Pediatric Hodgkin and Non-Hodgkin Lymphoma: What Role Do Viral Infections Play in the Development and Prognosis of This Cancer?

Adriana Do, Joanna Kaluturi, Aleezay Khan, Seiyong Lee, Shreya Rai, Saad Salman

Discussion

In choosing to investigate the role of viral infections in pediatric Hodgkin and Non-Hodgkin lymphoma, we were primarily driven by both our fascination with the topic. The prospect of exploring how viral factors might influence these cancers in children intrigued us, especially considering that while there is extensive research on adult lymphomas, pediatric cases are less well understood. Our aim was to arrange existing research into a cohesive overview that clarifies the current understanding of this area. We were deeply motivated by this opportunity, seeking to contribute valuable insights to the study of pediatric cancers and enhance our overall understanding of oncology.

Abstract

Lymphoma is a disorder with a variety of types that attack lymphatic tissues which basically includes lymphocytes, the fundamental part of the immune system. These enumerations are divided into two categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) which each have their particular clinical and biological features. HL consists of uncontrollable growth of special kinds of cells in the lymphoid tissues, which are called Reed-Sternberg cells. It also has an early stage characterized by the emergence of localized lymphadenopathy that can usually be managed with treatment. On the other hand, NHL covers a collection of different subtypes—some with slow course of progression while the others are much more aggressive—each having specific prognostic factors and response to selected treatment. The initiation of the lymphoma condition is caused by a series of gene-environmental interactions that include chromosomal translocations, mutations in oncogenes, tumor suppressor genes, and changes in the immune microenvironment. The evaluation of the functional and molecular accidents in the immune cells is provided by these: histopathology, immunophenotyping, and molecular techniques, followed by staging according to the Ann Arbor system. Among other treatments, it is chemotherapy, radiotherapy, targeted therapies, and immunotherapies that are the most widespread, yet new therapies like CAR T-cell therapy, are more beneficial to those of the earlier treatment who have shown resistance. In spite of some advances in the field of. lymphoma and ways to treat it, the problem, drug resistance and long-term complications still remain. Ongoing studies are a critical part of the task of making clear the molecular mechanisms of lymphoma pathogenesis and disease biology and therapies. Ongoing studies are a critical part of the task of making clear the molecular mechanisms which lead to the development and influencing the biological behavior of the disease with the treatment mainly focused on the human body.

Introduction

The lymphatic system is integral to both the circulatory and immune systems, managing the drainage of excess fluid and supporting immune responses. It consists of lymph, lymphatic vessels, plexuses, and lymph nodes. Lymph, which is the excess fluid, is collected by lymphatic vessels and returned to the bloodstream. Lymph nodes, distributed throughout the body, contain lymphocytes that play a critical role in immune defense by combating diseases. This fluid management and immune function are particularly significant when considering pediatric lymphoma, including both Hodgkin and Non-Hodgkin.

This paper investigates the role of viral infections in the development and prognosis of pediatric Hodgkin and Non-Hodgkin lymphoma. It thoroughly examines the relationship between viral infections and lymphoma development, exploring how specific viruses may contribute to the onset of these cancers. Through this analysis, the paper aims to provide a comprehensive understanding of how viral infections interplay with pediatric lymphoma .

Development

The development of pediatric Hodgkin and Non-Hodgkin lymphoma may be influenced by a wide range of factors, including the body’s immune system and the presence of viral infections.  Not only can these infections impact the onset of the disease, but also play a crucial role as to how the disease develops over time. After the body is attacked by a viral infection, the damage caused to the immune system leaves the patient more susceptible to develop other illnesses. Viruses such as Epstein-Barr virus and HIV are most commonly linked to the diagnosis of both Hodgkin and Non-Hodgkin lymphoma. Epstien-Barr virus is an infectious virus which attaches to white blood cells, rendering them unable to fight infections in the body properly after altering developing white blood cells. This leaves the patient immunocompromised as the now mutated white blood cells attack the non-mutated white blood cells. Like many other viral infections HIV also leaves the patient's immune system weakened, leaving the patient susceptible to both Hodgkin and Non-Hodgkin lymphoma.

Diagnosis

Signs and Symptoms: 

To diagnose patients with Hodgkin or Non-Hodgkin lymphoma, there are certain signs and symptoms that medical professionals assess. Typically patients with either type of lymphoma may present painless swollen lymph nodes, fatigue, fever, night sweats, unexplained weight loss, itchy skin, and reduced appetite. Parents of patients who suspect their child has lymphoma observe enlarged lymph nodes in the neck, underarm, or groin area.  The reason behind the swelling of lymph nodes is due to the overproduction of abnormal lymphocytes collecting in the lymph node.  However, not all patients present symptoms of either lymphomas due to differing circumstances, for instance, the symptoms can vary because of the location and type of lymphoma.

