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Lymphomas: How curable it is?
Understanding Its Prognosis!
Lymphoma is not one disease, but refers to a heterogeneous group of hematological malignancies associated with the lymphatic system, accounting to about 3% of cancers. The lymphatic system (lymph system) is integral part of our immune system and constitutes a network of lymphatic vessels that traverse throughout our body. The lymphatic system consists of lymph vessels, ducts and nodes, in which the lymphatic fluid circulates. Other lymphatic tissue in the body includes tonsils at the back of the mouth, spleen and thymus gland. Broadly, there are two main types of lymphoma- Hodgkin’s lymphoma and Non-Hodgkin’s lymphoma. They may also be classified based on the site of occurrences (cutaneous lymphoma, CNS lymphoma) or growth rate (slow growing/indolent and aggressive lymphoma), there are over 50 different types of lymphomas. The major components of lymphatic tissue are cells called Lymphocytes (a type of WBC), the two major types of lymphocytes are the B lymphocytes and the T lymphocytes. Both these cells function towards fighting infections and eliminating antigens. Lymphoma can begin anywhere in the lymphatic system, but most often begins in the nodes of neck, chest or under the arms. The abnormal lymphocytes in lymphoma may accumulate resulting in a swollen lymph node, which most often presents in neck or under the arm
The symptoms of lymphoma can be vague and may present as symptoms that mimic other diseases. On the other hand, low grade lymphomas may remain asymptomatic and enlarged lymph nodes may be incidentally found on a scan when performed for other indications. About 20% of all Hodgkin’s lymphoma patients present with fever , sweats or skin itch at the time of diagnosis in addition to an enlarged lymph node in neck or with in the chest. It has been observed that 10-20% of patients with limited disease and about 70% of patients with advanced disease , exhibit symptoms that include unexplained fever >38degreeC, drenching night sweats, unexplained weight loss >10% of body weight. Some of the other symptoms include persistent fatigue, coughing or trouble breathing, loss of appetite, itching etc. In case of lymphoma affecting the stomach or central nervous system, symptoms may include nausea, vomiting, seizures etc. Therefore recognizing lymphoma is challenging task.
Each type of lymphoma responds differently to specific types of treatment, hence a definitive diagnosis of the type is necessary to provide the right treatment for best outcome. When diagnosis of lymphoma is established, a staging investigation, usually involving a CT or PET scan, bone marrow biopsy and other blood tests helps determine the extent to which the lymphoma has spread throughout the body. Staging is also a vital parameter in prognosis and predicting outcome of the disease. However, unlike other cancers, it is not the only prognostic factor, as in case of lymphoma even advanced stage diseases have shown to have high cure rates.
Lymphoma: Indian Scenario
The estimated mortality rate due to NHL is higher in India than in North America or Western Europe. Diagnostic and treatment delays, incorrect diagnosis, inappropriate and suboptimal treatment are the possible reasons of poor outcome in India. The incidence of lymphoma is greater in men compared to women. In India, the male to female ratio of HDL is 5.5 : 1. The Non-Hodgkins type is more common than the HDL. According to Globocan (2012), the estimated incidence of non-Hodgkin's lymphoma (NHL) is 5/100,000 (385,741 new cases), with a mortality rate of 2.5/100,000 (199,630 deaths) worldwide. The incidence of Hodgkin’s lymphoma is about 1 in 25, 000 and one in eight lymphoma is a Hodgkin lymphoma. With the slow rise in the incidence of cancer in India, including lymphoma the obvious query is how far lymphomas are curable or what are the prognostic factors for this disease?
Prognostic factors help predict whether a person’s cancer will respond well to a specific treatment. An international prognostic index (IPI) has been developed in case of lymphomas to predict patient outcome. This tool or model was developed considering factors that may be divided into factors that are related to the disease, factors related to the patient and factors related to the therapy. This was primarily developed to calculate a score for aggressive or high-grade lymphoma. However they are useful in low and intermediate lymphomas also. A score of 1 is assigned to each parameters including – Age >60 years, LDH is elevated, greater than 1 extra nodal site, performance status (ECOG score 2-4) and Ann Arbor stage (III or IV). Depending on the total score, the percentage of relapse free and overall 5 year survival was predicted.
As there are many sub types of lymphoma, for purpose of understanding prognosis and prognostic factors in disease outcome, Hodgkin’s lymphoma may serve as a case here in this article.
