Hodgkin's lymphoma (Hodgkin's disease)

Hodgkin's lymphoma (Hodgkin's disease) is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, affecting mainly the tissue of the lymph nodes, spleen, liver and bone marrow.

Symptoms include painless lymphadenopathy, sometimes with fever, night sweats, gradual weight loss, pruritus, splenomegaly, and hepatomegaly. Diagnosis is based on lymph node biopsy. Treatment is 75% curative and consists of chemotherapy and/or radiation therapy.

In the United States, about 75,000 new cases of Hodgkin lymphoma are diagnosed each year. The male to female ratio is 1.4:1. Hodgkin lymphoma is rare before age 10 and most common between ages 15 and 40.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Causes and pathophysiology of Hodgkin lymphoma

Hodgkin lymphoma is the result of clonal transformation of B cells, which leads to the formation of binucleated Reed-Sternberg cells. The cause of the disease is unknown, but there is a relationship with heredity and environmental factors (eg, occupations such as woodworking; treatment with phenytoin, radiation therapy or chemotherapy; infection with Epstein-Barr virus, Mycobacterium tuberculosis herpes virus type 6, HIV). The risk of the disease is increased in individuals with a certain type of immune suppression (e.g., patients who have undergone transplantation, receiving immunosuppressants), in patients with congenital immunodeficiency states (e.g., ataxia-telangiectasia, Klinefelter, Chediak-Higashi, Wiskott-Aldrich syndromes), in patients with certain autoimmune diseases (rheumatoid arthritis, nontropical sprue, Sjogren's syndrome, SLE).

Most patients have a slowly progressive impairment of cellular immunity (T-cell function), which promotes the development of bacterial, atypical fungal, viral, and protozoan infections. Humoral immunity (antibody production) is also impaired in patients with progressive disease. Sepsis is often the cause of death.

[ 8 ], [ 9 ], [ 10 ], [ 11 ], [ 12 ], [ 13 ]

Symptoms of Hodgkin's disease

Most patients present with painless, enlarged cervical lymph nodes. However, pain in the affected area may occur after drinking alcohol, which is one of the early signs of the disease, although the mechanism of pain is unclear. Another manifestation of the disease occurs when the tumor spreads through the reticuloendothelial system to adjacent tissues. It is characterized by the early appearance of intense itching. Common symptoms include fever, night sweats, spontaneous weight loss (>10% of body weight over 6 months), and signs of damage to internal lymph nodes (mediastinal or retroperitoneal), visceral organs (liver), or bone marrow. Splenomegaly is often present, and hepatomegaly may develop. Sometimes Pel-Ebstein fever is present (alternating elevated and normal body temperature; high body temperature appears for several days, then changes to normal or low temperature over the next few days or weeks). Cachexia occurs as the disease progresses.

Bone involvement is often asymptomatic, but vertebral osteoblastic lesions (elephantine vertebrae) and, less commonly, pain due to osteolytic lesions and compression fractures may occur. Intracranial, gastric, and cutaneous lesions are rare and suggest HIV-associated Hodgkin lymphoma.

Local compressions by tumor masses often cause symptoms such as jaundice due to intrahepatic or extrahepatic bile duct obstruction; leg edema due to obstruction of lymphatics in the inguinal region or pelvis; dyspnea and wheezing with tracheobronchial compression; pulmonary abscesses or cavities due to infiltration of the lung parenchyma, which may simulate lobar consolidation or bronchopneumonia. Epidural invasion may result in spinal cord compression and cause paraplegia. Horner's syndrome and laryngeal paralysis may be caused by compression of the sympathetic cervical and recurrent laryngeal nerves by enlarged lymph nodes. Neuralgias may result from nerve root compression.