Medical Equipment:

In order to properly diagnose a patient with lymphoma there are a series of medical tests along with equipment used to make an accurate diagnosis. Physical exams, blood tests, bone marrow biopsy, lymph node biopsy, and imaging tests are used by specialists to determine the type and severity of lymphoma. During physical exams nurses and hematologists ask patients a series of questions regarding their symptoms, family history, and personal questions. While they conduct the examination they look for  pale skin, swollen lymph nodes, and an enlarged liver, in order to determine if the patient presents signs of lymphoma. Blood tests are used to identify lymphoma cells and are also used to test for other viruses which can affect treatment. A bone marrow biopsy is used to check the cells found in the patient’s bone marrow using a long thick needle that is inserted into the hip bone. A lymph node biopsy might also be called for the patient to check the cells of the lymphatic system. This test includes either a small part or the entire lymph node being removed for testing by pathologists who determine what type of lymphoma is found in the patient. Medical equipment is used for CT and PET scans to detect tumors, the spread, and other infections. 

Comparing Hodgkin vs Non-Hodgkin Diagnoses:

While both Hodgkin and Non-Hodgkin lymphomas can present with similar symptoms, their diagnoses differ in crucial ways. Hodgkin lymphoma is characterized by the presence of Reed-Sternberg cells, which are large abnormal cells typically found in lymph node biopsies and are shown in Figure 1. The identification of these cells through biopsy is a key step in diagnosing Hodgkin lymphoma. In contrast, non-Hodgkin lymphoma lacks Reed-Sternberg cells and can involve a broader spectrum of lymphoma subtypes, requiring additional diagnostic tools. Immunophenotyping and molecular testing are often necessary to classify non-Hodgkin lymphoma subtypes and tailor the treatment plan accordingly. Furthermore, bone marrow biopsies and lumbar punctures may be performed to evaluate if the lymphoma has spread to the central nervous system, which is more common in aggressive forms of non-Hodgkin lymphoma.

Figure 1: Reed-Sternberg cells present in Hodgkin lymphoma.

Medical Professions

Lymphoma, both Hodgkin’s and Non-Hodgkin’s, is usually treated by certain medical specialties, specifically oncologists and hematologists. Oncology is the general study and treatment of all cancers, including Lymphoma. Oncology is classified into three categories: medical, radiation, and surgical oncology. Medical oncology deals with an oncologist trained to use various therapies, such as hemotherapy, hormonal therapy, biological therapy, and targeted therapy to target and kill cancer cells. A medical oncologist is usually the main supportive care provider for a cancer patient, while also coordinating treatment given by other specialists. Radiation oncology, however, deals with an oncologist trained to use intense energy beams to precisely target cancer cells. Cancer cells immediately die after treatment, most as a result of the damage caused to the cells’ chromosomes and DNA. Both of these treatments are effective in treating Lymphoma, whether it is Hodgkin’s or Non-Hodgkin’s. However, both of these treatments involve the cost of healthy cells, which are just as susceptible to damage, and are prone to microscopic invasion by the malignant cell. Surgical oncology uses surgery to find and remove cancer cells, while also determining if cancer has spread to other various parts of the body. It is important that they also perform biopsies, samples of tissue from the human body for further analysis, to determine if cancer exists and the severity of it. Surgical oncology is performed to remove pre-cancerous tumors, determine if a tissue is cancerous by using it in biopsies, and to determine the severity and stage. There are also different approaches to this surgery; a tumor can be centered in one place, making it more effective of being surgically removed, with consideration of medical or radiation oncology succeeding the operation. It can also be an asset in treating cancer by combining it with other treatments. However, surgical oncology is rarely used to treat Lymphoma; in Hodgkin’s lymphoma, the cancer does not produce solid tumors able to be surgically removed. In Non-Hodgkin’s lymphoma, the cancer is not confined to one area of the body, and other treatments are considered more effective in eliminating it. The average annual salary of an oncologist after training is approximately $298,000, with a low percentile of $132,000 and a high percentile of $672,000.

Hematology is more focused on the study of the cause, prognosis, treatment, and prevention of diseases and disorders related to blood, especially from Lymphoma; it is distinct from oncology which is concerned with all cancers. Hematology can be classified as a subcategory of oncology. There are four major areas of study fundamental in hematology: hemoglobinopathy, hematologic malignancies, anemia and coagulopathy. Lymphoma is mostly concerned within hematologic malignancies, as it is concerned with the diagnosis and treatment of cancer in the bone marrow, blood and lymph nodes. Hematologists usually follow a similar procedure to oncologists in treating lymphoma (due to the fact they are a subcategory of oncologists), using  The average annual salary of a hematologist after training is approximately $277,000, with a low percentile of $106,000 and a high percentile of $724,000.

