Saira+Ahuja

=** Intravascular Large B Cell Lymphoma **=

Anita is a 65-year-old Indian woman living a quiet life in the small town of Almaden, CA. As a child, she lived in a part of India that is now Pakistan but as a Hindu was forced to resettle in New Delhi due to dangerous conditions during the partition. She later began studying as a medical student but dropped out before she finished as it was time for her to get married. Forty years ago, she left her home in India with her husband and two young children to move to the United States, where she dabbled a little in real estate but has mainly dedicated her life to her family and close friends. Though her children are now grown, she spends her weekdays taking care of her grandchildren after school while their parents are at work. She enjoys spending time with them and the rest of her family as well as playing cards with her husband and their friends.
 * Patient Background **

One day, she developed a fever and headache and began to feel fatigued. Having suffered from migraines her whole life and thinking this could be related, she rested for a few days but saw no improvement in her condition. After consulting her son-in-law, a physician, she went to the hospital. The doctors were unable to diagnose her condition and called it a fever of unknown origin. Her fever continued. Blood tests, MRI’s, PET scans, CT scans, biopsies, and many other tests were performed in order to diagnose whatever was afflicting Anita. Her PET scans were diffuse. When a PET scan is conducted, the patient is given a radioactive substance that shows areas of the body where there is rapid cell growth, an indication of cancer. Her diffuse results meant that the scan showed equal levels of radioactivity throughout the entire body. Her blood tests only indicated the presence of inflammation somewhere in her body. The doctors were unable to determine the cause of her illness and she was eventually sent to Stanford Hospital where the tests and lack of diagnosis continued. The fevers and other symptoms greatly affected her life. She was constantly fatigued, sweating, and suffering from headaches. She had also experienced weight loss and was beginning to lose sensation and motor function in her lower extremities.
 * History of Symptoms and Diagnosis **

The latter of her symptoms involving her lower extremities were characterized under the name of Cauda Equina Syndrome, where the nerve roots of the Cauda Equina (bundle of nerves at the base of the spine) are compressed or otherwise damaged and cause motor and sensory problems below the waist. This syndrome has many risks and causes, of which include, “a history of cancer, recent lumbar spine surgery, recent severe infection, massive herniated discs, spinal lesions and tumors, spinal infection or inflammation, violent injuries to the lower back, spinal arteriovenous malformations, [and] spinal hemorrhages.” (1) This syndrome diagnosis essentially did little to determine a cause for her illness.

After numerous tests and biopsies, her doctor decided to do a sural (calf) nerve (due to the cancer’s predilection for the central nervous system) and muscle biopsy in order to examine the pathology of the area and associated vasculature, and six months after the fevers began, a cancer was discovered: Intravascular large B cell lymphoma (IVLBC). At the time of her diagnosis, Anita was barely conscious or able to communicate. She had lost the ability to walk or experience sensation below the waist and was incontinent. Her doctors informed her family that her prognosis was dire. Due to the rarity of the cancer, the limited information that was published on IVLBC, their analysis of the Kaplan Meier curve (used to estimate survival), and Anita’s state of health, her doctors believed she had a 10% chance of making it through the next few days and a 5% chance of surviving more than a week.

IVLBC is an incredibly rare (incidence of less than one case per million people) and aggressive type of cancer in which lymphoma cells grow selectively within microvasculature (lumen of capillaries). (2) The chances of getting it, as described by my mother to us children in order to emphasize the rarity, are akin to getting bit by a shark who is being struck by lighting. Because of the cancer’s presence throughout the body in the microvasculature, there would be no “hot spots” in a PET scan (no distinct or isolated areas of rapid cell growth in the body), contributing to its difficult diagnosis. It is also difficult to diagnose because of one of the cancer’s hallmarks: “…the surprising degree of sparing of the surrounding tissue and the absence of lymphoma cells in the lymph nodes and reticuloendothelial system.” (3) Essentially, the cancer sticks to the microvasculature and doesn’t spread, making it near undetectable. Lymph node biopsy is also often done to test for cancers, especially to see if they have metastasized, and IVLBCs avoidance of those areas contribute to its difficult diagnosis. It is so rare (less than one person per million) and difficult to diagnose that it is most often discovered during autopsy. (4)The middle aged and elderly are most commonly afflicted, and it appears as though the rate may be slightly higher in men. (5) Fever is one of the most common symptoms, a result of the body trying to fight off the disease (and why signs of inflammation were observed in her blood tests). (6) The growth of lymphoma cells in the blood vessels likely led to the Cauda Equina Syndrome. The inability of blood to successfully supply the nerves through the now faulty capillaries resulted in Anita’s loss of sensation and motor function below the waist. While not all patients with IVLBC have Cauda Equina Syndrome, many do suffer deficiencies of the central nervous system due to the disrupted vascular network. (7)
 * The Cancer **

