Hodgkin’s lymphoma

Reed-Sternberg cells and Hodgkin cells that displace normal cells of the lymph node in any area of the body. Malignant cells are surrounded by a cellular infiltrate consisting of histiocytes, lymphocytes, monocytes, plasma cells and eosinophils.

This pathology is characterized by a specific character and a unique immunophenotype, which allows it to be distinguished from other similar diseases. In most cases, the specific cause of Hodgkin’s disease remains unknown; the involvement of the Epstein-Barr virus in the mechanism of its development is assumed.

What is the lymphatic system?

The lymphatic system is a complex network of organs, tissues and vessels that plays a key role in the body’s immune defense and maintaining homeostasis. It includes the following components:

1. Lymphoid organs: thymus, spleen, lymph nodes, tonsils, appendix and Peyer’s patches of the intestine;
2. Lymphatic vessels: capillaries, postcapillaries, collectors and trunks;
3. Lymph is an interstitial fluid that circulates through the lymphatic vessels;
4. Lymphoid cells: lymphocytes, plasma cells, macrophages and dendritic cells.

The lymphatic system performs a number of important functions, including filtration and detoxification of tissue fluid, transport of fats from the gastrointestinal tract, and participation in the body’s immune response.

Morbidity statistics

Statistics on the incidence of Hodgkin’s lymphoma over the past 5 years show relatively stable rates with a slight downward trend in developed countries.

According to the International Agency for Research on Cancer (IARC), the global incidence of Hodgkin lymphoma in 2020 was approximately 83,000 new cases, corresponding to an age-standardized incidence rate of 1.0 per 100,000 population [ 1 ].

In the United States, the incidence of Hodgkin lymphoma averaged 2.6 cases per 100,000 people per year from 2015 to 2019, according to the National Cancer Institute (NCI), with a slight decline of 1.5% per year over the past decade.

In the Russian Federation, approximately 3-4 new cases of Hodgkin’s lymphoma per 100,000 population are registered annually. The prevalence of the disease is approximately 30% of all lymphomas and about 0.5% of all malignant neoplasms in Russia [ 3 ].

It is important to note that the incidence has a direct age distribution with peaks in young (20-30 years) and old (over 55 years) age. In addition, there are geographic differences in incidence, which may be due to genetic factors, environmental conditions and the availability of diagnostic methods in different regions of the world [ 2 ].

Causes of Hodgkin’s Lymphoma

The manifestations and causes of Hodgkin’s lymphoma (HL) are varied and not always clear at initial diagnosis. The mechanism of development is often associated with the action of external and internal factors on the human body.

1. Genetic mutations play a major role in the development of the disease. The most significant mutations are in the genes of NFκB, JAK-STAT and PI3K-AKT signaling pathways.
2. The role of viruses in the etiology of Hodgkin’s lymphoma is currently being studied (Epstein-Barr, cytomegalovirus, herpes virus type 6). Epstein-Barr virus (EBV) is found in Reed-Sternberg tumor cells in some patients, especially in the mixed-cell variant of the disease.
3. Another triggering factor is immunodeficiency states (taking medications that suppress the immune system, HIV infection, congenital immunodeficiencies). Immunological disorders, namely, dysfunction of T-lymphocytes and natural killers, contribute to the evasion of tumor cells from the surveillance of the human immune system.
4. Additionally, environmental and occupational factors, such as exposure to ionizing radiation, are considered as potential risks.

Thus, we see that the causes of Hodgkin lymphoma development are a complex interaction of genetic, epigenetic, infectious, immunological and environmental factors.

Forms and classification of the disease

In modern oncohematology, several forms of Hodgkin’s lymphoma are distinguished, which are characterized by specific histological features.

According to the current WHO classification, there are two main types of this disease:

1. nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL);
2. classical Hodgkin lymphoma (cHL).

The first variant, also known as “lymphocyte-rich” or “lymphocyte-predominant,” is a distinct entity characterized by the presence of lymphocytic-histiocytic (L&H) cells in a B-lymphocyte-rich microenvironment.

Classical Hodgkin’s lymphoma, in turn, is divided into four histological variants. The histological variant of HL depends on the structure of the reactive microenvironment of tumor cells (cellular composition).

1. Classic Hodgkin’s lymphoma with nodular sclerosis— characterized by the formation of collagen strands dividing the tumor tissue into separate nodules.
   2. Classic Hodgkin’s lymphoma, rich in lymphocytes— characterized by the predominance of reactive lymphocytes in the microenvironment of Hodgkin’s and Reed-Sternberg tumor cells.
   3. Classic Hodgkin’s lymphoma, mixed cell— demonstrates a polymorphic cellular composition with the presence of Hodgkin’s cells, Reed-Sternberg cells and various inflammatory elements.
   4. Classic Hodgkin’s lymphoma with lymphocyte depletion— characterized by the predominance of tumor cells over the reactive microenvironment and pronounced fibrosis.

Each of these subtypes has its own characteristics of the course, prognosis and approaches to therapy, which emphasizes the importance of accurate histological assessment in the diagnosis of Hodgkin lymphoma.

