Hodgkin’s LymphomaInformative essay- by Jee Yoon Park on 20th-30th June 2016

This study involves identifying and acknowledging one of the three subtypes of blood cancer called Hodgkin’s lymphoma. The motive for this research is from the curiosity of oncology after watching House MD and the interest in knowing whether blood cancers are more transmittable than other cancers. This will provide information regarding the different types of Hodgkin’s lymphomas and their causes, symptoms, related statistics, method of diagnosis and the current approach to the disease in depth. It will also note the prognosis and the potential of curing it in the distant future. All references are from medical websites and textbooks.

Lymphoma is defined as a group of diseases involving abnormal cell growth in the lymphatic system that usually begins in lymphocytes [1]; thus this disease is sought to bring an immense affect to the immune system and is therefore classified as malignant neoplasms of the lymphoid, hematopoietic and related tissues [2]. Even though the disease is quite rare with an occurring rate of 4%, it is considered the most common blood cancer, with a survival rate varying from 50% to 80%. Lymphoma can be classified into two big categories- Hodgkin’s lymphomas (HL) and Non-Hodgkin’s lymphomas (NHL) which includes B-cell lymphoma, T-cell lymphoma, multiple myeloma and LPD (Lymphoproliferative disorders).

Before talking about Hodgkin’s lymphoma in depth, the knowledge of what the lymphatic system is and what it consists of is essential. The lymphatic system is a network of tissues (thin tubes) and organs (lymph nodes) that runs throughout the body, and some organs include: tonsils, adenoids, spleen and thymus. Tonsils and adenoids, being placed in the back of the throat, protect the entrance to the digestive system and the lungs from foreign organisms. Spleen is also a part of the lymphatic organ, in which contains two distinct types of tissues called red pulp and white pulp; red pulp filters damaged red blood cell and recycles them, and the lymphocyte containing white pulp helps the blood to pick up any sign of infection or illnesses. This system contributes a lot to the immune system as the primary function of the lymphatic system is to transport lymph, a fluid containing infection-fighting white blood cells, throughout the body [5]. Specifically, the lymphocytes living in lymph nodes fight bacteria and other infections. Moreover, the system has a role in maintaining fluid balance (by working in conjunction with the blood and immune systems to maintain homeostasis1) and absorbing fat and fat-soluble nutrients in the body. Although the overall circulation is similar, lymph flows in one direction. Looking specifically at lymph nodes, their shape has a resemblance to a small bean. The glands are all over the body, but can be seen easily under the arms, in each groin (top of legs), and in the neck [6]. Usually, these nodes cannot be observed; however, when there’s an infection, they swell and become visible as productions of the lymphocytes are triggered.

Lymphocyte is one of the subtypes of a white blood cell, and it primarily includes NK (Natural Killer) cells, B cells and T cells. These three cells are developed in the bone marrow, but they live mainly in lymph nodes [7]. B lymphocytes (CD-19 protein [9]) are adapted to the immune system by secreting

antibodies specific to one type of infection as they turn into plasma cells after coming in contact with the antigen. The infection is treated by the antibodies sticking to proteins on the surface of the foreign organisms to send signal to the immune system to eliminate them. As well, Cytotoxic T cells (CD-8 transmembrane glycoprotein [8]) are responsible for killing virus, TB (tuberculosis) bacteria, and potential cancerous cells. Helper T cells (CD-4 glycoprotein [10]) send signals to B cells to make antibodies and to macrophages and neutrophils to destroy ingested foreign microbes. Memory T cells have the ability to recognise an antigen they have contacted before and allow the system to reproduce at a quick rate and thus respond quicker than before. NK cells (CD-8 transmembrane glycoprotein [8]), like T cells, kill cells that have been infected or which they regard as malignant [7]. Thus, it can be considered as though the role of the lymphocyte is very important in the immune system, and thus problems that have arisen to it cause extensive damages to the human body.

Identifying whether the illness is HL or NHL is very important because the treatments for them are very different.

Approximately 2.6 per 100,000 people are diagnosed with HL every year, and it is responsible for 0.4 per 100,000 deaths [12]. It is responsible for 10% of all the lymphomas. This is a type of cancer that grows merely in the lymph nodes, rarely affecting the extranodal lymphoid tissue [11] which means it doesn’t necessarily spread to other parts of the body.

There are two types in Hodgkin’s lymphoma: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Again, this classical Hodgkin’s lymphoma can be divided into further subtypes- nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte-depleted (LDCHL), lymphocyte rich (LRCHL) and nodular lymphocyte predominant HL (NLPHL).