Staging of Hodgkin's disease

Once the diagnosis is established, the choice of therapy is determined by the stage of the disease. The staging system commonly used is the Ann Arbor staging system, which is based on the following data: external medical examination; results of instrumental studies, including CT of the chest, abdominal organs, and pelvis; bone marrow biopsy. Laparotomy is not a prerequisite. Other examinations to determine the stage of the disease may include PET scanning, functional cardiac and pulmonary tests.

Cotswold modification of the NN RBOR staging system for Hodgkin and non-Hodgkin lymphomas

Stage	Criteria
I	Lesion of one lymphoid zone
II	Lesion of 2 or more lymphoid zones on one side of the diaphragm
III	Involvement of the lymph nodes, spleen, or both on either side of the diaphragm
IV	Extranodal lesions (bone marrow, lungs, liver)

Subcategory E indicates involvement of extranodal areas adjacent to the affected lymph nodes (e.g., involvement of mediastinal lymph nodes, pulmonary hilum with infiltration of adjacent areas of lung tissue is classified as stage HE). The category classified as "A" indicates the absence of systemic symptoms, "B" indicates the presence of systemic symptoms (weight loss, fever, or night sweats). Systemic symptoms are usually found in stages III or IV (20-30% of patients); "X" is used to indicate the size of the lesion, which is greater than 10 cm in maximum dimension or greater than 1/3chest diameter on radiograph.

The letter A at any stage indicates the absence of systemic clinical manifestations in the patient. The letter B indicates the presence of at least one systemic symptom in the patient's history. The presence of systemic symptoms correlates with the response to treatment.

Diagnosis of Hodgkin's lymphoma

Hodgkin lymphoma is suspected in patients with painless lymphadenopathy or mediastinal adenopathy detected on routine chest radiography. Such lymphadenopathy may result from infectious mononucleosis, toxoplasmosis, cytomegalovirus infection, non-Hodgkin lymphoma, or leukemia. The chest radiographic appearance is similar to lung cancer, sarcoidosis, or tuberculosis.

Chest x-ray is usually followed by lymph node biopsy if CT or PET scan confirms the findings. If only the mediastinal nodes are enlarged, mediastinoscopy or a Chamberlain procedure (a limited left upper thoracotomy that allows biopsy of a mediastinal node using a medianoscope) is performed. CT-guided biopsy may also be recommended to diagnose lymphoma.

A complete blood count, ESR, alkaline phosphatase, liver and kidney function tests should be performed. Other tests should be performed depending on the indications (e.g. MRI for spinal cord symptoms, bone scan for ossalgia).

Biopsy reveals Reed-Sternberg cells (large binocular cells) in a characteristic heterogeneous cellular infiltrate consisting of histiocytes, lymphocytes, monocytes, plasma cells, and eosinophils. Classical Hodgkin lymphoma has 4 histologic subtypes; there is also a lymphocyte-predominant type. Certain antigens on Reed-Sternberg cells can help differentiate Hodgkin lymphoma from NHL and classical Hodgkin lymphoma with a lymphocyte-predominant type.

Abnormalities in other tests may be detected, but they are of little diagnostic value. A general blood test may show a slight polymorphonuclear leukocytosis. Lymphopenia is sometimes seen early on, becoming more severe as the disease progresses. Eosinophilia and thrombocytosis may be present in 20% of patients. Anemia, often microcytic, usually develops as the disease progresses. Anemia is characterized by impaired iron reutilization and low serum iron levels, low iron-binding capacity, and elevated bone marrow iron. Pancytopenia develops with bone marrow infiltration, which is typical of the lymphoid depletion type. Hypersplenism may occur in patients with marked splenomegaly. Serum alkaline phosphatase may be elevated, but this does not always indicate liver or bone marrow involvement. Increased levels of leukocyte alkaline phosphatase, serum haptoglobin, ESR and other acute phase indicators usually reflect disease activity.