IVLBC is a very rare subtype of diffuse B cell lymphomas, which are lymphomas of the B cells that are spread throughout the body. Because of IVLBCs incredibly rare nature, not a significant amount is known about the molecular mechanism of the disease. (8) When looking IVLBC, “The transition from a pre-neoplastic to a neoplastic condition seems to be determined by imbalance between cell proliferation and apoptosis, deregulation of major biochemical pathways for intracellular signal transmission, cell adhesion and migration, as well as expression of oncogenes and/or inhibition of tumor suppressor genes”. (9) All of the factors stated above are so called “hallmarks of cancer”, discussed in more depth below.
 * The Molecular Aspect **

While the specific mechanisms of most of the hallmarks (other than cell adhesion and migration) are unknown due to the rarity of IVLBC, their general effect can be inferred.

An “imbalance in cell proliferation and apoptosis” means the number of cells is increasing rapidly and the cells are not dying at the correct rate. This would explain the excessive accumulation of IVLBC cells in the lumen of the vasculature (specifically capillaries throughout the body).

A “deregulation of major biochemical pathways for intracellular signal transmission” could be related to the expression of defective molecules or proteins that cause the binding of IVLBC cells to the vascular endothelial cells and their permanence in those locations (this is described below in the discussion of cellular adhesion molecules).

The “cell adhesion and migration” is described next but the basics are simple: the IVLBC cells adhere to the vascular endothelial cells and have defects in their migratory mechanisms that ensure the lymphocytes migrate correctly through the vessels. Defects in certain cellular adhesion molecules (molecules that allow cells to stick to a certain area) such as CD11a or CD49 are a proposed mechanism for the intravascular localization of IVLBC cells. Essentially, the defective cells are able to bind to certain endothelial cell surface proteins that line the endothelial cells of the vascular system (CD54 and CD106 respectively) and accumulate in the vessels. (10) Another protein believed to be a marker of IVBLC is CD5. (11) While normally a protein that protects against autoimmunity on T and B cells, in the case of cancer, “CD5 expression plays a role in the fate of tumour-specific T cells, rendering lymphocytes tolerant and unable to recognize and eliminate malignant cells”. (12) These are only proposed mechanisms as the actual genes, their gene products, and their effects on the cancer are unknown. Some cases of IVBLC also contain cells that are missing certain receptors (integrins) and their respective targets (ligands) that mediate the migration of lymphocytes through the vasculature. (13) This leads to the lymphocytes conglomeration in the vessels and subsequent blockages, leading to further problems.

Finally, the “expression of oncogenes and/or inhibition of tumor suppressor genes” is a common characteristic of cancer. Oncogenes are genes that normally enable a cell to grow but in this case have a defect that causes uncontrollable growth (akin to pushing on the gas pedal in a car and not removing your foot). Tumor suppressor genes prevent uncontrollable cell growth and when defective are unable to prevent growth and lead to the uncontrollable growth they are supposed to control (like disabling the brake in a car).

The most common gene mutation is in the gene CD20. CD20 is a transmembrane protein present on B cells throughout the body, and as such is targeted for therapy in most B cell lymphomas. (14)

Anita's diagnosis of intravascular large B cell lymphoma and the limited understanding of the molecular mechanisms and prognosis of the disease led to her doctor’s search for an effective treatment that could potentially save Anita’s life. Because of IVLBC’s wide range of clinical manifestations and presentations, the therapies used vary drastically depending on the patient and specific pathology. Surgery is not an option with this type of cancer because of its diffuse presence throughout the miscrovasculature. In order to be effective, surgery would have to consist of accessing every micro vessel in the body and dissecting the cancer cells out of it, which is near impossible. One common therapy used to target IVLBC is Rituximab, which is a monoclonal antibody (proteins targeted to specific antigens) targeted at CD20, a transmembrane protein found on B cells. This drug is commonly used for B-cell cancers by providing anti-tumor effects, though its mechanism is not completely understood. (15) Essentially, the antibody binds to the CD20 on the B cells and marks them for destruction, eliminating all of the B cells in the body and hopefully, along with them, the cancer. The specificity of the antibody prevents the chemotherapy from marking other cells in the body for destruction, but the loss of the B-cells, which contribute heavily to the immune system, leaves the person receiving treatment susceptible to a plethora of other diseases and complications.
 * Treatment **