Both of these professions follow a general career pathway of most physician specialties; they require four years of undergraduate school fulfilling pre-med requirements, four years of medical school, and three to seven years of residency and training. A board certification and a medical license after residency is crucial to obtain in order to become a certified doctor. However, it is important for both career pathways to continue their education even after medical school in order to stay engaged within those fields. 

Treatments

The treatment of Hodgkin and Non-Hodgkin lymphoma typically differ based on the extent and type of lymphoma. For patients with Hodgkin lymphoma there are eight types of treatments used such as: surgery, chemotherapy, radiation therapy, high-dose chemotherapy with a stem cell transplant, targeted therapy, other drug therapy, and phototherapy. Surgery is used to try to remove most of the tumor and after chemotherapy is used to reduce the risk of the cancer returning. Chemotherapy is a treatment in which medicine is injected or ingested to prevent the growth along with the division of cancer cells.  Radiation therapy uses high powered x-rays, among other types of radiation, to kill and prevent the growth of cancer cells. During high-dose chemotherapy healthy stem cells are normally killed so a stem cell transplant is used to restore the numbers of the depleted cells. Targeted therapy uses medicine and other substances to block the actions of specific proteins or enzymes that play a part in the spread of cancer cells. Other drug therapy, for example steroid therapy, is created in a lab and used on the body to target and treat certain types of lymphoma. Phototherapy is used by medical professionals as another treatment for Hodgkin lymphoma by injecting a certain drug into the patient's vein to collect cancer cells. Once the cells have been collected the UV light is shined onto the area and it kills the cancer cells that have been collected. In terms of treating pediatric patients with Non-Hodgkin lymphoma there are several treatment options which include; chemotherapy, high-dose chemotherapy with a stem cell transplant, radiation therapy, targeted therapy, immunotherapy, surgery, and clinical trials. Immunotherapy is where the patient’s immune system is geared with the proper tools which will boost it and help it fight cancer cells. Clinical trials are also an option in a patient’s treatment plan. Proton beam radiation therapy uses streams of protons to make radiation instead of using traditional methods, this helps lessen the damage to healthy tissue in sensitive parts of the body, like the lungs and heart.

Statistics

Hodgkin’s Lymphoma had 83,000 global cases in 2020, including over 23,000 deaths. Higher prevalence was associated with higher-income countries, while a higher fatality rate was associated with lower-income countries. Many factors of a country’s general statistics include GDP per capita, smoking, obesity, and hypertension. It is also the most common cancer among people ages 15 - 19, although survival has improved due to the advancement of medicinal technology, such as antibody therapy. Groups more likely to develop Hodgkin’s Lymphoma include men, adolescents, young adults, those with a history of exposure to HIV / AIDS, autoimmune disease, and heredity from family. NL’s global age-standardized incidence rate was 0.98 per 100,000 people. The index was reported higher in European regions (e.g. 2.6 per 100,000 in North Europe), while it was lower in East Asia (0.44 per 100,000). Men had a 50% higher rate (1.2 per 100,000) compared to women (0.8 per 100,000). There is somewhat a correlation between a country’s HDI and its ASR, where it was 2.0 in very high HDI countries, 0.79 in high HDI, 0.69 in medium HDI, and 0.8 per 100,000 in low HDI. In contrast, NL’s global ASR in mortality varied significantly compared to incidence. There were a higher number of fatalities in regions such as West Asia (0.59) and North Africa (0.53), and a lower number in regions such as East Asia (0.13) and West Europe (0.17). Men had a 70% higher rate (0.33 per 100,000) compared to women (0.19 per 100,000). Correlation was found between a country’s mortality rate and its HDI, with 0.23 in very high HDI countries compared to 0.43 in low HDI countries.

Non-Hodgkin’s Lymphoma was ranked as the 11th most commonly-diagnosed cancer, with approximately 545,000 global cases of it in 2020, including 260,000 deaths. Global trends of NHL have significantly increased over years. Risk factors for NIH within a patient include pre-existing autoimmune diseases, medications, lifestyle, and genetics. NHL is also more prevalent in elderly, with diagnosis peaking at least at age 75. Correlation was found between a country’s prevalence of HIV and NIH in people ages 15 to 49, most of the countries investigated being in Africa. In over 180 countries investigated, the global age-standardized rate (ASR) was 5.8 per 100,000 people. Countries with a higher HDI typically reported more incidents and deaths of NHL, as 49.4% of incidents and 39.2% of deaths were in very high HDI countries, while 17.7% of incidents and 22.5% of deaths were reported in low and medium HDI countries. No correlation was determined as NHL fatality rates were high in prevalence (>28%) regardless of a country’s HDI. North America, North Europe, and Australia had fatality rates under 25%. It was significantly higher in low HDI countries, while differing more from 22.4% in Australia and New Zealand to 72.2% in Middle Africa. Africa usually had the highest fatality rate of NHL of 67%. NHL cases had a steady growth in developed countries such as the United States and Austria, but fluctuated heavily in low HDI countries. 30 countries showed an increasing trend of incidents in men such as in Malta, with a 3.2% average annual percent change (AAPC). Among women, countries such as Lithuania and South Korea had a 4.6% and 4.2% AAPC. 