Symptoms and diagnosis

Symptoms of Hodgkin’s lymphoma are divided into general and specific.

Common symptoms include:

1. Unexplained weight loss (more than 10% of body weight in 6 months);
2. Fever of unknown origin (above 38°C);
3. Profuse night sweats;
4. General weakness and fatigue;
5. Itchy skin;

Specific symptoms include:

1. Painless enlargement of one or more lymph nodes, most often in the neck, less often in the armpit or groin area
2. The appearance of cough, shortness of breath, chest pain (with damage to the mediastinal lymph nodes);
3. Abdominal pain (with damage to the lymph nodes of the abdominal cavity);
4. Hepatosplenomegaly.

Diagnostic methods for Hodgkin lymphoma include:

1. Examination with a thorough collection of anamnesis and external examination;
2. Comprehensive hematological tests (complete blood count with white blood cell count and erythrocyte sedimentation rate ESR);
3. Blood biochemistry with assessment of liver and kidney function;
4. Biopsy of the affected lymph node (LN) or its conglomerate with subsequent histological and immunohistochemical studies;
5. Multispiral tomography of the chest, abdominal cavity and pelvis with contrast
6. Ultrasound examination (US) of peripheral lymph nodes, abdominal organs and pelvis;
7. Computed tomography (CT) or magnetic resonance imaging (MRI).
8. Currently, the standard examination for HL is positron emission tomography with 18F-fluorodeoxyglucose, combined with CT (PET-CT);
9. If necessary, a bone marrow trephine biopsy and skeletal scintigraphy are performed.

Stages of the disease and their characteristics

The staging of the disease is determined using the Ann Arbor system (the Cotswold revision of staging adopted at the Ann Arbor conference). This staging system takes into account the number of lymphatic zones and areas involved in the tumor process, the location of the affected lymph nodes on one or both sides of the diaphragm, the presence or absence of extralymphatic spread of the tumor (E), a localized or disseminated process, and the presence or absence of systemic symptoms (A or B). According to the International Clinical Classification, there are 4 stages of HL.
Correct staging is of key importance for choosing the optimal treatment tactics and assessing the prognosis.

Treatment

The main treatment methods for HL include:

1. Polychemotherapy (PCT). Various combinations of cytostatic drugs are used. In pediatric patients and young adults, the first-line therapy includes OPPA, COPP\COPDac, ABVD, BEACOPPesc.
2. Radiation therapy (RT) to the areas of initial damage.
3. Targeted therapy. The use of monoclonal antibodies (eg, brentuximab vedotin) directed at specific molecular targets of tumor cells.
4. The use of immune checkpoint inhibitors (eg, nivolumab, pembrolizumab) has shown high efficacy in relapsed and refractory HL.
5. High-dose chemotherapy with autologous stem cell transplantation. It is used in refractory forms and relapses of the disease.

What are the chances of recovery?

In our center, treatment is carried out according to the LH-17 protocol, which is based on the German DAL-HD-95 protocol, the overall survival rate of which is 98% , which is comparable to the treatment results of the best European centers.

According to modern data, the overall 5-year survival rate for HL is about 85-90%. At early stages of the disease, the probability of complete cure reaches 95-98% . Even at widespread stages and unfavorable prognostic factors, the chances of long-term remission and potential cure remain high – about 80%.

Possible complications

The main categories of complications include:

1. Immunological disorders. Reduced immunity increases the risk of infectious diseases, including secondary infections;
2. Hematological complications: anemia, thrombocytopenia, neutropenia as a side effect of chemotherapy;
3. Compression syndromes: compression of large vessels, nerve trunks or organs by enlarged lymph nodes.
4. Paraneoplastic syndromes: nephrotic syndrome, autoimmune hemolytic anemia, dermatomyositis.

Question and Answer

How quickly does the disease progress?

The rate of progression varies widely and depends on many factors, including histologic subtype, stage of disease, and individual patient characteristics. In general, Hodgkin lymphoma is characterized by relatively slow growth compared to aggressive forms of non-Hodgkin lymphoma (NHL).

What is the difference between Hodgkin lymphoma and non-Hodgkin lymphoma?

The main differences between them are as follows:

1. Cellular composition;
2. Origin: HL develops predominantly from B lymphocytes, whereas NHL can arise from both B and T lymphocytes;
3. Pattern of spread: HL typically spreads sequentially through the lymph nodes, while NHL may have a more chaotic pattern of spread.

Is further medical observation necessary if the disease has been cured?

Yes, long-term follow-up after successful treatment of Hodgkin lymphoma is a mandatory standard of care for patients.

Bibliography:

1. World Health Organization (WHO). International Agency for Research on Cancer (IARC). Global Cancer Observatory (GLOBOCAN) 2020.
   URL: https://gco.iarc.fr/
2. European Cancer Information System (ECIS).
   URL: https://ecis.jrc.ec.europa.eu/
3. National Cancer Institute (NCI). Surveillance, Epidemiology, and End Results (SEER) Program.
   URL: https://seer.cancer.gov/statfacts/html/hodg.html