Classical Hodgkin’s Lymphoma includes all four of the subtypes mentioned above. In Nodular Sclerosis, patients are found having a scarred lymph node, and this is because oversized RS cells are mixed with normal white blood cells. Mixed cellularity CHL has lymph nodes in which contain many different types of cells, including RS cells. The other two types- lymphocyte depletion CHL and lymphocyte rich CHL are both very rare; LDCHL is usually aggressive and it shows lack of normal white blood cells but rather fluctuated levels of RS cells. The problem is that this usually is not diagnosed until it is spread throughout the whole body, which is stage IV of CHL due to lack of information and symptoms. Unlike LDCHL, LRCHL “may be diffuse or nodular in form and is characterised by presence of numerous normal- appearing lymphocytes and classic RS cells”. This can usually be diagnosed at an early stage and does not pose great risk to the patient as it has a low relapse rate, too.

Hodgkin’s Lymphoma is diagnosed when there is a presence of Reed-Sternberg cell. RS cells are several giant cells that are observed when a biopsy is carried out to test for lymphoma; most of them are B lymphocytes, classically considered crippled germinal centre B cells (they have not undergone hypermutation) to express their antibody. According to Pathologyatlas[16], there are variants of the RS cell; “Hodgkin’s cell which is atypical mononuclear Reed-Sternberg cell, which has same characteristics, but is mononucleated; Lacunar Reed-Sternberg cell which is large, with a single hyperlobated nucleus, multiple, small nucleoi and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space called lacunae; Pleomorphic Reed-Sternberg cell which has multiple irregular nuclei; Pop-corn Reed-Sternberg cell which is a small cell, which a very lobulated

nucleus and small nucleoli; Mummy Reed-Sternberg cell which has a compact nucleus, no nucleolus and basophilic cytoplasm.” (refer to figure for precise image)

The causes of HL is sought to be because of the genetic mutation of the DNA of the B lymphocytes, where the mutation accelerates rate of mitosis2, cause production of oversized cells and triggers inhibition of apoptosis3 which results in overpopulation of abnormal lymphocytes as they don’t die out. Even though reasons for such mutation is not yet identified, people with age of 20-29 or over 55; men; people inhabiting in US, Canada and northern Europe; affluences such as people from higher socioeconomic status; and people with infection with mononucleosis, especially Epstein-Barr virus or HIV, were more prone to contracting the illness.

There are several symptoms that arise from contracting HL. Constant fatigue, painless swelling of lymph nodes, fevers and chills4 , night sweats, chest pain, difficulty breathing, unexplained weight loss, loss of appetite, itching, increased sensitivity to the effects of alcohol or pain in the lymph nodes after drinking alcohol. If these symptoms are found, several tests may be carried out for a confirmation of exact diagnosis: blood tests to see if there is anything that indicates a possibility of cancer, imaging tests like CT scan9 and PET scan10 (refer to Figure 1 for more information) and sometimes even MRI scans11 may be used. The most accurate method to confirm a diagnosis, however, is to carry out a biopsy5 which involves removing a sample of the node for lab tests. The samples collected from the body using different biopsy methods are sent to a pathologist, and carries out a procedure called routine histology6 and immunohistochemistry7 (please refer to this hyperlink for more information if interested). Here, when making a diagnosis, it is crucial to differentiate HL with other possible diseases in which show similar symptoms and traits (d.dx8); these include: Cytomegalovirus, Infectious Mononucleosis, Non-Hodgkin Lymphoma , Physical Medicine and Rehabilitation for Systemic Lupus Erythematosus, Sarcoidosis, Serum Sickness, Small Cell Lung Cancer, Syphilis, Toxoplasmosis, Tuberculosis and many more.