Prognostic factors in Hodgkin’s lymphoma:
Hodgkin’s lymphoma has one of the highest cure rates (80-90%). However, about 15=20% of patients may remain resistant to cytotoxic treatment or relapse after primary treatment. Prognostic factors such as tissue biomarkers, number of tumor infiltrating macrophages, cytokine and chemokine levels in the body and DNA/RNA profile has shown promise in predicting risk of treatment failure. Some of the prognostic factors valuable in making decisions of treatment protocol include-
1. Stage of the tumor: In a limited stage disease, the presence of a bulky tumor as detected during staging is a negative predictor of outcome. Measurement of bulk is limited to a single largest mass. However, it could underestimate the total tumor burden in patients with diffuse disease. Spread of HL to extra lymphatic organs is also associated with poor outcome.
2. Age of the patient: Age impacts prognosis in two ways. One, older age is associated with higher co-morbidity and reduced tolerability of chemotherapeutic regimens unlike in younger patients. Also, age is also intrinsically associated with tumor biology, as HL is associated with bimodal age distribution. The standard treatment of HL (ABVD) consisting of (A)driamycin (also known as doxorubicin/(H)ydroxydaunorubicin, designated as H in CHOP, is not recommended to patients older than 70 years. Similarly intensified regimen such as BEACHOP- dose escalated regimen is also not recommended for patients above 60 years, due to pulmonary toxicity. In such situations, a antibody- drug conjugate may be a better option for patients’ above50 years.
3. Gender of the patient: It has been observed that males have a higher incidence rate as well as poorer prognosis when compared to women in case of HL. It is speculated that the pharmacokinetics of the drug and gender difference in metabolism of drugs (ABVD regimen) may hold the possible clue to the way females respond to treatment differently.
4. Haematological Parameters: About 40% of HL patients experience anemia. The cut-off point for prognosis is Hb levels <10.5g/dL. A lower level of Hemoglobin is associated with elevated levels of IL-6 and alterations in iron metabolism and therefore an important prognostic factor. An alteration in the WBC cell count is also a well-known prognostic factor. For lymphocytopenia the cut off is less than 8% or 600/microL. Similarly, the number of infiltrating macrophages in HL is strongly associated with prognosis.
5. Serum Albumin: Lower levels of albumin in serum are associated with very poor outcome in lymphoma. The cut-off score for prognosis is albumin levels of 4.0g/dL. The presence of albumin is associated with poor liver function as well as synthesis of cytokines.
6. Beta2-microglobulin: beta 2microglobulin is a protein secreted in all healthy individuals by B cells and is excreted through kidneys. Since in case of HL, inflammatory cytokines are high, they stimulate the production of beta 2 microglobulin in large quantities. Therefore elevated levels of beta 2 microglobulin usually found in about 5-30% of patients diagnosed, depending on the stage is known to be an important prognostic factor in relapse of the disease.
7. Besides the above prognostic factors, other factors such as the cytokine levels (IL-10, IL-6, CD30, TNF etc) or also known as the inflammatory markers also contribute towards understanding disease prognosis.
8. Genetic markers or chromosomal aberrations studied in the HRS cells (Hodgkin and Reed Sternberg cells, that are characteristic of HL) such as mutations in bcl2 gene expression (a regulatory protein that regulates cell death or apoptosis, is also associated with poor prognosis
Prognostic factor in choosing treatment protocol:
The best treatment protocol is chosen based on several predictive as well as prognostic factors. In case of indolent lymphoma, a watchful waiting may also be recommended. Radiation therapy is used when lymph nodes are localized. When chemotherapy or radiation given, it may destroy the bone marrow cells, and a bone marrow transplant may also be warranted. These bone marrow cells will help restore healthy cells in the body. New and improved therapeutics / biologics including monoclonal antibodies (Rituxan ®), radio immunotherapy, and Cytokine treatment such as IL-2 are being largely explored for treatment of lymphoma.
A plethora of prognostic factors are available for lymphomas. With advent of new effective treatments and evolution in the science of biomarkers and cancer genetics, new consensus is being arrived on how to integrate new research data and the understanding of prognostic factors to meaningfully arrive at a suitable treatment protocol. Needless to say, prognostic factors should help to stratify treatment according to the risk profile and identify patients at risk for failure. If this knowledge is not applied correctly, then it is likely that some of the prognostic factors thought to be important in the past may become meaningless when modern successful therapies are used. Therefore, the value of prognostic factors has to be updated periodically, and then adapted to new emerging biomarkers. There is hope for lymphoma patients, as research in immunotherapy is churning out new and effective therapies. These can variably counterbalance the adverse effects of some unfavorable clinical determinants.