered.
What lymphoma is most commonly identified in adult males?
Most lymphomas are identified primarily in adults (except Burkitt's). Mantle cell lymphoma is primarily seen in adult males.
What histologic feature(s) distinguish most cases of Hodgkin lymphoma from other types of lymphoma?
Most of the cells in the tumor are reactive hematologic or lymphoid cells with few neoplastic cells. The classic tumor cells are Hodgkin/Reed-Sternberg cells.
What are the neoplastic cells in thymoma?
They are epithelial cells which contain keratin. The lymphocytes were duped into coming for thymic selection, training, and differentiation, which they don't get from tumor cells.
How are follicular lymphomas graded and what is the clinical significance?
They are graded based on the number of large tumor cells per microscope field. In general the more large cells, the more aggressive the disease.
What oncogene is affected in the translocation between chromosomes 8 and 14 in Burkitt's lymphoma?
The cMYC oncogene located on chromosome 8 is translocated onto chromosome 14 to be juxtaposed next to the IGH gene. This results in deregulation of the MYC oncogene.
What is the major difference between nodular lymphocyte predominant Hodgkin lymphoma and the classic types?
The neoplastic cells of NLPHL look somewhat different (popcorn cells) and they express typical B-cell antigens such as CD20. The cells of classic Hodgkin lymphoma express CD30 and CD15 but not most other B-cell antigens.
What are the commonly encountered side effects to Tyrosine kinase inhibitors?
There are several S/E and adverse effects since the class targets many receptors. The drugs targeting the EGFR can cause rashes since EGFR is also expressed in keratinocytes. As a group these drugs can produce hypersensitivity and photosensitivity reactions, and may produce QT prolongation, liver abnormalities are also common as they are biotransformed through the hepatic system.
What are the two major types of lymphoma? List take home points regarding the epidemiology of lymphoma in children.
There are two major types of lymphoma: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). ● Lymphoma is the third most frequent childhood malignancy behind leukemia and central nervous system tumors (CNS) and accounts for approximately 12-15% of all childhood cancer. ● HL is the most common malignancy in children ages 10-19 years of age. ● The overall incidence of NHL increases with age. Male patients are affected more frequently than female patients. The incidence of NHL is highest in Caucasian children when compared to other ethnic groups.