Because there are many different types within HL, it is very difficult to be assertive of the precise treatment, and since the doctors approach patients differently according to their status. However, generally it can be seen as though there are four main methods to treat the disease. This is induction chemotherapy, salvage chemotherapy, radiation therapy and hemapoietic stem cell transplant. Firstly, treatment using chemotherapy often involves combination with radiation in people with early stage classical type of Hodgkin’s lymphoma; “this can be taken in pill form, through a vein in the arm or sometimes both methods… side effects of the chemotherapy again depends on the specific drugs that are given to the patients. Common side effects include nausea and hair loss. Serious long-term complications can occur, too.”[16] Hemapoietic stem cell transplant involves transplanation of multipotent hmscs, usually derived from bone marrow. This is used to replace the diseased bone marrow with healthy stem cells that will help grow a new bone marrow, and this would be used when there is a relapse (reoccurrence of the disease). Here, the appointed physician would be aware of all the side effects, and the goal of the treatment to maximise cure, minimise any complications that may occur during the treatment and weighing the risks of toxicity. (refer to [15] if more information regarding side effects of the treatment are needed)

Even though there are current treatments that are available for the patients, there are many researching doctors who are seeking for a new method of diagnosis and its cure, in which would be cheaper, and would be more efficient. Clinical trials are currently sought to be the most likely

method to developing a more effective lymphoma treatment and since this field has a lot of potential for future development, therapy and medication with less side effects may be anticipated in the distant future.

Definitions/ phrases that may need additional information

1. Homeostasis: the tendency of a system, especially the physiological system of the higher animals, to maintain internal stability, owing to the coordinated response of its parts to any situation or stimulus that would tend to disturb its normal condition or function.

2. Mitosis: a type of cell division that results in two daughter cells each having the same number and kind of chromosomes as the parent nucleus, typical of ordinary tissue growth

3. Apoptosis: the death of cells that occurs as a normal and controlled part of an organism's growth or development

4. Fevers and chills [13]: “defensive reaction by the body against infectious disease. When bacteria or viruses invade the body and cause tissue injury, one of the immune system’s responses is to produce pyrogens, in which they travel to the brain and disturb the functioning of the hypothalamus which regulates body temperature. The pyrogens inhibit heat-sensing neurons and excite cold-sensing ones, and deceive the hypothalamus to thinking the body is cooler than it actually is. In response the hypothalamus raises the body’s temperature above normal range, thus causing a fever.

5. Biopsy: there are different types of biopsy, and these are carried out according to the situation and the severity of the symptoms

Excisional or incisional biopsy (surgical): involves cutting through the skin to remove the lymph node. Excisional biopsy involves removing the whole lymph node, whereas incisional biopsy involves removing a part of the tumorous node. This provides enough sample of a tissue to make an accurate diagnosis.

Fine needle aspiration (FNA) or core needle biopsy: a very small needle is attached to the syringe to withdraw a small amount of fluid and tissue from the body. Slightly bigger needle is used in core needle biopsy to extract a bigger piece of tissue.

6. Routine histology: the pathologist looks at the slides inspects for any Reed-Sternberg cells and the cellular structure in which might show resemblance to a typical Hodgkin’s disease.

7. Immunohistochemistry: a process where a pathologist detects antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. “This test can show certain proteins, such as CD15 and CD30, on the surface of RS cells, which is shown in classical Hodgkin’s lymphoma.”

8. D.Dx (differential diagnosis): process of differentiating between two or more conditions that share similar signs or symptoms.

9. CT scan (Computed Tomography): uses x-rays to make detailed cross-sectional images of the body, shows detail in soft tissues, and therefore is useful to observe swollen lymph nodes or organs. CT scans are useful for looking for HL in the neck, chest, abdomen, and pelvis.

10. PET scan (Positron Emission Tomography): radioactive sugar is injected into the blood- it has a low radioactivity and will pass out of the body very quickly, in a day. The principle of using this is based on the fact that cancer cells absorb large amounts of sugar because they replicate at a high rate. Then, using a PET scanner, radioactivity in the body is detected, and thus shows if an enlarged lymph node contains HL, if small spots in the body is lymphoma in which may have been shown as normal on a CT scan, if HL is responding to the treatment and if HL is fully cured (as a part of prognosis and recovery).

11. MRI scan (Magnetic Resonance Imaging): even though this is rarely used to detect HL, this may be useful for detecting HL in CNS (Central Nervous System). MRI scans use radio waves and strong magnets to take detailed images of the soft tissues of the body.

Appendix

Graph 1: Occurring Rate of Hodgkin's Lymphoma

Table 1: Types of Hodgkin's Lymphoma

Figure 1: CT scan- enlarged lymph nodes, hepatomegaly and/or splenomegaly, lung nodules or infiltrates, and pleural effusions

Figure 2: PET scan- obtained with fluorodeoxyglucose (FDG) that shows increased FDG uptake in a mediastinal lymph node

Figure 3: Different stages of Hodgkin's Lymphoma

Figure 4: HRS cells and CHL shown under microscope

Figure 5: Different types of HRS cells under microscope

References

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