Along with Rituximab, a chemotherapy regimen known as “CHOP” (cyclophosphamide, doxorubicin, vincristine, prednisone) is also used. (16) Cyclophosphamide, “introduces alkyl radicals into DNA strands of cells and stops cancer cells from growing”. (17) Alkyl radicals are chemical compounds with free electrons. These free electrons bind to the DNA and cause cross linkages, preventing the cancer cells from undergoing normal cell division and leading to their eventual death. Doxorubicin both intercalates DNA and prevents its repair as well as generates free radicals which cause damage to “cellular membranes, DNA and proteins”. (18) Vincristine binds to tubulin, a component of microtubules which are used for mitosis (cell replication), and prevents cell replication. (19) Finally, prednisone is a steroid which, simply stated, minimizes the inflammatory response of the body by binding to receptors in the cytoplasm and leading to a variety of effects (lack of significant leukocyte migration to the area, disruption in inflammatory pathways, etc). (20)

While the CHOP regimen was often used for diffuse large B cell lymphomas (a form of non-Hodgkins lymphoma of which IVLBC is a subtype) in the past, the addition of Rituximab has significantly increased the effectiveness of the treatment. In a study conducted on the addition of Rituximab to the CHOP regimen, the three year survival rate increased by 20% (59% to 79%) and the overall survival rate increased by 9% (84% to 93%). (21) This study, along with other evidence, led the doctors to suggest that Anita be given R-CHOP (Rituximab combined with CHOP) therapy in order to combat the cancer inside her; however, they also explained there was a long list of side effects that she could experience as a result of this treatment. Infections, because of the low presence of white blood cells, could occur, and an infection during chemotherapy could manifest as something more serious than in a normal person, potentially leading to death. Other effects in the blood, such as a low red blood cell or platelet count, could leave her exhausted, out of breath, and more susceptible to bleeding. Extensive nausea would lead to weight loss, discomfort, and potentially dry mouth and mouth sores. Anita would also lose her hair, starting with that on her head and eventually spreading to include any hair on the body, including her eyebrows and eyelashes. (22) Because of all of these potential side effects, Anita would need to be monitored in the hospital while she was receiving the chemotherapy and for several days after. She would spend more than half of her time in an isolated hospital room. When Anita’s family was consulted about the course of action, the doctor’s belief that the chemotherapy may give her a chance at many more years of life and the family’s belief that she still had life to live outweighed the side effects that she would experience and the risk that the therapy would provide no benefits.

Imagine the IVLBC cells in Anita’s body that are being targeted by this chemotherapy regimen. All B cells are marked with the CD20 transmembrane protein as well as have an uncontrolled growth cycle due to mutations somewhere in the DNA. The Rituximab will mark B cells for destruction while the CHOP will act as a concurrent treatment, causing the aforementioned changes to cell DNA and preventing cell division and replication. By killing off B cells as well as preventing their proliferation, the hope is that the cancer will disappear. The hallmark of uncontrolled cell growth would be prevented through the death of already formed cancer cells and the prevention of further production of cancer cells. The rest of the hallmarks, including an imbalance in cellular signaling pathways and defects in cellular adhesion molecules, are controlled via the destruction of and prevention of more cancerous cells.

In Anita’s case, she was incredibly lucky. After 6 months of R-CHOP therapy, she was declared to be cancer free and remained so for 10 years before developing a second primary cancer (primary CNS leukemia discovered through mets in her brain). She is now tumor free from this second cancer as well, though she and her family have been informed by doctors that the cancer will likely return some day. Although she managed to survive her fight with the rare and aggressive IVLBC, she was not left completely unaffected. The cauda equina syndrome she experienced before her diagnosis that causes paralysis in her lower extremities had lasting effects, and Anita was unable to walk for 6 months. After physical therapy and time, she is now able to maneuver around her household, albeit slowly, with the help of a walker or canes.
 * Where is Anita Now? **

The reason Anita’s diagnosis took so long and this cancer is often discovered post-mortem is likely because of the lack of information present on IVLBC. The small number of patients who present with the disease and the variety of symptoms they exhibit make it even more difficult to pinpoint similarities and markers between all cases and target specific pathways or problems for treatment. Along with growing and more advanced technology, as more cases of IVLBC appear, patterns may be distinguishable and new therapies can be created in order to best treat those with this disease.
 * Implications **

Though IVLBC is an incredibly rare cancer with minuscule survival rates, this case of cancer was discovered with enough time for the doctors to draft a treatment plan that, although at times seemed as though it may not have worked, led to remission.
 * Apercu **



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