In the United States, approximately 2,000 children, or 25 per million, were diagnosed with Lymphoma in 2020. It accounts for 10 - 15% of all childhood cancers, behind Leukemia and brain tumors. Hodgkin’s Lymphoma is the most common type of Lymphoma in people ages 10 - 19 and the most common malignancy among adolescent patients ages 15 - 19. HL’s annual incident rate steadily increases while a child ages, from 1 per million of children ages 1 - 4 to over 30 per million in adolescents. The most common type of HL in children is CHL, accounting for 90% of cases, and NLPHL accounting for 10%. CHL can be categorized into four distinct types: nodular sclerosis CHL (NSCHL), mixed cellularity CHL (MCCHL), lymphocyte-rich CHL (LRCHL) and lymphocyte-depleted CHL (LDCHL). NSCHL peaks among individuals ages 15 - 35, while being the most common type, accounting for 50% of all HL patients younger than 10 and 70 - 75% of patients ages 10 - 19, MCCHL accounting for 30% and 15%, and LRCHL accounting for 14% and 6%. LDCHL is very rare in children, however, and MCCHL is associated with low socioeconomic status and non-European ethnicity. White children have a 30% higher incidence rate compared to Black and Hispanic children, while Asians and Pacific Islanders account for the lowest incidence rates by race. Male children are more likely to develop Lymphoma, with a 1.4%, 6.1%, and 13.3% HL incident rate in children ages 1 - 4, 5 - 9, and 10 - 14. Female children in contrast had an incident rate of 0.6%, 2.4%, and 10.4%. However, there were more incidents in adolescents 15 - 19 in female children, accounting for 31.4% compared to 29.4% in male children. NHL yielded similar results, with 10.3%, 16%, and 18% in male children, in contrast to 5.8%, 7.4%, and 9.5% in female children. In adolescents ages 15 - 19, 25.3% of incidents were from male children, while 14% of incidents were from female children.

Impacts

Children, who are diagnosed with lymphoma undergo chemotherapy, radiation and other such aggressive treatments, which could be effective but causes a range of side effects. These include fatigue, hair loss and weaker immune system, increasing chances of other infections and further health complications. 

In respect to long term impact, survivors of pediatric lymphoma have an increased risk of major health challenges. Risk of secondary cancer, chronic fatigue and cardiovascular issues are included in such major issues. While growth and development of the body of the children who received radiation therapy being the minor challenges a survivor of pediatric lymphoma could face. These include late growth spurt of puberty and weaker cognitive development leading to learning disabilities, difficulties with memory, attention, and processing speed, often referred to as "chemo brain."​ 

Along with such physical impact, survivors of pediatric lymphoma, there has been a significant psychological toll on these patients. Experiencing severe anxiety, fear and depression upon their diagnosis and treatment. They also face isolation due to the disruption of social interactions and schooling, causing emotional distress. Some of the long-term survivors of pediatric lymphoma have suffered from survivors' guilt and other chronic mental health illnesses. 

Families of children with lymphoma often face significant emotional challenges and considerable stress. Fearing for the child’s future along with guilt and anxiety which leads to anxiety, depression and even post-traumatic stress disorder (PTSD) . These emotional burdens lead to strained relationships and conflicts in the family. Societal perceptions of children with lymphoma can change drastically compared to healthy children. Due to this, these children, especially with those visible side effects, often face stigmatization for their illness. This sort of stigmatization leads to social isolation and difficulty in entering social circles even after post-treatment.

Conclusion

In conclusion, lymphoma remains a very complex, heterogeneous group of hematological malignancies involving difficult diagnosis and treatment modalities. Improvement in the understanding of its molecular and genetic bases has fostered formulation for targeted therapies toward better patient outcomes, yet there remain disparities in care pointing to a need for continued research on blood cancers and collaboration on needed actions by healthcare providers and advocacy groups representing patients. Future investigations should be directed toward the resistance of therapies, new biomarkers, and new treatments, including immunotherapy and CAR-T cell therapy. This requires a multidisciplinary approach to the comprehensive needs of patients, including genetic counseling and psychosocial support. Continued investment in lymphoma research and education will continue to enhance our understanding of the disease and assure access to effective therapies among persons diagnosed with lymphoma.

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