Histological subtypes of Hodgkin's lymphoma (WHO classification)

Histological type	Morphological features	Immunophenotype	Encounterability
Classical
Nodular sclerosis	Dense fibrous tissue around Hodgkin's nodules	CD15, CD30	67%
Mixed cell	Moderate number of Reed-Sternberg cells with mixed infiltrate	CD30	25%
Lymphoid predominance	Few Reed-Sternberg cells, many B cells, reticular sclerosis	CD30
Lymphoid depletion	Numerous Reed-Sternberg cells and intense fibrosis	CD30	Rarely
Nodular lymphoid predominance type
	Few neoplastic cells (L&H cells), many small B cells, nodular features	CD30-EMA

[ 14 ], [ 15 ]

Treatment of Hodgkin's lymphoma

Treatment of patients with stages IA, IIA, IB or IIB of the disease is usually carried out using chemotherapy in combination with radiation therapy. Such therapy leads to recovery of 80% of patients. In patients with the presence of the main tumor mass in the mediastinum, the duration of chemotherapy may be longer and various chemotherapy regimens are used before the start of radiation therapy.

Stage IIIA is usually treated with combination chemotherapy, with or without radiation therapy to the primary lesion. Cure is achieved in 75-80% of cases.

Stage IIIB requires polychemotherapy, sometimes in combination with radiation therapy. The use of radiation therapy alone does not lead to a cure. Recovery is achieved in 70-80% of cases.

In stages IVA or IVB, polychemotherapy is used according to the ABVD regimen [doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine], leading to complete remission in 70-80% of patients, with a 10-15-year disease-free survival in 50% of patients. The MOPP regimen [mechlorethamine, vincristine (Oncovin), procarbazine, prednisolone] is no longer used due to side effects, including secondary anemia. The following drugs are also effective: nitrosoureas, ifosfamide, cisplatin or carboplatin, etoposide. A promising combination of drugs is Stanford V, a 12-week chemotherapy regimen. Patients who do not achieve complete remission or who have a relapse of the disease within 12 months have a poor prognosis. In patients with relapsed or refractory disease who have responded to chemotherapy, autologous hematopoietic stem cell transplantation may be effective.

Complications of Hodgkin's disease therapy

Chemotherapy with MORR-like regimens increases the risk of secondary leukemia, which usually develops after 3 years. Chemotherapy and radiation therapy increase the risk of malignant solid tumors (eg, breast cancer, gastrointestinal tract, lung cancer, soft tissue sarcoma). Mediastinal irradiation increases the risk of coronary atherosclerosis. The risk of breast cancer increases in women 7 years after completion of radiation therapy to nearby lymph nodes.

Hodgkin's Lymphoma. Follow-up after completion of treatment

Grade	Program
Medical examination, complete blood count, platelets, ESR, blood chemistry	First 2 years - after 3-4 months, 3-5 years - after 6 months, > 5 years - after 12 months
Chest X-ray at each visit if chest CT was not performed	First 2 years - after 3 months, 3-5 years - after 6 months, > 5 years - after 12 months
CT scan of the chest organs	The first 2 years - after 6-8 months, 3-5 years - after 12 months, > 5 years if abnormalities are detected on radiography
KG of the abdominal cavity and pelvic organs	Stages I and II: first 5 years annually, other stages: first 2 years every 6 months, from 3 to 5 years - annually
Thyroid hormone levels	Every 6 months after neck irradiation
Annual mammogram 7 years after treatment	When irradiated above the diaphragm in patients under 30 years of age
Annual mammogram starting at age 37	For irradiation above the diaphragm in patients over 30 years of age

[ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ], [ 21 ], [ 22 ], [ 23 ], [ 24 ]

Prognosis for Hodgkin's lymphoma

In Hodgkin lymphoma, the absence of recurrence of the disease for 5 years is considered a cure; recurrence after 5 years is extremely rare. Chemotherapy with or without radiation therapy allows for a cure in more than 75% of newly diagnosed patients. The choice of treatment is quite complex and depends on the stage of the disease.